**Manifestations of HIV Infection**

[273] Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D, et al. Role for neuro‐ nal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci U S A. 2004

[274] Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's

[275] Kroner Z. The relationship between Alzheimer's disease and diabetes: Type 3 diabe‐

[276] Moyle G. Mechanisms of HIV and nucleoside reverse transcriptase inhibitor injury to

[277] Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, et al. The preva‐ lence and incidence of neurocognitive impairment in the HAART era. AIDS (London,

[278] Cook-Easterwood J, Middaugh LD, Griffin WC, 3rd, Khan I, Tyor WR. Highly active antiretroviral therapy of cognitive dysfunction and neuronal abnormalities in SCID

[279] Heaton RK, Clifford DB, Franklin DR, Jr., Woods SP, Ake C, Vaida F, et al. HIV-asso‐ ciated neurocognitive disorders persist in the era of potent antiretroviral therapy:

[280] Joska JA, Gouse H, Paul RH, Stein DJ, Flisher AJ. Does highly active antiretroviral therapy improve neurocognitive function? A systematic review. J Neurovirol. Mar;16

[281] Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the

[282] Letendre SL, McCutchan JA, Childers ME, Woods SP, Lazzaretto D, Heaton RK, et al. Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disor‐

[283] Winston A, Duncombe C, Li PC, Gill JM, Kerr SJ, Puls R, et al. Does choice of combi‐ nation antiretroviral therapy (cART) alter changes in cerebral function testing after 48 weeks in treatment-naive, HIV-1-infected individuals commencing cART? A

mice with HIV encephalitis. Exp Neurol. 2007 Jun;205 (2):506-12.

ALLRT cohort. AIDS (London, England). Jan 28;25 (3):357-65.

randomized, controlled study. Clin Infect Dis. Mar 15;50 (6):920-9.

disease--is this type 3 diabetes? J Alzheimers Dis. 2005 Feb;7 (1):63-80.

tes? Altern Med Rev. 2009 Dec;14 (4):373-9.

England). 2007 Sep 12;21 (14):1915-21.

mitochondria. Antivir Ther. 2005;10 Suppl 2:M47-52.

CHARTER Study. Neurology. 2010;75 (23):2087-96.

ders. Ann Neurol. 2004 Sep;56 (3):416-23.

Mar 2;101 (9):3100-5.

206 Current Perspectives in HIV Infection

(2):101-14.

**Chapter 10**

**Oral Manifestations of HIV**

http://dx.doi.org/10.5772/52941

specific conditions/diseases (CDC, 1993).

and community (Kaminu et al., 2002).

**1. Introduction**

(CDC, 1993).

Additional information is available at the end of the chapter

G.A. Agbelusi, O.M. Eweka, K.A. Ùmeizudike and M. Okoh

Human Immunodeficiency Virus (HIV) was first reported in USA. In June and July of 1981, the CDC published two reports on clusters of young homosexual men who developed op‐ portunistic infections that were chiefly detected in several immunodeficient individuals

Acquired Immunodeficiency Syndrome (AIDS) is a complex of symptoms and infections caused by the HIV virus as it impacts the immune system. It is an acquired infection, not hereditary. AIDS since its appearance in 1981 has spread to become a major cause of prema‐ ture death and so far a cure has not yet been found. The diagnosis of HIV/AIDS requires a positive HIV antibody test or evidence of HIV infection and the appearance of some very

AIDS is a global pandemic, 33.4 million people are currently living with the disease world‐ wide, and it has killed an estimated 2.4 million people, including 330,000 children (UNAIDS, 2010). Over three-quarters of these deaths occurred in Sub- Saharan Africa, retarding eco‐ nomic growth and destroying human capital. South Africa has the largest population of HIV

Oral lesions have been reported to be early clinical features of HIV infection (Greenspan et al., 1992). These lesions are often indicators of immune suppression and can be used for ear‐ ly testing, diagnosis and management of patients with HIV/AIDS. Oral lesions contribute to patients' morbidity, affecting the psychological and economic functioning of the individual

The overall prevalence of oral manifestations of HIV infection has changed since the advent of Highly Active Anti-Retroviral Therapy (HAART). Several Studies have shown reduction in prevalence of herpes labialis and periodontal diseases along with other lesions to more

and reproduction in any medium, provided the original work is properly cited.

© 2013 Agbelusi et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

patients in the world, followed by Nigeria and India (McNeil, 2007).

### **Chapter 10**

### **Oral Manifestations of HIV**

G.A. Agbelusi, O.M. Eweka, K.A. Ùmeizudike and M. Okoh

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52941

### **1. Introduction**

Human Immunodeficiency Virus (HIV) was first reported in USA. In June and July of 1981, the CDC published two reports on clusters of young homosexual men who developed op‐ portunistic infections that were chiefly detected in several immunodeficient individuals (CDC, 1993).

Acquired Immunodeficiency Syndrome (AIDS) is a complex of symptoms and infections caused by the HIV virus as it impacts the immune system. It is an acquired infection, not hereditary. AIDS since its appearance in 1981 has spread to become a major cause of prema‐ ture death and so far a cure has not yet been found. The diagnosis of HIV/AIDS requires a positive HIV antibody test or evidence of HIV infection and the appearance of some very specific conditions/diseases (CDC, 1993).

AIDS is a global pandemic, 33.4 million people are currently living with the disease world‐ wide, and it has killed an estimated 2.4 million people, including 330,000 children (UNAIDS, 2010). Over three-quarters of these deaths occurred in Sub- Saharan Africa, retarding eco‐ nomic growth and destroying human capital. South Africa has the largest population of HIV patients in the world, followed by Nigeria and India (McNeil, 2007).

Oral lesions have been reported to be early clinical features of HIV infection (Greenspan et al., 1992). These lesions are often indicators of immune suppression and can be used for ear‐ ly testing, diagnosis and management of patients with HIV/AIDS. Oral lesions contribute to patients' morbidity, affecting the psychological and economic functioning of the individual and community (Kaminu et al., 2002).

The overall prevalence of oral manifestations of HIV infection has changed since the advent of Highly Active Anti-Retroviral Therapy (HAART). Several Studies have shown reduction in prevalence of herpes labialis and periodontal diseases along with other lesions to more

© 2013 Agbelusi et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

than 30% after the institution of HAART (Ceballos-Salobrena et al., 1997), and in HIV-associ‐ ated opportunistic infections (Septowitz, 1998).

phocyte count falls below 200 cells per ml and the ratio of helper and suppressor cells is re‐

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 211

Oral lesions have been reported to be early clinical features of HIV infection (Greenspan et al., 1992). They are multiple and varied, and are occasionally the first sign that patients har‐ bour the virus. Studies have estimated that more than 90% of persons with HIV infection will have at least one oral manifestation during the course of their disease (Weinert et al., 1996). These lesions may be present in up to 50% of people with HIV infection and in up to 80% of those with a diagnosis of AIDS (Palmer et al., 1996). In cases where a person's HIV status is unknown the lesions provide a strong indication of the presence of HIV infection

Some of these lesions may have a predictive value, warning of a progression from HIV sero‐ positivity to clinically manifest as AIDS. They are often indicators of immune suppression and can be used for early testing, diagnosis and management of patients with HIV/AIDS (Scully et al., 1991; Arendorf et al., 1998; Agbelusi and Wright, 2005). Oral lesions in HIV may serve as markers for immune deterioration and disease progression and may also indi‐

They can therefore be used as an entry or end-point in therapy and vaccine trials and can be de‐ terminants of opportunistic infection and anti- HIV therapy, staging and classification systems

Oral lesions contribute to patients' morbidity, affecting the psychological and economic functioning of the individual and community (Kaminu et al., 2002). The pain of oral lesions can lead to increased morbidity. In cases like herpes zoster of the trigeminal nerve or facial nerve palsy facial aesthetics may be compromised. Some of the oral lesions have a fatal out‐ come e.g. Kaposi's sarcoma. Therefore, it is important to perform oral examinations routine‐ ly in the dental and medical settings (Patel et al., 2003), in those affected with HIV and

Predisposing factors to expression of oral lesions of AIDS include CD4 counts less than 200

Several studies done worldwide showed varying reports of oral lesions from 40% to 93% (Mir‐ owsky et al., 1998; Ramirez – Amardor et al., 1998; Ranganathan et al., 2000; Matee et al., 2000; Campisi et al., 2002). The prevalence of oral lesions seen in a German study showed 39% (Schmidt- Westhaunsen et al., 1997), in South Africa, 73% was reported by Kaminu and Nai‐ doo (2002). Nigerian reports also showed a prevalence of 36.4% - 84% in various studies done in

, viral load greater than 3000 copies/ml, xerostomia, poor oral hygiene and smok‐

versed, a diagnosis of AIDS is made.

**3. Oral manifestations of HIV**

**3.1. Significance of oral lesions of HIV**

cate poor prognosis (Adurogbangba et al., 2004).

patients at risk of the disease (Maeve et al., 2005).

**3.2. Epidemiology of oral lesions of HIV**

(Maeve et al., 2005).

cells/mm3

ing (Greenspan et al., 2001).

### **2. Literature review**

HIV has two primary strains: HIV-1 and HIV-2. HIV-1 is found throughout the world. HIV-2 is found primarily in West Africa, where the virus may have been in circulation since the 1960s–1970s (Beaupre et al., 2006).

Both HIV-1 and HIV-2 have several subtypes. The strains of HIV-1 can be classified into four groups: the "major" group M, the "outlier" group O and two new groups, N and P. These four groups may represent four separate introductions of simian immunodeficiency virus into hu‐ mans. Within group M there are known to be at least nine genetically distinct subtypes (or clades) of HIV-1. These are subtypes A, B, C, D, F, G, H, J and K (Lihana et al., 2009).

**Scheme 1.**

#### **2.1. Pathophysiology**

Human Immunodeficiency Virus (HIV) mainly affects white blood cells called T-lympho‐ cytes (T-cells) by attaching to a protein on the cell surface called CD4 (Cluster of differentia‐ tion 4), it is also expressed on the surface of monocytes, macrophages, and dendritic cells (Miceli, 1993).

HIV gains entry into the body through the blood or mucosal surfaces. The virus establishes itself within the lymphoid tissue, where it replicates and makes itself available to the cells of the immune system (such as T-Lymphocytes, monocytes and macrophages).

The hallmark of HIV disease is the progressive loss of CD4+ lymphocytes. Without interven‐ tion, an average of 60 to 80 cells/mm3 is lost every year; this loss is highly variable and oc‐ curs in periods of stability and rapid decline. The level of metabolic and mitotic activity of the host CD4 cell is believed to be a factor in the rate at which the disease progresses in indi‐ vidual patients.

With progressive CD4 lymphocyte depletion, immunosuppression becomes increasingly more severe with the emergence of pre-AIDS opportunistic infections. Once the CD4 lym‐ phocyte count falls below 200 cells per ml and the ratio of helper and suppressor cells is re‐ versed, a diagnosis of AIDS is made.

### **3. Oral manifestations of HIV**

than 30% after the institution of HAART (Ceballos-Salobrena et al., 1997), and in HIV-associ‐

HIV has two primary strains: HIV-1 and HIV-2. HIV-1 is found throughout the world. HIV-2 is found primarily in West Africa, where the virus may have been in circulation since

Both HIV-1 and HIV-2 have several subtypes. The strains of HIV-1 can be classified into four groups: the "major" group M, the "outlier" group O and two new groups, N and P. These four groups may represent four separate introductions of simian immunodeficiency virus into hu‐ mans. Within group M there are known to be at least nine genetically distinct subtypes (or

Human Immunodeficiency Virus (HIV) mainly affects white blood cells called T-lympho‐ cytes (T-cells) by attaching to a protein on the cell surface called CD4 (Cluster of differentia‐ tion 4), it is also expressed on the surface of monocytes, macrophages, and dendritic cells

HIV gains entry into the body through the blood or mucosal surfaces. The virus establishes itself within the lymphoid tissue, where it replicates and makes itself available to the cells of

The hallmark of HIV disease is the progressive loss of CD4+ lymphocytes. Without interven‐ tion, an average of 60 to 80 cells/mm3 is lost every year; this loss is highly variable and oc‐ curs in periods of stability and rapid decline. The level of metabolic and mitotic activity of the host CD4 cell is believed to be a factor in the rate at which the disease progresses in indi‐

With progressive CD4 lymphocyte depletion, immunosuppression becomes increasingly more severe with the emergence of pre-AIDS opportunistic infections. Once the CD4 lym‐

the immune system (such as T-Lymphocytes, monocytes and macrophages).

clades) of HIV-1. These are subtypes A, B, C, D, F, G, H, J and K (Lihana et al., 2009).

ated opportunistic infections (Septowitz, 1998).

the 1960s–1970s (Beaupre et al., 2006).

**2. Literature review**

210 Current Perspectives in HIV Infection

**Scheme 1.**

**2.1. Pathophysiology**

(Miceli, 1993).

vidual patients.

#### **3.1. Significance of oral lesions of HIV**

Oral lesions have been reported to be early clinical features of HIV infection (Greenspan et al., 1992). They are multiple and varied, and are occasionally the first sign that patients har‐ bour the virus. Studies have estimated that more than 90% of persons with HIV infection will have at least one oral manifestation during the course of their disease (Weinert et al., 1996). These lesions may be present in up to 50% of people with HIV infection and in up to 80% of those with a diagnosis of AIDS (Palmer et al., 1996). In cases where a person's HIV status is unknown the lesions provide a strong indication of the presence of HIV infection (Maeve et al., 2005).

Some of these lesions may have a predictive value, warning of a progression from HIV sero‐ positivity to clinically manifest as AIDS. They are often indicators of immune suppression and can be used for early testing, diagnosis and management of patients with HIV/AIDS (Scully et al., 1991; Arendorf et al., 1998; Agbelusi and Wright, 2005). Oral lesions in HIV may serve as markers for immune deterioration and disease progression and may also indi‐ cate poor prognosis (Adurogbangba et al., 2004).

They can therefore be used as an entry or end-point in therapy and vaccine trials and can be de‐ terminants of opportunistic infection and anti- HIV therapy, staging and classification systems

Oral lesions contribute to patients' morbidity, affecting the psychological and economic functioning of the individual and community (Kaminu et al., 2002). The pain of oral lesions can lead to increased morbidity. In cases like herpes zoster of the trigeminal nerve or facial nerve palsy facial aesthetics may be compromised. Some of the oral lesions have a fatal out‐ come e.g. Kaposi's sarcoma. Therefore, it is important to perform oral examinations routine‐ ly in the dental and medical settings (Patel et al., 2003), in those affected with HIV and patients at risk of the disease (Maeve et al., 2005).

Predisposing factors to expression of oral lesions of AIDS include CD4 counts less than 200 cells/mm3 , viral load greater than 3000 copies/ml, xerostomia, poor oral hygiene and smok‐ ing (Greenspan et al., 2001).

#### **3.2. Epidemiology of oral lesions of HIV**

Several studies done worldwide showed varying reports of oral lesions from 40% to 93% (Mir‐ owsky et al., 1998; Ramirez – Amardor et al., 1998; Ranganathan et al., 2000; Matee et al., 2000; Campisi et al., 2002). The prevalence of oral lesions seen in a German study showed 39% (Schmidt- Westhaunsen et al., 1997), in South Africa, 73% was reported by Kaminu and Nai‐ doo (2002). Nigerian reports also showed a prevalence of 36.4% - 84% in various studies done in the different geopolitical zones. (Onunu et al., 2002, Anteyi et al., 2003, Wright et al., 2005; Tai‐ wo et al., 2005; Taiwo et al., 2006; Arotiba et al., 2006; Adedigba et al., 2008).

WHO Collaboration centre on oral manifestations of the Human Immunodeficiency Virus uses strength of association of Oral lesions with HIV infection as basis for classification

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 213

(ECC/WHO, 1993)

Pseudomembraneous candidiasis Erythematous candidiasis Angular cheilitis Hairy leukoplakia Kaposi's sarcoma Non- Hodgkins lymphoma Periodontal diseases Linear gingival erythema (LGE) Necrotizing (ulcerative) gingivitis (NUG) Necrotizing (ulcerative) Periodontitis (NUP)

Candidiasis:

Bacterial infections

Mycobacterium avium intra-cellulare Mycobacterium tuberculosis Melanotic hyperpigmentation Necrotic (ulcerative) stomatitis Salivary gland diseases

Thrombocytopaenic purpura

Viral infections: Herpes simplex virus Human papilloma virus (HPV) Condyloma acuminatum Focal epithelial hyperplasia

Verruca vulgaris Varicella zoster Herpes zoster

*3.5.1. Oral candidiasis*

Xerostomia due to decreased salivary flow rate Unilateral or Bilateral swelling of major salivary glands

Ulceration NOS ( Not-otherwise specified)

GROUP 1: Lesions Strongly Associated with HIV infection:

GROUP 2: Lesions Less Commonly Associated with HIV Infection

**3.5. Clinical characteristics and diagnosis of oral lesions of HIV**

This is the most common intra-oral lesion seen among HIV infected individuals. In African studies, the prevalence ranged from 15% to more than 80% in HIV+ adults. The most com‐ mon organism involved with the presentation of candidiasis is *Candida albicans.* The pres‐

All studies carried out showed presence of oral lesions as a manifestation of HIV/AIDS infec‐ tion.

### **3.3. Importance of oral lesions of HIV for the dental profession**

The overall growth of the global AIDS epidemic appears to have stabilized, the annual number of new HIV infections has been steadily declining since the late 1990s and there are fewer AIDSrelated deaths due to the significant scale up of antiretroviral therapy over the past few years. Although the number of new infections has been falling, levels of new infections overall are still high, and with significant reductions in mortality, the number of people living with HIV (PLWA) worldwide has increased (UNAIDS, 2010). This increase in the number of PLWA trans‐ lates to the fact that the likelihood of an oral health care worker particularly the dentist treating a PLWA in high incidence areas is almost certain, therefore the dental team needs to be more in‐ volved in the prevention of spread and care of infected persons.

It is also important to note that the clinical problem of HIV infection poses one of the great‐ est challenges to Health Care Workers all over the world.

Some oral lesions of HIV/AIDS are ulcerative and painful, and so compromise the patients' ability to eat and swallow, subsequently leading to malnutrition and emaciation which wor‐ sens the already immunocompromized state. Hence prompt and early treatment of lesions is required.

The mode of spread of HIV also poses special danger to HCW particularly the dentist who works in an environment contaminated with blood, saliva and other body fluids and has close contact with his patients.

The dentist may possibly be the first health care provider to diagnose the condition from a high index of suspicion and results of diagnostic investigations prompted by the head/neck and or‐ al manifestations (Agbelusi and Wright, 2005). Dentists should have a good knowledge of oral lesions in HIV /AIDS and be able to recognize and accurately diagnose such lesions. Early treat‐ ment of oral lesions is also necessary to reduce morbidity and mortality in HIV-infected pa‐ tients. The need to maintain oral health to prevent complications like microbial infections which may be fatal in these patients cannot be over-emphasized.

Currently, viral load and CD4 status determination are used to initiate and monitor a patient's treatment. Diagnostic tests such as these place a greater responsibility on the dental practice team as they need to be aware of drug changes, new drugs and appropriate management of such patients. Some of the antiviral drugs may also have oral lesions as side effects.

#### **3.4. Classification of oral lesions of HIV**

Oral mucosal lesions are part of the clinical criteria in a number of HIV/AIDS classification systems currently in use. This classification can be based on the etiological factors or the strength of association. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaboration centre on oral manifestations of the Human Immunodeficiency Virus uses strength of association of Oral lesions with HIV infection as basis for classification (ECC/WHO, 1993)


### **3.5. Clinical characteristics and diagnosis of oral lesions of HIV**

#### *3.5.1. Oral candidiasis*

the different geopolitical zones. (Onunu et al., 2002, Anteyi et al., 2003, Wright et al., 2005; Tai‐

All studies carried out showed presence of oral lesions as a manifestation of HIV/AIDS infec‐

The overall growth of the global AIDS epidemic appears to have stabilized, the annual number of new HIV infections has been steadily declining since the late 1990s and there are fewer AIDSrelated deaths due to the significant scale up of antiretroviral therapy over the past few years. Although the number of new infections has been falling, levels of new infections overall are still high, and with significant reductions in mortality, the number of people living with HIV (PLWA) worldwide has increased (UNAIDS, 2010). This increase in the number of PLWA trans‐ lates to the fact that the likelihood of an oral health care worker particularly the dentist treating a PLWA in high incidence areas is almost certain, therefore the dental team needs to be more in‐

It is also important to note that the clinical problem of HIV infection poses one of the great‐

Some oral lesions of HIV/AIDS are ulcerative and painful, and so compromise the patients' ability to eat and swallow, subsequently leading to malnutrition and emaciation which wor‐ sens the already immunocompromized state. Hence prompt and early treatment of lesions is

The mode of spread of HIV also poses special danger to HCW particularly the dentist who works in an environment contaminated with blood, saliva and other body fluids and has

The dentist may possibly be the first health care provider to diagnose the condition from a high index of suspicion and results of diagnostic investigations prompted by the head/neck and or‐ al manifestations (Agbelusi and Wright, 2005). Dentists should have a good knowledge of oral lesions in HIV /AIDS and be able to recognize and accurately diagnose such lesions. Early treat‐ ment of oral lesions is also necessary to reduce morbidity and mortality in HIV-infected pa‐ tients. The need to maintain oral health to prevent complications like microbial infections which

Currently, viral load and CD4 status determination are used to initiate and monitor a patient's treatment. Diagnostic tests such as these place a greater responsibility on the dental practice team as they need to be aware of drug changes, new drugs and appropriate management of such

Oral mucosal lesions are part of the clinical criteria in a number of HIV/AIDS classification systems currently in use. This classification can be based on the etiological factors or the strength of association. EC-Clearinghouse on Oral Problems Related to HIV Infection and

patients. Some of the antiviral drugs may also have oral lesions as side effects.

wo et al., 2005; Taiwo et al., 2006; Arotiba et al., 2006; Adedigba et al., 2008).

**3.3. Importance of oral lesions of HIV for the dental profession**

volved in the prevention of spread and care of infected persons.

est challenges to Health Care Workers all over the world.

may be fatal in these patients cannot be over-emphasized.

**3.4. Classification of oral lesions of HIV**

tion.

212 Current Perspectives in HIV Infection

required.

close contact with his patients.

This is the most common intra-oral lesion seen among HIV infected individuals. In African studies, the prevalence ranged from 15% to more than 80% in HIV+ adults. The most com‐ mon organism involved with the presentation of candidiasis is *Candida albicans.* The pres‐ ence of oral Candida was associated with a *CD4 count of <200 cells/microl*, cigarette smoking and heroine/methadone use (Greenspan et al., 2000). The most common organism involved with the presentation of candidiasis is *Candida albicans,* but other non- albicans species, such as *C. glabrata, C. tropicalis, C. krusei* and *C. dublinieusis* can also cause the disease.

There are 3 frequently observed forms of oral candidiasis:


#### *3.5.1.1. Pseudomembraneous candidiasis*

It appears as creamy white curd-like plaques on the buccal mucosa, tongue and other oral mu‐ cosal surfaces (palate, lips etc.) that can be wiped away, leaving a red or bleeding underlying surface. The plaques consist of a mixture of fungal hyphae, desquamated epithelium, and in‐ flammatory cells. These plaques can appear anywhere on the oral and pharyngeal mucosa.

**Figure 2.** Pseudomembranous candidiasis on the palate

This appears as a red lesion commonly located on the palate, dorsum of the tongue (as areas of depapillation) and buccal mucosa. The lesions tend to be symptomatic with patients com‐ plaining of burning mouth and change of taste, most frequently while eating salty or spicy

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 215

*3.5.1.2. Erythematous candidiasis*

foods or drinking acidic beverages.

**Figure 3.** Erythematous candidiasis on the palate

**Figure 4.** Erythematous candidiasis on the tongue and angular cheilitis on the lips.

**Diagnosis:** In most clinical conditions, the presumptive diagnosis of oral candidiasis is made based on the typical clinical appearance. In this situation, the presumptive diagnosis is strengthened if the patient responds to an empirical trial of anti-fungal therapy.

When the clinical diagnosis of oral candidiasis is not clear, the diagnosis can be confirmed by obtaining a direct smear and performing either a *Potassium Hydroxide* (KOH) wet mount or *a Gram's stain* (Greenspan et al., 1992). The KOH wet mount typically shows presence of yeasts or pseudo-hyphae, and the gram stain shows gram- positive staining organisms that are much larger than bacteria. Obtaining oral fungal cultures is generally reserved for situa‐ tions when patients do not respond to therapy and anti-fungal resistance is suspected.

The pseudomembraneous variant was associated with severe immune suppression in sever‐ al studies where these clinical parameters were available (Schoidt et al., 1990; Tukutuku et al., 1990; Hodgson, 1997; Ranganathan et al., 2000). As with other causes of oral candidiasis, recurrences are common if the underlying problem persists.

**Figure 1.** Pseudomembranous and erythematous candidiasis on the dorsum of the tongue

**Figure 2.** Pseudomembranous candidiasis on the palate

#### *3.5.1.2. Erythematous candidiasis*

ence of oral Candida was associated with a *CD4 count of <200 cells/microl*, cigarette smoking and heroine/methadone use (Greenspan et al., 2000). The most common organism involved with the presentation of candidiasis is *Candida albicans,* but other non- albicans species, such

It appears as creamy white curd-like plaques on the buccal mucosa, tongue and other oral mu‐ cosal surfaces (palate, lips etc.) that can be wiped away, leaving a red or bleeding underlying surface. The plaques consist of a mixture of fungal hyphae, desquamated epithelium, and in‐ flammatory cells. These plaques can appear anywhere on the oral and pharyngeal mucosa.

**Diagnosis:** In most clinical conditions, the presumptive diagnosis of oral candidiasis is made based on the typical clinical appearance. In this situation, the presumptive diagnosis is

When the clinical diagnosis of oral candidiasis is not clear, the diagnosis can be confirmed by obtaining a direct smear and performing either a *Potassium Hydroxide* (KOH) wet mount or *a Gram's stain* (Greenspan et al., 1992). The KOH wet mount typically shows presence of yeasts or pseudo-hyphae, and the gram stain shows gram- positive staining organisms that are much larger than bacteria. Obtaining oral fungal cultures is generally reserved for situa‐ tions when patients do not respond to therapy and anti-fungal resistance is suspected.

The pseudomembraneous variant was associated with severe immune suppression in sever‐ al studies where these clinical parameters were available (Schoidt et al., 1990; Tukutuku et al., 1990; Hodgson, 1997; Ranganathan et al., 2000). As with other causes of oral candidiasis,

strengthened if the patient responds to an empirical trial of anti-fungal therapy.

recurrences are common if the underlying problem persists.

**Figure 1.** Pseudomembranous and erythematous candidiasis on the dorsum of the tongue

as *C. glabrata, C. tropicalis, C. krusei* and *C. dublinieusis* can also cause the disease.

There are 3 frequently observed forms of oral candidiasis:

**•** Pseudomembraneous candidiasis

*3.5.1.1. Pseudomembraneous candidiasis*

**•** Erythematous candidiasis

214 Current Perspectives in HIV Infection

**•** Angular Cheilitis

This appears as a red lesion commonly located on the palate, dorsum of the tongue (as areas of depapillation) and buccal mucosa. The lesions tend to be symptomatic with patients com‐ plaining of burning mouth and change of taste, most frequently while eating salty or spicy foods or drinking acidic beverages.

**Figure 3.** Erythematous candidiasis on the palate

**Figure 4.** Erythematous candidiasis on the tongue and angular cheilitis on the lips.

### *3.5.1.3. Angular cheilitis*

Presents as fissures or linear ulcers at the corners (commissures) of the mouth and often as‐ sociated with small white plaques, could be unilateral or bilateral. It can occur with or with‐ out the presence of erythematous candidiasis or pseudomembranous candidiasis. Angular cheilitis can also exist for an extensive period of time if left untreated.

Periodontal diseases associated with HIV infection along with some other oral lesions have important diagnostic values as they may alert the dentist to the presence of HIV in‐ fection (ECC/WHO,1993; Robinson et al., 2002). Their prognostic significance is due to their ability to predict a deteriorating immune status and progression from HIV to AIDS (Robinson et al., 1998; Soubry et al., 1995; Glick et al., 1994a; Glick et al., 1994b). Soubry et al (1995) evaluated 224 people with necrotizing periodontal disease. Overall, 81% were found to be HIV positive. When compared with the general population in their environ‐

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 217

This periodontal lesion presents as a persistent, distinct, intense, fiery red band extending 2-3mm apically from the free gingival margin. The erythema may be limited to the mar‐ ginal tissue, the attached gingiva in a punctate or diffuse form, or could extend into the alveolar mucosa. These erythematous changes are usually generalized but may be con‐ fined to few teeth. Unlike conventional marginal gingivitis, the associated teeth usually have little or no plaque formation (Narani & Epstein, 2001) thus regarded as a non-pla‐ que induced gingivitis, particularly as the degree of erythema is disproportionately in‐ tense to the amount of plaque seen (Holmstrup & Westergaard, 1998). The gingiva bleeds easily on tooth brushing or gentle probing or even spontaneously in some cases (Robin‐ son et al., 2002). No ulceration is however present. LGE is commonly first seen earlier in the course of HIV infection and may or may not serve as a precursor to necrotizing ulcer‐

Studies have revealed a microbiota comprising *Candida albicans, Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans, Fusobucterium nucleatum* and *Campylobacter rectus* (Murray et al., 1989; Murray et al., 1991). This microflora is consis‐ tent with that of conventional periodontitis. The Candida species isolated from some LGE lesions, suggests its possible aetiologic role (Lamster et al., 1994; Velegraki et al., 1999; Grbic et al., 1995). LGE has been classified under 'Gingival diseases of fungal origin', a separate periodontal disease entity at the 1999 International workshop for a Classification

The use of tobacco has been reported to affect the extent of gingival banding which is measured by the number of affected sites (Swango et al., 1991). The relationship of LGE to severe immune suppression is variable. This condition may (Ceballos et al., 1996; Holmes et al., 2002) or may not be associated with CD4 counts < 200 cells/mm3 (Grbic et

A major clinical hallmark of LGE is its non-responsiveness to conventional scaling and root planing. The differential diagnosis is conventional chronic gingivitis, a plaque-in‐

duced gingival condition which responds to conventional periodontal therapy.

ment, the HIV prevalence was only 30% which was much lower.

*3.5.2.1. Linear gingival erythema*

ative periodontitis (Glick & Holmstrup, 2000).

of Periodontal diseases and conditions (Armitage, 1999).

al., 1995; Davoodi et al., 2010).

**Figure 5.** Angular cheilits

#### *3.5.2. Periodontal diseases*

Since the first descriptions of the HIV in 1981, a considerable number of researches have fo‐ cused on the periodontal changes specifically associated with HIV infection. Earlier reports in‐ cluded unusual and severe forms of periodontal disease in HIV-infected individuals, particularly among homosexual males. These lesions ranged from severe gingivitis to ad‐ vanced, painful periodontitis characterized by spontaneous bleeding, bone exposure and fre‐ quently bone sequestration followed by the exfoliation of several teeth (Silverman et al., 1986; Winkler et al., 1988). An increased incidence of acute necrotizing ulcerative gingivitis (ANUG) was also reported in HIV-seropositive patients (Schiodt & Pindborg, 1987; Gornitsky & Peko‐ vie, 1987).

HIV-associated periodontal diseases were initially classified into four broad categories: HIVassociated gingivitis (HIV-G) (Winkler et al., 1988), HIV-associated periodontitis (HIV-P), ANUG and necrotizing stomatitis (NS) (Greenspan et al., 1990). Later classifications pro‐ posed that the term 'HIV-associated' be dropped in relation to periodontal disease because the conditions were also seen in non-HIV infected populations (Smith et al., 1993).

HIV-G is now known as linear gingival erythema (LGE), while HIV-P is referred to as ne‐ crotizing ulcerative periodontitis (NUP). Currently, the spectrum of periodontal diseases as‐ sociated with HIV includes linear gingival erythema, necrotizing diseases (NUG and NUP), and exarcabated chronic periodontitis. LGE, necrotizing ulcerative gingivitis (NUG) and NUP are classified under lesions strongly associated with HIV infection ((ECC/WHO, 1993; Armitage, 1999; Winkler et al., 1988). The exacerbated periodontitis described in HIV infect‐ ed patients is however not clinically distinguishable from that occurring in non-HIV-infect‐ ed populations (Robinson et al., 2002).

Periodontal diseases associated with HIV infection along with some other oral lesions have important diagnostic values as they may alert the dentist to the presence of HIV in‐ fection (ECC/WHO,1993; Robinson et al., 2002). Their prognostic significance is due to their ability to predict a deteriorating immune status and progression from HIV to AIDS (Robinson et al., 1998; Soubry et al., 1995; Glick et al., 1994a; Glick et al., 1994b). Soubry et al (1995) evaluated 224 people with necrotizing periodontal disease. Overall, 81% were found to be HIV positive. When compared with the general population in their environ‐ ment, the HIV prevalence was only 30% which was much lower.

#### *3.5.2.1. Linear gingival erythema*

*3.5.1.3. Angular cheilitis*

216 Current Perspectives in HIV Infection

**Figure 5.** Angular cheilits

vie, 1987).

*3.5.2. Periodontal diseases*

ed populations (Robinson et al., 2002).

Presents as fissures or linear ulcers at the corners (commissures) of the mouth and often as‐ sociated with small white plaques, could be unilateral or bilateral. It can occur with or with‐ out the presence of erythematous candidiasis or pseudomembranous candidiasis. Angular

Since the first descriptions of the HIV in 1981, a considerable number of researches have fo‐ cused on the periodontal changes specifically associated with HIV infection. Earlier reports in‐ cluded unusual and severe forms of periodontal disease in HIV-infected individuals, particularly among homosexual males. These lesions ranged from severe gingivitis to ad‐ vanced, painful periodontitis characterized by spontaneous bleeding, bone exposure and fre‐ quently bone sequestration followed by the exfoliation of several teeth (Silverman et al., 1986; Winkler et al., 1988). An increased incidence of acute necrotizing ulcerative gingivitis (ANUG) was also reported in HIV-seropositive patients (Schiodt & Pindborg, 1987; Gornitsky & Peko‐

HIV-associated periodontal diseases were initially classified into four broad categories: HIVassociated gingivitis (HIV-G) (Winkler et al., 1988), HIV-associated periodontitis (HIV-P), ANUG and necrotizing stomatitis (NS) (Greenspan et al., 1990). Later classifications pro‐ posed that the term 'HIV-associated' be dropped in relation to periodontal disease because

HIV-G is now known as linear gingival erythema (LGE), while HIV-P is referred to as ne‐ crotizing ulcerative periodontitis (NUP). Currently, the spectrum of periodontal diseases as‐ sociated with HIV includes linear gingival erythema, necrotizing diseases (NUG and NUP), and exarcabated chronic periodontitis. LGE, necrotizing ulcerative gingivitis (NUG) and NUP are classified under lesions strongly associated with HIV infection ((ECC/WHO, 1993; Armitage, 1999; Winkler et al., 1988). The exacerbated periodontitis described in HIV infect‐ ed patients is however not clinically distinguishable from that occurring in non-HIV-infect‐

the conditions were also seen in non-HIV infected populations (Smith et al., 1993).

cheilitis can also exist for an extensive period of time if left untreated.

This periodontal lesion presents as a persistent, distinct, intense, fiery red band extending 2-3mm apically from the free gingival margin. The erythema may be limited to the mar‐ ginal tissue, the attached gingiva in a punctate or diffuse form, or could extend into the alveolar mucosa. These erythematous changes are usually generalized but may be con‐ fined to few teeth. Unlike conventional marginal gingivitis, the associated teeth usually have little or no plaque formation (Narani & Epstein, 2001) thus regarded as a non-pla‐ que induced gingivitis, particularly as the degree of erythema is disproportionately in‐ tense to the amount of plaque seen (Holmstrup & Westergaard, 1998). The gingiva bleeds easily on tooth brushing or gentle probing or even spontaneously in some cases (Robin‐ son et al., 2002). No ulceration is however present. LGE is commonly first seen earlier in the course of HIV infection and may or may not serve as a precursor to necrotizing ulcer‐ ative periodontitis (Glick & Holmstrup, 2000).

Studies have revealed a microbiota comprising *Candida albicans, Porphyromonas gingivalis, Prevotella intermedia, Actinobacillus actinomycetemcomitans, Fusobucterium nucleatum* and *Campylobacter rectus* (Murray et al., 1989; Murray et al., 1991). This microflora is consis‐ tent with that of conventional periodontitis. The Candida species isolated from some LGE lesions, suggests its possible aetiologic role (Lamster et al., 1994; Velegraki et al., 1999; Grbic et al., 1995). LGE has been classified under 'Gingival diseases of fungal origin', a separate periodontal disease entity at the 1999 International workshop for a Classification of Periodontal diseases and conditions (Armitage, 1999).

The use of tobacco has been reported to affect the extent of gingival banding which is measured by the number of affected sites (Swango et al., 1991). The relationship of LGE to severe immune suppression is variable. This condition may (Ceballos et al., 1996; Holmes et al., 2002) or may not be associated with CD4 counts < 200 cells/mm3 (Grbic et al., 1995; Davoodi et al., 2010).

A major clinical hallmark of LGE is its non-responsiveness to conventional scaling and root planing. The differential diagnosis is conventional chronic gingivitis, a plaque-in‐ duced gingival condition which responds to conventional periodontal therapy.

**Figure 8.** Necrotizing ulcerative gingivitis

**Figure 9.** Necrotizing ulcerative gingivitis

*3.5.2.3. Necrotizing ulcerative periodontitis*

Necrotizing ulcerative periodontitis (NUP) may be an extension of NUG in HIV infected in‐ dividuals. It is characterized by soft tissue loss resulting from ulceration or necrosis with rapid destruction of the periodontal attachment and interproximal bone (EC-WHO 93, Win‐ kler & Robertson, 1992). Initially, the lesion manifests with severe, deep-seated jaw pain, in‐ terproximal necrosis and cratering. This severe pain is however not a consistent feature (Robinson et al., 1998; Masouredis et al., 1992). The bone may then be exposed, with subse‐ quent necrosis and sequestration, resulting in loosening of the teeth (Umeizudike et al., 2011a). There is thus radiographic evidence of bone loss. Few teeth are affected in most cases in either the premolar or molar region, but the lesion may be more generalized in severe NUP cases. A characteristic fetor oris is usually present. Deep pockets are not a characteris‐ tic feature of NUP because of the extensive gingival necrosis which often coincides with loss of alveolar bone. The lesion may bleed on probing with 50% of sites bleeding spontaneously (Winkler & Robertson, 1992). Most studies report a similar microbial component in both NUP lesions associated with HIV and conventional chronic periodontitis (Glick et al., 1994b; Murray et al., 1989; Murray et al., 1991). Human herpes-viruses such as cytomegalovirus

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 219

The use of tobacco has been reported to affect the extent of gingival banding which is measured by the number of affected sites (Swango et al, 1991). The relationship of LGE to severe immune suppression is variable. This condition may (Ceballos et al, 1996;

**Figure 6.** Linear gingival erythema

Figure 6. Linear gingival erythema

Figure 7. Linear gingival erythema in an anaemic patient **Figure 7.** Linear gingival erythema in an anaemic patient

#### **3.5.2.2. Necrotizing ulcerative gingivitis** Necrotizing ulcerative gingivitis (NUG) is defined using the presumptive diagnostic criterion ((ECC/WHO, 1993) as the destruction *3.5.2.2. Necrotizing ulcerative gingivitis*

hemorrhage and a characteristic fetor. The affected gingiva may be extremely painful or asymptomatic (Robinson et al, 1998). The anterior and lower teeth are often affected (Robinson et al, 1998). The gingival ulceration may be limited to single teeth or extend to several areas of the jaws. The clinical description of NUG is only limited to lesions involving the gingiva without any loss of periodontal attachment. NUG in HIV-associated lesions represents the same spectrum of acute necrotizing ulcerative gingivitis (ANUG) seen in patients without HIV infection but in HIV-infected individuals it progresses more rapidly (Winkler and Murray, 1987). Some of the organisms isolated from NUG lesions include Borrelia, gram-positive cocci, β-hemolytic streptococci and Candida albicans (Reichart et al, 1987). NUG has been associated with depleted CD4 lymphocyte counts in some studies (Ceballos et al, 1996). However, others have failed to establish this association (Barr et al, 1992). Necrotizing ulcerative gingivitis (NUG) is defined using the presumptive diagnostic criteri‐ on (ECC/WHO, 1993) as the destruction of one or more interdental papillae. In the acute stage of the disease, ulceration, necrosis and sloughing may be accompanied by hemorrhage and a characteristic fetor. The affected gingiva may be extremely painful or asymptomatic (Robinson et al., 1998). The anterior and lower teeth are often affected (Robinson et al., 1998). The gingival ulceration may be limited to single tooth or extend to several areas of the jaws. The clinical description of NUG is only limited to lesions involving the gingiva without any loss of periodontal attachment. NUG in HIV-associated lesions represents the same spec‐ trum of acute necrotizing ulcerative gingivitis (ANUG) seen in patients without HIV infec‐ tion but in HIV-infected individuals it progresses more rapidly (Winkler and Murray, 1987). Some of the organisms isolated from NUG lesions include Borrelia, gram-positive cocci, βhemolytic streptococci and *Candida albicans* (Reichart et al., 1987). NUG has been associated with depleted CD4 lymphocyte counts in some studies (Ceballos et al., 1996). However, oth‐ ers have failed to establish this association (Barr et al., 1992).

of one or more interdental papillae. In the acute stage of the disease, ulceration, necrosis and sloughing may be accompanied by

**Figure 8.** Necrotizing ulcerative gingivitis

**Figure 6.** Linear gingival erythema

Figure 7. Linear gingival erythema in an anaemic patient

*3.5.2.2. Necrotizing ulcerative gingivitis*

**3.5.2.2. Necrotizing ulcerative gingivitis**

**Figure 7.** Linear gingival erythema in an anaemic patient

et al, 1996). However, others have failed to establish this association (Barr et al, 1992).

ers have failed to establish this association (Barr et al., 1992).

Figure 6. Linear gingival erythema

218 Current Perspectives in HIV Infection

The use of tobacco has been reported to affect the extent of gingival banding which is measured by the number of affected sites (Swango et al, 1991). The relationship of LGE to severe immune suppression is variable. This condition may (Ceballos et al, 1996;

A major clinical hallmark of LGE is its non-responsiveness to conventional scaling and root planing. The differential diagnosis is conventional chronic gingivitis, a plaque-induced gingival condition which responds to conventional periodontal therapy.

Necrotizing ulcerative gingivitis (NUG) is defined using the presumptive diagnostic criterion ((ECC/WHO, 1993) as the destruction of one or more interdental papillae. In the acute stage of the disease, ulceration, necrosis and sloughing may be accompanied by hemorrhage and a characteristic fetor. The affected gingiva may be extremely painful or asymptomatic (Robinson et al, 1998). The anterior and lower teeth are often affected (Robinson et al, 1998). The gingival ulceration may be limited to single teeth or extend to several areas of the jaws. The clinical description of NUG is only limited to lesions involving the gingiva without any loss of periodontal attachment. NUG in HIV-associated lesions represents the same spectrum of acute necrotizing ulcerative gingivitis (ANUG) seen in patients without HIV infection but in HIV-infected individuals it progresses more rapidly (Winkler and Murray, 1987). Some of the organisms isolated from NUG lesions include Borrelia, gram-positive cocci, β-hemolytic streptococci and Candida albicans (Reichart et al, 1987). NUG has been associated with depleted CD4 lymphocyte counts in some studies (Ceballos

Necrotizing ulcerative gingivitis (NUG) is defined using the presumptive diagnostic criteri‐ on (ECC/WHO, 1993) as the destruction of one or more interdental papillae. In the acute stage of the disease, ulceration, necrosis and sloughing may be accompanied by hemorrhage and a characteristic fetor. The affected gingiva may be extremely painful or asymptomatic (Robinson et al., 1998). The anterior and lower teeth are often affected (Robinson et al., 1998). The gingival ulceration may be limited to single tooth or extend to several areas of the jaws. The clinical description of NUG is only limited to lesions involving the gingiva without any loss of periodontal attachment. NUG in HIV-associated lesions represents the same spec‐ trum of acute necrotizing ulcerative gingivitis (ANUG) seen in patients without HIV infec‐ tion but in HIV-infected individuals it progresses more rapidly (Winkler and Murray, 1987). Some of the organisms isolated from NUG lesions include Borrelia, gram-positive cocci, βhemolytic streptococci and *Candida albicans* (Reichart et al., 1987). NUG has been associated with depleted CD4 lymphocyte counts in some studies (Ceballos et al., 1996). However, oth‐

Holmes et al, 2002) or may not be associated with CD4 counts < 200 cells/mm3 (Grbic et al, 1995; Davoodi et al, 2010).

**Figure 9.** Necrotizing ulcerative gingivitis

#### *3.5.2.3. Necrotizing ulcerative periodontitis*

Necrotizing ulcerative periodontitis (NUP) may be an extension of NUG in HIV infected in‐ dividuals. It is characterized by soft tissue loss resulting from ulceration or necrosis with rapid destruction of the periodontal attachment and interproximal bone (EC-WHO 93, Win‐ kler & Robertson, 1992). Initially, the lesion manifests with severe, deep-seated jaw pain, in‐ terproximal necrosis and cratering. This severe pain is however not a consistent feature (Robinson et al., 1998; Masouredis et al., 1992). The bone may then be exposed, with subse‐ quent necrosis and sequestration, resulting in loosening of the teeth (Umeizudike et al., 2011a). There is thus radiographic evidence of bone loss. Few teeth are affected in most cases in either the premolar or molar region, but the lesion may be more generalized in severe NUP cases. A characteristic fetor oris is usually present. Deep pockets are not a characteris‐ tic feature of NUP because of the extensive gingival necrosis which often coincides with loss of alveolar bone. The lesion may bleed on probing with 50% of sites bleeding spontaneously (Winkler & Robertson, 1992). Most studies report a similar microbial component in both NUP lesions associated with HIV and conventional chronic periodontitis (Glick et al., 1994b; Murray et al., 1989; Murray et al., 1991). Human herpes-viruses such as cytomegalovirus have however been identified in some NUP lesions (Slot, 2004). Homosexuals and bisexual men appear to have a higher incidence of NUP compared to other cohorts of HIV positive individuals (Glick et al., 1994b). Several studies reveal an association between NUP and HIV progression (Masouredis et al., 1992; Winkler et al., 1988). NUP has also been reported to be one of the strongest predictors of severe immune suppression, characterized by low CD4 lymphocyte counts (Glick et al., 1994a; Glick et al., 1994b). Patients with NUP may however, have CD4 counts above 200 cells/mm3 , indicating that other factors such as high viral loads may be associated (Umeizudike et al., 2011a).

sion of NUP. The condition may lead to extensive denudation and eventual sequestration of bone (Williams et al., 1990). The condition is often associated with severe immune suppres‐ sion with low CD4 lymphocyte counts. This condition is similar to the cancrum oris (noma) a rare destructive condition described in nutritionally deprived individuals particularly chil‐ dren in Africa which progresses from ANUG (Osuji, 1990). Studies carried out by various individuals all around Nigeria did not show the presence of the disease, though the condi‐ tion was seen in Lagos University Teaching Hospital in a previously undiagnosed HIV sero‐

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 221

positive patient (Agbelusi and Eweka, 2011).

**Figure 12.** Necrotizing ulcerative stomatitis

**Figure 13.** Necrotizing ulcerative stomatitis

*3.5.2.5. Chronic periodontitis with an increased rate of attachment loss*

Rapid periodontal pocket formation has been reported in HIV infection in some controlled studies (Barr et al., 1992; Yeung et al., 1993; Robinson et al., 1996; Ndiaye et al., 1997; Ranga‐ nathan et al., 2007; Umeizudike et al., 2011b). Although, this is not a consistent finding (Scheutz et al., 1997).This accelerated periodontal attachment loss reported in HIV infected individuals could be the result of severe episodes of NUP. The clinical presentation of gingi‐ vitis and chronic periodontitis in HIV-positive individuals is the same as that occurring in non HIV infected populations. It is characterized by the rapid destruction of the periodontal tissues characterized by rapid pocket formation and attachment loss. Radiographic features

**Figure 10.** Necrotizing ulcerative periodontitis with sequestrum,

**Figure 11.** Radiograph of NUP showing extensive bone loss around 22.

### *3.5.2.4. Necrotizing ulcerative stomatitis*

This is a rare condition in HIV positive patients. It is characterized by a localized, acutely painful rapidly destructive lesion which is ulcerative and necrotic. The lesion may extend from the gingiva into the adjacent oral mucosa, resulting in extensive destruction of the un‐ derlying soft tissues and osseous tissues. It may occur as a separate condition or be an exten‐ sion of NUP. The condition may lead to extensive denudation and eventual sequestration of bone (Williams et al., 1990). The condition is often associated with severe immune suppres‐ sion with low CD4 lymphocyte counts. This condition is similar to the cancrum oris (noma) a rare destructive condition described in nutritionally deprived individuals particularly chil‐ dren in Africa which progresses from ANUG (Osuji, 1990). Studies carried out by various individuals all around Nigeria did not show the presence of the disease, though the condi‐ tion was seen in Lagos University Teaching Hospital in a previously undiagnosed HIV sero‐ positive patient (Agbelusi and Eweka, 2011).

**Figure 12.** Necrotizing ulcerative stomatitis

have however been identified in some NUP lesions (Slot, 2004). Homosexuals and bisexual men appear to have a higher incidence of NUP compared to other cohorts of HIV positive individuals (Glick et al., 1994b). Several studies reveal an association between NUP and HIV progression (Masouredis et al., 1992; Winkler et al., 1988). NUP has also been reported to be one of the strongest predictors of severe immune suppression, characterized by low CD4 lymphocyte counts (Glick et al., 1994a; Glick et al., 1994b). Patients with NUP may however,

, indicating that other factors such as high viral loads

have CD4 counts above 200 cells/mm3

220 Current Perspectives in HIV Infection

may be associated (Umeizudike et al., 2011a).

**Figure 10.** Necrotizing ulcerative periodontitis with sequestrum,

**Figure 11.** Radiograph of NUP showing extensive bone loss around 22.

This is a rare condition in HIV positive patients. It is characterized by a localized, acutely painful rapidly destructive lesion which is ulcerative and necrotic. The lesion may extend from the gingiva into the adjacent oral mucosa, resulting in extensive destruction of the un‐ derlying soft tissues and osseous tissues. It may occur as a separate condition or be an exten‐

*3.5.2.4. Necrotizing ulcerative stomatitis*

**Figure 13.** Necrotizing ulcerative stomatitis

#### *3.5.2.5. Chronic periodontitis with an increased rate of attachment loss*

Rapid periodontal pocket formation has been reported in HIV infection in some controlled studies (Barr et al., 1992; Yeung et al., 1993; Robinson et al., 1996; Ndiaye et al., 1997; Ranga‐ nathan et al., 2007; Umeizudike et al., 2011b). Although, this is not a consistent finding (Scheutz et al., 1997).This accelerated periodontal attachment loss reported in HIV infected individuals could be the result of severe episodes of NUP. The clinical presentation of gingi‐ vitis and chronic periodontitis in HIV-positive individuals is the same as that occurring in non HIV infected populations. It is characterized by the rapid destruction of the periodontal tissues characterized by rapid pocket formation and attachment loss. Radiographic features with evidence of alveolar bone loss are evident. The risk factors for periodontitis in HIV pos‐ itive patients include age, smoking pack-years, high viral load, *Fusobacterium nucleatum, Pre‐ votella intermedia, Actinobacillus actinomycetemcomitans*, neutrophil elastase and βglucuronidase (Alpagot et al., 2004).

The frequency of OHL is about 20% in those with otherwise symptom- free HIV infection and increases as the CD4 count falls and the clinical condition deteriorates (Aragues et al.,

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 223

Considerable research have provided a body of evidence that the *Epstein Barr virus (EBV)* is the likely cause of this lesion, which should probably now be renamed according to its aeti‐

Histologic features of OHL shows surface corrugation, thickening of the prickle- cell layer (acanthosis) with groups or layers of ballooning cells similar to koilocytes, absence of atypia and other features of dysplasia, lack of inflammatory cells infilteration in the epithelium or adjoining connective tissues (Greenspan et al., 1984). These features are not pathognomic of OHL. Evidence of presence of EBV is required for definitive diagnosis of OHL, although presumptive diagnosis can be made on clinical appearance alone and non-response to anti‐

This is the most common malignancy encountered in HIV/AIDS patients (Iain et al., 2000). Kaposi's sarcoma-associated herpes virus (KSHV)/Human Herpes Virus-8 (HHV-8) is the causative agent of the endothelial cell-derived tumour Kaposi's sarcoma (Sturzl et al., 2009). The lesions are commonly seen in homosexual men. The lesions are characterized by red‐ dish, bluish or purple, single or multiple macules or nodules. These are seen on the palate or gingivae and may ulcerate, gingival involvement may lead to underlying bone destruction and tooth mobility (Iain et al., 1992). Twenty two percent of the lesions are present intraoral‐ ly, with 45% of patients presenting with both skin and oral lesions (Tappero et al., 1993).

Biopsy is essential for a definitive diagnosis. It is considered pathognomonic of HIV infec‐

There is evidence that oral Kaposi's sarcoma lesions are associated with patients who have

lower CD4 counts than those with the skin lesions alone. (Iain et al., 2000)

1990; Feigel et al., 1991; Glick et al., 1994; Lifson et al., 1994).

fungal drugs. (ECC/WHO, 1993).

**Figure 15.** Hairy leukoplakia

*3.5.4. Kaposi's sarcoma*

tions.

ology as *"EBV Leukoplakia*" (Greenspan et al., 1984; Iain et al., 2000).

**Figure 14.** Deep periodontal pocket around tooth 16.

### *3.5.3. Oral Hairy Leukoplakia: (OHL)*

This lesion usually presents as asymptomatic, white, vertical, corrugated, hair-like projec‐ tions on the lateral borders of the tongue (bilaterally or unilaterally). It can spread to the dorsum of the tongue and on the ventral aspect to the floor of the mouth and occasional‐ ly on the adjacent buccal mucosa, when seen in these areas it is smooth and velvety not hair-like. Unlike candidiasis the lesion cannot be wiped off the mucosal surface (ECC/ WHO, 1993).

OHL was seen and investigated in 1981 by Greenspan et al., who published the initial report of its existence among homosexual men in San Francisco in 1984 (Greenspan et al.,1984).

It is slightly less common in women than in men, and it is also rare in children. In HIV posi‐ tive persons OHL heralds more rapid progressions of AIDS (Greenspan et al., 1984; Glick et al., 1994; Lifson et al., 1994).

The incidence of OHL is reported to be 20% in CDC II individuals, increasing as CD4 count falls and patient's clinical condition deteriorates (Glick et al., 1994; Lifson et al., 1994). It also appears during the late latency stages of HIV infection. Although the studies carried out by Greenspan et al in 2000, showed that the presence of OHL was not related to CD4 count but was associated with high viral load.

OHL prevalence rates ranged from 0% amongst Tanzanians (Schiodt et al., 1990) to 20% in Cape Town (Arendorf et al., 1998).

Although originally postulated to be pathognomonic for HIV infection, this lesion has sub‐ sequently been reported in other immune deficiency states as well as in immunocompetent individuals (Sirois, 1998) e.g. among organ or bone marrow recipients and those receiving long-term steroid therapy (King et al., 1994).

The frequency of OHL is about 20% in those with otherwise symptom- free HIV infection and increases as the CD4 count falls and the clinical condition deteriorates (Aragues et al., 1990; Feigel et al., 1991; Glick et al., 1994; Lifson et al., 1994).

Considerable research have provided a body of evidence that the *Epstein Barr virus (EBV)* is the likely cause of this lesion, which should probably now be renamed according to its aeti‐ ology as *"EBV Leukoplakia*" (Greenspan et al., 1984; Iain et al., 2000).

Histologic features of OHL shows surface corrugation, thickening of the prickle- cell layer (acanthosis) with groups or layers of ballooning cells similar to koilocytes, absence of atypia and other features of dysplasia, lack of inflammatory cells infilteration in the epithelium or adjoining connective tissues (Greenspan et al., 1984). These features are not pathognomic of OHL. Evidence of presence of EBV is required for definitive diagnosis of OHL, although presumptive diagnosis can be made on clinical appearance alone and non-response to anti‐ fungal drugs. (ECC/WHO, 1993).

**Figure 15.** Hairy leukoplakia

with evidence of alveolar bone loss are evident. The risk factors for periodontitis in HIV pos‐ itive patients include age, smoking pack-years, high viral load, *Fusobacterium nucleatum, Pre‐ votella intermedia, Actinobacillus actinomycetemcomitans*, neutrophil elastase and β-

This lesion usually presents as asymptomatic, white, vertical, corrugated, hair-like projec‐ tions on the lateral borders of the tongue (bilaterally or unilaterally). It can spread to the dorsum of the tongue and on the ventral aspect to the floor of the mouth and occasional‐ ly on the adjacent buccal mucosa, when seen in these areas it is smooth and velvety not hair-like. Unlike candidiasis the lesion cannot be wiped off the mucosal surface (ECC/

OHL was seen and investigated in 1981 by Greenspan et al., who published the initial report of its existence among homosexual men in San Francisco in 1984 (Greenspan et al.,1984).

It is slightly less common in women than in men, and it is also rare in children. In HIV posi‐ tive persons OHL heralds more rapid progressions of AIDS (Greenspan et al., 1984; Glick et

The incidence of OHL is reported to be 20% in CDC II individuals, increasing as CD4 count falls and patient's clinical condition deteriorates (Glick et al., 1994; Lifson et al., 1994). It also appears during the late latency stages of HIV infection. Although the studies carried out by Greenspan et al in 2000, showed that the presence of OHL was not related to CD4 count but

OHL prevalence rates ranged from 0% amongst Tanzanians (Schiodt et al., 1990) to 20% in

Although originally postulated to be pathognomonic for HIV infection, this lesion has sub‐ sequently been reported in other immune deficiency states as well as in immunocompetent individuals (Sirois, 1998) e.g. among organ or bone marrow recipients and those receiving

glucuronidase (Alpagot et al., 2004).

222 Current Perspectives in HIV Infection

**Figure 14.** Deep periodontal pocket around tooth 16.

*3.5.3. Oral Hairy Leukoplakia: (OHL)*

WHO, 1993).

al., 1994; Lifson et al., 1994).

was associated with high viral load.

Cape Town (Arendorf et al., 1998).

long-term steroid therapy (King et al., 1994).

#### *3.5.4. Kaposi's sarcoma*

This is the most common malignancy encountered in HIV/AIDS patients (Iain et al., 2000). Kaposi's sarcoma-associated herpes virus (KSHV)/Human Herpes Virus-8 (HHV-8) is the causative agent of the endothelial cell-derived tumour Kaposi's sarcoma (Sturzl et al., 2009). The lesions are commonly seen in homosexual men. The lesions are characterized by red‐ dish, bluish or purple, single or multiple macules or nodules. These are seen on the palate or gingivae and may ulcerate, gingival involvement may lead to underlying bone destruction and tooth mobility (Iain et al., 1992). Twenty two percent of the lesions are present intraoral‐ ly, with 45% of patients presenting with both skin and oral lesions (Tappero et al., 1993).

Biopsy is essential for a definitive diagnosis. It is considered pathognomonic of HIV infec‐ tions.

There is evidence that oral Kaposi's sarcoma lesions are associated with patients who have lower CD4 counts than those with the skin lesions alone. (Iain et al., 2000)

pseudomembrane, measuring over 1cm in diameter. These lesions are very painful and may persist for months causing difficulty in swallowing and impairment of speech and mastica‐ tion. Generally, an erythematous halo can be seen surrounding the ulcer and may be accom‐

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 225

Salivary gland diseases such as enlargement of the major salivary glands and xerostomia, was reported to be high in Northern Africa and Thailand (Nittayananta and Chungpanich,

Enlargement of the salivary glands due to infilteration by CD8 lymphocytes is seen in both adult and paediatric HIV infection (Schoidt et al., 1989). Some of these glands undergo cystic change, and such benign lymphoepithelial cysts occasionally cause pain. The cause of HIVrelated salivary gland diseases is unclear, for no etiological agents have been identified. It can represent a relatively beneficial host CD8 response - Diffuse Infilterative Lymphocytosis Syndrome (DILS) (Itescu et al., 1990), the lymphocytes may be anti- HIV CD8 cells. No evi‐

1997). Malnutrition, especially in Northern Africa may play a role.

panied by regional lymphadenopathy.

**Figure 17.** Minor apthous ulcers.

**Figure 18.** Major apthous ulcer.

*3.5.7. Salivary gland diseases*

**Figure 16.** Kaposi's sarcoma on the palate and gingiva

### *3.5.5. Non- Hogdkin's Lymphoma (NHL)*

This is an uncommon feature of HIV disease. It is however, the second most common malig‐ nancy in this condition, with 4% of patients developing NHL during the course of their dis‐ ease (Iain et al., 2000).

NHL of the oral cavity accounts for 3% of all malignant lymphomas, which tends to occur extranodally (Epstein et al., 1992).

Characteristically, oral tumours involve the fauces and gingivae but atypically may involve other sites such as the tongue (Borring et al., 1985).

It often clinically presents as a rapidly enlarging mass with associated bony destruction. Though the presentation varies, the pathogenesis of NHL remains obscure, but there has been much interest in the role of the Epstein Barr virus, with 50% of AIDS related tumours demonstrating EBV genomes and also aetiologic role of Human Herpes Virus-8 (HHV-8) (Boshoff et al., 1997). Survival rates are low and biopsy is essential for definitive diagnosis.

#### *3.5.6. Oral ulcers*

Around 50% of AIDS patients present with oral ulcerations during the course of their dis‐ ease. Recurrent aphthous ulcers (RAU) can be classified as **Minor aphthous Ulcers (MiAU) and Major Aphthous ulcers (MjAU)**.

**MiAU:** Occur in non- keratinized mucosa and their frequency in AIDS patients is not any different from that in the general population. RAU have a prolonged course in AIDS pa‐ tients as well as being more painful and difficult to treat. These ulcers are shallow in appear‐ ance, about 2-5mm in diameter, are generally covered with a whitish pseudomembrane and surrounded by an erythematous halo.

**MjAU:** Are generally seen in AIDS patients with severe immunodepression (median CD4 Tlymphocyte count 100 cells/mm3 or below) (Ramos-Gomez, 1997). These larger ulcers devel‐ op generally on the lateral border of the tongue, soft palate, floor of the mouth, buccal mucosa and oropharynx (occurring on both keratinized and non-keratinized surfaces). They are crater-like in appearance with elevated borders and covered with a white-yellowish pseudomembrane, measuring over 1cm in diameter. These lesions are very painful and may persist for months causing difficulty in swallowing and impairment of speech and mastica‐ tion. Generally, an erythematous halo can be seen surrounding the ulcer and may be accom‐ panied by regional lymphadenopathy.

**Figure 17.** Minor apthous ulcers.

**Figure 16.** Kaposi's sarcoma on the palate and gingiva

This is an uncommon feature of HIV disease. It is however, the second most common malig‐ nancy in this condition, with 4% of patients developing NHL during the course of their dis‐

NHL of the oral cavity accounts for 3% of all malignant lymphomas, which tends to occur

Characteristically, oral tumours involve the fauces and gingivae but atypically may involve

It often clinically presents as a rapidly enlarging mass with associated bony destruction. Though the presentation varies, the pathogenesis of NHL remains obscure, but there has been much interest in the role of the Epstein Barr virus, with 50% of AIDS related tumours demonstrating EBV genomes and also aetiologic role of Human Herpes Virus-8 (HHV-8) (Boshoff et al., 1997). Survival rates are low and biopsy is essential for definitive diagnosis.

Around 50% of AIDS patients present with oral ulcerations during the course of their dis‐ ease. Recurrent aphthous ulcers (RAU) can be classified as **Minor aphthous Ulcers (MiAU)**

**MiAU:** Occur in non- keratinized mucosa and their frequency in AIDS patients is not any different from that in the general population. RAU have a prolonged course in AIDS pa‐ tients as well as being more painful and difficult to treat. These ulcers are shallow in appear‐ ance, about 2-5mm in diameter, are generally covered with a whitish pseudomembrane and

**MjAU:** Are generally seen in AIDS patients with severe immunodepression (median CD4 T-

op generally on the lateral border of the tongue, soft palate, floor of the mouth, buccal mucosa and oropharynx (occurring on both keratinized and non-keratinized surfaces). They are crater-like in appearance with elevated borders and covered with a white-yellowish

or below) (Ramos-Gomez, 1997). These larger ulcers devel‐

*3.5.5. Non- Hogdkin's Lymphoma (NHL)*

extranodally (Epstein et al., 1992).

**and Major Aphthous ulcers (MjAU)**.

surrounded by an erythematous halo.

lymphocyte count 100 cells/mm3

other sites such as the tongue (Borring et al., 1985).

ease (Iain et al., 2000).

224 Current Perspectives in HIV Infection

*3.5.6. Oral ulcers*

**Figure 18.** Major apthous ulcer.

#### *3.5.7. Salivary gland diseases*

Salivary gland diseases such as enlargement of the major salivary glands and xerostomia, was reported to be high in Northern Africa and Thailand (Nittayananta and Chungpanich, 1997). Malnutrition, especially in Northern Africa may play a role.

Enlargement of the salivary glands due to infilteration by CD8 lymphocytes is seen in both adult and paediatric HIV infection (Schoidt et al., 1989). Some of these glands undergo cystic change, and such benign lymphoepithelial cysts occasionally cause pain. The cause of HIVrelated salivary gland diseases is unclear, for no etiological agents have been identified. It can represent a relatively beneficial host CD8 response - Diffuse Infilterative Lymphocytosis Syndrome (DILS) (Itescu et al., 1990), the lymphocytes may be anti- HIV CD8 cells. No evi‐ dence of Epstein-Barr virus or cytomegalovirus has been found in biopsies of salivary gland (Soberman et al., 1991) One report describes an association between HIV-SGD and HLA-DR5 and HLA-B35 cell-surface antigen (Schiodt et al.,1989).

persons, and potentially lethal (Cawson et al., 2002). Varicella-zoster may present with a prodrome of dental pain, preceding oral and unilateral vesicles on an erythematous base then appear in clusters, chiefly along the course of the nerve, giving the characteristic clini‐ cal picture of single dermatome involvement. Some lesions spread by viremia occur outside the dermatome. The vesicles turn to scabs in 1 week, and healing takes place in 2 to 3 weeks

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 227

and condition can be life threatening in HIV disease.

Figure 20.Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve

Figure 20.Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve

**Figure 20.** Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve

Figure 21.Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve.

Figure 21.Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve.

Brownish or brown black macular oral hyperpigmentation, typically associated with intraleukocytic melanin or pigment in the basal cell layer or lamina propria, with premature melanosomes has been described in HIV-infected patients (Langford et al., 1989; Porter et al., 1990). Often the cause is unknown, but identified causes include Zidovudine (AZT), Clofazimine, ketoconazole and hypoadrenocorticism as a result of adrenal Mycobacterium avium intracellulare infection (Porter et al., 1990). Usually does not

**Figure 21.** Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve.

Brownish or brown black macular oral hyperpigmentation, typically associated with intraleukocytic melanin or pigment in the basal cell layer or lamina propria, with premature melanosomes has been described in HIV-infected patients (Langford et al., 1989; Porter et al., 1990). Often the cause is unknown, but identified causes include Zidovudine (AZT), Clofazimine, ketoconazole and hypoadrenocorticism as a result of adrenal Mycobacterium avium intracellulare infection (Porter et al., 1990). Usually does not

Brownish or brown black macular oral hyperpigmentation, typically associated with intra‐ leukocytic melanin or pigment in the basal cell layer or lamina propria, with premature melanosomes has been described in HIV-infected patients (Langford et al., 1989; Porter et al., 1990). Often the cause is unknown, but identified causes include Zidovudine (AZT), Clofazimine, ketoconazole and hypoadrenocorticism as a result of adrenal Mycobacteri‐ um avium intracellulare infection (Porter et al., 1990). Usually does not respond to

Treatment may be topical (using lozenges or mouth rinses) or systemic depending on the severity of the disease and other

Treatment may be topical (using lozenges or mouth rinses) or systemic depending on the severity of the disease and other

**3.5.7.3. Melanotic hyperpigmentation**

**3.5.7.3. Melanotic hyperpigmentation**

*3.5.7.3. Melanotic hyperpigmentation*

respond to HAART.

respond to HAART.

HAART.

Figure 22.Melanotic hyperpigmentation

Figure 22.Melanotic hyperpigmentation

**3.6.1. Candidiasis**

**3.6.1. Candidiasis**

**3.6. Management of oral lesions of HIV**

**3.6. Management of oral lesions of HIV**

associated underlying conditions e.g. Diabetes, liver disease, xerostomia etc.

associated underlying conditions e.g. Diabetes, liver disease, xerostomia etc.

Adults and children with salivary glands enlargement seem to experience slower progres‐ sion of HIV disease (Katz et al., 1993).

Oral Mucoceles and ranulas are recently discovered to be oral manifestations of HIV infec‐ tion. Several reports are considering it as initial symptoms and early manifestations of HIV infection (Syebele et al., 2010; Kamulegeya et al., 2012).

**Figure 19.** Salivary gland swelling

### *3.5.7.1. Xerostomia*

This may be associated with the salivary gland enlargement but is also a common conse‐ quence of medications used by this population. Cytomegalovirus (CMV) has been demon‐ strated in the salivary gland of xerostomic patients (Greenspan et al., 1992). Symptomatic relief may be provided by salivary stimulants such as sugarless chewing gums or saliva sub‐ stitutes. Prevention of dental caries in people with xerostomia is extremely important, and the use of topical fluoride gels and rinses should be encouraged (Greenspan et al., 1996). In addition, management of xerostomia will improve oral comfort, the quality of speech and use of any prostheses (Narani et al., 2001).

#### *3.5.7.2. Herpes virus infections*

Varicella zoster (VZV) is a herpesvirus, and, like other herpesviruses, it causes both primary and recurrent infection and remains latent in neurons present in sensory ganglia. VZV is re‐ sponsible for two major clinical infections of humans: chickenpox (varicella) and shingles (herpes zoster [HZ]) (Greenburg et al., 2003 ).

Herpes zoster may indicate a poor prognosis of HIV infection (Scully et al., 1991). This can be an early complication of AIDS, where it is five times more common than HIV-negative persons, and potentially lethal (Cawson et al., 2002). Varicella-zoster may present with a prodrome of dental pain, preceding oral and unilateral vesicles on an erythematous base then appear in clusters, chiefly along the course of the nerve, giving the characteristic clini‐ cal picture of single dermatome involvement. Some lesions spread by viremia occur outside the dermatome. The vesicles turn to scabs in 1 week, and healing takes place in 2 to 3 weeks and condition can be life threatening in HIV disease.

Figure 20.Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve **Figure 20.** Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve

Figure 20.Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve

**3.5.7.3. Melanotic hyperpigmentation** Figure 21.Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve. **Figure 21.** Herpes zoster of the left maxillary branch and the right occipital branch of the trigeminal nerve.

#### basal cell layer or lamina propria, with premature melanosomes has been described in HIV-infected patients (Langford et al., 1989; **3.5.7.3. Melanotic hyperpigmentation** *3.5.7.3. Melanotic hyperpigmentation*

Figure 22.Melanotic hyperpigmentation

Figure 22.Melanotic hyperpigmentation

**3.6.1. Candidiasis**

**3.6.1. Candidiasis**

**3.6. Management of oral lesions of HIV**

**3.6. Management of oral lesions of HIV**

associated underlying conditions e.g. Diabetes, liver disease, xerostomia etc.

associated underlying conditions e.g. Diabetes, liver disease, xerostomia etc.

dence of Epstein-Barr virus or cytomegalovirus has been found in biopsies of salivary gland (Soberman et al., 1991) One report describes an association between HIV-SGD and HLA-

Adults and children with salivary glands enlargement seem to experience slower progres‐

Oral Mucoceles and ranulas are recently discovered to be oral manifestations of HIV infec‐ tion. Several reports are considering it as initial symptoms and early manifestations of HIV

This may be associated with the salivary gland enlargement but is also a common conse‐ quence of medications used by this population. Cytomegalovirus (CMV) has been demon‐ strated in the salivary gland of xerostomic patients (Greenspan et al., 1992). Symptomatic relief may be provided by salivary stimulants such as sugarless chewing gums or saliva sub‐ stitutes. Prevention of dental caries in people with xerostomia is extremely important, and the use of topical fluoride gels and rinses should be encouraged (Greenspan et al., 1996). In addition, management of xerostomia will improve oral comfort, the quality of speech and

Varicella zoster (VZV) is a herpesvirus, and, like other herpesviruses, it causes both primary and recurrent infection and remains latent in neurons present in sensory ganglia. VZV is re‐ sponsible for two major clinical infections of humans: chickenpox (varicella) and shingles

Herpes zoster may indicate a poor prognosis of HIV infection (Scully et al., 1991). This can be an early complication of AIDS, where it is five times more common than HIV-negative

DR5 and HLA-B35 cell-surface antigen (Schiodt et al.,1989).

infection (Syebele et al., 2010; Kamulegeya et al., 2012).

sion of HIV disease (Katz et al., 1993).

226 Current Perspectives in HIV Infection

**Figure 19.** Salivary gland swelling

use of any prostheses (Narani et al., 2001).

(herpes zoster [HZ]) (Greenburg et al., 2003 ).

*3.5.7.2. Herpes virus infections*

*3.5.7.1. Xerostomia*

hypoadrenocorticism as a result of adrenal Mycobacterium avium intracellulare infection (Porter et al., 1990). Usually does not respond to HAART. Brownish or brown black macular oral hyperpigmentation, typically associated with intraleukocytic melanin or pigment in the basal cell layer or lamina propria, with premature melanosomes has been described in HIV-infected patients (Langford et al., 1989; Porter et al., 1990). Often the cause is unknown, but identified causes include Zidovudine (AZT), Clofazimine, ketoconazole and hypoadrenocorticism as a result of adrenal Mycobacterium avium intracellulare infection (Porter et al., 1990). Usually does not respond to HAART. Brownish or brown black macular oral hyperpigmentation, typically associated with intra‐ leukocytic melanin or pigment in the basal cell layer or lamina propria, with premature melanosomes has been described in HIV-infected patients (Langford et al., 1989; Porter et al., 1990). Often the cause is unknown, but identified causes include Zidovudine (AZT), Clofazimine, ketoconazole and hypoadrenocorticism as a result of adrenal Mycobacteri‐ um avium intracellulare infection (Porter et al., 1990). Usually does not respond to HAART.

Treatment may be topical (using lozenges or mouth rinses) or systemic depending on the severity of the disease and other

Treatment may be topical (using lozenges or mouth rinses) or systemic depending on the severity of the disease and other

Brownish or brown black macular oral hyperpigmentation, typically associated with intraleukocytic melanin or pigment in the

Porter et al., 1990). Often the cause is unknown, but identified causes include Zidovudine (AZT), Clofazimine, ketoconazole and

cannot be held in the mouth long enough to be effective. Topical creams and ointments con‐ taining nystatin, ketoconazole, or clotrimazole may be useful in treating angular cheilitis. For patients with initial and recurring oropharyngeal candidiasis, a topical agent is general‐

Another therapeutic choice is Amphotericin B (0.1 mg/ml). Five to 10 ml of oral solution is

Ketoconazole (Nizoral) is a 200 mg tablet taken with food once daily. Patient compliance is usually good. Careful monitoring of liver function is necessary for long-term use because of reported side effects, including hepatotoxicity. Lack of efficacy of ketoconazole may occur

Fluconazole (Diflucan) is a triazole antifungal agent effective in treating candidiasis (100-mg

Itraconazole (100 mg capsules) may be used for the treatment of oral candidiasis (200 mg daily orally for 14 days. Salivary levels of itraconazole are maintained for several hours after

The recommendation to avoid systemic anti-fungal therapies in this setting is based on evi‐ dence that widespread use of systemic azoles is strongly linked with the development of drug-resistant candidiasis. Patients with concurrent oesophageal involvement or a CD4

should receive a systemic oral azole.

Ketoconazole, fluconazole, and itraconazole may interact with other medications including rifampicin, phenytoin, cyclosporin A, terfenadine, digoxin, coumarin-like medications, and

The treatment protocol for LGE is similar to that of conventional marginal gingivitis and consists of scaling and polishing of the affected sites and thorough root planing using chlo‐ rhexidine solution as an irrigant (Murray, 1994). Povidone-iodine (10%) solution may be beneficial for the irrigation because of its anaesthetic and antiseptic effects. According to Murray (1994), the rationale for scaling is to prevent the lesion from progressing to NUP, the more severe form. Typically, the patients are given oral hygiene instructions to achieve good home care, placed on chlorhexidine mouthrinses twice daily, re-assessed 2 to 3 weeks after

and no

229

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941

ly recommended, provided the patient has a CD4 count greater than 50 cells/mm3

used as a rinse and then expectorated three to four times daily (Greenspan, 1998).

**Systemic**: Fluconazole 150mg daily (Diflucan) for 2 weeks or more

because of poor absorption in those with an abnormally high gastric pH.

**•** Ketoconazole 200mg daily (Sporanox), for 2 weeks or more

tablet taken once daily for 2 weeks (Just-Nubling et al., 1991).

the initial therapeutic phase, and further recalled every 3 months.

**•** Miconazole 250mg daily for 2 weeks or more

**•** Itraconazole 100mg daily, for 2 weeks or more

administration (Smith et al., 1991).

count less than 50 cells/mm3

oral hypoglycemic medications.

*3.6.2. Linear gingival erythema*

oesophageal involvement.

**Figure 22.** Melanotic hyperpigmentation

#### **3.6. Management of oral lesions of HIV**

#### *3.6.1. Candidiasis*

Treatment may be topical (using lozenges or mouth rinses) or systemic depending on the severity of the disease and other associated underlying conditions e.g. Diabetes, liver dis‐ ease, xerostomia etc.

#### **Topical:**


Topical treatments are preferred because they limit systemic absorption, but the effective‐ ness depends entirely on patient compliance. Topical medications require that the patient hold medications in the mouth for 20 to 30 minutes.

Clotrimazole is an effective topical treatment (one oral troche [10-mg tablet]) when dis‐ solved in the mouth five times daily. Used less frequently, one vaginal troche can be dis‐ solved in the mouth daily.

Nystatin preparations include a suspension, a vaginal tablet, and an oral pastille. Regimens are nystatin tablets (one tablet, 100,000 units, dissolved in the mouth three times a day), or nystatin oral pastille (available as a 200,000 unit oral pastille, one or two pastilles dissolved slowly in the mouth five times a day). Nystatin suspension has a high sugar content and cannot be held in the mouth long enough to be effective. Topical creams and ointments con‐ taining nystatin, ketoconazole, or clotrimazole may be useful in treating angular cheilitis. For patients with initial and recurring oropharyngeal candidiasis, a topical agent is general‐ ly recommended, provided the patient has a CD4 count greater than 50 cells/mm3 and no oesophageal involvement.

Another therapeutic choice is Amphotericin B (0.1 mg/ml). Five to 10 ml of oral solution is used as a rinse and then expectorated three to four times daily (Greenspan, 1998).

**Systemic**: Fluconazole 150mg daily (Diflucan) for 2 weeks or more


**Figure 22.** Melanotic hyperpigmentation

228 Current Perspectives in HIV Infection

*3.6.1. Candidiasis*

ease, xerostomia etc.

**Topical:**

**3.6. Management of oral lesions of HIV**

**1.** Chlorhexidine (0.2%) mouth wash

**3.** Adhesive tablets: Miconazole 10mg

hold medications in the mouth for 20 to 30 minutes.

**4.** Miconazole oral gel- X2% daily

solved in the mouth daily.

Treatment may be topical (using lozenges or mouth rinses) or systemic depending on the severity of the disease and other associated underlying conditions e.g. Diabetes, liver dis‐

Topical treatments are preferred because they limit systemic absorption, but the effective‐ ness depends entirely on patient compliance. Topical medications require that the patient

Clotrimazole is an effective topical treatment (one oral troche [10-mg tablet]) when dis‐ solved in the mouth five times daily. Used less frequently, one vaginal troche can be dis‐

Nystatin preparations include a suspension, a vaginal tablet, and an oral pastille. Regimens are nystatin tablets (one tablet, 100,000 units, dissolved in the mouth three times a day), or nystatin oral pastille (available as a 200,000 unit oral pastille, one or two pastilles dissolved slowly in the mouth five times a day). Nystatin suspension has a high sugar content and

**2.** Lozenges: e.g. Nystatin (Mycostatin) 100,000 i.u; Clotrimazole (Mycelex) 1%

**5.** Suspension: e.g. Amphotericin B (0.5-1mg), Nystatin (100,000 i.u)

Ketoconazole (Nizoral) is a 200 mg tablet taken with food once daily. Patient compliance is usually good. Careful monitoring of liver function is necessary for long-term use because of reported side effects, including hepatotoxicity. Lack of efficacy of ketoconazole may occur because of poor absorption in those with an abnormally high gastric pH.

Fluconazole (Diflucan) is a triazole antifungal agent effective in treating candidiasis (100-mg tablet taken once daily for 2 weeks (Just-Nubling et al., 1991).

Itraconazole (100 mg capsules) may be used for the treatment of oral candidiasis (200 mg daily orally for 14 days. Salivary levels of itraconazole are maintained for several hours after administration (Smith et al., 1991).

The recommendation to avoid systemic anti-fungal therapies in this setting is based on evi‐ dence that widespread use of systemic azoles is strongly linked with the development of drug-resistant candidiasis. Patients with concurrent oesophageal involvement or a CD4 count less than 50 cells/mm3 should receive a systemic oral azole.

Ketoconazole, fluconazole, and itraconazole may interact with other medications including rifampicin, phenytoin, cyclosporin A, terfenadine, digoxin, coumarin-like medications, and oral hypoglycemic medications.

#### *3.6.2. Linear gingival erythema*

The treatment protocol for LGE is similar to that of conventional marginal gingivitis and consists of scaling and polishing of the affected sites and thorough root planing using chlo‐ rhexidine solution as an irrigant (Murray, 1994). Povidone-iodine (10%) solution may be beneficial for the irrigation because of its anaesthetic and antiseptic effects. According to Murray (1994), the rationale for scaling is to prevent the lesion from progressing to NUP, the more severe form. Typically, the patients are given oral hygiene instructions to achieve good home care, placed on chlorhexidine mouthrinses twice daily, re-assessed 2 to 3 weeks after the initial therapeutic phase, and further recalled every 3 months.

Non-responsive lesions could signal a possible candidal co-infection which may need to be treated concomitantly with topical antifungal rinses or systemic antifungal tablets such as fluconazole for 7 to 10 days (Murray, 1994). This has been shown to reduce the erythema associated with LGE. It must be borne in mind that LGE may still be refractory to treatment, hence, patient should be monitored closely for any signs of severe necrotizing periodontal conditions. The lesion has sometimes been known to undergo spontaneous remission for reasons yet unknown.

*3.6.5. Necrotizing ulcerative stomatitis*

mote wound healing (Williams et al., 1990).

*3.6.6. Chronic periodontitis with an increased rate of attachment loss*

The principles of the treatment are similar to that of necrotizing ulcerative periodontitis. It should begin with gross scaling to remove visible plaque and debridement of necrotic soft tissue. Povidone-iodine may be used for irrigation. Systemic metronidazole and chlorhexi‐ dine mouthrinses should be prescribed. Necrotic bone should be removed if present to pro‐

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 231

This should include conservative, non-surgical periodontal therapy which basically consists of scaling and polishing of all teeth, sub-gingival scaling and root planing of affected teeth. Detailed oral hygiene instructions should be given to the patient in order to achieve effective plaque control. This should include the use of 0.2% chlorhexidine mouthwashes twice daily at home. The overall health status of the patient, the degree of immune suppression, extent of periodontal attachment loss and patient's ability to perform effective oral hygiene are all the factors that should be taken into consideration when planning for elective periodontal surgical procedures and implant placement. The hematological profile of patients may be re‐ quired prior to these surgical procedures to monitor their overall health status. Periodontal maintenance recalls should be instituted at 2-3 monthly intervals initially, and later to 6 monthly intervals. Dentists should be ready to advise patients and provide dental treat‐ ments in a relaxed and calm atmosphere to minimize the patients stress and anxiety, as

these HIV positive patients are prone to psychological problems (Asher et al. 1993).

HIV should have some basic components (Winkler & Robertson, 1992).

**1.** Extensive debridement of necrotic tissues. **2.** Antimicrobial therapy (local and systemic)

curs after discontinuation of therapy (Scully et al., 1992).

**3.** Immediate follow up phase

**4.** Regular long-term maintenance

*3.6.7. Oral Hairy Leukoplakia (OHL)*

*3.6.8. Kaposi's sarcoma*

In summary, it should be noted that the treatment of periodontal diseases associated with

**OHL** is usually symptomless; complaints about the discomfort and appearance sometimes justify treatment (Barr, 1995). The lesions respond to high doses of acyclovir, ganciclovir, and also podophyllin and retinoin. Treatment is usually not indicated, but improved with antiretroviral therapy e.g. AZT, Ganciclovir, acyclovir or descyclovir. Hairy leukoplakia re‐

Treatment of oral kaposi's sarcoma is directed towards control of spread and palliation, for aesthetic reasons, pain or functional impairment. It is by radiotherapy or chemotherapy such as Vinblastin. Radiation therapy may be indicated for large, multiple lesions (Green‐

#### *3.6.3. Necrotizing ulcerative gingivitis*

The NUG lesion should be debrided thoroughly under topical anaesthesia to remove tissue slough, plaque and necrotic soft tissue in the initial phase of treatment. Irrigation should be done frequently with hydrogen peroxide or povidone iodine which is particularly advanta‐ geous because of its topical anaesthetic effect (Grassi et al., 1988). This should be accompa‐ nied by daily or alternate day visits for further debridement of affected areas for the first week with the gradual introduction of home plaque control measures to reinforce good oral hygiene. This initial phase of treatment is followed by scaling and thorough root planing if indicated. Systemic antibiotics such as metronidazole may be prescribed in severe cases of tissue loss or associated systemic effects. Topical chlorhexidine gluconate 0.12% mouthwash is prescribed. Patients are reassessed 1 month after resolution of the acute phase to deter‐ mine if further therapy is needed. Most of the lesions may resolve within a week (Robinson et al., 1998).

#### *3.6.4. Necrotizing ulcerative periodontitis*

The treatment of NUP involves the gentle debridement of the affected lesions, followed by sub-gingival scaling and root planing, irrigation with chlorhexidine gluconate (Grassi et al., 1988; Umeizudike et al., 2011a) or povidone-iodine. Oral hygiene instructions should be em‐ phasized alongside the home use of twice daily antimicrobial mouth-rinses such as 0.12% or 0.2% chlorhexidine gluconate. In severe NUP cases, systemic metronidazole 500mg loading dose and 250 mg four times daily for 5-7 days is the drug of choice. It has been shown to reduce acute pain and promote rapid healing. Metronidazole should be prescribed with cau‐ tion in patients with liver alteration or history of hepatitis (Winkler & Robertson, 1992). Al‐ ternatively, penicillin may be prescribed. However, it should be used with caution to avoid the proliferation of opportunistic infections such as candidiasis. Appropriate topical or sys‐ temic antifungal treatment may be used for patients who have concurrent oral candidiasis (Holmstrup & Samaranayake, 1990). There is a need to follow up these patients after the ini‐ tial phase of therapy to ensure adequate plaque control and reduce the incidence of delayed healing and continued rapid destruction (Winkler & Robertson, 1992). Oral hygiene aids such as interproximal brushes may be necessary to achieve better plaque control. Sequestra should be removed if present to facilitate wound healing (Umeizudike et al., 2011a) and may not always require antibiotic coverage (Robinson, 1991).

### *3.6.5. Necrotizing ulcerative stomatitis*

Non-responsive lesions could signal a possible candidal co-infection which may need to be treated concomitantly with topical antifungal rinses or systemic antifungal tablets such as fluconazole for 7 to 10 days (Murray, 1994). This has been shown to reduce the erythema associated with LGE. It must be borne in mind that LGE may still be refractory to treatment, hence, patient should be monitored closely for any signs of severe necrotizing periodontal conditions. The lesion has sometimes been known to undergo spontaneous remission for

The NUG lesion should be debrided thoroughly under topical anaesthesia to remove tissue slough, plaque and necrotic soft tissue in the initial phase of treatment. Irrigation should be done frequently with hydrogen peroxide or povidone iodine which is particularly advanta‐ geous because of its topical anaesthetic effect (Grassi et al., 1988). This should be accompa‐ nied by daily or alternate day visits for further debridement of affected areas for the first week with the gradual introduction of home plaque control measures to reinforce good oral hygiene. This initial phase of treatment is followed by scaling and thorough root planing if indicated. Systemic antibiotics such as metronidazole may be prescribed in severe cases of tissue loss or associated systemic effects. Topical chlorhexidine gluconate 0.12% mouthwash is prescribed. Patients are reassessed 1 month after resolution of the acute phase to deter‐ mine if further therapy is needed. Most of the lesions may resolve within a week (Robinson

The treatment of NUP involves the gentle debridement of the affected lesions, followed by sub-gingival scaling and root planing, irrigation with chlorhexidine gluconate (Grassi et al., 1988; Umeizudike et al., 2011a) or povidone-iodine. Oral hygiene instructions should be em‐ phasized alongside the home use of twice daily antimicrobial mouth-rinses such as 0.12% or 0.2% chlorhexidine gluconate. In severe NUP cases, systemic metronidazole 500mg loading dose and 250 mg four times daily for 5-7 days is the drug of choice. It has been shown to reduce acute pain and promote rapid healing. Metronidazole should be prescribed with cau‐ tion in patients with liver alteration or history of hepatitis (Winkler & Robertson, 1992). Al‐ ternatively, penicillin may be prescribed. However, it should be used with caution to avoid the proliferation of opportunistic infections such as candidiasis. Appropriate topical or sys‐ temic antifungal treatment may be used for patients who have concurrent oral candidiasis (Holmstrup & Samaranayake, 1990). There is a need to follow up these patients after the ini‐ tial phase of therapy to ensure adequate plaque control and reduce the incidence of delayed healing and continued rapid destruction (Winkler & Robertson, 1992). Oral hygiene aids such as interproximal brushes may be necessary to achieve better plaque control. Sequestra should be removed if present to facilitate wound healing (Umeizudike et al., 2011a) and may

reasons yet unknown.

230 Current Perspectives in HIV Infection

et al., 1998).

*3.6.3. Necrotizing ulcerative gingivitis*

*3.6.4. Necrotizing ulcerative periodontitis*

not always require antibiotic coverage (Robinson, 1991).

The principles of the treatment are similar to that of necrotizing ulcerative periodontitis. It should begin with gross scaling to remove visible plaque and debridement of necrotic soft tissue. Povidone-iodine may be used for irrigation. Systemic metronidazole and chlorhexi‐ dine mouthrinses should be prescribed. Necrotic bone should be removed if present to pro‐ mote wound healing (Williams et al., 1990).

#### *3.6.6. Chronic periodontitis with an increased rate of attachment loss*

This should include conservative, non-surgical periodontal therapy which basically consists of scaling and polishing of all teeth, sub-gingival scaling and root planing of affected teeth. Detailed oral hygiene instructions should be given to the patient in order to achieve effective plaque control. This should include the use of 0.2% chlorhexidine mouthwashes twice daily at home. The overall health status of the patient, the degree of immune suppression, extent of periodontal attachment loss and patient's ability to perform effective oral hygiene are all the factors that should be taken into consideration when planning for elective periodontal surgical procedures and implant placement. The hematological profile of patients may be re‐ quired prior to these surgical procedures to monitor their overall health status. Periodontal maintenance recalls should be instituted at 2-3 monthly intervals initially, and later to 6 monthly intervals. Dentists should be ready to advise patients and provide dental treat‐ ments in a relaxed and calm atmosphere to minimize the patients stress and anxiety, as these HIV positive patients are prone to psychological problems (Asher et al. 1993).

In summary, it should be noted that the treatment of periodontal diseases associated with HIV should have some basic components (Winkler & Robertson, 1992).


#### *3.6.7. Oral Hairy Leukoplakia (OHL)*

**OHL** is usually symptomless; complaints about the discomfort and appearance sometimes justify treatment (Barr, 1995). The lesions respond to high doses of acyclovir, ganciclovir, and also podophyllin and retinoin. Treatment is usually not indicated, but improved with antiretroviral therapy e.g. AZT, Ganciclovir, acyclovir or descyclovir. Hairy leukoplakia re‐ curs after discontinuation of therapy (Scully et al., 1992).

#### *3.6.8. Kaposi's sarcoma*

Treatment of oral kaposi's sarcoma is directed towards control of spread and palliation, for aesthetic reasons, pain or functional impairment. It is by radiotherapy or chemotherapy such as Vinblastin. Radiation therapy may be indicated for large, multiple lesions (Green‐ span et al., 1984). A single dose of 800 cGy or an equivalent fractionated dose is frequently used and produces a good response. Other local therapy may involve excision of exophytic lesions or intra- lesional injection of vinblastin (Iain et al., 2000).

There have been a number of studies that have shown that chewing gum increases salivary flow from patients with xerostomia of varying aetiology (Risheim et al., 1993). In some xe‐ rostomic patients, the initial stimulated salivary flow rate while chewing sugar free gum is seven times greater than the unstimulated flow rate. Chewing sugar free gum has been shown to be one of the most preferred treatments for xerostomia (Bjornstrom et al., 1990).

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 233

Management should be directed toward shortening the course of the disease, preventing post‐ herpetic neuralgia in patients over 50 years of age, and preventing dissemination in immuno‐ compromised patients. Acyclovir or the newer antiherpes drugs valacyclovir or famciclovir accelerate healing and reduce acute pain, but they do not reduce the incidence of postherpetic neuralgia. The newer drugs have greater bioavailability and are more effective in the treat‐

The hallmark of HIV disease is the progressive loss of CD4+ lymphocytes. Without interven‐ tion, an average of 60 to 80 cells/mm3 is lost every year; this loss is highly variable and oc‐ curs in periods of stability and rapid decline. High viral load is also considered to be one of the main indicators of the progression of HIV- induced immunosuppression. Several studies

The CD4 count and viral load measure the progression of the HIV disease. Several studies have shown high prevalence of oral lesions in patients with low CD4 count, <200 cells/mm3 and high viral load: >55,000 copies/ml. CD4 count < 200 cells/mm3 is used as criterion for ini‐ tiating HAART, which is consistent with the guidelines for initiating HAART treatment by

Presence of multiple lesions in infected HIV patients is also associated with severe immuno‐

The goals of HAART should be maximal and durable viral suppression. The aim is preser‐ vation and restoration of the immune system at minimal cost to the patient. This should im‐ prove the quality of life through ease of use of their regimen with minimal side-effects to enhance optimum adherence. This should translate into a reduction of HIV- related morbid‐ ity including oral manifestations. Reduction of viral burden will prevent progressive immu‐ nodeficiency, decrease the risk of the emergence of resistant viruses and possibly decrease

It has been shown in various studies that the prevalence of HIV-related oral lesions reduces significantly with HAART. The reported percentage decrease varied from 10% in a USA

ment of HZ. Supportive therapy, antibiotics and analgesics are also recommended.

have shown that the higher the viral load, the quicker the progression to AIDS.

**3.7. Oral lesions and relationship with CD4 count and viral load**

**•** Tabs Acyclovir200-400mg 5x daily for 1 week

*3.6.12. Herpes zoster*

WHO (2003).

suppression and AIDS.

**3.8. Oral lesions and response to HAART**

the risk of viral transmission (Fauci et al., 2000).

### *3.6.9. Oral ulcers*

Topical steroids can be effective in the treatment of MiAUand MjAU:


Ulcers are reevaluated after one week. If there is no improvement, alternative treatment should be considered, including systemic steroids e.g. Prednisolone.

Alternative forms of treatment have included **intralesional** injection with **Triamcinolone acetonide**.

Supportive therapy is necessary to aid healing of the ulcers, this includes:


#### *3.6.10. Salivary gland diseases*

No treatment is indicated for the salivary gland enlargement, although large cystic glands are sometimes removed surgically for cosmetic purposes. Radiation therapy has also been used to reduce the swelling.

#### *3.6.11. Xerostomia*

The management of xerostomia involves the use of both saliva substitutes and saliva stimu‐ lants. Patients with little or no responsive salivary gland tissue will need saliva substitutes. A properly balanced artificial saliva should be of neutral pH and contain electrolytes, in‐ cluding fluoride, to correspond to the composition of saliva.

Gustatory stimuli such as sugarless sweets containing citric and malic acid, chemically in‐ duce saliva production. Care must be taken that the acidic content does not result in the dis‐ solution of tooth enamel. Controlled studies have shown that pilocarpine is an effective stimulus to saliva production (Greenspan et al., 1987; Rieke et al., 1995), side effects, mainly the result of generalised parasympathetic stimulation, are the most common reason to dis‐ continue treatment.

There have been a number of studies that have shown that chewing gum increases salivary flow from patients with xerostomia of varying aetiology (Risheim et al., 1993). In some xe‐ rostomic patients, the initial stimulated salivary flow rate while chewing sugar free gum is seven times greater than the unstimulated flow rate. Chewing sugar free gum has been shown to be one of the most preferred treatments for xerostomia (Bjornstrom et al., 1990).

### *3.6.12. Herpes zoster*

span et al., 1984). A single dose of 800 cGy or an equivalent fractionated dose is frequently used and produces a good response. Other local therapy may involve excision of exophytic

Ulcers are reevaluated after one week. If there is no improvement, alternative treatment

Alternative forms of treatment have included **intralesional** injection with **Triamcinolone**

No treatment is indicated for the salivary gland enlargement, although large cystic glands are sometimes removed surgically for cosmetic purposes. Radiation therapy has also been

The management of xerostomia involves the use of both saliva substitutes and saliva stimu‐ lants. Patients with little or no responsive salivary gland tissue will need saliva substitutes. A properly balanced artificial saliva should be of neutral pH and contain electrolytes, in‐

Gustatory stimuli such as sugarless sweets containing citric and malic acid, chemically in‐ duce saliva production. Care must be taken that the acidic content does not result in the dis‐ solution of tooth enamel. Controlled studies have shown that pilocarpine is an effective stimulus to saliva production (Greenspan et al., 1987; Rieke et al., 1995), side effects, mainly the result of generalised parasympathetic stimulation, are the most common reason to dis‐

lesions or intra- lesional injection of vinblastin (Iain et al., 2000).

**ii.** Clobestasol 0.05% in Orabase – apply 3-4 times daily.

**iv.** Triamcinolone in Orabase – apply 3-4 times daily.

Topical steroids can be effective in the treatment of MiAUand MjAU:

should be considered, including systemic steroids e.g. Prednisolone.

**•** Xylocaine gel to relieve pain and Chlorhexidine mouth wash.

cluding fluoride, to correspond to the composition of saliva.

Supportive therapy is necessary to aid healing of the ulcers, this includes:

**i.** Fluocinonide gel 0.05% with Orabase - apply to ulcers four times daily.

**iii.** Dexamethasone elixir 0.5mg/ml – rinse with 20ml four times daily

*3.6.9. Oral ulcers*

232 Current Perspectives in HIV Infection

**acetonide**.

**•** Vitamin B complex i tds

**•** Tabs Vitamin C 300mg tds

*3.6.10. Salivary gland diseases*

used to reduce the swelling.

*3.6.11. Xerostomia*

continue treatment.

**•** Tabs Folic acid i daily

Management should be directed toward shortening the course of the disease, preventing post‐ herpetic neuralgia in patients over 50 years of age, and preventing dissemination in immuno‐ compromised patients. Acyclovir or the newer antiherpes drugs valacyclovir or famciclovir accelerate healing and reduce acute pain, but they do not reduce the incidence of postherpetic neuralgia. The newer drugs have greater bioavailability and are more effective in the treat‐ ment of HZ. Supportive therapy, antibiotics and analgesics are also recommended.

**•** Tabs Acyclovir200-400mg 5x daily for 1 week

### **3.7. Oral lesions and relationship with CD4 count and viral load**

The hallmark of HIV disease is the progressive loss of CD4+ lymphocytes. Without interven‐ tion, an average of 60 to 80 cells/mm3 is lost every year; this loss is highly variable and oc‐ curs in periods of stability and rapid decline. High viral load is also considered to be one of the main indicators of the progression of HIV- induced immunosuppression. Several studies have shown that the higher the viral load, the quicker the progression to AIDS.

The CD4 count and viral load measure the progression of the HIV disease. Several studies have shown high prevalence of oral lesions in patients with low CD4 count, <200 cells/mm3 and high viral load: >55,000 copies/ml. CD4 count < 200 cells/mm3 is used as criterion for ini‐ tiating HAART, which is consistent with the guidelines for initiating HAART treatment by WHO (2003).

Presence of multiple lesions in infected HIV patients is also associated with severe immuno‐ suppression and AIDS.

#### **3.8. Oral lesions and response to HAART**

The goals of HAART should be maximal and durable viral suppression. The aim is preser‐ vation and restoration of the immune system at minimal cost to the patient. This should im‐ prove the quality of life through ease of use of their regimen with minimal side-effects to enhance optimum adherence. This should translate into a reduction of HIV- related morbid‐ ity including oral manifestations. Reduction of viral burden will prevent progressive immu‐ nodeficiency, decrease the risk of the emergence of resistant viruses and possibly decrease the risk of viral transmission (Fauci et al., 2000).

It has been shown in various studies that the prevalence of HIV-related oral lesions reduces significantly with HAART. The reported percentage decrease varied from 10% in a USA study on 570 patients (Patton et al., 2000) to 50% in a Mexican study on selected 1000 HIV patients over a period of 12 years (Ramírez-Amador et al., 2003).

HIV-related oral manifestations of 10–50% following the introduction of HAART (Hodgson

1 Faculty of Dental Sciences, College of Medicine, University of Lagos, Lagos State, Nigeria

[1] Adedigba MA, Ogunbodede EO, Jeboda SO, Naidoo S (2008): Patterns of oral mani‐

[2] Adurogbangba MI, Aderinokun GA, Odaibo GN, Olaleye OD, Lawoyin TO (2004): Oro-facial lesions and CD4 counts in an adult population in Oyo state, Nigeria. Oral

[3] Agbelusi GA, Eweka OM (2011). Necrotising Stomatitis as a presenting symptom of

[4] Agbelusi GA, Wright AA (2005): Oral lesions as indicators of HIV infection among

[5] Alpagot T, Duzgunes N, Wolff LF, Lee A (2004): Risk factors for periodontitis in HIV

[6] Anteyi KO, Thacher TD, Yohanna S, Idoko JI( 2003): Oral manifestation of HIV/ AIDS

[7] Aragues M, Sanchez Perez J, Fraga J, Burgos E, Noguerado A, Garciadiez A (1990): Hairy Leukoplakia : a clinical histopathological and ultrastructural study in 33 pa‐

[8] Arendorf TM; Bredekamp B, Cloete CAC (1998): Oral manifestations of HIV infection

[9] Armitage GC(1999): Development of a classification system for periodontal diseases

[10] Arotiba JT, Arowojolu MO, Fasola AO, Denloye OO, Obiechina AE (2006): Oral man‐

[11] Asher RS, McDowell JD, Winquist H. (1993): HIV-related neuropsychiatric changes:

routine dental patients in Lagos, Nigeria. Oral Dis; 11: 370-373

in 600 South African patients. J. Oral Pathol Med. 27: 179-189.

ifestation of HIV/AIDS. Afr J Med Med Sci.;(35): 13-18.

concerns for dental professionals. J Am Dent Assoc 124:80.

2 School of Dental Sciences, College of Medicine, University of Benin, Edo State, Nigeria

festation of HIV/AIDS among 225 Nigerian patients. Oral Dis. 4: 314-316.

and M. Okoh2

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 235

, K.A. Ùmeizudike1

et al., 2006).

**Author details**

, O.M. Eweka1

G.A. Agbelusi1

**References**

Dis. 10: 319-326.

HIV. Scrip.org/journal/OJST. 1:1-4.

positive patients. J Periodont Res; 39: 149-157.

in Nigerian patients. Int. J. AIDS; 14: 395-398.

tients. Clin Exp Dermatol ; 15:335-339.

and conditions. Ann Periodontol; 4:1-6.

In a Spanish study on 154 subjects, Ceballos-Salobrena et al (2000) showed a 30% reduction of oral lesions, while Tappuni and Fleming (2001) reported a reduction of 24% in a study on 284 patients in the United Kingdom. Some looked at a particular oral manifestation (Cauda et al., 1999) as opposed to a range of oral lesions (Ceballos-Salobrena et al., 2000; Tappuni and Fleming, 2001; Eyeson et al., 2002; Ramírez-Amador et al., 2003).

Studies examining the effect of HAART on the prevalence of individual oral manifestations mainly reported on oral candidiasis, oral hairy leukoplakia, HIV-related periodontal diseas‐ es, Kaposi's sarcoma (KS), oral papilloma, and HIV-related salivary gland disease showed reduction in the prevalence (Patton et al., 2000; Schmidt-Westhausen et al., 2000; Tappuni et al., 2001).

Oral candidiasis (OC) has been shown to be one of the most common oral lesions in HIV patients. With the advent of HAART, most studies reported a decrease in the prevalence of Oral Candidiasis. In a study on 93 patients, 7% of patients on protease inhibitors (PI) had Oral Candidiasis, compared with 36% in non-PI-treated patients (Cauda et al., 1999). Schmidt-Westhausen et al (2000) detected Oral Candidiasis in 10/103 (9.7%) of their study subjects who had been on HAART for 4 weeks and in none after 6 months' therapy (n = 61). Tappuni and Fleming (2000) reported that the prevalence of Oral Candidiasis was about 50% less in patients on therapy (n = 89) compared with drug-naïve patients (n = 195). Con‐ versely, Patton et al (2000) found no significant difference in the prevalence of Oral Candi‐ diasis with the use of Protease Inhibitors (n = 507). In the same study, the prevalence of oral hairy leukoplakia (OHL) was found to decrease with therapy (Patton et al., 2000), in agree‐ ment with reports from other studies (Tappuni and Fleming, 2001).

The prevalence of HIV-associated periodontal diseases was reported to decrease significantly in an American cohort, from 4.8% to 1.7% with HAART (Patton et al., 2000), in concordance with findings in other studies (Ceballos-Salobrena et al., 2000; Tappuni and Fleming, 2001).

Kaposi's Sarcoma (KS) is one of the oral manifestations that is strongly associated with HIV, although its prevalence is quite low in this group (Ceballos-Salobrena et al., 2000), Studies from the USA (Patton et al., 2000) and Mexico (Ramírez-Amador et al., 2003) found no sig‐ nificant change in the occurrence of Kaposi Sarcoma with HAART.

Unlike most other oral manifestations of HIV, studies from the USA and the United King‐ dom(UK) described an increase in the prevalence of oral warts with HAART (Patton et al., 2000; Greenwood et al., 2002), which may reach statistical significance (Greenspan et al., 2001). Others looking at a different population (Mexicans) reported similar detection rates of oral warts, papillomas, condylomas and focal epithelial hyperplasia in HIV-positive subjects on HAART compared with those not on therapy (Ramírez-Amador et al., 2003).

Other lesions that are showing a trend of rising prevalence include HIV-related salivary gland disease (Patton et al., 2000). However, this was not supported by other studies (Ramír‐ ez-Amador et al., 2003). Studies from industrialized world report a decreased frequency of HIV-related oral manifestations of 10–50% following the introduction of HAART (Hodgson et al., 2006).

### **Author details**

study on 570 patients (Patton et al., 2000) to 50% in a Mexican study on selected 1000 HIV

In a Spanish study on 154 subjects, Ceballos-Salobrena et al (2000) showed a 30% reduction of oral lesions, while Tappuni and Fleming (2001) reported a reduction of 24% in a study on 284 patients in the United Kingdom. Some looked at a particular oral manifestation (Cauda et al., 1999) as opposed to a range of oral lesions (Ceballos-Salobrena et al., 2000; Tappuni

Studies examining the effect of HAART on the prevalence of individual oral manifestations mainly reported on oral candidiasis, oral hairy leukoplakia, HIV-related periodontal diseas‐ es, Kaposi's sarcoma (KS), oral papilloma, and HIV-related salivary gland disease showed reduction in the prevalence (Patton et al., 2000; Schmidt-Westhausen et al., 2000; Tappuni et

Oral candidiasis (OC) has been shown to be one of the most common oral lesions in HIV patients. With the advent of HAART, most studies reported a decrease in the prevalence of Oral Candidiasis. In a study on 93 patients, 7% of patients on protease inhibitors (PI) had Oral Candidiasis, compared with 36% in non-PI-treated patients (Cauda et al., 1999). Schmidt-Westhausen et al (2000) detected Oral Candidiasis in 10/103 (9.7%) of their study subjects who had been on HAART for 4 weeks and in none after 6 months' therapy (n = 61). Tappuni and Fleming (2000) reported that the prevalence of Oral Candidiasis was about 50% less in patients on therapy (n = 89) compared with drug-naïve patients (n = 195). Con‐ versely, Patton et al (2000) found no significant difference in the prevalence of Oral Candi‐ diasis with the use of Protease Inhibitors (n = 507). In the same study, the prevalence of oral hairy leukoplakia (OHL) was found to decrease with therapy (Patton et al., 2000), in agree‐

The prevalence of HIV-associated periodontal diseases was reported to decrease significantly in an American cohort, from 4.8% to 1.7% with HAART (Patton et al., 2000), in concordance with

Kaposi's Sarcoma (KS) is one of the oral manifestations that is strongly associated with HIV, although its prevalence is quite low in this group (Ceballos-Salobrena et al., 2000), Studies from the USA (Patton et al., 2000) and Mexico (Ramírez-Amador et al., 2003) found no sig‐

Unlike most other oral manifestations of HIV, studies from the USA and the United King‐ dom(UK) described an increase in the prevalence of oral warts with HAART (Patton et al., 2000; Greenwood et al., 2002), which may reach statistical significance (Greenspan et al., 2001). Others looking at a different population (Mexicans) reported similar detection rates of oral warts, papillomas, condylomas and focal epithelial hyperplasia in HIV-positive subjects

Other lesions that are showing a trend of rising prevalence include HIV-related salivary gland disease (Patton et al., 2000). However, this was not supported by other studies (Ramír‐ ez-Amador et al., 2003). Studies from industrialized world report a decreased frequency of

findings in other studies (Ceballos-Salobrena et al., 2000; Tappuni and Fleming, 2001).

on HAART compared with those not on therapy (Ramírez-Amador et al., 2003).

patients over a period of 12 years (Ramírez-Amador et al., 2003).

and Fleming, 2001; Eyeson et al., 2002; Ramírez-Amador et al., 2003).

ment with reports from other studies (Tappuni and Fleming, 2001).

nificant change in the occurrence of Kaposi Sarcoma with HAART.

al., 2001).

234 Current Perspectives in HIV Infection


2 School of Dental Sciences, College of Medicine, University of Benin, Edo State, Nigeria

### **References**


[12] Barr C, Lopez MR, Rua-Dobles A (1992): Periodontal changes by HIV serostatus in a cohort of homosexual and bisexual men. J Clin Periodontol 19: 794-801.

[25] Fauci AS, Bartlett JG, Goosby EP (2000): Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Panel on clinical practices for treat‐ ment of HIV infection conveyed by the department of health and Human services

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 237

[26] Feigel D W, Katz MH, Greenspan D (1991): The prevalence of oral lesions in HIV- in‐ fected homosexual and bisexual men: three San-Fransisco epidemiological cohorts .

[27] Glick M, Muzyka BC, Lurie D, Salkin LM (1994): Necrotising Ulcerative Periodonti‐ tis : a marker for immune deterioration and a predictor for the diagnosis of AIDS. J.

[28] Gornitsky M. Pekovie D (1987): Involvement of human immunodefiency virus (HIV)

[29] Grassi M, Williams CA, Winkler JR et al (1988): Management of HIV-associated pe‐ riodontal diseases. In Robertson, PB & GJS, ed. Perspectives on Oral Manifestations

[30] Grbic FT, Mitchelle-Lewis DA, Fine JB (1995): The relationship of candidosis to LGE in HIV- infected homosexual men and parenteral drug users. J. Periodontol. 66:

[31] Greenburg MS, Glick M (2003): ulcerative, vesicular and bullous lesions, Burket's or‐

[32] Greenspan D, Greenspan JS, Conant M, Peterson V, Silverman S, De Sonza Y (1984): Oral Hairy Leukoplakia in male homosexuals: evidence of association with both pap‐

[33] Greenspan D, Daniels TE (1987): Effectiveness of pilocarpine from postradiation xe‐

[34] Greenspan D, Greenspan JS, Schiodt M, Pindborg JJ. (1990.):In: AIDS and the mouth.

[35] Greenspan D, Greenspan JS (1996): HIV- related oral disease. The Lancet; 348:

[36] Greenspan JS, Barr CE, Sciubba JJ, Winkler J R (1992): Oral manifestations of HIV in‐

[37] Greenspan D (1998): Oral manifestation of HIV. HIV InSite Knowledge Base Chapter

[38] Greenspan D, Canchola AJ, MacPhail LA, Cheikh B, Greenspan JS (2001): Effect of highly active antiretroviral therapy on frequency of oral warts. Lancet 357:1411–1412.

[39] Greenwood I, Zakrzewska JM, Robinson PG (2002): Changes in the prevalence of HIV-associated mucosal disease at a dedicated clinic over 7 years. Oral Dis 8:90–94.

in gingival of patients with AIDS. Adv Exp Med Biol ;216: 553-62.

of AIDS. PSG Publishing Co., Inc., Littleton, pp. 119-130.

al Medicine. Diagnosis and treatment, 10th edition. 50-84.

illoma virus and a herpes group virus. Lancet 831-834.

fection. Oral Surg Oral Med Oral Pathol; 73: 142-144.

rostomia. Cancer. 59: 1123-1125

Copenhagen: Munksgaard.

and the Henry J Kaiser foundation.

AIDS; 5: 519-525.

30-37.

729-733.

Periodontol. 65: 393-397.


[25] Fauci AS, Bartlett JG, Goosby EP (2000): Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Panel on clinical practices for treat‐ ment of HIV infection conveyed by the department of health and Human services and the Henry J Kaiser foundation.

[12] Barr C, Lopez MR, Rua-Dobles A (1992): Periodontal changes by HIV serostatus in a

[13] Bjornstrom M, Axell T, Birkhed D (1990) Comparison between saliva stimulants and saliva substitutes from patients using symptoms related to dry mouth. A multi-cen‐ tre study. Swed Dent J. 14: 153-161 Boring CC, Brynes RK, Chan WC (1985): Increase

[14] Boring CC, Brynes RK, Chan WC (1985): Increase in high grade lymphomas in young

[15] Boshoff C, Whitby D, Talbot S (1997): Aetiology of AIDS- related kaposi's sarcoma

[16] Campisi G, Pizzo G, Mancuso S, Margiotta V (2002): Gender differences in HIV-relat‐ ed oral lesions: an Italian study. Oral Surg Oral Med Oral Pathol; 93 (3): 281-286.

[17] Cauda R, Tacconelli E, Tumbarelo M, Morace G, De Bernadis et al (1999): Role of pro‐ tease inhibitor in preventing recurrent oral candidosis in patients with HIV infection:

[18] Ceballos-Salobrena A, Aguirre-Urizar JM, Bagan-Sebastian JV (1996): Oral manifesta‐ tions associated with human immunodeficiency virus infection in a Spanish popula‐

[19] Ceballos-salobrena A, Gactan-Cepeda L A, Ceballos-Garcia L, Lezamz- Del Nalle D (1997): Oral lesions in HIV/AIDS patients undergoing Highly Active Anti-Retroviral Treatment including protease- inhibitors: a new face of oral AIDS. Oral Dis; 3 suppl

[20] Centers for Disease Control and Prevention (1993): Revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents

[21] Davoodi P, Hamian M, Nourbaksh R, Motamayel FA (2010): Oral Manifestations Re‐ lated To CD4 Lymphocyte Count in HIV-Positive Patients. J Dent Res Dent Clin Dent

[22] EC-Clearinghouse on oral Problems Related to HIV Infection and WHO Collabora‐ tion center on oral manifestations of the immunodeficiency Virus (ECC/WHO) (1993): Classification and diagnostic criteria for oral lesions in HIV infection. J Oral

[23] Epstein JB, Silverman S (1992): Head and neck malignancies associated with HIV in‐

[24] Eyeson JD, Tenant-Flowers M, Cooper DJ, Johnson NW, Warnakulasuriya KA (2002): Oral manifestations of an HIV positive cohort in the era of highly active anti-retrovi‐

ral therapy (HAART) in South London. J Oral Pathol Med 31:169–174.

cohort of homosexual and bisexual men. J Clin Periodontol 19: 794-801.

in high grade lymphomas in young men. Lancet; 1: 857-859.

men. Lancet; 1: 857-859.

236 Current Perspectives in HIV Infection

and lymphoma. Oral Dis. 3: S129-132.

tion. J Oral Pathol Med: 25: 523-526.

and adults . MMWR Recomm Rep. 41:1-19.

fection. Oral Surg. Oral Med. Oral Pathol; 73: 193-300.

1: S46-50

Prospect; 4(4):115-119.

Pathol Med 22:289-291.

a prospective case- control study. J AIDS; 21: 20-25


[40] Hodgson TA, Greenspan D, Greenspan JS (2006): Oral lesions of HIV diseases and HAART in industrialized countries. Adv. Dent. Res 19:57- 62.

[54] Matee M, Scheutz F, Moshy J. (2000): Occurrence of oral lesions in relation to clinical and immunological status among HIV-infected adult Tanzanians. Oral Dis; 6:

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 239

[55] Mckaig RG, Patton LL, Thomas JC, Strauss RP, Slade GD. (2000): Factors associated with periodontitis in an HIV infected southeast USA study. Oral dis. 6: 158-165.

[56] McNeil DG Jr (2007): "U.N. agency to say it overstated extent of HIV cases by mil‐

[57] Miceli MC, Parnes JR (1993): "Role of CD4 and CD8 in T cell activation and differen‐

[58] Mirowski GW, Hilton JF, Greenspan D, Canchola AJ, MacPhail LA, Maurer T, Berger TG, Greenspan JS. (1998): Association of cutaneous and oral diseases in HIV – infect‐

[59] Murray PA, Grassi M, Winkler JR (1989):. The microbiology of HIV associated perio‐

[60] Murray PA, Winkler JR, Peros WJ, French CK, Lippke JA (1991). DNA probe detec‐ tion of periodontal pathogens in HIV-associated periodontal lesions. Oral Microbiol

[61] Murray PA. (1994): Periodontal diseases in patients infected by human immunodefi‐

[62] Narani N, Epstein JB (2001): classifications of oral lesions in HIV infection. J clin Pe‐

[63] Ndiaye CF, Critchlow CW, Leggot PJ, Kiviat NB, Ndoye I, Robertson PB, Georgas KN (1997): Periodontal status of HIV-1 and HIV-2 seropositive and HIV seronegative female commercial sex workers in Senegal. J Periodontol; 68: 827-831. West Afr J

[64] Nittayananta W, Chungpanich S(1997): Oral lesions in a group of Thai people with

[66] Osuji OO (1990): Necrotizing ulcerative gingivitis and cancrum oris in Ibadan, Niger‐

[67] Palmer GD, Robinson PG, Challacombe SJ, Birnbaum W, Croser D, Erridge PL et al. (1996): Aetiological factors for oral manifestation of HIV infection. Oral Dis. 2:

[68] Patton LL, McKaig R, Strauss R, Rogers D, Eron JJ Jnr. (2000): Changing prevalence of oral manifestations of human immuno-deficiency virus in the era of protease in‐ hibitor therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 89:299–304.

[65] Onunu A N, Obueke N (2002): HIV- related oral diseases in Benin city,

106-111.

lions". New York Times.

ed men. Oral Dis. (1): 16-21.

Immunol: 6: 3440.

riodontol ; 28: 137-145.

AIDS. Oral Dis. 3:41-56.

ia. J Periodontol; 61: 769-772.

Med; 21: 9-11.

193-197.

tiation". Adv. Immunol. 53: 59–122.

dontal lesions. J Clin Periodontol 16: 636-642.

ciency virus. Periodontology 2000. (6): 50-67.


[54] Matee M, Scheutz F, Moshy J. (2000): Occurrence of oral lesions in relation to clinical and immunological status among HIV-infected adult Tanzanians. Oral Dis; 6: 106-111.

[40] Hodgson TA, Greenspan D, Greenspan JS (2006): Oral lesions of HIV diseases and

[41] Holmes HK, Stephen LX (2002): Oral lesions of HIV infection in developing coun‐

[42] Holmstrup P, Westergaard J (1998): HIV infection and periodontal diseases. Perio‐

[43] Iain LC, Hamburger J(2000): The significance of oral health in HIV disease. Sex Trans

[44] Itescu S, Brancato L, Buxbaum J (1990): A diffuse infiltrative CD8 lymphocytosis syn‐ drome in HIV infection: A host immune response associated with HLA-DR5. Ann In‐

[45] Just-Nubling G, Gentschew G, Meissner K (1991): Fluconazole prophylaxis of recur‐ rent oral candidiasis in HIV-positive patients. Eur J Clin Microbiol Infect Dis;10:

[46] Kaminu HN, Naidoo S (2002): Oral HIV lesions and oral health behavior of HIV-

[47] Katz MH, Mastrucci MT, Leggott PJ, Westenhouse J, Greenspan JS, Scott GB (1993): Prognostic significance of oral lesions in children with perinatally acquired HIV in‐

[48] King GN, Healy CM, Glover MT (1994): Prevalence and risk factors associated with hairy Leukoplakia, erythematous candidiasis and gingival hyperplasia in renal trans‐

[49] Lamster IB, Begg MD, Mitchell-Lewis D, et al (1994): Oral manifestations of HIV in‐ fection in homosexual men and intravenous drug users, Oral Surg Oral Med Oral

[50] Lifson AR, Hilton JF, Westenhouse JL (1994): Time from HIV seroconversion to oral candidiasis or Hairy Leukoplakia among homosexual and Bisexual men enrolled in

[51] Lihana RW, Khamadi SA , Lwembe RM, Kinyua JG, Muriuki JK et al (2009): HIV-1 subtype and viral tropism determination for evaluating antiretroviral therapy op‐ tions: an analysis of archived Kenyan blood samples. BMC Infec. Dis; 9:215-217.

[52] Maeve MC, Greenspan J, Challacombe SJ (2005). Oral lesions in infection with HIV.

[53] Masouredis CM, Katz MH, Greenspan D, Herrera C, Hollander H, Greenspan JS, Winkler JR (1992): Prevalence of HIV-associated periodontitis and gingivitis in HIVinfected patients attending an AIDS clinic. J Acquir Immune Defic Syndr 5: 479-483.

Positive patients attending the Queen Elizabeth II Hospital, SADJ 57:479.

plant recipients. OralSurg Oral Med Oral Pathol; 78:18-26.

HAART in industrialized countries. Adv. Dent. Res 19:57- 62.

tries. Oral Disease; 8(2): 40-43.

dontology 2000; (18): 37-46.

fection. Am J Dis Child 147 (1): 45-48.

three prospective cohorts. J AIDS; 8: 73- 79.

Bulletin of the World Health Organisation. 83: 700-706.

infection; 76: 236-243.

tern Med. 112: 3-10.

917-21.

238 Current Perspectives in HIV Infection

Pathol; 78: 163.


[69] Ramírez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, Ponce-de-Leon S (1998): Oral manifestations of HIV infection by gender and transmission category in Mexico City. J Oral Pathol Med 27 (3): 135-140.

[82] Schiodt M, BakilanaPB, Haza FR (1990): Oral candidiasis and hairy leukoplakia cor‐

Oral Manifestations of HIV http://dx.doi.org/10.5772/52941 241

[83] Schmidt- Westhausen AM, Priepke F, Bergman FJ, Riechart PA (2000): Decline in the rate of Oral opportunistic infections following introduction of HAART. J. Oral Path‐

[84] Scully C, McCarthy G (1992): Management of oral health in persons with HIV infec‐

[85] Septowitz KA (1998): Effect of HAART on natural history of AIDS- related opportun‐

[86] Silverman S Jr, Migliorati CA, Lozada-Nur F, Greenspan D, Conant MA (1986): Oral findings in people with or at high risk for AIDS: a study of 375 homosexual males. J

[88] Slots J (2004): Update on human cytomegalovirus in destructive periodontal diseases.

[89] Smith DE, Midgley J, Allan M (1991): Itraconazole versus ketaconazole in the treat‐ ment of oral and oesophageal candidiasis in patients infected with HIV. AIDS;

[90] Smith GLF, Felix DH, Wray D (1993): Current classification of HIV-associated perio‐

[91] Soberman N, Leonidas JC, Berdon WE, (1991): Parotid enlargement in children sero‐ positive for human immunodeficiency virus: imaging findings. AJR;157: 553-6. [92] Soubry R, Taelman H, Banyangiliki V et al (1995): Necrotising periodontal disease in HIV-1 infected patients: a 4 year study. In: Greenspan JS, Greenspan D, eds. Oral manifestations of HIV infection. Quintessence Publishing Co, Inc., Chicago,; 60-67. [93] Sturzl M, Konrad A, Alkharsah KR, Jochmann R, Mathias T et al (2009): The contri‐ bution of systems biology and reverse genetics to the understanding of kaposi's sar‐ coma-associated herpes virus pathogenesis in endothelial cells. Thomb. Haemot.;

[94] Swango PA, Kleinman DV, Konzelman JL(1991): HIV and periodontal Health: a

[95] Taiwo O, Okeke EN, Jalo PH, Danfillo IS (2006): Oral manifestation of HIV in Plateau

[96] Taiwo O, Okeke EN, Otoh EC, Danfillo IS (2005): Prevalence of HIV- related oral le‐

[97] Tappero JW, Conant MA, Wolfe SF (1993): Kaposi's sarcoma. J Am Acad. Dermatol;

study of military personnel with HIV J. Am Dent Assoc. 122 (8): 49-54.

state indigenes, Nigeria. West Afr. J. Med. (1): 32-37.

sions in Nigerian women. Nig J. Med; 14: 132-136.

relate with HIV infection. Oral Surg Oral Med Oral Pathol 69:591-596.

tion. Oral Surg Oral Med Oral Pathol; 73: 215-225.

[87] Sirois DA (1998): Oral Manifestation of HIV disease. 65:322-332

istic disorders. Lancet 351: 228-230.

Am Dent Assoc; 112: 187-192.

Oral Microbiol Immunol; 19:217.

dontal diseases. Br Dent J; 174: 102-105.

5:1367-71.

102: 1117-1134.

28: 371-395.

ol /Med; 29: 336-341.


[69] Ramírez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, Ponce-de-Leon S (1998): Oral manifestations of HIV infection by gender and transmission category in Mexico

[70] Ramírez-Amador V, Esquivel-Pedraza L, Sierra-Madero J, Anaya-Saavedra G, Gon‐ zalez-Ramírez I, Ponce-de-Leon S (2003): The changing clinical spectrum of human immunodeficiency virus (HIV)-related oral lesions in 1,000 consecutive patients: a 12-

[71] Ramos-Gomez FJ (1997): Oral aspects of HIV disease in children. Oral Dis. 3: S31-35.

[72] Ranganathan K, Reddy BV, Kumarasamy N, Solomon S, Viswanathan R et al. (2000) Oral lesions and conditions associated with human immunodeficiency virus infec‐

[73] Ranganathan K, Magesh KT, Kumarasamy N, Solomon S, Viswanathan R, Johnson NW (2007): Greater severity and extent of periodontal breakdown in 136 south Indi‐ an human immunodeficiency virus seropositive patients than in normal controls: A comparative study using community periodontal index of treatment needs. Indian J

[74] Reichart PA, Gelderblom HR, Becker J, Kuntz A. (1987): AIDS and the oral cavity. The HIV-infection: virology, etiology, origin, immunology, precautions and clinical

[75] Rieke JW, Hafermann MD, Johnson JT (1995): Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized

[76] Riley C, London JP, Burmester JA (1992): Periodontal health in 200 HIV positive pa‐

[77] Risheim H, Arneberg P (1993) Salivary stimulation by chewing gum and lozenges

[78] Robinson PG, Sheiham A, Challacombe SJ, Wren MWD, Zakrzewska JM (1998): Gin‐ gival Ulceration in HIV infection. A case series and case control study J Clin Perio‐

[79] Robinson PG, Adegboye A, Rowland RW, Yeung S, Johnson NW (2002): Periodontal

[80] Scheutz F, Matee MIN, Andsager L, Holm AM, Moshi J et al. (1997): Is there an asso‐ ciation between periodontal condition and HIV infection? J Clin Periodontol; 24:

[81] Schiodt M, Pindborg JJ (1987): AIDS and the oral cavity. Epidemiology and clinical oral manifestations of HIV infection: a review. Int. J of Oral Maxillofacial surg.; 16:

from rheumatic patients using xerostomia. Scand J Dent Res. 181: 40-43

observations in 110 patients. Int J Oral Maxillofac Surg; 16: 129-153.

clinical trials. Int J Rad Onc Biol Phys. 31: 661-669

diseases and HIV infection. Oral Diseases 8(2): 144-150.

tients. J. Oral pathol. Med. 21: 124-127.

year study in a referral center in Mexico. Medicine (Balt) 82:39–50.

tion in 300 South Indian patients. Oral Diseases. 6: 152-157.

City. J Oral Pathol Med 27 (3): 135-140.

240 Current Perspectives in HIV Infection

Dent Res. 18(2): 55-59.

dontol; 25: 260-267.

580-587.

1-14.


[98] Tappuni AR, Fleming GJ (2001): The effect of antiretroviral therapy on the prevalence of oral manifestations in HIV-infected patients: a UK study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 92:623–628.

**Chapter 11**

**Endocrine Manifestations of HIV Infection**

Human Immune deficiency Virus (HIV) infection has assumed pandemic proportion since after its identification as the causative agent of Acquired Immunodeficiency Syndrome (AIDS).The spectrum of HIV infection and AIDS is quite wide and variable. HIV infected patients have an increased risk of developing endocrine abnormalities [1]. The endocrine glands are affected in a variety of ways such as functional derangement, direct effects of HIV infection and the resultant immune suppression, effects of opportunistic infections both acute and chronic, invasion by neoplasms and the effects of the various medications used to treat HIV or any of the opportunistic infections associated with it (Table 1). While endocrine dysfunction has not been a prominent clinical feature of AIDS, all endocrine glands may be affected by the opportunistic infections and malignancies; as a result of antiretroviral treat‐ ment or indeed as a result of the direct invasion of the glands by the virus (Table 2). The introduction of anti-retroviral (ARV) drugs has significantly reduced both morbidity and mortality attributable to HIV infection [2]. The prolonged administration of these drugs

Apart from the effects of acute and chronic illnesses, the relentless progression of immune dysfunction in AIDS affects endocrine function through the activation of several cytokines, chemokines and antibody formation. The use of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is associated with multiple abnormalities in glu‐ cose and lipid metabolism such as insulin resistance, increased triglycerides and increased levels of low-density lipoprotein cholesterol. These metabolic disturbances might be due to a combination of factors, including the direct effect of medications, restoration to health; HIV disease as well as individual genetic predisposition. Of the available antiretroviral medica‐ tions, indinavir had been associated with causing the most insulin resistance and ritonavir

and reproduction in any medium, provided the original work is properly cited.

© 2013 Adamu Girei and Fatima; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

however, has led to new challenges for both physicians and patients [3- 8].

with causing the most hypertriglyceridemia.

Bakari Adamu Girei and Sani-Bello Fatima

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52684

**1. Introduction**


### **Endocrine Manifestations of HIV Infection**

Bakari Adamu Girei and Sani-Bello Fatima

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52684

### **1. Introduction**

[98] Tappuni AR, Fleming GJ (2001): The effect of antiretroviral therapy on the prevalence of oral manifestations in HIV-infected patients: a UK study. Oral Surg Oral Med Oral

[99] Tukutuku K, Muyembe – Tamfum L, Kayembe K (1990): Oral manifestation of AIDS in a heterosexual population in a Zaire hospital. J Oral Pathol Med 19: 232-234.

[100] Umeizudike KA, Savage KO, Ayanbadejo PO, Akanmu AS (2011a) Severe presenta‐ tion of Necrotizing Ulcerative Periodontitis in a Nigerian HIV Positive Patient- A

[101] Umeizudike KA, Savage KO, Ayanbadejo PO, Akanmu AS (2011b): Greater severity of periodontitis among HIV Positive Patients in Nigeria. J Dent Res 90 (Spec Iss B)

[102] UNAIDS: Joint United Nations Programme on HIV/AIDS (2010): Epidemiologic fact

[103] Velegraki A, Nicolatou O, Theodoridou M et al (1999): Paediatric AIDS-related linear gingival erythema; a form of erythematous candidiasis? J Oral Pathol Med; 28: 178.

[104] Weinert M, Grimes RM, Lynch DP (1996): Oral manifestation of HIV infection. 125;

[105] Williams CA, Winkler JR, Grassi M, Murray PA. (1990): HIV-associated periodontitis complicated by necrotizing stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol

[106] Winkler JR, Murray PA (1987): A potential intra-oral expression of AIDS may be rap‐ idly progressive periodontitis. Journal of the California Dental Association; 15:20

[107] Winkler JR, Grassi M, Murray PA (1988): Clinical description and aetiology of HIVassociated periodontal disease. In: Oral manifestations of AIDS. Proceedings of 1st. international symposium on oral manifestations. AIDS eds. Robertson PB and Green‐

[108] Winkler JR, Robertson PB (1992):Periodontal diseases associated with HIV infection

[109] Wright AA, Agbelusi GA (2005): Group II and III lesions in HIV positive Nigerians attending the general Hospital Lagos, Nigeria. Odonto- Stomatologie Tropicale; 112:

[110] Yeung SCH, Stewart GJ, Cooper DA, Sindhusake D (1993): Progression of periodon‐

tal disease in HIV seropositive patients. J. Periodontol; 64: 651-657.

Pathol Oral Radiol Endod 92:623–628.

Case report. Med Princ Pract. 20:374-376.

152991 AMER, www.dentalresearch.org

6:485-496.

242 Current Perspectives in HIV Infection

Endod 69:351-355.

span JS. 49-70.

19- 23.

Oral Med Oral pathol; 73: 145-150..

sheet on HIV and AIDS. www.UNAIDS.org

Human Immune deficiency Virus (HIV) infection has assumed pandemic proportion since after its identification as the causative agent of Acquired Immunodeficiency Syndrome (AIDS).The spectrum of HIV infection and AIDS is quite wide and variable. HIV infected patients have an increased risk of developing endocrine abnormalities [1]. The endocrine glands are affected in a variety of ways such as functional derangement, direct effects of HIV infection and the resultant immune suppression, effects of opportunistic infections both acute and chronic, invasion by neoplasms and the effects of the various medications used to treat HIV or any of the opportunistic infections associated with it (Table 1). While endocrine dysfunction has not been a prominent clinical feature of AIDS, all endocrine glands may be affected by the opportunistic infections and malignancies; as a result of antiretroviral treat‐ ment or indeed as a result of the direct invasion of the glands by the virus (Table 2). The introduction of anti-retroviral (ARV) drugs has significantly reduced both morbidity and mortality attributable to HIV infection [2]. The prolonged administration of these drugs however, has led to new challenges for both physicians and patients [3- 8].

Apart from the effects of acute and chronic illnesses, the relentless progression of immune dysfunction in AIDS affects endocrine function through the activation of several cytokines, chemokines and antibody formation. The use of protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) is associated with multiple abnormalities in glu‐ cose and lipid metabolism such as insulin resistance, increased triglycerides and increased levels of low-density lipoprotein cholesterol. These metabolic disturbances might be due to a combination of factors, including the direct effect of medications, restoration to health; HIV disease as well as individual genetic predisposition. Of the available antiretroviral medica‐ tions, indinavir had been associated with causing the most insulin resistance and ritonavir with causing the most hypertriglyceridemia.

© 2013 Adamu Girei and Fatima; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **a. Destruction of endocrine tissue**


#### **b. Interference with Endocrine function**


mosis and mycobacteria among others [9]. Furthermore, the pituitary may also be affected by

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 245

Despite the foregoing, evaluation of anterior pituitary reserve in HIV infected patients by TSH or gonadotropin stimulation has demonstrated a normal response in nearly all patients.

GH deficiency does not appear to be common [1]. Posterior pituitary function may be al‐ tered in HIV patients with Hyponatremia occurring in up to 50% of inpatients and about 20% of outpatients with AIDS; two-thirds of these patients are clinically euvolemic with se‐ rum arginine vasopressin levels that are inappropriately high for the serum osmolality, con‐ sistent with the syndrome of inappropriate antidiuretic hormone secretion [10 - 12]. The presence of Pneumocystis carinii pneumonia and/ or treatment with trimethoprim appears to be the most significant risk factors for this complication. Furthermore, central diabetes in‐

Although thyroid function tests are often abnormal in HIV patients, the prevalence of overt thyroid disorder is not significantly different from that of the general population [13]. Most asymptomatic patients with HIV infection have normal thyroid function. Some, however, ex‐ hibit increased serum total thyroxine (T4) and triiodothyronine (T3) concentrations. These in‐ creases are as a result of increases in serum thyroxine-binding globulin, the cause of which is unknown [14]. However, with progression of HIV infection and as the patients become more ill, serum T4 and T3 concentrations decline, as is obtained in most if not all chronically ill pa‐ tients; serum thyrotropin concentrations however remain normal or slightly depressed. These changes are as a result of reduction in serum binding proteins, decreased extrathyroidal con‐ version of T4 to T3, and decreased secretion of thyrotropin [13], [14]. Cytokines may be in‐ volved in some of these; especially the reduction in the peripheral conversion of T4 to T3 [15].

An increasing number of patients taking anti-HIV drugs are presenting with thyroid disor‐ ders as a result of improved immune function (immune reconstitution syndrome). Graves' disease is the commonest among immune reconstitution syndromes; others include Hashi‐ moto's thyroiditis and hypothyroidism. Autoimmune Thyroid Disease (AITD) occurs in 3% of women and 0.2% of men [13- 17]. Goddard proposed a staging of autoimmune manifesta‐

The prevalence of immune reconstitution Autoimmune Thyroid Disease (AITD) (Graves' disease, Hashimoto thyroiditis, and hypothyroidism) is about 3% for women and 0.2% for men. Patients with lower CD4 counts at baseline with greater increments in the CD4 counts

neoplasms such as cerebral lymphoma with peripheral involvement of the gland.

sipidus has been reported in AIDS patients with herpetic meningoencephalitis.

Suggesting that panhypopituitarism is rare in these patients.

**3. Thyroid dysfunction**

tions related to HIV/AIDS (table 3) [18].

following HAART are more likely to develop AITD.

• Antibodies

#### **c. Effects of medications**


#### **Table 1.** Mechanisms of Endocrine dysfunction in patients with HIV [1]

#### **a. Endocrinopathies as a result of direct effects of the virus.**


b. Endocrinopathies as a resultof structural destruction of gland.s


**Table 2.** Common Endocrine abnormalities in HIV infected patients [1].

#### **2. The pituitary**

Involvement of the pituitary gland is common in advanced HIV infection, at autopsy; varying degrees of infarction and necrosis are the most common findings occurring in nearly 10% of cases [1]. Also common are opportunistic Infections by CMV, Pneumocystis carinii, Toxoplas‐ mosis and mycobacteria among others [9]. Furthermore, the pituitary may also be affected by neoplasms such as cerebral lymphoma with peripheral involvement of the gland.

Despite the foregoing, evaluation of anterior pituitary reserve in HIV infected patients by TSH or gonadotropin stimulation has demonstrated a normal response in nearly all patients. Suggesting that panhypopituitarism is rare in these patients.

GH deficiency does not appear to be common [1]. Posterior pituitary function may be al‐ tered in HIV patients with Hyponatremia occurring in up to 50% of inpatients and about 20% of outpatients with AIDS; two-thirds of these patients are clinically euvolemic with se‐ rum arginine vasopressin levels that are inappropriately high for the serum osmolality, con‐ sistent with the syndrome of inappropriate antidiuretic hormone secretion [10 - 12]. The presence of Pneumocystis carinii pneumonia and/ or treatment with trimethoprim appears to be the most significant risk factors for this complication. Furthermore, central diabetes in‐ sipidus has been reported in AIDS patients with herpetic meningoencephalitis.

### **3. Thyroid dysfunction**

**a. Destruction of endocrine tissue**

**b. Interference with Endocrine function**

• Cytokines (tumour necrosis factor, interleukin-1, interferon)

• Non-specific inflammation

**c. Effects of medications**

• Anti Tuberculosis drugs. • Antifungal drugs. • Antiviral drugs. • Antibiotics.

**Table 1.** Mechanisms of Endocrine dysfunction in patients with HIV [1]

• HIV adrenalities and impaired adrenal reserve

• Idiopathic adrenohypophyseal necrosis

• Cytomegalovirus (CMV) adrenalitis

**Table 2.** Common Endocrine abnormalities in HIV infected patients [1].

**a. Endocrinopathies as a result of direct effects of the virus.**

b. Endocrinopathies as a resultof structural destruction of gland.s

• Mycobacterial infection, cryptococcosis, toxoplasmosis(pituitary, thyroid, adrenals)

• Haemorrhages and abscesses causing insufficiency of glands (pituitary, thyroid and adrenals)

Involvement of the pituitary gland is common in advanced HIV infection, at autopsy; varying degrees of infarction and necrosis are the most common findings occurring in nearly 10% of cases [1]. Also common are opportunistic Infections by CMV, Pneumocystis carinii, Toxoplas‐

• Cancer • Infection • Haemorrhage

244 Current Perspectives in HIV Infection

• Acute illness • Chronic illness

• Antibodies

• ARV's

• Hypercorticolism

• Hyperprolactinaemia • Primary hypogonadism • Growth factor

• AIDS wasting syndrome

• Pneumocystis thyroiditis

**2. The pituitary**

Although thyroid function tests are often abnormal in HIV patients, the prevalence of overt thyroid disorder is not significantly different from that of the general population [13]. Most asymptomatic patients with HIV infection have normal thyroid function. Some, however, ex‐ hibit increased serum total thyroxine (T4) and triiodothyronine (T3) concentrations. These in‐ creases are as a result of increases in serum thyroxine-binding globulin, the cause of which is unknown [14]. However, with progression of HIV infection and as the patients become more ill, serum T4 and T3 concentrations decline, as is obtained in most if not all chronically ill pa‐ tients; serum thyrotropin concentrations however remain normal or slightly depressed. These changes are as a result of reduction in serum binding proteins, decreased extrathyroidal con‐ version of T4 to T3, and decreased secretion of thyrotropin [13], [14]. Cytokines may be in‐ volved in some of these; especially the reduction in the peripheral conversion of T4 to T3 [15].

An increasing number of patients taking anti-HIV drugs are presenting with thyroid disor‐ ders as a result of improved immune function (immune reconstitution syndrome). Graves' disease is the commonest among immune reconstitution syndromes; others include Hashi‐ moto's thyroiditis and hypothyroidism. Autoimmune Thyroid Disease (AITD) occurs in 3% of women and 0.2% of men [13- 17]. Goddard proposed a staging of autoimmune manifesta‐ tions related to HIV/AIDS (table 3) [18].

The prevalence of immune reconstitution Autoimmune Thyroid Disease (AITD) (Graves' disease, Hashimoto thyroiditis, and hypothyroidism) is about 3% for women and 0.2% for men. Patients with lower CD4 counts at baseline with greater increments in the CD4 counts following HAART are more likely to develop AITD.


Interleukin-1 is a likely candidate as either a direct or an indirect adrenal stimulator. Its pro‐ duction by macrophages is stimulated by tumor necrosis factor, and the production by mac‐ rophages of both interleukin-1 and tumor necrosis factor is stimulated by HIV infection [33]. Interleukin-1 may affect the hypothalamus, pituitary, or adrenal glands in a variety of ways [29]. Interleukin-1 stimulates the release of corticotropin-releasing hormone from the hypo‐ thalamus into the portal circulation leading to the increases in corticotropin and consequent‐ ly cortisol secretion. Furthermore, Interleukin-1 has been shown to directly stimulate cultured pituitary cells to release corticotropin. Cultured adrenocortical cells secrete more cortisol when cocultured with mononuclear cells most likely as a result of a response to the production of interleukin-1 by mononuclear cells [30 - 32]. Interferon, another product of HIV-infected monocytes and macrophages, is also an immunomodulator of the hypothala‐

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 247

mo-pituitary-adrenal axis [34].

**Figure 1.** Effects of cytokines on the Hypothalamo-pituitary-adrenal axis.

**Table 3.** Stages of autoimmune manifestations in HIV/AIDS.

Thyroid dysfunction in HIV-positive individuals can result from gland destruction by op‐ portunistic pathogens such as Pneumocystis jirovecii which has been reported to cause a painful low uptake thyroiditis like picture with hyperthyroidism followed by hypothyroid‐ ism. Other opportunistic pathogens that could affect the thyroid gland in HIV infected indi‐ viduals include Cryptococcus neoformans, Aspergillosis and cytomegaloviurs [19 - 23]. The gland may also be invaded by Kaposi Sracoma with resultant hypothyroidism [24].

Overt Hypothyroidism should be treated with levothyroxine keeping in mind that drug in‐ teractions between levothyroxine and protease inhibitors have been reported, perhaps through the shared metabolic pathway of glucuronidation. In subclinical hypothyroidism however, the TSH level should be determined again within three months as the levels nor‐ malize within a year in up to 30% of affected patients. In cases of overt hyperthyroidism, it is paramount to establish whether it is as a result of Graves' disease, or thyroiditis and the appropriate therapy instituted.

### **4. Adrenal dysfunction**

Biochemical evidence of adrenal insufficiency is relatively common in hospitalized AIDS pa‐ tients occurring in almost a fifth of such patients however, only about 4% are clinically symptomatic patients [25]. Adrenal dysfunction may be suspected in HIV-infected patients with advanced stage of AIDS. High index of suspicion is required; subtle impairment of adrenal function is manifested as fatigue, hyponatremia or rarely with clinical symptoms of adrenal insufficiency. At autopsy, the adrenal gland shows evidence of both inflammation and necrosis1 , [26 - 28]. Adrenal secretion of aldosterone and adrenal androgens may also be impaired. In fact, there appears to be a shift from adrenal androgen and aldosterone produc‐ tion toward glucocorticoid production. However, the secretion of aldosterone in response to assumption of the upright posture and the administration of angiotensin II is normal. The mechanisms by which HIV might affect adrenal secretion appear to be dependent on effects of cytokines and other immunomodulatory substances on the hypothalamo-pituitary-adre‐ nal axis [29 - 32]. The potential sites of immune modulation of this is shown in this figure 1.

Interleukin-1 is a likely candidate as either a direct or an indirect adrenal stimulator. Its pro‐ duction by macrophages is stimulated by tumor necrosis factor, and the production by mac‐ rophages of both interleukin-1 and tumor necrosis factor is stimulated by HIV infection [33].

**Stage Features**

No autoimmune diseases are found.

resurgence of autoimmune disorders.

**Table 3.** Stages of autoimmune manifestations in HIV/AIDS.

246 Current Perspectives in HIV Infection

appropriate therapy instituted.

**4. Adrenal dysfunction**

and necrosis1

Stage I Acute HIV infection, the immune system is intact and autoimmune diseases may develop. Stage II The quiescent period without overt manifestations of AIDS associated with a declining

Stage III Immunosuppression with low CD4 count and the development of AIDS. CD8 T cells

Stage IV Restoration of immune competence following HAART. In this setting, there is a

gland may also be invaded by Kaposi Sracoma with resultant hypothyroidism [24].

Thyroid dysfunction in HIV-positive individuals can result from gland destruction by op‐ portunistic pathogens such as Pneumocystis jirovecii which has been reported to cause a painful low uptake thyroiditis like picture with hyperthyroidism followed by hypothyroid‐ ism. Other opportunistic pathogens that could affect the thyroid gland in HIV infected indi‐ viduals include Cryptococcus neoformans, Aspergillosis and cytomegaloviurs [19 - 23]. The

Overt Hypothyroidism should be treated with levothyroxine keeping in mind that drug in‐ teractions between levothyroxine and protease inhibitors have been reported, perhaps through the shared metabolic pathway of glucuronidation. In subclinical hypothyroidism however, the TSH level should be determined again within three months as the levels nor‐ malize within a year in up to 30% of affected patients. In cases of overt hyperthyroidism, it is paramount to establish whether it is as a result of Graves' disease, or thyroiditis and the

Biochemical evidence of adrenal insufficiency is relatively common in hospitalized AIDS pa‐ tients occurring in almost a fifth of such patients however, only about 4% are clinically symptomatic patients [25]. Adrenal dysfunction may be suspected in HIV-infected patients with advanced stage of AIDS. High index of suspicion is required; subtle impairment of adrenal function is manifested as fatigue, hyponatremia or rarely with clinical symptoms of adrenal insufficiency. At autopsy, the adrenal gland shows evidence of both inflammation

impaired. In fact, there appears to be a shift from adrenal androgen and aldosterone produc‐ tion toward glucocorticoid production. However, the secretion of aldosterone in response to assumption of the upright posture and the administration of angiotensin II is normal. The mechanisms by which HIV might affect adrenal secretion appear to be dependent on effects of cytokines and other immunomodulatory substances on the hypothalamo-pituitary-adre‐ nal axis [29 - 32]. The potential sites of immune modulation of this is shown in this figure 1.

, [26 - 28]. Adrenal secretion of aldosterone and adrenal androgens may also be

CD4 count indicative of some immunosuppression. Autoimmune diseases are not found.

predominate and diseases such as psoriasis and diffuse immune lymphocytic syndrome (similar to Sjogren's syndrome) may present or even be the initial manifestation of AIDS. Interleukin-1 may affect the hypothalamus, pituitary, or adrenal glands in a variety of ways [29]. Interleukin-1 stimulates the release of corticotropin-releasing hormone from the hypo‐ thalamus into the portal circulation leading to the increases in corticotropin and consequent‐ ly cortisol secretion. Furthermore, Interleukin-1 has been shown to directly stimulate cultured pituitary cells to release corticotropin. Cultured adrenocortical cells secrete more cortisol when cocultured with mononuclear cells most likely as a result of a response to the production of interleukin-1 by mononuclear cells [30 - 32]. Interferon, another product of HIV-infected monocytes and macrophages, is also an immunomodulator of the hypothala‐ mo-pituitary-adrenal axis [34].

**Figure 1.** Effects of cytokines on the Hypothalamo-pituitary-adrenal axis.

Both interleukin-1 and interferon thus have effects that could stimulate adrenal function. Conversely, adrenal function could be inhibited in patients with HIV infection as a result of polyclonal B-cell activation and the production of anti—adrenal-cell antibodies. The specific cellular or hormonal antigenic determinants and the pathogenetic importance of these anti‐ bodies are unclear. In addition to these mechanisms of adrenal dysfunction in patients with HIV infection, drugs which impair adrenal function directly such as Ketoconazole which in‐ hibits adrenal steroidogenesis, Rifampicin, phenytoin, and opiates which accelerate the deg‐ radation of cortisol and therefore lower serum cortisol concentrations are frequently prescribed in HIV infected patients. Although the resulting need for increased cortisol secre‐ tion is easily met in normal subjects, it may not be so in patients with HIV infection.

tients that are similar to features of hypercortisolism include muscle wasting and myopathy, dyslipidemia and visceral obesity and insulin resistance. From the foregoing, it seems possi‐ ble that some unknown factor(s) modulate tissue sensitivity to glucocorticoids in HIV infect‐

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 249

The observed glucocorticoid hypersensitivity in HIV infected patients seem to preferentially affect the brain, fat cells, the liver, the musculoskeletal system and the immune system. It is noteworthy that the hypothalamo-pituitary-adrenal axis is not affected suggesting that ap‐

There is evidence to suggest that glucocorticoid hypersensitivity in HIV/AIDS is mediated through one of the HIV-1 accessory proteins the virion-associated protein (Vpr). This is a 96 amino acid protein with multiple functions. This protein is known to act as a transcriptional activator of several viral promoters and as an enhancer of HIV-1 long terminal repeat pro‐ moter activated by Tat as well as enhances the replication of HIV-1 virus in lymphocyteand monocyte-derived cell lines. Furthermore, the protein also increases the translocation of the HIV-1 pre-integration complex into the nucleus promoting efficient infection of non-di‐

The protein circulates in HIV-1-infected individuals and has the capacity to penetrate cell membranes. This suggests that its effects have the potential to involve all cells including those not infected by HIV-1. It is indeed this protein that has been shown by Kino *et al* [36]to increase the tissue sensitivity to glucocorticoids by functioning as a coactivator of the GR on its responsive promoters. By inducing hypersensitivity to glucocorticoids, these proteins contribute to the proliferation of the virus indirectly by suppressing the host immune sys‐ tem. Extensive further clinical and basic investigations are crucial to examine the clinical im‐ portance of glucocorticoid hypersensitivity and to develop novel effective therapeutic

Although the involvement of the adrenal gland is common in HIV patients, routine screen‐ ing is not however recommended as adrenal insufficiency is a relatively rare complication of HIV infection. Its presence should however be considered, however, in those with dissemi‐ nated cytomegalovirus infection or tuberculosis. It should also be suspected, in patients with otherwise unexplained symptoms and signs compatible with adrenal insufficiency, such as anorexia, nausea, weight loss, and fatigue, and especially in patients with more specific manifestations of adrenal insufficiency, such as postural hypotension, hyponatremia, or hy‐ perkalemia. It is also reasonable to be concerned about adrenal reserve in patients who are about to undergo major stress, such as surgery. The simplest test is to measure the serum cortisol concentration in the morning, when it is highest in normal subjects. A concentration of 10 µg per deciliter (280 nmol per liter) or less suggests the presence of adrenal insufficien‐ cy. However, higher cortisol concentrations do not rule out the possibility of diminished adrenal reserve. If the basal serum cortisol concentration is low or the suspicion of adrenal insufficiency persists, provocative testing with corticotropin is indicated. Such testing in‐ volves measuring the serum cortisol concentration before and 30 and 60 minutes after the intravenous or intramuscular administration of 0.25 mg of cosyntropin. The cortisol concen‐ tration should increase by at least 7 µg per deciliter (196 nmol per liter) at 30 minutes and 11

propriate negative feedback sensitivity to glucocorticoids is preserved.

ed patients.

viding macrophages.

approaches in AIDS.

### **5. Glucocorticoids**

The adrenal corticosteroids ( Cortisol and Aldosterone), exert profound influences on many physiologic functions by virtue of their diverse roles in growth, development and mainte‐ nance of homeostasis [35]. The actions of these corticosteroids are mediated by intracellular receptor proteins, the glucocorticoid (GR) and mineralocorticoid (MR) receptors respective‐ ly. These receptors act as hormone-activated transcription factors which regulate the expres‐ sion of the glucocorticoid and mineralocorticoid target genes respectively. The GR is ubiquitous and is found in virtually all human tissues and organs [1, 35].

Glucocorticoids are essential to maintain the integrity of central nervous system and cardio‐ vascular function,as well as the maintenance of metabolic and immune function.

Tissue hypersensitivity to glucocorticoids was recently hypothesized in patients with Hu‐ man Immunodeficiency Virus type-1 infection via the accessory proteins Vpr and Tat which enhance GR transactivation [36]. Since HIV-1 long terminal repeat (LTR) and glucocorticoidresponsive promoters use the same set of co-activators, these proteins may stimulate HIV-1- LTR and glucocorticoid-inducible genes concurrently. The former may directly stimulate viral proliferation, while the latter may indirectly enhance viral propagation by suppressing the host immune system through glucocorticoid mediated mechanisms.

### **6. Glucocorticoid hypersensitivity in AIDS**

AIDS patients have several manifestations compatible with tissue hypersensitivity to gluco‐ corticoids [37]. Some of the manifestations include reduction of innate and cellular immuni‐ ty mediated through T helper 1 cells with resultant reduction in the secretion of interleukin (IL)-2, IL-12 and interferon and increased secretion of IL-4. These changes are similar to what obtains when exogenous glucocorticoids are administered as well as in hypercortisole‐ mic patients with endogenous Cushing's syndrome. Furthermore, hippocampal atrophy similar to what is observed in individuals who exhibit hypercortisolism is seen in HIV in‐ fected patients especially in pediatric AIDS patients. Other features seen in HIV/AIDS pa‐ tients that are similar to features of hypercortisolism include muscle wasting and myopathy, dyslipidemia and visceral obesity and insulin resistance. From the foregoing, it seems possi‐ ble that some unknown factor(s) modulate tissue sensitivity to glucocorticoids in HIV infect‐ ed patients.

Both interleukin-1 and interferon thus have effects that could stimulate adrenal function. Conversely, adrenal function could be inhibited in patients with HIV infection as a result of polyclonal B-cell activation and the production of anti—adrenal-cell antibodies. The specific cellular or hormonal antigenic determinants and the pathogenetic importance of these anti‐ bodies are unclear. In addition to these mechanisms of adrenal dysfunction in patients with HIV infection, drugs which impair adrenal function directly such as Ketoconazole which in‐ hibits adrenal steroidogenesis, Rifampicin, phenytoin, and opiates which accelerate the deg‐ radation of cortisol and therefore lower serum cortisol concentrations are frequently prescribed in HIV infected patients. Although the resulting need for increased cortisol secre‐

tion is easily met in normal subjects, it may not be so in patients with HIV infection.

ubiquitous and is found in virtually all human tissues and organs [1, 35].

the host immune system through glucocorticoid mediated mechanisms.

**6. Glucocorticoid hypersensitivity in AIDS**

vascular function,as well as the maintenance of metabolic and immune function.

The adrenal corticosteroids ( Cortisol and Aldosterone), exert profound influences on many physiologic functions by virtue of their diverse roles in growth, development and mainte‐ nance of homeostasis [35]. The actions of these corticosteroids are mediated by intracellular receptor proteins, the glucocorticoid (GR) and mineralocorticoid (MR) receptors respective‐ ly. These receptors act as hormone-activated transcription factors which regulate the expres‐ sion of the glucocorticoid and mineralocorticoid target genes respectively. The GR is

Glucocorticoids are essential to maintain the integrity of central nervous system and cardio‐

Tissue hypersensitivity to glucocorticoids was recently hypothesized in patients with Hu‐ man Immunodeficiency Virus type-1 infection via the accessory proteins Vpr and Tat which enhance GR transactivation [36]. Since HIV-1 long terminal repeat (LTR) and glucocorticoidresponsive promoters use the same set of co-activators, these proteins may stimulate HIV-1- LTR and glucocorticoid-inducible genes concurrently. The former may directly stimulate viral proliferation, while the latter may indirectly enhance viral propagation by suppressing

AIDS patients have several manifestations compatible with tissue hypersensitivity to gluco‐ corticoids [37]. Some of the manifestations include reduction of innate and cellular immuni‐ ty mediated through T helper 1 cells with resultant reduction in the secretion of interleukin (IL)-2, IL-12 and interferon and increased secretion of IL-4. These changes are similar to what obtains when exogenous glucocorticoids are administered as well as in hypercortisole‐ mic patients with endogenous Cushing's syndrome. Furthermore, hippocampal atrophy similar to what is observed in individuals who exhibit hypercortisolism is seen in HIV in‐ fected patients especially in pediatric AIDS patients. Other features seen in HIV/AIDS pa‐

**5. Glucocorticoids**

248 Current Perspectives in HIV Infection

The observed glucocorticoid hypersensitivity in HIV infected patients seem to preferentially affect the brain, fat cells, the liver, the musculoskeletal system and the immune system. It is noteworthy that the hypothalamo-pituitary-adrenal axis is not affected suggesting that ap‐ propriate negative feedback sensitivity to glucocorticoids is preserved.

There is evidence to suggest that glucocorticoid hypersensitivity in HIV/AIDS is mediated through one of the HIV-1 accessory proteins the virion-associated protein (Vpr). This is a 96 amino acid protein with multiple functions. This protein is known to act as a transcriptional activator of several viral promoters and as an enhancer of HIV-1 long terminal repeat pro‐ moter activated by Tat as well as enhances the replication of HIV-1 virus in lymphocyteand monocyte-derived cell lines. Furthermore, the protein also increases the translocation of the HIV-1 pre-integration complex into the nucleus promoting efficient infection of non-di‐ viding macrophages.

The protein circulates in HIV-1-infected individuals and has the capacity to penetrate cell membranes. This suggests that its effects have the potential to involve all cells including those not infected by HIV-1. It is indeed this protein that has been shown by Kino *et al* [36]to increase the tissue sensitivity to glucocorticoids by functioning as a coactivator of the GR on its responsive promoters. By inducing hypersensitivity to glucocorticoids, these proteins contribute to the proliferation of the virus indirectly by suppressing the host immune sys‐ tem. Extensive further clinical and basic investigations are crucial to examine the clinical im‐ portance of glucocorticoid hypersensitivity and to develop novel effective therapeutic approaches in AIDS.

Although the involvement of the adrenal gland is common in HIV patients, routine screen‐ ing is not however recommended as adrenal insufficiency is a relatively rare complication of HIV infection. Its presence should however be considered, however, in those with dissemi‐ nated cytomegalovirus infection or tuberculosis. It should also be suspected, in patients with otherwise unexplained symptoms and signs compatible with adrenal insufficiency, such as anorexia, nausea, weight loss, and fatigue, and especially in patients with more specific manifestations of adrenal insufficiency, such as postural hypotension, hyponatremia, or hy‐ perkalemia. It is also reasonable to be concerned about adrenal reserve in patients who are about to undergo major stress, such as surgery. The simplest test is to measure the serum cortisol concentration in the morning, when it is highest in normal subjects. A concentration of 10 µg per deciliter (280 nmol per liter) or less suggests the presence of adrenal insufficien‐ cy. However, higher cortisol concentrations do not rule out the possibility of diminished adrenal reserve. If the basal serum cortisol concentration is low or the suspicion of adrenal insufficiency persists, provocative testing with corticotropin is indicated. Such testing in‐ volves measuring the serum cortisol concentration before and 30 and 60 minutes after the intravenous or intramuscular administration of 0.25 mg of cosyntropin. The cortisol concen‐ tration should increase by at least 7 µg per deciliter (196 nmol per liter) at 30 minutes and 11 µg per deciliter (308 nmol per liter) at 60 minutes. Alternatively, a normal response is a con‐ centration twice the basal value at 60 minutes. Whether one considers the extent of a change in the cortisol concentration or the multiple of the basal value, the peak stimulated value should be 18 µg per deciliter (504 nmol per liter) or more for the response to be considered normal [48, 49]. Glucocorticoid therapy should be given only in cases of documented adre‐ nal insufficiency or when there is a medical emergency in which the possibility of adrenal crisis cannot be excluded.

**8. Gonadal dysfunction in female**

**9. Glucose homeostasis in HIV/AIDS**

non-oxidative glucose disposal.

later develop diabetes mellitus.

among those not receiving PI's4

and malignancies1

Ovarian dysfunction among female AIDS patients is less common. Amenorrhoea is seen in about a quarter of women during stress of illness; while failure of ovulation is seen among half of the female patients with low CD4 counts [44]. Early menopause has been seen in up to 8% of HIV-infected female patients. Androgen deficiency has been reported especially in women with significant weight loss. The reasons for the above observations are not clear, but could be as a result of intra-adrenal shunting toward cortisol production from androgen synthesis. Human chorionic gonadotropin levels suggest intact ovarian androgen produc‐ tion. Delivery of low doses of testosterone using transdermal patches improves functional

capacity without hirsuitism or virilisation but does not increase lean body mass [38].

thought to be protective against the development of diabetes mellitus1

Normal glucose metabolism is largely dependent on normal insulin secretion, insulin sensi‐ tivity and to a lesser extent on the influences of other hormones and cytokines. Before the advent of highly active anti-retroviral therapy (HAART), HIV infection on its own was

the following observations in clinically stable, symptomatic HIV-infected patients. These in‐ dividuals have been shown to have higher rates of insulin clearance and increased sensitivi‐ ty of peripheral tissues to insulin as well as an increase in noninsulin-mediated glucose uptake. The increase in glucose uptake is predominantly accounted for by an increase in

Pancreatic abnormalities are common in AIDS patients as a result of opportunistic infections

clinically significant pancreatic dysfunction. Clinically significant pancreatic dysfunction is usually as a result of therapeutic interventions; noteworthy in this regard is Pentamidine [45], which is used in the management of Pneumocystis carinii and may cause pancreatic βcell toxicity with resultant hypoglycaemia in the acute phase and some of these patients may

With the advent of HAART however, a new dysmetabolic syndrome with substantially in‐ creased risk for cardiovascular events emerged [46]. This syndrome has variable expressibil‐ ity; and includes insulin resistance, visceral adiposity, peripheral lipodystrophy, dyslipidaemia and glucose intolerance. Several studies have demonstrated an increased risk of diabetes among HIV infected individual on HAART especially when protease inhibitors (PIs) are included in the regimen. Among HIV infected minority patients in the USA for ex‐ ample, the prevalence of diabetes after three years of PI therapy was 12%, compared to none

ated with metabolic complication, there are evidences to suggest that virtually all classes of agents used in ART has the potential to cause metabolic derangements. Although the mech‐ anism by which ART drugs induce these metabolic changes are not fully clear; it has been

. However, the majority of these lesions are not extensive enough to cause

. However, although PI's are the most frequent agents associ‐

, this may be due to

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 251

### **7. Gonadal dysfunction in male**

Male gonadal dysfunction is common among AIDS patients. With more than two-thirds of male patients with advanced HIV disease exhibit of loss of libido and up to one-third of them having erective dysfunction [38, 39]. The prevalence and severity of male gonadal dys‐ function is directly proportional to disease severity. In advanced disease stages, biochemical hypogonadism is found in up to half of male AIDS patients. With the advent of HAART, the prevalence of male gonal dysfunction has reduced to about 20% among those receiving HAART [40]. Gonadal dysfunction in HIV/AIDS is usually attributable to secondary causes such as the effect of under nutrition, infection-inflammation and several drugs on gonado‐ tropin production. Other secondary causes include the role of cytokines produced in re‐ sponse to systemic illness may impair the secretion of gonadotropin-releasing hormone or gonadotropin [41]. Low levels of interleukin-1 enhance testicular steroidogenesis in vitro, whereas higher doses inhibit the binding of gonadotropin to Leydig cells and steroidogene‐ sis by these cells. Ketoconazole used in the treatment of fungal infections in HIV/AIDS pa‐ tients inhibits gonadal as well as adrenal steroid production and could therefore also contribute to the observed gonadal dysfunction.

Furthermore, hyperprolactinaemia and gynecomastia have been reported among HIV-in‐ fected patients [42]. Prolactin has for long been known to be an immunostimulatory hor‐ mone and is also known to be elevated in other immunostimulatory states such as systemic lupus erythematosis (SLE). Similarly, prolactin receptors are found in T and B lymphocytes as well as monocytes [43], while lymphocytes are known to produce a prolactin like protein. The men with low serum testosterone concentrations may have inappropriately normal se‐ rum gonadotropin concentrations, suggesting involvement of the pituitary gland or hypo‐ thalamus however, there is neither CT scans nor autopsy data provide evidence of pituitary or hypothalamic disease.

As sex hormone binding capacity increases in up to a third of HIV patients, the use of free testosterone assay is recommended for diagnosis. [38] Physiologic testosterone replacement that does not suppress endogenous gonadal function results in increased lean body mass, improved quality of life and reduction in depression. Standard therapy for hypogonadism has been intramuscular testosterone (enanthate or ciprionate esters) every 1–3 weeks to pro‐ vide 100 mg per week. Alternate transdermal or oral routes for androgen administration are also available. Prostate-specific antigen level should be monitored in elderly patients receiv‐ ing testosterone.

### **8. Gonadal dysfunction in female**

µg per deciliter (308 nmol per liter) at 60 minutes. Alternatively, a normal response is a con‐ centration twice the basal value at 60 minutes. Whether one considers the extent of a change in the cortisol concentration or the multiple of the basal value, the peak stimulated value should be 18 µg per deciliter (504 nmol per liter) or more for the response to be considered normal [48, 49]. Glucocorticoid therapy should be given only in cases of documented adre‐ nal insufficiency or when there is a medical emergency in which the possibility of adrenal

Male gonadal dysfunction is common among AIDS patients. With more than two-thirds of male patients with advanced HIV disease exhibit of loss of libido and up to one-third of them having erective dysfunction [38, 39]. The prevalence and severity of male gonadal dys‐ function is directly proportional to disease severity. In advanced disease stages, biochemical hypogonadism is found in up to half of male AIDS patients. With the advent of HAART, the prevalence of male gonal dysfunction has reduced to about 20% among those receiving HAART [40]. Gonadal dysfunction in HIV/AIDS is usually attributable to secondary causes such as the effect of under nutrition, infection-inflammation and several drugs on gonado‐ tropin production. Other secondary causes include the role of cytokines produced in re‐ sponse to systemic illness may impair the secretion of gonadotropin-releasing hormone or gonadotropin [41]. Low levels of interleukin-1 enhance testicular steroidogenesis in vitro, whereas higher doses inhibit the binding of gonadotropin to Leydig cells and steroidogene‐ sis by these cells. Ketoconazole used in the treatment of fungal infections in HIV/AIDS pa‐ tients inhibits gonadal as well as adrenal steroid production and could therefore also

Furthermore, hyperprolactinaemia and gynecomastia have been reported among HIV-in‐ fected patients [42]. Prolactin has for long been known to be an immunostimulatory hor‐ mone and is also known to be elevated in other immunostimulatory states such as systemic lupus erythematosis (SLE). Similarly, prolactin receptors are found in T and B lymphocytes as well as monocytes [43], while lymphocytes are known to produce a prolactin like protein. The men with low serum testosterone concentrations may have inappropriately normal se‐ rum gonadotropin concentrations, suggesting involvement of the pituitary gland or hypo‐ thalamus however, there is neither CT scans nor autopsy data provide evidence of pituitary

As sex hormone binding capacity increases in up to a third of HIV patients, the use of free testosterone assay is recommended for diagnosis. [38] Physiologic testosterone replacement that does not suppress endogenous gonadal function results in increased lean body mass, improved quality of life and reduction in depression. Standard therapy for hypogonadism has been intramuscular testosterone (enanthate or ciprionate esters) every 1–3 weeks to pro‐ vide 100 mg per week. Alternate transdermal or oral routes for androgen administration are also available. Prostate-specific antigen level should be monitored in elderly patients receiv‐

crisis cannot be excluded.

250 Current Perspectives in HIV Infection

**7. Gonadal dysfunction in male**

contribute to the observed gonadal dysfunction.

or hypothalamic disease.

ing testosterone.

Ovarian dysfunction among female AIDS patients is less common. Amenorrhoea is seen in about a quarter of women during stress of illness; while failure of ovulation is seen among half of the female patients with low CD4 counts [44]. Early menopause has been seen in up to 8% of HIV-infected female patients. Androgen deficiency has been reported especially in women with significant weight loss. The reasons for the above observations are not clear, but could be as a result of intra-adrenal shunting toward cortisol production from androgen synthesis. Human chorionic gonadotropin levels suggest intact ovarian androgen produc‐ tion. Delivery of low doses of testosterone using transdermal patches improves functional capacity without hirsuitism or virilisation but does not increase lean body mass [38].

### **9. Glucose homeostasis in HIV/AIDS**

Normal glucose metabolism is largely dependent on normal insulin secretion, insulin sensi‐ tivity and to a lesser extent on the influences of other hormones and cytokines. Before the advent of highly active anti-retroviral therapy (HAART), HIV infection on its own was thought to be protective against the development of diabetes mellitus1 , this may be due to the following observations in clinically stable, symptomatic HIV-infected patients. These in‐ dividuals have been shown to have higher rates of insulin clearance and increased sensitivi‐ ty of peripheral tissues to insulin as well as an increase in noninsulin-mediated glucose uptake. The increase in glucose uptake is predominantly accounted for by an increase in non-oxidative glucose disposal.

Pancreatic abnormalities are common in AIDS patients as a result of opportunistic infections and malignancies1 . However, the majority of these lesions are not extensive enough to cause clinically significant pancreatic dysfunction. Clinically significant pancreatic dysfunction is usually as a result of therapeutic interventions; noteworthy in this regard is Pentamidine [45], which is used in the management of Pneumocystis carinii and may cause pancreatic βcell toxicity with resultant hypoglycaemia in the acute phase and some of these patients may later develop diabetes mellitus.

With the advent of HAART however, a new dysmetabolic syndrome with substantially in‐ creased risk for cardiovascular events emerged [46]. This syndrome has variable expressibil‐ ity; and includes insulin resistance, visceral adiposity, peripheral lipodystrophy, dyslipidaemia and glucose intolerance. Several studies have demonstrated an increased risk of diabetes among HIV infected individual on HAART especially when protease inhibitors (PIs) are included in the regimen. Among HIV infected minority patients in the USA for ex‐ ample, the prevalence of diabetes after three years of PI therapy was 12%, compared to none among those not receiving PI's4 . However, although PI's are the most frequent agents associ‐ ated with metabolic complication, there are evidences to suggest that virtually all classes of agents used in ART has the potential to cause metabolic derangements. Although the mech‐ anism by which ART drugs induce these metabolic changes are not fully clear; it has been shown that indinavir, a PI dramatically inhibits glucose uptake in a dose dependent manner in adipocytes by selectively inhibiting the Glut-4 transporter function [47]. Furthermore, there is evidence at least in laboratory studies to show that indinavir down regulates the peroxisome proliferator–activated receptor -γ (PPAγ) receptor in adipocytes [48]. Obviously some genetic predisposition could explain why not all patients on PI's develop diabetes, or any of the other metabolic complications.

roid hormone-related protein. A HTLV-I gene product, *tax*,has been implicated in the activa‐ tion of the parathyroid hormone-related protein gene. Serum concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D are not elevated in HTLV-I—related hypercalcemia.

Wasting is an age-old terminal event of AIDS, even with the advent of HAART, wasting re‐ mains common affecting more than one-third of patients [57]. Unfortunately, weight loss is a significant predictor of mortality in HIV infection. Those with a body mass index (BMI) of

Currently, AIDS wasting syndrome is defined as body weight less than 90% of ideal weight or weight loss of more than 10% of body weight over 3 months. The condition is character‐ ised by a disproportionate loss of lean body mass with a relative sparing of body fat as the disease progresses this is associated with muscle wasting, weakness, increased resting ener‐ gy expenditure and hypertriglyceridemia. The exact mechanisms involved in the aetiology of this condition are not clear. However, the roles of Cytokine related increased energy ex‐ penditure and decreased appetite, diarrhoea, malabsorption and hypogonadism are likely

Management of this condition include optimal antiretroviral therapy and adequate nutri‐ tion. Testosterone (intramuscular/transdermal) has been successfully used to increase lean body mass in men with this syndrome, whereas it has also been shown to be safe and well tolerated in women. A number of agents like anabolic steroids (oxandrolone, nandrolone), megesrtol acetate, thalidomide, human chorionic gonadotropin, pentoxyfiline, amino acid mixtures and omega 3 fatty acids have been tried in this setting with variable efficacy but potential side effects. Only testosterone administration has proved useful to increase lean body mass, especially in conjunction with progressive resistance training. Administration of supraphysiologic doses of growth hormone is currently reserved for severe wasting refrac‐

HIV lipodystrophy syndrome is associated with metabolic derangements, changes in body composition and abnormal fat distribution. It has been most widely recognized since the era of HAART but can also be seen in antiretroviral-naïve patients [61]. It is characterized by phenotypic changes similar to those observed in Cushing's syndrome, such as like truncal obesity, buffalo hump, peripheral fat loss, atrophy of facial fat and breast enlargement in women. Considering some physical similarities to Cushing's syndrome, it has been termed as "a pseudo-Cushing's syndrome" though no other specific stigmata of Cushing's syn‐ drome (proximal muscle weakness, bruising and facial plethora) nor biochemical parame‐

are at 4.4-fold increased risk of mortality [58].

are at 2.2-fold increased risk of mortality, while those with a BMI less

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 253

**12. AID wasting syndrome**

mechanisms behind such wasting [59, 60].

**13. HIV lipodystrophy syndrome**

less than 18.4 kg/M2

tory to other treatments.

than 16 kg/M2

### **10. Bone mineral dysfunction**

Both osteoporosis and osteopenia are common among AIDS patients. Reduced bone mineral density is seen in almost three quarter of HIV-infected patients compared to about 30% in HIV-negative individuals of similar age [49]. Reduced vertebral bone density is associated with visceral adiposity among HIV-infected patients. Similarly, reduced bone density also occurs in HIV-infected children receiving HAART with maximum reduction seen among those with lipodystrophy. Several factors are thought to be responsible for the observed ef‐ fects on the skeleton. The effects of low GH and IGF1, hypogonadism and excess visceral adiposity are possible factors as they have been found to correlate significantly with verte‐ bral bone density [50 - 52]. Protease Inhibitors are also known to induce relative vitamin D deficiency and may also act as an additive factor.

### **11. Calcium and vitamin D balance**

Hypocalcemia is common in HIV infected patients occurring in more than 5% of them [53]. It appears the level of calcium has an inverse relationship with the stage of the disease and its severity. Factors responsible for hypocalcaemia in these patients include vitamin D defi‐ ciency and reduced parathyroid hormone (PTH ) level. The cause of the relatively reduced PTH is not known but may be as a result of the effects of cytokines; and presence of hypo‐ magnesemia which is relatively common among HIV infected patients especially those with chronic diarhoea. On the other hand, the cause of Vitamin D deficiency is multifactorial in the setting of HIV/AIDS and may include malabsorption, decreased hydroxylation as a re‐ sult of the effects of protease inhibitors. Furthermore, several therapeutic agents such as fo‐ scarnet, pentamidine, and ketoconazole, may affect calcium homeostasis [53].

Hypercalcemia is uncommon in AIDS. When present it is likely to be due to infectious, ma‐ lignant, or granulomatous processes [54 - 55]. Patients with lymphoma who have hypercal‐ cemia typically have increased serum 1,25-dihydroxyvitamin D concentrations, because the tumors contain vitamin D 1-hydroxylase and therefore convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Cultured lymphoma cells infected with HIV have the same syn‐ thetic activity. Human T-cell lymphotropic virus Type I (HTLV-I), a retrovirus linked to Tcell leukemia and lymphoma may be associated with hypercalcemia. Increased bone resorption in this syndrome may be due to lymphokines such as interleukin-2 or to parathy‐ roid hormone-related protein. A HTLV-I gene product, *tax*,has been implicated in the activa‐ tion of the parathyroid hormone-related protein gene. Serum concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D are not elevated in HTLV-I—related hypercalcemia.

### **12. AID wasting syndrome**

shown that indinavir, a PI dramatically inhibits glucose uptake in a dose dependent manner in adipocytes by selectively inhibiting the Glut-4 transporter function [47]. Furthermore, there is evidence at least in laboratory studies to show that indinavir down regulates the peroxisome proliferator–activated receptor -γ (PPAγ) receptor in adipocytes [48]. Obviously some genetic predisposition could explain why not all patients on PI's develop diabetes, or

Both osteoporosis and osteopenia are common among AIDS patients. Reduced bone mineral density is seen in almost three quarter of HIV-infected patients compared to about 30% in HIV-negative individuals of similar age [49]. Reduced vertebral bone density is associated with visceral adiposity among HIV-infected patients. Similarly, reduced bone density also occurs in HIV-infected children receiving HAART with maximum reduction seen among those with lipodystrophy. Several factors are thought to be responsible for the observed ef‐ fects on the skeleton. The effects of low GH and IGF1, hypogonadism and excess visceral adiposity are possible factors as they have been found to correlate significantly with verte‐ bral bone density [50 - 52]. Protease Inhibitors are also known to induce relative vitamin D

Hypocalcemia is common in HIV infected patients occurring in more than 5% of them [53]. It appears the level of calcium has an inverse relationship with the stage of the disease and its severity. Factors responsible for hypocalcaemia in these patients include vitamin D defi‐ ciency and reduced parathyroid hormone (PTH ) level. The cause of the relatively reduced PTH is not known but may be as a result of the effects of cytokines; and presence of hypo‐ magnesemia which is relatively common among HIV infected patients especially those with chronic diarhoea. On the other hand, the cause of Vitamin D deficiency is multifactorial in the setting of HIV/AIDS and may include malabsorption, decreased hydroxylation as a re‐ sult of the effects of protease inhibitors. Furthermore, several therapeutic agents such as fo‐

Hypercalcemia is uncommon in AIDS. When present it is likely to be due to infectious, ma‐ lignant, or granulomatous processes [54 - 55]. Patients with lymphoma who have hypercal‐ cemia typically have increased serum 1,25-dihydroxyvitamin D concentrations, because the tumors contain vitamin D 1-hydroxylase and therefore convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Cultured lymphoma cells infected with HIV have the same syn‐ thetic activity. Human T-cell lymphotropic virus Type I (HTLV-I), a retrovirus linked to Tcell leukemia and lymphoma may be associated with hypercalcemia. Increased bone resorption in this syndrome may be due to lymphokines such as interleukin-2 or to parathy‐

scarnet, pentamidine, and ketoconazole, may affect calcium homeostasis [53].

any of the other metabolic complications.

252 Current Perspectives in HIV Infection

**10. Bone mineral dysfunction**

deficiency and may also act as an additive factor.

**11. Calcium and vitamin D balance**

Wasting is an age-old terminal event of AIDS, even with the advent of HAART, wasting re‐ mains common affecting more than one-third of patients [57]. Unfortunately, weight loss is a significant predictor of mortality in HIV infection. Those with a body mass index (BMI) of less than 18.4 kg/M2 are at 2.2-fold increased risk of mortality, while those with a BMI less than 16 kg/M2 are at 4.4-fold increased risk of mortality [58].

Currently, AIDS wasting syndrome is defined as body weight less than 90% of ideal weight or weight loss of more than 10% of body weight over 3 months. The condition is character‐ ised by a disproportionate loss of lean body mass with a relative sparing of body fat as the disease progresses this is associated with muscle wasting, weakness, increased resting ener‐ gy expenditure and hypertriglyceridemia. The exact mechanisms involved in the aetiology of this condition are not clear. However, the roles of Cytokine related increased energy ex‐ penditure and decreased appetite, diarrhoea, malabsorption and hypogonadism are likely mechanisms behind such wasting [59, 60].

Management of this condition include optimal antiretroviral therapy and adequate nutri‐ tion. Testosterone (intramuscular/transdermal) has been successfully used to increase lean body mass in men with this syndrome, whereas it has also been shown to be safe and well tolerated in women. A number of agents like anabolic steroids (oxandrolone, nandrolone), megesrtol acetate, thalidomide, human chorionic gonadotropin, pentoxyfiline, amino acid mixtures and omega 3 fatty acids have been tried in this setting with variable efficacy but potential side effects. Only testosterone administration has proved useful to increase lean body mass, especially in conjunction with progressive resistance training. Administration of supraphysiologic doses of growth hormone is currently reserved for severe wasting refrac‐ tory to other treatments.

### **13. HIV lipodystrophy syndrome**

HIV lipodystrophy syndrome is associated with metabolic derangements, changes in body composition and abnormal fat distribution. It has been most widely recognized since the era of HAART but can also be seen in antiretroviral-naïve patients [61]. It is characterized by phenotypic changes similar to those observed in Cushing's syndrome, such as like truncal obesity, buffalo hump, peripheral fat loss, atrophy of facial fat and breast enlargement in women. Considering some physical similarities to Cushing's syndrome, it has been termed as "a pseudo-Cushing's syndrome" though no other specific stigmata of Cushing's syn‐ drome (proximal muscle weakness, bruising and facial plethora) nor biochemical parame‐ ters are associated with this syndrome. Normal cortisol level with its normal diurnal variation and adequate suppressibility to dexamethasone are also seen in HIV lipodystro‐ phy syndrome. However, it is very often associated with insulin resistance, hyperglycemia, and hypertriglyceridemia. In particular, dyslipidemia and diabetes mellitus are increasingly common among patients receiving HAART. management consist of exercise and lifestyle modification, switching to less-toxic NRTIs or PIs, fenofibrates to decrease serum triglycer‐ ide level, and use of insulin sensitizers like metformin to reduce visceral fat and thiazolidi‐ nediones to improve subcutaneous fat loss. Testosterone and anabolic steroids have no effect in reducing visceral fat in this syndrome.

[6] Cozzolino, M., Vidal, M., Arcidiacono, M. V., Tebas, P., Yarasheski, K. E., & Dusso, H. I. HIV-protease inhibitors impair vitamin D bioactivation to 1, 25-dihydroxyvita‐

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 255

[7] Hadigan, C., Borgonha, S., Rabe, J., Young, V., & Grinspoon, S. Increased rates of lip‐ olysis among HIV-infected men receiving highly active antiretroviral therapy. Me‐

[8] Madeddo G, Spanu A, Chessa F et al: Thyroid function in Human immunodeficiency virus patients treated with highly active antiretroviral therapy (HAART): a longitu‐

[9] Ferrerio, J., & Vinters, H. V. Pathology of pituitary gland in patients with acquired

[10] Vitting KE, Gardenswartz MH, Zabetakis PM, Frequency of hyponatraemia and non osmolar vasopressin release in the acquired immunodeficiency syndrome.JAMA

[11] Cusano AJ, Thies HL, Siegal FP, Hyponatraemia in patients with acquired immuno‐ deficiency syndrome.J AcquirImuneDeficSyndr HumRetrvirol(1990). , 3, 949-953.

[12] Agarwal, A., Soni, A., Ciechanowsky, M., Chander, P., & Treser, G. Hyponatraemia in patients with the acquired immunodeficiency syndrome. Nephron (1989). , 53,

[13] Hoffman CJ, Brown TT.Thyroid function abnormalities in HIV infected patients. Clin

[14] , 5., Bourdoux, P. P., De Wit, S. A., Servais, G. M., Clumeck, N., & Bonnyns, . Bio‐ chemical thyroid profile in patients infected with human immunodeficiency virus.

[15] Jimenez C, Moran SA, Sereti I: Graves' disease after interleukin-2 therapy in patients

[16] Nelson, M., et al. Thyroid dysfunction and relationship to antiretroviral therapy in HIV-positive individuals in the HAART era. J Acqu. ir Immune DeficSyndr. (1990). ,

[17] Madeddo G, Spanu A, Chessa F et al: Thyroid function in Human immunodeficiency virus patients treated with highly active antiretroviral therapy (HAART): a longitu‐

[18] Goddard, G. Z., Shoenfeld, Y. H. I. V., autoimmunity, ., & autoimmunity, reviews.

[19] Ragni, M. V., Dekker, A., De Rubertis, F. R., Watson, C. G., Skolnick, M. L., Goold, S. D., Finikiotis, M. W., Doshi, S., & Myers, D. J. (1991). Pneumocystis carinii infection presenting as necrotizing thyroiditis and hypothyroidism. Am J Clin Path, 01, 95-489.

immune deficiency syndrome (AIDS) Pathology. (1988). , 20, 211-5.

min D. AIDS. (2003). , 17, 513-20.

tabolism. (2002). , 51, 1143-7.

(1990). , 263, 973-978.

Infect Dis. (2007). , 45, 488-94.

Thy. roid. (1991). , 1, 147-9.

autoimmunity reviews : (2002).

with HIV infection : Thyroid 2004:14:1097-1102

dinal study. Clinical Endocrinol 2006:64:375-83.

317-321.

50, 113-14.

dinal study. Clinical Endocrinol 2006:64:375-83.

### **14. Conclusion**

Although HIV endocrinopathy is common, overt glandular failure is a rare clinical entity. HIV infection, acting by a number of mechanisms, may be responsible for subtle clinical and not-so-subtle biochemical abnormalities. Drug-induced endocrine toxicity is important cause of endocrinopathy in HIV infected patients.

### **Author details**

Bakari Adamu Girei and Sani-Bello Fatima

Endocrinology Unit, Department of Medicine, Ahmadu Bello University, Zaria, Nigeria

### **References**


[6] Cozzolino, M., Vidal, M., Arcidiacono, M. V., Tebas, P., Yarasheski, K. E., & Dusso, H. I. HIV-protease inhibitors impair vitamin D bioactivation to 1, 25-dihydroxyvita‐ min D. AIDS. (2003). , 17, 513-20.

ters are associated with this syndrome. Normal cortisol level with its normal diurnal variation and adequate suppressibility to dexamethasone are also seen in HIV lipodystro‐ phy syndrome. However, it is very often associated with insulin resistance, hyperglycemia, and hypertriglyceridemia. In particular, dyslipidemia and diabetes mellitus are increasingly common among patients receiving HAART. management consist of exercise and lifestyle modification, switching to less-toxic NRTIs or PIs, fenofibrates to decrease serum triglycer‐ ide level, and use of insulin sensitizers like metformin to reduce visceral fat and thiazolidi‐ nediones to improve subcutaneous fat loss. Testosterone and anabolic steroids have no

Although HIV endocrinopathy is common, overt glandular failure is a rare clinical entity. HIV infection, acting by a number of mechanisms, may be responsible for subtle clinical and not-so-subtle biochemical abnormalities. Drug-induced endocrine toxicity is important

Endocrinology Unit, Department of Medicine, Ahmadu Bello University, Zaria, Nigeria

[1] Sellmeyer, D. E., & Grunfeld, C. Endocrine and metabolic disturbances in Human Immunodeficiency virus infection and the acquired immune deficiency syndrome.

[2] Palella FJ Jr, Delaney KM, Moorman AC, et al.Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J

[3] Deeks, S. G., Smith, M., Holodny, M., Kahn, J. O. H. I. V., proteaseinhibitors, a., re‐

[4] Salehian, B., Bilas, J., Bazargam, M., & Abbasian, M. Prevalence and incidence of dia‐ betes in HIV infected minority patients on protease inhibitors J Nat Med Ass (2005). ,

[5] Hutchinson, J., Murphy, M., Harries, R., & Skinner, C. J. Galactorrhoea and hyperprolactinoma associated with protease inhibitors. Lancet. (2000). , 356, 1003-4.

view, for., & clinicians, J. A. M. JAMA (1997). , 145 EOF-53 EOF.

effect in reducing visceral fat in this syndrome.

cause of endocrinopathy in HIV infected patients.

Bakari Adamu Girei and Sani-Bello Fatima

End. Rev. (1996). , 17, 518-532.

Med (1998). , 338, 853-60.

97, 1088-92.

**14. Conclusion**

254 Current Perspectives in HIV Infection

**Author details**

**References**


[20] Guttler, R., Singer, P. A., Pneumocystis, carinii., & thyroiditis, . Report of three cases and review of the literature. Arch Intern Med. (1993). , 153, 393-396.

[34] Szebeni, J., Dieffenbach, C., Wahl, S. M., et al. Induction of alpha interferon by hu‐ man immunodeficiency virus type 1 in human monocyte-macrophage cultures. J Vi‐

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 257

[35] Guire, M. A. P., & Holbrook, N. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocrinol. Rev (1984). , 5, 25-44.

[36] Kino T, Gragerov A, Kopp JB, Stauber RH, Pavlakis GN &Chrousos GP. The HIV-1 virion-associated protein vpr is a coactivator of the human glucocorticoid receptor.

[37] Kino, T., & Chrousos, G. P. Glucocorticoid and mineralocorticoid resistance/hyper‐

[38] Mylonakis, E., Koutkia, P., & Grinspoon, S. Diagnosis and treatment of androgen de‐ ficiency in human immunodeficiency virus-infected men and women. Clin Infect Dis.

[39] Dobs AS, Dempsey MA, Ladenson PW, Polk BF.Endocrine disorders in men infected

[40] Rietschel, P., Corcoran, C., Stanley, T., Basgoz, N., Klibanski, A., & Grinspoon, S. Prevalence of hypogonadism among men with weight loss related to human immu‐ nodeficiency virus infection who were receiving highly active antiretroviral therapy.

[41] Calkins JH, Sigel MM, Nankin HR, Lin T. Interleukin-1 inhibits Leydig cell steroido‐

[42] Graff AS, Gonzalez SS, Baca VR, Ramirez ML, Daza LB etal.High serum prolactin levels in asymptomatic HIV-infected patients and in patients with Acquired Immune

[43] Rusell, D. H., Matrisian, L., Kibler, R., etal, , Prolactin, receptors., on, Human. T., lym‐ phocytes, B., their, modulation., & by, Cyclosporine. J. Immunol (1985). , 134,

[44] Grinspoon, S., Corcoran, C., Miller, K., Biller, Askari. H., Wang, E., et al. Body com‐ position and endocrine function in women with acquired immunodeficiency syn‐

[45] Perronne, C., Bricaire, F., Leport, C., Assan, D., Vilde, J. L., & Assan, R. Hypoglycae‐ mia and diabetes mellitus following parenteral pentamidinemesylate treatment in

[46] Hruz PW.Molecular mechanisms for altered glucose homeostasis in HIV infection.

[47] Murata, H., Hruz, P. W., & Mueckler, M. The mechanism of insulin resistance caused

by HIV protease inhibitor therapy J BiolChem (2000). , 275, 20251-4.

sensitivity syndromes. Journal of Endocrinology (2001). , 437-445.

with human immunodeficiency virus. Am J Med. (1988). , 84, 611-6.

genesis in primary culture. Endocrinology 1988; 123:1605–10.

drome wasting. J ClinEndocrinolMetab. (1997). , 82, 1332-7.

AIDS patients. Diabetic Med (1990). , 7, 585-9.

Am J Infectious Dis. (2006). , 2, 187-192.

deficiency syndrome. ClinImuunol. Immunopath (1994). , 72, 390-3.

Journal of ExperimentalMedicine1999;189: 51–62.

rol (1991). , 65, 6362-4.

(2001). , 33, 857-64.

3027-31.

Clin Infect Dis. (2000). , 31, 1240-4.


[34] Szebeni, J., Dieffenbach, C., Wahl, S. M., et al. Induction of alpha interferon by hu‐ man immunodeficiency virus type 1 in human monocyte-macrophage cultures. J Vi‐ rol (1991). , 65, 6362-4.

[20] Guttler, R., Singer, P. A., Pneumocystis, carinii., & thyroiditis, . Report of three cases

[21] Frank TS, LiVolsi VA, Connor AM.Cytomegalovirus infection of the thyroid in im‐

[22] Machac, J., Mejatheim, M., & Goldsmith, S. J. (1985). Gallium-67 citrate uptake in cryptococcal thyroiditis in a homosexual male. J Nucl Med Allied Sci , 29, 283-285.

[23] Martinez-Ocana, J. C., Romen, J., Llatjos, M., Sirera, G., & Clotet, B. Goiter as a mani‐ festation of disseminated aspergillosis in a patient with AIDS. Clin Infect Dis.(1993). ,

[24] Mollison, L. C., Mijch, A., Mc Bride, G., & Dwyer, B. 1991Hypothyroidism due to de‐ struction of the thyroid by Kaposi's sarcoma. Rev Infect Dis. 1991; , 13, 826-827.

[25] Membreno, L., Irony, I., Dere, W., Klein, R., Biglieri, E. G., & Cobb, E. Adrenocortical function in acquired immune deficiency syndrome. J ClinEndocrinolMetab. (1987). ,

[26] Tapper, M. L., Rotterdam, H. Z., Lemer, C. W., Al'Khafaji, K., & Seitzman, P. A. Adrenal necrosis in the acquired immunodeficiency syndrome. Ann Intern Med.

[27] Findling, J. W., Buggy, B. P., Gilson, I. H., Brummitt, C. F., & Bernstein, Raff. H. Lon‐ gitudinal evaluation of adrenocortical function in patients infected with the human

[28] Verges, B., Chavanet, P., Desgres, J., Vaillant, G., Waldner, A., Brim, J. M., & Putelat, R. Adrenal function in HIV infected patients. ActaEndocrinol (Copenh). (1989). , 121,

[29] Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor . Science 1987;238:522–4.

[30] Woloski BM, Smith EM, Meyer WJ, Fuller GM, Blalock JE.Corticotropin-releasing ac‐

[31] Whitcomb RW, Linehan WM, Wahl LM, Knazek RA.Monocytes stimulate cortisol production by cultured human adrenocortical cells. J ClinEndocrinolMetab (1988). ,

[32] Meyer, W. J. I. I. I., Smith, E. M., Richards, G. E., Cavallo, A., Morrill, achéal., & Bla‐ lock, J. E. In vivo immunoreactiveadrenocorticotropin (ACTH) production by human mononuclear leukocytes from normal and ACTH-deficient individuals. J ClinEndoc‐

[33] Merrill JE, Koyanagi Y, Chen ISY. Interleukin-1 and tumor necrosis factor α can be induced from mononuclear phagocytes by human immunodeficiency virus type 1

tivity of monokines. Science (1985). , 230, 1035-1037.

binding to the CD4 receptor . J Virol 1989; 63:4404–8.

immunodeficiency virus. J ClinEndocrinolMetab. (1994). , 79, 1091-1096.

and review of the literature. Arch Intern Med. (1993). , 153, 393-396.

munocompromised adults. Yale J Biol Med (1987). S, 60, 1.

17, 953-954.

256 Current Perspectives in HIV Infection

65, 482-7.

633-637.

66, 33-8.

rinolMetab (1987). , 64, 98-105.

(1984). , 100, 239-241.


[48] Caron M, Auclair M, Vigouroux C et al. the HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadi‐ pocyte differentiation and induces insulin resistance. Diabetes 2001; 50:1378-88.

[61] Miller, K. K., Daly, P. A., Sentochnik, D., Doweiko, J., Samore, M., Basgoz, N. O., et al., & Pseudo, . Pseudo-Cushing's syndrome in human immunodeficiency virus-in‐

Endocrine Manifestations of HIV Infection http://dx.doi.org/10.5772/52684 259

fected patients. Clin Infect Dis. (1998). , 27, 68-72.


[61] Miller, K. K., Daly, P. A., Sentochnik, D., Doweiko, J., Samore, M., Basgoz, N. O., et al., & Pseudo, . Pseudo-Cushing's syndrome in human immunodeficiency virus-in‐ fected patients. Clin Infect Dis. (1998). , 27, 68-72.

[48] Caron M, Auclair M, Vigouroux C et al. the HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadi‐ pocyte differentiation and induces insulin resistance. Diabetes 2001; 50:1378-88. [49] Tebas, P., Powderly, W. G., Claxton, S., Marin, D., Tantisiriwat, W., Teitelbaum, S. L., et al. Accelerated bone mineral loss in HIV-infected patients receiving potent antire‐

[50] Stagi, S., Bindi, G., Galluzzi, F., Galli, L., Salti, R., & de Martino, M. Changed bone status in human immunodeficiency virus type 1 (HIV-1) perinatally infected children

[51] Glass, A. R., & Eil, C. Ketoconazole-induced reduction in serum 1,25-dihydroxyvita‐ min D. and total serum calcium in hypercalcemic patients. J ClinEndocrinolMetab

[52] Effects of growth hormone-releasing hormone on bone turnover in human immuno‐ deficiency virus-infected men with fat accumulation. J ClinEndocrinolMetab.; ., 90,

[53] Kuehn EW, Anders HJ, Bogner JR, Obermaier J, Goebel FD, Schlöndorff D. Hypocal‐

[54] Adams JS, Fernandez M, Gacad MA, et al. Vitamin D metabolite-mediated hypercal‐ cemia and hypercalciuria in patients with AIDS- and non-AIDS-associated lympho‐

[55] Dodd RC, Newman SL, Bunn PA, Winkler CF, Cohen MS, Gray TK.Lymphokine-in‐ duced monocytic differentiation as a possible mechanism for the hypercalcemia asso‐

[56] Motokura, T., Fukumoto, S., Matsumoto, T., et al. Parathyroid hormone-related pro‐ tein in adult T-cell leukemia-lymphoma. Ann Intern Med (1989). , 111, 484-8.

[57] Wanke, Silva. M., Knox, T. A., Forrester, J., Speigelman, D., & Gorbach, S. L. Weight loss and wasting remain common complications in individuals infected with HIV in the era of highly active antiretroviral therapy. Clin Infect Dis. (2000). , 31, 803-5. [58] Anthropometric indices as predictors of survival in AIDS adults. Aquitaine Cohort, France, 1985-1997. Group d'Epidemiologie Clinique du Sida en Aquitaine (GECSA)

[59] Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR. Lipids, lipo‐ proteins, triglyceride clearance, and cytokines in human immunodeficiency virus in‐ fection and the acquired immunodeficiency syndrome . J ClinEndocrinolMetab 1992;

[60] Macallan, D. E., Noble, C., Baldwin, C., Jebb, S. A., Prentice, A. M., Coward, W. A., et al. Energy expenditure and wasting in human immunodeficiency virus infection. N

cemia in HIV infection and AIDS. J Intern Med. 1999;245:69–73.

ciated with adult T-cell lymph. oma. Cancer Res (1985). , 45, 2501-6.

is related to low serum free IGF-1. ClinEndocrinol (Oxf) (2004). , 61, 692-9.

troviral therapy. AIDS. (2000). F, 63-7.

(1988). , 66, 934-8.

ma . Blood 1989;73:235–9.

Eur J Epidemiol.; ., 16, 633-9.

Engl J Med. (1995). , 333, 83-8.

74:1045–52.

2154-60.

258 Current Perspectives in HIV Infection

**Chapter 12**

**Lipodystrophy: The Metabolic Link of HIV Infection**

Human lipodystrophies are a heterogeneous group of diseases characterized by generalized or partial fat loss. If localized, they are often associated with fat hypertrophy in other depots, varying according to the type of lipodystrophy. Lipodystrophies can be genetic, which is usually uncommon, or acquired. Genetic lipodystrophy is generally related to severe meta‐ bolic alterations including insulin resistance (IR) and its associated complications, such as glucose intolerance and diabetes, dyslipidemia, hepatic steatosis, polycystic ovaries, acan‐ thosis nigricans and early cardiovascular (CV) complications [1, 2]. The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familiar partial lipo‐ dystrophy (FPL) are the two most common types of genetic lipodystrophy [2]. Lipodystro‐ phies have been reported in the medical literature for more than 100 years [2, 3]. However, only 13 years ago, new lipodystrophy syndromes were recognized, being associated with vi‐ ral infection, specifically with the human immunodeficiency virus, in patients treated with combined antiretroviral therapy (cART) [4]. This has become the most frequent form of lipo‐ dystrophy [2]. Some first-generation antiretroviral drugs used in HIV patients are strongly

Human lipodystrophies leads to severe metabolic alterations resulting in premature CV com‐ plications. On the other hand, high adiposity, such as seen in obesity, also increases metabolic alterations and leads to increased CV risk. So, it seems that the two extremes, the absence or the excess of fat mass, are associated with the same metabolic and CV complications. The conse‐ quences of increased fat depots are markedly dependent upon their localization. Adipose tis‐ sue in the lower part of the body is able to expand and can therefore accumulate excessive energy from diet, store triglycerides, and it appears to be protective at the metabolic level [5].

> © 2013 Freitas et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**with Insulin-Resistance Syndrome**

Paula Freitas, Davide Carvalho, Selma Souto, António Sarmento and José Luís Medina

Additional information is available at the end of the chapter

related with peripheral lipoatrophy and metabolic alterations [1].

http://dx.doi.org/10.5772/52685

**1. Introduction**

## **Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome**

Paula Freitas, Davide Carvalho, Selma Souto, António Sarmento and José Luís Medina

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52685

### **1. Introduction**

Human lipodystrophies are a heterogeneous group of diseases characterized by generalized or partial fat loss. If localized, they are often associated with fat hypertrophy in other depots, varying according to the type of lipodystrophy. Lipodystrophies can be genetic, which is usually uncommon, or acquired. Genetic lipodystrophy is generally related to severe meta‐ bolic alterations including insulin resistance (IR) and its associated complications, such as glucose intolerance and diabetes, dyslipidemia, hepatic steatosis, polycystic ovaries, acan‐ thosis nigricans and early cardiovascular (CV) complications [1, 2]. The autosomal recessive congenital generalized lipodystrophy (CGL) and autosomal dominant familiar partial lipo‐ dystrophy (FPL) are the two most common types of genetic lipodystrophy [2]. Lipodystro‐ phies have been reported in the medical literature for more than 100 years [2, 3]. However, only 13 years ago, new lipodystrophy syndromes were recognized, being associated with vi‐ ral infection, specifically with the human immunodeficiency virus, in patients treated with combined antiretroviral therapy (cART) [4]. This has become the most frequent form of lipo‐ dystrophy [2]. Some first-generation antiretroviral drugs used in HIV patients are strongly related with peripheral lipoatrophy and metabolic alterations [1].

Human lipodystrophies leads to severe metabolic alterations resulting in premature CV com‐ plications. On the other hand, high adiposity, such as seen in obesity, also increases metabolic alterations and leads to increased CV risk. So, it seems that the two extremes, the absence or the excess of fat mass, are associated with the same metabolic and CV complications. The conse‐ quences of increased fat depots are markedly dependent upon their localization. Adipose tis‐ sue in the lower part of the body is able to expand and can therefore accumulate excessive energy from diet, store triglycerides, and it appears to be protective at the metabolic level [5].

© 2013 Freitas et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

By contrast, accumulation of fat in the upper part of the body is deleterious. Therefore, de‐ creased peripheral subcutaneous adipose tissue (SAT), and even more increased visceral adi‐ pose tissue (VAT), are strongly associated with metabolic alterations and IR [1].

that 50 % of adipocytes in the human subcutaneous fat mass are replaced approximately ev‐ ery eight years. Preadipocytes are recruited to become lipid-filled mature adipocytes at the same rate that adipocytes die, and in this way the fat mass is in constant flux, and adipocyte number is kept constant. Cellular death of fat cells in white adipose tissue occurs primarily by necrosis-like cell death, which involves macrophage recruitment and a subsequent in‐ flammatory response. This has been implicated in the metabolic complications of obesity. In‐ creased visceral fat mass leads to IR and a low-grade inflammation status in which many

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

263

Adipose tissue is not homogeneous but rather a tissue with specific regional compartments with varying roles and metabolic functions [14]. Individually considered, adipose tissue compartments have stronger associations with physiological and pathological processes than does total adipose tissue mass [15-17]. The upper-body adipose tissue, including viscer‐ al fat, is involved in fat storage after meals and the release of free fatty acids (FFA) between meals to feed the liver, muscles and other organs, therefore sparing glucose for the brain. Visceral fat has a more lipolytic profile than subcutaneous fat. Peripheral lower-body fat, in the femoro-gluteal region, is mainly used for its storage capacity, thereby buffering excess fat [7]. The femoro-gluteal fat depot is relatively insensitive to lipolytic stimuli and highly sensitive to anti-lipolytic stimuli, and may play a protective role by acting as a "sink" for circulating FFA [18]. This uptake of FFA prevents ectopic fat storage in the liver, skeletal muscle, and pancreas, which causes IR and beta-cell dysfunction [19]. The excessive lipolytic capacity of visceral fat (and probably subcutaneous upper-body depots as well) results in a condition referred as lipotoxicity (see section below on lipotoxicity) [7]. The reasons for the lower degree of expansibility of visceral adipocytes remain unknown. Visceral adipose tis‐ sue (VAT) differs histologically from subcutaneous adipose tissue (SAT): it has smaller adi‐ pocytes and a larger supply of nerves and vessels; VAT has many of the characteristics of

Adipose tissue can be subject of different influences and undergo different transformations. SAT has a lower mitochondria content and this contributes to adipocyte apoptosis and therefore, to more lipoatrophy. VAT, with a higher number of resident macrophages [21] and more 11βhydroxysteroid dehydrogenase activity than SAT [22], is predisposed to hy‐ pertrophy. Hypertrophied VAT from HIV-infected patients demonstrates mitochondrial dysfunction but not impairment of adipogenic gene expression in comparison with SAT [23]. cART can differentially alter fat development depending on the environment and phys‐ iology of the different compartments. In the case of lipoatrophy, because peripheral subcuta‐ neous adipocytes cannot store triglycerides, non-lipoatrophic fat depots such as VAT,

Subcutaneous adipocytes seem to be more susceptible to the deleterious effects of protease inhibitors (PIs) than visceral adipocytes [24]. Accordingly, studies performed on control hu‐ man SAT explants reveal that some PIs increase FFA, interleukin – 6 (IL-6) and TNF-α pro‐

probably buffers the increase in FFA, which worsens lipohypertrophy [8].

adipokines and other adipocyte and macrophage factors are involved [13].

brown adipose tissue turned into white adipose tissue [20].

**3. Lipohypertrophy and lipoatrophy**

With regards to the HIV-associated lipodystrophy, the available data suggest that this con‐ dition is caused by a complex interaction involving side effects of cART, disease related in‐ flammation, and individual characteristics [6]. At present, HIV-infected patients are exposed to an increased metabolic risk like the general population, resulting from ageing, increased weight and fat gain, high fat and energy food and marked sedentariness. Moreover, a num‐ ber of additional factors could worsen their metabolic profile, such as the ongoing HIV in‐ fection, the presence of lipodystrophy and the continuous use of antiretroviral drugs [7]. HIV-associated lipodystrophy is also associated with premature aging [8]resembling meta‐ bolic laminopathies and progeria [1]. Premature aging of HIV-infected patients affects bone, brain, vascular wall, muscles, kidney and liver, and results of the combined effects of longterm HIV-1 infection, depleted immune responses, the toxicity of some antiretrovirals and lipodystrophy. Cellular senescence seems to result from prelamin-A accumulation induced by some antiretroviral drugs, mitochondrial dysfunction and oxidative stress. In addition, increased cytokine release in lipodystrophy further contributes to premature aging and therefore, to early CV and hepatic disease risks [9].

We focus on adipocytes dysregulation in genetic and acquired lipodystrophy, with empha‐ sis on the most common form, HIV-lipodystrophy, fromthe etiology to its complications.

### **2. Adipose tissue biology –Three different adipose tissue compartments**

Adipocytes are a dynamic and highly regulated population of cells. Adipose tissue is char‐ acterized by a marked cellular heterogeneity among its cellular components: adipocytes, preadipocytes, fibroblasts, macrophages, lymphocytes, endothelial cells and multipotent stem cells, able to differentiate into several cell types. Adipose tissue can release regulatory factors (adipokines, cytokines, or chemokines) or metabolites (FFAs) capable of influencing other surrounding cells, thus establishing active cross-talk among cells within adipose tis‐ sue. [9]. Overall, fat tissue consists of approximately one third mature adipocytes. The re‐ maining two thirds are a combination of small blood vessels, nerve tissue, fibroblasts and preadipocytes in various stages of development. Preadipocytes have the ability to prolifer‐ ate and differentiate into mature adipocytes, conferring a constant functional plasticity on adipose tissue [10]. Preadipocytes mature in two steps: differentiation and then hypertro‐ phy. During the early maturation stage, an increased number of mitochondria are required [11, 12], resulting in small adipocytes, which are highly sensitive to insulin and that secrete high levels of adiponectin [12]. By contrast, older adipocytes increase in size (hypertrophy), their functional activities are lost and they become resistant to insulin. These adipocytes also exhibit decreased numbers of mitochondria with impaired mitochondrial reactive oxygen species (ROS) generated by the respiratory chain, which could have dual effects on adipo‐ cyte differentiation. New adipocytes form constantly to replace lost adipocytes, to the extent that 50 % of adipocytes in the human subcutaneous fat mass are replaced approximately ev‐ ery eight years. Preadipocytes are recruited to become lipid-filled mature adipocytes at the same rate that adipocytes die, and in this way the fat mass is in constant flux, and adipocyte number is kept constant. Cellular death of fat cells in white adipose tissue occurs primarily by necrosis-like cell death, which involves macrophage recruitment and a subsequent in‐ flammatory response. This has been implicated in the metabolic complications of obesity. In‐ creased visceral fat mass leads to IR and a low-grade inflammation status in which many adipokines and other adipocyte and macrophage factors are involved [13].

Adipose tissue is not homogeneous but rather a tissue with specific regional compartments with varying roles and metabolic functions [14]. Individually considered, adipose tissue compartments have stronger associations with physiological and pathological processes than does total adipose tissue mass [15-17]. The upper-body adipose tissue, including viscer‐ al fat, is involved in fat storage after meals and the release of free fatty acids (FFA) between meals to feed the liver, muscles and other organs, therefore sparing glucose for the brain. Visceral fat has a more lipolytic profile than subcutaneous fat. Peripheral lower-body fat, in the femoro-gluteal region, is mainly used for its storage capacity, thereby buffering excess fat [7]. The femoro-gluteal fat depot is relatively insensitive to lipolytic stimuli and highly sensitive to anti-lipolytic stimuli, and may play a protective role by acting as a "sink" for circulating FFA [18]. This uptake of FFA prevents ectopic fat storage in the liver, skeletal muscle, and pancreas, which causes IR and beta-cell dysfunction [19]. The excessive lipolytic capacity of visceral fat (and probably subcutaneous upper-body depots as well) results in a condition referred as lipotoxicity (see section below on lipotoxicity) [7]. The reasons for the lower degree of expansibility of visceral adipocytes remain unknown. Visceral adipose tis‐ sue (VAT) differs histologically from subcutaneous adipose tissue (SAT): it has smaller adi‐ pocytes and a larger supply of nerves and vessels; VAT has many of the characteristics of brown adipose tissue turned into white adipose tissue [20].

### **3. Lipohypertrophy and lipoatrophy**

By contrast, accumulation of fat in the upper part of the body is deleterious. Therefore, de‐ creased peripheral subcutaneous adipose tissue (SAT), and even more increased visceral adi‐

With regards to the HIV-associated lipodystrophy, the available data suggest that this con‐ dition is caused by a complex interaction involving side effects of cART, disease related in‐ flammation, and individual characteristics [6]. At present, HIV-infected patients are exposed to an increased metabolic risk like the general population, resulting from ageing, increased weight and fat gain, high fat and energy food and marked sedentariness. Moreover, a num‐ ber of additional factors could worsen their metabolic profile, such as the ongoing HIV in‐ fection, the presence of lipodystrophy and the continuous use of antiretroviral drugs [7]. HIV-associated lipodystrophy is also associated with premature aging [8]resembling meta‐ bolic laminopathies and progeria [1]. Premature aging of HIV-infected patients affects bone, brain, vascular wall, muscles, kidney and liver, and results of the combined effects of longterm HIV-1 infection, depleted immune responses, the toxicity of some antiretrovirals and lipodystrophy. Cellular senescence seems to result from prelamin-A accumulation induced by some antiretroviral drugs, mitochondrial dysfunction and oxidative stress. In addition, increased cytokine release in lipodystrophy further contributes to premature aging and

We focus on adipocytes dysregulation in genetic and acquired lipodystrophy, with empha‐ sis on the most common form, HIV-lipodystrophy, fromthe etiology to its complications.

**2. Adipose tissue biology –Three different adipose tissue compartments**

Adipocytes are a dynamic and highly regulated population of cells. Adipose tissue is char‐ acterized by a marked cellular heterogeneity among its cellular components: adipocytes, preadipocytes, fibroblasts, macrophages, lymphocytes, endothelial cells and multipotent stem cells, able to differentiate into several cell types. Adipose tissue can release regulatory factors (adipokines, cytokines, or chemokines) or metabolites (FFAs) capable of influencing other surrounding cells, thus establishing active cross-talk among cells within adipose tis‐ sue. [9]. Overall, fat tissue consists of approximately one third mature adipocytes. The re‐ maining two thirds are a combination of small blood vessels, nerve tissue, fibroblasts and preadipocytes in various stages of development. Preadipocytes have the ability to prolifer‐ ate and differentiate into mature adipocytes, conferring a constant functional plasticity on adipose tissue [10]. Preadipocytes mature in two steps: differentiation and then hypertro‐ phy. During the early maturation stage, an increased number of mitochondria are required [11, 12], resulting in small adipocytes, which are highly sensitive to insulin and that secrete high levels of adiponectin [12]. By contrast, older adipocytes increase in size (hypertrophy), their functional activities are lost and they become resistant to insulin. These adipocytes also exhibit decreased numbers of mitochondria with impaired mitochondrial reactive oxygen species (ROS) generated by the respiratory chain, which could have dual effects on adipo‐ cyte differentiation. New adipocytes form constantly to replace lost adipocytes, to the extent

pose tissue (VAT), are strongly associated with metabolic alterations and IR [1].

therefore, to early CV and hepatic disease risks [9].

262 Current Perspectives in HIV Infection

Adipose tissue can be subject of different influences and undergo different transformations. SAT has a lower mitochondria content and this contributes to adipocyte apoptosis and therefore, to more lipoatrophy. VAT, with a higher number of resident macrophages [21] and more 11βhydroxysteroid dehydrogenase activity than SAT [22], is predisposed to hy‐ pertrophy. Hypertrophied VAT from HIV-infected patients demonstrates mitochondrial dysfunction but not impairment of adipogenic gene expression in comparison with SAT [23]. cART can differentially alter fat development depending on the environment and phys‐ iology of the different compartments. In the case of lipoatrophy, because peripheral subcuta‐ neous adipocytes cannot store triglycerides, non-lipoatrophic fat depots such as VAT, probably buffers the increase in FFA, which worsens lipohypertrophy [8].

Subcutaneous adipocytes seem to be more susceptible to the deleterious effects of protease inhibitors (PIs) than visceral adipocytes [24]. Accordingly, studies performed on control hu‐ man SAT explants reveal that some PIs increase FFA, interleukin – 6 (IL-6) and TNF-α pro‐ duction through the activation of the proinflammatory nuclear factor – kB (NFkB) pathway. This PI-induced deleterious paracrine loop, between adipocytes and macrophages, similar to the observed in obesity, is not seen in VAT. These data indicate that SAT is more sensitive to the adverse effects of some PIs than VAT [8].

affected by molecules involved in signal transduction as well as drugs, compared with vis‐

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

265

Lipoatrophic adipose tissue is known to be characterized by smaller adipocytes, greater cell size variation, disruption of cell membranes, and signs of apoptosis as determined by immu‐ nohistochemistry staining, when compared with non-lipodystrophic adipose tissue. There is a marked difference in gene expression between dorsocervical and abdominal SAT, irrespec‐ tive of the lipodystrophy status, that lies in the expression of homeobox genes involved in organogenesis and regionalization. Disparate expression of such fundamental regulators of transcription might ultimately contribute to different patterns of differentiation and affect the susceptibility of the adipose tissue depot to cART-induced toxicity, perhaps making the

abdominal subcutaneous and femoro-gluteal depot more vulnerable to atrophy [27].

Morphologic alterations in lipoatrophy-prone areas of SAT have been confirmed at the level of gene expression [9]. Most studies report that these lipoatrophic areas show an abnormally low expression of the major adipogenic transcription factors peroxisome proliferator-activat‐ ed receptor -γ (PPARγ), sterol-regulatory element binding protein-1 (SREBP-1), and CCAAT/enhancer-binding protein-α (C/EBPα) [28-30]. Consequently, the expression of adi‐ pogenic differentiation-related genes is also decreased. For example, there is a reduction in the expression of genes for lipoprotein lipase and for the insulin-sensitive glucose transport‐ er GLUT 4 [28, 29], resulting in impaired fatty acid and glucose uptake, respectively, and thus leading to a deficit in the lipid-accretion capacity of SAT. Another major alteration de‐ tected, which is probably related to the impaired adipogenic gene expression, is reduced ex‐ pression of the adipokine genes adiponectin and leptin [28, 29]. In addition to impaired expression of adipogenetic–related genes, adipose tissue from patients with lipodystrophy, mainly those receiving NRTIs [31, 32] also show a reduction in mitochondrial DNA (mtDNA) levels. This decrease is associated with complex alterations in mitochondrial func‐ tion, such as reduced expression of mtDNA-encoded transcripts and compensatory up-reg‐ ulation of dysfunctional mitochondrial mass, that likely reduce the endogenous oxidative capacity of adipose tissue [33]. Moreover, increased oxidative stress and apoptosis have also been reported in lipoatrophic SAT [34]. Lipoatrophy is also accompanied by a state of chron‐ ic low-level inflammation [35]. High levels of expression of the inflammatory markers, TNFα, IL- 6; IL-8 and IL-18 have been reported in SAT from HIV-1-infected lipoatrophic patients [28, 30, 35-37]. Expression of TNFα and IL-6 mRNA in SAT of lipodystrophic patients corre‐ lates positively with tissue apoptosis and negatively with adipogenic marker expression, which is consistent with a role for pro-inflammatory cytokines in adipocyte viability and differentiation [30]. Unlike SAT, VAT did not exhibit impaired expression of adipogenic marker genes. However, it did show some similar changes in inflammatory markers, such as induction of TNF-α, whereas others differed from that of SAT, such as, for instance, lack of monocyte chemoattractant protein -1 (MCP-1] induction. In contrast, mitochondrial dys‐ function in VAT was found to be similar to that in SAT. Therefore, mtDNA depletion and signs of altered mitochondrial function are common to atrophic (subcutaneous) and hyper‐ trophic (visceral, dorsocervical) depots in HIV-1 lipodystrophy, indicating that mitochondri‐ al impairment cannot explain in a simple manner the final outcome for adipose depots, either in terms of lipoatrophy or lipohypertrophy [23]. Taken together, these observations indicate that different responses occurring in subcutaneous and visceral fat depots in lipo‐

ceral white adipose tissue [13].

### **4. Adipogenesis**

Individuals can differ remarkably in body fat distribution and the known differences in FFA uptake of adipose tissue compartments play a role in this difference. Premenopausal female SAT takes up more FFAs than male [25] and upper-body SAT takes up FFAs more avidly than femoral fat in men, but not in women. Gene expression, mRNA transcription of FA transporters and consequently facilitated FA transport was greater in the upper body in men and in the femoro-gluteal region in women. This novel FFA disposal pathway may also play a role in the development or maintenance of body fat distribution. On the other hand, direct FFA uptake in subcutaneous fat differs from fatty acid uptake from a meal in two respects: 1) direct FFA uptake is more efficient in women than in men and 2) in men there is no pref‐ erential direct FFA uptake in upper-body subcutaneous fat compared with femoral fat in women. These gender-based differences are consistent with this process as a mechanism to develop or maintain variations of body fat distribution between men and women, both lean and obese.The greater direct FFA uptake in abdominal over femoral fat in men could be due to the greater facilitation of inward fatty acid transport. Contrary to what is generally be‐ lieved, upper-body subcutaneous fat releases ~70 % of systemic FFAs in lean men and wom‐ en, whereas the leg contributes only ~20%; fatty acid uptake from a meal follows a similar pattern [26]. In non-obese men, the direct uptake/storage of FFAs in upper-body and leg fat mirrors this regional difference in FFA release, whereas in lean women, direct FFA uptake was similar in upper-body and femoral adipose tissue. This imbalance between release and direct reuptake in women could redistribute fatty acids toward leg fat. In obese women, the total FFA reuptake in leg fat was also significantly greater than in upper-body fat. It may be that some populations of fat cells, such as the smaller adipocytes, take up but do not actively release FFAs, whereas larger fat cells briskly release FFAs and do not take up FFAs under post-absorptive circumstances. In summary, there is a mechanism for adipocyte fatty acid uptake and storage that has yet to be understood, but which is independent of lipoprotein lipase and it's not thought to exist in the post-absorptive state [25].

Macrophage infiltration of the human adipose organ is a well-documented phenomenon that induces a low-grade chronic inflammation that is associated with IR. This reaction ap‐ pears to be related mainly to macrophage-produced cytokines (TNF-α and IL-6] capable of interfering with the normal activity of insulin receptors. The greater amount of macrophages and macrophage-secreted cytokines found in visceral fat is in line with the greater morbidity associated with these depots. Subcutaneous and visceral adipocytes have cell-autonomous properties due to inherently different progenitor cells that exhibit a different gene expres‐ sion pattern. Subcutaneous white adipose tissue responds better to the anti-lipolytic effects of insulin, secretes more adiponectin and less inflammatory cytokines, and is differentially affected by molecules involved in signal transduction as well as drugs, compared with vis‐ ceral white adipose tissue [13].

duction through the activation of the proinflammatory nuclear factor – kB (NFkB) pathway. This PI-induced deleterious paracrine loop, between adipocytes and macrophages, similar to the observed in obesity, is not seen in VAT. These data indicate that SAT is more sensitive

Individuals can differ remarkably in body fat distribution and the known differences in FFA uptake of adipose tissue compartments play a role in this difference. Premenopausal female SAT takes up more FFAs than male [25] and upper-body SAT takes up FFAs more avidly than femoral fat in men, but not in women. Gene expression, mRNA transcription of FA transporters and consequently facilitated FA transport was greater in the upper body in men and in the femoro-gluteal region in women. This novel FFA disposal pathway may also play a role in the development or maintenance of body fat distribution. On the other hand, direct FFA uptake in subcutaneous fat differs from fatty acid uptake from a meal in two respects: 1) direct FFA uptake is more efficient in women than in men and 2) in men there is no pref‐ erential direct FFA uptake in upper-body subcutaneous fat compared with femoral fat in women. These gender-based differences are consistent with this process as a mechanism to develop or maintain variations of body fat distribution between men and women, both lean and obese.The greater direct FFA uptake in abdominal over femoral fat in men could be due to the greater facilitation of inward fatty acid transport. Contrary to what is generally be‐ lieved, upper-body subcutaneous fat releases ~70 % of systemic FFAs in lean men and wom‐ en, whereas the leg contributes only ~20%; fatty acid uptake from a meal follows a similar pattern [26]. In non-obese men, the direct uptake/storage of FFAs in upper-body and leg fat mirrors this regional difference in FFA release, whereas in lean women, direct FFA uptake was similar in upper-body and femoral adipose tissue. This imbalance between release and direct reuptake in women could redistribute fatty acids toward leg fat. In obese women, the total FFA reuptake in leg fat was also significantly greater than in upper-body fat. It may be that some populations of fat cells, such as the smaller adipocytes, take up but do not actively release FFAs, whereas larger fat cells briskly release FFAs and do not take up FFAs under post-absorptive circumstances. In summary, there is a mechanism for adipocyte fatty acid uptake and storage that has yet to be understood, but which is independent of lipoprotein

lipase and it's not thought to exist in the post-absorptive state [25].

Macrophage infiltration of the human adipose organ is a well-documented phenomenon that induces a low-grade chronic inflammation that is associated with IR. This reaction ap‐ pears to be related mainly to macrophage-produced cytokines (TNF-α and IL-6] capable of interfering with the normal activity of insulin receptors. The greater amount of macrophages and macrophage-secreted cytokines found in visceral fat is in line with the greater morbidity associated with these depots. Subcutaneous and visceral adipocytes have cell-autonomous properties due to inherently different progenitor cells that exhibit a different gene expres‐ sion pattern. Subcutaneous white adipose tissue responds better to the anti-lipolytic effects of insulin, secretes more adiponectin and less inflammatory cytokines, and is differentially

to the adverse effects of some PIs than VAT [8].

**4. Adipogenesis**

264 Current Perspectives in HIV Infection

Lipoatrophic adipose tissue is known to be characterized by smaller adipocytes, greater cell size variation, disruption of cell membranes, and signs of apoptosis as determined by immu‐ nohistochemistry staining, when compared with non-lipodystrophic adipose tissue. There is a marked difference in gene expression between dorsocervical and abdominal SAT, irrespec‐ tive of the lipodystrophy status, that lies in the expression of homeobox genes involved in organogenesis and regionalization. Disparate expression of such fundamental regulators of transcription might ultimately contribute to different patterns of differentiation and affect the susceptibility of the adipose tissue depot to cART-induced toxicity, perhaps making the abdominal subcutaneous and femoro-gluteal depot more vulnerable to atrophy [27].

Morphologic alterations in lipoatrophy-prone areas of SAT have been confirmed at the level of gene expression [9]. Most studies report that these lipoatrophic areas show an abnormally low expression of the major adipogenic transcription factors peroxisome proliferator-activat‐ ed receptor -γ (PPARγ), sterol-regulatory element binding protein-1 (SREBP-1), and CCAAT/enhancer-binding protein-α (C/EBPα) [28-30]. Consequently, the expression of adi‐ pogenic differentiation-related genes is also decreased. For example, there is a reduction in the expression of genes for lipoprotein lipase and for the insulin-sensitive glucose transport‐ er GLUT 4 [28, 29], resulting in impaired fatty acid and glucose uptake, respectively, and thus leading to a deficit in the lipid-accretion capacity of SAT. Another major alteration de‐ tected, which is probably related to the impaired adipogenic gene expression, is reduced ex‐ pression of the adipokine genes adiponectin and leptin [28, 29]. In addition to impaired expression of adipogenetic–related genes, adipose tissue from patients with lipodystrophy, mainly those receiving NRTIs [31, 32] also show a reduction in mitochondrial DNA (mtDNA) levels. This decrease is associated with complex alterations in mitochondrial func‐ tion, such as reduced expression of mtDNA-encoded transcripts and compensatory up-reg‐ ulation of dysfunctional mitochondrial mass, that likely reduce the endogenous oxidative capacity of adipose tissue [33]. Moreover, increased oxidative stress and apoptosis have also been reported in lipoatrophic SAT [34]. Lipoatrophy is also accompanied by a state of chron‐ ic low-level inflammation [35]. High levels of expression of the inflammatory markers, TNFα, IL- 6; IL-8 and IL-18 have been reported in SAT from HIV-1-infected lipoatrophic patients [28, 30, 35-37]. Expression of TNFα and IL-6 mRNA in SAT of lipodystrophic patients corre‐ lates positively with tissue apoptosis and negatively with adipogenic marker expression, which is consistent with a role for pro-inflammatory cytokines in adipocyte viability and differentiation [30]. Unlike SAT, VAT did not exhibit impaired expression of adipogenic marker genes. However, it did show some similar changes in inflammatory markers, such as induction of TNF-α, whereas others differed from that of SAT, such as, for instance, lack of monocyte chemoattractant protein -1 (MCP-1] induction. In contrast, mitochondrial dys‐ function in VAT was found to be similar to that in SAT. Therefore, mtDNA depletion and signs of altered mitochondrial function are common to atrophic (subcutaneous) and hyper‐ trophic (visceral, dorsocervical) depots in HIV-1 lipodystrophy, indicating that mitochondri‐ al impairment cannot explain in a simple manner the final outcome for adipose depots, either in terms of lipoatrophy or lipohypertrophy [23]. Taken together, these observations indicate that different responses occurring in subcutaneous and visceral fat depots in lipo‐ dystrophic patients are likely to be related to intrinsic differences in fat physiology and/or capacity to react to the same insult. One adipose depot (visceral) enlarges in size and ap‐ proaches its fat storage capacity threshold (as in obesity) merely because another adipose depot (subcutaneous) cannot [38]. A direct role for HIV-1 infection has been proposed by an‐ alyzing SAT from untreated HIV-1-infected patients ("naïve") as compared to healthy con‐ trols. Early histological studies did not indicate clear mitochondrial or inflammatory-related disturbances [39], but subsequent gene expression studies have shown a significant decrease in the expression of the adipocyte differentiation controller PPARγ and some impairment in the expression of genes encoding mitochondrial proteins and proteins specifically related to adipocyte metabolism, including adiponectin and 11β-steroid dehydrogenase type-1, the en‐ zyme responsible for glucocorticoid activation [9, 29]. Some signs of inflammatory response have also been reported [29]. All these alterations are further enhanced in SAT oflipody‐ strophic patients. Therefore, it appears that HIV-1 infection initiates a first wave of altera‐ tions in adipose tissue that is amplified by cART and ultimately results in lipoatrophy [9].

### **5. Congenital generalized lipodystrophies**

Generalized lipodystrophies are rare disorders that may be congenital or acquired. The ge‐ netic lipodystrophies have been reported in about 1000 patients [2]. The congenital general‐ ized lipodystrophy (CGL) Berardinelli-Seip syndrome (BSCL), is an autosomal recessive disorder initially reported by Berardinelli [3] and Seip [40] with frequent parental consan‐ guinity [41-44]. It has been proposed that Berardinelli-Seip syndrome could be a Portuguese disease, later spread by the Portuguese across the world [45].

**A** 

and may also be involved in adipocyte differentiation [49-51].

**6. Mortality in generalized lipodystrophies**

**Figure 1.** A: Two sisters with Berardinelli-Seip syndrome B: Women with Berardinelli-Seip syndrome

biogenesis of caveolae and regulates expression of caveolins 1 and 3 [53].

Type 2 CGL is due to BSCL2 gene mutations. This gene is located in chromosome11q13 and encodes a protein called seipin [48]. Seipin appears to play a role in lipid droplet formation

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

267

Patients with BSCL2 mutations have the most severe variety of CGL and are born without any body fat [2]. Two other genes were identified for CGL: caveolin 1 (CAV1) [52] and poly‐ merase I and transcript release factor (PTRF) [53]. Caveolin 1 is the main component of cav‐ eolae, specialized microdomains seen in abundance on adipocyte membranes [54]. It binds fatty acids and translocates them to lipid droplets. PTRF (also known as cavin) is involved in

Patients with generalized lipodystrophies are predisposed to develop acute pancreatitis, cir‐ rhosis, endstage diabetic renal disease requiring transplantation, and blindness due to diabet‐ ic retinopathy. Many patients with FPL die of coronary heart disease or cardiomyopathy and rhythm disturbances [55-57]. Sudden death has been reported during childhood in CGL, type 4, likely due to arrhythmias [58]. Patients with HIV-lipodystrophy are predisposed to develop‐

Patients with CGL are recognized at birth or soon thereafter due to a near-total lack of body fat and prominent muscularity that causes a severe and striking phenotype (Figure 2A and 2B). Diabetes develops during infancy or most often during the teenage years. Hepatosple‐ nomegaly, umbilical prominence or hernia, acanthosis nigricans, voracious appetite and ac‐ celerated growth can occur. Female patients develop hirsutism, may have clitoromegaly, oligomenorrhea and polycystic ovaries. Other uncommon manifestations include hypertro‐ phic cardiomyopathy, mild mental retardation, and focal lytic lesions in the appendicular bones after puberty [41, 42]. Diabetes and its complications, hyperlipidemia and recurrent attacks of acute pancreatitis, hepatic steatosis and occasionally cirrhosis are the causes of morbidity and mortality [2].

At least 4 molecularly distinct forms of congenital lipodystrophy have been defined, with the mutations of the enzyme acyltransferase 1-acylglycerol-3-phosphate O- acyltransferase 2 (AGPAT2) or (BSCL1- locus 1) and Berardinelli-Seip (BSCL2 - locus 2) being both responsi‐ ble for 95 % of gene mutations. AGPAT2 has been mapped in chromosomes 9q34. AGPATs are critical enzymes involved in the biosynthesis of triglycerides and phospholipids from glycerol-3-phosphate. They catalyze acylation of fatty acids at the sn-2 position of glycerol moiety and convert lysophosphatidic acid to phosphatidic acid [2, 46]. AGPAT2 is highly ex‐ pressed in the adipose tissue, and its deficiency may cause lipodystrophy by limiting trigly‐ ceride or phospholipid biosynthesis [47].

**Figure 1.** A: Two sisters with Berardinelli-Seip syndrome B: Women with Berardinelli-Seip syndrome

Type 2 CGL is due to BSCL2 gene mutations. This gene is located in chromosome11q13 and encodes a protein called seipin [48]. Seipin appears to play a role in lipid droplet formation and may also be involved in adipocyte differentiation [49-51].

Patients with BSCL2 mutations have the most severe variety of CGL and are born without any body fat [2]. Two other genes were identified for CGL: caveolin 1 (CAV1) [52] and poly‐ merase I and transcript release factor (PTRF) [53]. Caveolin 1 is the main component of cav‐ eolae, specialized microdomains seen in abundance on adipocyte membranes [54]. It binds fatty acids and translocates them to lipid droplets. PTRF (also known as cavin) is involved in biogenesis of caveolae and regulates expression of caveolins 1 and 3 [53].

### **6. Mortality in generalized lipodystrophies**

dystrophic patients are likely to be related to intrinsic differences in fat physiology and/or capacity to react to the same insult. One adipose depot (visceral) enlarges in size and ap‐ proaches its fat storage capacity threshold (as in obesity) merely because another adipose depot (subcutaneous) cannot [38]. A direct role for HIV-1 infection has been proposed by an‐ alyzing SAT from untreated HIV-1-infected patients ("naïve") as compared to healthy con‐ trols. Early histological studies did not indicate clear mitochondrial or inflammatory-related disturbances [39], but subsequent gene expression studies have shown a significant decrease in the expression of the adipocyte differentiation controller PPARγ and some impairment in the expression of genes encoding mitochondrial proteins and proteins specifically related to adipocyte metabolism, including adiponectin and 11β-steroid dehydrogenase type-1, the en‐ zyme responsible for glucocorticoid activation [9, 29]. Some signs of inflammatory response have also been reported [29]. All these alterations are further enhanced in SAT oflipody‐ strophic patients. Therefore, it appears that HIV-1 infection initiates a first wave of altera‐ tions in adipose tissue that is amplified by cART and ultimately results in lipoatrophy [9].

Generalized lipodystrophies are rare disorders that may be congenital or acquired. The ge‐ netic lipodystrophies have been reported in about 1000 patients [2]. The congenital general‐ ized lipodystrophy (CGL) Berardinelli-Seip syndrome (BSCL), is an autosomal recessive disorder initially reported by Berardinelli [3] and Seip [40] with frequent parental consan‐ guinity [41-44]. It has been proposed that Berardinelli-Seip syndrome could be a Portuguese

Patients with CGL are recognized at birth or soon thereafter due to a near-total lack of body fat and prominent muscularity that causes a severe and striking phenotype (Figure 2A and 2B). Diabetes develops during infancy or most often during the teenage years. Hepatosple‐ nomegaly, umbilical prominence or hernia, acanthosis nigricans, voracious appetite and ac‐ celerated growth can occur. Female patients develop hirsutism, may have clitoromegaly, oligomenorrhea and polycystic ovaries. Other uncommon manifestations include hypertro‐ phic cardiomyopathy, mild mental retardation, and focal lytic lesions in the appendicular bones after puberty [41, 42]. Diabetes and its complications, hyperlipidemia and recurrent attacks of acute pancreatitis, hepatic steatosis and occasionally cirrhosis are the causes of

At least 4 molecularly distinct forms of congenital lipodystrophy have been defined, with the mutations of the enzyme acyltransferase 1-acylglycerol-3-phosphate O- acyltransferase 2 (AGPAT2) or (BSCL1- locus 1) and Berardinelli-Seip (BSCL2 - locus 2) being both responsi‐ ble for 95 % of gene mutations. AGPAT2 has been mapped in chromosomes 9q34. AGPATs are critical enzymes involved in the biosynthesis of triglycerides and phospholipids from glycerol-3-phosphate. They catalyze acylation of fatty acids at the sn-2 position of glycerol moiety and convert lysophosphatidic acid to phosphatidic acid [2, 46]. AGPAT2 is highly ex‐ pressed in the adipose tissue, and its deficiency may cause lipodystrophy by limiting trigly‐

**5. Congenital generalized lipodystrophies**

disease, later spread by the Portuguese across the world [45].

morbidity and mortality [2].

266 Current Perspectives in HIV Infection

ceride or phospholipid biosynthesis [47].

Patients with generalized lipodystrophies are predisposed to develop acute pancreatitis, cir‐ rhosis, endstage diabetic renal disease requiring transplantation, and blindness due to diabet‐ ic retinopathy. Many patients with FPL die of coronary heart disease or cardiomyopathy and rhythm disturbances [55-57]. Sudden death has been reported during childhood in CGL, type 4, likely due to arrhythmias [58]. Patients with HIV-lipodystrophy are predisposed to develop‐ ing coronary heart disease [59]. Patients with congenital Berardinelli-Seip lipodystrophy fre‐ quently develop hypertrophic cardiomyopathy that can lead to death from cardiac failure [41]. In individuals with BSCL, ventricular dysfunction and hypertrophic cardiomyopathy are of‐ ten observed. In cardiac biopsies performed in eight individuals with BSCL, the presence of subendocardial fibrosis and an abnormal architecture in the left ventricular lumen was ob‐ served [60, 61]. Hypertrophic cardiomyopathy in BSCL patients has been correlated with high plasmatic insulin levels, which activate the type 1 insulin-like growth receptors, present in large quantities in the myocardial tissue, that stimulate cell growth [62, 63]. In addition, the presence of IR and hypertriglyceridemia in individuals with BSCL may predispose them to premature atherosclerosis. Individuals who have mutations on chromosome 11 (BSCL2) seemed to present more severe symptoms than those who had mutations in BSCL1, with a high incidence of premature deaths. Cardiomyopathy was three times more frequent in those with BSCL2 mutations than in individuals with alterations in BSCL1 [42].

norrhea, hirsutism, polycystic ovarian syndrome, mild to moderate myopathy, cardiomyop‐ athy, and conduction system abnormalities indicative of multisystem dystrophy can occur [2, 55, 56, 77]. The identification of the first gene for FPL, Dunnigan variety, i.e. LMNA, on chro‐ mosome 1q21-22 [2, 78-81], an integral component of nuclear lamin, was made in 1998. There‐ after, four other genes were identified: PPARγ [82-84], a key transcription factor involved in adipocyte differentiation; v-AKT murine thymoma oncogene homolog 2 (AKT2) [85], in‐ volved in downstream insulin signaling; and cell death-inducing DNA fragmentation factor alike effector c (CIDEC) [86] and perilipin 1 (PLIN1) [87], both involved in lipid droplet formation [2, 88]. Adipocyte loss is due to premature cell death resulting from disruption of the nuclear envelope [87, 89]. Defective adipocyte differentiation seems to be the cause of the lipo‐ dystrophy of PPARγ and AKT2 mutations. Fibrosis of adipose tissue with small adipocytes is

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

269

There are other rare genetic syndromes whose molecular basis remains unknown, namely atypical progeroid syndrome [90], Hutchinson-Gilford progeria syndrome [91], SHORT-as‐

Patients with FPL syndromes display mixed lipodystrophy with subcutaneous lipoatrophy and central fat accumulation. Those with FPLD2 also have an increased amount of fat in the cervico-facial area compared to patients without these mutations. Therefore, a single protein mutation leads to two opposing fat localization phenotypes [8]. Importantly, mutations in LMNA are also responsible for metabolic laminopathies resembling the metabolic syndrome (MS) and Hutchinson-Gilford progeria, a severe syndrome of premature aging [94]. Prelamin A is implicated in increased oxidative stress and in the occurrence of cellular senescence [8].

The onset of subcutaneous fat loss in patients with AGL usually occurs during childhood [95]. The pattern and extent of fat loss is quite variable and most patients have generalized loss of fat, but a few of them have areas such as intra-abdominal and bone marrow fat spared. AGL patients are highly likely to develop severe hepatic steatosis and fibrosis, dia‐ betes, and hypertriglyceridemia [2]. The pathogenesis of fat loss remains unknown. Panni‐ culitis may precede loss of fat. Lipodystrophy can be associated with autoimmune diseases such as juvenile dermatomyositis [95]. Chronic hepatitis with autoimmune features and low serum complement 4 levels, suggesting involvement of the classical complement pathway in

Fat loss occurs gradually in a symmetric fashion, first affecting the face and then spreading downward. Most patients lose fat from the face, neck, upper extremities, and trunk, and subcutaneous fat from the lower abdomen and legs is spared. Many patients accumulate ex‐

sociated lipodystrophy [92], and Wiedemann-Rautenstrauch syndrome [93].

**10.1. Acquired Generalized Lipodystrophy(AGL) – Lawrence syndrome**

**10.2. Acquired partial lipodystrophy–Barraquer-Simons syndrome**

responsible for the lipodystrophy of PLIN1 mutations [2, 87].

**10. Acquired lipodystrophies**

the pathogenesis of fat loss, has been reported [96].

### **7. Mandibuloacral Dysplasia (MAD)-associated lipodystrophy**

MAD is characterized by skeletal abnormalities such as mandibular and clavicular hypoplasia and acroosteolysis [64], progeroid manifestations, partial or generalized lipodystrophy and metabolic complications, among other clinical features [65, 66]. Patients with MAD harbor mu‐ tations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) [67, 68]. ZMPSTE24 is in‐ volved in post-translational proteolytic processing of prelamin A to mature laminA [2].

### **8. Autoinflammatory syndromes**

A syndrome of joint contractures, muscle atrophy, microcytic anemia, and panniculitis-in‐ duced (JMP) lipodystrophy was reported by Garg in three patients, belonging to two pedi‐ grees, who were from Portugal and Mexico [69]. Three other patients have been reported from Japan [70, 71]. Mutations in PSMB8 may trigger an autoinflammatory response resulting in in‐ filtration of adipose tissue with lymphocytes and other immune cells and adipocytes [2]. The other autoinflammatory syndrome is the chronic atypical neutrophilic dermatosis with lipo‐ dystrophy and elevated temperature (CANDLE) syndrome. The mode of inheritance seems to be autosomal recessive, but the molecular basis remains unknown [2, 72, 73].

### **9. Familial Partial Lipodystrophy(FPL)**

FPL is characterized by the onset of fat loss from the limbs and other regions of the body, usu‐ ally during childhood, adolescence or adulthood. Many regions of the body, such as the face, neck, and intra-abdominal region are spared, and patients accumulate excess body fat in the non-lipodystrophic regions [74-76]. Metabolic complications, acanthosis nigricans, oligoame‐ norrhea, hirsutism, polycystic ovarian syndrome, mild to moderate myopathy, cardiomyop‐ athy, and conduction system abnormalities indicative of multisystem dystrophy can occur [2, 55, 56, 77]. The identification of the first gene for FPL, Dunnigan variety, i.e. LMNA, on chro‐ mosome 1q21-22 [2, 78-81], an integral component of nuclear lamin, was made in 1998. There‐ after, four other genes were identified: PPARγ [82-84], a key transcription factor involved in adipocyte differentiation; v-AKT murine thymoma oncogene homolog 2 (AKT2) [85], in‐ volved in downstream insulin signaling; and cell death-inducing DNA fragmentation factor alike effector c (CIDEC) [86] and perilipin 1 (PLIN1) [87], both involved in lipid droplet formation [2, 88]. Adipocyte loss is due to premature cell death resulting from disruption of the nuclear envelope [87, 89]. Defective adipocyte differentiation seems to be the cause of the lipo‐ dystrophy of PPARγ and AKT2 mutations. Fibrosis of adipose tissue with small adipocytes is responsible for the lipodystrophy of PLIN1 mutations [2, 87].

There are other rare genetic syndromes whose molecular basis remains unknown, namely atypical progeroid syndrome [90], Hutchinson-Gilford progeria syndrome [91], SHORT-as‐ sociated lipodystrophy [92], and Wiedemann-Rautenstrauch syndrome [93].

Patients with FPL syndromes display mixed lipodystrophy with subcutaneous lipoatrophy and central fat accumulation. Those with FPLD2 also have an increased amount of fat in the cervico-facial area compared to patients without these mutations. Therefore, a single protein mutation leads to two opposing fat localization phenotypes [8]. Importantly, mutations in LMNA are also responsible for metabolic laminopathies resembling the metabolic syndrome (MS) and Hutchinson-Gilford progeria, a severe syndrome of premature aging [94]. Prelamin A is implicated in increased oxidative stress and in the occurrence of cellular senescence [8].

### **10. Acquired lipodystrophies**

ing coronary heart disease [59]. Patients with congenital Berardinelli-Seip lipodystrophy fre‐ quently develop hypertrophic cardiomyopathy that can lead to death from cardiac failure [41]. In individuals with BSCL, ventricular dysfunction and hypertrophic cardiomyopathy are of‐ ten observed. In cardiac biopsies performed in eight individuals with BSCL, the presence of subendocardial fibrosis and an abnormal architecture in the left ventricular lumen was ob‐ served [60, 61]. Hypertrophic cardiomyopathy in BSCL patients has been correlated with high plasmatic insulin levels, which activate the type 1 insulin-like growth receptors, present in large quantities in the myocardial tissue, that stimulate cell growth [62, 63]. In addition, the presence of IR and hypertriglyceridemia in individuals with BSCL may predispose them to premature atherosclerosis. Individuals who have mutations on chromosome 11 (BSCL2) seemed to present more severe symptoms than those who had mutations in BSCL1, with a high incidence of premature deaths. Cardiomyopathy was three times more frequent in those with

BSCL2 mutations than in individuals with alterations in BSCL1 [42].

**8. Autoinflammatory syndromes**

268 Current Perspectives in HIV Infection

**9. Familial Partial Lipodystrophy(FPL)**

**7. Mandibuloacral Dysplasia (MAD)-associated lipodystrophy**

MAD is characterized by skeletal abnormalities such as mandibular and clavicular hypoplasia and acroosteolysis [64], progeroid manifestations, partial or generalized lipodystrophy and metabolic complications, among other clinical features [65, 66]. Patients with MAD harbor mu‐ tations in lamin A/C (LMNA) or zinc metalloproteinase (ZMPSTE24) [67, 68]. ZMPSTE24 is in‐ volved in post-translational proteolytic processing of prelamin A to mature laminA [2].

A syndrome of joint contractures, muscle atrophy, microcytic anemia, and panniculitis-in‐ duced (JMP) lipodystrophy was reported by Garg in three patients, belonging to two pedi‐ grees, who were from Portugal and Mexico [69]. Three other patients have been reported from Japan [70, 71]. Mutations in PSMB8 may trigger an autoinflammatory response resulting in in‐ filtration of adipose tissue with lymphocytes and other immune cells and adipocytes [2]. The other autoinflammatory syndrome is the chronic atypical neutrophilic dermatosis with lipo‐ dystrophy and elevated temperature (CANDLE) syndrome. The mode of inheritance seems to

FPL is characterized by the onset of fat loss from the limbs and other regions of the body, usu‐ ally during childhood, adolescence or adulthood. Many regions of the body, such as the face, neck, and intra-abdominal region are spared, and patients accumulate excess body fat in the non-lipodystrophic regions [74-76]. Metabolic complications, acanthosis nigricans, oligoame‐

be autosomal recessive, but the molecular basis remains unknown [2, 72, 73].

#### **10.1. Acquired Generalized Lipodystrophy(AGL) – Lawrence syndrome**

The onset of subcutaneous fat loss in patients with AGL usually occurs during childhood [95]. The pattern and extent of fat loss is quite variable and most patients have generalized loss of fat, but a few of them have areas such as intra-abdominal and bone marrow fat spared. AGL patients are highly likely to develop severe hepatic steatosis and fibrosis, dia‐ betes, and hypertriglyceridemia [2]. The pathogenesis of fat loss remains unknown. Panni‐ culitis may precede loss of fat. Lipodystrophy can be associated with autoimmune diseases such as juvenile dermatomyositis [95]. Chronic hepatitis with autoimmune features and low serum complement 4 levels, suggesting involvement of the classical complement pathway in the pathogenesis of fat loss, has been reported [96].

#### **10.2. Acquired partial lipodystrophy–Barraquer-Simons syndrome**

Fat loss occurs gradually in a symmetric fashion, first affecting the face and then spreading downward. Most patients lose fat from the face, neck, upper extremities, and trunk, and subcutaneous fat from the lower abdomen and legs is spared. Many patients accumulate ex‐ cess subcutaneous fat in the hips and legs. Metabolic complications are rare. Misra et al sug‐ gest that the fat loss involves autoimmune-mediated destruction of adipocytes because the patients have low serum levels of complement 3 and complement 3-nephritic factor, which blocks degradation of the enzyme C3 convertase [95]. It is possible that the C3-nephritic fac‐ tor induces lysis of adipocytes expressing factor D [97].

gluteal) and visceral fat accumulation, generally associated with metabolic abnormalities [4, 100-103] and increased risk of CV diseases [104, 105], similar to what occurs in congenital lipodystrophies [4, 59]. Lipohypertrophy usually represents a central visceral fat accumula‐ tion in the abdomen and trunk, but can also be found in breasts (in women), dorsocervical region ("buffalo hump"), double chin, lipomas, and within the muscle and liver [59, 106]. Lipoatrophy and lipohypertrophy are frequently associated (mixed form), but they also can occur independently of each other [59]. This HIV-associated lipodystrophy has been pro‐ posed to be a age-related fat redistribution condition that could amplify age-related co-mor‐ bidities and lead to their earlier occurrence [8]. Also, hyperlactenemia and bone

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

271

Owing to a lack of a consensus on the definition of lipodystrophy and lipodystrophy syn‐ drome in HIV-infected patients, its exact prevalence is not known [6]. In the early 2000s, about half of HIV-infected patients undergoing cART were diagnosed as lipodystrophic (20-80%) [109]. Abnormalities in peripheral and central fat masses are clinically evident in 20-35 % of pa‐ tients after approximately 12-24 months of cART [59, 107, 110, 111]. With the new anti-retrovi‐ ral agents, the probability of developing lipoatrophy has decreased in western countries as the pattern of cART prescription has significantly changed [112]. In the study of Nguyen, lipodys‐ trophy has become less frequent since 2003 [112]. Two widely used thymidine analogs from the first class of ART, stavudine and zidovudine, are responsible for lipoatrophy and now they have been replaced by a new generation of potent NRTIs. Although metabolic toxicity of boost‐ ed PIs is far less than of first-generation protease inhibitors (PIs), they are still considered re‐ sponsible for increased CV risk. The new classes of ART, fusion inhibitors (F20), integrase inhibitors (raltegravir) or entry inhibitors (anti-CCR5, maraviroc) have not yet been shown to

HIV-infected patients can have 4 different phenotypes of body fat composition: no lipodys‐ trophy, isolated peripheral lipoatrophy, isolated central fat accumulation and a mixed form of lipodystrophy (or redistribution syndrome) [100]. About 50% of patients with HIV-associ‐ ated lipodystrophy display mixed forms, with the loss of limb fat and marked expansion of VAT [113]. The high frequency of this association suggests that these two opposite pheno‐ types could be, at least in part, causally related [8]. Also, HIV patients may have a picture similar to partial lipodystrophy patients with peripheral fat atrophy and hypertrophied cen‐ tral fat depots. Thus, there are similarities between HIV lipodystrophy and genetic forms.

There is a possible role of the virus contribution for lipodystrophy i.e. the HIV or hepatitis in‐ fection affects fat tissue before any ART. Monocytes are relatively resistant to HIV infection, but differentiated macrophages are highly susceptible and tissue macrophages have been found to harbor HIV-1 [118]. Infected macrophages release pro-inflammatory cytokines. Sys‐ temic inflammation associated with HIV infection might promote monocyte migration across the vascular endothelium, leading to an increased number of activated macrophages in fat

demineralization can occur [107, 108].

alter metabolic parameters or fat distribution [8, 112-117].

**11. HIV-lipodystrophy and related factors**

### **10.3. Localized lipodystrophy**

Localized lipodystrophies present focal loss of subcutaneous fat, usually causing one or more dimples, and in general occurs due to subcutaneous injection of various drugs (Figure 4), panniculitis, pressure, and other mechanisms [98].

**Figure 2.** Patient with lipohypertrophy related to subcutaneous administration of pegvisomant.

#### **10.4. Lipodystrophy associated with HIV-infection**

The impressive progress resulting from the discovery of drugs able to control HIV infection on a long-term basis, has offered most patients a prolonged lifespan, possibly as long as that observed in non-infected subjects [7]. Suppression of viral replication has become a treat‐ ment goal that can be reached with the use ofcART. After the introduction of protease inhib‐ itors (PIs) in 1996, as a component of highly active antiretroviral therapy, the morbidity and mortality associated with HIV has dramatically been reduced [99]. However, patients devel‐ op a syndrome of fat redistribution with peripheral fat loss (face, upper limbs and femorogluteal) and visceral fat accumulation, generally associated with metabolic abnormalities [4, 100-103] and increased risk of CV diseases [104, 105], similar to what occurs in congenital lipodystrophies [4, 59]. Lipohypertrophy usually represents a central visceral fat accumula‐ tion in the abdomen and trunk, but can also be found in breasts (in women), dorsocervical region ("buffalo hump"), double chin, lipomas, and within the muscle and liver [59, 106]. Lipoatrophy and lipohypertrophy are frequently associated (mixed form), but they also can occur independently of each other [59]. This HIV-associated lipodystrophy has been pro‐ posed to be a age-related fat redistribution condition that could amplify age-related co-mor‐ bidities and lead to their earlier occurrence [8]. Also, hyperlactenemia and bone demineralization can occur [107, 108].

Owing to a lack of a consensus on the definition of lipodystrophy and lipodystrophy syn‐ drome in HIV-infected patients, its exact prevalence is not known [6]. In the early 2000s, about half of HIV-infected patients undergoing cART were diagnosed as lipodystrophic (20-80%) [109]. Abnormalities in peripheral and central fat masses are clinically evident in 20-35 % of pa‐ tients after approximately 12-24 months of cART [59, 107, 110, 111]. With the new anti-retrovi‐ ral agents, the probability of developing lipoatrophy has decreased in western countries as the pattern of cART prescription has significantly changed [112]. In the study of Nguyen, lipodys‐ trophy has become less frequent since 2003 [112]. Two widely used thymidine analogs from the first class of ART, stavudine and zidovudine, are responsible for lipoatrophy and now they have been replaced by a new generation of potent NRTIs. Although metabolic toxicity of boost‐ ed PIs is far less than of first-generation protease inhibitors (PIs), they are still considered re‐ sponsible for increased CV risk. The new classes of ART, fusion inhibitors (F20), integrase inhibitors (raltegravir) or entry inhibitors (anti-CCR5, maraviroc) have not yet been shown to alter metabolic parameters or fat distribution [8, 112-117].

HIV-infected patients can have 4 different phenotypes of body fat composition: no lipodys‐ trophy, isolated peripheral lipoatrophy, isolated central fat accumulation and a mixed form of lipodystrophy (or redistribution syndrome) [100]. About 50% of patients with HIV-associ‐ ated lipodystrophy display mixed forms, with the loss of limb fat and marked expansion of VAT [113]. The high frequency of this association suggests that these two opposite pheno‐ types could be, at least in part, causally related [8]. Also, HIV patients may have a picture similar to partial lipodystrophy patients with peripheral fat atrophy and hypertrophied cen‐ tral fat depots. Thus, there are similarities between HIV lipodystrophy and genetic forms.

### **11. HIV-lipodystrophy and related factors**

cess subcutaneous fat in the hips and legs. Metabolic complications are rare. Misra et al sug‐ gest that the fat loss involves autoimmune-mediated destruction of adipocytes because the patients have low serum levels of complement 3 and complement 3-nephritic factor, which blocks degradation of the enzyme C3 convertase [95]. It is possible that the C3-nephritic fac‐

Localized lipodystrophies present focal loss of subcutaneous fat, usually causing one or more dimples, and in general occurs due to subcutaneous injection of various drugs (Figure

**Figure 2.** Patient with lipohypertrophy related to subcutaneous administration of pegvisomant.

The impressive progress resulting from the discovery of drugs able to control HIV infection on a long-term basis, has offered most patients a prolonged lifespan, possibly as long as that observed in non-infected subjects [7]. Suppression of viral replication has become a treat‐ ment goal that can be reached with the use ofcART. After the introduction of protease inhib‐ itors (PIs) in 1996, as a component of highly active antiretroviral therapy, the morbidity and mortality associated with HIV has dramatically been reduced [99]. However, patients devel‐ op a syndrome of fat redistribution with peripheral fat loss (face, upper limbs and femoro-

**10.4. Lipodystrophy associated with HIV-infection**

tor induces lysis of adipocytes expressing factor D [97].

4), panniculitis, pressure, and other mechanisms [98].

**10.3. Localized lipodystrophy**

270 Current Perspectives in HIV Infection

There is a possible role of the virus contribution for lipodystrophy i.e. the HIV or hepatitis in‐ fection affects fat tissue before any ART. Monocytes are relatively resistant to HIV infection, but differentiated macrophages are highly susceptible and tissue macrophages have been found to harbor HIV-1 [118]. Infected macrophages release pro-inflammatory cytokines. Sys‐ temic inflammation associated with HIV infection might promote monocyte migration across the vascular endothelium, leading to an increased number of activated macrophages in fat [118]. Several studies reported that the severity of HIV infection is associated with an in‐ creased prevalence of lipodystrophy [59, 119], probably as a consequence of persistent HIV-in‐ fected macrophages in adipose tissue, which could enhance local inflammation.

**12. Protease inhibitors**

PIs affect multiple metabolic pathways and are associated with lipohypertrophy, lipoatrophy, atherogenic dyslipidemia and IR, [125, 126]. Studies in-vitro reported that PIs are able to alter a number of adipocyte functions, including differentiation, expression of transcriptase factors involved in adipogenesis, cell survival, cytokine production, mitochondrial function and IR [127]. PIs may cause lipodystrophy by inhibiting ZMPSTE24, resulting in accumulation of tox‐ ic farnesylated prelamin A [128], increased oxidative stress and altered adipokine and cyto‐ kine production [89, 127, 129]. The adverse effect of PIs could also result from the induction of

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

273

Different PIs might affect key intranuclear genes, causing reduction in levels of RNA encod‐ ing SREBP-1, which changes the expression of PPAR γ [28]. The levels reduction of intranu‐ clear SREBP-1 leads to a decreased adipocyte differentiation and an altered release of adipocytokines [132]. PIs can inhibit lipogenesis and stimulate lipolysis [28, 132-135], and

**13. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)**

NRTIs are analogs that inhibit the viral reverse transcriptase enzyme. The thymidine NRTIs (zidovudine, stavudine and didanosine) cause mitochondrial toxicity by mitochondrial DNA polymerase inhibition and by causing DNA mitochondrial mutations [31, 137, 138]. These dis‐ turbances result in apoptosis of peripheral adipocytes and lead to lipoatrophy [31]. NRTIs are also associated with fat hypertrophy in visceral depots [113, 139, 140]. Nucleoside analogues may inhibit adipogenesis and adipocyte differentiation, promote lipolysis, and exert synergis‐ tic toxic effects when associated to PIs [31, 141-143]. Moreover, NRTIs promote lipolysis and

In western countries, long-term HIV-infected patients present several age-related comorbid‐ ities earlier than the general population [145], and display signs of premature aging [8]. New hypotheses were recently suggested about the pathophysiology of fat redistribution, pro‐ posing that mitochondrial toxicity was involved in lipoatrophy and in fat hypertrophy. HIVassociated lipodystrophy could be an age-related fat redistribution that could amplify agerelated comorbidities and their earlier occurrence [8]. Mitochondria play an important role in adipocyte differentiation and function. At physiological low levels, ROS could act as sec‐ ondary messengers to activate adipogenesis and lipogenesis, resulting in increased adipo‐ cyte number and size. In hepatic cells, oxidative stress activates the transcription factor SREBP1c, which is highly expressed in adipocytes and increases lipogenesis and lipid accu‐

endoplasmic reticulum stress or the inhibition of the proteasome [130, 131].

may induce IR by inhibiting glucose transporter 4 expression (GLUT4) [136].

the subsequent efflux of non-esterified fatty acids from adipose tissue [142, 144].

**14. Mitochondrial toxicity and fat redistribution**

mulation [146]. At higher levels, ROS could inhibit differentiation [8].

ART-naïve HIV-positive patients have increased TNF-α expression compared with uninfect‐ ed controls [29], which is consistent with increased inflammation. TNF-α alters adipocyte function and differentiation, in part through the inhibition of PPARγ expression [120]. In‐ fected macrophages might also release viral proteins (such as Vpr and Nef) that can impact on adjacent adipocytes and lead to decreased PPARγ activity and inhibition of adipogenesis [121, 122]. Although lipodystrophy is uncommon in ART-naïve patients [113], the HIV infec‐ tion of macrophages could itself result in low-grade fat inflammation and lead to the release of viral proteins that affect neighboring adipocytes and decrease their differentiation.

The development of lipodystrophy and metabolic toxicities is partially related to the indi‐ vidual drugs included in cART regimens, associated with other risk factors [123] such as gender and pre-HIV-infection body composition, disease-specific factors such as the nadir levels of CD4+ lymphocytes and the duration of HIV infection [110, 123, 124]. The most sig‐ nificant risk factors associated with lipoatrophy are exposure to and duration of nucleoside thymidine analogues (most commonly stavudine), age, severity of disease markers (CD4 lymphocyte count and plasma HIV viral load), therapy duration, and belonging to the Cau‐ casian race. On the other hand, the most common statistically significant risk factors for lipo‐ hypertrophy are therapy duration, PI administration, markers of disease severity, and age. We cannot forget that along the years, patients have done multiple regimes and combina‐ tions of antiretroviral drugs, which makes it difficult to identify different risks with different drugs, and studies therefore report conflicting results [6].

**Figure 3.** FFA uptake by gender (SAT - abdominal subcutaneous adipose tissue; VAT – visceral adipose tissue; FFA – free fat acids)

### **12. Protease inhibitors**

[118]. Several studies reported that the severity of HIV infection is associated with an in‐ creased prevalence of lipodystrophy [59, 119], probably as a consequence of persistent HIV-in‐

ART-naïve HIV-positive patients have increased TNF-α expression compared with uninfect‐ ed controls [29], which is consistent with increased inflammation. TNF-α alters adipocyte function and differentiation, in part through the inhibition of PPARγ expression [120]. In‐ fected macrophages might also release viral proteins (such as Vpr and Nef) that can impact on adjacent adipocytes and lead to decreased PPARγ activity and inhibition of adipogenesis [121, 122]. Although lipodystrophy is uncommon in ART-naïve patients [113], the HIV infec‐ tion of macrophages could itself result in low-grade fat inflammation and lead to the release

of viral proteins that affect neighboring adipocytes and decrease their differentiation.

drugs, and studies therefore report conflicting results [6].

free fat acids)

The development of lipodystrophy and metabolic toxicities is partially related to the indi‐ vidual drugs included in cART regimens, associated with other risk factors [123] such as gender and pre-HIV-infection body composition, disease-specific factors such as the nadir levels of CD4+ lymphocytes and the duration of HIV infection [110, 123, 124]. The most sig‐ nificant risk factors associated with lipoatrophy are exposure to and duration of nucleoside thymidine analogues (most commonly stavudine), age, severity of disease markers (CD4 lymphocyte count and plasma HIV viral load), therapy duration, and belonging to the Cau‐ casian race. On the other hand, the most common statistically significant risk factors for lipo‐ hypertrophy are therapy duration, PI administration, markers of disease severity, and age. We cannot forget that along the years, patients have done multiple regimes and combina‐ tions of antiretroviral drugs, which makes it difficult to identify different risks with different

**Figure 3.** FFA uptake by gender (SAT - abdominal subcutaneous adipose tissue; VAT – visceral adipose tissue; FFA –

fected macrophages in adipose tissue, which could enhance local inflammation.

272 Current Perspectives in HIV Infection

PIs affect multiple metabolic pathways and are associated with lipohypertrophy, lipoatrophy, atherogenic dyslipidemia and IR, [125, 126]. Studies in-vitro reported that PIs are able to alter a number of adipocyte functions, including differentiation, expression of transcriptase factors involved in adipogenesis, cell survival, cytokine production, mitochondrial function and IR [127]. PIs may cause lipodystrophy by inhibiting ZMPSTE24, resulting in accumulation of tox‐ ic farnesylated prelamin A [128], increased oxidative stress and altered adipokine and cyto‐ kine production [89, 127, 129]. The adverse effect of PIs could also result from the induction of endoplasmic reticulum stress or the inhibition of the proteasome [130, 131].

Different PIs might affect key intranuclear genes, causing reduction in levels of RNA encod‐ ing SREBP-1, which changes the expression of PPAR γ [28]. The levels reduction of intranu‐ clear SREBP-1 leads to a decreased adipocyte differentiation and an altered release of adipocytokines [132]. PIs can inhibit lipogenesis and stimulate lipolysis [28, 132-135], and may induce IR by inhibiting glucose transporter 4 expression (GLUT4) [136].

### **13. Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)**

NRTIs are analogs that inhibit the viral reverse transcriptase enzyme. The thymidine NRTIs (zidovudine, stavudine and didanosine) cause mitochondrial toxicity by mitochondrial DNA polymerase inhibition and by causing DNA mitochondrial mutations [31, 137, 138]. These dis‐ turbances result in apoptosis of peripheral adipocytes and lead to lipoatrophy [31]. NRTIs are also associated with fat hypertrophy in visceral depots [113, 139, 140]. Nucleoside analogues may inhibit adipogenesis and adipocyte differentiation, promote lipolysis, and exert synergis‐ tic toxic effects when associated to PIs [31, 141-143]. Moreover, NRTIs promote lipolysis and the subsequent efflux of non-esterified fatty acids from adipose tissue [142, 144].

### **14. Mitochondrial toxicity and fat redistribution**

In western countries, long-term HIV-infected patients present several age-related comorbid‐ ities earlier than the general population [145], and display signs of premature aging [8]. New hypotheses were recently suggested about the pathophysiology of fat redistribution, pro‐ posing that mitochondrial toxicity was involved in lipoatrophy and in fat hypertrophy. HIVassociated lipodystrophy could be an age-related fat redistribution that could amplify agerelated comorbidities and their earlier occurrence [8]. Mitochondria play an important role in adipocyte differentiation and function. At physiological low levels, ROS could act as sec‐ ondary messengers to activate adipogenesis and lipogenesis, resulting in increased adipo‐ cyte number and size. In hepatic cells, oxidative stress activates the transcription factor SREBP1c, which is highly expressed in adipocytes and increases lipogenesis and lipid accu‐ mulation [146]. At higher levels, ROS could inhibit differentiation [8].

**15. Cortisol and fat redistribution**

**16. Aging**

Patients with hypercortisolism also have an acquired form of lipodystrophy [1], character‐ ized by fat hypertrophy in the upper body with increased VAT and decreased limb fat. Cor‐ tisol can activate adipocyte differentiation and hypertrophy, mainly in visceral fat depots, because of the higher expression of glucocorticoid receptors (GR-α) and the 11β-hydroxyste‐ roid dehydrogenase type 1 (11β-HSD-1) that transforms inactive cortisone into active corti‐ sol in adipocytes from central depots [22]. In addition, cortisol induces IR and increases lipolysis in adipocytes [22]. It has been hypothesized that glucocorticoid activation is in‐ volved in cART-linked central fat hypertrophy [8]. Higher ratios of urinary cortisol:cortisone metabolites and higher subcutaneous 11β-HSD-1 expression are observed in patients with severe lipodystrophy compared with those without [149]. In cART-naïve patients, 11β-HSD-1 expression increases in both abdominal and thigh SAT after 12 months of ART, but only in patients with lipohypertrophy or without lipoatrophy [150]. Because TNF-α expres‐ sion in fat is related to that of 11β-HSD-1 [149], inflammation is linked to glucocorticoid acti‐ vation [8]. TNF-α activates 11-β-hydroxysteroid dehydrogenase (HSD)-type 1, and this enzyme's activity is higher in visceral fat compared with subcutaneous fat. Visceral fat is able to locally produce cortisol, which could act inside the adipocytes and increase lipid ac‐ cumulation [151]. Other hormones, such as growth hormone and testosterone, can modulate the activity of 11β-HSD-1. It is interesting to note that HIV-infected patients with lipodystro‐ phy often present with a relative decrease in growth hormone [152] and testosterone levels. Moreover, when patients with visceral fat hypertrophy are treated with growth hormone, a reduced amount of visceral fat is reported, together with improved metabolic status [153].

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

275

In the general population, age is associated with central fat redistribution, mitochondrial im‐ pairment and increased levels of pro-inflammatory cytokines [154]. Aging adipocytes re‐ lease more pro-inflammatory cytokines than young ones [155]. Aging is physiologically associated with fat redistribution, oxidative stress and low-grade inflammation. In the gen‐ eral population, the interaction between the proinflammatory state and genetic background potentially triggers the onset of age-related inflammatory diseases such as atherosclerosis, sarcopenia and frailty. Decreased immune response leading to immunosenescence is also probably involved in early aging [8, 156]. Aging and some cARTs result in mitochondrial dysfunction and oxidative stress, which lead to cellular senescence. Moreover, some PIs in‐

A role for genetics is also probable in HIV-lipodystrophy. TNF-α gene promoter polymor‐ phism is associated with lipodystrophy, but this association has not been confirmed in larg‐

duce the accumulation of the pro-senescent protein prelaminA [8].

**17. Genetic factors and HIV-lipodystrophy**

**Figure 4.** Acquired partial lipodystrophy - Barraquer-Simons syndrome

Excessive VAT releases increased visceral adipocyte-FFAs, adipokines and cytokines. In‐ deed, activated macrophages, which have an M1 proinflammatory phenotype, invade ex‐ panded adipose tissue; upon invasion, their production of proinflammatory cytokines and chemokines increases. This could lead to the decreased secretion of adiponectin by adipo‐ cytes in response to TNF-α [36]. Increased abdominal fat lipolysis increases ectopic fat depo‐ sition within tissues (liver, skeletal muscle and heart). Subsequently, these derivatives overwhelm mitochondrial oxidative capacity and activate stress kinases, leading to IR. This situation, known as lipotoxicity, associates ectopic depots of triglycerides in non-adipose tis‐ sues that buffer excess fatty acid derivatives [147]. Moreover, a paracrine loop is present be‐ tween adipocytes and macrophages; macrophage-secreted cytokines (TNF-α and IL-6] activate the NFkB pathway in adipocytes, resulting in increased IL-6 and FFA production. Saturated FFA can, in turn, activate the Toll-like receptor-4 (TLR-4) on macrophages and adipocytes, thereby increasing the proinflammatory loop. This paracrine loop has been re‐ ported in obesity as a result of macrophages infiltrating fat [148].

### **15. Cortisol and fat redistribution**

Patients with hypercortisolism also have an acquired form of lipodystrophy [1], character‐ ized by fat hypertrophy in the upper body with increased VAT and decreased limb fat. Cor‐ tisol can activate adipocyte differentiation and hypertrophy, mainly in visceral fat depots, because of the higher expression of glucocorticoid receptors (GR-α) and the 11β-hydroxyste‐ roid dehydrogenase type 1 (11β-HSD-1) that transforms inactive cortisone into active corti‐ sol in adipocytes from central depots [22]. In addition, cortisol induces IR and increases lipolysis in adipocytes [22]. It has been hypothesized that glucocorticoid activation is in‐ volved in cART-linked central fat hypertrophy [8]. Higher ratios of urinary cortisol:cortisone metabolites and higher subcutaneous 11β-HSD-1 expression are observed in patients with severe lipodystrophy compared with those without [149]. In cART-naïve patients, 11β-HSD-1 expression increases in both abdominal and thigh SAT after 12 months of ART, but only in patients with lipohypertrophy or without lipoatrophy [150]. Because TNF-α expres‐ sion in fat is related to that of 11β-HSD-1 [149], inflammation is linked to glucocorticoid acti‐ vation [8]. TNF-α activates 11-β-hydroxysteroid dehydrogenase (HSD)-type 1, and this enzyme's activity is higher in visceral fat compared with subcutaneous fat. Visceral fat is able to locally produce cortisol, which could act inside the adipocytes and increase lipid ac‐ cumulation [151]. Other hormones, such as growth hormone and testosterone, can modulate the activity of 11β-HSD-1. It is interesting to note that HIV-infected patients with lipodystro‐ phy often present with a relative decrease in growth hormone [152] and testosterone levels. Moreover, when patients with visceral fat hypertrophy are treated with growth hormone, a reduced amount of visceral fat is reported, together with improved metabolic status [153].

### **16. Aging**

**Figure 4.** Acquired partial lipodystrophy - Barraquer-Simons syndrome

274 Current Perspectives in HIV Infection

ported in obesity as a result of macrophages infiltrating fat [148].

Excessive VAT releases increased visceral adipocyte-FFAs, adipokines and cytokines. In‐ deed, activated macrophages, which have an M1 proinflammatory phenotype, invade ex‐ panded adipose tissue; upon invasion, their production of proinflammatory cytokines and chemokines increases. This could lead to the decreased secretion of adiponectin by adipo‐ cytes in response to TNF-α [36]. Increased abdominal fat lipolysis increases ectopic fat depo‐ sition within tissues (liver, skeletal muscle and heart). Subsequently, these derivatives overwhelm mitochondrial oxidative capacity and activate stress kinases, leading to IR. This situation, known as lipotoxicity, associates ectopic depots of triglycerides in non-adipose tis‐ sues that buffer excess fatty acid derivatives [147]. Moreover, a paracrine loop is present be‐ tween adipocytes and macrophages; macrophage-secreted cytokines (TNF-α and IL-6] activate the NFkB pathway in adipocytes, resulting in increased IL-6 and FFA production. Saturated FFA can, in turn, activate the Toll-like receptor-4 (TLR-4) on macrophages and adipocytes, thereby increasing the proinflammatory loop. This paracrine loop has been re‐

In the general population, age is associated with central fat redistribution, mitochondrial im‐ pairment and increased levels of pro-inflammatory cytokines [154]. Aging adipocytes re‐ lease more pro-inflammatory cytokines than young ones [155]. Aging is physiologically associated with fat redistribution, oxidative stress and low-grade inflammation. In the gen‐ eral population, the interaction between the proinflammatory state and genetic background potentially triggers the onset of age-related inflammatory diseases such as atherosclerosis, sarcopenia and frailty. Decreased immune response leading to immunosenescence is also probably involved in early aging [8, 156]. Aging and some cARTs result in mitochondrial dysfunction and oxidative stress, which lead to cellular senescence. Moreover, some PIs in‐ duce the accumulation of the pro-senescent protein prelaminA [8].

### **17. Genetic factors and HIV-lipodystrophy**

A role for genetics is also probable in HIV-lipodystrophy. TNF-α gene promoter polymor‐ phism is associated with lipodystrophy, but this association has not been confirmed in larg‐ er studies [157]. Interestingly, stavudine-induced lipoatrophy is linked to the HLA-B100\*4001 allele, which is located in close proximity to the TNF-α gene; this observation further supports the theory that there is a role for inflammation in lipoatrophy [158]. Apo C3-455 also plays a role in lipoatrophy, and two variants of the adipogenic β2 receptor seems to be involved in fat accumulation, whereas PPARγ variants are not involved [159]. The toxicity of ART also depends on a patient's metabolism, in part genetically determined.

**19. Lipotoxicity**

Lipotoxicity is a possible explanation for the development of metabolic syndrome (MS) and diabetes in multiple pathological situations, from obesity to lipodystrophies of distinct ori‐ gin. According to the lipotoxicity theory, excess availability of fatty acids or a limited capaci‐ ty to metabolize them in organs and tissues elicits most of the alterations that are characteristic of MS, especially IR. The toxicity of fatty acids toward β-cells may lead to al‐ tered insulin production. Actually, high FA levels can induce a reduction in GLUT2 on β cell surfaces and induce a decrease in insulin secretion [19]. Increased availability and, ultimate‐ ly, increased accumulation of fat into skeletal muscle tends to promote IR; and fatty acid lev‐ els in liver that exceed the capacity of this organ to oxidize or export them, lead to the increased accumulation of fat that is often associated with MS. All of these events could re‐ sult from alterations in fat metabolism or excess intake of fat-enriched nutrients, but they could also arise as a result of intrinsic alterations in the capacity of adipose tissue to store and thereby buffer the excessive accumulation of fatty acids in other tissues and organs [163]. One hypothesis consistent with the appearance of MS in ART-associated lipodystro‐ phy syndrome is lipotoxicity resulting from limitations in the capacity of subcutaneous fat to store the appropriate amounts of fat and the subsequent diversion of fatty acids to ectopic sites [164]. Several arguments in support of lipotoxicity as a major contributor to MS in dis‐ tinct human pathologies come from the paradoxically common metabolic alterations found in the obesity and in lipodystrophies of genetic origin. According to the lipotoxicity theory, the fat stored in adipose tissue is biologically inert and the observed metabolic alterations are primarily caused by the increased exposure of cells to non-esterified fatty acid. Thus, in obese patients, it is not the amount of fat stored in adipose tissue that elicits metabolic dys‐ functions, but rather the balance between the availability of those fatty acids to tissues and organs and the capacity of the organs to eliminate them through triglyceride storage in adi‐ pose tissue, or oxidation [165]. A complementary concept is the idea that there is a threshold for adipose tissue expansibility; once it's reached, as it occurs in obese individuals, appropri‐ ate storage of fatty acids inside adipocytes in their inert and esterified form is impaired, de‐ termining the extent of lipotoxicity [164]. Either a total or partial lack of adipose tissue storage capacity causes an increase in circulating lipid levels and is associated with ectopic lipid accumulation in non-fat tissues such as liver, skeletal muscle and pancreas. These alter‐ ations lead to non-alcoholic fatty liver diseases, hepatic and muscle IR and development of type 2 diabetes. Adipokine deficiency further contributes to metabolic alterations (e.g. hy‐ perphagia) owing to an associated leptin deficiency, which also contributes to positive ener‐

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

277

gy balance and potential lipotoxicity through increased fat intake [94].

IR occurs in about one-third of patients on certain PI-based regimens, although the thymi‐ dine NRTIs have also been associated [166]. Asymptomatic type 2 diabetes mellitus is diag‐

**20. Insulin resistance**

### **18. Role of inflammation**

Even if infectivity of adipocytes by HIV has been contested, the ability of the virus to modify adipocyte phenotype has been shown in some studies [160, 161]. Moreover, macrophages and dendritic cells present in lipodystrophic adipose tissue could be infected, which could modify their characteristics [7]. Macrophage infiltration is observed in adipose tissue from patients with HIV-related lipodystrophy together with decreased adipokine and increased pro-inflammatory cytokine production [162]. Some anti-retrovirals increase oxidative stress and generation of reactive species, which results in decreased production of adiponectin and leptin by adipocytes and increased production of pro-inflammatory cytokines [7].

**Figure 5.** Patient with mixed lipodystrophy (absence of subcutaneous peripheral fat in arms, legs and face and in‐ creased abdominal fat mass)

### **19. Lipotoxicity**

er studies [157]. Interestingly, stavudine-induced lipoatrophy is linked to the HLA-B100\*4001 allele, which is located in close proximity to the TNF-α gene; this observation further supports the theory that there is a role for inflammation in lipoatrophy [158]. Apo C3-455 also plays a role in lipoatrophy, and two variants of the adipogenic β2 receptor seems to be involved in fat accumulation, whereas PPARγ variants are not involved [159]. The toxicity of ART also depends on a patient's metabolism, in part genetically determined.

Even if infectivity of adipocytes by HIV has been contested, the ability of the virus to modify adipocyte phenotype has been shown in some studies [160, 161]. Moreover, macrophages and dendritic cells present in lipodystrophic adipose tissue could be infected, which could modify their characteristics [7]. Macrophage infiltration is observed in adipose tissue from patients with HIV-related lipodystrophy together with decreased adipokine and increased pro-inflammatory cytokine production [162]. Some anti-retrovirals increase oxidative stress and generation of reactive species, which results in decreased production of adiponectin and

**Figure 5.** Patient with mixed lipodystrophy (absence of subcutaneous peripheral fat in arms, legs and face and in‐

leptin by adipocytes and increased production of pro-inflammatory cytokines [7].

**18. Role of inflammation**

276 Current Perspectives in HIV Infection

creased abdominal fat mass)

Lipotoxicity is a possible explanation for the development of metabolic syndrome (MS) and diabetes in multiple pathological situations, from obesity to lipodystrophies of distinct ori‐ gin. According to the lipotoxicity theory, excess availability of fatty acids or a limited capaci‐ ty to metabolize them in organs and tissues elicits most of the alterations that are characteristic of MS, especially IR. The toxicity of fatty acids toward β-cells may lead to al‐ tered insulin production. Actually, high FA levels can induce a reduction in GLUT2 on β cell surfaces and induce a decrease in insulin secretion [19]. Increased availability and, ultimate‐ ly, increased accumulation of fat into skeletal muscle tends to promote IR; and fatty acid lev‐ els in liver that exceed the capacity of this organ to oxidize or export them, lead to the increased accumulation of fat that is often associated with MS. All of these events could re‐ sult from alterations in fat metabolism or excess intake of fat-enriched nutrients, but they could also arise as a result of intrinsic alterations in the capacity of adipose tissue to store and thereby buffer the excessive accumulation of fatty acids in other tissues and organs [163]. One hypothesis consistent with the appearance of MS in ART-associated lipodystro‐ phy syndrome is lipotoxicity resulting from limitations in the capacity of subcutaneous fat to store the appropriate amounts of fat and the subsequent diversion of fatty acids to ectopic sites [164]. Several arguments in support of lipotoxicity as a major contributor to MS in dis‐ tinct human pathologies come from the paradoxically common metabolic alterations found in the obesity and in lipodystrophies of genetic origin. According to the lipotoxicity theory, the fat stored in adipose tissue is biologically inert and the observed metabolic alterations are primarily caused by the increased exposure of cells to non-esterified fatty acid. Thus, in obese patients, it is not the amount of fat stored in adipose tissue that elicits metabolic dys‐ functions, but rather the balance between the availability of those fatty acids to tissues and organs and the capacity of the organs to eliminate them through triglyceride storage in adi‐ pose tissue, or oxidation [165]. A complementary concept is the idea that there is a threshold for adipose tissue expansibility; once it's reached, as it occurs in obese individuals, appropri‐ ate storage of fatty acids inside adipocytes in their inert and esterified form is impaired, de‐ termining the extent of lipotoxicity [164]. Either a total or partial lack of adipose tissue storage capacity causes an increase in circulating lipid levels and is associated with ectopic lipid accumulation in non-fat tissues such as liver, skeletal muscle and pancreas. These alter‐ ations lead to non-alcoholic fatty liver diseases, hepatic and muscle IR and development of type 2 diabetes. Adipokine deficiency further contributes to metabolic alterations (e.g. hy‐ perphagia) owing to an associated leptin deficiency, which also contributes to positive ener‐ gy balance and potential lipotoxicity through increased fat intake [94].

### **20. Insulin resistance**

IR occurs in about one-third of patients on certain PI-based regimens, although the thymi‐ dine NRTIs have also been associated [166]. Asymptomatic type 2 diabetes mellitus is diag‐ nosed in 5-10 % of patients [126]. The new-generation PIs appear to have a milder IR effect and the prevalence of diabetes is lower than described in the early 2000s. Its prevalence, however, remains higher than in the general population at the same age. In particular, pa‐ tients with severe lipodystrophy are more prone to develop IR [7]. The pathogenesis of glu‐ cose metabolism disorders is still unclear and, although a direct effect of potent antiretroviral combinations is certainly involved, it is likely that multiple factors play a role, including genetic predisposition, cytokine and hormonal alterations, changes in the immune system, non-antiretroviral drug-induced toxic effects, opportunistic diseases, and perhaps the HIV infection itself [167]. Risk factors for the development of IR in HIV-positive popula‐ tion include duration of ART, PI treatment, concurrent fat redistribution syndrome, dyslipi‐ demia, increasing age, hepatitis C virus co-infection, as well as pharmacological treatment with pentamidine or megestrol acetate [100, 167-169].

PIs (including indinavir, amprenavir, nelfinavir, and ritonavir) have been shown to induce IR in vitro by reducing glucose transport mediated by the glucose transporter 4, a receptor involved in glucose uptake [136]. The deleterious impact of some PIs on adipocytes through the inhibition of GLUT4 transporters was directly demonstrated in healthy controls, after given these molecules for a few weeks [169-171]. Several PIs can interfere with nuclear tran‐ scription factors, leading to decreased adiponectin levels, which also leads to IR [123]. Some PIs might also cause mitochondrial toxicity [172]. Additionally, the increase in FFA levels as‐ sociated with PIs, as well as with fat redistribution, might also have a role in the develop‐ ment of IR (*see* lipotoxicity) [173].

**Figure 6.** Genetic and adquiredlipodystrophies (CGL – congenital generalized lipodystrophy; BSS – Berardinelli-Seip syndrome; cART- combined antiretroviral therapy; NRTI – nucleoside and nucleotide reverse transcriptase inhibitors; PI - protease inhibitors; FPL- familiar partial lipodystrophy; MADL- mandibuloacral dysplasia associated lipodystrophy;

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

279

Various mechanisms involved in ART-related dyslipidemia have been described: reduction in the catabolism of VLDL, increased VLDL production, impaired catabolism of FFA, in‐ creased liver triglyceride synthesis, increased secretion of apolipoprotein B-containing lipo‐ proteins, reduced expression of LDL receptors, reduced degradation of SREBP, and reduction in FXR (farnesoid X receptor) [175]. The first hypothesized mechanism is based upon the structural similarity between the catalytic region of HIV-1 protease and two hu‐ man proteins involved in lipid metabolism: the cytoplasmic retinoic acid-binding protein type 1 (CRABP-1) and the low-density lipoprotein-receptor-related protein (LRP). PIs proba‐ bly bind to CRABP-1 and erroneously inhibit the formation of cis-9-retinoic acid, leading to increased apoptosis of peripheral adipocytes, decreased lipid storage and increased lipid re‐ lease into the bloodstream. Similarly, PIs may inhibit the normal functioning of LRP and in‐ terfere with fatty acid storage in the adipocytes [167, 176]. Furthermore, data from in vitro and in vivo studies suggest that PIs may prevent proteasomal degradation of nascent apoli‐ poprotein B, a key protein component of circulating triglycerides, leading to increased pro‐ duction of VLDL particles. An upregulation of metabolic pathways leading to an excessive production of VLDL can also be caused by the PI-induced intra-hepatocyte accumulation of nuclear transcription factors involved in the metabolism of apolipoprotein B, such as SRBPs. In addition, the levels of lipoprotein particles containing apolipoprotein C-III and apolipo‐

In the general population, MS is described as an association of increased upper-body fat, particularly in the visceral area, with IR responsible for and revealed by metabolic altera‐

adapted from Agarwal&Garg. Ann Rev Genomics Human Genet 2006; 7: 175-199]

protein E are increased in PI-treated patients [176-179].

**22. Metabolic syndrome**

### **21. Dyslipidemia**

A number of HIV-infected patients present dyslipidemia, increased cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides together with decreased HDL. This profile has been associated with the presence of a MS, resulting from an increased visceral fat amount with IR [7].

In patients receiving cART, the prevalence of hyperlipidemia ranges from 28 to 80% in dif‐ ferent studies [167, 174], and it includes hypertriglyceridemia in the majority of cases [123]. Dyslipidemia is frequently, but not always, associated with fat redistribution syndrome: al‐ though lipid and glucose metabolism alterations are more common in patients with body-fat abnormalities, they are also observed in those without these morphological changes [167].

Several pathogenetic mechanisms have been proposed to explain cART-associated hyperli‐ pidemia, which seems to result from a complex and multifactorial pathologic process: possi‐ bly HIV infection itself, leading in some cases to permanent low grade inflammation with abnormal levels of some pro-inflammatory cytokines; lipodystrophy itself, as in the genetic forms, with decreased lower-body fat depots and increased visceral fat; and antiretroviral molecules (PIs, NNRTIs and some NRTIs) [7].

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome http://dx.doi.org/10.5772/52685 279

**Figure 6.** Genetic and adquiredlipodystrophies (CGL – congenital generalized lipodystrophy; BSS – Berardinelli-Seip syndrome; cART- combined antiretroviral therapy; NRTI – nucleoside and nucleotide reverse transcriptase inhibitors; PI - protease inhibitors; FPL- familiar partial lipodystrophy; MADL- mandibuloacral dysplasia associated lipodystrophy; adapted from Agarwal&Garg. Ann Rev Genomics Human Genet 2006; 7: 175-199]

Various mechanisms involved in ART-related dyslipidemia have been described: reduction in the catabolism of VLDL, increased VLDL production, impaired catabolism of FFA, in‐ creased liver triglyceride synthesis, increased secretion of apolipoprotein B-containing lipo‐ proteins, reduced expression of LDL receptors, reduced degradation of SREBP, and reduction in FXR (farnesoid X receptor) [175]. The first hypothesized mechanism is based upon the structural similarity between the catalytic region of HIV-1 protease and two hu‐ man proteins involved in lipid metabolism: the cytoplasmic retinoic acid-binding protein type 1 (CRABP-1) and the low-density lipoprotein-receptor-related protein (LRP). PIs proba‐ bly bind to CRABP-1 and erroneously inhibit the formation of cis-9-retinoic acid, leading to increased apoptosis of peripheral adipocytes, decreased lipid storage and increased lipid re‐ lease into the bloodstream. Similarly, PIs may inhibit the normal functioning of LRP and in‐ terfere with fatty acid storage in the adipocytes [167, 176]. Furthermore, data from in vitro and in vivo studies suggest that PIs may prevent proteasomal degradation of nascent apoli‐ poprotein B, a key protein component of circulating triglycerides, leading to increased pro‐ duction of VLDL particles. An upregulation of metabolic pathways leading to an excessive production of VLDL can also be caused by the PI-induced intra-hepatocyte accumulation of nuclear transcription factors involved in the metabolism of apolipoprotein B, such as SRBPs. In addition, the levels of lipoprotein particles containing apolipoprotein C-III and apolipo‐ protein E are increased in PI-treated patients [176-179].

#### **22. Metabolic syndrome**

nosed in 5-10 % of patients [126]. The new-generation PIs appear to have a milder IR effect and the prevalence of diabetes is lower than described in the early 2000s. Its prevalence, however, remains higher than in the general population at the same age. In particular, pa‐ tients with severe lipodystrophy are more prone to develop IR [7]. The pathogenesis of glu‐ cose metabolism disorders is still unclear and, although a direct effect of potent antiretroviral combinations is certainly involved, it is likely that multiple factors play a role, including genetic predisposition, cytokine and hormonal alterations, changes in the immune system, non-antiretroviral drug-induced toxic effects, opportunistic diseases, and perhaps the HIV infection itself [167]. Risk factors for the development of IR in HIV-positive popula‐ tion include duration of ART, PI treatment, concurrent fat redistribution syndrome, dyslipi‐ demia, increasing age, hepatitis C virus co-infection, as well as pharmacological treatment

PIs (including indinavir, amprenavir, nelfinavir, and ritonavir) have been shown to induce IR in vitro by reducing glucose transport mediated by the glucose transporter 4, a receptor involved in glucose uptake [136]. The deleterious impact of some PIs on adipocytes through the inhibition of GLUT4 transporters was directly demonstrated in healthy controls, after given these molecules for a few weeks [169-171]. Several PIs can interfere with nuclear tran‐ scription factors, leading to decreased adiponectin levels, which also leads to IR [123]. Some PIs might also cause mitochondrial toxicity [172]. Additionally, the increase in FFA levels as‐ sociated with PIs, as well as with fat redistribution, might also have a role in the develop‐

A number of HIV-infected patients present dyslipidemia, increased cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides together with decreased HDL. This profile has been associated with the presence of a MS, resulting from an increased visceral fat

In patients receiving cART, the prevalence of hyperlipidemia ranges from 28 to 80% in dif‐ ferent studies [167, 174], and it includes hypertriglyceridemia in the majority of cases [123]. Dyslipidemia is frequently, but not always, associated with fat redistribution syndrome: al‐ though lipid and glucose metabolism alterations are more common in patients with body-fat abnormalities, they are also observed in those without these morphological changes [167].

Several pathogenetic mechanisms have been proposed to explain cART-associated hyperli‐ pidemia, which seems to result from a complex and multifactorial pathologic process: possi‐ bly HIV infection itself, leading in some cases to permanent low grade inflammation with abnormal levels of some pro-inflammatory cytokines; lipodystrophy itself, as in the genetic forms, with decreased lower-body fat depots and increased visceral fat; and antiretroviral

with pentamidine or megestrol acetate [100, 167-169].

ment of IR (*see* lipotoxicity) [173].

molecules (PIs, NNRTIs and some NRTIs) [7].

**21. Dyslipidemia**

278 Current Perspectives in HIV Infection

amount with IR [7].

In the general population, MS is described as an association of increased upper-body fat, particularly in the visceral area, with IR responsible for and revealed by metabolic altera‐ tions, including increased LDL, decreased HDL, increased triglycerides, increased glycemia or diabetes and increased blood pressure [180-182]. All these parameters constitute a con‐ stellation of major CV risk factors [180]. This situation also includes low-grade inflammation and a prothrombotic state [7].

protein levels and abnormal proinflammatory and prothrombotic indices [197], all suggest a

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

**IR, Adipokines and Lipodystrophy in HIV Infection**

ART: Protease inhibitors Nucleoside reverse transcriptase inhibitors

> Patient related factors: Genetic

http://dx.doi.org/10.5772/52685

281

Diet

Age

Low testosterone Oxidative stress HCV infection

Environment

Insulin Resistance

Metabolic Syndrome Cardiovascular Disease Risk

**Figure 7.** The relationship between HIV infection, lipodystrophy, ART, insulin resistance, adipokines, metabolic altera‐

Endothelial cells have been shown to be variably permissive for HIV infection. The HIV virus itself is able to penetrate coronary artery and brain microvascular endothelial cell membranes and to initiate inflammatory and biochemical intracellular reactions [198, 199]. The activation of endothelium induced by either HIV infection itself or by a leukocyte-mediated inflammato‐ ry cascade triggered by the same virus leads to an increased expression of endothelial cellular adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1], E-selectin, P-selectin, thrombomodulin, tissue plasminogen activator (tPA), and PAI-1. A significant association between increasing serum concentrations of adhe‐ sion molecules and risk of future myocardial infarction has been shown in apparently healthy men and women, and these molecules are now considered as soluble biomarkers of endothe‐ lial inflammation and early atherosclerosis [200, 201]. Increased serum levels of ICAM-1, VCAM-1, E-selectin, and thrombomodulin were demonstrated in patients with advanced HIV infection and opportunistic diseases. A correlation between ICAM-1 concentrations and the progression of disease as well as the reduction of CD4 lymphocyte count was also reported. If

 Glucose tolerance or Diabetes; Dyslipidemia; Fibrinolysis and Coagulation Disturbances (PAI‐1, tPA)

state of increased atherosclerotic risk [123].

Disease related factors (HIV infection)

tions, metabolic syndrome and cardiovascular disease risk

Lipid metabolism disturbances

and fat redistribution: Visceral fat Subcutaneous fat

FFA ( Dyslipidemia)

Hormones (Leptin, Resistin, Adiponectin)

Cytokines (TNF‐)

The pathophysiology of MS is complex – genetic factors, aging and weight gain associated with sedentariness and food habits constitute major risk factors. Also, decreased mitochon‐ drial function related to aging [183] and an age-related redistribution of fat towards the cen‐ tral, visceral areas are involved, leading to IR and metabolic abnormalities [7].

The components of the HIV lipodystrophy syndrome(s) bear a striking resemblance to those of MS [123]. Both can present hyperinsulinemia, glucose intolerance, central or abdominal obesity, hypertension, atherogenic lipid profile, hyperuricemia, prothromboticand proin‐ flammatory states [123].

Liver lesions of nonalcoholic steatohepatitis (or NASH) are a complication of MS, with a possible evolution towards severe liver complications such as cirrhosis. HIV-infected pa‐ tients, with IR in the context of a severe lipodystrophy, present an increased risk of liver le‐ sions [184]. Moreover, as HCV infection has been associated with steatosis and hepatic IR resulting from viral or metabolic effects, HCV co-infection could aggravate the metabolic and liver status of HIV-infected patients [185]. HIV-infected patients with MS are more like‐ ly to have higher values of carotid intima-media thickness (cIMT) and detectable coronary artery calcium score [186].

### **23. Clinical sequelae associated with HIV and HIV-lipodystrophy**

Different studies suggest that the CV risk is increased among HIV-infected patients on cART and the responsible mechanisms are complex: in addition to the direct effect of the virus on the vasculature, the toxicity of antiretroviral drugs and the set of metabolic alterations ag‐ gregated in the MS are involved [187]. Whether the increased CV risk is due to HIV infection itself, to ART, or to a synergistic interaction between these factors, remains to be established [167]. HIV infection itself may increase CV risk. The HIV surface glycoprotein gp120 can stimulate endothelial cell production of tissue factor, an early step in the development of atherosclerosis [188]. Both HIV infection and ART promote atherosclerosis and its clinical manifestations through inflammatory mechanisms involving endothelial cells, either direct‐ ly or indirectly, and also by inducing lipid alterations [189, 190].

Furthermore, some data suggest that endothelial dysfunction, impaired fibrinolysis, and ex‐ cess inflammation are more common in HIV-positive patients than in general population, which may contribute to an increased CV risk [191]. At the same time, cIMT and coronary calcification assessments suggest increased incidence of atherosclerotic disease and prema‐ ture occurrence of arterial atherosclerotic lesions among HIV-infected individuals [192]. Sur‐ rogate markers of atherosclerosis, including abnormal cIMT [193, 194], altered endothelial reactivity [195], abnormal coronary calcium scores [196], higher than expected C-reactive protein levels and abnormal proinflammatory and prothrombotic indices [197], all suggest a state of increased atherosclerotic risk [123].

tions, including increased LDL, decreased HDL, increased triglycerides, increased glycemia or diabetes and increased blood pressure [180-182]. All these parameters constitute a con‐ stellation of major CV risk factors [180]. This situation also includes low-grade inflammation

The pathophysiology of MS is complex – genetic factors, aging and weight gain associated with sedentariness and food habits constitute major risk factors. Also, decreased mitochon‐ drial function related to aging [183] and an age-related redistribution of fat towards the cen‐

The components of the HIV lipodystrophy syndrome(s) bear a striking resemblance to those of MS [123]. Both can present hyperinsulinemia, glucose intolerance, central or abdominal obesity, hypertension, atherogenic lipid profile, hyperuricemia, prothromboticand proin‐

Liver lesions of nonalcoholic steatohepatitis (or NASH) are a complication of MS, with a possible evolution towards severe liver complications such as cirrhosis. HIV-infected pa‐ tients, with IR in the context of a severe lipodystrophy, present an increased risk of liver le‐ sions [184]. Moreover, as HCV infection has been associated with steatosis and hepatic IR resulting from viral or metabolic effects, HCV co-infection could aggravate the metabolic and liver status of HIV-infected patients [185]. HIV-infected patients with MS are more like‐ ly to have higher values of carotid intima-media thickness (cIMT) and detectable coronary

**23. Clinical sequelae associated with HIV and HIV-lipodystrophy**

ly or indirectly, and also by inducing lipid alterations [189, 190].

Different studies suggest that the CV risk is increased among HIV-infected patients on cART and the responsible mechanisms are complex: in addition to the direct effect of the virus on the vasculature, the toxicity of antiretroviral drugs and the set of metabolic alterations ag‐ gregated in the MS are involved [187]. Whether the increased CV risk is due to HIV infection itself, to ART, or to a synergistic interaction between these factors, remains to be established [167]. HIV infection itself may increase CV risk. The HIV surface glycoprotein gp120 can stimulate endothelial cell production of tissue factor, an early step in the development of atherosclerosis [188]. Both HIV infection and ART promote atherosclerosis and its clinical manifestations through inflammatory mechanisms involving endothelial cells, either direct‐

Furthermore, some data suggest that endothelial dysfunction, impaired fibrinolysis, and ex‐ cess inflammation are more common in HIV-positive patients than in general population, which may contribute to an increased CV risk [191]. At the same time, cIMT and coronary calcification assessments suggest increased incidence of atherosclerotic disease and prema‐ ture occurrence of arterial atherosclerotic lesions among HIV-infected individuals [192]. Sur‐ rogate markers of atherosclerosis, including abnormal cIMT [193, 194], altered endothelial reactivity [195], abnormal coronary calcium scores [196], higher than expected C-reactive

tral, visceral areas are involved, leading to IR and metabolic abnormalities [7].

and a prothrombotic state [7].

280 Current Perspectives in HIV Infection

flammatory states [123].

artery calcium score [186].

### **IR, Adipokines and Lipodystrophy in HIV Infection**

**Figure 7.** The relationship between HIV infection, lipodystrophy, ART, insulin resistance, adipokines, metabolic altera‐ tions, metabolic syndrome and cardiovascular disease risk

Endothelial cells have been shown to be variably permissive for HIV infection. The HIV virus itself is able to penetrate coronary artery and brain microvascular endothelial cell membranes and to initiate inflammatory and biochemical intracellular reactions [198, 199]. The activation of endothelium induced by either HIV infection itself or by a leukocyte-mediated inflammato‐ ry cascade triggered by the same virus leads to an increased expression of endothelial cellular adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1), vascular adhesion molecule 1 (VCAM-1], E-selectin, P-selectin, thrombomodulin, tissue plasminogen activator (tPA), and PAI-1. A significant association between increasing serum concentrations of adhe‐ sion molecules and risk of future myocardial infarction has been shown in apparently healthy men and women, and these molecules are now considered as soluble biomarkers of endothe‐ lial inflammation and early atherosclerosis [200, 201]. Increased serum levels of ICAM-1, VCAM-1, E-selectin, and thrombomodulin were demonstrated in patients with advanced HIV infection and opportunistic diseases. A correlation between ICAM-1 concentrations and the progression of disease as well as the reduction of CD4 lymphocyte count was also reported. If circulating adhesion molecules indicate vascular endothelium injury, it seems clear that endo‐ thelium injury is associated with the progression and severity of HIV disease [202]. cART should reduce the endothelial damage by controlling HIV infection, but it would also contrib‐ ute to stimulating endothelial activation by deranging both lipid and glucose metabolism [167]. Some PIs, as ritonavir and indinavir are able to directly cause endothelial dysfunction, with mitochondrial DNA damage and cell death, independently of lipid profile [203]. cART may promote atherosclerosis both by direct effects on endothelial cells and by indirect effects associated with metabolic disturbances [167].

and reduced exercise, lipodystrophy, dyslipidemia, altered glucose tolerance with IR and low-grade infection with the ongoing drug-induced inflammation. It is important to be aware of these alterations and to apply risk-modification strategies to reduce CV risk in the

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

283

, Davide Carvalho, Selma Souto, António Sarmento and José Luís Medina

Department of Endocrinology, Centro Hospitalar São João and University of Porto Medical

[1] Capeau J, Magre J, Caron-Debarle M, Lagathu C, Antoine B, Bereziat V, et al. Human lipodystrophies: genetic and acquired diseases of adipose tissue. Endocr Dev.

[2] Garg A. Lipodystrophies: Genetic and Acquired Body Fat Disorders. J Clin Endocri‐

[3] Berardinelli W. An undiagnosed endocrinometabolic syndrome: report of 2 cases. J

[4] Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiv‐

[5] Snijder MB, Dekker JM, Visser M, Bouter LM, Stehouwer CD, Yudkin JS, et al. Trunk fat and leg fat have independent and opposite associations with fasting and postload

[6] Tershakovec AM, Frank I, Rader D. HIV-related lipodystrophy and related factors.

[7] Capeau J. From lipodystrophy and insulin resistance to metabolic syndrome: HIV in‐

[8] Caron-Debarle M, Lagathu C, Boccara F, Vigouroux C, Capeau J. HIV-associated lip‐ odystrophy: from fat injury to premature aging. Trends Mol Med. 2010 May;16 [5]:

[9] Giralt M, Domingo P, Villarroya F. Adipose tissue biology and HIV-infection. Best

HIV-infected patients.

School, Porto, Portugal

2010;19:1-20.

218-29.

nol Metab. 2011 Aug 24.

\*Address all correspondence to: paula\_freitas@sapo.pt

Clin Endocrinol Metab. 1954 Feb;14 [2]:193-204.

Atherosclerosis. 2004 May;174 [1]:1-10.

ing HIV protease inhibitors. AIDS. 1998 May 7;12 [7]:F51-8.

Pract Res Clin Endocrinol Metab. 2011 Jun;25 [3]:487-99.

glucose levels: the Hoorn study. Diabetes Care. 2004 Feb;27 [2]:372-7.

fection, treatment and aging. Curr Opin HIV AIDS. 2007 Jul;2 [4]:247-52.

**Author details**

Paula Freitas\*

**References**

Elevated serum levels of PAI-1, tPA, and CRP, as well as reduced serum levels of adiponec‐ tin could be considered biochemical markers of endothelial dysfunction, metabolic altera‐ tions, and CV risk in HIV-infected patients [192]. Some authors suggested that the pathogenetic mechanism responsible for carotid lesions associated with HIV infection may be more similar to an inflammatory process than to the classical atherogenesis [204, 205]. Some retrospective and prospective studies have shown that the incidence of myocardial in‐ farction in HIV-positive subjects treated with ART tends to be higher than in the general population, particularly in those receiving a PI-based treatment [206]. However, reports from large observational studies demonstrate that there is still considerable controversy re‐ garding the association of cART, particularly PI-based combinations, with increased inci‐ dence of coronary heart disease risk [167].

Moreover, prospective studies involving large cohorts of HIV-infected patients have docu‐ mented an increased incidence of myocardial infarction and cerebrovascular diseases in as‐ sociation with a prolonged exposure to cART. However, the absolute risk of CV events remains low, and should be balanced against the remarkable benefits ofcART in terms of im‐ provement in immune function and related morbidity and mortality [167].

In other words, incidence of CV disease in successfully cART-treated HIV-infected patients is low. However, the risk of CV disease is increased compared with that of uninfected peo‐ ple. This fact is due in great part to a higher prevalence of underlying traditional CV risk factors that are mostly host dependent. HIV may additionally contribute through immune activation, inflammation, and immunodeficiency. In a more modest way than HIV infection, the type of ART may also contribute, mainly through the impact on metabolic and body fat parameters, and possibly through other factors that are currently unclear. From the CV per‐ spective, the benefits of ART outweigh any potential risk [207, 208].

### **24. Conclusions**

Human lipodystrophies are a heterogeneous group of diseases with generalized or partial fat loss. They include rare genetic conditions or more frequent acquired forms, and may be old, or more recent, such as HIV-related lipodystrophy. Almost all lipodystrophies are asso‐ ciated with metabolic alterations including IR, diabetes, dyslipidemia and early CV disease. In this new context of increased aging of HIV-infected patients, increased metabolic and CV complications are to be expected due to high incidences of smoking status, over-nutrition and reduced exercise, lipodystrophy, dyslipidemia, altered glucose tolerance with IR and low-grade infection with the ongoing drug-induced inflammation. It is important to be aware of these alterations and to apply risk-modification strategies to reduce CV risk in the HIV-infected patients.

### **Author details**

circulating adhesion molecules indicate vascular endothelium injury, it seems clear that endo‐ thelium injury is associated with the progression and severity of HIV disease [202]. cART should reduce the endothelial damage by controlling HIV infection, but it would also contrib‐ ute to stimulating endothelial activation by deranging both lipid and glucose metabolism [167]. Some PIs, as ritonavir and indinavir are able to directly cause endothelial dysfunction, with mitochondrial DNA damage and cell death, independently of lipid profile [203]. cART may promote atherosclerosis both by direct effects on endothelial cells and by indirect effects

Elevated serum levels of PAI-1, tPA, and CRP, as well as reduced serum levels of adiponec‐ tin could be considered biochemical markers of endothelial dysfunction, metabolic altera‐ tions, and CV risk in HIV-infected patients [192]. Some authors suggested that the pathogenetic mechanism responsible for carotid lesions associated with HIV infection may be more similar to an inflammatory process than to the classical atherogenesis [204, 205]. Some retrospective and prospective studies have shown that the incidence of myocardial in‐ farction in HIV-positive subjects treated with ART tends to be higher than in the general population, particularly in those receiving a PI-based treatment [206]. However, reports from large observational studies demonstrate that there is still considerable controversy re‐ garding the association of cART, particularly PI-based combinations, with increased inci‐

Moreover, prospective studies involving large cohorts of HIV-infected patients have docu‐ mented an increased incidence of myocardial infarction and cerebrovascular diseases in as‐ sociation with a prolonged exposure to cART. However, the absolute risk of CV events remains low, and should be balanced against the remarkable benefits ofcART in terms of im‐

In other words, incidence of CV disease in successfully cART-treated HIV-infected patients is low. However, the risk of CV disease is increased compared with that of uninfected peo‐ ple. This fact is due in great part to a higher prevalence of underlying traditional CV risk factors that are mostly host dependent. HIV may additionally contribute through immune activation, inflammation, and immunodeficiency. In a more modest way than HIV infection, the type of ART may also contribute, mainly through the impact on metabolic and body fat parameters, and possibly through other factors that are currently unclear. From the CV per‐

Human lipodystrophies are a heterogeneous group of diseases with generalized or partial fat loss. They include rare genetic conditions or more frequent acquired forms, and may be old, or more recent, such as HIV-related lipodystrophy. Almost all lipodystrophies are asso‐ ciated with metabolic alterations including IR, diabetes, dyslipidemia and early CV disease. In this new context of increased aging of HIV-infected patients, increased metabolic and CV complications are to be expected due to high incidences of smoking status, over-nutrition

provement in immune function and related morbidity and mortality [167].

spective, the benefits of ART outweigh any potential risk [207, 208].

associated with metabolic disturbances [167].

282 Current Perspectives in HIV Infection

dence of coronary heart disease risk [167].

**24. Conclusions**

Paula Freitas\* , Davide Carvalho, Selma Souto, António Sarmento and José Luís Medina

\*Address all correspondence to: paula\_freitas@sapo.pt

Department of Endocrinology, Centro Hospitalar São João and University of Porto Medical School, Porto, Portugal

### **References**


[10] Sethi JK, Vidal-Puig AJ. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res. 2007 Jun;48 [6]: 1253-62.

[23] Villarroya J, Giralt M, Villarroya F. Mitochondrial DNA: an up-and-coming actor in white adipose tissue pathophysiology. Obesity (Silver Spring). 2009 Oct;17 [10]:

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

285

[24] Kovsan J, Osnis A, Maissel A, Mazor L, Tarnovscki T, Hollander L, et al. Depot-spe‐ cific adipocyte cell lines reveal differential drug-induced responses of white adipo‐ cytes--relevance for partial lipodystrophy. Am J Physiol Endocrinol Metab. 2009 Feb;

[25] Shadid S, Koutsari C, Jensen MD. Direct free fatty acid uptake into human adipo‐ cytes in vivo: relation to body fat distribution. Diabetes. 2007 May;56 [5]:1369-75. [26] Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in hu‐

[27] Sevastianova K, Sutinen J, Greco D, Sievers M, Salmenkivi K, Perttila J, et al. Com‐ parison of dorsocervical with abdominal subcutaneous adipose tissue in patients with and without antiretroviral therapy-associated lipodystrophy. Diabetes. 2011 Jul;

[28] Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, et al. Association be‐ tween altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin re‐

[29] Giralt M, Domingo P, Guallar JP, Rodriguez de la Concepcion ML, Alegre M, Domi‐ ngo JC, et al. HIV-1 infection alters gene expression in adipose tissue, which contrib‐ utes to HIV- 1/HAART-associated lipodystrophy. Antivir Ther. 2006;11 [6]:729-40. [30] Jan V, Cervera P, Maachi M, Baudrimont M, Kim M, Vidal H, et al. Altered fat differ‐ entiation and adipocytokine expression are inter-related and linked to morphological changes and insulin resistance in HIV-1-infected lipodystrophic patients. Antivir

[31] Nolan D, Hammond E, Martin A, Taylor L, Herrmann S, McKinnon E, et al. Mito‐ chondrial DNA depletion and morphologic changes in adipocytes associated with nucleoside reverse transcriptase inhibitor therapy. AIDS. 2003 Jun 13;17 [9]:1329-38. [32] Pace CS, Martin AM, Hammond EL, Mamotte CD, Nolan DA, Mallal SA. Mitochon‐ drial proliferation, DNA depletion and adipocyte differentiation in subcutaneous adipose tissue of HIV-positive HAART recipients. Antivir Ther. 2003 Aug;8 [4]:

[33] Villarroya F, Domingo P, Giralt M. Mechanisms of antiretroviral-induced mitochon‐ drial dysfunction in adipocytes and adipose tissue: in-vitro, animal and human adi‐

[34] McComsey GA, Libutti DE, O'Riordan M, Shelton JM, Storer N, Ganz J, et al. Mito‐ chondrial RNA and DNA alterations in HIV lipoatrophy are linked to antiretroviral

pose tissue studies. Curr Opin HIV AIDS. 2007 Jul;2 [4]:261-7.

therapy and not to HIV infection. Antivir Ther. 2008;13 [5]:715-22.

man obesity. J Clin Invest. 2004 Jun;113 [11]:1582-8.

sistance. Lancet. 2002 Mar 23;359 [9311]:1026-31.

1814-20.

296 [2]:E315-22.

60 [7]:1894-900.

Ther. 2004 Aug;9 [4]:555-64.

323-31.


[23] Villarroya J, Giralt M, Villarroya F. Mitochondrial DNA: an up-and-coming actor in white adipose tissue pathophysiology. Obesity (Silver Spring). 2009 Oct;17 [10]: 1814-20.

[10] Sethi JK, Vidal-Puig AJ. Thematic review series: adipocyte biology. Adipose tissue function and plasticity orchestrate nutritional adaptation. J Lipid Res. 2007 Jun;48 [6]:

[11] De Pauw A, Tejerina S, Raes M, Keijer J, Arnould T. Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am J Pathol. 2009

[12] Koh EH, Park JY, Park HS, Jeon MJ, Ryu JW, Kim M, et al. Essential role of mitochon‐ drial function in adiponectin synthesis in adipocytes. Diabetes. 2007 Dec;56 [12]:

[13] Gil A, Olza J, Gil-Campos M, Gomez-Llorente C, Aguilera CM. Is adipose tissue met‐ abolically different at different sites? Int J Pediatr Obes. 2011 Sep;6 Suppl 1:13-20.

[14] Despres JP, Nadeau A, Tremblay A, Ferland M, Moorjani S, Lupien PJ, et al. Role of deep abdominal fat in the association between regional adipose tissue distribution

[15] Kelley DE, Thaete FL, Troost F, Huwe T, Goodpaster BH. Subdivisions of subcutane‐ ous abdominal adipose tissue and insulin resistance. Am J Physiol Endocrinol Metab.

[16] Schoen RE, Evans RW, Sankey SS, Weissfeld JL, Kuller L. Does visceral adipose tis‐ sue differ from subcutaneous adipose tissue in fatty acid content? Int J Obes Relat

[17] Ross R, Shaw KD, Rissanen J, Martel Y, de Guise J, Avruch L. Sex differences in lean and adipose tissue distribution by magnetic resonance imaging: anthropometric rela‐

[18] Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia. 2002 Sep;45

[19] Ohtsubo K, Chen MZ, Olefsky JM, Marth JD. Pathway to diabetes through attenua‐ tion of pancreatic beta cell glycosylation and glucose transport. Nat Med. 2011 Sep;17

[20] Cinti S. Between brown and white: novel aspects of adipocyte differentiation. Ann

[21] Aron-Wisnewsky J, Tordjman J, Poitou C, Darakhshan F, Hugol D, Basdevant A, et al. Human adipose tissue macrophages: m1 and m2 cell surface markers in subcuta‐ neous and omental depots and after weight loss. J Clin Endocrinol Metab. 2009 Nov;

[22] Morton NM. Obesity and corticosteroids: 11beta-hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease. Mol Cell Endocrinol. 2010 Mar 25;316 [2]:

and glucose tolerance in obese women. Diabetes. 1989 Mar;38 [3]:304-9.

1253-62.

284 Current Perspectives in HIV Infection

2973-81.

Sep;175 [3]:927-39.

2000 May;278 [5]:E941-8.

[9]:1201-10.

[9]:1067-75.

94 [11]:4619-23.

154-64.

Med. 2011 Mar;43 [2]:104-15.

Metab Disord. 1996 Apr;20 [4]:346-52.

tionships. Am J Clin Nutr. 1994 Jun;59 [6]:1277-85.


[35] Lagathu C, Kim M, Maachi M, Vigouroux C, Cervera P, Capeau J, et al. HIV antire‐ troviral treatment alters adipokine expression and insulin sensitivity of adipose tis‐ sue in vitro and in vivo. Biochimie. 2005 Jan;87 [1]:65-71.

[47] Agarwal AK, Garg A. Congenital generalized lipodystrophy: significance of trigly‐ ceride biosynthetic pathways. Trends Endocrinol Metab. 2003 Jul;14 [5]:214-21.

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

287

[48] Magre J, Delepine M, Khallouf E, Gedde-Dahl T, Jr., Van Maldergem L, Sobel E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on

[49] Szymanski KM, Binns D, Bartz R, Grishin NV, Li WP, Agarwal AK, et al. The lipo‐ dystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A. 2007 Dec 26;104

[50] Fei W, Shui G, Gaeta B, Du X, Kuerschner L, Li P, et al. Fld1p, a functional homo‐ logue of human seipin, regulates the size of lipid droplets in yeast. J Cell Biol. 2008

[51] Payne VA, Grimsey N, Tuthill A, Virtue S, Gray SL, Dalla Nora E, et al. The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentia‐

[52] Kim CA, Delepine M, Boutet E, El Mourabit H, Le Lay S, Meier M, et al. Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lip‐

[53] Hayashi YK, Matsuda C, Ogawa M, Goto K, Tominaga K, Mitsuhashi S, et al. Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dys‐ trophy with generalized lipodystrophy. J Clin Invest. 2009 Sep;119 [9]:2623-33.

[54] Garg A, Agarwal AK. Caveolin-1: a new locus for human lipodystrophy. J Clin Endo‐

[55] Garg A, Speckman RA, Bowcock AM. Multisystem dystrophy syndrome due to nov‐ el missense mutations in the amino-terminal head and alpha-helical rod domains of

[56] Subramanyam L, Simha V, Garg A. Overlapping syndrome with familial partial lipo‐ dystrophy, Dunnigan variety and cardiomyopathy due to amino-terminal heterozy‐

[57] Hegele RA. Familial partial lipodystrophy: a monogenic form of the insulin resist‐

[58] Rajab A, Straub V, McCann LJ, Seelow D, Varon R, Barresi R, et al. Fatal cardiac ar‐ rhythmia and long-QT syndrome in a new form of congenital generalized lipodystro‐ phy with muscle rippling (CGL4] due to PTRF-CAVIN mutations. PLoS Genet. 2010

[59] Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected

gous missense lamin A/C mutations. Clin Genet. 2010 Jul;78 [1]:66-73.

odystrophy. J Clin Endocrinol Metab. 2008 Apr;93 [4]:1129-34.

the lamin A/C gene. Am J Med. 2002 May;112 [7]:549-55.

ance syndrome. Mol Genet Metab. 2000 Dec;71 [4]:539-44.

adults. N Engl J Med. 2005 Jan 6;352 [1]:48-62.

chromosome 11q13. Nat Genet. 2001 Aug;28 [4]:365-70.

[52]:20890-5.

Feb 11;180 [3]:473-82.

tion. Diabetes. 2008 Aug;57 [8]:2055-60.

crinol Metab. 2008 Apr;93 [4]:1183-5.

Mar;6 [3]:e1000874.


[47] Agarwal AK, Garg A. Congenital generalized lipodystrophy: significance of trigly‐ ceride biosynthetic pathways. Trends Endocrinol Metab. 2003 Jul;14 [5]:214-21.

[35] Lagathu C, Kim M, Maachi M, Vigouroux C, Cervera P, Capeau J, et al. HIV antire‐ troviral treatment alters adipokine expression and insulin sensitivity of adipose tis‐

[36] Lihn AS, Richelsen B, Pedersen SB, Haugaard SB, Rathje GS, Madsbad S, et al. In‐ creased expression of TNF-alpha, IL-6, and IL-8 in HALS: implications for reduced adiponectin expression and plasma levels. Am J Physiol Endocrinol Metab. 2003

[37] Sevastianova K, Sutinen J, Kannisto K, Hamsten A, Ristola M, Yki-Jarvinen H. Adi‐ pose tissue inflammation and liver fat in patients with highly active antiretroviral therapy-associated lipodystrophy. Am J Physiol Endocrinol Metab. 2008 Jul;295

[38] Villarroya F, Domingo P, Giralt M. Drug-induced lipotoxicity: lipodystrophy associ‐ ated with HIV-1 infection and antiretroviral treatment. Biochim Biophys Acta. 2010

[39] Nolan D, Hammond E, James I, McKinnon E, Mallal S. Contribution of nucleosideanalogue reverse transcriptase inhibitor therapy to lipoatrophy from the population

[40] Seip M. Lipodystrophy and gigantism with associated endocrine manifestations. A

[41] Van Maldergem L, Magre J, Khallouf TE, Gedde-Dahl T, Jr., Delepine M, Trygstad O, et al. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystro‐

[42] Agarwal AK, Simha V, Oral EA, Moran SA, Gorden P, O'Rahilly S, et al. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol

[43] Pardini VC, Victoria IM, Rocha SM, Andrade DG, Rocha AM, Pieroni FB, et al. Lep‐ tin levels, beta-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. J Clin Endocrinol Metab. 1998 Feb;83 [2]:

[44] Magre J, Delepine M, Van Maldergem L, Robert JJ, Maassen JA, Meier M, et al. Prev‐ alence of mutations in AGPAT2 among human lipodystrophies. Diabetes. 2003 Jun;

[45] Van Maldergem L, Da Silva H, Freitas P, D' Abronzo FH. Berardinelli-Seip Syn‐

[46] Garg A, Wilson R, Barnes R, Arioglu E, Zaidi Z, Gurakan F, et al. A gene for congeni‐ tal generalized lipodystrophy maps to human chromosome 9q34. J Clin Endocrinol

drome: a new Portuguese disease? Eur J Hum Genet. 1998 [6]:74A.

sue in vitro and in vivo. Biochimie. 2005 Jan;87 [1]:65-71.

to the cellular level. Antivir Ther. 2003 Dec;8 [6]:617-26.

phy. J Med Genet. 2002 Oct;39 [10]:722-33.

Metab. 2003 Oct;88 [10]:4840-7.

Metab. 1999 Sep;84 [9]:3390-4.

503-8.

52 [6]:1573-8.

new diencephalic syndrome? Acta Paediatr. 1959 Nov;48:555-74.

Nov;285 [5]:E1072-80.

Mar;1801 [3]:392-9.

[1]:E85-91.

286 Current Perspectives in HIV Infection


[60] Afifi AK, Mire-Salman J, Najjar S. The myopahtology of congenital generalized lipo‐ dystrophy light and electron microscopic observations. Johns Hopkins Med J. 1976 Dec;139 SUPPL:61-8.

[72] Torrelo A, Patel S, Colmenero I, Gurbindo D, Lendinez F, Hernandez A, et al. Chron‐ ic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

289

[73] Ramot Y, Czarnowicki T, Maly A, Navon-Elkan P, Zlotogorski A. Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature Syndrome:

[74] Dunnigan MG, Cochrane MA, Kelly A, Scott JW. Familial lipoatrophic diabetes with dominant transmission. A new syndrome. Q J Med. 1974 Jan;43 [169]:33-48.

[75] Kobberling J, Dunnigan MG. Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state. J Med Genet. 1986 Apr;23 [2]:

[76] Garg A, Peshock RM, Fleckenstein JL. Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab.

[77] Garg A. Gender differences in the prevalence of metabolic complications in familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab. 2000 May;85 [5]:

[78] Peters JM, Barnes R, Bennett L, Gitomer WM, Bowcock AM, Garg A. Localization of the gene for familial partial lipodystrophy (Dunnigan variety) to chromosome

[79] Cao H, Hegele RA. Nuclear lamin A/C R482Q mutation in canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet. 2000 Jan 1;9 [1]:

[80] Shackleton S, Lloyd DJ, Jackson SN, Evans R, Niermeijer MF, Singh BM, et al. LMNA, encoding lamin A/C, is mutated in partial lipodystrophy. Nat Genet. 2000

[81] Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, et al. Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan varie‐ ty) reveal recurrent missense mutations in the globular C-terminal domain of lamin

[82] Agarwal AK, Garg A. A novel heterozygous mutation in peroxisome proliferator-ac‐ tivated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin

[83] Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactiva‐ tion-deficient mutant, in familial partial lipodystrophy. Diabetes. 2002 Dec;51 [12]:

[84] Semple RK, Chatterjee VK, O'Rahilly S. PPAR gamma and human metabolic disease.

(CANDLE) syndrome. J Am Acad Dermatol. 2010 Mar;62 [3]:489-95.

A Case Report. Pediatr Dermatol. 2010 Jun 9.

1q21-22. Nat Genet. 1998 Mar;18 [3]:292-5.

A/C. Am J Hum Genet. 2000 Apr;66 [4]:1192-8.

Endocrinol Metab. 2002 Jan;87 [1]:408-11.

J Clin Invest. 2006 Mar;116 [3]:581-9.

120-7.

1776-82.

109-12.

3586-90.

Feb;24 [2]:153-6.

1999 Jan;84 [1]:170-4.


[72] Torrelo A, Patel S, Colmenero I, Gurbindo D, Lendinez F, Hernandez A, et al. Chron‐ ic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol. 2010 Mar;62 [3]:489-95.

[60] Afifi AK, Mire-Salman J, Najjar S. The myopahtology of congenital generalized lipo‐ dystrophy light and electron microscopic observations. Johns Hopkins Med J. 1976

[61] Bjornstad PG, Foerster A, Ihlen H. Cardiac findings in generalized lipodystrophy.

[62] Chandalia M, Garg A, Vuitch F, Nizzi F. Postmortem findings in congenital general‐

[63] Bhayana S, Siu VM, Joubert GI, Clarson CL, Cao H, Hegele RA. Cardiomyopathy in

[64] Young LW, Radebaugh JF, Rubin P, Sensenbrenner JA, Fiorelli G, McKusick VA. New syndrome manifested by mandibular hypoplasia, acroosteolysis, stiff joints and cutaneous atrophy (mandibuloacral dysplasia) in two unrelated boys. Birth Defects

[65] Simha V, Agarwal AK, Oral EA, Fryns JP, Garg A. Genetic and phenotypic heteroge‐ neity in patients with mandibuloacral dysplasia-associated lipodystrophy. J Clin En‐

[66] Freidenberg GR, Cutler DL, Jones MC, Hall B, Mier RJ, Culler F, et al. Severe insulin resistance and diabetes mellitus in mandibuloacral dysplasia. Am J Dis Child. 1992

[67] Novelli G, Muchir A, Sangiuolo F, Helbling-Leclerc A, D'Apice MR, Massart C, et al. Mandibuloacral dysplasia is caused by a mutation in LMNA-encoding lamin A/C.

[68] Agarwal AK, Fryns JP, Auchus RJ, Garg A. Zinc metalloproteinase, ZMPSTE24, is mutated in mandibuloacral dysplasia. Hum Mol Genet. 2003 Aug 15;12 [16]:

[69] Garg A, Hernandez MD, Sousa AB, Subramanyam L, Martinez de Villarreal L, dos Santos HG, et al. An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J Clin Endo‐

[70] Horikoshi A, Iwabuchi S, Iizuka Y, Hagiwara T, Amaki I. [A case of partial lipodys‐ trophy with erythema, dactylic deformities, calcification of the basal ganglia, immu‐ nological disorders and low IQ level (author's transl]. Rinsho Shinkeigaku. 1980 Mar;

[71] Tanaka M, Miyatani N, Yamada S, Miyashita K, Toyoshima I, Sakuma K, et al. He‐ reditary lipo-muscular atrophy with joint contracture, skin eruptions and hyper-

gamma-globulinemia: a new syndrome. Intern Med. 1993 Jan;32 [1]:42-5.

ized lipodystrophy. J Clin Endocrinol Metab. 1995 Oct;80 [10]:3077-81.

congenital complete lipodystrophy. Clin Genet. 2002 Apr;61 [4]:283-7.

Dec;139 SUPPL:61-8.

288 Current Perspectives in HIV Infection

Acta Paediatr Suppl. 1996 Jun;413:39-43.

Orig Artic Ser. 1971 Jun;7 [7]:291-7.

docrinol Metab. 2003 Jun;88 [6]:2821-4.

Am J Hum Genet. 2002 Aug;71 [2]:426-31.

crinol Metab. 2010 Sep;95 [9]:E58-63.

Jan;146 [1]:93-9.

1995-2001.

20 [3]:173-80.


[85] George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004 May 28;304 [5675]:1325-8.

[98] Garg A. Lipodystrophies. Am J Med. 2000 Feb;108 [2]:143-52.

Mar 26;338 [13]:853-60.

19;353 [9170]:2093-9.

[99] Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immuno‐ deficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

291

[100] Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diag‐ nosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodys‐ trophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet. 1999 Jun

[101] Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, et al. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS. 1998 Oct 22;12 [15]:F167-73.

[102] Thiebaut R, Daucourt V, Mercie P, Ekouevi DK, Malvy D, Morlat P, et al. Lipodystro‐ phy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine Cohort, France, 1999. Groupe d'Epidemiologie Clinique du Syndrome d'Immunode‐

[103] Dube MP, Johnson DL, Currier JS, Leedom JM. Protease inhibitor-associated hyper‐

[104] Carr A. HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management.

[105] Hawkins T. Appearance-related side effects of HIV-1 treatment. AIDS Patient Care

[106] Chen D, Misra A, Garg A. Clinical review 153: Lipodystrophy in human immunode‐ ficiency virus-infected patients. J Clin Endocrinol Metab. 2002 Nov;87 [11]:4845-56.

[107] Mallon PW, Miller J, Cooper DA, Carr A. Prospective evaluation of the effects of anti‐ retroviral therapy on body composition in HIV-1-infected men starting therapy.

[108] John M, Moore CB, James IR, Nolan D, Upton RP, McKinnon EJ, et al. Chronic hyper‐ lactatemia in HIV-infected patients taking antiretroviral therapy. AIDS. 2001 Apr

[109] Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet. 2000 Oct 21;356

[110] Martinez E, Mocroft A, Garcia-Viejo MA, Perez-Cuevas JB, Blanco JL, Mallolas J, et al. Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors:

[111] Heath KV, Hogg RS, Singer J, Chan KJ, O'Shaughnessy MV, Montaner JS. Antiretro‐ viral treatment patterns and incident HIV-associated morphologic and lipid abnor‐

a prospective cohort study. Lancet. 2001 Feb 24;357 [9256]:592-8.

ficience Acquise en Aquitaine. Clin Infect Dis. 2000 Dec;31 [6]:1482-7.

glycaemia. Lancet. 1997 Sep 6;350 [9079]:713-4.

AIDS. 2003 Apr;17 Suppl 1:S141-8.

STDS. 2006 Jan;20 [1]:6-18.

AIDS. 2003 May 2;17 [7]:971-9.

13;15 [6]:717-23.

[9239]:1423-30.


[98] Garg A. Lipodystrophies. Am J Med. 2000 Feb;108 [2]:143-52.

[85] George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science. 2004

[86] Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, et al. Partial lipo‐ dystrophy and insulin resistant diabetes in a patient with a homozygous nonsense

[87] Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med. 2011 Feb

[88] Olofsson SO, Bostrom P, Andersson L, Rutberg M, Levin M, Perman J, et al. Trigly‐ ceride containing lipid droplets and lipid droplet-associated proteins. Curr Opin Lip‐

[89] Caron M, Auclair M, Donadille B, Bereziat V, Guerci B, Laville M, et al. Human lipo‐ dystrophies linked to mutations in A-type lamins and to HIV protease inhibitor ther‐ apy are both associated with prelamin A accumulation, oxidative stress and

[90] Garg A, Subramanyam L, Agarwal AK, Simha V, Levine B, D'Apice MR, et al. Atypi‐ cal progeroid syndrome due to heterozygous missense LMNA mutations. J Clin En‐

[91] Merideth MA, Gordon LB, Clauss S, Sachdev V, Smith AC, Perry MB, et al. Pheno‐ type and course of Hutchinson-Gilford progeria syndrome. N Engl J Med. 2008 Feb

[92] Sensenbrenner JA, Hussels IE, Levin LS. A low birthweight syndrome, ? Rieger syn‐

[93] O'Neill B, Simha V, Kotha V, Garg A. Body fat distribution and metabolic variables in patients with neonatal progeroid syndrome. Am J Med Genet A. 2007 Jul 1;143A

[94] Garg A, Agarwal AK. Lipodystrophies: disorders of adipose tissue biology. Biochim

[95] Misra A, Garg A. Clinical features and metabolic derangements in acquired general‐ ized lipodystrophy: case reports and review of the literature. Medicine (Baltimore).

[96] Hegele RA, Cao H, Liu DM, Costain GA, Charlton-Menys V, Rodger NW, et al. Se‐ quencing of the reannotated LMNB2 gene reveals novel mutations in patients with

[97] Mathieson PW, Wurzner R, Oliveria DB, Lachmann PJ, Peters DK. Complementmediated adipocyte lysis by nephritic factor sera. J Exp Med. 1993 Jun 1;177 [6]:

acquired partial lipodystrophy. Am J Hum Genet. 2006 Aug;79 [2]:383-9.

premature cellular senescence. Cell Death Differ. 2007 Oct;14 [10]:1759-67.

mutation in CIDEC. EMBO Mol Med. 2009 Aug;1 [5]:280-7.

May 28;304 [5675]:1325-8.

idol. 2008 Oct;19 [5]:441-7.

docrinol Metab. 2009 Dec;94 [12]:4971-83.

Biophys Acta. 2009 Jun;1791 [6]:507-13.

drome. Birth Defects Orig Artic Ser. 1975;11 [2]:423-6.

24;364 [8]:740-8.

290 Current Perspectives in HIV Infection

7;358 [6]:592-604.

[13]:1421-30.

1827-31.

2003 Mar;82 [2]:129-46.


malities in a population-based chort. J Acquir Immune Defic Syndr. 2002 Aug 1;30 [4]:440-7.

[124] Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella FJ, Jr., et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population.

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

293

[125] Periard D, Telenti A, Sudre P, Cheseaux JJ, Halfon P, Reymond MJ, et al. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss

[126] Grinspoon S. Mechanisms and strategies for insulin resistance in acquired immune

[127] Caron M, Vigouroux C, Bastard JP, Capeau J. Adipocyte dysfunction in response to antiretroviral therapy: clinical, tissue and in-vitro studies. Curr Opin HIV AIDS. 2007

[128] Hudon SE, Coffinier C, Michaelis S, Fong LG, Young SG, Hrycyna CA. HIV-protease inhibitors block the enzymatic activity of purified Ste24p. Biochem Biophys Res

[129] Lagathu C, Eustace B, Prot M, Frantz D, Gu Y, Bastard JP, et al. Some HIV antiretro‐ virals increase oxidative stress and alter chemokine, cytokine or adiponectin produc‐

tion in human adipocytes and macrophages. Antivir Ther. 2007;12 [4]:489-500. [130] Flint OP, Noor MA, Hruz PW, Hylemon PB, Yarasheski K, Kotler DP, et al. The role of protease inhibitors in the pathogenesis of HIV-associated lipodystrophy: cellular

[131] Djedaini M, Peraldi P, Drici MD, Darini C, Saint-Marc P, Dani C, et al. Lopinavir coinduces insulin resistance and ER stress in human adipocytes. Biochem Biophys Res

[132] Caron M, Auclair M, Vigouroux C, Glorian M, Forest C, Capeau J. The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance.

[133] Dowell P, Flexner C, Kwiterovich PO, Lane MD. Suppression of preadipocyte differ‐ entiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem.

[134] Lenhard JM, Furfine ES, Jain RG, Ittoop O, Orband-Miller LA, Blanchard SG, et al. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral

[135] Caron M, Auclair M, Sterlingot H, Kornprobst M, Capeau J. Some HIV protease in‐ hibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and

[136] Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by

HIV protease inhibitor therapy. J Biol Chem. 2000 Jul 7;275 [27]:20251-4.

adipocyte differentiation. AIDS. 2003 Nov 21;17 [17]:2437-44.

mechanisms and clinical implications. Toxicol Pathol. 2009;37 [1]:65-77.

HIV Cohort Study. Circulation. 1999 Aug 17;100 [7]:700-5.

deficiency syndrome. Clin Infect Dis. 2003;37 Suppl 2:S85-90.

AIDS. 2001 Jul 27;15 [11]:1389-98.

Commun. 2008 Sep 19;374 [2]:365-8.

Commun. 2009 Aug 14;386 [1]:96-100.

Diabetes. 2001 Jun;50 [6]:1378-88.

2000 Dec 29;275 [52]:41325-32.

Res. 2000 Aug;47 [2]:121-9.

Jul;2 [4]:268-73.


[124] Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella FJ, Jr., et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS. 2001 Jul 27;15 [11]:1389-98.

malities in a population-based chort. J Acquir Immune Defic Syndr. 2002 Aug 1;30

[112] Nguyen A, Calmy A, Schiffer V, Bernasconi E, Battegay M, Opravil M, et al. Lipodys‐ trophy and weight changes: data from the Swiss HIV Cohort Study, 2000-2006. HIV

[113] Miller J, Carr A, Emery S, Law M, Mallal S, Baker D, et al. HIV lipodystrophy: preva‐ lence, severity and correlates of risk in Australia. HIV Med. 2003 Jul;4 [3]:293-301. [114] Mallon PW. Antiretroviral therapy-induced lipid alterations: in-vitro, animal and hu‐

[115] van Leuven SI, Sankatsing RR, Vermeulen JN, Kastelein JJ, Reiss P, Stroes ES. Athe‐ rosclerotic vascular disease in HIV: it is not just antiretroviral therapy that hurts the

[116] Saves M, Raffi F, Capeau J, Rozenbaum W, Ragnaud JM, Perronne C, et al. Factors related to lipodystrophy and metabolic alterations in patients with human immuno‐ deficiency virus infection receiving highly active antiretroviral therapy. Clin Infect

[117] Calmy A, Hirschel B, Cooper DA, Carr A. A new era of antiretroviral drug toxicity.

[118] Crowe SM, Westhorpe CL, Mukhamedova N, Jaworowski A, Sviridov D, Bukrinsky M. The macrophage: the intersection between HIV infection and atherosclerosis. J

[119] Jacobson DL, Knox T, Spiegelman D, Skinner S, Gorbach S, Wanke C. Prevalence of, evolution of, and risk factors for fat atrophy and fat deposition in a cohort of HIV-

[120] Bastard JP, Maachi M, Lagathu C, Kim MJ, Caron M, Vidal H, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cyto‐

[121] Otake K, Omoto S, Yamamoto T, Okuyama H, Okada H, Okada N, et al. HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors. AIDS. 2004 Jan 23;18 [2]:189-98. [122] Shrivastav S, Kino T, Cunningham T, Ichijo T, Schubert U, Heinklein P, et al. Human immunodeficiency virus (HIV)-1 viral protein R suppresses transcriptional activity of peroxisome proliferator-activated receptor {gamma} and inhibits adipocyte differen‐ tiation: implications for HIV-associated lipodystrophy. Mol Endocrinol. 2008 Feb;22

[123] Falutz J. Therapy insight: Body-shape changes and metabolic complications associat‐ ed with HIV and highly active antiretroviral therapy. Nat Clin Pract Endocrinol Met‐

infected men and women. Clin Infect Dis. 2005 Jun 15;40 [12]:1837-45.

man studies. Curr Opin HIV AIDS. 2007 Jul;2 [4]:282-92.

heart! Curr Opin HIV AIDS. 2007 Jul;2 [4]:324-31.

Dis. 2002 May 15;34 [10]:1396-405.

Antivir Ther. 2009;14 [2]:165-79.

Leukoc Biol. 2010 Apr;87 [4]:589-98.

kine Netw. 2006 Mar;17 [1]:4-12.

[2]:234-47.

ab. 2007 Sep;3 [9]:651-61.

[4]:440-7.

292 Current Perspectives in HIV Infection

Med. 2008 Mar;9 [3]:142-50.


[137] Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nu‐ cleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet. 1999 Sep 25;354 [9184]: 1112-5.

flammatory changes in the interaction between adipocytes and macrophages. Arte‐

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

295

[149] Sutinen J, Kannisto K, Korsheninnikova E, Nyman T, Ehrenborg E, Andrew R, et al. In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11betahydroxysteroid dehydrogenase type 1 in adipose tissue. Diabetologia. 2004 Oct;47

[150] Kratz M, Purnell JQ, Breen PA, Thomas KK, Utzschneider KM, Carr DB, et al. Re‐ duced adipogenic gene expression in thigh adipose tissue precedes human immuno‐ deficiency virus-associated lipoatrophy. J Clin Endocrinol Metab. 2008 Mar;93 [3]:

[151] Gougeon ML, Penicaud L, Fromenty B, Leclercq P, Viard JP, Capeau J. Adipocytes targets and actors in the pathogenesis of HIV-associated lipodystrophy and metabol‐

[152] Rietschel P, Hadigan C, Corcoran C, Stanley T, Neubauer G, Gertner J, et al. Assess‐ ment of growth hormone dynamics in human immunodeficiency virus-related lipo‐

[153] Lo JC, Mulligan K, Noor MA, Schwarz JM, Halvorsen RA, Grunfeld C, et al. The ef‐ fects of recombinant human growth hormone on body composition and glucose me‐ tabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab.

[154] Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from

[155] Wu D, Ren Z, Pae M, Guo W, Cui X, Merrill AH, et al. Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J Immunol. 2007 Oct 1;179 [7]:

[156] Effros RB, Fletcher CV, Gebo K, Halter JB, Hazzard WR, Horne FM, et al. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future

[157] Tarr PE, Taffe P, Bleiber G, Furrer H, Rotger M, Martinez R, et al. Modeling the influ‐ ence of APOC3, APOE, and TNF polymorphisms on the risk of antiretroviral thera‐

[158] Wangsomboonsiri W, Mahasirimongkol S, Chantarangsu S, Kiertiburanakul S, Char‐ oenyingwattana A, Komindr S, et al. Association between HLA-B\*4001 and lipodys‐ trophy among HIV-infected patients from Thailand who received a stavudine-

containing antiretroviral regimen. Clin Infect Dis. 2010 Feb 15;50 [4]:597-604.

py-associated lipid disorders. J Infect Dis. 2005 May 1;191 [9]:1419-26.

rioscler Thromb Vasc Biol. 2007 Jan;27 [1]:84-91.

ic alterations. Antivir Ther. 2004 Apr;9 [2]:161-77.

dystrophy. J Clin Endocrinol Metab. 2001 Feb;86 [2]:504-10.

studies in humans. Mech Ageing Dev. 2007 Jan;128 [1]:92-105.

research directions. Clin Infect Dis. 2008 Aug 15;47 [4]:542-53.

[10]:1668-71.

959-66.

2001 Aug;86 [8]:3480-7.

4829-39.


flammatory changes in the interaction between adipocytes and macrophages. Arte‐ rioscler Thromb Vasc Biol. 2007 Jan;27 [1]:84-91.

[149] Sutinen J, Kannisto K, Korsheninnikova E, Nyman T, Ehrenborg E, Andrew R, et al. In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing's syndrome is associated with increased regeneration of cortisol by 11betahydroxysteroid dehydrogenase type 1 in adipose tissue. Diabetologia. 2004 Oct;47 [10]:1668-71.

[137] Brinkman K, Smeitink JA, Romijn JA, Reiss P. Mitochondrial toxicity induced by nu‐ cleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet. 1999 Sep 25;354 [9184]:

[138] McComsey G, Bai RK, Maa JF, Seekins D, Wong LJ. Extensive investigations of mito‐ chondrial DNA genome in treated HIV-infected subjects: beyond mitochondrial

[139] van Vonderen MG, van Agtmael MA, Hassink EA, Milinkovic A, Brinkman K, Geerl‐ ings SE, et al. Zidovudine/lamivudine for HIV-1 infection contributes to limb fat loss.

[140] Boothby M, McGee KC, Tomlinson JW, Gathercole LL, McTernan PG, Shojaee-Mora‐ die F, et al. Adipocyte differentiation, mitochondrial gene expression and fat distri‐ bution: differences between zidovudine and tenofovir after 6 months. Antivir Ther.

[141] Reiss P, Casula M, de Ronde A, Weverling GJ, Goudsmit J, Lange JM. Greater and more rapid depletion of mitochondrial DNA in blood of patients treated with dual (zidovudine+didanosine or zidovudine+zalcitabine) vs. single (zidovudine) nucleo‐

[142] Hadigan C, Borgonha S, Rabe J, Young V, Grinspoon S. Increased rates of lipolysis among human immunodeficiency virus-infected men receiving highly active antire‐

[143] Roche R, Poizot-Martin I, Yazidi CM, Compe E, Gastaut JA, Torresani J, et al. Effects of antiretroviral drug combinations on the differentiation of adipocytes. AIDS. 2002

[144] van Vonderen MG, Blumer RM, Hassink EA, Sutinen J, Ackermans MT, van Agtmael MA, et al. Insulin sensitivity in multiple pathways is differently affected during zido‐ vudine/lamivudine-containing compared with NRTI-sparing combination antiretro‐

[145] Guaraldi G, Baraboutis IG. Evolving perspectives on HIV-associated lipodystrophy syndrome: moving from lipodystrophy to non-infectious HIV co-morbidities. J Anti‐

[146] Sekiya M, Hiraishi A, Touyama M, Sakamoto K. Oxidative stress induced lipid accu‐ mulation via SREBP1c activation in HepG2 cells. Biochem Biophys Res Commun.

[147] Szendroedi J, Roden M. Ectopic lipids and organ function. Curr Opin Lipidol. 2009

[148] Suganami T, Tanimoto-Koyama K, Nishida J, Itoh M, Yuan X, Mizuarai S, et al. Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced in‐

viral therapy. J Acquir Immune Defic Syndr. 2010 Feb 1;53 [2]:186-93.

side reverse transcriptase inhibitors. HIV Med. 2004 Jan;5 [1]:11-4.

troviral therapy. Metabolism. 2002 Sep;51 [9]:1143-7.

microb Chemother. 2009 Sep;64 [3]:437-40.

2008 Oct 31;375 [4]:602-7.

Feb;20 [1]:50-6.

DNA depletion. J Acquir Immune Defic Syndr. 2005 Jun 1;39 [2]:181-8.

1112-5.

294 Current Perspectives in HIV Infection

PLoS One. 2009;4 [5]:e5647.

2009;14 [8]:1089-100.

Jan 4;16 [1]:13-20.


[159] Zanone Poma B, Riva A, Nasi M, Cicconi P, Broggini V, Lepri AC, et al. Genetic poly‐ morphisms differently influencing the emergence of atrophy and fat accumulation in HIV-related lipodystrophy. AIDS. 2008 Sep 12;22 [14]:1769-78.

[172] Mukhopadhyay A, Wei B, Zullo SJ, Wood LV, Weiner H. In vitro evidence of inhibition of mitochondrial protease processing by HIV-1 protease inhibitors in yeast: a possible

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

297

contribution to lipodystrophy syndrome. Mitochondrion. 2002 Oct;1 [6]:511-8.

redistribution. Metabolism. 2002 Feb;51 [2]:260-6.

clearance in mice. J Lipid Res. 2002 Sep;43 [9]:1458-63.

ol Chem. 2001 Oct 5;276 [40]:37514-9.

Jan-Mar;13 [1]:49-56.

Dec;7 [12]:1327-31.

1643-51.

25;112 [17]:2735-52.

Suppl 1]:S10-6.

[173] Meininger G, Hadigan C, Laposata M, Brown J, Rabe J, Louca J, et al. Elevated con‐ centrations of free fatty acids are associated with increased insulin response to stand‐ ard glucose challenge in human immunodeficiency virus-infected subjects with fat

[174] Calza L, Manfredi R, Chiodo F. Hyperlipidaemia in patients with HIV-1 infection re‐ ceiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical

[175] Estrada V, Portilla J. Dyslipidemia related to antiretroviral therapy. AIDS Rev. 2011

[176] Liang JS, Distler O, Cooper DA, Jamil H, Deckelbaum RJ, Ginsberg HN, et al. HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med. 2001

[177] Riddle TM, Schildmeyer NM, Phan C, Fichtenbaum CJ, Hui DY. The HIV protease inhibitor ritonavir increases lipoprotein production and has no effect on lipoprotein

[178] Riddle TM, Kuhel DG, Woollett LA, Fichtenbaum CJ, Hui DY. HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accu‐ mulation of activated sterol regulatory element-binding proteins in the nucleus. J Bi‐

[179] Zaera MG, Miro O, Pedrol E, Soler A, Picon M, Cardellach F, et al. Mitochondrial in‐ volvement in antiretroviral therapy-related lipodystrophy. AIDS. 2001 Sep 7;15 [13]:

[180] Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diag‐ nosis and management of the metabolic syndrome: an American Heart Association/ National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005 Oct

[181] Gazzaruso C, Sacchi P, Garzaniti A, Fratino P, Bruno R, Filice G. Prevalence of meta‐ bolic syndrome among HIV patients. Diabetes Care. 2002 Jul;25 [7]:1253-4.

[182] Wand H, Calmy A, Carey DL, Samaras K, Carr A, Law MG, et al. Metabolic syn‐ drome, cardiovascular disease and type 2 diabetes mellitus after initiation of antire‐

[183] Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med. 2006 May;119 [5

troviral therapy in HIV infection. AIDS. 2007 Nov 30;21 [18]:2445-53.

course and management. Int J Antimicrob Agents. 2003 Aug;22 [2]:89-99.


[172] Mukhopadhyay A, Wei B, Zullo SJ, Wood LV, Weiner H. In vitro evidence of inhibition of mitochondrial protease processing by HIV-1 protease inhibitors in yeast: a possible contribution to lipodystrophy syndrome. Mitochondrion. 2002 Oct;1 [6]:511-8.

[159] Zanone Poma B, Riva A, Nasi M, Cicconi P, Broggini V, Lepri AC, et al. Genetic poly‐ morphisms differently influencing the emergence of atrophy and fat accumulation in

[160] Maurin T, Saillan-Barreau C, Cousin B, Casteilla L, Doglio A, Penicaud L. Tumor ne‐ crosis factor-alpha stimulates HIV-1 production in primary culture of human adipo‐

[161] Sankale JL, Tong Q, Hadigan CM, Tan G, Grinspoon SK, Kanki PJ, et al. Regulation of adiponectin in adipocytes upon exposure to HIV-1. HIV Med. 2006 May;7 [4]:268-74.

[162] Hammond E, Nolan D. Adipose tissue inflammation and altered adipokine and cyto‐ kine production in antiretroviral therapy-associated lipodystrophy. Curr Opin HIV

[163] Unger RH, Clark GO, Scherer PE, Orci L. Lipid homeostasis, lipotoxicity and the

[164] Giralt M, Diaz-Delfin J, Gallego-Escuredo JM, Villarroya J, Domingo P, Villarroya F. Lipotoxicity on the basis of metabolic syndrome and lipodystrophy in HIV-1-infected patients under antiretroviral treatment. Curr Pharm Des. 2010 Oct;16 [30]:3371-8. [165] Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the Metabolic Syndrome--an allostatic perspective. Biochim Biophys Acta. 2010 Mar;1801 [3]:338-49.

[166] Brown TT, Li X, Cole SR, Kingsley LA, Palella FJ, Riddler SA, et al. Cumulative expo‐ sure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS. 2005 Sep 2;19 [13]:

[167] Calza L, Manfredi R, Pocaterra D, Chiodo F. Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy. J In‐

[168] Behrens GM, Boerner AR, Weber K, van den Hoff J, Ockenga J, Brabant G, et al. Im‐ paired glucose phosphorylation and transport in skeletal muscle cause insulin resist‐ ance in HIV-1-infected patients with lipodystrophy. J Clin Invest. 2002 Nov;110 [9]:

[169] Noor MA, Flint OP, Maa JF, Parker RA. Effects of atazanavir/ritonavir and lopinavir/ ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro

[170] Schambelan M, Benson CA, Carr A, Currier JS, Dube MP, Gerber JG, et al. Manage‐ ment of metabolic complications associated with antiretroviral therapy for HIV-1 in‐ fection: recommendations of an International AIDS Society-USA panel. J Acquir

[171] Hruz PW. Molecular Mechanisms for Altered Glucose Homeostasis in HIV Infection.

and clinically. AIDS. 2006 Sep 11;20 [14]:1813-21.

Immune Defic Syndr. 2002 Nov 1;31 [3]:257-75.

Am J Infect Dis. 2006;2 [3]:187-92.

metabolic syndrome. Biochim Biophys Acta. 2010 Mar;1801 [3]:209-14.

HIV-related lipodystrophy. AIDS. 2008 Sep 12;22 [14]:1769-78.

cytes. Exp Cell Res. 2005 Apr 1;304 [2]:544-51.

AIDS. 2007 Jul;2 [4]:274-81.

1375-83.

296 Current Perspectives in HIV Infection

1319-27.

fect. 2008 Jul;57 [1]:16-32.


[184] Lemoine M, Barbu V, Girard PM, Kim M, Bastard JP, Wendum D, et al. Altered hep‐ atic expression of SREBP-1 and PPARgamma is associated with liver injury in insu‐ lin-resistant lipodystrophic HIV-infected patients. AIDS. 2006 Feb 14;20 [3]:387-95.

[197] Fisher SD, Miller TL, Lipshultz SE. Impact of HIV and highly active antiretroviral therapy on leukocyte adhesion molecules, arterial inflammation, dyslipidemia, and

Lipodystrophy: The Metabolic Link of HIV Infection with Insulin-Resistance Syndrome

http://dx.doi.org/10.5772/52685

299

[198] Stefano GB, Salzet M, Bilfinger TV. Long-term exposure of human blood vessels to HIV gp120, morphine, and anandamide increases endothelial adhesion of monocytes: un‐

coupling of nitric oxide release. J Cardiovasc Pharmacol. 1998 Jun;31 [6]:862-8.

[199] Ren Z, Yao Q, Chen C. HIV-1 envelope glycoprotein 120 increases intercellular adhe‐ sion molecule-1 expression by human endothelial cells. Lab Invest. 2002 Mar;82 [3]:

[200] Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM, Jr., et al. Cir‐ culating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atheroscle‐ rosis and incident coronary heart disease cases: the Atherosclerosis Risk In

[201] Jager A, van Hinsbergh VW, Kostense PJ, Emeis JJ, Nijpels G, Dekker JM, et al. In‐ creased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study. Diabetes. 2000 Mar;49 [3]:

[202] Galea P, Vermot-Desroches C, Le Contel C, Wijdenes J, Chermann JC. Circulating cell adhesion molecules in HIV1-infected patients as indicator markers for AIDS progres‐

[203] Zhong DS, Lu XH, Conklin BS, Lin PH, Lumsden AB, Yao Q, et al. HIV protease in‐ hibitor ritonavir induces cytotoxicity of human endothelial cells. Arterioscler Thromb

[204] Maggi P, Perilli F, Lillo A, Carito V, Epifani G, Bellacosa C, et al. An ultrasoundbased comparative study on carotid plaques in HIV-positive patients vs. atheroscler‐ otic and arteritis patients: atherosclerotic or inflammatory lesions? Coron Artery Dis.

[205] Coll B, Parra S, Alonso-Villaverde C, Aragones G, Montero M, Camps J, et al. The role of immunity and inflammation in the progression of atherosclerosis in patients

[206] Stein JH. Managing cardiovascular risk in patients with HIV infection. J Acquir Im‐

[207] Martinez E, Larrousse M, Gatell JM. Cardiovascular disease and HIV infection: host,

[208] Sabin CA, d'Arminio Monforte A, Friis-Moller N, Weber R, El-Sadr WM, Reiss P, et al. Changes over time in risk factors for cardiovascular disease and use of lipid-low‐ ering drugs in HIV-infected individuals and impact on myocardial infarction. Clin

Communities (ARIC) study. Circulation. 1997 Dec 16;96 [12]:4219-25.

atherosclerosis. Atherosclerosis. 2006 Mar;185 [1]:1-11.

sion. Res Immunol. 1997 Feb;148 [2]:109-17.

with HIV infection. Stroke. 2007 Sep;38 [9]:2477-84.

virus, or drugs? Curr Opin Infect Dis. 2009 Feb;22 [1]:28-34.

mune Defic Syndr. 2005 Feb 1;38 [2]:115-23.

Infect Dis. 2008 Apr 1;46 [7]:1101-10.

Vasc Biol. 2002 Oct 1;22 [10]:1560-6.

2007 Feb;18 [1]:23-9.

245-55.

485-91.


[197] Fisher SD, Miller TL, Lipshultz SE. Impact of HIV and highly active antiretroviral therapy on leukocyte adhesion molecules, arterial inflammation, dyslipidemia, and atherosclerosis. Atherosclerosis. 2006 Mar;185 [1]:1-11.

[184] Lemoine M, Barbu V, Girard PM, Kim M, Bastard JP, Wendum D, et al. Altered hep‐ atic expression of SREBP-1 and PPARgamma is associated with liver injury in insu‐ lin-resistant lipodystrophic HIV-infected patients. AIDS. 2006 Feb 14;20 [3]:387-95.

[185] Howard AA, Lo Y, Floris-Moore M, Klein RS, Fleischer N, Schoenbaum EE. Hepatitis C virus infection is associated with insulin resistance among older adults with or at

[186] Mangili A, Jacobson DL, Gerrior J, Polak JF, Gorbach SL, Wanke CA. Metabolic syn‐ drome and subclinical atherosclerosis in patients infected with HIV. Clin Infect Dis.

[187] Triant VA, Grinspoon SK. Vascular dysfunction and cardiovascular complications.

[188] Schecter AD, Berman AB, Yi L, Mosoian A, McManus CM, Berman JW, et al. HIV en‐ velope gp120 activates human arterial smooth muscle cells. Proc Natl Acad Sci U S

[189] de Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis. 2004

[190] Thomas CM, Smart EJ. How HIV protease inhibitors promote atherosclerotic lesion

[191] Koppel K, Bratt G, Schulman S, Bylund H, Sandstrom E. Hypofibrinolytic state in HIV-1-infected patients treated with protease inhibitor-containing highly active anti‐

[192] Kamin DS, Grinspoon SK. Cardiovascular disease in HIV-positive patients. AIDS.

[193] Mercie P, Thiebaut R, Aurillac-Lavignolle V, Pellegrin JL, Yvorra-Vives MC, Cipriano C, et al. Carotid intima-media thickness is slightly increased over time in HIV-1-in‐

[194] Currier JS, Kendall MA, Henry WK, Alston-Smith B, Torriani FJ, Tebas P, et al. Pro‐ gression of carotid artery intima-media thickening in HIV-infected and uninfected

[195] Stein JH, Klein MA, Bellehumeur JL, McBride PE, Wiebe DA, Otvos JD, et al. Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation. 2001 Jul 17;104 [3]:

[196] Meng Q, Lima JA, Lai H, Vlahov D, Celentano DD, Strathdee SA, et al. Coronary ar‐ tery calcification, atherogenic lipid changes, and increased erythrocyte volume in black injection drug users infected with human immunodeficiency virus-1 treated

with protease inhibitors. Am Heart J. 2002 Oct;144 [4]:642-8.

retroviral therapy. J Acquir Immune Defic Syndr. 2002 Apr 15;29 [5]:441-9.

risk of HIV infection. AIDS. 2007 Mar 12;21 [5]:633-41.

Curr Opin HIV AIDS. 2007 Jul;2 [4]:299-304.

formation. Curr Opin Lipidol. 2007 Oct;18 [5]:561-5.

fected patients. HIV Med. 2005 Nov;6 [6]:380-7.

adults. AIDS. 2007 May 31;21 [9]:1137-45.

2007 May 15;44 [10]:1368-74.

A. 2001 Aug 28;98 [18]:10142-7.

Apr;4 [4]:213-22.

298 Current Perspectives in HIV Infection

2005 Apr 29;19 [7]:641-52.

257-62.


**Chapter 13**

**HIV/AIDS: Vertical Transmission**

Additional information is available at the end of the chapter

In The Eight Millennium Development Goals, the World Health Organization proposed to attempt at reverting the world negative HIV/AIDS epidemics through disease prevention and treatment for the year 2015. Attaining virtual elimination of Vertical Transmission (Pre‐

The current chapter will address topics related to epidemiologic, pathophysiological, diag‐ nostic and therapeutic aspects of vertical transmission of the Human Immunodeficiency Vi‐ rus (HIV). Such information will enable the reader to understand how the health strategies aiming at preventing transmission to the fetus have turned into a paradigm of Perinatal Medicine, since the implementation of a series of biomedical interventions has proven to be successful to prevent transmission of HIV from an infected pregnant mother to her child.

Prevalence of Vertical Transmission (VT) in the different regions of the world varies with geographic location and, specifically, with the economic resources invested by the different countries to support various strategies applied to health care policies that aim at the preven‐ tion and treatment of infected mothers. Proof of thereof is the fact that in countries with gov‐ ernment programs in which the economic support is sufficient to implement the planned

HIV epidemics are showing a trend towards stabilization worldwide. Thus, in 2009 approxi‐ mately 2.6 million persons became newly infected by the virus, representing 19% fewer than

and reproduction in any medium, provided the original work is properly cited.

© 2013 Rubio; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

strategies for VT prevention, the prevalence of perinatal infection is under 2% [2,3].

vention of mother-to-child transmission, PMTCT) worldwide is one of such aims [1].

Enrique Valdés Rubio

http://dx.doi.org/10.5772/53204

**1. Introduction**

**2. Epidemiology**

World Epidemiological Status

**Chapter 13**

### **HIV/AIDS: Vertical Transmission**

### Enrique Valdés Rubio

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53204

### **1. Introduction**

In The Eight Millennium Development Goals, the World Health Organization proposed to attempt at reverting the world negative HIV/AIDS epidemics through disease prevention and treatment for the year 2015. Attaining virtual elimination of Vertical Transmission (Pre‐ vention of mother-to-child transmission, PMTCT) worldwide is one of such aims [1].

The current chapter will address topics related to epidemiologic, pathophysiological, diag‐ nostic and therapeutic aspects of vertical transmission of the Human Immunodeficiency Vi‐ rus (HIV). Such information will enable the reader to understand how the health strategies aiming at preventing transmission to the fetus have turned into a paradigm of Perinatal Medicine, since the implementation of a series of biomedical interventions has proven to be successful to prevent transmission of HIV from an infected pregnant mother to her child.

### **2. Epidemiology**

#### World Epidemiological Status

Prevalence of Vertical Transmission (VT) in the different regions of the world varies with geographic location and, specifically, with the economic resources invested by the different countries to support various strategies applied to health care policies that aim at the preven‐ tion and treatment of infected mothers. Proof of thereof is the fact that in countries with gov‐ ernment programs in which the economic support is sufficient to implement the planned strategies for VT prevention, the prevalence of perinatal infection is under 2% [2,3].

HIV epidemics are showing a trend towards stabilization worldwide. Thus, in 2009 approxi‐ mately 2.6 million persons became newly infected by the virus, representing 19% fewer than

© 2013 Rubio; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

the newly infected in 1999 and more than a fifth less (21%) of the estimates in 1997. In fact, in 33 countries the incidence of infection has fallen by 25%. This includes 22 countries of the Sub-Saharan African region, the zone with the highest number of new cases worldwide (Ethiopia, Nigeria, South Africa, Zambia and Zimbabwe). In Eastern, Central and Western Europe, Central and Northern Asia the incidence of HIV infection has remained stable for the past five years. However in some high income countries infection rates have increased due to sex practices between homosexuals. Central Asia and Eastern Europe continue with high transmission rates among drug addicts and their sexual partners [4].

VT prevention programs is only marginally superior to that reported in countries with low

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 303

According to reports from 2006, the estimated number of seropositive subjects in Latin America is 1.7 millions, with 140,000 new cases and 65,000 deaths. Two thirds of the infected individuals live in four countries: Argentina, Brazil, Colombia and Mexico. The main agent responsible for the infection is HIV-1. The most commonly isolated genotype is type B, fol‐

In the American countries that compose the Southern Cone, HIV/AIDS epidemiological sur‐ veillance is carried out through mandatory notification (passive mechanism) and in some,

Most of such Latin American countries have implemented, since the second half of the 90s, an Antenatal Prevention of Mother To Child Transmission (APMTCT) program, consisting of the early voluntary diagnosis of HIV infection in the gestating population, universal ac‐ cess to antiretroviral therapy (ART) for the mother-child binomial, the C-section surgery and suppression of lactation, a program that aims at eliminating vertical transmission as a route

The main route of transmission in Latin America is represented by sex between men. There has been a significant increase in transmission through heterosexual intercourse since 1990. With the exception of Argentina, where initially transmission was mainly represented by needle sharing during drug injection, with a current dramatic drop, estimates of new cases of transmission through such route in 2005 do not exceed 5%. On the other hand, there is concern in the area, regarding the relationship between HIV and drug addition, since it has been demonstrated that illicit drug abuse, regardless of the route of administration, favors

In view of the above stated, it is possible to conclude that the features of the epidemics in the Southern Cone have varied, showing a trend to impoverishment, feminization, and shift to‐ wards homosexual and scholar populations. Moreover, the fact of the most affected age group is between 20 and 39 years is of great importance, since it demonstrates that the most‐ ly affected population is that representing the childbearing age, a situation that has a direct impact on VT risk. The latter warrants the importance of implementing human sexuality ed‐ ucation to all levels of the population, providing the necessary information and recognizing the right of women to be informed to enable them to take the appropriate measures to pro‐

The rate of HIV seropositive pregnant women fluctuates in the different countries of the Re‐ gion, between 3 and 7/1000. It is estimated that more than 2 million HIV (+) women get pregnant and 90% of them belong to developing countries, thus between 370,000 and 500,000 infected children are born annually, that die mostly because of the disease [4]. Preg‐ nancy would play a protective role for maternal mortality among HIV (+) women. Such ef‐ fect would be related to the low pregnancy rates achieved among women at advanced stages of the disease. [2]. Conversely, in developed countries, the rate of maternal mortality has decreased significantly since the introduction of the Highly Active Antiretroviral Thera‐

through active surveillance by means of sentinel centers [2].

tect themselves and prevent HIV infection. [2-4].

or moderate income [4].

lowed by types F and A [2].

of infection [2,3].

risk behaviors [2].

Regarding vertical transmission, an estimate of 370,000 children became infected with HIV during perinatal and lactation periods in 2009. Such figure is quite lower than the estimated 500,000 newly infected children in 2001. The latter has been possible thanks to Vertical Transmission (VT) prevention healthcare strategies that have been planned and implement‐ ed. Accordingly, the WHO and the UNAIDS proposed to virtually eliminate such transmis‐ sion route by 2015. To accomplish such goal, besides the efforts already implemented, they stated the importance of controlling the infection among youngsters. It is estimated that more than half of seropositive persons are girls and women [1,4].

In the Sub-Saharan African region, there are 8 times more infected women than men among persons aged between 15 and 24. Most of women are infected during unsafe heterosexual sexual activity. Such situation is the main responsible for the fact that such countries are as‐ sembling 90% of the children infected worldwide. Despite of the latter, the incidence of sub‐ jects with a carrier status among children under 15 years of age has declined in 32% in South Africa, the country in which AIDS is the main cause of maternal death and that accounts for 35% of deaths in children under 5 years of age. Accordingly, worldwide data show that only 15% of women in whom the carrier status had been detected during their perinatal period stayed subsequently on lifelong antiretroviral therapy [4].

It is estimated that approximately 4.9 million people in Asia were seropositive during 2009. Such figure is similar to those reported in the previous years, thus reflecting that the epi‐ demics has stabilized. In such continent, the number of infected children under the age of 15 has increased marginally, from 140,000 in 2005 to 160,000 in 2009 and AIDS-related deaths have dropped in 15% since 2004 [4].

In Western Europe, epidemiology indicators regarding maternal carrier status have evolved favorably. The estimated prevalence of infection among pregnant women in the United Kingdom is 0.2% and HIV screening coverage in gestating women is 90%. The latter has re‐ sulted in a sustained decline of VT from 12% in 1999 to 2% in 2007 [4,5].

In North America the carrier status has reached stability and VT has evidenced a dramatic decrease. In Canada, infection of the newborn has decreased from 5.2% in 1997 to 2.7% in 2012, and when the seropositive mother was administered HAART, such figure reached 0.4% [4,6].

In Central and South America the number of affected children under 15 years of age is still low, with approximately 4000 new cases during 2009, in spite of the fact that the coverage of VT prevention programs is only marginally superior to that reported in countries with low or moderate income [4].

the newly infected in 1999 and more than a fifth less (21%) of the estimates in 1997. In fact, in 33 countries the incidence of infection has fallen by 25%. This includes 22 countries of the Sub-Saharan African region, the zone with the highest number of new cases worldwide (Ethiopia, Nigeria, South Africa, Zambia and Zimbabwe). In Eastern, Central and Western Europe, Central and Northern Asia the incidence of HIV infection has remained stable for the past five years. However in some high income countries infection rates have increased due to sex practices between homosexuals. Central Asia and Eastern Europe continue with

Regarding vertical transmission, an estimate of 370,000 children became infected with HIV during perinatal and lactation periods in 2009. Such figure is quite lower than the estimated 500,000 newly infected children in 2001. The latter has been possible thanks to Vertical Transmission (VT) prevention healthcare strategies that have been planned and implement‐ ed. Accordingly, the WHO and the UNAIDS proposed to virtually eliminate such transmis‐ sion route by 2015. To accomplish such goal, besides the efforts already implemented, they stated the importance of controlling the infection among youngsters. It is estimated that

In the Sub-Saharan African region, there are 8 times more infected women than men among persons aged between 15 and 24. Most of women are infected during unsafe heterosexual sexual activity. Such situation is the main responsible for the fact that such countries are as‐ sembling 90% of the children infected worldwide. Despite of the latter, the incidence of sub‐ jects with a carrier status among children under 15 years of age has declined in 32% in South Africa, the country in which AIDS is the main cause of maternal death and that accounts for 35% of deaths in children under 5 years of age. Accordingly, worldwide data show that only 15% of women in whom the carrier status had been detected during their perinatal period

It is estimated that approximately 4.9 million people in Asia were seropositive during 2009. Such figure is similar to those reported in the previous years, thus reflecting that the epi‐ demics has stabilized. In such continent, the number of infected children under the age of 15 has increased marginally, from 140,000 in 2005 to 160,000 in 2009 and AIDS-related deaths

In Western Europe, epidemiology indicators regarding maternal carrier status have evolved favorably. The estimated prevalence of infection among pregnant women in the United Kingdom is 0.2% and HIV screening coverage in gestating women is 90%. The latter has re‐

In North America the carrier status has reached stability and VT has evidenced a dramatic decrease. In Canada, infection of the newborn has decreased from 5.2% in 1997 to 2.7% in 2012, and when the seropositive mother was administered HAART, such figure reached

In Central and South America the number of affected children under 15 years of age is still low, with approximately 4000 new cases during 2009, in spite of the fact that the coverage of

sulted in a sustained decline of VT from 12% in 1999 to 2% in 2007 [4,5].

high transmission rates among drug addicts and their sexual partners [4].

more than half of seropositive persons are girls and women [1,4].

stayed subsequently on lifelong antiretroviral therapy [4].

have dropped in 15% since 2004 [4].

302 Current Perspectives in HIV Infection

0.4% [4,6].

According to reports from 2006, the estimated number of seropositive subjects in Latin America is 1.7 millions, with 140,000 new cases and 65,000 deaths. Two thirds of the infected individuals live in four countries: Argentina, Brazil, Colombia and Mexico. The main agent responsible for the infection is HIV-1. The most commonly isolated genotype is type B, fol‐ lowed by types F and A [2].

In the American countries that compose the Southern Cone, HIV/AIDS epidemiological sur‐ veillance is carried out through mandatory notification (passive mechanism) and in some, through active surveillance by means of sentinel centers [2].

Most of such Latin American countries have implemented, since the second half of the 90s, an Antenatal Prevention of Mother To Child Transmission (APMTCT) program, consisting of the early voluntary diagnosis of HIV infection in the gestating population, universal ac‐ cess to antiretroviral therapy (ART) for the mother-child binomial, the C-section surgery and suppression of lactation, a program that aims at eliminating vertical transmission as a route of infection [2,3].

The main route of transmission in Latin America is represented by sex between men. There has been a significant increase in transmission through heterosexual intercourse since 1990. With the exception of Argentina, where initially transmission was mainly represented by needle sharing during drug injection, with a current dramatic drop, estimates of new cases of transmission through such route in 2005 do not exceed 5%. On the other hand, there is concern in the area, regarding the relationship between HIV and drug addition, since it has been demonstrated that illicit drug abuse, regardless of the route of administration, favors risk behaviors [2].

In view of the above stated, it is possible to conclude that the features of the epidemics in the Southern Cone have varied, showing a trend to impoverishment, feminization, and shift to‐ wards homosexual and scholar populations. Moreover, the fact of the most affected age group is between 20 and 39 years is of great importance, since it demonstrates that the most‐ ly affected population is that representing the childbearing age, a situation that has a direct impact on VT risk. The latter warrants the importance of implementing human sexuality ed‐ ucation to all levels of the population, providing the necessary information and recognizing the right of women to be informed to enable them to take the appropriate measures to pro‐ tect themselves and prevent HIV infection. [2-4].

The rate of HIV seropositive pregnant women fluctuates in the different countries of the Re‐ gion, between 3 and 7/1000. It is estimated that more than 2 million HIV (+) women get pregnant and 90% of them belong to developing countries, thus between 370,000 and 500,000 infected children are born annually, that die mostly because of the disease [4]. Preg‐ nancy would play a protective role for maternal mortality among HIV (+) women. Such ef‐ fect would be related to the low pregnancy rates achieved among women at advanced stages of the disease. [2]. Conversely, in developed countries, the rate of maternal mortality has decreased significantly since the introduction of the Highly Active Antiretroviral Thera‐ py (HAART). Moreover, the latter has increased the probability of achieving pregnancy, thus decreasing the rate of stillbirths and gestation-related diseases [7].

mitted through sex between men and women as compared to those transmitted through ho‐ mosexual intercourse. This has shifted the epidemics towards heterosexual population

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 305

To summarize, HIV VT in the region is responsible for a low percentage of people reported with HIV/AIDS, but is accountable for most of the children affected by the infection in the Southern Cone. An important reduction of transmission by means of such exposition route, reaching levels very close to the proposed goals, has been evidenced. Such decline might probably be explained by the wide coverage and effectiveness of the measures propounded

The Human Immunodeficiency Virus (HIV) is a lentivirus that belongs to the Retroviridae family. Two types of HIV have been identified: HIV-1, the most common, results in acquired immunodeficiency syndrome and death, and HIV-2, affecting mainly inhabitants or visitors from Western Africa, is transmitted less effectively and results in a more indolent disease with subsequent AIDS and death. They share less than 50% sequence homology. Through phylogenetic analysis, HIV-1 strains can be divided into two large groups: The M (Major) group in turn divided into 10 subtypes (from A to J) and the O (Outlier) group. The eventual importance of HIV-1 typification lies in developing antibody screening techniques, diagnos‐ ing the infection in the newborn, and in the quantification of plasma viral RNA for follow

This monostranded RNA virus incorporates its genetic material into the host cell DNA, in‐ fecting cells that express CD4 antigen on their surface, such as helper T cells, macrophages,

Once the infection has occurred, the patient may present a primoinfection characterized by mononucleosis–like non-specific symptoms, where antibody production is triggered. Subse‐ quently the patient undergoes a silent carrier phase. The latter used to last between 9 and 11 years before the emergence of antiretroviral therapy. As the immune system is being pro‐ gressively involved, the host becomes more susceptible to suffer opportunistic infections, cancers and dementia / encephalopathy, which are complications that enable labeling such stage as AIDS stage. In further consensus, the following findings were added: CD4 count

The genome of HIV-1 is relatively small, and composed of genes coding for structural, regu‐ latory and accessory proteins. The viral particle joins the cells of the susceptible host, among which are T cells, monocytes, macrophages, follicular dendritic cells and microglial cells. A

, uterine cervix cancer, lung tuberculosis and recurrent pneumonia [13,16,17].

groups, with a higher impact among female populations [2,3].

**3. Virology and Natural History of the Infection**

central nervous system cells and even placental cells [13,16,17].

by the health authorities to tackle the issue [2,3].

up of infected patients [13, 14,15].

**4. Viral Replication Mechanism**

under 200/mm3

Since the beginning of the pandemics, the importance of VT as transmission route has been clear. However, not even the most optimistic would have thought that PMTCT would turn into an example of effective biomedical intervention to prevent HIV transmission. It is im‐ portant to point that most of Latin American countries have healthcare programs aiming at decreasing VT (PMTCT) that are based on the early prenatal voluntary screening for infec‐ tion, the offering of antiretroviral therapies (ARVT), the C-section [8], substitution of breast‐ feeding [9] and multidisciplinary management during pregnancy. Regarding antenatal carrier status diagnosis, it is important to note that there are studies that reveal that between 25 and 55% of the total number of pregnant women who accept the test do not schedule a subsequent visit to know the results, thus they do not receive therapy. The latter suggests that fast intrapartum tests should be implemented on pregnant women unaware of their se‐ rologic condition. This is supported by a recent study carried out in Peru. The study con‐ cluded that the use of fast result tests (oral or blood) is a strategy advisable to decrease VT risk, in populations where PMTCT coverage does not reach the expected goals [10].

Pharmacological measures that have been implemented to decrease VT in the Southern re‐ gion of America, were based on the ACTG 076 protocol [11] involving therapeutic antiretro‐ viral management aiming at obtaining low or undetectable maternal viral loads, without toxic and/or teratogenic fetal effects. Such protocol consisted on the administration of Zidovudine to the mother during pregnancy and delivery, as well as to the newborn until the 6th week of life, together with indication of an elective C-section operation and contraindication of breast‐ feeding. Such scheme managed to decrease VT in the region, from 29% to 5.6% during 2001. [2] Subsequently, due to the emergence of new evidence supporting that triple-drug therapy was even more effective than monotherapy for VT prevention, a protocol was designed using a combination of reverse transcriptase and protease inhibitors. Such schemes were named together HAART. Thanks to such therapy, VT has dropped to figures close to 1% [2].

Because of the implementation and coverage of healthcare government programs in coun‐ tries of the region, only few pregnant women have viral loads higher than 1000 copies/ml in the proximity of delivery. The latter is responsible for the VT drop estimated as 1%. [2] A recent study assessed the risk of VT in pregnant women who were administered PMTCT and concluded that the VT risk was 0.097 (95% IC; 0.030-0.163). This reflects a reduction of transmission risk related to such route in almost 40% regarding VT before the implementa‐ tion of such program [12].

Chile, where an early detection program and timely treatment are currently being carried out, is probably one of the countries in the region having reached the best VT rates. This is a result of healthcare strategies aiming an adequate and permanently updated diagnosis of the behavior of the epidemics in the country. The proportion of female HIV carriers has in‐ creased as compared to that of males, due to the fact that the main transmission route is sex (93.6%). Such figure together with the impact of viral transmission both through homosexu‐ al as well as bisexual intercourse (46.1%), positions the monogamous heterosexual woman as the highest risk population (51.1%). Moreover, there is a sustained increase of cases trans‐ mitted through sex between men and women as compared to those transmitted through ho‐ mosexual intercourse. This has shifted the epidemics towards heterosexual population groups, with a higher impact among female populations [2,3].

To summarize, HIV VT in the region is responsible for a low percentage of people reported with HIV/AIDS, but is accountable for most of the children affected by the infection in the Southern Cone. An important reduction of transmission by means of such exposition route, reaching levels very close to the proposed goals, has been evidenced. Such decline might probably be explained by the wide coverage and effectiveness of the measures propounded by the health authorities to tackle the issue [2,3].

### **3. Virology and Natural History of the Infection**

py (HAART). Moreover, the latter has increased the probability of achieving pregnancy,

Since the beginning of the pandemics, the importance of VT as transmission route has been clear. However, not even the most optimistic would have thought that PMTCT would turn into an example of effective biomedical intervention to prevent HIV transmission. It is im‐ portant to point that most of Latin American countries have healthcare programs aiming at decreasing VT (PMTCT) that are based on the early prenatal voluntary screening for infec‐ tion, the offering of antiretroviral therapies (ARVT), the C-section [8], substitution of breast‐ feeding [9] and multidisciplinary management during pregnancy. Regarding antenatal carrier status diagnosis, it is important to note that there are studies that reveal that between 25 and 55% of the total number of pregnant women who accept the test do not schedule a subsequent visit to know the results, thus they do not receive therapy. The latter suggests that fast intrapartum tests should be implemented on pregnant women unaware of their se‐ rologic condition. This is supported by a recent study carried out in Peru. The study con‐ cluded that the use of fast result tests (oral or blood) is a strategy advisable to decrease VT

risk, in populations where PMTCT coverage does not reach the expected goals [10].

together HAART. Thanks to such therapy, VT has dropped to figures close to 1% [2].

tion of such program [12].

304 Current Perspectives in HIV Infection

Because of the implementation and coverage of healthcare government programs in coun‐ tries of the region, only few pregnant women have viral loads higher than 1000 copies/ml in the proximity of delivery. The latter is responsible for the VT drop estimated as 1%. [2] A recent study assessed the risk of VT in pregnant women who were administered PMTCT and concluded that the VT risk was 0.097 (95% IC; 0.030-0.163). This reflects a reduction of transmission risk related to such route in almost 40% regarding VT before the implementa‐

Chile, where an early detection program and timely treatment are currently being carried out, is probably one of the countries in the region having reached the best VT rates. This is a result of healthcare strategies aiming an adequate and permanently updated diagnosis of the behavior of the epidemics in the country. The proportion of female HIV carriers has in‐ creased as compared to that of males, due to the fact that the main transmission route is sex (93.6%). Such figure together with the impact of viral transmission both through homosexu‐ al as well as bisexual intercourse (46.1%), positions the monogamous heterosexual woman as the highest risk population (51.1%). Moreover, there is a sustained increase of cases trans‐

Pharmacological measures that have been implemented to decrease VT in the Southern re‐ gion of America, were based on the ACTG 076 protocol [11] involving therapeutic antiretro‐ viral management aiming at obtaining low or undetectable maternal viral loads, without toxic and/or teratogenic fetal effects. Such protocol consisted on the administration of Zidovudine to the mother during pregnancy and delivery, as well as to the newborn until the 6th week of life, together with indication of an elective C-section operation and contraindication of breast‐ feeding. Such scheme managed to decrease VT in the region, from 29% to 5.6% during 2001. [2] Subsequently, due to the emergence of new evidence supporting that triple-drug therapy was even more effective than monotherapy for VT prevention, a protocol was designed using a combination of reverse transcriptase and protease inhibitors. Such schemes were named

thus decreasing the rate of stillbirths and gestation-related diseases [7].

The Human Immunodeficiency Virus (HIV) is a lentivirus that belongs to the Retroviridae family. Two types of HIV have been identified: HIV-1, the most common, results in acquired immunodeficiency syndrome and death, and HIV-2, affecting mainly inhabitants or visitors from Western Africa, is transmitted less effectively and results in a more indolent disease with subsequent AIDS and death. They share less than 50% sequence homology. Through phylogenetic analysis, HIV-1 strains can be divided into two large groups: The M (Major) group in turn divided into 10 subtypes (from A to J) and the O (Outlier) group. The eventual importance of HIV-1 typification lies in developing antibody screening techniques, diagnos‐ ing the infection in the newborn, and in the quantification of plasma viral RNA for follow up of infected patients [13, 14,15].

This monostranded RNA virus incorporates its genetic material into the host cell DNA, in‐ fecting cells that express CD4 antigen on their surface, such as helper T cells, macrophages, central nervous system cells and even placental cells [13,16,17].

Once the infection has occurred, the patient may present a primoinfection characterized by mononucleosis–like non-specific symptoms, where antibody production is triggered. Subse‐ quently the patient undergoes a silent carrier phase. The latter used to last between 9 and 11 years before the emergence of antiretroviral therapy. As the immune system is being pro‐ gressively involved, the host becomes more susceptible to suffer opportunistic infections, cancers and dementia / encephalopathy, which are complications that enable labeling such stage as AIDS stage. In further consensus, the following findings were added: CD4 count under 200/mm3 , uterine cervix cancer, lung tuberculosis and recurrent pneumonia [13,16,17].

### **4. Viral Replication Mechanism**

The genome of HIV-1 is relatively small, and composed of genes coding for structural, regu‐ latory and accessory proteins. The viral particle joins the cells of the susceptible host, among which are T cells, monocytes, macrophages, follicular dendritic cells and microglial cells. A

high affinity bond is generated between the gp 120 of the viral surface and the CD4 receptor molecule on the host cell. Cell membranes fuse together and the virus enters the cell, uncov‐ ering its RNA. It is propounded that after infection, it is the downregulation of CD4 expres‐ sion on the infected cell surface that prevents a superinfection, enables an efficacious replication of the virus, and decreases the possibility of early cell death or apoptosis. During an early stage, the viral reverse transcriptase is activated together with other factors, and complete double stranded DNA copies are formed from the viral RNA. Such DNA copy is transported to the cell nucleus and binds to the host cell DNA through the viral integrase, generating the so-called provirus. The provirus may remain latent during a period of time. The host factors that influence the latency period duration are unknown. In activated cells, proviral transcription generates genomic RNA for its incorporation into new virions and messenger RNA that will be translated into structural proteins and several regulator and ac‐ cessory proteins that facilitate viral replication, assembling and release [13,16,17].

that renders her more susceptible to certain infections. Based on the latter, it has been postu‐ lated that pregnancy might influence the course of the infection. Such hypothesis has been thoroughly discussed, and currently the conclusion is that gestation does not have adverse effects on survival or on the expression of the disease. Such conclusion is supported by the fact that the absolute CD4 count and the viral load remain stable during pregnancy in un‐

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 307

Almost all clinical disorders described in HIV-infected adults may appear in infants, howev‐ er their rates of onset might be different in both life periods. The evolution of disease among infants infected during the perinatal stage is faster than in adults. This has raised questions such as if the developing immune system in fetuses and newborns represents a better ground for viral replication or is less efficient for infection control. Immaturity of the im‐ mune system of fetuses, newborns and infants causes two pathophysiological differences between adults and children: B cells are seldom susceptible to HIV infection and their circu‐ lating values remain normal; however such cells show abnormalities in infected children as compared to infected adults. As the infant has been exposed to few external antigens (and thus has a limited immune memory), the resulting immune dysfunction is more severe than in adults. Because of the poor development of T and B cell memory, children infected in per‐ inatal stages are more vulnerable to antibody-mediated pyogenic infections than infected

Almost as soon as the infected cells die, they are replaced, until the degree of the immune dysfunction is such as to make the immune control of the virus inefficient. Thus, the clinical

The main HIV transmission risk factor for females worldwide is sexual intercourse. More than 90% of HIV-AIDS-infected women have acquired the infection through heterosexual transmission. In most of the cases, such women had sexual intercourse only with their stable spouse, thus attesting for their vulnerability to transmission, which is directly related to

The reasons explaining why women are more susceptible to be infected by HIV than men are varied. Thus, healthcare staff must be aware of such factors and therefore generate a sympathetic and empathic environment to achieve a good physician-patient relationship.



their sexual partner's behavior (bisexuality, drug addictions, promiscuity) [3].

Among such reasons, the following should be considered:

a disturbance of the indemnity of the vaginal mucosa.

anisms (pubertal and postmenopausal women) are at higher risk.

treated pregnant women [7,13,16 -18].

conditions defining AIDS are progressively met.

**5. HIV behavior in women**

adults [13,16,17].

The adult immune system has several components that are critical for HIV infection, such as B and T cells, antigen-presenting cells, major histocompatibility antigens (types I and II), natural killer cells, cytokines and complement. Before an infection or antigenic stimulation, B cells are always "naïve". Following their stimulation, they generate two HIV specific sub‐ groups that actively secrete antibodies against the virus. Likewise, there are "innocent" and other T cells with specific memory as a result of a prior exposure to the virus. In the great majority of the infected people HIV invasion disrupts normal immune reactions and induces a chronic progressive, polymorphic dysfunction that, at a given time, makes the individual susceptible to opportunistic infections, cancers, neurological disorders and premature death. The initial HIV infection in adults is frequently followed 2 to 6 weeks later by an acute viral syndrome that manifests with fever, pharyngitis, myalgia, tender lymphadenopathies, nonspecific rash and lasts from 7 to 14 days. There is an acute drop of circulating lymphocyte counts, with a fairly rapid normalization of figures. However, CD4+ T cell counts do not fully regain baseline values. During such period viral replication and dissemination to lymph nodes and mononuclear / macrophagic cells occur speedily [13,16,17].

The circulating viral load is high in the initial absence of an effective antibody response. Typically, IgM appear one or two months after HIV exposure, followed by IgG (specifically anti-gp 120/41) and the development of an anti-p24 response that fades out in more ad‐ vanced stages of the infection. Shortly afterwards, anti-gp120 and gp41 antibodies emerge, and persist for a lifetime. As anti–HIV antibody titers increase, the circulating viral load de‐ creases and the infected subjects initiate an asymptomatic phase that commonly lasts from 3 to 11 years. During such asymptomatic phase viral replication is extremely intense, as well as is the destruction and replacement of CD4+ T cells. It should be taken into consideration that before causing a gradual CD4+ T cell depletion, HIV infection causes a CD4+ T cell dys‐ function. Chemoprophylaxis, antibody-related cell-mediated cytotoxicity, intracellular anti‐ microbial activity and disorders of cytokine production also occur due to monocyte and macrophage dysfunction caused by the HIV infection [13,16,17].

During pregnancy, the mother undergoes a modulation of her immune response character‐ ized by a TH2 response (humoral type) more prominent than TH1-type (cellular) response that renders her more susceptible to certain infections. Based on the latter, it has been postu‐ lated that pregnancy might influence the course of the infection. Such hypothesis has been thoroughly discussed, and currently the conclusion is that gestation does not have adverse effects on survival or on the expression of the disease. Such conclusion is supported by the fact that the absolute CD4 count and the viral load remain stable during pregnancy in un‐ treated pregnant women [7,13,16 -18].

Almost all clinical disorders described in HIV-infected adults may appear in infants, howev‐ er their rates of onset might be different in both life periods. The evolution of disease among infants infected during the perinatal stage is faster than in adults. This has raised questions such as if the developing immune system in fetuses and newborns represents a better ground for viral replication or is less efficient for infection control. Immaturity of the im‐ mune system of fetuses, newborns and infants causes two pathophysiological differences between adults and children: B cells are seldom susceptible to HIV infection and their circu‐ lating values remain normal; however such cells show abnormalities in infected children as compared to infected adults. As the infant has been exposed to few external antigens (and thus has a limited immune memory), the resulting immune dysfunction is more severe than in adults. Because of the poor development of T and B cell memory, children infected in per‐ inatal stages are more vulnerable to antibody-mediated pyogenic infections than infected adults [13,16,17].

Almost as soon as the infected cells die, they are replaced, until the degree of the immune dysfunction is such as to make the immune control of the virus inefficient. Thus, the clinical conditions defining AIDS are progressively met.

### **5. HIV behavior in women**

high affinity bond is generated between the gp 120 of the viral surface and the CD4 receptor molecule on the host cell. Cell membranes fuse together and the virus enters the cell, uncov‐ ering its RNA. It is propounded that after infection, it is the downregulation of CD4 expres‐ sion on the infected cell surface that prevents a superinfection, enables an efficacious replication of the virus, and decreases the possibility of early cell death or apoptosis. During an early stage, the viral reverse transcriptase is activated together with other factors, and complete double stranded DNA copies are formed from the viral RNA. Such DNA copy is transported to the cell nucleus and binds to the host cell DNA through the viral integrase, generating the so-called provirus. The provirus may remain latent during a period of time. The host factors that influence the latency period duration are unknown. In activated cells, proviral transcription generates genomic RNA for its incorporation into new virions and messenger RNA that will be translated into structural proteins and several regulator and ac‐

306 Current Perspectives in HIV Infection

cessory proteins that facilitate viral replication, assembling and release [13,16,17].

lymph nodes and mononuclear / macrophagic cells occur speedily [13,16,17].

macrophage dysfunction caused by the HIV infection [13,16,17].

The circulating viral load is high in the initial absence of an effective antibody response. Typically, IgM appear one or two months after HIV exposure, followed by IgG (specifically anti-gp 120/41) and the development of an anti-p24 response that fades out in more ad‐ vanced stages of the infection. Shortly afterwards, anti-gp120 and gp41 antibodies emerge, and persist for a lifetime. As anti–HIV antibody titers increase, the circulating viral load de‐ creases and the infected subjects initiate an asymptomatic phase that commonly lasts from 3 to 11 years. During such asymptomatic phase viral replication is extremely intense, as well as is the destruction and replacement of CD4+ T cells. It should be taken into consideration that before causing a gradual CD4+ T cell depletion, HIV infection causes a CD4+ T cell dys‐ function. Chemoprophylaxis, antibody-related cell-mediated cytotoxicity, intracellular anti‐ microbial activity and disorders of cytokine production also occur due to monocyte and

During pregnancy, the mother undergoes a modulation of her immune response character‐ ized by a TH2 response (humoral type) more prominent than TH1-type (cellular) response

The adult immune system has several components that are critical for HIV infection, such as B and T cells, antigen-presenting cells, major histocompatibility antigens (types I and II), natural killer cells, cytokines and complement. Before an infection or antigenic stimulation, B cells are always "naïve". Following their stimulation, they generate two HIV specific sub‐ groups that actively secrete antibodies against the virus. Likewise, there are "innocent" and other T cells with specific memory as a result of a prior exposure to the virus. In the great majority of the infected people HIV invasion disrupts normal immune reactions and induces a chronic progressive, polymorphic dysfunction that, at a given time, makes the individual susceptible to opportunistic infections, cancers, neurological disorders and premature death. The initial HIV infection in adults is frequently followed 2 to 6 weeks later by an acute viral syndrome that manifests with fever, pharyngitis, myalgia, tender lymphadenopathies, nonspecific rash and lasts from 7 to 14 days. There is an acute drop of circulating lymphocyte counts, with a fairly rapid normalization of figures. However, CD4+ T cell counts do not fully regain baseline values. During such period viral replication and dissemination to

> The main HIV transmission risk factor for females worldwide is sexual intercourse. More than 90% of HIV-AIDS-infected women have acquired the infection through heterosexual transmission. In most of the cases, such women had sexual intercourse only with their stable spouse, thus attesting for their vulnerability to transmission, which is directly related to their sexual partner's behavior (bisexuality, drug addictions, promiscuity) [3].

> The reasons explaining why women are more susceptible to be infected by HIV than men are varied. Thus, healthcare staff must be aware of such factors and therefore generate a sympathetic and empathic environment to achieve a good physician-patient relationship. Among such reasons, the following should be considered:

> - Sexual transmission of the virus is several times more common from men to women than vice versa. Women with thinned vaginal mucosa or lacking the physiological defense mech‐ anisms (pubertal and postmenopausal women) are at higher risk.

> - Asymptomatic sexually transmitted vaginosis is commonly underdiagnosed and results in a disturbance of the indemnity of the vaginal mucosa.


test. Therefore, screening requires the participation of staff trained in "counseling", which has reinforced the decision to undergo the test among women. This has shown to be of most importance for the generation of awareness about the disease, adherence to therapy and the incorporation of behaviors by the carrier to prevent transmission to her personal environ‐ ment [20-24]. Pre and post-conceptional counseling is understood as a "confidential dia‐ logue between a questioner and a counselor aiming at empowering women to face stress, decision making regarding HIV/AIDS during pregnancy and discussion of the elements for prevention of vertical transmission". It is important to recommend the following topics to be

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 309

The most popular methods worldwide are tests that screen for specific antibodies against viral antigens. The most used technique for screening is Enzyme Linked Immunosorb‐ ent Assay (ELISA). The most used technique for infection confirmation is the Western

The ELISA test uses antigens derived from the intact virus and binds them to microtitration wells. The serum or plasma from the patient is added into the wells and if there are antibod‐ ies against HIV they bind to the antigen present. A chromogen substrate is also provided to evidence the potentially bound enzyme and the intensity of the color generated is read on a spectrophotometer. Color reading is proportional to the amount of the enzyme-antibody complex that bound the HIV antigen present in the wells. Commercially available tests have sensitivity and specificity rates between 98 and 100%. The disadvantage of such tests is they detect antibodies and thus may yield false positive results if transmission occurred shortly before the test. Such time lapse is known as window period, which may last between 3 and 6 months. For such reason, fourth generation ELISA is recommended. Such test is able to de‐ tect simultaneously Ag p24 and its respective antibodies, and therefore it can shorten the window period to approximately 30 days, with 99.9% sensitivity and 99.5% specificity. De‐ spite the latter, it is important to point that the positive predictive value of this test during pregnancy is approximately 50%, because it is applied to a low prevalence population, and

Additionally, in pregnant women with unknown serology status and attending consultation for labor or medical situations where pregnancy termination is imminent, services should have rapid diagnostic techniques. Despite their non-optimal specificity and sensitivity, posi‐

addressed upon counseling:


– Breastfeeding-related risks.

**7. Diagnosis**

blot technique [25].



therefore a confirmation test is mandatory (Western blot) [16].



Regarding the last point and aiming at identifying other prevention methods, recent studies have demonstrated that the use of tenofovir gel might be a useful tool to prevent infection. In fact, a South African study concluded that the pre and post-coital prophylactic use of such microbicide among women aged between 18 and 40 reduced HIV infection in 39% and HSV-2 infection in 51%. [19] On the other hand, circumcision in adults has proven to be ef‐ fective to prevent infection among seronegative males with an HIV+ partner. The latter has led the UNAIDS and WHO to recommend such intervention in countries with high preva‐ lence [4]. Finally, there are also studies that propose the use of tenofovir prior to sexual in‐ tercourse in infected or high-risk couples. All these prophylactic measures should be assessed with further adequately designed studies.

Probably due to such reasons and in light of the pooled data in developing and developed countries, the proportion of HIV carrier women has increased as compared to that of men. The cause is that the main transmission route is sex. The latter together with the impact of viral transmission route in homo and heterosexual mode, have transformed heterosexual monogamous women into the highest risk population. Moreover, there is a sustained in‐ crease of cases transmitted by sexual intercourse between men and women as compared to those transmitted through homosexual intercourse. This has shifted the epidemics towards population groups with a lower social-economic level and with a clear decrease of females in higher school education levels [2, 3, 16,17].

Epidemiology studies suggest that the observed prevalence among women in childbearing age is comparable to prevalence in pregnant women. On the other hand, pregnancy rates in seropositive women that have not developed AIDS are comparable to those seen among un‐ infected women, while among women who developed the disease the probability of getting pregnant is quite lower [13-15].

### **6. Management of seropositive pregnant woman for Vertical Transmission Prevention**

Most of women discover their carrier status or their disease during pregnancy or subse‐ quently after birth upon screening of their offspring. With regard to the need for screening of all women during their pre and/or post-conception consultation, the American College of Obstetricians and Gynecologists recommends carrying it out on a routine basis, which is a conduct commonly adopted in many countries of the world. In fact, in most of these coun‐ tries, such screening is performed together with the mandatory pre-test counseling act, with the informed consent and with the willfulness of individuals in the decision to undergo the test. Therefore, screening requires the participation of staff trained in "counseling", which has reinforced the decision to undergo the test among women. This has shown to be of most importance for the generation of awareness about the disease, adherence to therapy and the incorporation of behaviors by the carrier to prevent transmission to her personal environ‐ ment [20-24]. Pre and post-conceptional counseling is understood as a "confidential dia‐ logue between a questioner and a counselor aiming at empowering women to face stress, decision making regarding HIV/AIDS during pregnancy and discussion of the elements for prevention of vertical transmission". It is important to recommend the following topics to be addressed upon counseling:


### **7. Diagnosis**




Probably due to such reasons and in light of the pooled data in developing and developed countries, the proportion of HIV carrier women has increased as compared to that of men. The cause is that the main transmission route is sex. The latter together with the impact of viral transmission route in homo and heterosexual mode, have transformed heterosexual monogamous women into the highest risk population. Moreover, there is a sustained in‐ crease of cases transmitted by sexual intercourse between men and women as compared to those transmitted through homosexual intercourse. This has shifted the epidemics towards population groups with a lower social-economic level and with a clear decrease of females

Epidemiology studies suggest that the observed prevalence among women in childbearing age is comparable to prevalence in pregnant women. On the other hand, pregnancy rates in seropositive women that have not developed AIDS are comparable to those seen among un‐ infected women, while among women who developed the disease the probability of getting

Most of women discover their carrier status or their disease during pregnancy or subse‐ quently after birth upon screening of their offspring. With regard to the need for screening of all women during their pre and/or post-conception consultation, the American College of Obstetricians and Gynecologists recommends carrying it out on a routine basis, which is a conduct commonly adopted in many countries of the world. In fact, in most of these coun‐ tries, such screening is performed together with the mandatory pre-test counseling act, with the informed consent and with the willfulness of individuals in the decision to undergo the

**6. Management of seropositive pregnant woman for Vertical**

rejection of high-risk sexual intercourse difficult.

assessed with further adequately designed studies.

in higher school education levels [2, 3, 16,17].

pregnant is quite lower [13-15].

**Transmission Prevention**

among monogamous females.

308 Current Perspectives in HIV Infection

The most popular methods worldwide are tests that screen for specific antibodies against viral antigens. The most used technique for screening is Enzyme Linked Immunosorb‐ ent Assay (ELISA). The most used technique for infection confirmation is the Western blot technique [25].

The ELISA test uses antigens derived from the intact virus and binds them to microtitration wells. The serum or plasma from the patient is added into the wells and if there are antibod‐ ies against HIV they bind to the antigen present. A chromogen substrate is also provided to evidence the potentially bound enzyme and the intensity of the color generated is read on a spectrophotometer. Color reading is proportional to the amount of the enzyme-antibody complex that bound the HIV antigen present in the wells. Commercially available tests have sensitivity and specificity rates between 98 and 100%. The disadvantage of such tests is they detect antibodies and thus may yield false positive results if transmission occurred shortly before the test. Such time lapse is known as window period, which may last between 3 and 6 months. For such reason, fourth generation ELISA is recommended. Such test is able to de‐ tect simultaneously Ag p24 and its respective antibodies, and therefore it can shorten the window period to approximately 30 days, with 99.9% sensitivity and 99.5% specificity. De‐ spite the latter, it is important to point that the positive predictive value of this test during pregnancy is approximately 50%, because it is applied to a low prevalence population, and therefore a confirmation test is mandatory (Western blot) [16].

Additionally, in pregnant women with unknown serology status and attending consultation for labor or medical situations where pregnancy termination is imminent, services should have rapid diagnostic techniques. Despite their non-optimal specificity and sensitivity, posi‐ tive results on such tests should be able to generate the recommendation of preventive measures during the peripartum period, with prior patient informed consent [5,10].

Nevertheless, opportunistic infections (Pneumocystis jirovecii, Herpes Zoster, etc.) and prevalent diseases such as tuberculosis and malaria are those with more aggressive course in seropositive pregnant women and increase significantly maternal and perinatal morbidity

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 311

Vertical transmission is one of the mostly studied transmission routes, thus it is possible to share some conclusions regarding the moment of transmission to the fetus or newborn and


Fortunately, the gravid status does not seem to have an impact on the course or the natural history of HIV infection, since although a decrease in CD4+ T cell counts has been described during pregnancy, they return to baseline values after delivery [17]. In the absence of com‐ plications such as drug addictions or chronic medical diseases, the incidence of obstetric pathology does not increase; spontaneous abortion, intrauterine growth restriction, preterm delivery and stillbirth are within the expected prevalence range. However, the risk of infec‐ tious complications increases among pregnant women with a significant impairment of the

A seropositive gestating woman should be clinically addressed based on a multidisciplinary and thorough assessment of her initial health status. The latter should include a full physical examination, especially observing those signs that guide diagnosis towards an opportunistic infectious pathology and assessing the current immune status. Upon indicating the thera‐ peutic and/or prophylactic antiretroviral treatment, a risk versus benefit assessment should be carried out to evaluate the effectiveness of the pharmacological scheme and the eventual

The following laboratory tests might be performed in addition to the routine tests that should be requested for pregnant women at the beginning of their prenatal follow-up [4,16]:

and mortality. [28]

the factors that increase VT risk [14,16].





immune system (CD4 < 300/dl) [18].

Infectious parameters:

teratogenic and toxic effects on mother and fetus.



canal.

Moment of transmission to the product of conception:


The confirmation Western blot technique is carried out with a nitrocellulose strip to which HIV shell proteins are added. Patient serum is applied on the strips: any antibody against such virus present in serum will bind to its specific antigen. This generates a series of dark bands. By comparing the band position with a control, it is possible to determine if the pa‐ tient's blood contains HIV-specific antibodies [16].

On occasions, individuals with recent infection or in the process of structuring a complete antibody response yield undetermined responses. In such cases, the test should be repeated within one to two months.

PCR tests are sensitive and useful to confirm the infection status. They are able to detect very small amounts of virus and they do not rely on an antibody response to infection. PCR is used in clinical practice to establish the infection status on infants born to infected moth‐ ers and potentially within the window period between infection and presence of detectable specific antibodies. PCR and other amplification techniques have been improved to quantify HIV RNA. There is considerable interest on perfecting reliable tests to detect the virus in or‐ al fluids or urine, since they are easy to collect without causing either disturbance to the pa‐ tient or risks to the collector. Moreover, they can be especially helpful in children and adults in whom vein access can be difficult [16].

Assessment of HIV infection status is complex in children under the age of 6 months be‐ cause of gestation and early lactation immunology. The most commonly used tests in adults are based on the detection of IgG antibodies against the virus. During pregnancy, maternal IgG crosses easily the placenta towards fetal circulation, where it remains until 18 months after birth. For such reason, assessment of the HIV infection status in infants requires testing other than ELISA and Western blot. The options are virus cultures and PCR, as well as de‐ tection of IgA antibodies directed against HIV [14,16].

### **8. HIV and Pregnancy**

According to epidemiological studies, pregnancy rates among seropositive women that have not presented AIDS are comparable to rates in uninfected women. The probability of becoming pregnant is quite lower among women who develop AIDS. Despite of certain con‐ tradictory evidence, latest studies seem to confirm that pregnancy does not affect the course or the complications of the disease [26].

As for the role played by the viral load or the immune condition of the pregnant woman, there is evidence supporting a close relationship between high viral loads and higher VT risk. However there is not a viral load warranting a virus-free neonate. Mother-to-child transmission is possible despite viral levels being undetectable in the mother. On the other hand, maternal CD4 concentrations < 700 cells/mm relate to a higher VT risk [27].

Nevertheless, opportunistic infections (Pneumocystis jirovecii, Herpes Zoster, etc.) and prevalent diseases such as tuberculosis and malaria are those with more aggressive course in seropositive pregnant women and increase significantly maternal and perinatal morbidity and mortality. [28]

Vertical transmission is one of the mostly studied transmission routes, thus it is possible to share some conclusions regarding the moment of transmission to the fetus or newborn and the factors that increase VT risk [14,16].

Moment of transmission to the product of conception:




Obstetric factors that favor VT:


tive results on such tests should be able to generate the recommendation of preventive

The confirmation Western blot technique is carried out with a nitrocellulose strip to which HIV shell proteins are added. Patient serum is applied on the strips: any antibody against such virus present in serum will bind to its specific antigen. This generates a series of dark bands. By comparing the band position with a control, it is possible to determine if the pa‐

On occasions, individuals with recent infection or in the process of structuring a complete antibody response yield undetermined responses. In such cases, the test should be repeated

PCR tests are sensitive and useful to confirm the infection status. They are able to detect very small amounts of virus and they do not rely on an antibody response to infection. PCR is used in clinical practice to establish the infection status on infants born to infected moth‐ ers and potentially within the window period between infection and presence of detectable specific antibodies. PCR and other amplification techniques have been improved to quantify HIV RNA. There is considerable interest on perfecting reliable tests to detect the virus in or‐ al fluids or urine, since they are easy to collect without causing either disturbance to the pa‐ tient or risks to the collector. Moreover, they can be especially helpful in children and adults

Assessment of HIV infection status is complex in children under the age of 6 months be‐ cause of gestation and early lactation immunology. The most commonly used tests in adults are based on the detection of IgG antibodies against the virus. During pregnancy, maternal IgG crosses easily the placenta towards fetal circulation, where it remains until 18 months after birth. For such reason, assessment of the HIV infection status in infants requires testing other than ELISA and Western blot. The options are virus cultures and PCR, as well as de‐

According to epidemiological studies, pregnancy rates among seropositive women that have not presented AIDS are comparable to rates in uninfected women. The probability of becoming pregnant is quite lower among women who develop AIDS. Despite of certain con‐ tradictory evidence, latest studies seem to confirm that pregnancy does not affect the course

As for the role played by the viral load or the immune condition of the pregnant woman, there is evidence supporting a close relationship between high viral loads and higher VT risk. However there is not a viral load warranting a virus-free neonate. Mother-to-child transmission is possible despite viral levels being undetectable in the mother. On the other

hand, maternal CD4 concentrations < 700 cells/mm relate to a higher VT risk [27].

measures during the peripartum period, with prior patient informed consent [5,10].

tient's blood contains HIV-specific antibodies [16].

in whom vein access can be difficult [16].

tection of IgA antibodies directed against HIV [14,16].

within one to two months.

310 Current Perspectives in HIV Infection

**8. HIV and Pregnancy**

or the complications of the disease [26].



Fortunately, the gravid status does not seem to have an impact on the course or the natural history of HIV infection, since although a decrease in CD4+ T cell counts has been described during pregnancy, they return to baseline values after delivery [17]. In the absence of com‐ plications such as drug addictions or chronic medical diseases, the incidence of obstetric pathology does not increase; spontaneous abortion, intrauterine growth restriction, preterm delivery and stillbirth are within the expected prevalence range. However, the risk of infec‐ tious complications increases among pregnant women with a significant impairment of the immune system (CD4 < 300/dl) [18].

A seropositive gestating woman should be clinically addressed based on a multidisciplinary and thorough assessment of her initial health status. The latter should include a full physical examination, especially observing those signs that guide diagnosis towards an opportunistic infectious pathology and assessing the current immune status. Upon indicating the thera‐ peutic and/or prophylactic antiretroviral treatment, a risk versus benefit assessment should be carried out to evaluate the effectiveness of the pharmacological scheme and the eventual teratogenic and toxic effects on mother and fetus.

The following laboratory tests might be performed in addition to the routine tests that should be requested for pregnant women at the beginning of their prenatal follow-up [4,16]:

Infectious parameters:



and teratogenic effects (Table 2). The use of Zidovudine is recommended within the scheme. Zidovudine has been the only drug to enter a protocol and that has demonstrated efficacy in the protection of the fetus from vertical transmission. However, new studies have demon‐

**Non-nucleosidic reverse transcriptase Inhibitors**

**Protease inhibitors**

Abacavir C Didanosine (ddI) B Lamivudine (3TC) C Lamivudine + Zidovudine (Convivir) C Stavudine (d4T Zalcitabine) C Zidovudine (ZDZ, AZT) C

Delavirdine C Efavirenz \* X Nevirapine C

Amprenavir \* X Indinavir C Nelfinavir X Ritonavir B Saquinavir B

C: Risks cannot be ruled out. However, a potential benefit might justify its use.

**10. Management Protocol in the Prevention of Vertical Transmission**

The first formalized intent in prevention of VT was that assessed by a joint study carried out in France and the United States, attempting at the evaluation of a management protocol (Clinical Group Protocol 076-ACTG 076) [11], consisting of a study and follow up of HIV+ pregnant women that had a gestational age between weeks 14 and 34, without antiretroviral therapy or indications for such therapy, with CD4+ T cell count > or equal to 200 cells/mm3

.

**Table 1.** ANTIRETROVIRAL AGENTS,Nucleosidic reverse transcriptase inhibitors

A: Controlled studies show no risk B: No evidence of risks in humans

**Table 2.** FDA Drug Category Rankings (Drugs and pregnancy)

D: Positive evidence of risk. X: Contraindicated in pregnancy.

**(ACTG 076)**

**Generic name FDA Classs**

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 313

strated the efficacy of other antiretroviral drugs in VT reduction.


Immunological parameters:


Sequential detection of the viral load and CD4 counts are used to predict the risk of a rapid disease progression in the pregnant woman and the eventual VT in such patient group. However, as an intent to identify a more cost-effective test than the latter, the role of HIV typification through sequential study of specific bands offered by the Western blot techni‐ que has been studied recently. Such preliminary studies demonstrated that the absence of anti pol antibodies was associated with an acute infection. Although it is true that the lack of anti gag p39 antibodies was related to a rapid disease progression and a higher probability of infection of the newborn, such absence was not as statistically significant to predict a higher risk for VT. Therefore, such diagnostic tool needs still to be upheld by further studies before it becomes indicated for clinical use. [29]

All antenatal diagnostic assessments may be carried out without contradictions, except for those involving invasive techniques that imply an additional infection risk to the fetus (cho‐ rionic villus biopsy, amniocentesis, cordocentesis).

### **9. Antiretroviral therapy during pregnancy**

The aim of antiretroviral therapy during pregnancy is to decrease the maternal viral load to undetectable levels without causing deleterious or teratogenic effects on the product of con‐ ception, and on the other hand, to decrease the risk of vertical transmission. To attain such goal, there are currently 14 antiretroviral drugs available (Table 1). Such drugs must be used within schemes individually adapted for each patient. Drug selection should be based on the prior treatment of the woman (if she were under any), the current status of the patient and her motivation, the viral load, drug resistance, CD4+ T cell counts, and associated toxic and teratogenic effects (Table 2). The use of Zidovudine is recommended within the scheme. Zidovudine has been the only drug to enter a protocol and that has demonstrated efficacy in the protection of the fetus from vertical transmission. However, new studies have demon‐ strated the efficacy of other antiretroviral drugs in VT reduction.


**Table 1.** ANTIRETROVIRAL AGENTS,Nucleosidic reverse transcriptase inhibitors


**Table 2.** FDA Drug Category Rankings (Drugs and pregnancy)


312 Current Perspectives in HIV Infection




Immunological parameters:


before it becomes indicated for clinical use. [29]

rionic villus biopsy, amniocentesis, cordocentesis).

**9. Antiretroviral therapy during pregnancy**


gondii, Chagas disease, Malaria, etc.).




Sequential detection of the viral load and CD4 counts are used to predict the risk of a rapid disease progression in the pregnant woman and the eventual VT in such patient group. However, as an intent to identify a more cost-effective test than the latter, the role of HIV typification through sequential study of specific bands offered by the Western blot techni‐ que has been studied recently. Such preliminary studies demonstrated that the absence of anti pol antibodies was associated with an acute infection. Although it is true that the lack of anti gag p39 antibodies was related to a rapid disease progression and a higher probability of infection of the newborn, such absence was not as statistically significant to predict a higher risk for VT. Therefore, such diagnostic tool needs still to be upheld by further studies

All antenatal diagnostic assessments may be carried out without contradictions, except for those involving invasive techniques that imply an additional infection risk to the fetus (cho‐

The aim of antiretroviral therapy during pregnancy is to decrease the maternal viral load to undetectable levels without causing deleterious or teratogenic effects on the product of con‐ ception, and on the other hand, to decrease the risk of vertical transmission. To attain such goal, there are currently 14 antiretroviral drugs available (Table 1). Such drugs must be used within schemes individually adapted for each patient. Drug selection should be based on the prior treatment of the woman (if she were under any), the current status of the patient and her motivation, the viral load, drug resistance, CD4+ T cell counts, and associated toxic



### **10. Management Protocol in the Prevention of Vertical Transmission (ACTG 076)**

The first formalized intent in prevention of VT was that assessed by a joint study carried out in France and the United States, attempting at the evaluation of a management protocol (Clinical Group Protocol 076-ACTG 076) [11], consisting of a study and follow up of HIV+ pregnant women that had a gestational age between weeks 14 and 34, without antiretroviral therapy or indications for such therapy, with CD4+ T cell count > or equal to 200 cells/mm3 . The group that was administered placebo was compared to the group receiving AZT (orally during pregnancy, injectable during delivery and as syrup to the newborn for 6 weeks). Re‐ sults showed that transmission was 8.3% with AZT and 25% with placebo, which is equiva‐ lent to a reduction in 67% (p= 0,00006). (Table 3)

ing the third trimester of gestation (weeks 34-36) should be made. However, due to the potential toxic effects of therapeutic drugs, it is suggested their use is limited to the periods of maximum effectiveness considering risks and benefits of such exposure to the motherchild binomial. Anyway, AZT should be added to the therapeutic scheme if possible, even in cases in which such drug was not used during the antepartum period, since it has proven to be helpful to decrease vertical transmission even in abbreviated schemes (intrapartum

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 315

Based on the above-mentioned, HAART type ART should be indicated in the following sit‐

Within the HAART concept, the selection of the NRTI combination to be used should follow the efficacy of the latter in reducing VT, considering the potential teratogenic effects and the eventual toxicity to the mother-child binomial. Based on the teratogenesis risk classification of the FDA, NRTI are classed as B or C. The largest experience involves Zidovudine (AZT or ZDV) that has demonstrated being quite a safe drug, with low resistance and high efficacy to prevent VT. In addition, the association of ZDV and Lamivudine (ZDV/3TC) has demonstrat‐ ed to be more effective than ZDV as monotherapy in mother-to-child transmission preven‐ tion. Such combination does not imply higher toxicity or risk of teratogenesis [2-6, 30-34]. Regarding the search for the third drug, Lopinavir-Ritonavir has demonstrated efficacy and safety in VT prevention. The association of Saquinavir reinforced with Ritonavir has gath‐ ered enough evidence to suggest that such combination is a good supplementary alternative

Although Nevirapine (NVP) has been widely indicated and has demonstrated being effec‐ tive in the prevention of mother-to-child transmission mostly in developing countries with low economical resources, the use of such drug has been related to the development of viral resistance both in mothers as in children who were infected despite the received prophylax‐ is. Moreover, mothers who were administered Nevirapine had a higher incidence of toxic effects (hepatic, hypersensitivity) in particular pregnant women with CD4+ T cell counts higher than 250 cells/ml. The above mentioned suggests that such indication should be con‐ sidered among patients never having received Nevirapine and with CD4+ T cell counts un‐ der 250 cells/ml. When such drug is used in the intrapartum period, it is advisable to indicate ZDV y Lamivudine (3TC) for 7 days both to the mother as well as to the newborn,

The following are among the drugs that should not be indicated during pregnancy: Efavir‐ enz, Nelfinavir and the association of d4T (Stavudine) and ddI (Didanosine). All share tera‐

In 2010 the World Health Organization stressed the importance of offering a lifelong antire‐ troviral therapy to patients with a carrier condition recognized during pregnancy. The

to reduce the risk of viral resistance to Nevirapine and other NNTRI [30-34].

togenicity and toxicity risk for the mother-child binomial [30-36].

**2.** In pregnant women with viral loads higher than 100,000 copies/ml from 14 weeks

**1.** In seropositive pregnant women without prior treatment from week 24

**3.** In case of seroconversion during pregnancy it should be indicated at once

to render the pharmacological therapy more effective [26].

and postpartum) [4,5,34].

uations: [34]


**Table 3.** ACTG 076 PROTOCOL

### **11. High Activity Antiretroviral (ART) Therapy (HAART)**

The first attempt at a successful pharmacological scheme to control VT was achieved by the ACTG 076 protocol. Such protocol together with elective C-section and suppression of lacta‐ tion (biomedical measures) achieved a decrease in VT from 29% to 5.6% [11]. Although the latter is true, new evidence demonstrated that the triple drug therapy was more effective than monotherapy or bitherapy to prevent Vertical Transmission (VT). A protocol, that com‐ bined the biomedical preventive measures already mentioned and the indication of three an‐ tiretroviral drugs was designed. Such drugs included nucleosidic and non-nucleosidic reverse transcriptase inhibitors (NRTI and NNRTI respectively) and Protease inhibitors (PI), and together formed a series of schemes known as highly active antiretroviral therapy (HAART). It is by virtue of the latter that VT has decreased to values close to 1.0 [2-6, 30-34].

It is a known fact that VT may occur among seropositive pregnant women during pregnan‐ cy (35%), delivery (65%) and lactation (14%-29%) and that there are factors that increase the risk of fetal infection (Primoinfection, Sexually transmitted diseases and CD4+ T cell counts). The most important of such factors is maternal viral load [27]. Loads under 1000 copies/ml have significantly lower risks of VT, however there is no evidence pointing to the minimal load that exempts from risk. The latter supports the need to use a highly active antiretroviral therapy (HAART) with the highest effectiveness and safety to reach, hopefully, undetectable viral load levels. With such purpose, and considering that most of transmissions to the new‐ born occur during the peripartum period, an attempt at reaching the lowest viral loads dur‐ ing the third trimester of gestation (weeks 34-36) should be made. However, due to the potential toxic effects of therapeutic drugs, it is suggested their use is limited to the periods of maximum effectiveness considering risks and benefits of such exposure to the motherchild binomial. Anyway, AZT should be added to the therapeutic scheme if possible, even in cases in which such drug was not used during the antepartum period, since it has proven to be helpful to decrease vertical transmission even in abbreviated schemes (intrapartum and postpartum) [4,5,34].

Based on the above-mentioned, HAART type ART should be indicated in the following sit‐ uations: [34]

**1.** In seropositive pregnant women without prior treatment from week 24

The group that was administered placebo was compared to the group receiving AZT (orally during pregnancy, injectable during delivery and as syrup to the newborn for 6 weeks). Re‐ sults showed that transmission was 8.3% with AZT and 25% with placebo, which is equiva‐

lent to a reduction in 67% (p= 0,00006). (Table 3)

Prepartum:

Intrapartum:

until delivery Postpartum:

**Table 3.** ACTG 076 PROTOCOL

314 Current Perspectives in HIV Infection

AZT between weeks 14 and 34: AZT 100 mg po 5 times per day or AZT 200 mg po 3 times per day or AZT 300 mg po 2 times per day

AZT 2 mg/kg intravenous during one

AZT to the neonate from 8 to 12 hours after birth in 2 mg/kg doses (syrup) every 6 hours during the first 6 weeks of life

**11. High Activity Antiretroviral (ART) Therapy (HAART)**

hour,Followed by continuous infusion of 1 mg/kg

The first attempt at a successful pharmacological scheme to control VT was achieved by the ACTG 076 protocol. Such protocol together with elective C-section and suppression of lacta‐ tion (biomedical measures) achieved a decrease in VT from 29% to 5.6% [11]. Although the latter is true, new evidence demonstrated that the triple drug therapy was more effective than monotherapy or bitherapy to prevent Vertical Transmission (VT). A protocol, that com‐ bined the biomedical preventive measures already mentioned and the indication of three an‐ tiretroviral drugs was designed. Such drugs included nucleosidic and non-nucleosidic reverse transcriptase inhibitors (NRTI and NNRTI respectively) and Protease inhibitors (PI), and together formed a series of schemes known as highly active antiretroviral therapy (HAART). It is by virtue of the latter that VT has decreased to values close to 1.0 [2-6, 30-34]. It is a known fact that VT may occur among seropositive pregnant women during pregnan‐ cy (35%), delivery (65%) and lactation (14%-29%) and that there are factors that increase the risk of fetal infection (Primoinfection, Sexually transmitted diseases and CD4+ T cell counts). The most important of such factors is maternal viral load [27]. Loads under 1000 copies/ml have significantly lower risks of VT, however there is no evidence pointing to the minimal load that exempts from risk. The latter supports the need to use a highly active antiretroviral therapy (HAART) with the highest effectiveness and safety to reach, hopefully, undetectable viral load levels. With such purpose, and considering that most of transmissions to the new‐ born occur during the peripartum period, an attempt at reaching the lowest viral loads dur‐


Within the HAART concept, the selection of the NRTI combination to be used should follow the efficacy of the latter in reducing VT, considering the potential teratogenic effects and the eventual toxicity to the mother-child binomial. Based on the teratogenesis risk classification of the FDA, NRTI are classed as B or C. The largest experience involves Zidovudine (AZT or ZDV) that has demonstrated being quite a safe drug, with low resistance and high efficacy to prevent VT. In addition, the association of ZDV and Lamivudine (ZDV/3TC) has demonstrat‐ ed to be more effective than ZDV as monotherapy in mother-to-child transmission preven‐ tion. Such combination does not imply higher toxicity or risk of teratogenesis [2-6, 30-34].

Regarding the search for the third drug, Lopinavir-Ritonavir has demonstrated efficacy and safety in VT prevention. The association of Saquinavir reinforced with Ritonavir has gath‐ ered enough evidence to suggest that such combination is a good supplementary alternative to render the pharmacological therapy more effective [26].

Although Nevirapine (NVP) has been widely indicated and has demonstrated being effec‐ tive in the prevention of mother-to-child transmission mostly in developing countries with low economical resources, the use of such drug has been related to the development of viral resistance both in mothers as in children who were infected despite the received prophylax‐ is. Moreover, mothers who were administered Nevirapine had a higher incidence of toxic effects (hepatic, hypersensitivity) in particular pregnant women with CD4+ T cell counts higher than 250 cells/ml. The above mentioned suggests that such indication should be con‐ sidered among patients never having received Nevirapine and with CD4+ T cell counts un‐ der 250 cells/ml. When such drug is used in the intrapartum period, it is advisable to indicate ZDV y Lamivudine (3TC) for 7 days both to the mother as well as to the newborn, to reduce the risk of viral resistance to Nevirapine and other NNTRI [30-34].

The following are among the drugs that should not be indicated during pregnancy: Efavir‐ enz, Nelfinavir and the association of d4T (Stavudine) and ddI (Didanosine). All share tera‐ togenicity and toxicity risk for the mother-child binomial [30-36].

In 2010 the World Health Organization stressed the importance of offering a lifelong antire‐ troviral therapy to patients with a carrier condition recognized during pregnancy. The WHO proposed two prophylactic treatment schemes (A and B) for pregnant women who did not meet the criterion of a certain CD4+ T cell count (<350/ mm3 ). A third option (B+) as appeared recently, aiming at implementing the HAART for a lifetime to all seropositive pregnant women regardless of their CD4+ T cell count (Table 4). This new option has the following advantages: it simplifies drug supply, since it relates drugs to national antiretrovi‐ ral therapy programs, protects against VT, prevents transmission to seronegative partners and prevents discontinuation of the follow up of therapies already implemented by the pa‐ tients. It finally suggests that such new option should be evaluated depending on the reality of each country [31].

**11.1. Toxic and Side effects of ART**

**11.2. Protease inhibitors and hyperglycemia**

assessment ACTG 076 [11].

creased infectious morbidity between 7 and 10 fold [33].

The eventual toxic effect of such medications on the mother-child binomial is among the as‐ pects that need to be assessed for the election of the pharmacological treatment. According to study reports, approximately 80% of gestating women under treatment developed some side effect such as anemia, nausea, vomiting, hepatic enzyme disorders or hyperglycemia [26,35-37]. Because of this, it is important to know which are the side and toxic effects of the

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 317

In non-pregnant women, the use of protease inhibitors has been related to the development of different degrees of carbohydrate Intolerance. This should be considered when they are

Reverse transcriptase nucleoside inhibitors are recognized for their induction of mitochon‐ drial dysfunction due to their affinity for mitochondrial DNA-polymerase gamma. Such ef‐ fect is more intense for Stavudine (d4T), ddI (Didanosine) and less intense for ZDV (Zidovudine), 3TC (Lamivudine), ABC (Abacavir) and TDF (Tenofir). Additionally, these drugs are also related to lactic acidosis in cases with concomitant hepatic steatosis. Such as‐ sociation would be higher with the use of d4T (Stavudine) with an estimated rate of 0,8% and 1,2% per year per treated patient. [26, 35-37]. Clinical manifestations of this condition are varied and include polyneuritis, myopathies, cardiopathies, hepatic steatosis and lactic acidosis. Not uncommonly patients develop a condition similar to the HELLP Syndrome that should be considered when addressing differential diagnoses. Finally, there are reports about uninfected children, born to seropositive mothers that received ZDV or ZDV/Lamivu‐ dine (ZDV/3TC) during pregnancy, who developed mitochondrial dysfunction –related symptoms during the first months of life. Such finding was not confirmed with the protocol

Regarding the mode of delivery in seropositive pregnant women who did not receive ART or had partial indication of ART, elective C-section at week 38 (a surgical procedure carried out before the initiation of labor and without premature rupture of membranes) has demon‐ strated a decrease of VT risk in one half. [8,38]. Recent studies propose the option of vaginal delivery to be used according to the obstetric conditions in seropositive women with viral load under 1000 copies/ml and prior patient consent. Such indication is supported by the fact that C-section benefits are indeed difficult to evaluate and moreover, data retrieved from a large number of patients did not evidence a higher reduction of VT among patients with viral loads < 1000 copies/ml that underwent C-section. Furthermore, C-section in‐

When facing the vaginal delivery option, episiorrhaphy and forceps or spatulas should be avoided. Invasive procedures such as amniocentesis, chorionic villus biopsy and invasive monitoring might increase fetal exposure to infected maternal blood, and thus should also

drugs that are commonly used, in order to identify them and treat them accordingly.

used during pregnancy since they may trigger gestational diabetes [26,35-37].

**11.3. Mitochondrial toxicity and nucleosidic reverse transcriptase inhibitors**


**Table 4.** Note: "Triple ARVs" refers to the use of one of the recommended 3-drug fully suppressive treatment options. For the drug abbreviations in the table: AZT (azidothymidine, zidovudine [ZDV]); NVP (nevirapine); 3TC (lamivudine).a Recommended in WHO 2010 PMTCT guidelines b True only for EFV-based first-line ART; NVP-based ART not recommended for prophylaxis (CD4 >350) c Formal recommendations for Option B+ have not been made, but presumably ART would start at diagnosis. Options for PMTCT programs

### **11.1. Toxic and Side effects of ART**

WHO proposed two prophylactic treatment schemes (A and B) for pregnant women who

appeared recently, aiming at implementing the HAART for a lifetime to all seropositive pregnant women regardless of their CD4+ T cell count (Table 4). This new option has the following advantages: it simplifies drug supply, since it relates drugs to national antiretrovi‐ ral therapy programs, protects against VT, prevents transmission to seronegative partners and prevents discontinuation of the follow up of therapies already implemented by the pa‐ tients. It finally suggests that such new option should be evaluated depending on the reality

**Woman Receives:**

**Treatment Prophylaxis Infant receives:**

(for CD4 count > 350 cells/ mm3)

AZT/3TC

breastfeeding

*prophylaxis*b:

**Table 4.** Note: "Triple ARVs" refers to the use of one of the recommended 3-drug fully suppressive treatment options. For the drug abbreviations in the table: AZT (azidothymidine, zidovudine [ZDV]); NVP (nevirapine); 3TC (lamivudine).a Recommended in WHO 2010 PMTCT guidelines b True only for EFV-based first-line ART; NVP-based ART not recommended for prophylaxis (CD4 >350) c Formal recommendations for Option B+ have not been made, but

*Same for treatment and*

Regardless of CD4 count, triple ARVs starting as soon as diagnosed,c continued for life

as 14 weeks gestation

*Antepartum*: AZT starting as early

*Intrapartum*: at onset of labour, single-dose NVP and first dose of

*Postpartum*: daily AZT/3TC through 7 days postpartum

*Same initial ARVs for both*b: Triple ARVs starting as early as 14 weeks gestation and continued intrapartum and through childbirth if not breastfeeding or until 1 week after cessation of all

). A third option (B+) as

Daily NVP from birth until 1 week after cessation of all breastfeeding; or, if not breastfeeding or if mother is on treatment, through age

Daily NVP or AZT from birth through age 4–6 weeks regardless of infant feeding

Daily NVP or AZT from birth through age 4–6 weeks regardless of infant feeding

4–6 weeks

method

method

did not meet the criterion of a certain CD4+ T cell count (<350/ mm3

of each country [31].

316 Current Perspectives in HIV Infection

(for CD4 count ≤ 350 cells/mm3 )

*Option Aa* Triple ARVs starting as soon as

*Option B*<sup>a</sup> *Same initial ARVs for both*b*:*

*Option B+ Same for treatment and prophylaxis*b:

diagnosed, *continued for life*

Triple ARVs starting as soon as diagnosed, *continued for life*

Regardless of CD4 count, triple ARVs starting as soon as diagnosed,c continued for life

presumably ART would start at diagnosis. Options for PMTCT programs

The eventual toxic effect of such medications on the mother-child binomial is among the as‐ pects that need to be assessed for the election of the pharmacological treatment. According to study reports, approximately 80% of gestating women under treatment developed some side effect such as anemia, nausea, vomiting, hepatic enzyme disorders or hyperglycemia [26,35-37]. Because of this, it is important to know which are the side and toxic effects of the drugs that are commonly used, in order to identify them and treat them accordingly.

#### **11.2. Protease inhibitors and hyperglycemia**

In non-pregnant women, the use of protease inhibitors has been related to the development of different degrees of carbohydrate Intolerance. This should be considered when they are used during pregnancy since they may trigger gestational diabetes [26,35-37].

### **11.3. Mitochondrial toxicity and nucleosidic reverse transcriptase inhibitors**

Reverse transcriptase nucleoside inhibitors are recognized for their induction of mitochon‐ drial dysfunction due to their affinity for mitochondrial DNA-polymerase gamma. Such ef‐ fect is more intense for Stavudine (d4T), ddI (Didanosine) and less intense for ZDV (Zidovudine), 3TC (Lamivudine), ABC (Abacavir) and TDF (Tenofir). Additionally, these drugs are also related to lactic acidosis in cases with concomitant hepatic steatosis. Such as‐ sociation would be higher with the use of d4T (Stavudine) with an estimated rate of 0,8% and 1,2% per year per treated patient. [26, 35-37]. Clinical manifestations of this condition are varied and include polyneuritis, myopathies, cardiopathies, hepatic steatosis and lactic acidosis. Not uncommonly patients develop a condition similar to the HELLP Syndrome that should be considered when addressing differential diagnoses. Finally, there are reports about uninfected children, born to seropositive mothers that received ZDV or ZDV/Lamivu‐ dine (ZDV/3TC) during pregnancy, who developed mitochondrial dysfunction –related symptoms during the first months of life. Such finding was not confirmed with the protocol assessment ACTG 076 [11].

Regarding the mode of delivery in seropositive pregnant women who did not receive ART or had partial indication of ART, elective C-section at week 38 (a surgical procedure carried out before the initiation of labor and without premature rupture of membranes) has demon‐ strated a decrease of VT risk in one half. [8,38]. Recent studies propose the option of vaginal delivery to be used according to the obstetric conditions in seropositive women with viral load under 1000 copies/ml and prior patient consent. Such indication is supported by the fact that C-section benefits are indeed difficult to evaluate and moreover, data retrieved from a large number of patients did not evidence a higher reduction of VT among patients with viral loads < 1000 copies/ml that underwent C-section. Furthermore, C-section in‐ creased infectious morbidity between 7 and 10 fold [33].

When facing the vaginal delivery option, episiorrhaphy and forceps or spatulas should be avoided. Invasive procedures such as amniocentesis, chorionic villus biopsy and invasive monitoring might increase fetal exposure to infected maternal blood, and thus should also be avoided. The use of oxytocin has no contraindications, as opposed to ergot-derivatives that might present an eventual synergic action in association to Protease Inhibitors that would exaggerate vasoconstriction and ischemia, and therefore are contraindicated [39].

iorrhaphy and all procedures involving the use of instruments should be avoided

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 319

**7.** Intrapartum intravenous ZDV should be used regardless of the delivery mode chosen.

**8.** ZDV suspension should be administered orally for 6 weeks starting from 8 to 12 hours from birth, to all newborns to HIV+ mothers. The recommended ZDV dose for term newborns is 2 mg/Kg/dose every 6 hours p.o. or 1.5 mg/Kg/dose every 6 hours intrave‐ nous. The same dose should be administered every 12 hours in preterm newborns of

**9.** If Nevirapine is administered intrapartum, ZDV/3TC must be associated for 7 days after

**11.** The newborn should be administered ZDV suspension, orally, for 6 weeks starting from 8 to 12 hours after birth. The recommended AZT dose for term newborns is 2 mg/ Kg/ dose every 6 hours orally or 1.5 mg/Kg/dose every 6 hours intravenous. The same dose should be administered every 12 hours in preterm newborns of less than 35 weeks gestation.

**12.** Newborns to mothers who received NVP as part of mother-to-child transmission pre‐ vention should receive, besides ZDV, 2 doses of 2 mg/Kg of NVP oral solution. The first dose should be administered the earliest as possible postpartum and the second should

**13.** The newborns to mothers who did not receive the mother-to-child transmission preven‐ tion protocol, or who just received intrapartum prophylaxis, should be administered

A seropositive gestating woman should be clinically addressed based on a multidisciplinary and thorough assessment of her initial health status. The latter should include a full physical examination, especially observing those signs that guide diagnosis towards an opportunistic infectious pathology and assessing the current immune status.Once the effectiveness of bio‐ medical healthcare provisions for the prevention of MTCT (mother-to-child-transmission) is demonstrated, it is important to ensure collection of epidemiological history in order to ach‐ ieve an adequate report, key data to reassess the design and the effectiveness of preventive programs. To achieve such aims, it is critical to maintain and improve diagnosis and pri‐ mary prevention of the infection among women in childbearing age. ON the other hand, it is important to prevent high rates of unwanted pregnancies and abortions that are direct indi‐ cators of risk behaviors in such population group. Likewise, one should aim at achieving 100% screening during the first trimester, also at the possibility of repeating it during the third trimester and at training maternity staff on rapid testing for carrier status detection

(forceps or spatulas).

less than 35 weeks gestational age.

be administered at 48 to 72 hours of life.

the AZT scheme and 1 to 2 NVP doses.

**13. Conclusion**

delivery to reduce the risk of developing NVP resistance.

**10.** Lactation should be suppressed with cabergoline or bromocriptin.

During delivery (C-section or vaginal delivery), the indication of intravenous administration of ZDV to the mother should be the rule, since fetal plasma levels of such drug, reached by transplacental route, ensure an adequate pre-exposition prophylaxis. Such indication togeth‐ er with the administration of ZDV suspension orally to the newborn during six weeks in‐ creases the preventive effect on infection transmission. This is regardless of the mother being administered ZDV within the therapeutic scheme or even in the event of resistance to ZDV. Finally, the use of Nevirapine (200 mg one time only dose) should only be indicated to patients with late initiation of the prevention protocol, on patients with a viral load > 1000 copies/ml or in the case of diagnosis of maternal carrier status during labor [4,5,33,34].

There is evidence pointing that among patients that are not treated within an antiretroviral management protocol, transmission to the newborn through breastfeeding ranges between 5% and 14% [9,40]. Free and cell-bound virus has been isolated from breast milk through PCR techniques and viral culture. Such cells are more numerous in the colostrum and in breast milk secreted during the immediate puerperium. The latter, in association with the immature immune system of the newborn, make transmission through breastfeeding higher during the first month of life. All the above-mentioned, warrant the recommendation to sup‐ press lactation in countries where infantile malnutrition and diarrheic syndrome - related mortality are low [34].

### **12. Summary of Mother-to-child Prevention Management**


iorrhaphy and all procedures involving the use of instruments should be avoided (forceps or spatulas).


### **13. Conclusion**

be avoided. The use of oxytocin has no contraindications, as opposed to ergot-derivatives that might present an eventual synergic action in association to Protease Inhibitors that would exaggerate vasoconstriction and ischemia, and therefore are contraindicated [39].

During delivery (C-section or vaginal delivery), the indication of intravenous administration of ZDV to the mother should be the rule, since fetal plasma levels of such drug, reached by transplacental route, ensure an adequate pre-exposition prophylaxis. Such indication togeth‐ er with the administration of ZDV suspension orally to the newborn during six weeks in‐ creases the preventive effect on infection transmission. This is regardless of the mother being administered ZDV within the therapeutic scheme or even in the event of resistance to ZDV. Finally, the use of Nevirapine (200 mg one time only dose) should only be indicated to patients with late initiation of the prevention protocol, on patients with a viral load > 1000 copies/ml or in the case of diagnosis of maternal carrier status during labor [4,5,33,34].

There is evidence pointing that among patients that are not treated within an antiretroviral management protocol, transmission to the newborn through breastfeeding ranges between 5% and 14% [9,40]. Free and cell-bound virus has been isolated from breast milk through PCR techniques and viral culture. Such cells are more numerous in the colostrum and in breast milk secreted during the immediate puerperium. The latter, in association with the immature immune system of the newborn, make transmission through breastfeeding higher during the first month of life. All the above-mentioned, warrant the recommendation to sup‐ press lactation in countries where infantile malnutrition and diarrheic syndrome - related

**1.** Every pregnant woman should be offered the possibility of undergoing HIV testing not later than upon the second pregnancy follow-up visit within the first trimester of gesta‐

**2.** A quick HIV test for HIV diagnosis enabling immediate action to be taken should be offered to women who arrive to delivery without having their test results available,

**3.** ART is recommended to prevent HIV vertical transmission in pregnant women without prior therapy between gestation weeks 20 and 28. The use of ZDV in association with

**4.** Viral loads should be followed up 6 weeks after initiation of ART during gestation and

**5.** Elective C-section should be indicated at 39 weeks in HIV+ women without ART over pregnancy, in women that do not have a viral load result upon weeks 34-36, in those with a viral load > 1.000 copies/ ml or in women co-infected with Hepatitis C virus. **6.** In the event a pregnant woman meets the conditions for a vaginal delivery, her con‐ sent should be obtained after being informed about the eventual associated risks. Epis‐

even if tests have been carried out. Counseling and consent are mandatory.

**12. Summary of Mother-to-child Prevention Management**

tion, and depending on resources, also within the third trimester.

subsequently on a monthly basis until gestation weeks 34 and 36.

mortality are low [34].

318 Current Perspectives in HIV Infection

Lamivudine is recommended.

A seropositive gestating woman should be clinically addressed based on a multidisciplinary and thorough assessment of her initial health status. The latter should include a full physical examination, especially observing those signs that guide diagnosis towards an opportunistic infectious pathology and assessing the current immune status.Once the effectiveness of bio‐ medical healthcare provisions for the prevention of MTCT (mother-to-child-transmission) is demonstrated, it is important to ensure collection of epidemiological history in order to ach‐ ieve an adequate report, key data to reassess the design and the effectiveness of preventive programs. To achieve such aims, it is critical to maintain and improve diagnosis and pri‐ mary prevention of the infection among women in childbearing age. ON the other hand, it is important to prevent high rates of unwanted pregnancies and abortions that are direct indi‐ cators of risk behaviors in such population group. Likewise, one should aim at achieving 100% screening during the first trimester, also at the possibility of repeating it during the third trimester and at training maternity staff on rapid testing for carrier status detection during labor, for those pregnant women without having accessed an AMTCPP (Antenatal Mother-to-Child Prevention Program).

**Author details**

**References**

on June 30th.

on June 30th 2012.

Enrique Valdés Rubio\*

Address all correspondence to: evaldes@vtr.net

Universidad de Chile. Santiago, Chile

Maternal –Fetal Medicine Unit. Obstetrics and Gynecology Department. Hospital Clínico

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 321

[1] The Millennium Development Goals. (2012). Eight goals for 2015. Found in: http:// www.who.int/topics/millennium\_development\_goals/diseases/es/index.html Access

[2] Valdés, E., Candia, P., & Lattes, K. (2009). Transmisión Vertical de VIH y SIDA: Real‐

[3] Valdés, E., Sepúlveda, A., Candia, P., Sepúlveda, C., & Lattes, K. (2011). VIH/SIDA: Comportamiento epidemiológico de la transmisión vertical en el contexto general de

[4] UNAIDS. (2010). Global Report. Found in: http://www.unaids.org/globalreport/glob‐

[5] Royal College of Obstetricians and Gynaecologists. (2010). Management of HIV in pregnancy. Green-top Guideline N°39 June. Found in: http://www.rcog.org.uk/ womens-health/clinical-guidance/management-hiv-pregnancy-green-top-39 Access

[6] Forbes, J., Alimenti, A., Singer, J., Brophy, J., Bitnun, A., Sanson, L., et al. (2012). A

[7] Blair, J. M., Hanson, D. L., Jones, J. L., et al. (2004). Trends in pregnancy rates among women with human immunodeficiency virus. *Obstet Gynecol*, 103, 663-668.

[8] M5 The European Mode of Delivery Collaboration. (1999). Elective caesarean-section versus vaginal delivery in prevention of vertical HIV-1 transmission: a randomized

[9] Coutsoudis, A., Pillay, K., Spooner, E., Kuhn, L., & Coovadia, H. M. (1999). Influence of infant feeding patterns on early mother to child transmission of HIV-1 in Durban

[10] Melvin, Z., Alarcon, A. J., Velasquez, J. C., et al. (2004). Rapid HIV type 1 testing of women presenting in late pregnancy with unknown HIV status in Lima, Peru. *Aids*

South Africa: A prospective cohort study. *Lancet*, 354(9177), 471-477.

idad epidemiológica del Cono Sur Progr Obstet Ginecol. 52(12), 719-24.

la infección en Chile. *Rev Chil Obstet Ginecol*, 76(1), 52-57.

national review of vertical HIV transmission. *AIDS*, 26(6).

al\_report.htm Access on June 30th 2012.

clinical trial. *Lancet*, 353, 1035-9.

*Research- Human retroviruses*, 20(10), 1046-1052.

Finally, MTCT prevention strategy has been based on the ongoing revision of the pooled evidence, therefore it is of key importance to continue evaluating new conducts that enable identification of other aspects: the eventual induction of antiviral resistance and toxicity on the pregnant woman and the newborn and their potential impacts on further quality of life, the use of micronutrients and their impact on MTCT decrease, assessment of the vaginal de‐ livery option in gestating women with low viral load, and sperm wash as an element to re‐ duce MTCT [40].

### **Nomenclature**

*VT*: Vertical Transmission:

*HIV*: Human Immunodeficiency Human

*AIDS*: Acquired Immune Deficiency Syndrome

*PMTCT*: Prevention of mother-to-child transmission

*AMTCPP*: Antenatal Mother-to-Child Prevention Program

*UNAIDS*: Joint United Nations Program on HIV/AIDS

*ART*: Antiretroviral Therapy

*HAART*: Highly Active Antiretroviral Treatment

*NRTI*: Nucleoside reverse transcriptase inhibitor

*NNRTI*: Non nucleoside reverse transcriptase inhibitor

*PI*: Protease inhibitor

*AZT or ZDV*: zidovudine

*NVP*: Nevirapine

*3TC*: Lamivudine

d4T: Stavudine

ddI: Didanosine

### **Author details**

during labor, for those pregnant women without having accessed an AMTCPP (Antenatal

Finally, MTCT prevention strategy has been based on the ongoing revision of the pooled evidence, therefore it is of key importance to continue evaluating new conducts that enable identification of other aspects: the eventual induction of antiviral resistance and toxicity on the pregnant woman and the newborn and their potential impacts on further quality of life, the use of micronutrients and their impact on MTCT decrease, assessment of the vaginal de‐ livery option in gestating women with low viral load, and sperm wash as an element to re‐

Mother-to-Child Prevention Program).

320 Current Perspectives in HIV Infection

duce MTCT [40].

**Nomenclature**

*VT*: Vertical Transmission:

*ART*: Antiretroviral Therapy

*PI*: Protease inhibitor

*NVP*: Nevirapine

*3TC*: Lamivudine

d4T: Stavudine

ddI: Didanosine

*AZT or ZDV*: zidovudine

*HIV*: Human Immunodeficiency Human

*AIDS*: Acquired Immune Deficiency Syndrome

*PMTCT*: Prevention of mother-to-child transmission

*UNAIDS*: Joint United Nations Program on HIV/AIDS

*HAART*: Highly Active Antiretroviral Treatment

*NRTI*: Nucleoside reverse transcriptase inhibitor

*NNRTI*: Non nucleoside reverse transcriptase inhibitor

*AMTCPP*: Antenatal Mother-to-Child Prevention Program

Enrique Valdés Rubio\*

Address all correspondence to: evaldes@vtr.net

Maternal –Fetal Medicine Unit. Obstetrics and Gynecology Department. Hospital Clínico Universidad de Chile. Santiago, Chile

### **References**


[11] Connor, E. M., Sperling, R. S., & Gelber, R. (1994). Reduction of maternal- infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. *N Engl J Med*, 331(18), 1173-80.

[26] Abarzúa, F. (2012). VIH y Embarazo. Capítulo 21. pag Found in: www.acog.cl/educa‐

HIV/AIDS: Vertical Transmission http://dx.doi.org/10.5772/53204 323

[27] The European Collaborative Study. (1999). Maternal viral load and vertical transmis‐ sion of HIV-1: an important factor but not the only one. *AIDS*, 13, 1377-1385.

[28] Khan, M., Pillay, T., Moodley, J. M., et al. (2001). Maternal mortality associated with tuberculosis-HIV-1 co-infection in Durban, South Africa. *AIDS*, 15, 1857-1863.

[29] Duri, K., Müller, F., Gumbo, F., Kurewa, N., Rusakaniko, S., Chirenje, M., et al. (2011). Human Immunodeficiency Virus (HIV) types Western blot (WB) band pro‐ files as potential surrogate markers of HIV disease progression and predictors of ver‐ tical transmission in a cohort of infected but antiretroviral therapy naïve pregnant

[30] El Beitune, P., Duarte, G., Quintana, S. M., Figueiro-Filho, E. A., Marcolin, A. C., & Abduch, R. (2004). Antiretroviral therapy during pregnancy and early neonatal life:

consequences for HIV-exposed uninfected children. *Braz J Infect Dis*, 8, 140-50.

[31] Use of antiretroviral drugs for treating pregnant women and preventing HIV infec‐ tion in infants Programmatic update. (2012). Abril. Found in: http:// www.who.int/hiv/pub/mtct/programmatic\_update2012/en/index.html Access on

[32] Abarzúa, F., Pérez, C., Callejas, C., Yombi, J. C., & Vandercam, B. (2004). Ausencia de transmisión perinatal de VIH en 40 embarazadas tratadas con terapia anti-retroviral

[33] Abarzúa, F., Nuñez, F., Hubinont, C., Bernard, P., Yombi, J. C., & Vandercam, B. (2005). Human immunodeficiency virus (HIV) infection in pregnancy: antiretroviral

[34] Guía Clínica (2010). Síndrome de Inmunodeficiencia Adquirida. VIH/SIDA. Found in : www.redsalud.gov.cl/portal/url/item/7220fdc4340c44a9e04001011f0113b9.pdf Ac‐

[35] Poirier, M. C., Olivero, O. A., Walker, D. M., & Walker, V. E. (2004). Perinatal geno‐ toxicity and carcinogenicity of anti-retroviral nucleoside analog drugs. *Toxicol Appl*

[36] Brogly, S. B., Ylitalo, N., Mofenson, L. M., Oleske, J., Van Dyke, R., Crain, M. J., Ab‐ zug, M. J., Brady, M., Jean-Philippe, P., Hughes, M. D., & Seage, G. R. 3rd. (2007). In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mito‐

[37] Lorenzini, P., Spicher, V. M., Laubereau, B., Hirschel, B., Kind, C., Rudin, C , et al. (1998). Antiretroviral therapies in pregnancy: maternal, fetal and neonatal effects. Swiss HIV Cohort Study, the Swiss Collaborative HIV and Pregnancy study, and the

treatment (ART) and mode of delivery. *Rev Chil Infectol*, 22, 327-37.

chondrial dysfunction in HIV-uninfected children. *AIDS*, 21, 929-38.

Swiss Neonatal AHIV study. *AIDS*, 12(18), F241-7.

women in Harare, Zimbabwe. *BMC infectious Diseases*, 11, 7.

de alta potencia. *Rev Chil Obstet Ginecol*, 69, 232-8.

ción.php?sort=ddAccess on June 30th., 413-23.

June 30th.

cess on June 30th 2012

*Pharmacol*, 199(2), 151-61.


[26] Abarzúa, F. (2012). VIH y Embarazo. Capítulo 21. pag Found in: www.acog.cl/educa‐ ción.php?sort=ddAccess on June 30th., 413-23.

[11] Connor, E. M., Sperling, R. S., & Gelber, R. (1994). Reduction of maternal- infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. *N*

[12] Read, J., Cahn, P., Losso, M., Pinto, J., et al. (2007). Management of Human Immuno‐ deficiency Virus-Infected Pregnant Women at Latin American and Caribbean Sites.

[13] Valdés, E. (2002). VIH-SIDA y embarazo: actualización y realidad en Chile. *Rev Chil*

[14] Burns, D. N., Nourjah, P., Minkoff, H., Korelitz, J., Biggar, R. J., Landesman, S., Ru‐ binstein, A., Wright, D., & Nugent, R. P. (1996). Changes in CD4+ and CD8+ cell lev‐ els during pregnancy and post partum in women seropositive and seronegative for

[15] Minkoff, H. L., Willoughby, A., Mendez, H., Moroso, G., Holman, S., Goedert, J. J., & Landesman, S. H. (1990). Serious infections during pregnancy among women with

[16] Capítulo "VIH- SIDA y embarazo". (2006 ). E. Valdés. Libro "Urgencias y complica‐ ciones en Obstetricia" M García Huidobro. *J Hasbún. Editorial Mediterráneo*, 447. [17] "Mujer y VIH". (2002). *E. Herane, E. Valdés. Libro SIDA. C. Sepúlveda A. Afani. Editorial*

[18] French, R., & Broklehurst, P. (1998). The effect of pregnancy on survival in women infected with HIV: a systematic review of the literature and meta-analysis. *Br. J Ob‐*

[19] Wade, A.S, et al. (2005). HIV infection and sexually transmitted infections among

[20] De Bruyn, M., & Paxton, S. (2005). HIV testing of pregnant women-what is needed to

[21] Dhai, A., & Noble, R. (2005). Ethical issues in HIV. *Best Pract Res Clin Obstet Gynaecol*,

[22] Bowden, FJ. (2005). Reconsidering HIV testing-consent is still the key. *Sex Health*, 2,

[23] Chou, R., Smits, A. K., Huffman, L. H., Fu, R., & Korthuis, P. T. (2005). US Preventive Services Task Force. Prenatal screening for HIV: A review of the evidence for the U.S.

[24] Campos-Outcalt, D. (2007). Time to revise your HIV testing routine. *J Fam Pract*, 56,

[25] Winn, H., & Hobbins, J. (2000). Clinical Maternal-Fetal Medicine. Parthenon Publish

human immunodeficiency virus-1. *Am J Obstet Gynecol*, 174, 1461-8.

advanced HIV infection. *Am J Obstet Gynecol*, 162, 30-4.

men who have sex with men in Senegal. *AIDS*, 19, 2133-2140.

Preventive Services Task Force. *Ann Intern Med*, 143, 38-54.

protect positive women's needs and rights? *Sex Health*, 2, 143-51.

*Engl J Med*, 331(18), 1173-80.

322 Current Perspectives in HIV Infection

*Obstet Ginecol*, 67, 160-6.

*Obstet Gynecol J*, 109(6), 1358-1367.

*Mediterráneo. Tercera edición*, 721.

*stet Gynecol*, 105, 827-35.

19, 255-67.

165-7.

283-4.

Group; Cap 26.


[38] Read, J. S., & Newell, M. K. (2005). Efficacy and safety of cesarean delivery for pre‐ vention of mother-to-child transmission of HIV-1. *Cochrane Database Syst Rev* [4], CD005479.

**Chapter 14**

**Reproductive Health Challenges of Living with HIV-**

The human immunodeficiency Virus (HIV) pandemic is one of the most serious health crisis faced by the world today. An estimated 34 million people were living with HIV/AIDS as at 2010 [1]. A disproportionate burden has been placed on women and children who continue to experience high rates of new infection and HIV-related illness and death. Availability and use of antiretroviral drugs has changed the landscape of HIV/AIDS bringing about a change in the perception of HIV from an incurable deadly disease to a chronic manageable illness. As effective HIV treatments become more widespread, HIV-infected individuals in sub Sa‐ haran Africa are living longer, healthier lives. Many HIV-affected couples (sero-discordant and sero-concordant) are now considering long-term life projects including options for safer reproduction or procreation. There has also been increase in advocacy to expand the capaci‐ ty for the health care system particularly in Africa to provide the sexual and reproductive health services that HIV infected persons in Africa desperately need [2]. This decade has witnessed greater commitment to sexual and reproductive health and HIV linkages particu‐ larly in the developed world. More recent opportunities include policy developments within the Global Fund to Fight AIDS, Tuberculosis and Malaria to accept proposals that form link‐ ages with sexual and reproductive health within the overall frameworks of HIV, tuberculo‐ sis (TB) and malaria. There has also been a renewed commitment by the United States of America to international sexual and reproductive health through support of the United Na‐ tions Population Fund and the repeal of the Mexico City Policy, also known as the "global gag rule", a United States government policy that hitherto prohibited non-governmental or‐ ganizations from receiving federal funding for performing or promoting abortion services in other countries. A large body of evidence suggests that reproductive technologies can help HIV-affected couples to safely conceive with minimal risk of HIV transmission to their part‐

> © 2013 Erhabor et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Infection in Sub Saharan Africa**

Additional information is available at the end of the chapter

O. Erhabor, T.C. Adias and C.I. Akani

http://dx.doi.org/10.5772/52682

**1. Introduction**


## **Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa**

O. Erhabor, T.C. Adias and C.I. Akani

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52682

### **1. Introduction**

[38] Read, J. S., & Newell, M. K. (2005). Efficacy and safety of cesarean delivery for pre‐

[39] Safety and Toxicity of individual Antiretroviral Agents in pregnancy. (2012). Found in: http://img.thebody.com/hivatis/pdfs/pregnancy\_guide.pdf Access on June 30th.

[40] Semprini, A. E., Vucetich, A., & Hollander, L. (2004). Sperm washing, use of HAART

and role of elective caesarean section. *Curr Opin Obstet Gynecol*, 16, 465-70.

CD005479.

324 Current Perspectives in HIV Infection

vention of mother-to-child transmission of HIV-1. *Cochrane Database Syst Rev* [4],

The human immunodeficiency Virus (HIV) pandemic is one of the most serious health crisis faced by the world today. An estimated 34 million people were living with HIV/AIDS as at 2010 [1]. A disproportionate burden has been placed on women and children who continue to experience high rates of new infection and HIV-related illness and death. Availability and use of antiretroviral drugs has changed the landscape of HIV/AIDS bringing about a change in the perception of HIV from an incurable deadly disease to a chronic manageable illness. As effective HIV treatments become more widespread, HIV-infected individuals in sub Sa‐ haran Africa are living longer, healthier lives. Many HIV-affected couples (sero-discordant and sero-concordant) are now considering long-term life projects including options for safer reproduction or procreation. There has also been increase in advocacy to expand the capaci‐ ty for the health care system particularly in Africa to provide the sexual and reproductive health services that HIV infected persons in Africa desperately need [2]. This decade has witnessed greater commitment to sexual and reproductive health and HIV linkages particu‐ larly in the developed world. More recent opportunities include policy developments within the Global Fund to Fight AIDS, Tuberculosis and Malaria to accept proposals that form link‐ ages with sexual and reproductive health within the overall frameworks of HIV, tuberculo‐ sis (TB) and malaria. There has also been a renewed commitment by the United States of America to international sexual and reproductive health through support of the United Na‐ tions Population Fund and the repeal of the Mexico City Policy, also known as the "global gag rule", a United States government policy that hitherto prohibited non-governmental or‐ ganizations from receiving federal funding for performing or promoting abortion services in other countries. A large body of evidence suggests that reproductive technologies can help HIV-affected couples to safely conceive with minimal risk of HIV transmission to their part‐

© 2013 Erhabor et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ner and baby. However, for most couples particularly in low income countries in sub Sahar‐ an Africa, such technologies are neither geographically nor economically accessible. In sub-Saharan Africa where HIV is endemic, 63% of women have an unmet need for sexual and reproductive health services, there is a high incidence of unintended pregnancies, a signifi‐ cant number of women do not know their HIV status, many women have limited access to sexual and reproductive health information and services (family planning, management of sexually transmitted diseases, HIV prevention and maternal health) to help them protect themselves from the triad of unwanted pregnancy, HIV infection and HIV transmission to their sexual partners and their children. With HIV now considered to be a chronic managea‐ ble disease, attention is shifting to offering and improving quality of life particularly by the provision of reproductive health options/care to men and women living with HIV-1.

viruses and diseases (HIV/AIDS, malaria and tuberculosis), corruption in government that have often committed serious human right abuses and violations, failed central planning, high levels of illiteracy, lack of access to foreign capital, and frequent tribal and military conflict (ranging from guerrilla warfare to genocide). According to the United Nation's Human Development Report in 2003, the bottom 25 ranked nations (151st to 175th) were all African [6].Poverty, illiteracy, malnutrition and inadequate water supply and sanita‐ tion, as well as poor health, affect a large proportion of the people who reside in the Afri‐ can continent. About 80.5% of the Sub-Saharan Africa population lives on less than \$2.50 per person per day in 2005 [7]. Africa faces several daunting challenges with regards to access to basic health services like their counterparts in most developed countries of the world. The healthcare system and infrastructure are suboptimal. This is often due to fun‐ damental limitations in funding, lack of adequate qualified health professional and equip‐ ment as well as deep rooted, institutionalized and chronic corruption among the political class and bureaucratic compensation and corruption among civil servants [8]. Africa re‐ mains the world's most corrupt continent. Corruption is the abuse of entrusted power for private gain, in public and private sectors [9]. This vice has contributed to a large extent to the stunted development and impoverishment seen in many African states. The Afri‐ can union estimates that corruption among the political class is costing the continent more than \$150 billion dollars per year. These are funds that could be used to improve the health infrastructure and quality of life of people of people in the continent but rather are laundered out of developing countries to banks in the developed world thus perpe‐ trating poverty among African people. Industrialized countries have continued to encour‐ age corruption in Africa and perpetuation of poverty among people in the African continent by providing crooked African leaders with a safe haven for their looted funds rather than repatriating such funds back and ensuring that they are used to enhance the infrastructural development of the continent. Corruption is endemic and continues to thrive in the African continent for several reasons; institutional weakness and criminal collaboration between the executive and the legislative and judicial arms of government, non-existence of the principle of rule of law, political god fatherism, institutional failure and criminal collaboration between civil servants and politicians. Corruption is a canker‐ worm that continues to weaken societies, ruins lives, and impedes development in the Af‐ rican continent [10]. This is further compounded by the high incidence of infectious diseases (HIV, TB and Malaria). Africa is plagued by poverty, malnutrition, poor sanita‐ tion, disease, high mortality rate, conflict, wars and crime. These challenges have a signif‐ icant negative effect on life expectance in the continent. The continent has the world's shortest life expectancy. Citizens of Sub-Saharan African countries are much more likely to die prematurely, than people in wealthier parts of the world. Children under- the age of 5 years are more likely to die from malaria, respiratory tract infections, diarrhoea, peri‐ natal conditions, measles and HIV/AIDS while those who survive the first 5 years of life are likely to die before their 60th birthday from HIV/AIDS, tuberculosis, and maternal mortality (for women as a result of pregnancy-related mortality). According to the CIA World Fact book 2009 [11], the life expectancy at birth of the world is 67.2 years (65.0 years for males and 69.5 years for females). The United Nations World Population Pros‐

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

327

A healthcare workforce that is highly motivated and well informed on the evidence –based practices in sexual and reproductive health options for persons living with HIV/AIDS is cru‐ cial to meeting the sexual and reproductive needs of PLWHA in Africa. A high morale and productive workforce are the driving force for the success of any reproductive health pro‐ gramme. Unless these staffs are motivated and have high morale, they may become a stum‐ bling block to the success and scaling –up of sexual and reproductive health services [3]. There are several challenges associated with meeting the sexual and reproductive health needs of persons living with HIV/AIDS in Africa; suboptimal antenatal care, absence of evi‐ dence-based and affordable assisted reproductive technologies, inadequate number of ap‐ propriately trained healthcare workers, suboptimal health infrastructure, lack of enabling legislation and policies on sexual and reproductive health of HIV-infected persons, chal‐ lenge of stigmatization and discrimination, unprofessional negative attitudes towards PLWHA desiring to procreate. The aim of this chapter is to highlight the reproductive health concerns associated with living with HIV infection in sub Saharan Africa.

### **2. History of Africa**

Africa is the world's second-largest and second-most-populous continent in the planet, af‐ ter Asia. With 1,032,532,874 billion people as at 2011 [4]. It accounts for about 14.72% of the world's human population. At about 30.2 million km² (11.7 million sq miles) includ‐ ing adjacent islands, it covers 6% of the Earths' total surface area and 20.4% of the total land area [5]. It is made up of 54 member states. Western Sahara although a member of the African union, its sovereignty is being disputed by Morocco. South Sudan has be‐ come Africa newest nation having recently separated from North Sudan. The population of Africa is estimated at greater than one billion people. Africa account for a significant 14% of the world's population. Africa contains the Nile River system which is the worlds longest. It also prides itself as the continent with the world's largest Sahara desert. Africa is surrounded by the Mediterranean Sea (north) and the Suez Canal and the Red sea (northwest), the Indian Ocean (east) and the Atlantic Ocean (west). Although endowed with abundant natural resources, Africa remains the world's poorest and most underde‐ veloped continent, the result of a variety of causes that may include the spread of deadly viruses and diseases (HIV/AIDS, malaria and tuberculosis), corruption in government that have often committed serious human right abuses and violations, failed central planning, high levels of illiteracy, lack of access to foreign capital, and frequent tribal and military conflict (ranging from guerrilla warfare to genocide). According to the United Nation's Human Development Report in 2003, the bottom 25 ranked nations (151st to 175th) were all African [6].Poverty, illiteracy, malnutrition and inadequate water supply and sanita‐ tion, as well as poor health, affect a large proportion of the people who reside in the Afri‐ can continent. About 80.5% of the Sub-Saharan Africa population lives on less than \$2.50 per person per day in 2005 [7]. Africa faces several daunting challenges with regards to access to basic health services like their counterparts in most developed countries of the world. The healthcare system and infrastructure are suboptimal. This is often due to fun‐ damental limitations in funding, lack of adequate qualified health professional and equip‐ ment as well as deep rooted, institutionalized and chronic corruption among the political class and bureaucratic compensation and corruption among civil servants [8]. Africa re‐ mains the world's most corrupt continent. Corruption is the abuse of entrusted power for private gain, in public and private sectors [9]. This vice has contributed to a large extent to the stunted development and impoverishment seen in many African states. The Afri‐ can union estimates that corruption among the political class is costing the continent more than \$150 billion dollars per year. These are funds that could be used to improve the health infrastructure and quality of life of people of people in the continent but rather are laundered out of developing countries to banks in the developed world thus perpe‐ trating poverty among African people. Industrialized countries have continued to encour‐ age corruption in Africa and perpetuation of poverty among people in the African continent by providing crooked African leaders with a safe haven for their looted funds rather than repatriating such funds back and ensuring that they are used to enhance the infrastructural development of the continent. Corruption is endemic and continues to thrive in the African continent for several reasons; institutional weakness and criminal collaboration between the executive and the legislative and judicial arms of government, non-existence of the principle of rule of law, political god fatherism, institutional failure and criminal collaboration between civil servants and politicians. Corruption is a canker‐ worm that continues to weaken societies, ruins lives, and impedes development in the Af‐ rican continent [10]. This is further compounded by the high incidence of infectious diseases (HIV, TB and Malaria). Africa is plagued by poverty, malnutrition, poor sanita‐ tion, disease, high mortality rate, conflict, wars and crime. These challenges have a signif‐ icant negative effect on life expectance in the continent. The continent has the world's shortest life expectancy. Citizens of Sub-Saharan African countries are much more likely to die prematurely, than people in wealthier parts of the world. Children under- the age of 5 years are more likely to die from malaria, respiratory tract infections, diarrhoea, peri‐ natal conditions, measles and HIV/AIDS while those who survive the first 5 years of life are likely to die before their 60th birthday from HIV/AIDS, tuberculosis, and maternal mortality (for women as a result of pregnancy-related mortality). According to the CIA World Fact book 2009 [11], the life expectancy at birth of the world is 67.2 years (65.0 years for males and 69.5 years for females). The United Nations World Population Pros‐

ner and baby. However, for most couples particularly in low income countries in sub Sahar‐ an Africa, such technologies are neither geographically nor economically accessible. In sub-Saharan Africa where HIV is endemic, 63% of women have an unmet need for sexual and reproductive health services, there is a high incidence of unintended pregnancies, a signifi‐ cant number of women do not know their HIV status, many women have limited access to sexual and reproductive health information and services (family planning, management of sexually transmitted diseases, HIV prevention and maternal health) to help them protect themselves from the triad of unwanted pregnancy, HIV infection and HIV transmission to their sexual partners and their children. With HIV now considered to be a chronic managea‐ ble disease, attention is shifting to offering and improving quality of life particularly by the

provision of reproductive health options/care to men and women living with HIV-1.

concerns associated with living with HIV infection in sub Saharan Africa.

**2. History of Africa**

326 Current Perspectives in HIV Infection

A healthcare workforce that is highly motivated and well informed on the evidence –based practices in sexual and reproductive health options for persons living with HIV/AIDS is cru‐ cial to meeting the sexual and reproductive needs of PLWHA in Africa. A high morale and productive workforce are the driving force for the success of any reproductive health pro‐ gramme. Unless these staffs are motivated and have high morale, they may become a stum‐ bling block to the success and scaling –up of sexual and reproductive health services [3]. There are several challenges associated with meeting the sexual and reproductive health needs of persons living with HIV/AIDS in Africa; suboptimal antenatal care, absence of evi‐ dence-based and affordable assisted reproductive technologies, inadequate number of ap‐ propriately trained healthcare workers, suboptimal health infrastructure, lack of enabling legislation and policies on sexual and reproductive health of HIV-infected persons, chal‐ lenge of stigmatization and discrimination, unprofessional negative attitudes towards PLWHA desiring to procreate. The aim of this chapter is to highlight the reproductive health

Africa is the world's second-largest and second-most-populous continent in the planet, af‐ ter Asia. With 1,032,532,874 billion people as at 2011 [4]. It accounts for about 14.72% of the world's human population. At about 30.2 million km² (11.7 million sq miles) includ‐ ing adjacent islands, it covers 6% of the Earths' total surface area and 20.4% of the total land area [5]. It is made up of 54 member states. Western Sahara although a member of the African union, its sovereignty is being disputed by Morocco. South Sudan has be‐ come Africa newest nation having recently separated from North Sudan. The population of Africa is estimated at greater than one billion people. Africa account for a significant 14% of the world's population. Africa contains the Nile River system which is the worlds longest. It also prides itself as the continent with the world's largest Sahara desert. Africa is surrounded by the Mediterranean Sea (north) and the Suez Canal and the Red sea (northwest), the Indian Ocean (east) and the Atlantic Ocean (west). Although endowed with abundant natural resources, Africa remains the world's poorest and most underde‐ veloped continent, the result of a variety of causes that may include the spread of deadly pects 2006 Revision put the world's life expectancy at birth at 66.57 years (64.52 years for males and 68.76 years for females).Women on the average are found to live longer than men with the exception of Zimbabwe, Afghanistan, Swaziland and Lesotho [12].Countries in Africa particularly those with a high HIV/AIDS prevalence have must lower life ex‐ pectancies [11]. Provision of low technology, safer, affordable and readily available repro‐ ductive health options particularly for PLWHA in Africa is a crucial but often unaddressed component of HIV prevention programme. The aim of this chapter is to evaluate the sexual and reproductive health challenges associated with HIV infection in sub Saharan Africa.

ity in the developed world show that the risk of death as a result of pregnancy and child birth is approximately 1 in 7000 compared to 1 in 23 for women living in many parts of Afri‐ ca where antenatal care is poor or non-existent [13]. Antenatal care is an opportunity to reach the mothers and young girls in a safe non-stigmatising environment. The importance of developing links between sexual and reproductive health and HIV services is widely rec‐ ognized. Four priority areas for linkages has been identified– learning about one's HIV sta‐ tus, promoting safer sex, optimizing links between HIV and sexually transmitted infection services and integrating HIV with maternal and infant health. These priorities could lead to significant public health benefits and improve efficient use of resources particularly in re‐ source –constrained settings in Africa. There are many challenges and issues that affect re‐ productive health choices particularly for persons living with HIV in Africa. They include; paucity of evidenced-based information regarding safe pregnancy and Prevention of Mother To Child Transmission (PMTCT) of HIV, absence of universal access to Voluntary Counsel‐ ling and Testing (VCT) services, negative attitudes by society and un-informed healthcare workers towards PLWHA desiring to have children, lack of universal access to condoms, contraceptives medications and Highly Active Antiretroviral Therapy (HAART), sup-opti‐ mal levels of skilled sexual and reproductive health staffs, lack of service infrastructures and absence of legislation on the reproductive health right of PLWHA. All these factors nega‐ tively affects and complicates the ability of PLWHA to make evidenced based reproductive

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

329

Antenatal care creates an opportunity for women to access HIV testing and counselling. It is the port of entry to accessing HIV prevention and care. In 2001, CDC modified the recom‐ mendations for pregnant women to emphasize HIV screening as a routine part of prenatal care, simplification of the testing process so that pre-test counselling would not pose a barri‐ er, and flexibility of the consent process to allow multiple types of informed consent [14].Many pregnant women particularly in Africa do not know their HIV serostatus. Many particularly those in rural settings lack adequate information on the benefit of antenatal care for themselves and their babies. High level of illiteracy, inequalities in access to healthcare services, being pregnant at an early age, women dependence economically on men, limited mobility, poverty, religious and cultural restrictions, being a member of a marginalized community or population remains major barriers or stumbling blocks that militate against access to effective antenatal particularly in resource-constrained settings in sub Saharan Af‐ rica [15]. Women all over the world will most likely accept VCT services if it is offered espe‐ cially in settings where there is universal access to HAART and evidenced-based effective sexual and reproductive services rendered by staff who are appropriately trained to render the best possible evidenced-based counselling about HIV and other STIs as well as afforda‐ ble and readily available reproductive health options with empathy rather than being judge‐ mental. Humiliating and stigmatising attitudes and breaches of confidentiality of antenatal women can create a barrier that can potentially prevent women from accessing sexual and

There are several ways to possibly enhance the uptake of VCT services in Africa. They in‐ clude approaches such as the "opt-out" approach, use of traditional voluntary counselling

health choices particularly in many sub Saharan African settings.

reproductive health services even when they are available.

**Figure 1.**

### **3. Challenge of suboptimal antenatal services in Africa**

Organized preventive screening programmes for antenatal care were first introduced in Western Europe in the twentieth century with the hope that routine antenatal care would contribute to a reduction in maternal and infant mortality rates. Figures on maternal mortal‐ ity in the developed world show that the risk of death as a result of pregnancy and child birth is approximately 1 in 7000 compared to 1 in 23 for women living in many parts of Afri‐ ca where antenatal care is poor or non-existent [13]. Antenatal care is an opportunity to reach the mothers and young girls in a safe non-stigmatising environment. The importance of developing links between sexual and reproductive health and HIV services is widely rec‐ ognized. Four priority areas for linkages has been identified– learning about one's HIV sta‐ tus, promoting safer sex, optimizing links between HIV and sexually transmitted infection services and integrating HIV with maternal and infant health. These priorities could lead to significant public health benefits and improve efficient use of resources particularly in re‐ source –constrained settings in Africa. There are many challenges and issues that affect re‐ productive health choices particularly for persons living with HIV in Africa. They include; paucity of evidenced-based information regarding safe pregnancy and Prevention of Mother To Child Transmission (PMTCT) of HIV, absence of universal access to Voluntary Counsel‐ ling and Testing (VCT) services, negative attitudes by society and un-informed healthcare workers towards PLWHA desiring to have children, lack of universal access to condoms, contraceptives medications and Highly Active Antiretroviral Therapy (HAART), sup-opti‐ mal levels of skilled sexual and reproductive health staffs, lack of service infrastructures and absence of legislation on the reproductive health right of PLWHA. All these factors nega‐ tively affects and complicates the ability of PLWHA to make evidenced based reproductive health choices particularly in many sub Saharan African settings.

pects 2006 Revision put the world's life expectancy at birth at 66.57 years (64.52 years for males and 68.76 years for females).Women on the average are found to live longer than men with the exception of Zimbabwe, Afghanistan, Swaziland and Lesotho [12].Countries in Africa particularly those with a high HIV/AIDS prevalence have must lower life ex‐ pectancies [11]. Provision of low technology, safer, affordable and readily available repro‐ ductive health options particularly for PLWHA in Africa is a crucial but often unaddressed component of HIV prevention programme. The aim of this chapter is to evaluate the sexual and reproductive health challenges associated with HIV infection in

sub Saharan Africa.

328 Current Perspectives in HIV Infection

**Figure 1.**

**3. Challenge of suboptimal antenatal services in Africa**

Organized preventive screening programmes for antenatal care were first introduced in Western Europe in the twentieth century with the hope that routine antenatal care would contribute to a reduction in maternal and infant mortality rates. Figures on maternal mortal‐ Antenatal care creates an opportunity for women to access HIV testing and counselling. It is the port of entry to accessing HIV prevention and care. In 2001, CDC modified the recom‐ mendations for pregnant women to emphasize HIV screening as a routine part of prenatal care, simplification of the testing process so that pre-test counselling would not pose a barri‐ er, and flexibility of the consent process to allow multiple types of informed consent [14].Many pregnant women particularly in Africa do not know their HIV serostatus. Many particularly those in rural settings lack adequate information on the benefit of antenatal care for themselves and their babies. High level of illiteracy, inequalities in access to healthcare services, being pregnant at an early age, women dependence economically on men, limited mobility, poverty, religious and cultural restrictions, being a member of a marginalized community or population remains major barriers or stumbling blocks that militate against access to effective antenatal particularly in resource-constrained settings in sub Saharan Af‐ rica [15]. Women all over the world will most likely accept VCT services if it is offered espe‐ cially in settings where there is universal access to HAART and evidenced-based effective sexual and reproductive services rendered by staff who are appropriately trained to render the best possible evidenced-based counselling about HIV and other STIs as well as afforda‐ ble and readily available reproductive health options with empathy rather than being judge‐ mental. Humiliating and stigmatising attitudes and breaches of confidentiality of antenatal women can create a barrier that can potentially prevent women from accessing sexual and reproductive health services even when they are available.

There are several ways to possibly enhance the uptake of VCT services in Africa. They in‐ clude approaches such as the "opt-out" approach, use of traditional voluntary counselling and testing strategies as well as making antenatal visit as interactive and activity based. These approaches are more likely to provide the much needed coverage [16]. There has been argument as to whether the "opt-out" approach negates the principle of informed consent [17] particularly in African settings where many antenatal women are reluctant to challenge health care procedures. It is important however to note that "opt-out" approach does not in any way compromise the principle of informed consent. This approach assumes that testing is an intrinsic part of an effective and holistic antenatal care. The women are informed about what test is required as well as the importance of testing to the mother and the developing baby with an opportunity given to women to refuse testing if they so desire.

for childbearing have significant influences on the African woman's reproductive intentions [21]. Availability and use of antiretroviral drugs has changed the landscape of HIV/AIDS bringing about a change in the perception of HIV from an incurable deadly disease to a chronic manageable illness. As effective HIV treatments become more widespread, HIV-in‐ fected individuals are living longer, healthier lives. Many HIV-affected couples (sero-dis‐ cordant and sero-concordant) are considering options for safer reproduction. A large body of evidence suggests that reproductive technologies can help HIV-affected couples to safely conceive with minimal risk of HIV transmission to their partner and baby. However, for most couples particularly in low income countries in sub Saharan Africa, such technologies are neither geographically nor economically accessible. With HIV now considered to be a chronic manageable disease, attention is shifting to offering and improving quality of life particularly by the provision of reproductive health options/care to men and women living with HIV-1. Many HIV-infected men and women are now expressing their desire to father or mother a child. Assisted reproductive technologies, including intrauterine insemination (IUI), in vitro fertilisation (IVF) and intracytoplasmatic sperm injection (ICSI) in combination with semen washing have been used to decrease the risk of HIV -1 transmission in HIV-1 infected discordant couples with an HIV-1-infected man. Previous report indicates that in HIV-positive men taking HAART, seminal viral load is decreased but not eliminated and fertilization should be achieved through sperm washing to offer maximum protection for the uninfected female. Pregnant HIV-positive women on antiretroviral medication have a reduced risk of transmitting the virus, but should still be counselled about the possibility to further limit the chances of infecting their infant through elective Caesarean section. HIV se‐ ro-discordant couples with strong desire for childbearing have a dilemma of risking HIV in‐ fection or infecting their spouse. Some risk transmission of HIV infection to reproduce. Over two-thirds of 104 surveyed couple wanting to procreate reported unprotected sex with their partner in the past 6 months. Most respondents, regardless of serostatus, said that viral load testing and awareness of post-exposure prevention had no effect on their condom use. A paucity of interventions targeting sero-discordant couples on contraceptive choices is at odds with a strong cultural importance in Africa attached to having children. HIV discord‐ ance in Africa creates a serious dilemma for fertility decision-making in couples. Stigma, dis‐ crimination, and non-disclosure fuel HIV transmission between partners. A previous study [22] in Nigeria a country in the Western part of Africa that investigated the reproductive health concerns among persons living with HIV/AIDS in the Niger Delta of Nigeria has shown that a significant number of PLWHA in Nigeria have conception dreams. The main reasons for wanting to procreate included: ensuring lineage continuity and posterity (52.3%), securing relationships (27.0%) and pressure from relatives to reproduce (20.7%). Single subjects were more inclined to have children (76.3%) compared to married (51.5%), widowed (18.2%) and separated/divorced (11.1%) (p=0.03). Of the 111 subjects that indicated their desire to have children, women were more inclined to have children (64.5%) compared to men (47.7%). The major concern among the 84 (43.1%) subjects not desiring more children were the fear of infecting sero-discordant partner and baby (57.1%), fear of dying and leav‐ ing behind orphans (28.6%) and the fear that they may become too ill and unable to finan‐ cially support the child (14.3%). Persons with no formal education were more likely to have

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

331

There is also the need to foster more male involvement in antenatal care in Africa. Evidence has shown that involving men in the reproductive health care of their partners rather than basing antenatal care exclusively on women can potentially enhance the pregnancy experi‐ ence, reduces incidence of gender-based violence, promote the likelihood of getting a joint consent, facilitate HIV prevention, compliance to HAART in partner in which it is indicated as well as enables a holistic uptake of sexual and reproductive health service for couples. There are several challenges that militate against male-gender involvement in antenatal care particularly in Africa; cultural and religious beliefs, obstacles of working fathers, prevalence of polygamy and maintenance by men of multiple sex partners [18-19].

When HIV infection is diagnosed, health-care providers should strongly encourage patients to disclose their HIV status to their spouses, current sex partners, and previous sex partners and recommend that these partners be tested for HIV infection. Health departments can as‐ sist patients by notifying, counselling, and providing HIV testing for partners without dis‐ closing the patient's identity [20]. Policy allowing providers to inform patients who receive a new diagnosis of HIV infection that they might be contacted by health department staff for a voluntary interview to discuss notification of their partners may play a beneficial role and facilitate uptake of sexual and reproductive health services in Africa. A disproportionate burden has been placed on women and children who continue to experience high rate of new HIV infection and HIV-related illness and death. Most children living with HIV acquire the infection through Mother to Child Transmission (MTCT) which can occur during preg‐ nancy, during delivery or during breastfeeding.

#### **3.1. A strong cultural and religious attachment to having children puts PLWHA under pressure to procreate**

Being HIV positive has been shown to modify but not remove the reproductive desires of individuals. Diversity existed in reproductive intentions among PLWHA. Some HIV posi‐ tive individuals wished to avoid pregnancy. Fears of partner and infant infection and hav‐ ing a previously infected baby were important factors deterring some individuals from considering having children. There is also strongly perceived community disapproval asso‐ ciated with HIV and reproduction. Strong desires to experience parenthood, mediated by prevailing social and cultural norms that encouraged childbearing in society have also been reported. Motherhood is seen as an important component of married women's identity and important for women's social status in Africa. Family, husbands and societal expectations for childbearing have significant influences on the African woman's reproductive intentions [21]. Availability and use of antiretroviral drugs has changed the landscape of HIV/AIDS bringing about a change in the perception of HIV from an incurable deadly disease to a chronic manageable illness. As effective HIV treatments become more widespread, HIV-in‐ fected individuals are living longer, healthier lives. Many HIV-affected couples (sero-dis‐ cordant and sero-concordant) are considering options for safer reproduction. A large body of evidence suggests that reproductive technologies can help HIV-affected couples to safely conceive with minimal risk of HIV transmission to their partner and baby. However, for most couples particularly in low income countries in sub Saharan Africa, such technologies are neither geographically nor economically accessible. With HIV now considered to be a chronic manageable disease, attention is shifting to offering and improving quality of life particularly by the provision of reproductive health options/care to men and women living with HIV-1. Many HIV-infected men and women are now expressing their desire to father or mother a child. Assisted reproductive technologies, including intrauterine insemination (IUI), in vitro fertilisation (IVF) and intracytoplasmatic sperm injection (ICSI) in combination with semen washing have been used to decrease the risk of HIV -1 transmission in HIV-1 infected discordant couples with an HIV-1-infected man. Previous report indicates that in HIV-positive men taking HAART, seminal viral load is decreased but not eliminated and fertilization should be achieved through sperm washing to offer maximum protection for the uninfected female. Pregnant HIV-positive women on antiretroviral medication have a reduced risk of transmitting the virus, but should still be counselled about the possibility to further limit the chances of infecting their infant through elective Caesarean section. HIV se‐ ro-discordant couples with strong desire for childbearing have a dilemma of risking HIV in‐ fection or infecting their spouse. Some risk transmission of HIV infection to reproduce. Over two-thirds of 104 surveyed couple wanting to procreate reported unprotected sex with their partner in the past 6 months. Most respondents, regardless of serostatus, said that viral load testing and awareness of post-exposure prevention had no effect on their condom use. A paucity of interventions targeting sero-discordant couples on contraceptive choices is at odds with a strong cultural importance in Africa attached to having children. HIV discord‐ ance in Africa creates a serious dilemma for fertility decision-making in couples. Stigma, dis‐ crimination, and non-disclosure fuel HIV transmission between partners. A previous study [22] in Nigeria a country in the Western part of Africa that investigated the reproductive health concerns among persons living with HIV/AIDS in the Niger Delta of Nigeria has shown that a significant number of PLWHA in Nigeria have conception dreams. The main reasons for wanting to procreate included: ensuring lineage continuity and posterity (52.3%), securing relationships (27.0%) and pressure from relatives to reproduce (20.7%). Single subjects were more inclined to have children (76.3%) compared to married (51.5%), widowed (18.2%) and separated/divorced (11.1%) (p=0.03). Of the 111 subjects that indicated their desire to have children, women were more inclined to have children (64.5%) compared to men (47.7%). The major concern among the 84 (43.1%) subjects not desiring more children were the fear of infecting sero-discordant partner and baby (57.1%), fear of dying and leav‐ ing behind orphans (28.6%) and the fear that they may become too ill and unable to finan‐ cially support the child (14.3%). Persons with no formal education were more likely to have

and testing strategies as well as making antenatal visit as interactive and activity based. These approaches are more likely to provide the much needed coverage [16]. There has been argument as to whether the "opt-out" approach negates the principle of informed consent [17] particularly in African settings where many antenatal women are reluctant to challenge health care procedures. It is important however to note that "opt-out" approach does not in any way compromise the principle of informed consent. This approach assumes that testing is an intrinsic part of an effective and holistic antenatal care. The women are informed about what test is required as well as the importance of testing to the mother and the developing

There is also the need to foster more male involvement in antenatal care in Africa. Evidence has shown that involving men in the reproductive health care of their partners rather than basing antenatal care exclusively on women can potentially enhance the pregnancy experi‐ ence, reduces incidence of gender-based violence, promote the likelihood of getting a joint consent, facilitate HIV prevention, compliance to HAART in partner in which it is indicated as well as enables a holistic uptake of sexual and reproductive health service for couples. There are several challenges that militate against male-gender involvement in antenatal care particularly in Africa; cultural and religious beliefs, obstacles of working fathers, prevalence

When HIV infection is diagnosed, health-care providers should strongly encourage patients to disclose their HIV status to their spouses, current sex partners, and previous sex partners and recommend that these partners be tested for HIV infection. Health departments can as‐ sist patients by notifying, counselling, and providing HIV testing for partners without dis‐ closing the patient's identity [20]. Policy allowing providers to inform patients who receive a new diagnosis of HIV infection that they might be contacted by health department staff for a voluntary interview to discuss notification of their partners may play a beneficial role and facilitate uptake of sexual and reproductive health services in Africa. A disproportionate burden has been placed on women and children who continue to experience high rate of new HIV infection and HIV-related illness and death. Most children living with HIV acquire the infection through Mother to Child Transmission (MTCT) which can occur during preg‐

**3.1. A strong cultural and religious attachment to having children puts PLWHA under**

Being HIV positive has been shown to modify but not remove the reproductive desires of individuals. Diversity existed in reproductive intentions among PLWHA. Some HIV posi‐ tive individuals wished to avoid pregnancy. Fears of partner and infant infection and hav‐ ing a previously infected baby were important factors deterring some individuals from considering having children. There is also strongly perceived community disapproval asso‐ ciated with HIV and reproduction. Strong desires to experience parenthood, mediated by prevailing social and cultural norms that encouraged childbearing in society have also been reported. Motherhood is seen as an important component of married women's identity and important for women's social status in Africa. Family, husbands and societal expectations

baby with an opportunity given to women to refuse testing if they so desire.

of polygamy and maintenance by men of multiple sex partners [18-19].

nancy, during delivery or during breastfeeding.

**pressure to procreate**

330 Current Perspectives in HIV Infection

children irrespective of their positive HIV status (66.7%) compared to persons educated to tertiary education level (37.0%) (p=0.01). Out of the 111 subjects that desired to have more children, only 58% had gone for reproductive health counselling with HIV counsellors. Rea‐ sons for not seeking advice were anticipated negative reactions and discrimination from the counsellors. A significant number of subjects were only aware of some reproductive health options available to reduce risk of infecting their partners and or baby such as artificial vagi‐ nal insemination, intrauterine insemination, caesarean section, avoidance of breast feeding and offering prenatal pre-exposure prophylaxis to the foetus. They were unaware of other options such as sperm washing, IVF and ICSI. Of the 43.1% not anticipating more children, 36.9% were anticipating adoption.

Given the importance of procreation in African settings and the lack of low –technology and af‐ fordable assisted reproduction services, HIV-infected couples are faced with a serious dilem‐ ma about making an informed decision to procreate. Many PLWHA in Africa who have a desire to have children do not seek reproductive health counselling from HIV counsellors. Reasons for not seeking counselling were anticipated negative reactions and stigmatization from the coun‐ sellors resulting from their negative attitude towards unprotected sexual activity and child bearing by HIV-infected couples. HIV-infected individuals and their partners are requiring ed‐ ucation and counselling regarding HIV disease and reproduction and HIV counsellors particu‐ larly in Africa do not seem to have access to evidenced -based information that the HIVinfected population desperately need to enable them make informed reproductive health decisions. Previous report suggest that there is need to draw up a protocol for reproductive counselling of HIV infected that have a desire for conception [30]. HIV counsellors need to come to terms with the fact that simply encouraging HIV- infected couples to abstain from procrea‐ tion may no longer be a realistic strategy, particularly in sub Saharan Africa where there is strong cultural attachment to having children. In the absence of counselling that recognizes the desire and importance of having children, couples may knowingly take on the risks of transmission in order to have children. Sharing our evidenced- based best practices about HIV transmission and reproductive health options while recognizing patient goals may help couples minimize risk and reduce the harm of unprotected sex. However, the great risks taken by HIV –infected per‐ sons desiring to procreate could be minimized through counselling and close monitoring by re‐

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

333

Reproductive health knowledge among HIV-infected subjects desiring to procreate in Africa is poor. Most PLWHA in Africa are unaware of reproductive health options such as sperm washing, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) available to reduce risk of infecting their partners and or baby. A significant number of men taking HAART have lower seminal concentration of HIV, and sexual transmission may be reduced. However, a certain percentage of aviraemic men retain viral presence in semen, and unpro‐ tected intercourse to achieve fertilization must be discouraged as it carries the risk of sexual transmission of the virus. HIV-discordant couples should be informed that sperm washing can remove HIV from semen, allowing conception without the risk of infection for the sero‐ negative female and eventually the child. In HIV-positive women, perinatal transmission of HIV can be curtailed to less than 2% by using HAART to decrease maternal viral load and offering prenatal pre-exposure prophylaxis of the foetus, and elective Caesarean section. Each intervention carries specific risks and benefits. The contribution of each preventive arm in achieving foetal protection can only be crudely measured and optimal obstetric manage‐ ment must involve discussion with the pregnant woman of the pros and cons of each strat‐ egy. HIV-affected couples who want to have children is presented with at least three distinct and daunting clinical challenges. The first is dealing with stigma arising from many health care providers' negative attitude towards sexual activity and child bearing by HIV infected couples [31] and stigmatization from immediate family members and society [32]. The sec‐ ond is maintaining the mother's health before, during and after pregnancy. The third is pre‐ venting vertical transmission from mother to child as well as preventing HIV transmission to the partner in sero-discordant relationship. Several approaches have been suggested to re‐

productive health care provider.

A significant number of PLWHA in Africa desire to have children irrespective of the HIV positive status. Women are more inclined to have children compared to men. Persons with no formal education are more inclined to have children irrespective of their positive HIV status compared to persons educated to tertiary education level. The main reasons for want‐ ing a child included: ensuring lineage continuity and posterity, securing relationships and pressure from relatives to reproduce. There may be several reasons for this association, in‐ cluding the fact that better educated people generally having greater access to information particularly the mode of transmission of HIV than those who have less formal education, and are more likely to make informed decisions and act on information given. In addition, better educated people generally have better jobs and greater access to money and other re‐ sources which can help them lead healthier lives. Also single persons living with HIV are more likely to want to have children compared to married, separated and widowed subjects. Regardless of interpersonal and public health concerns, studies in both resource-rich and re‐ source-limited settings suggest that HIV-infected men and women desire children [23 – 25]. In addition, in resource limited settings, couples often desire larger families. The reasons for this are debated but likely include among others, the strong cultural attachment to having children, stigmatization associated with childlessness, role of children with inheritance, the importance of children in agricultural economies, the importance of childbearing on the sta‐ tus of women, the role of children as caretakers of the elderly, and high rates of infant mor‐ tality [26]. Previous report indicated that forty percent of HIV infected women desired more children and women with fewer children were more likely to become pregnant [27].

PLWHA are often not wanting to procreate because of the fear of infecting sero-discordant partner and baby, fear of dying and living behind orphans and the fear that they may be‐ come too ill and unable to financially support the child.Previous report indicates that the major challenges faced by HIV-infected subjects not desiring to procreate included: risk of HIV transmission to partner and child and failure of health systems to offer safe methods of reproduction [28]. Identifying the determinants of the decision to have children among serodiscordant couples will help in setting reproductive intervention priorities in resource-poor countries. The gender of the positive partner affects the factors associated with a desire for children. Interventions targeting sero-discordant couples should explore contraceptive choices, the cultural importance of children, and partner communication [29].

Given the importance of procreation in African settings and the lack of low –technology and af‐ fordable assisted reproduction services, HIV-infected couples are faced with a serious dilem‐ ma about making an informed decision to procreate. Many PLWHA in Africa who have a desire to have children do not seek reproductive health counselling from HIV counsellors. Reasons for not seeking counselling were anticipated negative reactions and stigmatization from the coun‐ sellors resulting from their negative attitude towards unprotected sexual activity and child bearing by HIV-infected couples. HIV-infected individuals and their partners are requiring ed‐ ucation and counselling regarding HIV disease and reproduction and HIV counsellors particu‐ larly in Africa do not seem to have access to evidenced -based information that the HIVinfected population desperately need to enable them make informed reproductive health decisions. Previous report suggest that there is need to draw up a protocol for reproductive counselling of HIV infected that have a desire for conception [30]. HIV counsellors need to come to terms with the fact that simply encouraging HIV- infected couples to abstain from procrea‐ tion may no longer be a realistic strategy, particularly in sub Saharan Africa where there is strong cultural attachment to having children. In the absence of counselling that recognizes the desire and importance of having children, couples may knowingly take on the risks of transmission in order to have children. Sharing our evidenced- based best practices about HIV transmission and reproductive health options while recognizing patient goals may help couples minimize risk and reduce the harm of unprotected sex. However, the great risks taken by HIV –infected per‐ sons desiring to procreate could be minimized through counselling and close monitoring by re‐ productive health care provider.

children irrespective of their positive HIV status (66.7%) compared to persons educated to tertiary education level (37.0%) (p=0.01). Out of the 111 subjects that desired to have more children, only 58% had gone for reproductive health counselling with HIV counsellors. Rea‐ sons for not seeking advice were anticipated negative reactions and discrimination from the counsellors. A significant number of subjects were only aware of some reproductive health options available to reduce risk of infecting their partners and or baby such as artificial vagi‐ nal insemination, intrauterine insemination, caesarean section, avoidance of breast feeding and offering prenatal pre-exposure prophylaxis to the foetus. They were unaware of other options such as sperm washing, IVF and ICSI. Of the 43.1% not anticipating more children,

A significant number of PLWHA in Africa desire to have children irrespective of the HIV positive status. Women are more inclined to have children compared to men. Persons with no formal education are more inclined to have children irrespective of their positive HIV status compared to persons educated to tertiary education level. The main reasons for want‐ ing a child included: ensuring lineage continuity and posterity, securing relationships and pressure from relatives to reproduce. There may be several reasons for this association, in‐ cluding the fact that better educated people generally having greater access to information particularly the mode of transmission of HIV than those who have less formal education, and are more likely to make informed decisions and act on information given. In addition, better educated people generally have better jobs and greater access to money and other re‐ sources which can help them lead healthier lives. Also single persons living with HIV are more likely to want to have children compared to married, separated and widowed subjects. Regardless of interpersonal and public health concerns, studies in both resource-rich and re‐ source-limited settings suggest that HIV-infected men and women desire children [23 – 25]. In addition, in resource limited settings, couples often desire larger families. The reasons for this are debated but likely include among others, the strong cultural attachment to having children, stigmatization associated with childlessness, role of children with inheritance, the importance of children in agricultural economies, the importance of childbearing on the sta‐ tus of women, the role of children as caretakers of the elderly, and high rates of infant mor‐ tality [26]. Previous report indicated that forty percent of HIV infected women desired more

children and women with fewer children were more likely to become pregnant [27].

choices, the cultural importance of children, and partner communication [29].

PLWHA are often not wanting to procreate because of the fear of infecting sero-discordant partner and baby, fear of dying and living behind orphans and the fear that they may be‐ come too ill and unable to financially support the child.Previous report indicates that the major challenges faced by HIV-infected subjects not desiring to procreate included: risk of HIV transmission to partner and child and failure of health systems to offer safe methods of reproduction [28]. Identifying the determinants of the decision to have children among serodiscordant couples will help in setting reproductive intervention priorities in resource-poor countries. The gender of the positive partner affects the factors associated with a desire for children. Interventions targeting sero-discordant couples should explore contraceptive

36.9% were anticipating adoption.

332 Current Perspectives in HIV Infection

Reproductive health knowledge among HIV-infected subjects desiring to procreate in Africa is poor. Most PLWHA in Africa are unaware of reproductive health options such as sperm washing, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) available to reduce risk of infecting their partners and or baby. A significant number of men taking HAART have lower seminal concentration of HIV, and sexual transmission may be reduced. However, a certain percentage of aviraemic men retain viral presence in semen, and unpro‐ tected intercourse to achieve fertilization must be discouraged as it carries the risk of sexual transmission of the virus. HIV-discordant couples should be informed that sperm washing can remove HIV from semen, allowing conception without the risk of infection for the sero‐ negative female and eventually the child. In HIV-positive women, perinatal transmission of HIV can be curtailed to less than 2% by using HAART to decrease maternal viral load and offering prenatal pre-exposure prophylaxis of the foetus, and elective Caesarean section. Each intervention carries specific risks and benefits. The contribution of each preventive arm in achieving foetal protection can only be crudely measured and optimal obstetric manage‐ ment must involve discussion with the pregnant woman of the pros and cons of each strat‐ egy. HIV-affected couples who want to have children is presented with at least three distinct and daunting clinical challenges. The first is dealing with stigma arising from many health care providers' negative attitude towards sexual activity and child bearing by HIV infected couples [31] and stigmatization from immediate family members and society [32]. The sec‐ ond is maintaining the mother's health before, during and after pregnancy. The third is pre‐ venting vertical transmission from mother to child as well as preventing HIV transmission to the partner in sero-discordant relationship. Several approaches have been suggested to re‐ duce risk of horizontal transmission for HIV-affected couples who want to conceive chil‐ dren. These approaches includes the use of ; male sperm washing, IUI, ICSI, screening and pre-treatment for Sexually Transmitted Infections (STI's), Delay in procreation until viral load is controlled, limited, timed unprotected sexual encounters, female artificial insemina‐ tion, self-insemination and circumcision. Experience among couples in whom the male was (HIV) seropositive who underwent assisted reproductive technologies (ART) in order to at‐ tain family goals while minimizing the risk of HIV transmission indicated that all female re‐ cipients tested seronegative for HIV at 3 and 6 months post-embryo transfer. All delivered babies (n = 8) tested seronegative for HIV at birth and 3 months postpartum and that ART should be considered for HIV serodiscordant couples who desire to have children in order to minimize the risk of viral infection [33]. Several people play a role in reproductive health decision making of PLWHA; the relatives who used traditional norms to encourage procrea‐ tion; the health workers who violates the autonomy and human rights of HIV-infected by using their medical knowledge to dissuade clients from childbearing by preaching mandato‐ ry contraception [34] and the health care system that do not recognize and meet the sexual and reproductive health needs of their clients [35]. Health care providers in Africa must real‐ ize that it is their responsibility to offer information to enable HIV-infected persons arrive at their own informed decisions on their reproductive and sexual health needs regardless of the health professional's opinion. Similarly, there may be need to offer additional training to enable counsellors' particularly in sub Saharan Africa offer evidenced- based sexual and re‐ productive health information to their clients. Reproductive health policies in this HIV/AIDS era are lacking in most African settings. It is recommended that sero-discordant couples who desire to have children should undergo assisted fertility treatment such as sperm wash‐ ing, intra uterine insemination and in-vitro fertilization to avoid HIV transmission to their partners [36]. However cost implication is a major issue affecting the feasibility of offering assisted fertility treatment such as sperm washing, intra uterine insemination and in-vitro fertilization particularly among low socioeconomic people. There is a major challenge with the development of evidenced- based, cost- effective and best-practice guidelines in most settings in Africa to optimize the sexual and reproductive health service rendered to persons living with HIV/AIDS. In resource-limited settings, couples should be counselled on ovula‐ tion cycles and may engage in timed unprotected sex only during the fertile period of the woman's monthly cycle to facilitate conception while reducing number of exposures. If the man is HIV-negative with a positive partner, partners can be taught artificial insemination, timed to the woman's fertile period. For couples in which both partners are positive, there may be need for a careful and informed natural conception when their viral loads have fall‐ en to below the level of detection.

ca are women. Among young men and women aged 15 to 24 years, for every one man, four women are infected with HIV. There were 12-13 infected women to 10 infected men in 2001 [37]. Biological, cultural and socio-economic factors contribute to women's greater vulnera‐ bility to HIV/AIDS. Women are 4 times more at risk of becoming infected with HIV dur‐ ing unprotected vaginal intercourse than men. The vagina's greater area of susceptible tissue and micro trauma that occurs during sexual intercourse makes women more physio‐ logically more vulnerable [38]. Semen has higher viral load than vaginal fluids and the se‐ men stays longer in the female genital tract after sexual intercourse which increases the chances of HIV transmission. The synergy between HIV and sexually transmitted infec‐ tion (STIs) is another biological factor that makes women more vulnerable to HIV. This is especially significant among African women. Most STI cases in women often go untreat‐ ed, symptoms are often latent, women diagnosed with STIs are often stigmatised and ma‐ jority have no access to medical treatments [39]. Socio-economic factors including women's lack of access to education, personal income, and economic dependence on men perpetu‐ ate women's lower status. Moreover widespread poverty often drives these vulnerable women into commercial sex work. Furthermore men control over condom use- the main tool for reducing the risk of sexual transmission of HIV puts women at risk of HIV. Cultur‐ al practices inherent in Africa such as forced marriage, polygamy, female genital mutila‐ tion and older men's preferences for sex with younger women, Sexual violence coercion at home and in the work place during job hiring, promotion and to avoid dismissal are com‐ mon practices, use of women as bait by companies to secure contracts, sexual abuse of or‐ phans and domestic workers further complicates female gender vulnerability to HIV [40]. Moreover, women are more subjected to HIV stigma and discrimination. In Africa, the HIV virus that causes AIDS is transmitted through two major routes. The first, which accounts for 80 per cent of the cases, is through unprotected sex between men and women. This is followed by HIV transmission from mother to child during pregnancy, labour and breast‐ feeding, which is responsible for about 20 per cent of the cases. There are several biologi‐ cal, social and cultural reasons why women and girls in Africa are more vulnerable to HIV infection. Gender inequalities that exist in African society, women have less access to infor‐ mation than men, they are less likely to make informed decisions and act on information given, they have less access to education, and better jobs, money and other resources which can help them lead healthier lives. During vaginal sex, which is commonly practiced in Af‐ rica, the chance of HIV transmission from a man to a woman is two to three times greater than transmission from a woman to a man. This is due to the biological make up of the fe‐ male genital tract. The female genital tract has a larger area of exposed tissue. Young girls are especially vulnerable when they have sex with older men because because the genital

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

335

tract of young girls are immature, prone to tear and invasion by HIV.

There has never been a better time than this to target and integrate sexual and reproductive health, family planning and HIV/AIDS services particularly in Africa. Most sceptics errone‐ ously often consider reproductive health to be a euphemism for abortion services. It is wor‐ thy to note that reproductive health covers a broad range of women's health issues including detecting and treating sexually transmitted infections and supporting HIV-infect‐ ed women's desire to have children safely. Integration of HIV and reproductive health has

### **4. Lack of integration between sexual and reproductive, family planning and existing HIV /AIDS services**

There is increasing concern that Sub-Saharan Africa is the region where more women are infected by HIV than men. About 60 per cent of people living with HIV infections in Afri‐ ca are women. Among young men and women aged 15 to 24 years, for every one man, four women are infected with HIV. There were 12-13 infected women to 10 infected men in 2001 [37]. Biological, cultural and socio-economic factors contribute to women's greater vulnera‐ bility to HIV/AIDS. Women are 4 times more at risk of becoming infected with HIV dur‐ ing unprotected vaginal intercourse than men. The vagina's greater area of susceptible tissue and micro trauma that occurs during sexual intercourse makes women more physio‐ logically more vulnerable [38]. Semen has higher viral load than vaginal fluids and the se‐ men stays longer in the female genital tract after sexual intercourse which increases the chances of HIV transmission. The synergy between HIV and sexually transmitted infec‐ tion (STIs) is another biological factor that makes women more vulnerable to HIV. This is especially significant among African women. Most STI cases in women often go untreat‐ ed, symptoms are often latent, women diagnosed with STIs are often stigmatised and ma‐ jority have no access to medical treatments [39]. Socio-economic factors including women's lack of access to education, personal income, and economic dependence on men perpetu‐ ate women's lower status. Moreover widespread poverty often drives these vulnerable women into commercial sex work. Furthermore men control over condom use- the main tool for reducing the risk of sexual transmission of HIV puts women at risk of HIV. Cultur‐ al practices inherent in Africa such as forced marriage, polygamy, female genital mutila‐ tion and older men's preferences for sex with younger women, Sexual violence coercion at home and in the work place during job hiring, promotion and to avoid dismissal are com‐ mon practices, use of women as bait by companies to secure contracts, sexual abuse of or‐ phans and domestic workers further complicates female gender vulnerability to HIV [40]. Moreover, women are more subjected to HIV stigma and discrimination. In Africa, the HIV virus that causes AIDS is transmitted through two major routes. The first, which accounts for 80 per cent of the cases, is through unprotected sex between men and women. This is followed by HIV transmission from mother to child during pregnancy, labour and breast‐ feeding, which is responsible for about 20 per cent of the cases. There are several biologi‐ cal, social and cultural reasons why women and girls in Africa are more vulnerable to HIV infection. Gender inequalities that exist in African society, women have less access to infor‐ mation than men, they are less likely to make informed decisions and act on information given, they have less access to education, and better jobs, money and other resources which can help them lead healthier lives. During vaginal sex, which is commonly practiced in Af‐ rica, the chance of HIV transmission from a man to a woman is two to three times greater than transmission from a woman to a man. This is due to the biological make up of the fe‐ male genital tract. The female genital tract has a larger area of exposed tissue. Young girls are especially vulnerable when they have sex with older men because because the genital tract of young girls are immature, prone to tear and invasion by HIV.

duce risk of horizontal transmission for HIV-affected couples who want to conceive chil‐ dren. These approaches includes the use of ; male sperm washing, IUI, ICSI, screening and pre-treatment for Sexually Transmitted Infections (STI's), Delay in procreation until viral load is controlled, limited, timed unprotected sexual encounters, female artificial insemina‐ tion, self-insemination and circumcision. Experience among couples in whom the male was (HIV) seropositive who underwent assisted reproductive technologies (ART) in order to at‐ tain family goals while minimizing the risk of HIV transmission indicated that all female re‐ cipients tested seronegative for HIV at 3 and 6 months post-embryo transfer. All delivered babies (n = 8) tested seronegative for HIV at birth and 3 months postpartum and that ART should be considered for HIV serodiscordant couples who desire to have children in order to minimize the risk of viral infection [33]. Several people play a role in reproductive health decision making of PLWHA; the relatives who used traditional norms to encourage procrea‐ tion; the health workers who violates the autonomy and human rights of HIV-infected by using their medical knowledge to dissuade clients from childbearing by preaching mandato‐ ry contraception [34] and the health care system that do not recognize and meet the sexual and reproductive health needs of their clients [35]. Health care providers in Africa must real‐ ize that it is their responsibility to offer information to enable HIV-infected persons arrive at their own informed decisions on their reproductive and sexual health needs regardless of the health professional's opinion. Similarly, there may be need to offer additional training to enable counsellors' particularly in sub Saharan Africa offer evidenced- based sexual and re‐ productive health information to their clients. Reproductive health policies in this HIV/AIDS era are lacking in most African settings. It is recommended that sero-discordant couples who desire to have children should undergo assisted fertility treatment such as sperm wash‐ ing, intra uterine insemination and in-vitro fertilization to avoid HIV transmission to their partners [36]. However cost implication is a major issue affecting the feasibility of offering assisted fertility treatment such as sperm washing, intra uterine insemination and in-vitro fertilization particularly among low socioeconomic people. There is a major challenge with the development of evidenced- based, cost- effective and best-practice guidelines in most settings in Africa to optimize the sexual and reproductive health service rendered to persons living with HIV/AIDS. In resource-limited settings, couples should be counselled on ovula‐ tion cycles and may engage in timed unprotected sex only during the fertile period of the woman's monthly cycle to facilitate conception while reducing number of exposures. If the man is HIV-negative with a positive partner, partners can be taught artificial insemination, timed to the woman's fertile period. For couples in which both partners are positive, there may be need for a careful and informed natural conception when their viral loads have fall‐

**4. Lack of integration between sexual and reproductive, family planning**

There is increasing concern that Sub-Saharan Africa is the region where more women are infected by HIV than men. About 60 per cent of people living with HIV infections in Afri‐

en to below the level of detection.

334 Current Perspectives in HIV Infection

**and existing HIV /AIDS services**

There has never been a better time than this to target and integrate sexual and reproductive health, family planning and HIV/AIDS services particularly in Africa. Most sceptics errone‐ ously often consider reproductive health to be a euphemism for abortion services. It is wor‐ thy to note that reproductive health covers a broad range of women's health issues including detecting and treating sexually transmitted infections and supporting HIV-infect‐ ed women's desire to have children safely. Integration of HIV and reproductive health has the potential to produce important HIV-related outcomes. Recent international consensus statements have urged the strengthening of these linkages [41]. In order to reduce HIV-in‐ fected births, infant and child mortality, the number of children orphaned by AIDS and ma‐ ternal mortality, adding family planning and reproductive health to PMTCT, VCT and ARV programmes makes a logical and a programmatic sense.

**6. Non-protection of the reproductive rights of PLWHA in Africa**

It is increasing clear particularly that a significant majority of PLWHA in Africa are of reproduc‐ tive age, that conception and reproductive options for this population are important issues for health care delivery and research and that HIV-seropositive individuals deserve full reproduc‐ tive rights like every other person [44]. International reproductive guidelines shifted a decade ago from recommending avoidance of pregnancy to recognizing conception and parenting as realistic options and rights for people with HIV infection and their partners [45]. Mindful of this indisputable fact, US Centers for Disease Control and Prevention (CDC) has encouraged infor‐ mation and support for HIV-affected couples who want to explore their reproductive options [14]. There are many persons who plays a role in reproductive health decision making of per‐ sons living with HIV/AIDS: The relatives who used traditional norms to encourage procrea‐ tion; the health workers who violates the autonomy and human rights of HIV-infected by using their medical knowledge to dissuade clients from childbearing by preaching mandatory con‐ traception [34] and health care system that does not recognize and meet the sexual and repro‐ ductive health needs of their clients [35].Health care providers in Africa must realize that it is their responsibility to offer information to enable HIV-infected persons arrive at their own in‐ formed decisions on their reproductive and sexual health needs regardless of the health profes‐ sional's opinion. Similarly, there may need to offer additional training to enable counsellors' offer evidenced- based sexual and reproductive health information to their clients. Reproduc‐ tive health policies in this HIV/AIDS era are lacking in most African settings. It is recommend‐ ed that sero-discordant couples who desire to have children should undergo assisted fertility treatment such as sperm washing, intra uterine insemination and *in-vitro* fertilization to avoid HIV transmission to their partners [36, 46]. However cost implication is a major issue affecting the feasibility of offering assisted fertility treatment such as sperm washing, intra uterine in‐ semination and *in-vitro* fertilization particularly among low socioeconomic people. There is a major challenge with the development of evidenced- based, cost effective and best-practice guidelines locally in most African setting to help optimize the sexual and reproductive health service rendered to persons living with HIV/AIDS particularly in the Africa. Like it is in other developed countries in the world. HIV-infected couples wanting to procreate in Africa should be counselled on ovulation cycles, timed sex only during the fertile period of the woman's monthly cycle to facilitate conception while reducing number of exposures. If the man is HIVnegative with a positive partner, partners can be taught artificial insemination, timed to the woman's fertile period. For couples in which both partners are positive, there may be need for a careful and informed natural conception when their viral loads have fallen to below the level of detection. There is the need to support the sexual and reproductive rights of HIV-infected indi‐ viduals. Additional training needs to be offered to HIV counsellors on evidence- based best and affordable practices regarding reproductive health issues among persons living with HIV. Pol‐ icies that support the availability and accessibility to relevant reproductive and sexual health services including contraception and procreation needs to be developed. Public enlightenment programmes on HIV is needed to reduce the stigmatization that HIV-infected persons face from family members and their communities. Developing and testing safer conception methods that reduce HIV transmission to HIV-seronegative partners in serodiscordant couples and reduce

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

337

### **5. HIV–infected need information and services on safe procreation and the health system is unable to provide evidenced-based answers**

Data from most settings in Africa increasingly demonstrate that some HIV-infected women par‐ ticularly those on ARVs as they begin to feel better and function more normally due to the ef‐ fect of treatment on reduction on viral load, would like to become pregnant [42]. It is a growing expectation that the health system should have the ability to counsel HIV-positive women on the risk and benefits of child bearing and to respect the reproductive intentions, choices and rights including access to contraception and other reproductive health services. Previous report [22] indicates that reproductive health knowledge among HIV-infected subjects desiring to procre‐ ate was poor. Subjects were unaware of reproductive health options such as sperm washing, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) available to reduce risk of infecting their partners and or baby. A significant number of men taking HAART have lower seminal concentration of HIV, and sexual transmission may be reduced. However, a certain per‐ centage of aviraemic men retain viral presence in semen, and unprotected intercourse to ach‐ ieve fertilization must be discouraged as it carries the risk of sexual transmission of the virus. HIV-discordant couples should be informed that sperm washing can remove HIV from semen, allowing conception without the risk of infection for the seronegative female and eventually the child. In HIV-positive women, perinatal transmission of HIV can be curtailed to less than 2% by using HAART to decrease maternal viral load and offering prenatal pre-exposure prophylaxis of the foetus, and elective Caesarean section. Each intervention carries specific risks and bene‐ fits. The contribution of each preventive arm in achieving foetal protection can only be crudely measured and optimal obstetric management must involve discussion with the pregnant wom‐ an of the pros and cons of each strategy. Several approaches have been suggested to reduce risk of horizontal transmission for HIV-affected couples who want to conceive children. These ap‐ proaches includes the use of ; male sperm washing, IUI, ICSI, screening and pre-treatment for Sexually Transmitted Infections (STI's), delay in procreation until viral load is controlled, limit‐ ed, timed unprotected sexual encounters, female artificial insemination, self-insemination and circumcision. Accurate and accessible information to make informed choices and safe, pleasur‐ able sexual relationships possible is best delivered through peer education and health profes‐ sionals trained on empathetic approaches to sensitive issues [43]. Interventions based on positive prevention, which combine protection of personal health with avoiding HIV/STI trans‐ mission to partners, are recommended.

### **6. Non-protection of the reproductive rights of PLWHA in Africa**

the potential to produce important HIV-related outcomes. Recent international consensus statements have urged the strengthening of these linkages [41]. In order to reduce HIV-in‐ fected births, infant and child mortality, the number of children orphaned by AIDS and ma‐ ternal mortality, adding family planning and reproductive health to PMTCT, VCT and ARV

**5. HIV–infected need information and services on safe procreation and**

Data from most settings in Africa increasingly demonstrate that some HIV-infected women par‐ ticularly those on ARVs as they begin to feel better and function more normally due to the ef‐ fect of treatment on reduction on viral load, would like to become pregnant [42]. It is a growing expectation that the health system should have the ability to counsel HIV-positive women on the risk and benefits of child bearing and to respect the reproductive intentions, choices and rights including access to contraception and other reproductive health services. Previous report [22] indicates that reproductive health knowledge among HIV-infected subjects desiring to procre‐ ate was poor. Subjects were unaware of reproductive health options such as sperm washing, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) available to reduce risk of infecting their partners and or baby. A significant number of men taking HAART have lower seminal concentration of HIV, and sexual transmission may be reduced. However, a certain per‐ centage of aviraemic men retain viral presence in semen, and unprotected intercourse to ach‐ ieve fertilization must be discouraged as it carries the risk of sexual transmission of the virus. HIV-discordant couples should be informed that sperm washing can remove HIV from semen, allowing conception without the risk of infection for the seronegative female and eventually the child. In HIV-positive women, perinatal transmission of HIV can be curtailed to less than 2% by using HAART to decrease maternal viral load and offering prenatal pre-exposure prophylaxis of the foetus, and elective Caesarean section. Each intervention carries specific risks and bene‐ fits. The contribution of each preventive arm in achieving foetal protection can only be crudely measured and optimal obstetric management must involve discussion with the pregnant wom‐ an of the pros and cons of each strategy. Several approaches have been suggested to reduce risk of horizontal transmission for HIV-affected couples who want to conceive children. These ap‐ proaches includes the use of ; male sperm washing, IUI, ICSI, screening and pre-treatment for Sexually Transmitted Infections (STI's), delay in procreation until viral load is controlled, limit‐ ed, timed unprotected sexual encounters, female artificial insemination, self-insemination and circumcision. Accurate and accessible information to make informed choices and safe, pleasur‐ able sexual relationships possible is best delivered through peer education and health profes‐ sionals trained on empathetic approaches to sensitive issues [43]. Interventions based on positive prevention, which combine protection of personal health with avoiding HIV/STI trans‐

**the health system is unable to provide evidenced-based answers**

programmes makes a logical and a programmatic sense.

336 Current Perspectives in HIV Infection

mission to partners, are recommended.

It is increasing clear particularly that a significant majority of PLWHA in Africa are of reproduc‐ tive age, that conception and reproductive options for this population are important issues for health care delivery and research and that HIV-seropositive individuals deserve full reproduc‐ tive rights like every other person [44]. International reproductive guidelines shifted a decade ago from recommending avoidance of pregnancy to recognizing conception and parenting as realistic options and rights for people with HIV infection and their partners [45]. Mindful of this indisputable fact, US Centers for Disease Control and Prevention (CDC) has encouraged infor‐ mation and support for HIV-affected couples who want to explore their reproductive options [14]. There are many persons who plays a role in reproductive health decision making of per‐ sons living with HIV/AIDS: The relatives who used traditional norms to encourage procrea‐ tion; the health workers who violates the autonomy and human rights of HIV-infected by using their medical knowledge to dissuade clients from childbearing by preaching mandatory con‐ traception [34] and health care system that does not recognize and meet the sexual and repro‐ ductive health needs of their clients [35].Health care providers in Africa must realize that it is their responsibility to offer information to enable HIV-infected persons arrive at their own in‐ formed decisions on their reproductive and sexual health needs regardless of the health profes‐ sional's opinion. Similarly, there may need to offer additional training to enable counsellors' offer evidenced- based sexual and reproductive health information to their clients. Reproduc‐ tive health policies in this HIV/AIDS era are lacking in most African settings. It is recommend‐ ed that sero-discordant couples who desire to have children should undergo assisted fertility treatment such as sperm washing, intra uterine insemination and *in-vitro* fertilization to avoid HIV transmission to their partners [36, 46]. However cost implication is a major issue affecting the feasibility of offering assisted fertility treatment such as sperm washing, intra uterine in‐ semination and *in-vitro* fertilization particularly among low socioeconomic people. There is a major challenge with the development of evidenced- based, cost effective and best-practice guidelines locally in most African setting to help optimize the sexual and reproductive health service rendered to persons living with HIV/AIDS particularly in the Africa. Like it is in other developed countries in the world. HIV-infected couples wanting to procreate in Africa should be counselled on ovulation cycles, timed sex only during the fertile period of the woman's monthly cycle to facilitate conception while reducing number of exposures. If the man is HIVnegative with a positive partner, partners can be taught artificial insemination, timed to the woman's fertile period. For couples in which both partners are positive, there may be need for a careful and informed natural conception when their viral loads have fallen to below the level of detection. There is the need to support the sexual and reproductive rights of HIV-infected indi‐ viduals. Additional training needs to be offered to HIV counsellors on evidence- based best and affordable practices regarding reproductive health issues among persons living with HIV. Pol‐ icies that support the availability and accessibility to relevant reproductive and sexual health services including contraception and procreation needs to be developed. Public enlightenment programmes on HIV is needed to reduce the stigmatization that HIV-infected persons face from family members and their communities. Developing and testing safer conception methods that reduce HIV transmission to HIV-seronegative partners in serodiscordant couples and reduce superinfection in HIV-seroconcordant couples is a crucial component of HIV prevention pro‐ gramme that needs to be urgently addressed in Africa [47].

Sexually transmitted infection including HIV have always been imbued with stigma and discrimination particularly in Africa particularly due to their negative association with be‐ haviour considered by society as deviant or immoral [52]. Stigma generally refers to nega‐ tively perceived defining characteristics either tangible or intangible. It is an attribute used to set the infected person or group from the normalized social order. It has a way of devalu‐ ing a person [53]. Similarly; societies have historically reacted with fear to disfiguring, debil‐ itating, and fatal diseases and have translated this aversion into discriminatory actions against the infected [54]. The HIV/AIDS pandemic has presented the world with a condition that combines these characteristics – and it has frequently been met with stigma and dis‐ crimination, a reaction dubbed "the second epidemic" [55]. HIV infection affects women and men's view of parenthood. It has a negative impact on their ability to have children, related not only to psychosocial aspects such as stigma and discrimination and decreased sexual ac‐ tivity, but also to the clinical impact of HIV infection and sexually transmitted infections (STIs) on fertility [56-57]. Learning more about stigma is important given the growing asser‐ tions that testing is a 'critical gateway' to HIV prevention and treatment. As access to HIV testing and treatment improves, providers increasingly need to understand and address how stigma acts as a barrier to services. There is need to develop programs to address the negative service provider attitudes towards HIV-positive women, especially those wanting children. Stigma and discrimination is a population and health system level barrier that dis‐ courages HIV-infected women and men from seeking reproductive health counselling and

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

339

HIV-related stigmatization, discrimination and denial continue to characterize the pandemic in Africa and present a major challenge to the effectiveness of prevention, sexual and repro‐ ductive care and treatment programmes. Much of the societal and individual reaction to‐ wards people with HIV/AIDS is stigma and discrimination oriented. Stigmatization and discrimination occurs in a variety of forms. It ranges from societal level responses such as coercive government policies and laws, to apathy and denial of the HIV epidemic. At the individual level, the internalization of these societal responses may result in an individual's self-exclusion from information, treatment and care. Stigmatization and discrimination are often explored through socio-cultural understandings of illness and disease transmission and its manifestations at societal and individual level. Contexts of discrimination include employment, health care systems, and travel and migration restrictions. Although there are widespread reports of HIV-related discrimination throughout the world there has also been significant progress towards reducing these practices. In addition to what is being done there is still much that we need to understand about the forms and contexts of stigmatiza‐ tion and discrimination if we are to succeed in our efforts to control the HIV epidemic par‐ ticularly in Africa [58]. Stigma and discrimination in Africa can be challenged. One way to reduce their impact is at the legislative level, it is also vital to focus on community-based interventions. These projects target stigmatization manifested in a wide range of community contexts, including: family and immediate community, workplace, health services, religion

other sexual and reproductive health counselling.

and the media.

### **7. Challenge of HIV-related stigma and discrimination**

HIV-related stigma and discrimination remains an enormous barrier to the fight against AIDS. Fear of discrimination often prevents people from getting tested, seeking treatment and admitting their HIV status publicly. Since laws and policies alone cannot reverse the stigma that surrounds HIV infection, AIDS education in Africa needs to be scaled-up to combat the ignorance that causes people to discriminate. The fear and prejudice that lies at the core of HIV and AIDS discrimination needs to be tackled at both community and nation‐ al levels. There is strong ethical imperative to support the sexual and reproductive health needs of HIV-infected individuals allowing them to make informed decisions about their re‐ productive health. Increasingly, fertility clinics in developed countries are offering their services to HIV-serodiscordant couples where the woman is seropositive and in HIV-sero‐ concordant relationships. Reproductive health care workers in Africa can learn from the evi‐ denced- based best practices in the developed world to ensure that like their counterparts in most developed countries, HIV infected persons particularly in Africa can access the best quality reproductive and sexual health service. Recent advances in HIV clinical care and as‐ sisted reproduction technique (ART) procedures directed at reducing the risk of viral trans‐ mission during gamete transfer particularly where good healthcare is available has significantly reduced the risk of transmission of HIV among discordant couples to 1-2%. Promotion of risk reduction counselling, screening for sexually transmitted diseases and lower genital tract disease, assessment of options for birth control, and pre-conception coun‐ selling should be integral components of gynaecologic health care for HIV-infected women.

Since the beginning of the human immunodeficiency virus (HIV) epidemic, stigma and dis‐ crimination (SAD) have been identified as the major obstacles to effective responses to HIV [48]. HIV-affected couples who desire sexual and reproductive health services are faced with at least three distinct and daunting challenges. The first is dealing with stigma arising from many health care providers' negative attitude towards sexual activity and child bear‐ ing by HIV infected couples [49] and stigmatization from immediate family members and society [32]. The second is maintaining the mother's health before, during and after preg‐ nancy. The third is preventing vertical transmission from mother to child as well as prevent‐ ing HIV transmission to the partner in sero-discordant relationship. HIV/AIDS-related SAD has been extensively documented among health care providers. There have been many re‐ ports from health care settings of HIV testing without consent, breaches of confidentiality, labelling, gossip, verbal harassment, differential treatment, and even denial of treatment. HIV-infected-individuals who feel stigmatized by health care providers face problems ac‐ cessing HIV testing and other sexual and reproductive health care services [50]. The fear of stigma impedes prevention efforts, including discussions of safer sex and the prevention of mother-to-child transmission [51].

Sexually transmitted infection including HIV have always been imbued with stigma and discrimination particularly in Africa particularly due to their negative association with be‐ haviour considered by society as deviant or immoral [52]. Stigma generally refers to nega‐ tively perceived defining characteristics either tangible or intangible. It is an attribute used to set the infected person or group from the normalized social order. It has a way of devalu‐ ing a person [53]. Similarly; societies have historically reacted with fear to disfiguring, debil‐ itating, and fatal diseases and have translated this aversion into discriminatory actions against the infected [54]. The HIV/AIDS pandemic has presented the world with a condition that combines these characteristics – and it has frequently been met with stigma and dis‐ crimination, a reaction dubbed "the second epidemic" [55]. HIV infection affects women and men's view of parenthood. It has a negative impact on their ability to have children, related not only to psychosocial aspects such as stigma and discrimination and decreased sexual ac‐ tivity, but also to the clinical impact of HIV infection and sexually transmitted infections (STIs) on fertility [56-57]. Learning more about stigma is important given the growing asser‐ tions that testing is a 'critical gateway' to HIV prevention and treatment. As access to HIV testing and treatment improves, providers increasingly need to understand and address how stigma acts as a barrier to services. There is need to develop programs to address the negative service provider attitudes towards HIV-positive women, especially those wanting children. Stigma and discrimination is a population and health system level barrier that dis‐ courages HIV-infected women and men from seeking reproductive health counselling and other sexual and reproductive health counselling.

superinfection in HIV-seroconcordant couples is a crucial component of HIV prevention pro‐

HIV-related stigma and discrimination remains an enormous barrier to the fight against AIDS. Fear of discrimination often prevents people from getting tested, seeking treatment and admitting their HIV status publicly. Since laws and policies alone cannot reverse the stigma that surrounds HIV infection, AIDS education in Africa needs to be scaled-up to combat the ignorance that causes people to discriminate. The fear and prejudice that lies at the core of HIV and AIDS discrimination needs to be tackled at both community and nation‐ al levels. There is strong ethical imperative to support the sexual and reproductive health needs of HIV-infected individuals allowing them to make informed decisions about their re‐ productive health. Increasingly, fertility clinics in developed countries are offering their services to HIV-serodiscordant couples where the woman is seropositive and in HIV-sero‐ concordant relationships. Reproductive health care workers in Africa can learn from the evi‐ denced- based best practices in the developed world to ensure that like their counterparts in most developed countries, HIV infected persons particularly in Africa can access the best quality reproductive and sexual health service. Recent advances in HIV clinical care and as‐ sisted reproduction technique (ART) procedures directed at reducing the risk of viral trans‐ mission during gamete transfer particularly where good healthcare is available has significantly reduced the risk of transmission of HIV among discordant couples to 1-2%. Promotion of risk reduction counselling, screening for sexually transmitted diseases and lower genital tract disease, assessment of options for birth control, and pre-conception coun‐ selling should be integral components of gynaecologic health care for HIV-infected women.

Since the beginning of the human immunodeficiency virus (HIV) epidemic, stigma and dis‐ crimination (SAD) have been identified as the major obstacles to effective responses to HIV [48]. HIV-affected couples who desire sexual and reproductive health services are faced with at least three distinct and daunting challenges. The first is dealing with stigma arising from many health care providers' negative attitude towards sexual activity and child bear‐ ing by HIV infected couples [49] and stigmatization from immediate family members and society [32]. The second is maintaining the mother's health before, during and after preg‐ nancy. The third is preventing vertical transmission from mother to child as well as prevent‐ ing HIV transmission to the partner in sero-discordant relationship. HIV/AIDS-related SAD has been extensively documented among health care providers. There have been many re‐ ports from health care settings of HIV testing without consent, breaches of confidentiality, labelling, gossip, verbal harassment, differential treatment, and even denial of treatment. HIV-infected-individuals who feel stigmatized by health care providers face problems ac‐ cessing HIV testing and other sexual and reproductive health care services [50]. The fear of stigma impedes prevention efforts, including discussions of safer sex and the prevention of

gramme that needs to be urgently addressed in Africa [47].

338 Current Perspectives in HIV Infection

mother-to-child transmission [51].

**7. Challenge of HIV-related stigma and discrimination**

HIV-related stigmatization, discrimination and denial continue to characterize the pandemic in Africa and present a major challenge to the effectiveness of prevention, sexual and repro‐ ductive care and treatment programmes. Much of the societal and individual reaction to‐ wards people with HIV/AIDS is stigma and discrimination oriented. Stigmatization and discrimination occurs in a variety of forms. It ranges from societal level responses such as coercive government policies and laws, to apathy and denial of the HIV epidemic. At the individual level, the internalization of these societal responses may result in an individual's self-exclusion from information, treatment and care. Stigmatization and discrimination are often explored through socio-cultural understandings of illness and disease transmission and its manifestations at societal and individual level. Contexts of discrimination include employment, health care systems, and travel and migration restrictions. Although there are widespread reports of HIV-related discrimination throughout the world there has also been significant progress towards reducing these practices. In addition to what is being done there is still much that we need to understand about the forms and contexts of stigmatiza‐ tion and discrimination if we are to succeed in our efforts to control the HIV epidemic par‐ ticularly in Africa [58]. Stigma and discrimination in Africa can be challenged. One way to reduce their impact is at the legislative level, it is also vital to focus on community-based interventions. These projects target stigmatization manifested in a wide range of community contexts, including: family and immediate community, workplace, health services, religion and the media.

### **8. Need for the development and implementation of affordable, readily available, low technology and safer conception services**

so the CAPRISA 004 trial showed that the use of 1% tenofovir topical gel reduced the rate of HIV acquisition by 39% in heterosexual seronegative women [63]. The use of PrEP is rap‐ idly growing as an important component of safer conception programs for HIV-serodiscord‐ ant couples [47, 64]. In the face of the high HIV prevalence in most African setting, it is expedient that low –technology, safer conception methods that is feasible, affordable and

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

341

Several studies have reported on the efficacy of sperm washing in combination with IUI in terms of pregnancy rates, live birth rates, and HIV transmission incidence [65- 67]. However, evaluation of the efficacy of this safer conception strategy is limited by methodological is‐ sues, including small sample sizes, lack of standardized protocols, and non-rigorous study designs. For example, most studies reported only on retrospective data and very few used control groups. Sperm washing and insemination lower transmission risk for HIV-negative women who want to have children with HIV-positive men. Data from the European experi‐ ence which included a 14 years of follow up for 1,036 sero-discordant couples with an HIV-

**Intracytoplasmic sperm injection (ICSI).**ICSI is a high-technology in vitro fertilization pro‐ cedure in which a single sperm is injected into an egg. It is a popular assisted reproduction technique used as a safe conception technique in HIV seropositive men and their partners. Previous reports have shown that ICSI is particularly useful and effective in the prevention of HIV among serodiscordant couples in which the man is HIV-seropositive [46, 69]. How‐ ever there are a number of challenges associated with its utility particularly in Africa. These include high cost, increased risk of multiple pregnancies and the risk of use of an HIV-in‐ fected gamete [68]. It is crucial to introduce harm-reduction methods and safer conception methods for people with HIV infection in settings where assisted reproductive technologies are unavailable and unaffordable. However, these strategies are not feasible on a wide‐ spread basis in resource-constrained settings. Sperm washing and ICSI is not feasible in most resource-constrained settings. Its high cost, the invasive nature of the procedure, the high number of cancelled cycles, increased risk of multiple pregnancies and potential dan‐ ger of using an HIV-infected gamete all militate against the use of ICSI. The most practicable method in most settings in Africa is vaginal insemination with an uninfected male partner's sperm during the fertile time of the woman's menstrual cycle. Several studies in Africa have evaluated the outcome of natural concention in HIV sero-discordant couples. Ryder and col‐ leagues [70] studied 178 married HIV sero-discordant couples in the Democratic Republic of Congo between 1987 to 1990. Couples engaged in unprotected sex during the moment ovu‐ lation period and resulted in the birth of 24 children and one sero -conversion. Similarly a cross sectional study [71] involving 55 HIV-positive Nigeria women on antiretroviral thera‐ py married to HIV-sero-negative men indicated that younger women compared to older women were more likely to pursue natural conception options than assisted reproduction.

positive male resulted in 580 pregnancies and no HIV sero conversions [68].

are acceptable is implemented.

**8.1. Sperm washing with intrauterine insemination**

Many HIV-infected men and women are now expressing their desire to have children. Al‐ though no conception methods are 100% risk -free of HIV infection other than those that use fresh sperm from an HIV negative donor or adoption. The strong desire among Afri‐ cans to have their own biological children makes these options untenable for many PLWHA. However there is several risk reduction method for safer conception in which the HIV in‐ fected partner is on antiretroviral therapy to achieve a significant reduction of viral load and increase in CD4 count. Assisted reproductive technologies, including intrauterine in‐ semination (IUI), in vitro fertilisation (IVF) and intracytoplasmatic sperm injection (ICSI) in combination with semen washing have been used to decrease the risk of HIV -1 transmis‐ sion in HIV-1-infected discordant couples with an HIV-1-infected man particularly in devel‐ oped countries. Previous report indicates that in HIV-positive men taking HAART, seminal viral load is decreased to undetectable limits but not eliminated and fertilization should be achieved through sperm washing to offer maximum protection for the uninfected female. Pregnant HIV-positive women on antiretroviral medication have a reduced risk of transmit‐ ting the virus, but should still be counselled about the possibility to further limit the chan‐ ces of infecting their infant through elective Caesarean section. HIV sero-discordant couples with strong desire for childbearing have a dilemma of risking HIV infection or infecting their spouse. Some risk transmission of HIV infection to reproduce. Majority of HIV –infect‐ ed couples wanting to procreate are having unprotected sex with their partners. Most per‐ sons living with HIV infection need information on viral load testing, awareness of postexposure prevention and condom use. A paucity of interventions targeting HIV serodiscordant couples on contraceptive choices is at odds with a strong cultural importance in Africa attached to having children. HIV discordance creates a serious dilemma for fertility decision-making in couples. However, majority of these risk reduction method for safer con‐ ception are either unavailable regionally in Africa or unaffordable. Other low-technology and readily available and affordable option that could be used in Africa and other re‐ source- constrained settings include; timed unprotected sexual intercourse for HIV concord‐ ant couples, vaginal insemination of fresh semen into the vagina via a disposable pipette or syringe, for HIV positive men with sero negative partners, the use of antiretroviral drugs by the HIV-infected male partner to lower HIV viral load in seminal plasma to undetecta‐ ble levels, use of pre-exposure prophylaxis (PrEP) by the HIV sero-negative female part‐ ner prior to and following timed unprotected sex at the female partners ovulation period. It is vital that couples practice safer sex practices after conception and throughout the preg‐ nancy. Previous report [59] has shown that HIV horizontal seroconversion occurred in cou‐ ples who reported unsafe sex practices during pregnancy after conception. American researchers and clinicians have advocated the possibilities of using PrEP for safer concep‐ tion [60]. A Recent study has indicated the potential role of PrEP in the prevention of het‐ erosexual HIV transmission [61]. Similarly, the Pre-exposure Prophylaxis Initiative (IPrEx) trial using tenofovir/ emtricitabine has shown that PrEP is safe and capable of producing a reduction in HIV infection risk in HIV-seronegative men who have sex with men [62]. Al‐ so the CAPRISA 004 trial showed that the use of 1% tenofovir topical gel reduced the rate of HIV acquisition by 39% in heterosexual seronegative women [63]. The use of PrEP is rap‐ idly growing as an important component of safer conception programs for HIV-serodiscord‐ ant couples [47, 64]. In the face of the high HIV prevalence in most African setting, it is expedient that low –technology, safer conception methods that is feasible, affordable and are acceptable is implemented.

#### **8.1. Sperm washing with intrauterine insemination**

**8. Need for the development and implementation of affordable, readily**

Many HIV-infected men and women are now expressing their desire to have children. Al‐ though no conception methods are 100% risk -free of HIV infection other than those that use fresh sperm from an HIV negative donor or adoption. The strong desire among Afri‐ cans to have their own biological children makes these options untenable for many PLWHA. However there is several risk reduction method for safer conception in which the HIV in‐ fected partner is on antiretroviral therapy to achieve a significant reduction of viral load and increase in CD4 count. Assisted reproductive technologies, including intrauterine in‐ semination (IUI), in vitro fertilisation (IVF) and intracytoplasmatic sperm injection (ICSI) in combination with semen washing have been used to decrease the risk of HIV -1 transmis‐ sion in HIV-1-infected discordant couples with an HIV-1-infected man particularly in devel‐ oped countries. Previous report indicates that in HIV-positive men taking HAART, seminal viral load is decreased to undetectable limits but not eliminated and fertilization should be achieved through sperm washing to offer maximum protection for the uninfected female. Pregnant HIV-positive women on antiretroviral medication have a reduced risk of transmit‐ ting the virus, but should still be counselled about the possibility to further limit the chan‐ ces of infecting their infant through elective Caesarean section. HIV sero-discordant couples with strong desire for childbearing have a dilemma of risking HIV infection or infecting their spouse. Some risk transmission of HIV infection to reproduce. Majority of HIV –infect‐ ed couples wanting to procreate are having unprotected sex with their partners. Most per‐ sons living with HIV infection need information on viral load testing, awareness of postexposure prevention and condom use. A paucity of interventions targeting HIV serodiscordant couples on contraceptive choices is at odds with a strong cultural importance in Africa attached to having children. HIV discordance creates a serious dilemma for fertility decision-making in couples. However, majority of these risk reduction method for safer con‐ ception are either unavailable regionally in Africa or unaffordable. Other low-technology and readily available and affordable option that could be used in Africa and other re‐ source- constrained settings include; timed unprotected sexual intercourse for HIV concord‐ ant couples, vaginal insemination of fresh semen into the vagina via a disposable pipette or syringe, for HIV positive men with sero negative partners, the use of antiretroviral drugs by the HIV-infected male partner to lower HIV viral load in seminal plasma to undetecta‐ ble levels, use of pre-exposure prophylaxis (PrEP) by the HIV sero-negative female part‐ ner prior to and following timed unprotected sex at the female partners ovulation period. It is vital that couples practice safer sex practices after conception and throughout the preg‐ nancy. Previous report [59] has shown that HIV horizontal seroconversion occurred in cou‐ ples who reported unsafe sex practices during pregnancy after conception. American researchers and clinicians have advocated the possibilities of using PrEP for safer concep‐ tion [60]. A Recent study has indicated the potential role of PrEP in the prevention of het‐ erosexual HIV transmission [61]. Similarly, the Pre-exposure Prophylaxis Initiative (IPrEx) trial using tenofovir/ emtricitabine has shown that PrEP is safe and capable of producing a reduction in HIV infection risk in HIV-seronegative men who have sex with men [62]. Al‐

**available, low technology and safer conception services**

340 Current Perspectives in HIV Infection

Several studies have reported on the efficacy of sperm washing in combination with IUI in terms of pregnancy rates, live birth rates, and HIV transmission incidence [65- 67]. However, evaluation of the efficacy of this safer conception strategy is limited by methodological is‐ sues, including small sample sizes, lack of standardized protocols, and non-rigorous study designs. For example, most studies reported only on retrospective data and very few used control groups. Sperm washing and insemination lower transmission risk for HIV-negative women who want to have children with HIV-positive men. Data from the European experi‐ ence which included a 14 years of follow up for 1,036 sero-discordant couples with an HIVpositive male resulted in 580 pregnancies and no HIV sero conversions [68].

**Intracytoplasmic sperm injection (ICSI).**ICSI is a high-technology in vitro fertilization pro‐ cedure in which a single sperm is injected into an egg. It is a popular assisted reproduction technique used as a safe conception technique in HIV seropositive men and their partners. Previous reports have shown that ICSI is particularly useful and effective in the prevention of HIV among serodiscordant couples in which the man is HIV-seropositive [46, 69]. How‐ ever there are a number of challenges associated with its utility particularly in Africa. These include high cost, increased risk of multiple pregnancies and the risk of use of an HIV-in‐ fected gamete [68]. It is crucial to introduce harm-reduction methods and safer conception methods for people with HIV infection in settings where assisted reproductive technologies are unavailable and unaffordable. However, these strategies are not feasible on a wide‐ spread basis in resource-constrained settings. Sperm washing and ICSI is not feasible in most resource-constrained settings. Its high cost, the invasive nature of the procedure, the high number of cancelled cycles, increased risk of multiple pregnancies and potential dan‐ ger of using an HIV-infected gamete all militate against the use of ICSI. The most practicable method in most settings in Africa is vaginal insemination with an uninfected male partner's sperm during the fertile time of the woman's menstrual cycle. Several studies in Africa have evaluated the outcome of natural concention in HIV sero-discordant couples. Ryder and col‐ leagues [70] studied 178 married HIV sero-discordant couples in the Democratic Republic of Congo between 1987 to 1990. Couples engaged in unprotected sex during the moment ovu‐ lation period and resulted in the birth of 24 children and one sero -conversion. Similarly a cross sectional study [71] involving 55 HIV-positive Nigeria women on antiretroviral thera‐ py married to HIV-sero-negative men indicated that younger women compared to older women were more likely to pursue natural conception options than assisted reproduction.

### **9. Factors to consider before implementation of safer conception in sub Saharan Africa**

unprotected sex accompanied by periconceptionPrEP for the HIV seronegative female part‐ ner in serodisconcordant relationship could form part of a harm-reduction strategy to re‐ duce exposure to HIV when planning conception in resource-limited settings. There is the need to increase the awareness, understanding, and acceptability of readily available, af‐ fordable, evidenced-based, low-technology and safer conception strategies among PLWHA in Africa. Evidenced based –best practices needs to be implemented in Africa to avoid HIV transmission enabling HIV-affected couples to embark on safer childbearing and to prevent the risk of mother-to-child HIV transmission as well as infection of the uninfected partners particularly in sero-discordance relationships. Countries in Africa must now come to terms that failure of the health system to engage HIV-seropositive women and men in fertility management and denying safer conception services to PLWHA who want to conceive a

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

343

1 Department of Medical Laboratory Science, Usmanu Danfodio University Sokoto, Nigeria

3 Department of Obstetrics and Gynaecology, University of Port Harcourt Teaching Hospi‐

[2] Stratchan, M., Kwateng-Addo, A., Hardel, K., et al. (2004). An analysis of family planning content in HIV/AIDS, VCT and PMTCT policies in 16 countries. Policy

[3] Kober, K,van., & Damme, W. (2004). Access to antiretroviral treatment in Southern

[5] Richard Sandbrook (1985). The Politics of Africa's Economic Stagnation. Cambridge

[6] The developing world is poorer than we thought, but no less successful in the fight

[1] UNAIDS (2011). Report of the global AIDS epidemic. November 2011.

Working Paper Series, Washington DC Policy Project, 2004.(9)

[4] Sayre AP. Africa, Twenty-First Century Books. (1999). 0-76131-367-2.

Africa: WHO will do the job? Lancet; , 364(982), 103-107.

University Press, Cambridge, 1985 passim.

against poverty.World Bank.

child is unethical and a deprivation of their fundamental reproductive right.

and C.I. Akani3

2 Bayelsa State College of Health Technology, Bayelsa State, Nigeria

\*Address all correspondence to: n\_osaro@yahoo.com

**Author details**

tal, Nigeria

**References**

O. Erhabor1\*, T.C. Adias2

National medical societies such as the American Society of Reproductive Medicine and the American College of Obstetricians /Gynaecologist has re-affirmed that it is unethical to re‐ fuse to provide safer conception services to PLWHA [72].The protection of the sexual and reproductive health of all people including PLWHA has been recognized as a fundamental human right. PLWHA particularly in Africa have the right to choose to have children and to access non-judgemental, non-stigmatised and non-discriminatory evidenced-based quality sexual and reproductive services. There are however factors that need to be considered in implementing safer conception intervention; the feasibility, availability and affordability of the intervention, the need for antiretroviral therapy to ensure a low viral load, high CD4 count, absence of AIDS defining symptoms and STIs, the need for couple anticipating con‐ ception to be in a stable relationship [73], consideration of fertility problems in HIV-infected population, concomitant low success rate with assisted reproductive technologies in PLWHA, low pregnancy rate and high fetal death rates among HIV-infected women [74].

### **10. Conclusion**

Sustained and increased investment in sexual and reproductive health services in Africa promises tremendous benefits to women, families and societies. In addition to improved health, sexual and reproductive health services contribute to economic growth, societal and gender equity, and democratic governance. Evidence has shown that a significant number of HIV-infected persons in Africa desire to have children irrespective of their positive sero sta‐ tus. There is the need to support the sexual and reproductive rights of HIV-infected individ‐ uals. Additional training needs to be offered to HIV counsellors on evidenced- based best and affordable practices regarding reproductive health issues among persons living with HIV. There is the urgent need to develop policies that support the availability and accessibil‐ ity to relevant reproductive and sexual health services including contraception and procrea‐ tion. There is also the need for public enlightenment programmes on HIV to reduce the stigmatization that HIV-infected persons in sub Saharan Africa face from family members and their communities. Implementation of explicit policies recognizing reproductive rights and choice of HIV-infected in Africa as well as support for health counselling and service interventions that advance safer and healthier reproductive options for HIV positive indi‐ viduals is advocated. Intrauterine insemination (IUI) and Intracytoplasmic sperm injection ICSI does not seem a cost-effective option in Africa and other resource-constrained settings. However vaginal insemination with the sperm of an HIV-seronegative male partner is high‐ ly feasible and has been found to be reasonably acceptable to both men and women and re‐ duces the risk of transmission of HIV from infected women to their uninfected partners. This may be a practicable, affordable, low- technology, safer conception option that may need to be implemented in Africa and other resource-limited settings. There is increasing advocacy that timed, limited, unprotected sex for HIV-seroconcordant couples, and timed, unprotected sex accompanied by periconceptionPrEP for the HIV seronegative female part‐ ner in serodisconcordant relationship could form part of a harm-reduction strategy to re‐ duce exposure to HIV when planning conception in resource-limited settings. There is the need to increase the awareness, understanding, and acceptability of readily available, af‐ fordable, evidenced-based, low-technology and safer conception strategies among PLWHA in Africa. Evidenced based –best practices needs to be implemented in Africa to avoid HIV transmission enabling HIV-affected couples to embark on safer childbearing and to prevent the risk of mother-to-child HIV transmission as well as infection of the uninfected partners particularly in sero-discordance relationships. Countries in Africa must now come to terms that failure of the health system to engage HIV-seropositive women and men in fertility management and denying safer conception services to PLWHA who want to conceive a child is unethical and a deprivation of their fundamental reproductive right.

### **Author details**

**9. Factors to consider before implementation of safer conception in sub**

National medical societies such as the American Society of Reproductive Medicine and the American College of Obstetricians /Gynaecologist has re-affirmed that it is unethical to re‐ fuse to provide safer conception services to PLWHA [72].The protection of the sexual and reproductive health of all people including PLWHA has been recognized as a fundamental human right. PLWHA particularly in Africa have the right to choose to have children and to access non-judgemental, non-stigmatised and non-discriminatory evidenced-based quality sexual and reproductive services. There are however factors that need to be considered in implementing safer conception intervention; the feasibility, availability and affordability of the intervention, the need for antiretroviral therapy to ensure a low viral load, high CD4 count, absence of AIDS defining symptoms and STIs, the need for couple anticipating con‐ ception to be in a stable relationship [73], consideration of fertility problems in HIV-infected population, concomitant low success rate with assisted reproductive technologies in PLWHA, low pregnancy rate and high fetal death rates among HIV-infected women [74].

Sustained and increased investment in sexual and reproductive health services in Africa promises tremendous benefits to women, families and societies. In addition to improved health, sexual and reproductive health services contribute to economic growth, societal and gender equity, and democratic governance. Evidence has shown that a significant number of HIV-infected persons in Africa desire to have children irrespective of their positive sero sta‐ tus. There is the need to support the sexual and reproductive rights of HIV-infected individ‐ uals. Additional training needs to be offered to HIV counsellors on evidenced- based best and affordable practices regarding reproductive health issues among persons living with HIV. There is the urgent need to develop policies that support the availability and accessibil‐ ity to relevant reproductive and sexual health services including contraception and procrea‐ tion. There is also the need for public enlightenment programmes on HIV to reduce the stigmatization that HIV-infected persons in sub Saharan Africa face from family members and their communities. Implementation of explicit policies recognizing reproductive rights and choice of HIV-infected in Africa as well as support for health counselling and service interventions that advance safer and healthier reproductive options for HIV positive indi‐ viduals is advocated. Intrauterine insemination (IUI) and Intracytoplasmic sperm injection ICSI does not seem a cost-effective option in Africa and other resource-constrained settings. However vaginal insemination with the sperm of an HIV-seronegative male partner is high‐ ly feasible and has been found to be reasonably acceptable to both men and women and re‐ duces the risk of transmission of HIV from infected women to their uninfected partners. This may be a practicable, affordable, low- technology, safer conception option that may need to be implemented in Africa and other resource-limited settings. There is increasing advocacy that timed, limited, unprotected sex for HIV-seroconcordant couples, and timed,

**Saharan Africa**

342 Current Perspectives in HIV Infection

**10. Conclusion**

O. Erhabor1\*, T.C. Adias2 and C.I. Akani3

\*Address all correspondence to: n\_osaro@yahoo.com

1 Department of Medical Laboratory Science, Usmanu Danfodio University Sokoto, Nigeria

2 Bayelsa State College of Health Technology, Bayelsa State, Nigeria

3 Department of Obstetrics and Gynaecology, University of Port Harcourt Teaching Hospi‐ tal, Nigeria

### **References**


[7] Couch JF, Atkinson KE, Shughart WF (1992). Ethics Laws and the Outside Earnings of Politicians: The Case of Alabama's `Legislator-Educators'" Public Choice. , 73(2), 135-45.

[23] Frodsham, L. C., Boag, F., Barton, S., & Gilling-Smith, C. (2006). Human immunodefi‐ ciency virus infection and fertility care in the United Kingdom: Demand and supply.

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

345

[24] Myer, L., Morroni, C., & Rebe, K. (2007). Prevalence and determinants of fertility in‐ tentions of HIV-infected women and men receiving antiretroviral therapy in South

[25] Matthews LT, Mukherjee JS (2009). Strategies for harm reduction among HIV-affect‐

[26] Sonko SI. (1994). Fertility and culture in Sub-Saharan Africa: A review. *International*

[27] Allen, S., Meinzen-Derr, J., Kautzman, M., Zulu, I., Trask, S., Fideli, U., et al. (2003). Sexual behaviour of HIV discordant couples after HIV counselling and testin. g.

[28] Beyeza-Kashesya, J., Kaharuza, F., Mirembe, F., Neema, S., Ekstrom, A. M., & Ku‐

[29] Beyeza-Kashesya, J., Ekstrom, A. M., Kaharuza, F., Mirembe, F., Neema, S., & Ku‐ lane, A. (2010). My partner wants a child: a cross-sectional study of the determinants of the desire for children among mutually disclosed sero-discordant couples receiv‐

[30] Barreiro, P., Duerr, A., Beckerman, K., & Soriano, V. (2006). Reproductive options for

[31] de Bruyn, M. (2004). Living with HIV: Challenges in reproductive health care in

[32] Kalichman SC, Simbayi LC (2003). HIV testing attitudes, AIDS stigma and voluntary HIV counselling and testing in a black township in Cape Town, South Africa. Sex

[33] Peña, J. E., Klein, J., Thornton, M. H., & 2nd, Sauer. M. V. (2003). Providing assisted reproductive care to male haemophiliacs infected with human immunodeficiency vi‐

[34] Stern AM (2005). Sterilized in the name of public health: race, immigration and re‐ productive control in modern California. Am J Public Health, 2005; , 95, 1128-1138. [35] Sauer M V (2003). Providing fertility care to those with HIV: Time to re-examine

[36] Semprini, A. E., Levi-Setti, P., Bozzo, M., et al. (1992). Insemination of HIV-negative women with processed semen of HIV-positive partners. *Lancet*, 340, 1317-1319. [37] Geeta RG (2002). How men's power over women fuel the HIV epidemics.Br Med J; ,

*Fertility and Sterility*, 285 EOF-289 EOF.

*Social Science Journal*.

lane, A. 2 EOF-12 EOF.

TransmInfec; , 79, 42-447.

324(7331), 183-184.

AIDS

Africa. *AIDS Patient Care and STDs*, 278 EOF-285 EOF.

ed couples who want to conceive. AIDS Behav; , 1, 5-11.

ing care in Uganda. BMC Public Health; 13, 10, 247.

rus: preliminary experience. *Haemophilia*, 9(3), 309-316.

HIV-serodiscordant couples. AIDS Rev; 8(3), , 158 EOF-70 EOF.

South Africa. African Journal of Reproductive Health; , 8(1), 92-98.

healthcare policy. The American Journal of Bioethics , 3(1), 33-40.


[23] Frodsham, L. C., Boag, F., Barton, S., & Gilling-Smith, C. (2006). Human immunodefi‐ ciency virus infection and fertility care in the United Kingdom: Demand and supply. *Fertility and Sterility*, 285 EOF-289 EOF.

[7] Couch JF, Atkinson KE, Shughart WF (1992). Ethics Laws and the Outside Earnings of Politicians: The Case of Alabama's `Legislator-Educators'" Public Choice. , 73(2),

[8] Transparency International, The anti-corruption catalyst: realising the MDGs by

[9] Transparency International. Corruption PerceptionsIndex, TransparencyInternation‐

[12] United Nations. (2006). revision of the United Nations World Population Prospects

[13] Carroli, G., Rooney, C., & Villar, J. (2001). How effective is antenatal care in prevent‐ ing maternal mortality and serious morbidity? An overview of the evidence. Pae‐

[14] CDC ((2001). ). Revised recommendations for HIV screening of pregnant women.

[15] Almeida SD, Barros MB (2005). Equity and access to health care for pregnant women in Campinas (SP), Brazil. RevistaPanamericana de SaludPublica; , 17(1), 15-25.

[16] O', Connor. K. E., & Mac, Donald. S. E. (2002). Aiming for zero: preventing motherto-child transmission of HIV. Canadian Medical Association Journal; , 166(7),

[18] Mullick, S., Kunene, B., & Wanjiru, M. Involving men in maternity care: health serv‐ ice delivery issues. Agenda: Special focus on Gender, Culture and Rights (Special

[19] UNAIDS/02.31E (2002). Keeping the promise. Summary of the Declaration of Com‐ mitment on HIV/AIDS. United Nations General Assembly Special Session on HIV/

[20] CDC (1998). HIV partner counselling and referral services guidance. Atlanta, GA: US

[21] Cooper, D., Harries, J., Myer, L., Orner, P., & Bracken, H. (2007). Life is still going on. Reproductive intentions among HIV-positive women and men in South Africa. So‐

[22] Erhabor, O., Akani, C. I., & Eyindah, . (2012). Reproductive health options among HIV-infected persons in the low-income Niger Delta of Nigeria. HIV AIDS (Auckl); ,

[17] IPAS (2005). Reproductive rights for women affected by HIV/AIDS.

AIDS (UNGASS), June 2001.Geneva: UNAIDS., 25-27.

Department of Health and Human Services, CDC.

cial Science and Medicine; , 65(2), 274-278.

[11] CIA-The World Fact book (2008). Rank order HIV/AIDS-Adult prevalence rate.

(2015). Transparency International, and www.transparency.org.

135-45.

344 Current Perspectives in HIV Infection

al, www.transparency.org.

[10] CIA World Fact book 2009.

report, for. , 2005-2010.

diatrPerinatEpidemiol ; , 15(1), 1-42.

MMWR; 50 ( ):63-85.(RR-19)

909-910.

4, 29-35.

(124-135), 124-135.


[38] Peter, K. L., Kristen, R., Willard, C., (2002, , & , H. I. V. A. I. D. (2002). HIV/AIDS evolving impact on global health. In: Ron Valdisiern (ed). Dawning answers: How the HIV/AIDS epidemic has strengthened public health. New York. Oxford press.

[52] Goldin, C. (1994). Stigmatization and AIDS: Critical issues in public health." Social

Reproductive Health Challenges of Living with HIV-Infection in Sub Saharan Africa

http://dx.doi.org/10.5772/52682

347

[53] Norbert, G., & Somerville, M. (1994). Stigmatization, scapegoating and discrimina‐ tion in sexually transmitted diseases: Overcoming them and us. Social Science and

[54] Angelo, A., & Reynolds, N. (1995). Stigma, HIV and AIDS: An exploration and elabo‐ ration of a stigma trajectory." Social Science and Medicine; , 41(3), 303-315.

[55] Somerville, Margaret and Andrew Orkin ((1989). ). "Human rights, discrimination

[56] Zaba, B., & Gregson, S. (1998). Measuring the impact of HIV on fertility in Afri‐ ca..HIV-related stigma and discrimination have been shown to impede prevention,

[57] Paiva, V., Filipe, E. V., Santos, N., Lima, T. N. ., & Segurado, A. (2003). The right to love: The desire for parenthood among men living with HIV. *Reproductive Health*

[58] Malcolm, A., Aggleton, P., Bronfman, M., Galvão, J., Mane, P., & Verrall, J. (1998). HIV-related stigmatization and discrimination: Its forms and contexts.Critical Public

[59] Mandelbrot, L., Heard, I., Henrion, E., & Henrion, R. (1997). Natural conception in

[60] Lampe MA, Smith DK, Anderson GJ, Edwards AE, Nesheim SR (2011). Achieving safe conception in HIV-discordant couples: the potential role of oral pre-exposure

[61] Baeten, J., Celum, C., et al. (2011). The partners PrEP Study Team. Antiretroviral preexposure prophylaxis for HIV-1 prevention among heterosexual African men and women: the Partners PrPE Study(Abstract MOAX01) 6th IAS Conference on HIV

[62] Grant RM, Lama JR, Anderson PL, et al (2011). Pre-exposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med; , 363, 2587-2599.

[63] Abdool, Karim. Q., Abdool, Karim. S. S., Frohlich, J. A., et al. (2010). Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV

[64] Mathews, L. T., Baeten, J. M., Celum, C., & Bangsberg, D. R. (2010). Periconception pre-exposure prophylaxis to prevent HIV transmission: benefits, risks and challenges

[65] Semiprini AE (2000). Viral transmission in ART risks for patients and healthcare pro‐

HIV-negative women with HIV-infected partners.*Lancet* . 13, 2314-2315.

prophylaxis (PrEP) in the United States. Am J Obstet Gynecol.204: 488.

Pathogenesis, Treatment and Prevention. July Rome Italy., 17-20.

and AIDS: Concepts and issues."AIDS; 3(1): S -S287., 283.

Science and Medicine; , 39(9), 1359-1366.

care and treatment. AIDS; , 12(1), 341-350.

infection in women. Science; 329: 1168.

to implementation.AIDS; , 24, 1975-1982.

viders. Hum Reprod; 15:69.

Medicine; , 39(3), 1359-1366.

*Matters*, 11(22), 91-100.

Health; , 8(4), 347-370.


[52] Goldin, C. (1994). Stigmatization and AIDS: Critical issues in public health." Social Science and Medicine; , 39(9), 1359-1366.

[38] Peter, K. L., Kristen, R., Willard, C., (2002, , & , H. I. V. A. I. D. (2002). HIV/AIDS evolving impact on global health. In: Ron Valdisiern (ed). Dawning answers: How the HIV/AIDS epidemic has strengthened public health. New York. Oxford press.

[40] Gomez AC, Marin VB (1996). Gender, culture and power: Barriers to HIV-prevent.

[41] The Glion Call to Action on family planning and HIV/AIDS in women and children"

[42] Coopera, D., et al. (2005). Reproductive intentions and choices among HIV-infected individuals in Cape Town, South Africa. Lessons for reproductive policy and service provision from a qualitative study", Policy Brief, Women's Health Research Unit and Infectious Diseases epidemiology Unit, University of Cape Town, South Africa and

[43] Shapiro, K., & Ray, S. (2007). Sexual health for people living with HIV. Reproductive

[44] Mantell JE, Smit JA, Stein ZA (2009). The right to choose parenthood among HIV-in‐

[45] Fakoya, A., Lamba, H., Mackie, N., et al. (2008). British HIV Association, BASHH and FSRH guidelines for the management of the sexual and reproductive health of peo‐

[46] Ohi, J. P. M., Wittemer, C., et al. (2003). Assisted reproduction techniques for HIV se‐ rodiscordant couples: 18 months of experience. Hum Reprod; , 18, 1244-1249.

[47] Chadwick, R. J., Mantell, J. E., Moodley, J., Harries, J., Zweigenthal, V., & Cooper, D. (2011). Safer conception interventions for HIV-affected couples: implications for re‐

[48] Nyblade, L., & Mac, Quarrie. K. (2006). Can We Measure HIV/AIDS-related Stigma and Discrimination? Current Knowledge about Quantifying Stigma in Developing Countries. Washington, DC: United States Agency for International Development.

[49] Shelton JD, Peterson EA. (2004). The imperative for family planning in ART therapy

[50] Sayles, J. N., Wong, Kinsler. J. J., Martins, D., & Cunningham, W. E. (2009). The asso‐ ciation of stigma and self-reported access to medical care and antiretroviral therapy adherence in persons living with HIV/AIDS. J Gen Intern Med; , 24(10), 1101-1108.

[51] Obermeyer, C. M., & Osborn, M. (2007). The utilization of testing and counselling for HIV: a review of the social and behavioural evidence. Am J Public Health; , 97(10),

[39] UNAIDS (1997). Women and AIDS. UNAIDS point of view. UNAIDS. Geneva.

ion strategies for women. Journal of Sex Research; , 33(4), 355-362.

a consensus advocacy statement from a consultation in May 2004.

the population council, New York, September 2005.

fected women and men. J Public Health Policy. ; , 30, 367-378.

ple li. ving with HIV infection 2008. HIV Med; , 9, 681-720.

source-constrained settings. Top AntivirMed ; , 19(4), 148-55.

Health Matter; , 15(29), 67-92.

346 Current Perspectives in HIV Infection

in Africa. *Lancet*, 364, 1916-1918.

1762-1774.


[66] Manigart, Y., Rozenberg, S., Barlow, P., Ge-rard, M., Bartrand, E., & Delvigne, A. (2006). ART out-come in HIV-infected patients. Hum Reprod; , 21, 2935-2940.

**Section 5**

**Prevention and Treatment of HIV Infection**


**Prevention and Treatment of HIV Infection**

[66] Manigart, Y., Rozenberg, S., Barlow, P., Ge-rard, M., Bartrand, E., & Delvigne, A. (2006). ART out-come in HIV-infected patients. Hum Reprod; , 21, 2935-2940.

[67] Savasi, V., Ferrazzi, E., Lanzani, C., Oneta, M., Parrilla, B., & Persico, T. (2007). Safety of sperm washing and ART outcome in 741 HIV-1 sero-discordant couples. Hum Re‐

[68] Bujan, L., Hollander, L., Coudert, M., Gilling-Smith, C., Vucetich, A., Guibert, J., Ver‐ nazza, P., Ohl, J., Weigel, M., Englert, Y., Semprini, A. E., Th, C. R. E. A., & network, E. (2007). Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: results from the European CREAThE network. AIDS; ,

[69] Kashima, K., Takakuka, K., Suzuki, M., et al. (2009). Studies of assisted reproduction techniques (ART) for HIV-1 discordant couples using washed sperm and the nested PCR method: a comparison of the pregnancy rates in HIV-1 discordant couples and

[70] Ryder, R. W., Kamenga, C., Jinju, M., Mbuyi, N., Mbu, l., & Behets, F. (2005). Preg‐ nancy and HIV-1 incidence in 178 married couples with discordant HIV-1 serostatus: additional experience at an HIV-1 counselling centre in the Democratic Republic of

[71] Ezeanochie, M., Olagbuji, B., Ande, A., & Oboro, V. (2009). Fertility preferences, con‐ dom use and concerns among HIV-positive women in serodiscordant relationships

[72] Kambin, S., & Batzer, F. (2004). Assisted reproductive technology in HIV serodis‐ cordant couples. Sexuality, Reproduction and Menopause.2004; , 2, 92-100.

[73] Gilling-Smith, C., Nicopoullos, Semprini. A. E., Frodsham, L. C., (2006, , & , H. I. (2006). HIV and reproductive care-a review of current practice; , 113, 869-878.

[74] Englert, Y., Lesage, B., Van Vooren, J. P., et al. (2004). Medically assisted reproduc‐ tion in the presence of chronic viral disease. Hum Reprod Update; , 10, 149-162.

in the era of antiretroviral therapy. Int J GynaecolObstet; , 10, 97-98.

control couples. Jpn J Infec Dis.2009; , 62, 173-176.

the Congo. Trop Med Int Health: , 482-487.

prod; , 22, 772-777.

348 Current Perspectives in HIV Infection

21(14), 1909-14.

**Chapter 15**

**The Downside of an Effective cART: The Immune**

The prognosis of patients infected with human immunodeficiency virus (HIV) type 1 has dramatically improved since the advent of the highly active antiretroviral therapy (HAART), which have enabled sustained suppression of HIV replication and recovery of CD4+ T cells count [1-3]. However, many patients in resource-poor settings still start HAART at a late stage of HIV infection when they already have advanced immunodeficien‐ cy [4,5]. Immune reconstitution in HIV infected patients is characterized by replenishment of immune cells depleted directly or indirectly by HIV infection, by regeneration of primary and secondary lymphoid organs, by restoration of pathogen-specific T, B and NK cells and by a regulation of the reconstituted immune system [2]. It is unclear whether complete im‐ mune reconstitution ever occurs but individuals with human immunodeficiency virus infec‐ tion starting antiretroviral therapy when they are very immunodeficient are susceptible to immune reconstitution disorders. This phenomenon is known as a multitude of names in‐ cluding "immune reconstitution inflammatory syndrome (IRIS)", "immune reconstitution or restoration disease" (IRD) or immune reconstitution syndrome" and includes various forms of a clinical deterioration as a consequence of a rapid and dysregulated restoration of anti‐ gen specific immune responses causing an exuberant inflammatory reaction and a cytokines storm [1-3]. This was first noted following the introduction of zidovudine monotherapy in the early 1990s, when localized forms of *Mycobacterium avium intracellulare* (MAI) infection where observed in association with the recovery rather than failure of cellular immune re‐ sponse [6]. Later, in 1992, *French MA et al* showed that the disease associated with Mycobac‐ terium avium complex (MAC) infection occurred after nucleoside analogue therapy and correlated with restoration of delayed hypersensitivity (DTH) responses to mycobacterial

> © 2013 Colomba and Rubino; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

**Restoration Disease**

http://dx.doi.org/10.5772/53352

**1. Introduction**

antigens [7].

Claudia Colomba and Raffaella Rubino

Additional information is available at the end of the chapter

## **The Downside of an Effective cART: The Immune Restoration Disease**

Claudia Colomba and Raffaella Rubino

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53352

### **1. Introduction**

The prognosis of patients infected with human immunodeficiency virus (HIV) type 1 has dramatically improved since the advent of the highly active antiretroviral therapy (HAART), which have enabled sustained suppression of HIV replication and recovery of CD4+ T cells count [1-3]. However, many patients in resource-poor settings still start HAART at a late stage of HIV infection when they already have advanced immunodeficien‐ cy [4,5]. Immune reconstitution in HIV infected patients is characterized by replenishment of immune cells depleted directly or indirectly by HIV infection, by regeneration of primary and secondary lymphoid organs, by restoration of pathogen-specific T, B and NK cells and by a regulation of the reconstituted immune system [2]. It is unclear whether complete im‐ mune reconstitution ever occurs but individuals with human immunodeficiency virus infec‐ tion starting antiretroviral therapy when they are very immunodeficient are susceptible to immune reconstitution disorders. This phenomenon is known as a multitude of names in‐ cluding "immune reconstitution inflammatory syndrome (IRIS)", "immune reconstitution or restoration disease" (IRD) or immune reconstitution syndrome" and includes various forms of a clinical deterioration as a consequence of a rapid and dysregulated restoration of anti‐ gen specific immune responses causing an exuberant inflammatory reaction and a cytokines storm [1-3]. This was first noted following the introduction of zidovudine monotherapy in the early 1990s, when localized forms of *Mycobacterium avium intracellulare* (MAI) infection where observed in association with the recovery rather than failure of cellular immune re‐ sponse [6]. Later, in 1992, *French MA et al* showed that the disease associated with Mycobac‐ terium avium complex (MAC) infection occurred after nucleoside analogue therapy and correlated with restoration of delayed hypersensitivity (DTH) responses to mycobacterial antigens [7].

© 2013 Colomba and Rubino; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

### **2. Definition and epidemiology**

IRIS is a well established entity still lacking of a consistent definition due to a wide variety of pathogens and disease processes involved. It has been associated with herpetic, mycobac‐ terial and cryptococcal infections, Kaposi's sarcoma, non – Hodgkin lymphoma and pro‐ gressive multifocal leukoencephalopathy. Non AIDS defining pathologies such as sarcoidosis, Graves disease and rheumatic disease can also occur [1-3]. General case defini‐ tions have been proposed by *Shelburne et al* (2009), *French MA et al* (2004) and by *Robertson J et al* (2006) [8,9,10] but diagnostic criteria for IRIS have not been standardized except for TB-IRIS [3, 11]. This syndrome can be elicited by infectious and non infectious antigens and may arise in two different settings, depending on whether HAART was started in a patient treated for an ongoing opportunistic infection or in a clinically stable patient with or without requiring primary prophylaxis [2]. "Unsmasking IRIS" is an immune response against an in‐ fection that was subclinical before the initiation of HAART whereas "paradoxical IRIS" indi‐ cates a condition in which the opportunistic infection is present and treated at the time of initiation of HAART and worsens on therapy. Unmasking IRIS usually presents within the first three months of therapy and viable pathogens may be isolated from samples obtained from affected body sites, particularly when there is tissue necrosis. Paradoxical IRIS is com‐ mon during the first three months of HAART but may present later and frequently immune response is against non viable pathogens. It occurs in 8-43% of patients with treated tubercu‐ losis and in 4-66% of patients with treated cryptococcal infection becoming an important concern in poor resources countries [1-3]. Paradoxical IRIS is also exemplified by immune recovery, which occurs in eyes previously affected by cytomegalovirus (CMV) retinitis. Par‐ ticularly in paradoxical IRIS, clinicians need to exclude alternative explanations for deterio‐ ration, such as failure to treat the opportunistic infection or failure of HAART because of poor adherence or drug resistance [3].

The immune restoration outcomes range from minimal morbidity to fatal progression [15]. The immune restoration shows a biphasic pattern and is demonstrated by a decrease in plas‐ ma HIV RNA levels by more than 1 log10 copies/ml and an increase in CD4 + T cells count from baseline [1,2,16]. Initial recovery of the immune system consists in an increase in mem‐ ory T cells followed by an increase in thymic production of naïve T cells [1,2,16-20]. In addi‐ tion there is the recovery of reduced or damaged secondary lymphoid organs such as the gut and the mesentheric associated lymphoid tissue, which are often lost due to chronic HIV- mediated inflammation [21]. The initial and rapid rise of CD4 + T memory cells re‐ leased from compartments into circulation can be detrimental and a mild OI can appear as an overwhelming infection because memory T cells respond to their antigens more readily

The Downside of an Effective cART: The Immune Restoration Disease

http://dx.doi.org/10.5772/53352

353

CD8 + T cells also increase during the first two months of HAART and then tend to return to

Differentiation between an opportunistic infection with normal presentation and a disorder with a presentation compatible with unmasking IRIS is particularly difficult and the differ‐ ences between intended HAART – associated immune reconstitution and undesired mani‐ festations of IRIS is probably a continuum [3].The damage may indicate a failure of the

The differential diagnosis includes failure of the antimicrobial therapy in patient with active infection, manifestations of a new opportunistic infection, unmasking of an ongoing, previ‐ ously undiagnosed infection or manifestation of a diagnosed, ongoing infection in a previ‐ ously unrecognized site of involvement [1-3,16]. Drug toxicity must be ruled out. For example, hepatitis flares in patients coinfected with hepatitis B virus or hepatitis C virus may be the result of IRIS in the liver or of HAART- associated hepatotoxicity [2, 24].In occur‐ ring IRIS, inflammation is atypical in presentation or more exaggerated than in immunodefi‐ ciency disease being characterized by pain, suppuration and necrosis and examination of affected tissue or body fluids samples reveals evidence of an immune response with scarcity

IRIS may be estimated to occur in 10% to 50 % of patients starting HAART with similar per‐ centages occurring in children and the incidence varies with the AIDS-defining illness [1-3]. Differences reported in the incidence of IRIS between opportunistic infections seem to be re‐ lated to CD4+ T cells count at baseline [3]. IRIS is common in patients starting HAART with a low CD4 + T cells count and a CMV retinitis or cryptococcal meningitis whereas Kaposi's sarcoma and TB-IRIS have also been described at an high count of CD4 + T cells count [3,25]. Moreover, the variation reported in frequency is due to differences in case definitions and, above all, to differences in study populations with heterogeneous risk profiles and underly‐ ing burden of opportunistic infections [1,2]. In a recent meta-analysis and systematic review including 54 cohort studies and 13.103 patients starting HAART of whom 1699 develope IRIS, the lowest to highest incidence of IRIS by previously diagnosed opportunistic illness resulted 6,4% in patients with Kaposi's sarcoma (based on two studies), 12,2% in patients with Herpes Zoster (based on one study), 15,7% in patients with tuberculosis (based on 16 studies), 16,7% in patients with progressive multifocal leukoencephalopathy (based on two studies), 19,5% in patients with cryptococcal meningitis (based on six studies) and 37,7% in

immune system to properly regulate the potency of the immune response [23].

of pathogens, infiltrating lymphocytes and granulomatous reaction [1-3].

than naïve T cells [2,22].

baseline [18].

Some authors suggested using terms of "simultaneous IRIS" for patients who develop IRIS and a newly diagnosed opportunistic infection (OI) at the same time and "delayed IRIS" for those with an OI in which IRIS manifests sometimes thereafter [12].

However, although several case definitions for IRIS have been proposed, certain minimum criteria should be fulfilled in order to diagnose it. First of all, there must be the temporal as‐ sociation between initiation of HAART and subsequent development of symptoms of an in‐ flammatory localized or systemic process, characterized by worsening of clinical or laboratory parameters despite "favorable" evolution of the HIV surrogate markers [1,2]. A rise in blood CD4 + T cells is commonly seen in IRIS but it is not an essential element for the diagnosis and is only a supportive criterion in both of the general case definitions for IRIS [9,10]. *Philips P et al* found that about 10% of patients with Mycobacterium avium complex immune restoration disease haven't an increased CD4+ T cells count [13]. Neverthless, a lack of rise in blood CD4 + T cells doesn't indicate that there has been no restoration of functional T lymphocyte response. On the other hand, IRIS has been described at higher CD4 + T cells count, suggesting that functional status of cells has a role in the pathogenesis of IRIS too. Therefore a falling plasma viral load is a more important indicator than CD4 T cells count recovery [14].

The immune restoration outcomes range from minimal morbidity to fatal progression [15]. The immune restoration shows a biphasic pattern and is demonstrated by a decrease in plas‐ ma HIV RNA levels by more than 1 log10 copies/ml and an increase in CD4 + T cells count from baseline [1,2,16]. Initial recovery of the immune system consists in an increase in mem‐ ory T cells followed by an increase in thymic production of naïve T cells [1,2,16-20]. In addi‐ tion there is the recovery of reduced or damaged secondary lymphoid organs such as the gut and the mesentheric associated lymphoid tissue, which are often lost due to chronic HIV- mediated inflammation [21]. The initial and rapid rise of CD4 + T memory cells re‐ leased from compartments into circulation can be detrimental and a mild OI can appear as an overwhelming infection because memory T cells respond to their antigens more readily than naïve T cells [2,22].

**2. Definition and epidemiology**

352 Current Perspectives in HIV Infection

poor adherence or drug resistance [3].

recovery [14].

IRIS is a well established entity still lacking of a consistent definition due to a wide variety of pathogens and disease processes involved. It has been associated with herpetic, mycobac‐ terial and cryptococcal infections, Kaposi's sarcoma, non – Hodgkin lymphoma and pro‐ gressive multifocal leukoencephalopathy. Non AIDS defining pathologies such as sarcoidosis, Graves disease and rheumatic disease can also occur [1-3]. General case defini‐ tions have been proposed by *Shelburne et al* (2009), *French MA et al* (2004) and by *Robertson J et al* (2006) [8,9,10] but diagnostic criteria for IRIS have not been standardized except for TB-IRIS [3, 11]. This syndrome can be elicited by infectious and non infectious antigens and may arise in two different settings, depending on whether HAART was started in a patient treated for an ongoing opportunistic infection or in a clinically stable patient with or without requiring primary prophylaxis [2]. "Unsmasking IRIS" is an immune response against an in‐ fection that was subclinical before the initiation of HAART whereas "paradoxical IRIS" indi‐ cates a condition in which the opportunistic infection is present and treated at the time of initiation of HAART and worsens on therapy. Unmasking IRIS usually presents within the first three months of therapy and viable pathogens may be isolated from samples obtained from affected body sites, particularly when there is tissue necrosis. Paradoxical IRIS is com‐ mon during the first three months of HAART but may present later and frequently immune response is against non viable pathogens. It occurs in 8-43% of patients with treated tubercu‐ losis and in 4-66% of patients with treated cryptococcal infection becoming an important concern in poor resources countries [1-3]. Paradoxical IRIS is also exemplified by immune recovery, which occurs in eyes previously affected by cytomegalovirus (CMV) retinitis. Par‐ ticularly in paradoxical IRIS, clinicians need to exclude alternative explanations for deterio‐ ration, such as failure to treat the opportunistic infection or failure of HAART because of

Some authors suggested using terms of "simultaneous IRIS" for patients who develop IRIS and a newly diagnosed opportunistic infection (OI) at the same time and "delayed IRIS" for

However, although several case definitions for IRIS have been proposed, certain minimum criteria should be fulfilled in order to diagnose it. First of all, there must be the temporal as‐ sociation between initiation of HAART and subsequent development of symptoms of an in‐ flammatory localized or systemic process, characterized by worsening of clinical or laboratory parameters despite "favorable" evolution of the HIV surrogate markers [1,2]. A rise in blood CD4 + T cells is commonly seen in IRIS but it is not an essential element for the diagnosis and is only a supportive criterion in both of the general case definitions for IRIS [9,10]. *Philips P et al* found that about 10% of patients with Mycobacterium avium complex immune restoration disease haven't an increased CD4+ T cells count [13]. Neverthless, a lack of rise in blood CD4 + T cells doesn't indicate that there has been no restoration of functional T lymphocyte response. On the other hand, IRIS has been described at higher CD4 + T cells count, suggesting that functional status of cells has a role in the pathogenesis of IRIS too. Therefore a falling plasma viral load is a more important indicator than CD4 T cells count

those with an OI in which IRIS manifests sometimes thereafter [12].

CD8 + T cells also increase during the first two months of HAART and then tend to return to baseline [18].

Differentiation between an opportunistic infection with normal presentation and a disorder with a presentation compatible with unmasking IRIS is particularly difficult and the differ‐ ences between intended HAART – associated immune reconstitution and undesired mani‐ festations of IRIS is probably a continuum [3].The damage may indicate a failure of the immune system to properly regulate the potency of the immune response [23].

The differential diagnosis includes failure of the antimicrobial therapy in patient with active infection, manifestations of a new opportunistic infection, unmasking of an ongoing, previ‐ ously undiagnosed infection or manifestation of a diagnosed, ongoing infection in a previ‐ ously unrecognized site of involvement [1-3,16]. Drug toxicity must be ruled out. For example, hepatitis flares in patients coinfected with hepatitis B virus or hepatitis C virus may be the result of IRIS in the liver or of HAART- associated hepatotoxicity [2, 24].In occur‐ ring IRIS, inflammation is atypical in presentation or more exaggerated than in immunodefi‐ ciency disease being characterized by pain, suppuration and necrosis and examination of affected tissue or body fluids samples reveals evidence of an immune response with scarcity of pathogens, infiltrating lymphocytes and granulomatous reaction [1-3].

IRIS may be estimated to occur in 10% to 50 % of patients starting HAART with similar per‐ centages occurring in children and the incidence varies with the AIDS-defining illness [1-3]. Differences reported in the incidence of IRIS between opportunistic infections seem to be re‐ lated to CD4+ T cells count at baseline [3]. IRIS is common in patients starting HAART with a low CD4 + T cells count and a CMV retinitis or cryptococcal meningitis whereas Kaposi's sarcoma and TB-IRIS have also been described at an high count of CD4 + T cells count [3,25].

Moreover, the variation reported in frequency is due to differences in case definitions and, above all, to differences in study populations with heterogeneous risk profiles and underly‐ ing burden of opportunistic infections [1,2]. In a recent meta-analysis and systematic review including 54 cohort studies and 13.103 patients starting HAART of whom 1699 develope IRIS, the lowest to highest incidence of IRIS by previously diagnosed opportunistic illness resulted 6,4% in patients with Kaposi's sarcoma (based on two studies), 12,2% in patients with Herpes Zoster (based on one study), 15,7% in patients with tuberculosis (based on 16 studies), 16,7% in patients with progressive multifocal leukoencephalopathy (based on two studies), 19,5% in patients with cryptococcal meningitis (based on six studies) and 37,7% in patients with cytomegalovirus retinitis (based on ten studies). In the same review IRIS de‐ veloped in 16,1% of unselected patients starting HAART and the incidence of IRIS associat‐ ed with tuberculosis and cryptococcal meningitis seemed to be lower in cohorts from low and middle income countries probably due to limited diagnostic capacity in these settings. The strength of this affirmation is supported by the evidence of an high incidence of IRIS associated uveitis in all settings: inflammatory reactions, even if moderate, are more likely to be recognized in the eye than in other organs [3].

protozoan as Leishmania species or a fungus as Cryptococcus neoformans granulomatous

The Downside of an Effective cART: The Immune Restoration Disease

http://dx.doi.org/10.5772/53352

355

*Price P et al* suggested a genetic predisposition and certain genes have been associated with an increased susceptibility to development of IRIS in presence of mycobacteria and herpes‐ viruses. The TNF α-308\*2 carried in linkage disequilibrium with HLA-A2,-B44,-DR4 and without BAT1 (intron 10)\*2 is more common in patients with herpesvirus-associated IRIS and is not present in any patients who has experienced mycobacterial IRIS. Therefore TNF α polymorphisms should be considered in the context of the adjacent MHC alleles. The ab‐ sence of C allele of IL6-174 together with TNF α - 308\*1 confers an increased relative risk for mycobacterial IRIS probably due to a limited TNF-mediated bactericidal activity and to a lower TNFα production in monocytes [29]. The CMV retinitis IRD patients have over 4 years on HAART progressively increased plasma levels of bioavailable IL-6 and of soluble CD30, a type 2 (T2) immune response marker and 92% of them result homozygous for IL12B-3'UTR\* 1 suggesting a dysregulation of the T1/T2 balance [30,31]. Th1 cells are charac‐ terized by the production of interferon γ and elicit proinflammatory responses. Th2 cells produce antiinflammatory and immunosuppressive cytokines (i.e. interleukin 10). [31,32 ]. These considerations suggest that IRIS could be sustained form several immunopathological mechanisms and that further studies need to better establish the role of cytokines in the dif‐

In addition to the reconstitution of immune cell numbers and function, redistribution of lymphocytes, defects in regulatory function, changes in Th cell profile are also involved [23]. Mycobacterial IRIS usually presents with suppuration of lympho nodes or other organ af‐ fected because of an activation of Th 17 lymphocytes inducing inflammation mediated by neutrophils [33]. Production of cytokines inducing cellular proliferation is the main mecha‐ nism of IRIS-Kaposi [34]. An unbalanced immune reconstitution of effector and regulatory T cells in patients receiving HAART has been noted. In particular, two types of T cells seem to take part to the development of the disease: the proinflammatory Th 17 lymphocytse and the T regulatory cells. The latter are implied in preventing collateral damage from exuberant inflammatory responses and may be defective in number and function during IRIS [1,2,23,31]. A role has been hypotized for NK cells by killer immunoglobulin-like receptors

Actually serological markers for IRIS diagnosis are lacking. Inflammatory markers, cyto‐ kines and chemokines are shown to be elevated in IRIS, specially IL 6. Paradoxical TB-IRIS has been associated with elevation of interleukin(IL) -4, IL -6, IL-7, IFN (interferon) γ and tumor necrosis factor alpha (TNF-α) and cryptococcal meningitis with increased pre-HAART levels of C reactive protein (CRP), IL-4 e IL-17 and lower levels of vascular endo‐ thelial growth factor (VEGF), granulocytes colony-stimulating factor (G-CSF) and TNF-α

To sum up, IRIS has been associated with certain human leucocyte antigen (HLA) profiles and regulatory cytokine genes polymorphisms but further research is needed to evaluate their potential role in identifying patients at risk, developing better therapeutics and moni‐

activity. Macrophages are inappropriately activated in IRIS-TB [1].

CD4 + - T helper cells type 1 inflammation predominates [1-3].

ferent forms of IRIS [31].

during clinical events [1,31,35].

toring response to therapy.

Risk factors for IRIS are difficult to establish because of the cohorts differ with regards to the study populations and the type of IRIS examined. Anyway, several risk factors for IRIS has been identified and, first of all, the presence of an opportunistic infection at the time of ini‐ tiation of HAART, specially for TB and cryptococcal diseases [1,2]. *Müller M et colleagues* re‐ ported an analysis stratified by median CD4+ T cells count at the beginning of HAART showing the different incidence of IRIS [Tab. 1, 3]. Male sex and younger age have been identified as significant predictors too [15,26].

Initiation of HAART soon after treatment for an opportunistic infection is considered a risk factor too [1-3,15].

A shorter interval between the treatment of an opportunistic infection and the initiation of HAART is associated with a higher risk of IRIS in these patients [1-3,15].

### **3. Pathogenesis**

The immunopathological process is still poorly understood but is strictly related with the provoking pathogen and with host. In fact, some people develop IRIS and others, with simi‐ lar clinical status and risk factors, do not. It remains unclear if the disease mechanisms asso‐ ciated with IRIS are the same for each OI or if there are microbial-driven specific immune responses that result in different pathologies for each pathogen [12]. Several studies using a simian immunodeficiency virus model indicate differential expression of viral peptides by distinct MHC alleles, which could influence the aggressiveness of the immune response di‐ rected toward SIV [27].

Essentially any pathogen that can cause an opportunistic infection in patients with impaired cellular immune responses can provoke IRIS. It also appears that HIV infection itself can cause IRIS [28]. Two patients were reported with HIV encephalitis after effective HAART. Neuropathological features consisted in massive CD8+/CD4- lymphocytes brain infiltration and in a diffuse microglial hyperplasia [28].

The antigenic stimulus in infectious conditions are either intact viable organism or dead or‐ ganism and their residual antigens whereas autoimmunity to innate antigens are involved in the non-infectious causes of the syndrome [1-3].

If the pathogen is viral, i.e. CMV or JC, CD8 + - T lymphocytes predominate in inflammatory cells infiltrates whereas if the pathogen is tuberculous or non tuberculous mycobacteria, a protozoan as Leishmania species or a fungus as Cryptococcus neoformans granulomatous CD4 + - T helper cells type 1 inflammation predominates [1-3].

patients with cytomegalovirus retinitis (based on ten studies). In the same review IRIS de‐ veloped in 16,1% of unselected patients starting HAART and the incidence of IRIS associat‐ ed with tuberculosis and cryptococcal meningitis seemed to be lower in cohorts from low and middle income countries probably due to limited diagnostic capacity in these settings. The strength of this affirmation is supported by the evidence of an high incidence of IRIS associated uveitis in all settings: inflammatory reactions, even if moderate, are more likely to

Risk factors for IRIS are difficult to establish because of the cohorts differ with regards to the study populations and the type of IRIS examined. Anyway, several risk factors for IRIS has been identified and, first of all, the presence of an opportunistic infection at the time of ini‐ tiation of HAART, specially for TB and cryptococcal diseases [1,2]. *Müller M et colleagues* re‐ ported an analysis stratified by median CD4+ T cells count at the beginning of HAART showing the different incidence of IRIS [Tab. 1, 3]. Male sex and younger age have been

Initiation of HAART soon after treatment for an opportunistic infection is considered a risk

A shorter interval between the treatment of an opportunistic infection and the initiation of

The immunopathological process is still poorly understood but is strictly related with the provoking pathogen and with host. In fact, some people develop IRIS and others, with simi‐ lar clinical status and risk factors, do not. It remains unclear if the disease mechanisms asso‐ ciated with IRIS are the same for each OI or if there are microbial-driven specific immune responses that result in different pathologies for each pathogen [12]. Several studies using a simian immunodeficiency virus model indicate differential expression of viral peptides by distinct MHC alleles, which could influence the aggressiveness of the immune response di‐

Essentially any pathogen that can cause an opportunistic infection in patients with impaired cellular immune responses can provoke IRIS. It also appears that HIV infection itself can cause IRIS [28]. Two patients were reported with HIV encephalitis after effective HAART. Neuropathological features consisted in massive CD8+/CD4- lymphocytes brain infiltration

The antigenic stimulus in infectious conditions are either intact viable organism or dead or‐ ganism and their residual antigens whereas autoimmunity to innate antigens are involved

If the pathogen is viral, i.e. CMV or JC, CD8 + - T lymphocytes predominate in inflammatory cells infiltrates whereas if the pathogen is tuberculous or non tuberculous mycobacteria, a

HAART is associated with a higher risk of IRIS in these patients [1-3,15].

be recognized in the eye than in other organs [3].

identified as significant predictors too [15,26].

factor too [1-3,15].

354 Current Perspectives in HIV Infection

**3. Pathogenesis**

rected toward SIV [27].

and in a diffuse microglial hyperplasia [28].

in the non-infectious causes of the syndrome [1-3].

*Price P et al* suggested a genetic predisposition and certain genes have been associated with an increased susceptibility to development of IRIS in presence of mycobacteria and herpes‐ viruses. The TNF α-308\*2 carried in linkage disequilibrium with HLA-A2,-B44,-DR4 and without BAT1 (intron 10)\*2 is more common in patients with herpesvirus-associated IRIS and is not present in any patients who has experienced mycobacterial IRIS. Therefore TNF α polymorphisms should be considered in the context of the adjacent MHC alleles. The ab‐ sence of C allele of IL6-174 together with TNF α - 308\*1 confers an increased relative risk for mycobacterial IRIS probably due to a limited TNF-mediated bactericidal activity and to a lower TNFα production in monocytes [29]. The CMV retinitis IRD patients have over 4 years on HAART progressively increased plasma levels of bioavailable IL-6 and of soluble CD30, a type 2 (T2) immune response marker and 92% of them result homozygous for IL12B-3'UTR\* 1 suggesting a dysregulation of the T1/T2 balance [30,31]. Th1 cells are charac‐ terized by the production of interferon γ and elicit proinflammatory responses. Th2 cells produce antiinflammatory and immunosuppressive cytokines (i.e. interleukin 10). [31,32 ]. These considerations suggest that IRIS could be sustained form several immunopathological mechanisms and that further studies need to better establish the role of cytokines in the dif‐ ferent forms of IRIS [31].

In addition to the reconstitution of immune cell numbers and function, redistribution of lymphocytes, defects in regulatory function, changes in Th cell profile are also involved [23]. Mycobacterial IRIS usually presents with suppuration of lympho nodes or other organ af‐ fected because of an activation of Th 17 lymphocytes inducing inflammation mediated by neutrophils [33]. Production of cytokines inducing cellular proliferation is the main mecha‐ nism of IRIS-Kaposi [34]. An unbalanced immune reconstitution of effector and regulatory T cells in patients receiving HAART has been noted. In particular, two types of T cells seem to take part to the development of the disease: the proinflammatory Th 17 lymphocytse and the T regulatory cells. The latter are implied in preventing collateral damage from exuberant inflammatory responses and may be defective in number and function during IRIS [1,2,23,31]. A role has been hypotized for NK cells by killer immunoglobulin-like receptors activity. Macrophages are inappropriately activated in IRIS-TB [1].

Actually serological markers for IRIS diagnosis are lacking. Inflammatory markers, cyto‐ kines and chemokines are shown to be elevated in IRIS, specially IL 6. Paradoxical TB-IRIS has been associated with elevation of interleukin(IL) -4, IL -6, IL-7, IFN (interferon) γ and tumor necrosis factor alpha (TNF-α) and cryptococcal meningitis with increased pre-HAART levels of C reactive protein (CRP), IL-4 e IL-17 and lower levels of vascular endo‐ thelial growth factor (VEGF), granulocytes colony-stimulating factor (G-CSF) and TNF-α during clinical events [1,31,35].

To sum up, IRIS has been associated with certain human leucocyte antigen (HLA) profiles and regulatory cytokine genes polymorphisms but further research is needed to evaluate their potential role in identifying patients at risk, developing better therapeutics and moni‐ toring response to therapy.

### **4. Clinical settings**

Lots of clinical manifestation have been described in occurring IRIS.

Several pathogens have been associated with IRIS, including JC virus, herpes viruses, BK vi‐ rus, Parvovirus B19, human T lymphotropic virus type 2, Epstein Barr virus, HHV 8, Cyto‐ megalovirus, Cryptococcus neoformans, Toxoplasma gondii. Mycobacterium tuberculosis, Mycobacterium leprae and Mycobacterium avium complex (MAC) contribute too [1-3,15]. The antigens driving IRIS often belong to opportunistic pathogens but sometimes IRIS can be a result of HIV- specific responses [1-3,15].

the presence of contrast enhancement suggest an inflammatory response and is indicative of PML-IRIS. The response to steroids confirms the diagnosis. The prognosis of delayed PML-

The Downside of an Effective cART: The Immune Restoration Disease

http://dx.doi.org/10.5772/53352

357

A stroke occurring after initiation of HAART can be due to a vasculitis in the context of a VZV-IRIS [51]. Genital ulceration related to Herpes Simplex virus and genital warts related to human papillomavirus are frequently observed [1]. Most commonly CMV is associated with CMV-IRIS retinitis, vitreitis and uveitis with loss of visual acuity and floaters [1, 52].

Cryptococcus neoformans is frequently involved in IRIS development. It can provoke a CNS associated IRIS and a non-CNS IRIS: the first results in an aseptic recurrence of meningitis or rarely in a cryptococcoma; the second is more common and is a lymphoadenitis or a media‐ stinitis or rarely a cavitary pneumonia. In a patient with cryptococcal meningitis rapidly worsening because of headache, nausea and vomiting after HAART initiation IRIS has to be considered above all in presence of sterile inflammation of the CSF, residual cryptococcal antigens and absence of viable yeast on culture. Patients with Cryptococcus neoformans as‐ sociated IRIS has usually higher opening pressure, white cell count and glucose levels than patients with Cryptococcus neoformans infection only. Neuroimaging is usually not useful in cryptococcal meningitis diagnosis but in occurring IRIS evidence of meningeal or choroid plexus enhancement or linear perivascular enhancement in the sulci at CT scan is frequent and represent a sign of inflammation [54-57]. Patients with cryptococcal meningitis particu‐ larly with IRIS are likely to develop a communicating idrocephalus due to blockage of CSF absorption at the arachnoid villi by cryptococcal antigens and by the inflammatory cells. This is a serious condition that may require drainage by repeated lumbar punctures [48].

There is only a case report of immune reconstitution syndrome occurring in a patient with Candida meningitis in the literature and a case report of visual loss and detection of EBV in CSF by PCR after initiation of HAART [12, 58]. In few cases Toxoplasma gondi is the re‐

Some patients may develop a severe progressive encephalitis after initiation of HAART with seizures, altered mental status, coma and death. HIV may be detectable in CSF even when results undetectable in blood. MRI can show diffuse multifocal white matter changes with

Given the known associations of Kaposi's sarcoma with human herpesvirus 8 and non Hodgkin lymphoma with Epstein Barr virus it is not surprising to observe these cancers oc‐ curring or worsening in the context of IRIS [12,60-63]. Both clinical sudden progression of established lesions and new Kaposi sarcoma have been described after HAART initiation [12, 60-62]. HIV-infected patients starting HAART may present manifestations of autoim‐ mune disease like most frequently sarcoidosis and Graves disease but also systemic lupus erythematosus, rheumatoid arthritis, Reiter's syndrome, polymyositis and Guillain-Barrè syndrome [1-3, 64-70]. At last, high levels of CNS inflammation have been demonstrated in the hippocampus of patients successfully treated with HAART and IRIS could contribute to

pathogenetic mechanism leading to a cognitive impairment [12].

IRIS is worse than the form that begins simultaneously [49,50].

CMV ventriculitis without retinal damage has been described [53].

sponsible agent of CNS-IRIS [59].

associated cerebral edema [12,28].

TB-IRIS manifestations include worsening respiratory symptoms, fever, lymphonode en‐ largement and suppuration, appearance of new infiltrates and mediastinal lymphoadenop‐ athy on chest radiograph, visceral or cutaneous abscesses, pleural and pericardial effusion and rarely intracranial tubercoloma, acute renal failure, meningitis and cognitive impair‐ ment. Moreover abdominal TB-IRIS can present with non-specific abdominal pain and ob‐ structive jaundice. Differential diagnosis from drug-resistant tuberculosis is difficult [15,36-39]. MAC remains the most reported atypical mycobacterium and the most common manifestation in MAC-IRIS is fever with suppurative painful lymphadenitis followed by pulmonary disease but involvement of joints, spine, skin and soft tissue has also been re‐ ported. In contrast to disseminated MAC disease of advanced AIDS, MAC-IRIS usually presents as localized disease [40]. Mycobacterial IRIS has to be distinguished from sarcoido‐ sis that can also occur in the context of IRIS [1]. Measurement of a delayed-type hypersensi‐ tivity response to tuberculin by a skin test may help to differentiate immune reconstitutionassociated sarcoidosis from mycobacterial IRIS, because a response is absent in patients with sarcoidosis but is often present in patients with mycobacterial IRIS [1,2,7, 41,42].

Patients with Pneumocystis jirovecii IRIS manifest recurrence of fever, worsening hypoxia and fresh pulmonary infiltrates on chest radiograph. In addition to the general risk factors, PaO2 < 70 mmHg and a recent completion of steroid therapy for Pneumocystis jirovecii pneumonia promote IRIS [1, 43,44].

CNS-IRIS occurs at much lower frequencies with about 0,9-1,5% of patients developing some CNS-IRIS after initiating HAART [45-47]. The heightened immune response in a rela‐ tively closed space leads to raised intracranial pressure, with potentially irreversible dam‐ age. Diagnosis of CNS-IRIS is difficult because CNS is a region of limited access and requires pathological confirmation and invasive procedures. A worsening of clinical neuro‐ logical status can be accompanied by new neuroradiological findings or by deterioration of previous findings with T cell infiltrates into the CNS. Depending on the severity of CNS-IRIS it may be classified as asymptomatic, symptomatic and catastrophic. Asymptomatic CNS-IRIS consists in radiological changes only, such as increased enhancement. Sympto‐ matic CNS-IRIS is characterized by clinical deterioration in neurological function with new changes on MRI scan of brain. In the catastrophic CNS-IRIS severe neurological deficits oc‐ cur such as coma and imminent signs of cerebral herniation [12, 45-48]. JC virus is the causa‐ tive agent of PML and one of the most devastating of the OIs associated with IRIS leading to a 42% mortality. Of the approximate 5% of HIV + patients who develop PML up to 19% are PML-IRIS patients. Differential diagnosis between PML and PML-IRIS can be done by MRI: the presence of contrast enhancement suggest an inflammatory response and is indicative of PML-IRIS. The response to steroids confirms the diagnosis. The prognosis of delayed PML-IRIS is worse than the form that begins simultaneously [49,50].

**4. Clinical settings**

356 Current Perspectives in HIV Infection

Lots of clinical manifestation have been described in occurring IRIS.

be a result of HIV- specific responses [1-3,15].

pneumonia promote IRIS [1, 43,44].

Several pathogens have been associated with IRIS, including JC virus, herpes viruses, BK vi‐ rus, Parvovirus B19, human T lymphotropic virus type 2, Epstein Barr virus, HHV 8, Cyto‐ megalovirus, Cryptococcus neoformans, Toxoplasma gondii. Mycobacterium tuberculosis, Mycobacterium leprae and Mycobacterium avium complex (MAC) contribute too [1-3,15]. The antigens driving IRIS often belong to opportunistic pathogens but sometimes IRIS can

TB-IRIS manifestations include worsening respiratory symptoms, fever, lymphonode en‐ largement and suppuration, appearance of new infiltrates and mediastinal lymphoadenop‐ athy on chest radiograph, visceral or cutaneous abscesses, pleural and pericardial effusion and rarely intracranial tubercoloma, acute renal failure, meningitis and cognitive impair‐ ment. Moreover abdominal TB-IRIS can present with non-specific abdominal pain and ob‐ structive jaundice. Differential diagnosis from drug-resistant tuberculosis is difficult [15,36-39]. MAC remains the most reported atypical mycobacterium and the most common manifestation in MAC-IRIS is fever with suppurative painful lymphadenitis followed by pulmonary disease but involvement of joints, spine, skin and soft tissue has also been re‐ ported. In contrast to disseminated MAC disease of advanced AIDS, MAC-IRIS usually presents as localized disease [40]. Mycobacterial IRIS has to be distinguished from sarcoido‐ sis that can also occur in the context of IRIS [1]. Measurement of a delayed-type hypersensi‐ tivity response to tuberculin by a skin test may help to differentiate immune reconstitutionassociated sarcoidosis from mycobacterial IRIS, because a response is absent in patients with

sarcoidosis but is often present in patients with mycobacterial IRIS [1,2,7, 41,42].

Patients with Pneumocystis jirovecii IRIS manifest recurrence of fever, worsening hypoxia and fresh pulmonary infiltrates on chest radiograph. In addition to the general risk factors, PaO2 < 70 mmHg and a recent completion of steroid therapy for Pneumocystis jirovecii

CNS-IRIS occurs at much lower frequencies with about 0,9-1,5% of patients developing some CNS-IRIS after initiating HAART [45-47]. The heightened immune response in a rela‐ tively closed space leads to raised intracranial pressure, with potentially irreversible dam‐ age. Diagnosis of CNS-IRIS is difficult because CNS is a region of limited access and requires pathological confirmation and invasive procedures. A worsening of clinical neuro‐ logical status can be accompanied by new neuroradiological findings or by deterioration of previous findings with T cell infiltrates into the CNS. Depending on the severity of CNS-IRIS it may be classified as asymptomatic, symptomatic and catastrophic. Asymptomatic CNS-IRIS consists in radiological changes only, such as increased enhancement. Sympto‐ matic CNS-IRIS is characterized by clinical deterioration in neurological function with new changes on MRI scan of brain. In the catastrophic CNS-IRIS severe neurological deficits oc‐ cur such as coma and imminent signs of cerebral herniation [12, 45-48]. JC virus is the causa‐ tive agent of PML and one of the most devastating of the OIs associated with IRIS leading to a 42% mortality. Of the approximate 5% of HIV + patients who develop PML up to 19% are PML-IRIS patients. Differential diagnosis between PML and PML-IRIS can be done by MRI: A stroke occurring after initiation of HAART can be due to a vasculitis in the context of a VZV-IRIS [51]. Genital ulceration related to Herpes Simplex virus and genital warts related to human papillomavirus are frequently observed [1]. Most commonly CMV is associated with CMV-IRIS retinitis, vitreitis and uveitis with loss of visual acuity and floaters [1, 52]. CMV ventriculitis without retinal damage has been described [53].

Cryptococcus neoformans is frequently involved in IRIS development. It can provoke a CNS associated IRIS and a non-CNS IRIS: the first results in an aseptic recurrence of meningitis or rarely in a cryptococcoma; the second is more common and is a lymphoadenitis or a media‐ stinitis or rarely a cavitary pneumonia. In a patient with cryptococcal meningitis rapidly worsening because of headache, nausea and vomiting after HAART initiation IRIS has to be considered above all in presence of sterile inflammation of the CSF, residual cryptococcal antigens and absence of viable yeast on culture. Patients with Cryptococcus neoformans as‐ sociated IRIS has usually higher opening pressure, white cell count and glucose levels than patients with Cryptococcus neoformans infection only. Neuroimaging is usually not useful in cryptococcal meningitis diagnosis but in occurring IRIS evidence of meningeal or choroid plexus enhancement or linear perivascular enhancement in the sulci at CT scan is frequent and represent a sign of inflammation [54-57]. Patients with cryptococcal meningitis particu‐ larly with IRIS are likely to develop a communicating idrocephalus due to blockage of CSF absorption at the arachnoid villi by cryptococcal antigens and by the inflammatory cells. This is a serious condition that may require drainage by repeated lumbar punctures [48].

There is only a case report of immune reconstitution syndrome occurring in a patient with Candida meningitis in the literature and a case report of visual loss and detection of EBV in CSF by PCR after initiation of HAART [12, 58]. In few cases Toxoplasma gondi is the re‐ sponsible agent of CNS-IRIS [59].

Some patients may develop a severe progressive encephalitis after initiation of HAART with seizures, altered mental status, coma and death. HIV may be detectable in CSF even when results undetectable in blood. MRI can show diffuse multifocal white matter changes with associated cerebral edema [12,28].

Given the known associations of Kaposi's sarcoma with human herpesvirus 8 and non Hodgkin lymphoma with Epstein Barr virus it is not surprising to observe these cancers oc‐ curring or worsening in the context of IRIS [12,60-63]. Both clinical sudden progression of established lesions and new Kaposi sarcoma have been described after HAART initiation [12, 60-62]. HIV-infected patients starting HAART may present manifestations of autoim‐ mune disease like most frequently sarcoidosis and Graves disease but also systemic lupus erythematosus, rheumatoid arthritis, Reiter's syndrome, polymyositis and Guillain-Barrè syndrome [1-3, 64-70]. At last, high levels of CNS inflammation have been demonstrated in the hippocampus of patients successfully treated with HAART and IRIS could contribute to pathogenetic mechanism leading to a cognitive impairment [12].

### **5. Treatment and prevention**

Till now, on the grounds of available data, it appears prudent that HAART should be initiat‐ ed before the onset of severe immunodeficiency. A detailed evaluation should be done for identification of opportunistic infections before HAART initiation. Patients with high risk features for the development of IRIS should be identified and OIs should be optimally treat‐ ed if present [1-3, 71-73]. In the context of opportunistic infections, the benefit of reducing the likelihood of IRIS by deferring HAART must be balanced with the risk of delaying HAART, above all if patients are severely immunodeficient. The ACTG 5164 is a random‐ ized trial comparing immediate versus deferred antiretroviral therapy initiation in patients presenting with acute OIs. Significant reduction in clinical progression or death among pa‐ tients who received antiretroviral therapy within 14 days of presenting with acute OI versus those who deferred antiretroviral therapy until after OI had been treated was found and the incidence of immune reconstitution events resulted similar between groups [73].

**6. Conclusions**

strategies could be improved.

**Author details**

spro, Palermo, Italy

**References**

Claudia Colomba and Raffaella Rubino

\*Address all correspondence to: claudia.colomba@libero.it

dian J Med Res 2011; 134: 866-877.

fect Dis 2009; 48: 101-107.

The majority of patients with IRIS have a self-limiting disease course but associated morbid‐ ity places a considerable burden on the health care system. Morbidity and mortality rates vary according to the pathogen and organ involved. Mortality is usually uncommon with the exception of the setting of opportunistic infections involving the CNS [1]. Lethality rang‐ es from about 3% in patients with tuberculosis to more than 20% in patients with cryptococ‐ cal meningitis, with an higher early mortality in resource-limited settings due to probable underdiagnoses [3]. The occurrence of IRIS and its contribution to mortality in a given set‐ ting is affected by the relative importance of different infections, the degree of access to fa‐ cilities for diagnosis of such illnesses and the extent of screening for and treatment of opportunistic infections before starting HAART [80].Research efforts should be focused on increasing knowledge about IRIS so that diagnostic tests and prevention and treatment

IRIS-TB 20,7% 17,7%

IRIS- CMV retinitis 37,7% No studies

IRIS-cryptococcal meningitis 28,3% 2%

Dipartimento di Scienze per la Promozione della Salute, Università di Palermo, Via del Ve‐

[1] Surendra KS et al. HIV & immune reconstitution inflammatory syndrome (IRIS). In‐

[2] French MA. Immune reconstitution inflammatory syndrome: a reappraisal. Clin In‐

**Table 1.** Development of IRIS in analysis stratified by median CD4+ cells count at the start of HAART [3]

**CD4 < 50 μl CD4 > 50 μl**

The Downside of an Effective cART: The Immune Restoration Disease

http://dx.doi.org/10.5772/53352

359

To date, literature is lacking about the optimal time of HAART initiation following a treat‐ ment of opportunistic infections with exception of tuberculosis/HIV coinfection. Regarding this concern the most recent WHO and DHHS guidelines recommend the initiation of HAART between 2 and 8 weeks after starting treatment against tuberculosis for patients with a CD4 count < 200/µl [71,72].

Actually management of patients with IRIS was founded upon clinical observations and ex‐ pert opinions only. In general non steroidal anti-inflammatory drugs should be reserved for milder manifestations and steroids for cases with severe inflammation. Interruption of HAART is rarely necessary but could be considered in life threatening situations or when pathogens involved are not controllable by specific antimicrobial therapy, as JC virus [15]. Stopping HAART may improve symptoms but there is no guarantee that the condition will not recur once HAART is resumed [74]. In a randomized controlled trial, *Meintjes G et al* reported the utility of prednisolone (1.5 mg/kg per day for two weeks followed by 0.75 mg/kg per day for further two weeks) in the treatment of paradoxical tuberculosis-IRIS with worsening chest radiograph, enlarging lymph node, serous effusion and cold abscess, CNS manifestations, tracheal compression due to lymphadenopathy and acute respiratory dis‐ tress syndrome (ARDS). For atypical mycobacterial – IRIS treatment is similar to TB-IRIS. Surgical excision of profoundly enlarged nodes or debridement of necrotic areas is anecdo‐ tally reported [75,76]. Cryptococcal meningoencephalitis IRIS requires prompt control of raised intracranial pressure and hydrocephalus by serial lumbar punctures. Corticosteroids are indicated for cerebral oedema and ARDS in pulmonary cryptococcosis [48,77-78]. The development of PCP-IRIS after discontinuation of steroid therapy suggest a role for the rein‐ troduction of steroids in these patients [44]. In cases of ocular CMV-IRIS systemic or perioc‐ ular steroid injections have been used bur a clear benefit has not been demonstrated. The role of corticosteroids in PML-IRIS is not clear and a long term treatment may be necessary until T memory cells and a more directed immune response against JC virus predominates [50,79]. Unfortunately increased risk of progression of herpes zoster and Kaposi's sarcoma and reactivation of latent infections have also been reported with corticosteroids.

### **6. Conclusions**

**5. Treatment and prevention**

358 Current Perspectives in HIV Infection

with a CD4 count < 200/µl [71,72].

Till now, on the grounds of available data, it appears prudent that HAART should be initiat‐ ed before the onset of severe immunodeficiency. A detailed evaluation should be done for identification of opportunistic infections before HAART initiation. Patients with high risk features for the development of IRIS should be identified and OIs should be optimally treat‐ ed if present [1-3, 71-73]. In the context of opportunistic infections, the benefit of reducing the likelihood of IRIS by deferring HAART must be balanced with the risk of delaying HAART, above all if patients are severely immunodeficient. The ACTG 5164 is a random‐ ized trial comparing immediate versus deferred antiretroviral therapy initiation in patients presenting with acute OIs. Significant reduction in clinical progression or death among pa‐ tients who received antiretroviral therapy within 14 days of presenting with acute OI versus those who deferred antiretroviral therapy until after OI had been treated was found and the

incidence of immune reconstitution events resulted similar between groups [73].

and reactivation of latent infections have also been reported with corticosteroids.

To date, literature is lacking about the optimal time of HAART initiation following a treat‐ ment of opportunistic infections with exception of tuberculosis/HIV coinfection. Regarding this concern the most recent WHO and DHHS guidelines recommend the initiation of HAART between 2 and 8 weeks after starting treatment against tuberculosis for patients

Actually management of patients with IRIS was founded upon clinical observations and ex‐ pert opinions only. In general non steroidal anti-inflammatory drugs should be reserved for milder manifestations and steroids for cases with severe inflammation. Interruption of HAART is rarely necessary but could be considered in life threatening situations or when pathogens involved are not controllable by specific antimicrobial therapy, as JC virus [15]. Stopping HAART may improve symptoms but there is no guarantee that the condition will not recur once HAART is resumed [74]. In a randomized controlled trial, *Meintjes G et al* reported the utility of prednisolone (1.5 mg/kg per day for two weeks followed by 0.75 mg/kg per day for further two weeks) in the treatment of paradoxical tuberculosis-IRIS with worsening chest radiograph, enlarging lymph node, serous effusion and cold abscess, CNS manifestations, tracheal compression due to lymphadenopathy and acute respiratory dis‐ tress syndrome (ARDS). For atypical mycobacterial – IRIS treatment is similar to TB-IRIS. Surgical excision of profoundly enlarged nodes or debridement of necrotic areas is anecdo‐ tally reported [75,76]. Cryptococcal meningoencephalitis IRIS requires prompt control of raised intracranial pressure and hydrocephalus by serial lumbar punctures. Corticosteroids are indicated for cerebral oedema and ARDS in pulmonary cryptococcosis [48,77-78]. The development of PCP-IRIS after discontinuation of steroid therapy suggest a role for the rein‐ troduction of steroids in these patients [44]. In cases of ocular CMV-IRIS systemic or perioc‐ ular steroid injections have been used bur a clear benefit has not been demonstrated. The role of corticosteroids in PML-IRIS is not clear and a long term treatment may be necessary until T memory cells and a more directed immune response against JC virus predominates [50,79]. Unfortunately increased risk of progression of herpes zoster and Kaposi's sarcoma

The majority of patients with IRIS have a self-limiting disease course but associated morbid‐ ity places a considerable burden on the health care system. Morbidity and mortality rates vary according to the pathogen and organ involved. Mortality is usually uncommon with the exception of the setting of opportunistic infections involving the CNS [1]. Lethality rang‐ es from about 3% in patients with tuberculosis to more than 20% in patients with cryptococ‐ cal meningitis, with an higher early mortality in resource-limited settings due to probable underdiagnoses [3]. The occurrence of IRIS and its contribution to mortality in a given set‐ ting is affected by the relative importance of different infections, the degree of access to fa‐ cilities for diagnosis of such illnesses and the extent of screening for and treatment of opportunistic infections before starting HAART [80].Research efforts should be focused on increasing knowledge about IRIS so that diagnostic tests and prevention and treatment strategies could be improved.


**Table 1.** Development of IRIS in analysis stratified by median CD4+ cells count at the start of HAART [3]

### **Author details**

Claudia Colomba and Raffaella Rubino

\*Address all correspondence to: claudia.colomba@libero.it

Dipartimento di Scienze per la Promozione della Salute, Università di Palermo, Via del Ve‐ spro, Palermo, Italy

### **References**


[3] Müller M et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lan‐ cet Infect Dis 2010; 10: 251-261.

[16] Hirsch HH et al. Immune Reconstitution in HIV-infected patients. Clin Infect Dis

The Downside of an Effective cART: The Immune Restoration Disease

http://dx.doi.org/10.5772/53352

361

[17] Bucy RP et al. Initial increase in blood CD4(+) lymphocytes after HIVantiretroviral therapy reflects redistribution from lymphoid tissues. J Clin Invest 1999; 103:

[18] Pakker NG et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation. Nat Med

[19] Kauffmann GR et al.CD4-T lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV Co‐

[20] Battegay M et al. Immunological recovery and antiretroviral therapy in HIV-1 infec‐

[21] Guadalupe M et al. Severe CD4 + T cell depletivo in gut lypmphoid tissue during pri‐ mary human immunodeficiency virus type 1 infection and substantial delay in resto‐ ration following highly active antiretroviral therapy. J Virol 2003; 77: 11708-11717. [22] Berard M et al. Qualitative differences between naïve and memory T cells. Immunol‐

[23] Seddiki N et al. Proliferation of weakly suppressive regulatory CD4 + T - cells is asso‐ ciated with over-active CD4 + T – cell responses in HIV-positive patients with myco‐

[25] Crowe SM et al. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV infected persons. J Acquir Im‐

[26] Ratnam I et al. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1 infected cohort. Clin Infect Dis 2006;

[27] Mankowski JL et al. Natural host genetic resistance to lentiviral CNS disease: a neu‐ roprotective MHC class I allele in SIV-infected macaques. PLoS ONE 2008; 3: e3603.

[28] Miller RF et al. CD8 + lymphocytosis in HIV-1 infected patients with immune resto‐

[29] Price P et al. Polymorphisms in cytokine genes define subpopulations of HIV-1 pa‐ tients who experienced immune restoration diseases. AIDS 2002; 16: 2043-2047. [30] Stone SF et al. Cytomegalovirus (CMV) retinitis immune restoration disease occurs during HAART- induced restoration of a CMV specific immune responses within a

predominant Th2 cytokine environment. J Infect Dis 2002; 185 (12): 1813-1817.

ration induced by HAART. Acta Neuropathol 2004; 108 (1): 17-23.

bacterial immune restoration disease. Eur J Immunol 2009; 39: 391-402.

[24] Soriano V et al. Antiretroviral drugs and liver injury. AIDS 2008; 22: 1-13.

hort Study. Arch Intern Med 2003; 163: 2187-2195.

tion. Lancet Infect Dis 2006; 6: 280-287.

mune Defic Syndr 1991; 4: 770-776.

2004; 38: 1159-1166.

1391-1398.

1998; 4: 208-214.

ogy 2002; 106: 127-138.

42(3): 418-427.


[16] Hirsch HH et al. Immune Reconstitution in HIV-infected patients. Clin Infect Dis 2004; 38: 1159-1166.

[3] Müller M et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lan‐

[4] The Antiretroviral Therapy in Lower Income Countries (ART-LINC) Collaboration and ART Cohort Collaboration (ART-CC) groups. Mortality of HIV-1-infected pa‐ tients in the first year of antiretroviral therapy: comparison between low-income and

[5] Keiser O et al. Antiretroviral therapy in resource limited settings 1996-2006: patients characteristics, treatment regimens and monitoring in Sub-saharan Africa, Asia and

[6] French MA et al. Zidovudine – induced restoration of cell mediated immunity to my‐ cobacteria in immunodeficient HIV- infected patients. AIDS 1992; 6: 1293-1297.

[7] French et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000; 1:

[8] Shelburne ISA et al. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine 2002; 81:

[9] French MA et al. Immune restoration disease after antiretroviral therapy. AIDS 2004;

[10] Robertson J et al. Immune reconstitution syndrome in HIV: validating a case defini‐ tion and identifying clinical predictors in person initiating antiretroviral therapy.

[11] Meintjes G et al. Tuberculosis associated immune reconstitution inflammatory syn‐ drome: case definition for use in resource limited settings. Lancet Infect Dis 2008; 8:

[12] Johnson T et al. Neurological complications of immune reconstitutio in HIV-infected

[13] Philips P et al. Non tuberculous mycobacteria immune reconstitution syndrome in HIV- infected patients: spectrum of disease and long-term follow up. Clin Infect Dis

[14] Lawn SD et al. Immune reconstitution disease associated with mycobacterial infec‐ tions in HIV- infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5:

[15] Murdoch DM et al. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Research and Thera‐

cet Infect Dis 2010; 10: 251-261.

107-115.

360 Current Perspectives in HIV Infection

213-217.

516-523.

361-373.

py 2007; 4:9.

2005; 41: 1483-97.

18: 1615-27.

Clin Infect Dis 2006; 42: 1639-1646.

populations. Ann N Y Acad Sci 2010; 1184: 106-120.

high-income countries. Lancet 2006; 367: 817-824.

Latin America. Trop Med Int Health 2008; 13: 870-879.


[31] Kestens L et al. Immunopathogenesis of the immune reconstitution disease in HIV patients responding to antiretroviral therapy. Curr Opinion HIV AIDS 2008; 3: 419-424.

[46] Torok ME et al. Immune reconstitution disease of the central nervous system. Curr

The Downside of an Effective cART: The Immune Restoration Disease

http://dx.doi.org/10.5772/53352

363

[47] Gray F et al. Central nervous system immune reconstitution disease in acquired im‐ munodeficiency syndrome patients receiving highly active antiretroviral treatment. J

[48] Venkataramana A et al. Immune reconstitution inflammatory syndrome in the CNS

[49] Wyen C et al. Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death. J Acquir Immune Defic

[50] Tan K et al. PML-IRIS in patients with HIV infection. Clinical manifestation and

[51] Newsome SD et al. Varicella-zoster virus vasculopathy and central nervous system immune reconstitution inflammatory syndrome with human immunodeficiency vi‐

[52] Jacobson MA et al. Cytomegalovirus retinitis after initiation of highly active antire‐

[53] Janowicz DM et al. Successful treatment of CMV ventriculitis immune reconstitution

[54] Bicanic T et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009; 51:

[56] York J et al. Raised intracranial pressure complicating cryptococcal meningitis: im‐ mune reconstitution inflammatory syndrome or recurrent cryptococcal disease? J In‐

[57] Boelaert JR et al. Relapsing meningitis caused by persistent cryptococcal antigens and immune reconstitution after the initiation of highly active antiretroviral therapy.

[58] Berkeley JL et al. Fatal immune reconstitution inflammatory syndrome with human immunodeficiency virus infection and Candida meningitis: case report and review of

[59] Tsambiras PE et al. Case report. Toxoplasma encephalitis after initiation of HAART.

[60] Connick E et al. Immune reconstitution inflammatory syndrome associated with Ka‐ posi sarcoma during potent antiretroviral therapy. Clin Infect Dis 2004; 39: 1852-1855.

[55] Jarvis JN et al. HIV-associated cryptococcal meningitis. AIDS 2007; 21: 2119-2129.

of HIV- infected patients. Neurology 2006; 67: 383-388.

treatment with steroids. Neurology 2009; 72: 1458-1464.

troviral therapy. Lancet 1997; 349 (9063): 1443-1445.

rus infection treated with steroids. J neurovirol 2009; 15: 288-291.

syndrome. J Neurol Neurosurg Psychiatry 2005; 76: 891-892.

Opin HIV AIDS 2008; 438-445.

Neurovirol 2005; 11 (3): 16-22.

Syndr 2004; 37: 1263-1268.

130-134.

fect 2005; 51: 165-171.

AIDS 2004; 18: 1223-1224.

literature. J neurovirol 2008; 14: 267-176.

AIDS Read 2001; 11: 608-610, 615-616.


[46] Torok ME et al. Immune reconstitution disease of the central nervous system. Curr Opin HIV AIDS 2008; 438-445.

[31] Kestens L et al. Immunopathogenesis of the immune reconstitution disease in HIV patients responding to antiretroviral therapy. Curr Opinion HIV AIDS 2008; 3:

[32] Singh N et al. Immune reconstitution syndrome associated with opportunistic myco‐

[33] French MA. The immunopathogenesis of mycobacterial immune restoration disease.

[34] Tamburini J et al. Cytokine pattern in Kaposi's sarcoma associated with immune re‐ storation disease in HIV and tuberculosis co-infected patients. AIDS 2007; 21:

[35] Stone SF et al. Plasma bioavailable interleukin-6 is elevated in human immunodefi‐ ciency virus infected patients who experience herpesvirus associated immune resto‐ ration disease after start of highly active antiretroviral therapy. J Inf Dis 2001;

[36] Lawn SD et al. Immune reconstitution disease associated with mycobacterial infec‐ tions in HIV- infected individuals receiving antiretrovirals. Lancet Infect Dis 2005;

[37] Jehle AW et al. Acute renal failure on immune reconstitution in an HIV-positive pa‐

[38] Narita M et al. Paradoxical worsening of tuberculosis following antiretroviral thera‐

[39] Vidal JE et al. Paradoxical reaction during treatment of tuberculous brain abscess in a

[40] Philip P et al. Non tuberculous mycobacterial immune reconstitution syndrome in HIV- infected patients: spectrum of the disease and long-term follow up. Clin Infect

[41] Haramati LB et al. Newly diagnosed pulmonary sarcoidosis in HIV-infected patients.

[42] Foulon G et al. Sarcoidosis in HIV-infected patients in the era of highly active antire‐

[43] Wislez M et al. Acute respiratory failure following HAART introduction in patient treated for Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 2001; 164:

[44] Jagannathan P et al. Life-threatening immune reconstitution inflammatory syndrome after Pneumocystis pneumonia: a cautionary case series. AIDS 2009; 23: 1794-1796. [45] McCombe JA et al. Neurologic immune reconstitution inflammatory syndrome in

HIV/AIDS: outcome and epidemiology. Neurology 2009; 72: 835-841.

py in patients with AIDS. Am J Respir Crit Care Med 1998; 158: 157-161.

patient with AIDS. Rev Inst Med Trop Sao Paulo 2003; 45(3): 177-178.

tient with miliary tuberculosis. Clin Infect Dis 2004; 38(4): e32-35.

419-424.

362 Current Perspectives in HIV Infection

1980-1983.

184:1073–1077.

5(6): 361-373.

Dis 2005; 41: 1483-97.

847-851.

Radiology 2001; 218: 242-246.

troviral therapy. Clin Infect Dis 2004; 38: 418-425.

ses. Lancet Infect Dis 2007; 7: 395-401.

Lancet Infect Dis 2006; 6: 461-2.


[61] Leidner RS et al. Recrudescent Kaposi's sarcoma after initiation of HAART: a mani‐ festation of immune reconstitution syndrome. AIDS Patient Care STDs 2005; 19: 635-644.

[76] Aberg JA et al. Localized osteomyelitis due to Mycobacterium avium complex in pa‐ tient with human immunodeficiency virus receiving highly active antiretroviral ther‐

The Downside of an Effective cART: The Immune Restoration Disease

http://dx.doi.org/10.5772/53352

365

[77] Perfect JR et al. Clinical practice guidelines for the management of cryptococcal dis‐ ease: 2010 update by the infectious diseases society of America. Clin Infect Dis 2010.

[78] McComsey GA et al. Placebo-controlled trial of prednisone in advanced HIV-1 infec‐

[79] Du Pasquier RA et al. Inflammatory reaction in progressive multifocal leukencephal‐

[80] Davies MA et al. Assessing the contribution of the immune reconstitution inflamma‐ tory syndrome to mortality in developing country antiretroviral therapy programs.

opathy: harmful or beneficial?. J Neurovirol 2003; 9 (1): 25-31.

apy. Clin Infect Dis 2002; 35 (1): e 8-13.

tion. AIDS 2001; 15: 321-327.

Clin Infect Dis 2009; 49:973-975.

50: 291-322.


[76] Aberg JA et al. Localized osteomyelitis due to Mycobacterium avium complex in pa‐ tient with human immunodeficiency virus receiving highly active antiretroviral ther‐ apy. Clin Infect Dis 2002; 35 (1): e 8-13.

[61] Leidner RS et al. Recrudescent Kaposi's sarcoma after initiation of HAART: a mani‐ festation of immune reconstitution syndrome. AIDS Patient Care STDs 2005; 19:

[62] Bower M et al. Immune reconstitution inflammatory syndrome associated with Ka‐

[63] Jaffe HW et al. Immune reconstitution and risk of Kaposi sarcoma and non-Hodgk‐

[64] Crum NF et al. Graves disease: an increasingly recognized immune reconstitution

[65] Knysz B et al. Graves' disease as an immune reconstitution syndrome in an HIV-1 positive patient commencing effective antiretroviral therapy: case report and review

[66] Vos F et al. Graves' disease during immune reconstitution in HIV infected patients

[67] Calza L et al. Systemic and discoid lupus erythematosus in HIV-infected patients treated with highly active antiretroviral therapy. Int J STD AIDS 2003; 14: 356-359. [68] Bell C et al. A case of immune reconstitution rheumatoid arthritis. Int J STD AIDS

[69] Piliero PJ et al. Guillain-Barrè syndrome associated with immune reconstitution. Clin

[70] Neuman S et al. Reiter's syndrome as manifestation of immune reconstitution syn‐ drome in an HIV infected patient: successful treatment with doxycycline. Cli Infect

[71] Panel on Antiretroviral Guidelines for the Use of Antiretroviral Agents in HIV-1 in‐ fected Adults and Adolescents. Department of Health and Human Services. March

[72] Center for Disease Control and Prevention. Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-1 Infected Adults and Adolescents. MMWR 2009.

[73] Zolopa A et al. Immediate vs deferred ART in the setting of acute AIDS-related op‐ portunistic infection: final results of a randomized strategy trial. ACTG A5164. Pro‐ gram and abstracts of the 15th Conference on Retroviruses and Opportunistic

[74] Lipman M et al. Immune reconstitution inflammatory syndrome in HIV. Curr Opin

[75] Lawn SD et al. Pyomyositis and cutaneous abscesses due to Mycobacterium avium: an immune reconstitution manifestation in a patient with AIDS. Clin Infect Dis 2004;

ing lymphoma in HIV-infected adults. AIDS 2011; 25: 1395-1403.

posi's sarcoma. J Clin Oncol 2005; 23: 5224-5228.

of literature. Viral Immunol 2006; 19: 102-107.

treated with HAART. Scand J Infect Dis 2006; 38: 124-126.

Infections 2008; Boston, Massachusetts. Abstract 142.

syndrome. AIDS 2006; 20: 466-469.

2002; 13: 580-581.

Infect Dis 2003; 36: e 111-114.

Dis 2003; 36: 1628-1629.

Infect Dis 2006; 19: 20-25.

38 (3): 461-463.

2012.

635-644.

364 Current Perspectives in HIV Infection


**Chapter 16**

**HIV Infection and Viral Hepatitis in Drug Abusers**

The epidemiology of HIV infection and viral hepatitis among injection drug users (IDUs) is changing in western countries; reductions in the epidemic of blood-borne infections, such as HIV infection, and viral hepatitis among drug users are probably related to the generaliza‐ tion of harm-reduction interventions and to the treatment of both HIV/AIDS and substance abuse. Opioid substitution therapy for the treatment of patients with heroin dependence, needle exchange programmes, access to Highly Active Antiretroviral Therapy (HAART) and supervised injecting facilities, among other preventive interventions, have contributed

Surveillance of HIV infection in Spain is available in 15 out of the country's 17 autonomous regions. According to the National AIDS Programme, 2,264 new HIV infections were diag‐

As previously reported [2], the beginning of the HIV epidemic in Spain was largely driven by IDUs and the initial decrease in the rates of infection were reported more than a decade ago [3]. In 2009, 77% of new HIV infections were reported as sexually transmitted and IDUs

The HIV epidemic among IDUs continues to develop differently across different parts of Eu‐ rope. In the European Union, the reported rates of newly diagnosed cases of HIV infection in IDUs are mostly stable or in decline [4]. Data on newly reported cases of HIV infection in IDUs for 2009 suggest that rates of infection are still declining in Europe, following a peak in 2002, which was due to outbreaks in eastern countries. Reductions in the rates of HIV infec‐ tion in IDUs are partially the result of better preventive interventions and access to care

and reproduction in any medium, provided the original work is properly cited.

© 2013 Sanvisens et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

Arantza Sanvisens, Ferran Bolao, Gabriel Vallecillo, Marta Torrens, Daniel Fuster, Santiago Pérez-Hoyos,

to reduce the impact of the HIV epidemic among drug users.

represented less than 8% of cases [1].

nosed in 2009, which represents 79 cases per million of the population [1].

Jordi Tor, Inmaculada Rivas and Robert Muga

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53074

**1. Introduction**

### **HIV Infection and Viral Hepatitis in Drug Abusers**

Arantza Sanvisens, Ferran Bolao, Gabriel Vallecillo, Marta Torrens, Daniel Fuster, Santiago Pérez-Hoyos, Jordi Tor, Inmaculada Rivas and Robert Muga

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53074

### **1. Introduction**

The epidemiology of HIV infection and viral hepatitis among injection drug users (IDUs) is changing in western countries; reductions in the epidemic of blood-borne infections, such as HIV infection, and viral hepatitis among drug users are probably related to the generaliza‐ tion of harm-reduction interventions and to the treatment of both HIV/AIDS and substance abuse. Opioid substitution therapy for the treatment of patients with heroin dependence, needle exchange programmes, access to Highly Active Antiretroviral Therapy (HAART) and supervised injecting facilities, among other preventive interventions, have contributed to reduce the impact of the HIV epidemic among drug users.

Surveillance of HIV infection in Spain is available in 15 out of the country's 17 autonomous regions. According to the National AIDS Programme, 2,264 new HIV infections were diag‐ nosed in 2009, which represents 79 cases per million of the population [1].

As previously reported [2], the beginning of the HIV epidemic in Spain was largely driven by IDUs and the initial decrease in the rates of infection were reported more than a decade ago [3]. In 2009, 77% of new HIV infections were reported as sexually transmitted and IDUs represented less than 8% of cases [1].

The HIV epidemic among IDUs continues to develop differently across different parts of Eu‐ rope. In the European Union, the reported rates of newly diagnosed cases of HIV infection in IDUs are mostly stable or in decline [4]. Data on newly reported cases of HIV infection in IDUs for 2009 suggest that rates of infection are still declining in Europe, following a peak in 2002, which was due to outbreaks in eastern countries. Reductions in the rates of HIV infec‐ tion in IDUs are partially the result of better preventive interventions and access to care

© 2013 Sanvisens et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

[5,6], however, Spain is one of the western European countries reporting high rates of newly diagnosed HIV infection among IDUs between 2004 and 2009 (Figure 1)[4].

eastern Europe, east Asia and southeast Asia have the largest populations of IDUs infected

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

369

Two major risk factors for HBV infection include the IDU his/herself and unprotected sex [18-21]. Studies among drug users from the United States have shown that 70% of cases are infected within five years of initiating drug use [22] and that 38%-89% of IDUs from Europe

In 2004, 16% of acute viral hepatitis reported to the Center for Disease Control in the United

In any case, the epidemiology of hepatitis B virus infection in drug users and other subpo‐ pulations at risk may vary according to the extent of preventive immunization; in Spain, the

In this study among IDUs and non-IDUs seeking treatment of substance abuse in Barcelona, Spain, we aimed to analyse trends in the epidemiology of HIV, HCV and HBV infections.

Prospective study in a cohort of patients admitted to substance abuse treatment pro‐ grammes in three teaching hospitals between January 1997 and December 2006. The treat‐ ment units are located in Barcelona (Hospital del Mar), Badalona (Hospital Universitari Germans Trias i Pujol) and L'Hospitalet de Llobregat (Hospital Universitari de Bellvitge).

Patients admitted to treatment were referred from primary care centres and the principal criterion for admission was the severity of addiction. Patients were required to be older than 18 years and the main objective of admission was to control signs and symptoms of with‐ drawal. Upon admission, we collected socio-demographic characteristics, the history of sub‐ stance abuse (main drug, age at first drug use, route of administration, history of opioid substitution treatment) and blood samples to test for HIV infection, HCV infection and HBV

The blood samples were tested by Enzyme ImmunoAssay (EIA) for antibodies to HIV infec‐

At discharge, patients were referred to their primary care providers. Pharmacological treat‐ ment was recommended in the majority of cases and all patients were advised to continue

For the purposes of this study, patients who were admitted more than once between 1997 and 2006 were analysed only with regard to the first admission. Similarly, data from two

and North America have markers of HBV infection in cross-sectional studies [23].

States had recent use of injected drugs as a risk factor [24].

first selective hepatitis B vaccination programme began in 1984 [25].

with viral hepatitis [4,17].

**2. Patients and methods**

**2.1. Setting and study population**

(HBcAb) infection, as previously reported [26,27].

tion and the results were confirmed by Western blot.

hospitals were controlled so that no duplicate patients existed.

with medical visits at the outpatient clinics.

**Figure 1.** Newly diagnosed HIV infections among IDUs from Europe and central Asia in 2009. Source: *Annual Report 2011*, European Monitoring Centre for Drugs and Drug Addiction(4).

Several studies have shown that IDUs are at increased risk of sexually transmitted HIV in‐ fection [7,8] and other authors have shown higher rates of HIV infection among recent and younger IDUs [9,10].

Non-injecting drug users (non-IDUs) are not exposed to blood-borne infections, but remain at risk of sexually transmitted diseases including HIV. Some studies have found a relation‐ ship between non-IDU and the increased risk of HIV and other sexually transmitted diseas‐ es [11,12]. Moreover, there have been reports on the causal relationship between alcohol drinking and the risk of HIV infection [13-15].

### **1.1. Hepatitis B and C**

About 80% of individuals exposed to hepatitis C virus (HCV) infection and 5% of adults ex‐ posed to hepatitis B virus (HBV) infection develop chronic liver disease. Cirrhosis and hepa‐ tocellular carcinoma are the most important sequelae of these infections [16].

It is well known that HCV infection is highly prevalent among drug users and that many IDUs contract the infection early in the course of injecting drugs; this implies that there may be only a small time window for initiating preventive interventions to reduce transmission of HCV infection.

About 10 million IDUs (range 6.0-15.2 million) worldwide were anti-HCV positive in 2010 and 1.2 million IDUs (range 0.3-2.7 million) were HBV infected (HBsAg positive). Geograph‐ ical differences exist in the distribution of blood-borne infections among drug users and eastern Europe, east Asia and southeast Asia have the largest populations of IDUs infected with viral hepatitis [4,17].

Two major risk factors for HBV infection include the IDU his/herself and unprotected sex [18-21]. Studies among drug users from the United States have shown that 70% of cases are infected within five years of initiating drug use [22] and that 38%-89% of IDUs from Europe and North America have markers of HBV infection in cross-sectional studies [23].

In 2004, 16% of acute viral hepatitis reported to the Center for Disease Control in the United States had recent use of injected drugs as a risk factor [24].

In any case, the epidemiology of hepatitis B virus infection in drug users and other subpo‐ pulations at risk may vary according to the extent of preventive immunization; in Spain, the first selective hepatitis B vaccination programme began in 1984 [25].

In this study among IDUs and non-IDUs seeking treatment of substance abuse in Barcelona, Spain, we aimed to analyse trends in the epidemiology of HIV, HCV and HBV infections.

### **2. Patients and methods**

[5,6], however, Spain is one of the western European countries reporting high rates of newly

**Figure 1.** Newly diagnosed HIV infections among IDUs from Europe and central Asia in 2009. Source: *Annual Report*

Several studies have shown that IDUs are at increased risk of sexually transmitted HIV in‐ fection [7,8] and other authors have shown higher rates of HIV infection among recent and

Non-injecting drug users (non-IDUs) are not exposed to blood-borne infections, but remain at risk of sexually transmitted diseases including HIV. Some studies have found a relation‐ ship between non-IDU and the increased risk of HIV and other sexually transmitted diseas‐ es [11,12]. Moreover, there have been reports on the causal relationship between alcohol

About 80% of individuals exposed to hepatitis C virus (HCV) infection and 5% of adults ex‐ posed to hepatitis B virus (HBV) infection develop chronic liver disease. Cirrhosis and hepa‐

It is well known that HCV infection is highly prevalent among drug users and that many IDUs contract the infection early in the course of injecting drugs; this implies that there may be only a small time window for initiating preventive interventions to reduce transmission

About 10 million IDUs (range 6.0-15.2 million) worldwide were anti-HCV positive in 2010 and 1.2 million IDUs (range 0.3-2.7 million) were HBV infected (HBsAg positive). Geograph‐ ical differences exist in the distribution of blood-borne infections among drug users and

tocellular carcinoma are the most important sequelae of these infections [16].

*2011*, European Monitoring Centre for Drugs and Drug Addiction(4).

drinking and the risk of HIV infection [13-15].

younger IDUs [9,10].

368 Current Perspectives in HIV Infection

**1.1. Hepatitis B and C**

of HCV infection.

diagnosed HIV infection among IDUs between 2004 and 2009 (Figure 1)[4].

### **2.1. Setting and study population**

Prospective study in a cohort of patients admitted to substance abuse treatment pro‐ grammes in three teaching hospitals between January 1997 and December 2006. The treat‐ ment units are located in Barcelona (Hospital del Mar), Badalona (Hospital Universitari Germans Trias i Pujol) and L'Hospitalet de Llobregat (Hospital Universitari de Bellvitge).

Patients admitted to treatment were referred from primary care centres and the principal criterion for admission was the severity of addiction. Patients were required to be older than 18 years and the main objective of admission was to control signs and symptoms of with‐ drawal. Upon admission, we collected socio-demographic characteristics, the history of sub‐ stance abuse (main drug, age at first drug use, route of administration, history of opioid substitution treatment) and blood samples to test for HIV infection, HCV infection and HBV (HBcAb) infection, as previously reported [26,27].

The blood samples were tested by Enzyme ImmunoAssay (EIA) for antibodies to HIV infec‐ tion and the results were confirmed by Western blot.

At discharge, patients were referred to their primary care providers. Pharmacological treat‐ ment was recommended in the majority of cases and all patients were advised to continue with medical visits at the outpatient clinics.

For the purposes of this study, patients who were admitted more than once between 1997 and 2006 were analysed only with regard to the first admission. Similarly, data from two hospitals were controlled so that no duplicate patients existed.

All the participants gave their consent for the determination of HIV and hepatitis serology. The methods utilized to perform this study complied with ethical standards for medical re‐ search and with principles of good clinical practice.

The baseline characteristics of the patients according to the antecedent of IDU/non-IDU are presented in Table 1. The majority of non-IDUs cases were patients with alcohol use disorders.

The main drug of abuse in IDUs patients was opiates (57.8%) and the median duration of drug abuse was 12 years (IQR:5 – 17 years); 28.9% of them were receiving methadone at ad‐ mission. Non-IDU patients were significantly older (37 years, IQR 30 – 45 years) than in IDU (32 years, IQR 28 – 37 years) (p<0.05). The non-IDU were admitted mostly (65.1%) during the 2002 – 2006 period, whereas IDUs were admitted mostly (63%) during the 1997 – 2001 period (p<0.05). As expected, the prevalence of HCV infection was significantly higher in IDUs (86.6%) than in non-IDUs (9.7%) (p< 0.05). In this sense, the prevalence of hepatitis B virus infection (HBcAb-positive) was significantly higher in IDUs (56.8%) than in non-IDUs

**Male** 726 (78.5) 1188 (78.8) 0.840 **Age** *median [IQR]* 37 [30-45] 32 [28-37] <0.05 **Year of admission***median [IQR]* 2003 [2000-2005] 2000 [1998-2003] <0.05

(n=1888) *median [IQR]* 10 [5-18] 12 [5-17] 0.079 **HIV positive** 26 (2.8) 636 (42.2) <0.05 **HCV positive** (n=2394) 88 (9.7) 1284 (86.6) <0.05 **HBcAb positive** (n=1890) 136 (17.7) 636 (56.8) <0.05

**Antecedent of imprisonment** (n=2291) 168 (19.4) 716 (50.2) <0.05 **Methadone\*** (n=1499) 46 (7.7) 261 (28.9) <0.05

**Table 1.** Characteristics of IDU and non-IDU patients admitted to substance abuse treatment programmes in the

323 (34.9) 602 (65.1)

231 (25.1) 432 (46.9) 258 (28.0)

**Non-IDU IDU**

*N (%) n (%)*

N=925 N=1507 p-value

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

371

949 (63.0)

867 (57.8) 124 (8.3)

558 (37.0) <0.05

509 (33.9) <0.05

(17.7%) (p<0.05) (Table 1).

Period of admission 1997-2001 2002-2006

Duration of drug abuse, years

**Main drug of abuse** (n=2421)

\* Available in two hospitals

Barcelona area, Spain, 1997-2006.

Opiates Alcohol Other

### **2.2. Statistical analysis**

Bivariate analyses were performed on the characteristics of patients according to the route of drug administration: 1) non-IDU patients were defined as those individuals without a histo‐ ry of injection drug use; 2) IDU patients were defined as those with current or past use of intravenous drug use. The bivariate analyses included the χ<sup>2</sup> Pearson test for categorical var‐ iables and Student's t test for continuous variables.

Prevalent cases correspond to patients that tested HIV, HCV or HBV-positive at admission.

Incident cases were defined as those HIV-seronegative patients at admission that subse‐ quently became HIV-positive during follow-up.

We carried out a direct measurement of HIV incidence based on the follow-up of the initial‐ ly HIV-seronegative patients. However, due to the relatively low percentage (44%) of pa‐ tients that underwent new HIV tests, we used a sensitivity analysis in a scenario based on the absence of new infections among those not re-tested for HIV infection during follow-up. Sensitivity analysis is useful in predicting the outcome of a decision if a situation turns out to be different compared to that which was previously assumed. By creating a given set of scenarios, the method can determine how changes in one variable will impact on the results.

All incidence rates were calculated in person-years with the number of HIV infections (inci‐ dent cases) in the numerator and the sum of follow-up times in the denominator.

Joinpoint regression models were fitted to analyse changes in trends of HIV and viral hepa‐ titis over time. These models evaluate changes that are produced on a logarithmic scale with a binomial distribution for the prevalence of infection and a Poisson distribution for the inci‐ dence of infection.

Descriptive analyses of the data were performed with STATA, version 8.0 (Stata Corp., Col‐ lege Station, TX, USA). For the Joinpoint regression models, we used the US National Can‐ cer Institute's Joinpoint Regression Program software [28].

P values less than 0.05 (p<0.05) were considered statistically significant.

### **3. Results**

#### **3.1. Characteristics of the study population**

Between January 1997 and December 2006 there were 3,318 admissions corresponding to 2,488 patients, of which 2,432 were eligible. Median age at admission was 34 years (IQR: 29 - 40 years) and 78.7% were men. A total of 925 (38%) patients were non-IDUs and 1,507 (62%) were current or past IDUs.

The baseline characteristics of the patients according to the antecedent of IDU/non-IDU are presented in Table 1. The majority of non-IDUs cases were patients with alcohol use disorders.

All the participants gave their consent for the determination of HIV and hepatitis serology. The methods utilized to perform this study complied with ethical standards for medical re‐

Bivariate analyses were performed on the characteristics of patients according to the route of drug administration: 1) non-IDU patients were defined as those individuals without a histo‐ ry of injection drug use; 2) IDU patients were defined as those with current or past use of

Prevalent cases correspond to patients that tested HIV, HCV or HBV-positive at admission. Incident cases were defined as those HIV-seronegative patients at admission that subse‐

We carried out a direct measurement of HIV incidence based on the follow-up of the initial‐ ly HIV-seronegative patients. However, due to the relatively low percentage (44%) of pa‐ tients that underwent new HIV tests, we used a sensitivity analysis in a scenario based on the absence of new infections among those not re-tested for HIV infection during follow-up. Sensitivity analysis is useful in predicting the outcome of a decision if a situation turns out to be different compared to that which was previously assumed. By creating a given set of scenarios, the method can determine how changes in one variable will impact on the results. All incidence rates were calculated in person-years with the number of HIV infections (inci‐

Joinpoint regression models were fitted to analyse changes in trends of HIV and viral hepa‐ titis over time. These models evaluate changes that are produced on a logarithmic scale with a binomial distribution for the prevalence of infection and a Poisson distribution for the inci‐

Descriptive analyses of the data were performed with STATA, version 8.0 (Stata Corp., Col‐ lege Station, TX, USA). For the Joinpoint regression models, we used the US National Can‐

Between January 1997 and December 2006 there were 3,318 admissions corresponding to 2,488 patients, of which 2,432 were eligible. Median age at admission was 34 years (IQR: 29 - 40 years) and 78.7% were men. A total of 925 (38%) patients were non-IDUs and 1,507 (62%)

dent cases) in the numerator and the sum of follow-up times in the denominator.

Pearson test for categorical var‐

search and with principles of good clinical practice.

iables and Student's t test for continuous variables.

quently became HIV-positive during follow-up.

intravenous drug use. The bivariate analyses included the χ<sup>2</sup>

cer Institute's Joinpoint Regression Program software [28].

**3.1. Characteristics of the study population**

P values less than 0.05 (p<0.05) were considered statistically significant.

**2.2. Statistical analysis**

370 Current Perspectives in HIV Infection

dence of infection.

**3. Results**

were current or past IDUs.

The main drug of abuse in IDUs patients was opiates (57.8%) and the median duration of drug abuse was 12 years (IQR:5 – 17 years); 28.9% of them were receiving methadone at ad‐ mission. Non-IDU patients were significantly older (37 years, IQR 30 – 45 years) than in IDU (32 years, IQR 28 – 37 years) (p<0.05). The non-IDU were admitted mostly (65.1%) during the 2002 – 2006 period, whereas IDUs were admitted mostly (63%) during the 1997 – 2001 period (p<0.05). As expected, the prevalence of HCV infection was significantly higher in IDUs (86.6%) than in non-IDUs (9.7%) (p< 0.05). In this sense, the prevalence of hepatitis B virus infection (HBcAb-positive) was significantly higher in IDUs (56.8%) than in non-IDUs (17.7%) (p<0.05) (Table 1).


**Table 1.** Characteristics of IDU and non-IDU patients admitted to substance abuse treatment programmes in the Barcelona area, Spain, 1997-2006.

### **3.2. HIV infection**

Table 2 shows the prevalence and incidence of HIV infection in non-IDUs according to the year of admission. Regarding HIV prevalence, 2.8% (95% CI: 1.8-4.1) of patients were HIVpositive at admission with the highest prevalence of infection observed in 1999 (8.3%).

Table 3 shows the prevalence and incidence of HIV infection in IDUs according to the year of admission, ultimately showing values slightly lower than the rates registered since 1999.

Trends of HIV prevalence in non-IDUs is shown in the upper part of Figure 2 (Graphic A). Overall, changes in HIV prevalence were not statistically significant, in spite of the model

In terms of HIV incidence (Figure 2, Graphic B), the model shows statistically significant dif‐

The trend of HIV prevalence in IDUs showed a significant (p=0.01) decline between 1997 and 2006 (Figure 3, Graphic A). With respect to HIV incidence among IDUs, no changes in the trends of infection rate were detected after adjusting the regression model (p=0.944)

**HIV PREVALENCE HIV INCIDENCE**

**Patients followed**

 124 (45.1) (39.1-51.2) 151 84 (55.6) 45.3 1 2.21 (0.3-15.7) 84 (43.5) (36.4-50.8) 109 63 (57.8) 102.4 2 1.95 (0.5-7.8) 83 (44.4) (37.1-51.8) 104 52 (50.0) 133.3 5 3.75 (1.6-9.0) 71 (41.8) (34.3-59.6) 99 47 (47.5) 153.5 3 1.95 (0.6-6.1) 53 (42.7) (33.9-51.9) 71 29 (40.8) 163.3 4 2.45 (0.9-6.5) 59 (38.6) (30.8-46.8) 94 35 (37.2) 168.9 3 1.77 (0.6-5.5) 50 (42.7) (33.6-52.2) 67 31 (46.3) 174.0 6 3.45 (1.5-7.7) 53 (42.7) (33.9-51.9) 71 31 (43.7) 175.6 5 2.85 (1.2-6.8) 34 (39.5) (29.1-50.7) 52 21 (40.4) 160.4 4 2.49 (0.9-6.6) 25 (32.1) (21.9-43.6) 53 17 (32.1) 138.8 3 2.16 (0.7-6.7) **1997-2006** 636 (42.2) (39.7-44.7) 871 410 (47.1) 1415.5 36 2.54 (1.8-3.5)

**Table 3.** HIV serial prevalence and HIV serial incidence in IDUs by year of admission to substance abuse treatment

In sensitivity analysis, the rate of HIV infection among non-IDUs was 0.19x100 p-y (95% CI:

In sensitivity analysis, trends of HIV incidence for non-IDU patients remained unchanged with respect to the direct method. However, HIV incidence for IDUs significantly decreased over time in the best scenario (no new infections among those lost to follow-up, p=0.04).

programmes in the Barcelona area, Spain, 1997-2006.

0.07-0.45) and 1.08 x100p-y (95% CI: 0.5-1.5) among IDUs.

*n (%) 95% CI n (%) x100 p-y 95% CI*

**P-Y**

**Incident**

**cases Incident rate**

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

373

**Patients at risk**

indicating a decrease in prevalence over time (p=0.24).

ferences over time (p=0.004).

(Figure 3, Graphic B).

Among the 899 non-IDU, HIV-negative patients, 364 (40.5%) were followed-up for a median of 2.3 years (IQR: 0.9 – 4.1 years; 1060 p-y); only five patients acquired HIV infection during follow-up (incidence rate 0.47 x 100 p-y; 95% CI: 0.2-1.1).

The prevalence of HIV in IDUs was 42.2% (636/1507). The highest prevalence was observed in 1997 (45.1%) and the lowest in 2006 (32.1%).

Among the 871 IDUs, HIV-negative patients, 47.1% were followed for a median of 2.7 years (IQR: 1.2 - 5.2 years, 1415.5 p-y) and 36 acquired HIV infection (incidence rate 2.54 x 100 p-y (95% CI: 1.8-3.5); the highest rate of infection was observed in 1999 (3.7 x 100p-y). Patients followed-up were similar to those not followed regarding the proportion of male/female, the main drug of abuse and the prevalence of HCV infection and HBV (HBcAb) infection.


**Table 2.** HIV serial prevalence and HIV serial incidence among non-IDUs by year of admission to substance abuse treatment programmes in the Barcelona area, Spain, 1997-2006.

Table 3 shows the prevalence and incidence of HIV infection in IDUs according to the year of admission, ultimately showing values slightly lower than the rates registered since 1999.

**3.2. HIV infection**

372 Current Perspectives in HIV Infection

Table 2 shows the prevalence and incidence of HIV infection in non-IDUs according to the year of admission. Regarding HIV prevalence, 2.8% (95% CI: 1.8-4.1) of patients were HIVpositive at admission with the highest prevalence of infection observed in 1999 (8.3%).

Among the 899 non-IDU, HIV-negative patients, 364 (40.5%) were followed-up for a median of 2.3 years (IQR: 0.9 – 4.1 years; 1060 p-y); only five patients acquired HIV infection during

The prevalence of HIV in IDUs was 42.2% (636/1507). The highest prevalence was observed

Among the 871 IDUs, HIV-negative patients, 47.1% were followed for a median of 2.7 years (IQR: 1.2 - 5.2 years, 1415.5 p-y) and 36 acquired HIV infection (incidence rate 2.54 x 100 p-y (95% CI: 1.8-3.5); the highest rate of infection was observed in 1999 (3.7 x 100p-y). Patients followed-up were similar to those not followed regarding the proportion of male/female, the main drug of abuse and the prevalence of HCV infection and HBV (HBcAb) infection.

> **Patients followed**

**1997** 0 (0.0) -- 51 24 (47.1) 13.7 0 0.00 --

**1999** 5 (8.3) (2.8-18.4) 55 25 (45.5) 52.1 0 0.00 --

**2000** 2 (2.7) (0.3-9.4) 72 24 (33.3) 71.1 0 0.00 --

**2001** 1 (1.3) (0.03-7.0) 76 34 (44.7) 93.9 0 0.00 --

**2002** 4 (3.9) (1.1-9.6) 99 44 (44.4) 112.8 0 0.00 --

**2003** 2 (1.7) (0.2-6.0) 116 50 (43.1) 138.3 1 0.72 (0.1-5.1)

**2004** 3 (2.5) (0.5-7.0) 119 50 (42.0) 170.1 1 0.59 (0.1-4.2)

**2005** 3 (2.5) (0.5-7.0) 118 35 (29.7) 184.9 1 0.54 (0.1-3.8)

**2006** 4 (2.9) (0.8-7.2) 134 48 (35.8) 185.3 1 0.54 (0.1-3.8)

**1997-2006** 26 (2.8) (1.8-4.1) 899 364 (40.5) 1060 5 0.47 (0.2-1.1)

**Table 2.** HIV serial prevalence and HIV serial incidence among non-IDUs by year of admission to substance abuse

treatment programmes in the Barcelona area, Spain, 1997-2006.

**1998** 2 (3.3) (0.4-11.3) 59 30 (50.8) 37.8 1 2.65 (0.4-18.8)

*n (%) 95% CI n (%) x100 p-y 95% CI*

**P-Y**

**Incident**

**cases Incident rate**

**HIV PREVALENCE HIV INCIDENCE**

**Patients at risk**

follow-up (incidence rate 0.47 x 100 p-y; 95% CI: 0.2-1.1).

in 1997 (45.1%) and the lowest in 2006 (32.1%).

Trends of HIV prevalence in non-IDUs is shown in the upper part of Figure 2 (Graphic A). Overall, changes in HIV prevalence were not statistically significant, in spite of the model indicating a decrease in prevalence over time (p=0.24).

In terms of HIV incidence (Figure 2, Graphic B), the model shows statistically significant dif‐ ferences over time (p=0.004).

The trend of HIV prevalence in IDUs showed a significant (p=0.01) decline between 1997 and 2006 (Figure 3, Graphic A). With respect to HIV incidence among IDUs, no changes in the trends of infection rate were detected after adjusting the regression model (p=0.944) (Figure 3, Graphic B).


**Table 3.** HIV serial prevalence and HIV serial incidence in IDUs by year of admission to substance abuse treatment programmes in the Barcelona area, Spain, 1997-2006.

In sensitivity analysis, the rate of HIV infection among non-IDUs was 0.19x100 p-y (95% CI: 0.07-0.45) and 1.08 x100p-y (95% CI: 0.5-1.5) among IDUs.

In sensitivity analysis, trends of HIV incidence for non-IDU patients remained unchanged with respect to the direct method. However, HIV incidence for IDUs significantly decreased over time in the best scenario (no new infections among those lost to follow-up, p=0.04).

#### **3.3. Viral hepatitis**

The prevalence of HCV infection and HBV (HBcAb) infection in non-IDUs was 9.7%, and 17.7%, respectively. The prevalence of HCV in the years analysed oscillated between 6.8% and 15.6%, but differences were not statistically significant (p=0.589) (Figure 4, Graphic A). As expected, the prevalence of HCV infection in IDUs was high (86.6%) and changes over the years analysed were negligible (p=0.240) (Figure 5, Graphic A).

The prevalence of HBV (HBcAb) infection in non-IDUs oscillated between 8.3% and 22.9%, and changes over time were not statistically significant (p=0.696) (Figure 4, Graphic B). HBV (HBcAb) infection was observed in 56.8% of IDUs, which oscillated between 48.8% and 64.3% in the years analysed. Analysis of the trend did not show statistically significant dif‐ ferences during the period analysed (p=0.218) (Figure 5, Graphic B).

Graphic B

**Figure 3.** Trends in HIV prevalence (Graphic A) and HIV incidence (Graphic B) in IDUs admitted to substance abuse

treatment programmes in the Barcelona area, Spain, 1997- 2006.

Graphic A

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

375

**Figure 2.** Trends in HIV prevalence (Graphic A) and HIV incidence (Graphic B) in non-IDU patients admitted to sub‐ stance abuse treatment programmes in the Barcelona area, Spain, 1997- 2006.

**3.3. Viral hepatitis**

374 Current Perspectives in HIV Infection

The prevalence of HCV infection and HBV (HBcAb) infection in non-IDUs was 9.7%, and 17.7%, respectively. The prevalence of HCV in the years analysed oscillated between 6.8% and 15.6%, but differences were not statistically significant (p=0.589) (Figure 4, Graphic A). As expected, the prevalence of HCV infection in IDUs was high (86.6%) and changes over

The prevalence of HBV (HBcAb) infection in non-IDUs oscillated between 8.3% and 22.9%, and changes over time were not statistically significant (p=0.696) (Figure 4, Graphic B). HBV (HBcAb) infection was observed in 56.8% of IDUs, which oscillated between 48.8% and 64.3% in the years analysed. Analysis of the trend did not show statistically significant dif‐

Graphic A

Graphic B

**Figure 2.** Trends in HIV prevalence (Graphic A) and HIV incidence (Graphic B) in non-IDU patients admitted to sub‐

stance abuse treatment programmes in the Barcelona area, Spain, 1997- 2006.

the years analysed were negligible (p=0.240) (Figure 5, Graphic A).

ferences during the period analysed (p=0.218) (Figure 5, Graphic B).

**Figure 3.** Trends in HIV prevalence (Graphic A) and HIV incidence (Graphic B) in IDUs admitted to substance abuse treatment programmes in the Barcelona area, Spain, 1997- 2006.

Graphic B

**Figure 5.** Prevalence of HCV infection (Graphic A) and HBV infection (Graphic B) in IDUs admitted to treatment pro‐

grammes in the Barcelona area, Spain, 1997- 2006.

Graphic A

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

377

Graphic B

**Figure 4.** Prevalence of HCV infection (Graphic A) and HBV infection (Graphic B) in non-IDUs admitted to treatment

programmes in the Barcelona area, Spain, 1997- 2006.

376 Current Perspectives in HIV Infection

Graphic A

**Figure 5.** Prevalence of HCV infection (Graphic A) and HBV infection (Graphic B) in IDUs admitted to treatment pro‐ grammes in the Barcelona area, Spain, 1997- 2006.

### **4. Discussion**

Results from this cohort of patients seeking substance abuse treatment indicate that drug users, irrespective of the main route of drug administration, are at increased risk of HIV in‐ fection and viral hepatitis. In fact, the prevalence of HIV infection and HCV infection in non-IDU patients is 2.8% and 9.7%, respectively. Several studies analysing risky sexual behaviour of drug and alcohol abusers suggest an association between cocaine, ampheta‐ mines or alcohol abuse and the sexual transmission of HIV [19-24], which could explain the relatively high prevalence of HIV infection among non-IDU patients from this study [29-34]. Despite the relatively high prevalence of HIV infection, there was a trend in the decline of HIV incidence among the non-IDUs. To some extent, the incidence of HIV infection was low (0.47 per 100 p-y) and the results shown here indicate that non-IDUs have a fivefold lower risk of HIV than the IDUs, as shown in a previous study [35].

tern of infection shows clear geographical differences [17]. In fact, rates of HBcAb-positive

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

379

Because of the high rate of both HCV and HBV infection, the probability of coinfection in IDUs is high. In this sense, vaccination against HBV must be prioritized for all susceptible

There are several limitations to this study that need to be mentioned. First of all, a propor‐ tion of patients, HIV-seronegative, were not re-tested for HIV infection during follow-up de‐ spite the fact that many of them were regularly visited in their primary care centres; in this sense, assessment of risk behaviour and awareness of drug use disorders by health care pro‐ fessionals are key components for developing preventive interventions. Second, in this study assessment of HBV infection was limited to one marker of infection; in other words, more accurate estimation of chronic carriers of HBV infection, susceptibility to infection or immunization due to HBV vaccination was not available. For the HCV pattern of infection we only analysed antibodies against HCV and RNA-HCV was not available; it is well known that a minority (10-15%) of the individuals infected with HCV clear the virus during the natural history of the disease. Third, in this study we did not analyse the impact of sexu‐ al transmission of HIV and viral hepatitis on the results shown here. In this sense, drug-ad‐ dicted women have been reported to have a higher risk of HIV infection than drug-addicted

In contrast, the strength of this cross-sectional and longitudinal study is based on data col‐ lected at three centres that provide clinical care and treatment for the majority of severe drug addicts in Barcelona and its metropolitan area. Having data from the three hospitals adds external validity to the results and may reflect changes in the epidemiology of HIV and viral hepatitis in young adults seeking treatment for substance abuse in an urban area.

In summary, since 1997 we observed a significant decline in the prevalence of HIV infection in IDUs, however, background prevalence of HIV and viral hepatitis is still high thus sug‐ gesting that prevention efforts and treatment of substance abuse are necessary to further re‐

duce transmission of blood-borne infections in this population.

varied widely between countries from 4.2% in Slovenia to 85.0% in Mexico [17].

drug users.

men [48].

**Nomenclature**

IDU= Injecting Drug User.

HCV= Hepatitis C virus. HBV= Hepatitis B virus.

HIV= Human Immunodeficiency Virus.

AIDS= Acquired Immunodeficiency Syndrome. HAART= Highly Active Antiretroviral Therapy.

HBsAg= Surface Antigen of Hepatitis B Virus.

The observed decline in the prevalence of HIV infection among IDUs is likely the result of some preventive interventions introduced in Spain at the beginning of 1990s. Harm-reduc‐ tion interventions to reduce the impact of the HIV epidemic associated with heroin depend‐ ence included the access to opioid substitution therapy with methadone and the needle exchange programmes, among other interventions. Our findings indicate that HIV infection among IDUs from metropolitan Barcelona has stabilized and that rates of new infections are moderate with respect to reports from other cities [36-38]. In addition, our results agree with those reported nationally, indicating that sexual transmission now represents 80% of new HIV infections in Spain [39]. Further, our results show that the proportion of IDUs being ad‐ mitted for substance abuse treatment is declining, suggesting a decrease in the number of IDUs in Spain [40].

Data from European countries show tendencies toward a low rate of HIV infection in drug users. For example, Poland, Finland and Germany have considerably reduced the rates of infection to two cases per million inhabitants in 2007 [41]. In this study, we determined an overall rate of infection of 2.54 per 100 p-y between 1997 and 2006, which is similar to that observed in other studies [6].

In contrast, the decline in the prevalence of HIV infection is not accompanied by a decline in HCV prevalence [42,43]. This observation suggests that IDUs still maintain non-sterile injec‐ tion practices. The HIV and hepatitis C virus are transmitted primarily by large or repeated direct percutaneous exposures to contaminated blood. In Spain, IDU is a factor in 28% of all contemporary AIDS cases and it accounts for more than 60% of new hepatitis C infections in Europe and the USA [1,44].

It is well known that the majority of IDUs become infected with hepatitis C during their first year of injecting and that because of its infectivity HCV spreads more rapidly than HIV [45,46,47].

In this study, the prevalence of HBV is high. A recent systematic review suggests that worldwide around 1.2 million IDUs are chronic carriers of HBV infection and that the pat‐ tern of infection shows clear geographical differences [17]. In fact, rates of HBcAb-positive varied widely between countries from 4.2% in Slovenia to 85.0% in Mexico [17].

Because of the high rate of both HCV and HBV infection, the probability of coinfection in IDUs is high. In this sense, vaccination against HBV must be prioritized for all susceptible drug users.

There are several limitations to this study that need to be mentioned. First of all, a propor‐ tion of patients, HIV-seronegative, were not re-tested for HIV infection during follow-up de‐ spite the fact that many of them were regularly visited in their primary care centres; in this sense, assessment of risk behaviour and awareness of drug use disorders by health care pro‐ fessionals are key components for developing preventive interventions. Second, in this study assessment of HBV infection was limited to one marker of infection; in other words, more accurate estimation of chronic carriers of HBV infection, susceptibility to infection or immunization due to HBV vaccination was not available. For the HCV pattern of infection we only analysed antibodies against HCV and RNA-HCV was not available; it is well known that a minority (10-15%) of the individuals infected with HCV clear the virus during the natural history of the disease. Third, in this study we did not analyse the impact of sexu‐ al transmission of HIV and viral hepatitis on the results shown here. In this sense, drug-ad‐ dicted women have been reported to have a higher risk of HIV infection than drug-addicted men [48].

In contrast, the strength of this cross-sectional and longitudinal study is based on data col‐ lected at three centres that provide clinical care and treatment for the majority of severe drug addicts in Barcelona and its metropolitan area. Having data from the three hospitals adds external validity to the results and may reflect changes in the epidemiology of HIV and viral hepatitis in young adults seeking treatment for substance abuse in an urban area.

In summary, since 1997 we observed a significant decline in the prevalence of HIV infection in IDUs, however, background prevalence of HIV and viral hepatitis is still high thus sug‐ gesting that prevention efforts and treatment of substance abuse are necessary to further re‐ duce transmission of blood-borne infections in this population.

### **Nomenclature**

**4. Discussion**

378 Current Perspectives in HIV Infection

IDUs in Spain [40].

observed in other studies [6].

Europe and the USA [1,44].

[45,46,47].

Results from this cohort of patients seeking substance abuse treatment indicate that drug users, irrespective of the main route of drug administration, are at increased risk of HIV in‐ fection and viral hepatitis. In fact, the prevalence of HIV infection and HCV infection in non-IDU patients is 2.8% and 9.7%, respectively. Several studies analysing risky sexual behaviour of drug and alcohol abusers suggest an association between cocaine, ampheta‐ mines or alcohol abuse and the sexual transmission of HIV [19-24], which could explain the relatively high prevalence of HIV infection among non-IDU patients from this study [29-34]. Despite the relatively high prevalence of HIV infection, there was a trend in the decline of HIV incidence among the non-IDUs. To some extent, the incidence of HIV infection was low (0.47 per 100 p-y) and the results shown here indicate that non-IDUs have a fivefold lower

The observed decline in the prevalence of HIV infection among IDUs is likely the result of some preventive interventions introduced in Spain at the beginning of 1990s. Harm-reduc‐ tion interventions to reduce the impact of the HIV epidemic associated with heroin depend‐ ence included the access to opioid substitution therapy with methadone and the needle exchange programmes, among other interventions. Our findings indicate that HIV infection among IDUs from metropolitan Barcelona has stabilized and that rates of new infections are moderate with respect to reports from other cities [36-38]. In addition, our results agree with those reported nationally, indicating that sexual transmission now represents 80% of new HIV infections in Spain [39]. Further, our results show that the proportion of IDUs being ad‐ mitted for substance abuse treatment is declining, suggesting a decrease in the number of

Data from European countries show tendencies toward a low rate of HIV infection in drug users. For example, Poland, Finland and Germany have considerably reduced the rates of infection to two cases per million inhabitants in 2007 [41]. In this study, we determined an overall rate of infection of 2.54 per 100 p-y between 1997 and 2006, which is similar to that

In contrast, the decline in the prevalence of HIV infection is not accompanied by a decline in HCV prevalence [42,43]. This observation suggests that IDUs still maintain non-sterile injec‐ tion practices. The HIV and hepatitis C virus are transmitted primarily by large or repeated direct percutaneous exposures to contaminated blood. In Spain, IDU is a factor in 28% of all contemporary AIDS cases and it accounts for more than 60% of new hepatitis C infections in

It is well known that the majority of IDUs become infected with hepatitis C during their first year of injecting and that because of its infectivity HCV spreads more rapidly than HIV

In this study, the prevalence of HBV is high. A recent systematic review suggests that worldwide around 1.2 million IDUs are chronic carriers of HBV infection and that the pat‐

risk of HIV than the IDUs, as shown in a previous study [35].

HIV= Human Immunodeficiency Virus.

IDU= Injecting Drug User.

AIDS= Acquired Immunodeficiency Syndrome.

HAART= Highly Active Antiretroviral Therapy.

HCV= Hepatitis C virus.

HBV= Hepatitis B virus.

HBsAg= Surface Antigen of Hepatitis B Virus.

HBcAb= Hepatitis B core Antibody. EIA= Enzyme Immunoassay. IQR= Interquartile Range. CI= Confidence Interval. RNA= Ribonucleic Acid

### **Acknowledgments**

This work was partially funded by grants from the Ministry of Science and Innovation, Spain (grants RD06/001, RD06/006 and PI07/0342), Ministry of Health (grant EC11-042) and Ministry of Education (grant 2010-0945).

**References**

de Ciencia e Innovación; 2010.

2006;20(6):442-448.

1:S29-33.

10.1136/sti.2005.019299.

2002;156(7):641-653.

2003;35(4):445-453.

[1] Vigilancia epidemiológica del VIH en España. Nuevos diagnósticos de VIH en Espa‐ ña. Periodo 2003-2009. Ministerio de Sanidad, Política Social e Igualdad, Ministerio

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

381

[2] Hernandez-Aguado I, Avino MJ, Perez-Hoyos S, Gonzalez-Aracil J, Ruiz-Perez I, Torrella A, et al. Human immunodeficiency virus (HIV) infection in parenteral drug users: evolution of the epidemic over 10 years. Valencian Epidemiology and Preven‐

[3] Castilla J, Lorenzo JM, Izquierdo A, Lezaun ME, Lopez I, Moreno-Iribas C, et al. Characteristics and trends of newly diagnosed HIV-infections, 2000-2004. Gac Sanit

[4] European Monitoring Centre for Drugs and Drug Addiction. Annual report 2011: The state of the drug problems in Europe. EMCDDA, Lisbon, November 2011. http://

[5] Muga R, Sanvisens A, Bolao F, Tor J, Santesmases J, Pujol R, et al. Significant reduc‐ tions of HIV prevalence but not of hepatitis C virus infections in injection drug users from metropolitan Barcelona: 1987-2001. Drug Alcohol Depend 2006;82 Suppl

[6] Hurtado I, Alastrue I, Ferreros I, del Amo J, Santos C, Tasa T, et al. Trends in HIV testing, serial HIV prevalence and HIV incidence among people attending a Center for AIDS Prevention from 1988 to 2003. Sex Transm Infect 2007;83(1):23-28. DOI:

[7] Celentano DD, Latimore AD, Mehta SH. Variations in sexual risks in drug users: emerging themes in a behavioral context. Curr HIV/AIDS Rep 2008;5(4):212-218. [8] Nelson KE, Galai N, Safaeian M, Strathdee SA, Celentano DD, Vlahov D. Temporal trends in the incidence of human immunodeficiency virus infection and risk behav‐ ior among injection drug users in Baltimore, Maryland, 1988-1998. Am J Epidemiol

[9] Chitwood DD, Comerford M, Sanchez J. Prevalence and risk factors for HIV among sniffers, short-term injectors, and long-term injectors of heroin. J Psychoactive Drugs

[10] Miller CL, Wood E, Spittal PM, Li K, Frankish JC, Braitstein P, et al. The future face of coinfection: prevalence and incidence of HIV and hepatitis C virus coinfection among young injection drug users. J Acquir Immune Defic Syndr 2004;36(2):743-749.

[11] Jenness SM, Neaigus A, Hagan H, Murrill CS, Wendel T. Heterosexual HIV and sex‐ ual partnerships between injection drug users and noninjection drug users. AIDS Pa‐

tient Care STDS 2010;24(3):175-181. DOI:10.1089/apc.2009.0227.

tion of HIV Disease Study Group. Int J Epidemiol 1999;28(2):335-340.

www.emcdda.europa.eu/attachements.cfm/att\_143743\_EN\_EMCD‐

DA\_AR2011\_EN.pdf (accessed 30 July 2012)

### **Author details**

Arantza Sanvisens1 , Ferran Bolao2 , Gabriel Vallecillo3 , Marta Torrens4 , Daniel Fuster5,8, Santiago Pérez-Hoyos6 , Jordi Tor5 , Inmaculada Rivas7 and Robert Muga1\*

\*Address all correspondence to: rmuga.germanstrias@gencat.cat

1 Department of Internal Medicine and AIDS Vaccine Research Project – HIVACAT. Hospi‐ tal Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma Barcelona, Spain

2 Department of Internal Medicine. Hospital Universitari de Bellvitge, L'Hospitalet de Llo‐ bregat, Universitat de Barcelona, Spain

3 Department of Internal Medicine and Institute of Neuropsychiatry & Addictions. Parc de Salut Mar, Barcelona, Universitat Autònoma Barcelona, Spain

4 Institute of Neuropsychiatry & Addictions. Parc de Salut Mar, Barcelona, Universitat Au‐ tònoma Barcelona, Spain

5 Department of Internal Medicine. Hospital Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma Barcelona, Spain

6 Department of Preventive Medicine and Public Health. Vall d'Hebrón Institut de Recerca. Universitat Autònoma Barcelona, Spain

7 Municipal Centre for Substance Abuse Treatment (Centro Delta). IMSP Badalona, Spain

8 Section of General Internal Medicine. Boston Medical Center, Boston University School of Medicine; Boston (MA), U.S.A.

### **References**

HBcAb= Hepatitis B core Antibody.

Ministry of Education (grant 2010-0945).

bregat, Universitat de Barcelona, Spain

Universitat Autònoma Barcelona, Spain

Universitat Autònoma Barcelona, Spain

Medicine; Boston (MA), U.S.A.

, Ferran Bolao2

, Jordi Tor5

\*Address all correspondence to: rmuga.germanstrias@gencat.cat

Salut Mar, Barcelona, Universitat Autònoma Barcelona, Spain

This work was partially funded by grants from the Ministry of Science and Innovation, Spain (grants RD06/001, RD06/006 and PI07/0342), Ministry of Health (grant EC11-042) and

, Gabriel Vallecillo3

, Inmaculada Rivas7

1 Department of Internal Medicine and AIDS Vaccine Research Project – HIVACAT. Hospi‐ tal Universitari Germans Trias i Pujol, Badalona, Universitat Autònoma Barcelona, Spain

2 Department of Internal Medicine. Hospital Universitari de Bellvitge, L'Hospitalet de Llo‐

3 Department of Internal Medicine and Institute of Neuropsychiatry & Addictions. Parc de

4 Institute of Neuropsychiatry & Addictions. Parc de Salut Mar, Barcelona, Universitat Au‐

5 Department of Internal Medicine. Hospital Universitari Germans Trias i Pujol, Badalona,

6 Department of Preventive Medicine and Public Health. Vall d'Hebrón Institut de Recerca.

7 Municipal Centre for Substance Abuse Treatment (Centro Delta). IMSP Badalona, Spain

8 Section of General Internal Medicine. Boston Medical Center, Boston University School of

, Marta Torrens4

and Robert Muga1\*

, Daniel Fuster5,8,

EIA= Enzyme Immunoassay. IQR= Interquartile Range. CI= Confidence Interval. RNA= Ribonucleic Acid

380 Current Perspectives in HIV Infection

**Acknowledgments**

**Author details**

Arantza Sanvisens1

Santiago Pérez-Hoyos6

tònoma Barcelona, Spain


[12] Strathdee SA, Sherman SG. The role of sexual transmission of HIV infection among injection and non-injection drug users. J Urban Health 2003;80(4 Suppl 3):iii7-14.

haviors, and preventive measures among Seattle injection drug users aged 18-30 years, 1994-2004. J Urban Health 2007;84(3):436-454. DOI:10.1007/s11524-007-9178-2.

HIV Infection and Viral Hepatitis in Drug Abusers

http://dx.doi.org/10.5772/53074

383

[25] Salleras L, Bruguera M, Taberner JL, Dominguez A, Batalla J, Buti M, et al. Effective‐ ness of the mass antihepatitis B program in preadolescents in Catalonia. Med Clin

[26] Muga R, Roca J, Egea JM, Tor J, Sirera G, Rey-Joly C, et al. Mortality of HIV-positive and HIV-negative heroin abusers as a function of duration of injecting drug use. J

[27] Rivas I, Martinez E, Sanvisens A, Bolao F, Tor J, Torrens M, et al. Hepatitis B virus serum profiles in injection drug users and rates of immunization over time in Barce‐ lona: 1987-2006. Drug Alcohol Depend 2010;110(3):234-9. DOI:10.1016/j.drugalcdep.

[28] US National Cancer Institute Software. Jointpoint Regression Program. 2010;3.4.3.

[29] Wang B, Li X, Stanton B, Zhang L, Fang X. Alcohol Use, Unprotected Sex, and Sexu‐ ally Transmitted Infections Among Female Sex Workers in China. Sex Transm Dis

[30] Baliunas D, Rehm J, Irving H, Shuper P. Alcohol consumption and risk of incident human immunodeficiency virus infection: a meta-analysis. Int J Public Health

[31] Booth RE, Kwiatkowski CF, Chitwood DD. Sex related HIV risk behaviors: differen‐ tial risks among injection drug users, crack smokers, and injection drug users who

[32] de Azevedo RC, Botega NJ, Guimaraes LA. Crack users, sexual behavior and risk of

[33] Colfax G, Santos GM, Chu P, Vittinghoff E, Pluddemann A, Kumar S, et al. Ampheta‐ mine-group substances and HIV. Lancet 2010;376(9739):458-474. DOI:10.1016/

[34] Van Tieu H, Koblin BA. HIV, alcohol, and noninjection drug use. Curr Opin HIV

[35] Kellogg TA, McFarland W, Perlman JL, Weinstock H, Bock S, Katz MH, et al. HIV incidence among repeat HIV testers at a county hospital, San Francisco, California,

[36] Kozlov AP, Shaboltas AV, Toussova OV, Verevochkin SV, Masse BR, Perdue T, et al. HIV incidence and factors associated with HIV acquisition among injection drug users in St Petersburg, Russia. AIDS 2006;20(6):901-906. DOI:10.1097/01.aids.

(Barc) 2003;121 Suppl 1:79-82.

2010.03.005.

Acquir Immune Defic Syndr 2000;23(4):332-338.

2010;37(10):629-36. DOI:10.1097/OLQ.0b013e3181e2118a.

2010;55(3):159-166. DOI:10.1007/s00038-009-0095-x.

smoke crack. Drug Alcohol Depend 2000;58(3):219-226.

AIDS 2009;4(4):314-318. DOI:10.1097/COH.0b013e32832aa902.

USA. J Acquir Immune Defic Syndr 2001;28(1):59-64.

HIV infection. Rev Bras Psiquiatr 2007;29(1):26-30.

S0140-6736(10)60753-2.

0000218555.36661.9c.


haviors, and preventive measures among Seattle injection drug users aged 18-30 years, 1994-2004. J Urban Health 2007;84(3):436-454. DOI:10.1007/s11524-007-9178-2.

[25] Salleras L, Bruguera M, Taberner JL, Dominguez A, Batalla J, Buti M, et al. Effective‐ ness of the mass antihepatitis B program in preadolescents in Catalonia. Med Clin (Barc) 2003;121 Suppl 1:79-82.

[12] Strathdee SA, Sherman SG. The role of sexual transmission of HIV infection among injection and non-injection drug users. J Urban Health 2003;80(4 Suppl 3):iii7-14. [13] Howe CJ, Cole SR, Ostrow DG, Mehta SH, Kirk GD. A prospective study of alcohol consumption and HIV acquisition among injection drug users. AIDS 2011;25(2):

[14] Zakhari S, Li TK. Determinants of alcohol use and abuse: Impact of quantity and fre‐ quency patterns on liver disease. Hepatology 2007;46(6):2032-2039. DOI:10.1002/hep.

[15] Shuper PA, Neuman M, Kanteres F, Baliunas D, Joharchi N, Rehm J. Causal consid‐ erations on alcohol and HIV/AIDS--a systematic review. Alcohol Alcohol 2010;45(2):

[16] Te HS, Jensen DM. Epidemiology of hepatitis B and C viruses: a global overview.

[17] Nelson PK, Mathers BM, Cowie B, Hagan H, Des Jarlais D, Horyniak D, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of sys‐ tematic reviews. Lancet 2011;378(9791):571-583. DOI:10.1016/S0140-6736(11)61097-0.

[18] Mast EE, Weinbaum CM, Fiore AE, Alter MJ, Bell BP, Finelli L, et al. A comprehen‐ sive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) Part II: immunization of adults. MMWR Recomm Rep

[19] Kuo I, Sherman SG, Thomas DL, Strathdee SA. Hepatitis B virus infection and vacci‐ nation among young injection and non-injection drug users: missed opportunities to

[20] Alter MJ. Epidemiology and prevention of hepatitis B. Semin Liver Dis 2003;23(1):

[21] Goldstein ST, Alter MJ, Williams IT, Moyer LA, Judson FN, Mottram K, et al. Inci‐ dence and risk factors for acute hepatitis B in the United States, 1982-1998: implica‐ tions for vaccination programs. J Infect Dis 2002;185(6):713-719. DOI:10.1086/339192.

[22] Garfein RS, Vlahov D, Galai N, Doherty MC, Nelson KE. Viral infections in shortterm injection drug users: the prevalence of the hepatitis C, hepatitis B, human im‐ munodeficiency, and human T-lymphotropic viruses. Am J Public Health 1996;86(5):

[23] Levine OS, Vlahov D, Koehler J, Cohn S, Spronk AM, Nelson KE. Seroepidemiology of hepatitis B virus in a population of injecting drug users. Association with drug in‐

[24] Burt RD, Hagan H, Garfein RS, Sabin K, Weinbaum C, Thiede H. Trends in hepatitis B virus, hepatitis C virus, and human immunodeficiency virus prevalence, risk be‐

Clin Liver Dis 2010;14(1):1-21, vii. DOI:10.1016/j.cld.2009.11.009.

prevent infection. Drug Alcohol Depend 2004;73(1):69-78.

jection patterns. Am J Epidemiol 1995;142(3):331-341.

221-228. DOI:10.1097/QAD.0b013e328340fee2.

159-166. DOI:10.1093/alcalc/agp091.

2006;55(RR-16):1-33; quiz CE1-4.

39-46. DOI:10.1055/s-2003-37583.

655-661.

22010.

382 Current Perspectives in HIV Infection


[37] Duan S, Xiang LF, Yang YC, Ye RH, Jia MH, Luo HB, et al. Incidence and risk factors on HIV infection among injection drug users in Dehong prefecture area of Yunnan province. Zhonghua Liu Xing Bing Xue Za Zhi 2009;30(12):1226-1229.

**Chapter 17**

**Prevention of Sexually Transmitted HIV Infection**

Bio-medical prevention of sexually transmitted HIV infection is an evolving area in the field of HIV. In recent years, multiple studies have demonstrated the efficacy of diverse biomedical interventions to prevent the sexual acquisition of HIV infection in specific populations. The major developments in the field of prevention of sexual transmission of HIV include male circumcision, HIV viral suppression of HIV infected individuals (Treatment of positives), use of antiretrovirals before exposure to HIV (Pre-exposure prophylaxis), and use of microbicides. Some of these highly controlled studies demonstrated high levels of protection ranging from 55 to more than 90% when a single intervention has been studied. However, in real world situations, it is foreseeable that individuals will have the opportunity and option to choose, and ideally to combine, appropriate interventions according to their background, attitudes,

**Male circumcision:** Male circumcision effectively decreases rates of heterosexual transmission of HIV: There is now ample scientific evidence that male circumcision reduces the risk of acquiring HIV through heterosexual intercourse in males by approximately 51 to 60%, thus exceeding the 30 percent risk reduction set as a target for an AIDS vaccine. This level of protection is similar to the 67.5% relative reduction in the risk of maternal-infant transmission of HIV with the use of zidovudine in HIV infected pregnant women; currently one of the most successful strategies to prevent HIV infection in a selected population, newborns. The evidence of the effectiveness of male circumcision in decreasing the risk of HIV infection in males is so compelling that in March 2007, the World Health Organization and the Joint United Nations Programme on HIV/AIDS held a technical consultation on male circumcision and produced a document that stated that male circumcision should be recognized as an efficacious interven‐ tion for the prevention of heterosexually acquired HIV infection in men. Male circumcision (MC) has been proven to be a potent HIV prevention strategy, reducing risk of HIV acquisition in heterosexual men by 50-60%. One of the most successful interventions to prevent the

> © 2013 Castro and Alcaide; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

> © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

and reproduction in any medium, provided the original work is properly cited.

Jose G. Castro and Maria L. Alcaide

preferences and availability of methods.

http://dx.doi.org/10.5772/54168

**1. Introduction**

Additional information is available at the end of the chapter


### **Prevention of Sexually Transmitted HIV Infection**

Jose G. Castro and Maria L. Alcaide

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54168

### **1. Introduction**

[37] Duan S, Xiang LF, Yang YC, Ye RH, Jia MH, Luo HB, et al. Incidence and risk factors on HIV infection among injection drug users in Dehong prefecture area of Yunnan

[38] Hurtado Navarro I, Alastrue I, Del Amo J, Santos C, Ferreros I, Tasa T, et al. Differen‐ ces between women and men in serial HIV prevalence and incidence trends. Eur J

[39] Valoración de los nuevos diagnósticos de VIH en España a partir de los sistemas de notificación de casos de las CCAA. Periodo 2003-2008. Ministerio de Sanidad y Políti‐ ca Social, Ministerio de Ciencia e Innovación;2009. http://www.isciii.es/htdocs/pdf/

[40] Sanchez-Niubo A, Domingo-Salvany A, Melis GG, Brugal MT, Scalia-Tomba G. Two methods to analyze trends in the incidence of heroin and cocaine use in Barcelona

[41] European Monitoring centre for Drugs and Drug Addiction. Drug-related infectious diseases and drug-related deaths. http://www.emcdda.europa.eu/situation/diseases-

[42] Somaini B, Wang J, Perozo M, Kuhn F, Meili D, Grob P, et al. A continuing concern: HIV and hepatitis testing and prevalence among drug users in substitution pro‐ grammes in Zurich, Switzerland. AIDS Care 2000;12(4):449-460. DOI:

[43] van Beek I, Dwyer R, Dore GJ, Luo K, Kaldor JM. Infection with HIV and hepatitis C virus among injecting drug users in a prevention setting: retrospective cohort study.

[44] Centers for Disease Control and Prevention (CDC). HIV Infection Among Injection-

[45] Thorpe LE, Ouellet LJ, Levy JR, Williams IT, Monterroso ER. Hepatitis C virus infec‐ tion: prevalence, risk factors, and prevention opportunities among young injection drug users in Chicago, 1997-1999. J Infect Dis 2000;182(6):1588-1594. DOI:

[46] Garfein RS, Vlahov D, Galai N, Doherty MC, Nelson KE. Viral infections in short-term injection drug users: the prevalence of the hepatitis C, hepatitis B, human immunodefi‐ ciency, and human T-lymphotropic viruses. Am J Public Health 1996;86(5):655-661.

[47] Hagan H, Des Jarlais DC. HIV and HCV infection among injecting drug users. Mt Si‐

[48] Evans JL, Hahn JA, Page-Shafer K, Lum PJ, Stein ES, Davidson PJ, et al. Gender dif‐ ferences in sexual and injection risk behavior among active young injection drug users in San Francisco (the UFO Study). J Urban Health 2003;80(1):137-146. DOI:

Drug Users --- 34 States, 2004--2007. MMWR 2009;58:1291-1295.

province. Zhonghua Liu Xing Bing Xue Za Zhi 2009;30(12):1226-1229.

Epidemiol 2008;23(6):435-440. DOI:10.1007/s10654-008-9246-2.

nuevos\_diagnosticos\_ccaa.pdf. (accessed 30 july 2012)

[Spain]. Gac Sanit 2007;21(5):397-403.

384 Current Perspectives in HIV Infection

and-deaths/1 (accessed 30 july 2012).

10.1080/09540120050123855.

BMJ 1998;317(7156):433-437.

nai J Med 2000;67(5-6):423-428.

10.1093/jurban/jtg137.

10.1086/317607.

Bio-medical prevention of sexually transmitted HIV infection is an evolving area in the field of HIV. In recent years, multiple studies have demonstrated the efficacy of diverse biomedical interventions to prevent the sexual acquisition of HIV infection in specific populations. The major developments in the field of prevention of sexual transmission of HIV include male circumcision, HIV viral suppression of HIV infected individuals (Treatment of positives), use of antiretrovirals before exposure to HIV (Pre-exposure prophylaxis), and use of microbicides. Some of these highly controlled studies demonstrated high levels of protection ranging from 55 to more than 90% when a single intervention has been studied. However, in real world situations, it is foreseeable that individuals will have the opportunity and option to choose, and ideally to combine, appropriate interventions according to their background, attitudes, preferences and availability of methods.

**Male circumcision:** Male circumcision effectively decreases rates of heterosexual transmission of HIV: There is now ample scientific evidence that male circumcision reduces the risk of acquiring HIV through heterosexual intercourse in males by approximately 51 to 60%, thus exceeding the 30 percent risk reduction set as a target for an AIDS vaccine. This level of protection is similar to the 67.5% relative reduction in the risk of maternal-infant transmission of HIV with the use of zidovudine in HIV infected pregnant women; currently one of the most successful strategies to prevent HIV infection in a selected population, newborns. The evidence of the effectiveness of male circumcision in decreasing the risk of HIV infection in males is so compelling that in March 2007, the World Health Organization and the Joint United Nations Programme on HIV/AIDS held a technical consultation on male circumcision and produced a document that stated that male circumcision should be recognized as an efficacious interven‐ tion for the prevention of heterosexually acquired HIV infection in men. Male circumcision (MC) has been proven to be a potent HIV prevention strategy, reducing risk of HIV acquisition in heterosexual men by 50-60%. One of the most successful interventions to prevent the

© 2013 Castro and Alcaide; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

acquisition of HIV infection in heterosexual men is circumcision, which has reduced HIV risk by 50-60% among heterosexual men in sub-Saharan Africa. The uptake of male circumcision in traditionally non-circumcision communities have been varied and influenced by different factor. In the US males from racial and ethnic minorities are less likely to be circumcised and also more likely to become infected with HIV so a recently published analyses showed that newborn circumcision resulted in lower expected HIV-related treatment costs and a slight increase in quality-adjusted life years.

**Microbicides:** Given the theoretical advantages of a microbicide (controlled by women, no need for male cooperation) the search for an effective product was elusive until investigators from CAPRISA 004 study reported at the World AIDS conference in 2010 in Vienna, that 1% tenofovir gel used with coitus reduced HIV risk by 39% among 889 South African women. Sub-analyses of the data showed that protection was more pronounced (54%) in women with higher adherence to the gel. Several studies are under way with other products and with alternative delivery systems that will alleviate the need for strict adherence to its use before

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

387

**2. Bio-medical interventions to prevent hiv sexually transmitted infection**

Male circumcision is the surgical procedure that consists in the removal of some or all the foreskin of the penis [1]. The word "circumcision" comes from the Latin circum (meaning "around") and caedere (meaning "to cut") [2]. The foreskin is a continuation of the skin from the shaft of the penis, which covers the glans penis and the urethral meatus. The foreskin is attached to the glans by the frenulum, a highly vascularized tissue of the penis. Male circum‐ cision is one of the oldest surgical procedures known, traditionally undertaken as a mark of cultural identity or religious importance [3]. Rates of male circumcision are different around the word and related to cultural and religious beliefs [4]. Historically, male circumcision has been associated with religious practice and ethnic identity. Circumcision was practiced among ancient Semitic peoples including Egyptians and Jews, with the earliest records depicting the practice coming from Egyptian tomb artwork (from the Sixth Dynasty, 2345-2181 B.C.) and wall paintings dating from around 2300 BC [3]. Muslims are the largest religious group to practice male circumcision. As an Abrahamic faith, Muslims practice circumcision, as a confirmation of their relationship with God, and the practice is also known as tahera, meaning purification [3]. With the global spread of Islam from the 7th century AD, circumcision was widely adopted among previously non-circumcising peoples. In some regions, male circum‐ cision was already a cultural tradition prior to the arrival of Islam (for example among the Poro in West Africa, and in Timor in SE Asia). [5-7] Circumcision has also been practice for non-religious reasons for many thousand of years in sub-Saharan Africa, and in many ethnic groups around the world, including aboriginal Australasians, the Aztecs and Mayans in the Americas, inhabitants of the Philippines and eastern Indonesia and various pacific Islands, including Fiji and the Polynesian islands [3]. In the majority of these cultures, circumcision is an integral part of a rite of passage to manhood, although originally it may have been a test of bravery and endurance. Male circumcision traditionally has been done for medical and non medical reasons (including religious or cultural reasons). When it is practiced for non-medical reasons it is typically performed in the neonatal period or just before the adolescence. The practice of circumcision, in particular of neonatal circumcision remains highly controversial despite recent evidence of the medical benefits, including decreased risk of heterosexual acquisition of HIV infection by men, decreased risk of acquisition of several sexually trans‐ mitted infections, decreased risk of urinary tract infection and recent evidence of decreased

and after sex.

**2.1. Male circumcision**

**Treatment of Positives:** Since the early years of the epidemic, it was demonstrated that the use of antiretrovirals in infected pregnant women decreased the likelihood of HIV infection in the new born. Additional studies demonstrated that the key factor in the transmission of the infection from the mother to the newborn was the maternal HIV viral load; and then the suppression of HIV by the administration of antiretrovirals became the standard of care in the management of HIV infected pregnant women. This practice led to the almost eradication of congenital HIV infection in communities with access to medications. Circumstantial evidence suggested that the same principle could be applied to the sexual transmission of HIV as in general there is correlation between the HIV viral load in blood and genital secretions. In 2011 a breakthrough study proved that treatment of HIV positive decreased the likelihood of sexual transmission in more than 96% in discordant heterosexual couples.

**Pre-exposure prophylaxis (PrEP) in MSM and heterosexual men and women:** PrEP involves the use of antiretroviral medications before potential HIV exposure to prevent infection. In recent years several studies suggested the possible efficacy of the use of TDF/FTC as PrEP; but in the last six months, several controlled studies have provided definitive proof of its efficacy in certain populations: iPrEx was a study that randomized 2499 HIV-negative MSM or transgender women who have sex with men to take oral daily tenofovir and emtricitabine (FTC/TDF) or placebo. Overall, 100 subjects became infected during the study (36 in the FTC/ TDF group and 64 in the placebo group), indicating a 44% reduction in the HIV incidence. The Partners PrEP Study was a phase III, randomized, double blind, placebo-controlled, three arm trial of oral daily (FTC/TDF) PrEP for the prevention of HIV acquisition by HIV seronegative partner in HIV serodiscordant partnerships. The independent DSMB recommended that the results of the study be publically reported, nearly 2 years earlier than expected, and the placebo arm discontinued, because clear demonstration of HIV protection due to PrEP. The TDF2A was a double-blind, randomized, trial of daily oral FTC/TDF or placebo for prevention of HIV acquisition in young (18-39) women and men in Bostwana. A total of 1219 individuals were randomized, about 30% of the study population did not complete follow up. Adherence to PrEP overall was estimated to be approximately 84%. Overall 9 HIV infections occurred among those assigned to FTC/TDF compared to 24 among those assigned to placebo, translating to an efficacy for HIV protection of 63%. All these studies shown that PrEP is a viable biomedical intervention that can be use for the prevention of sexually transmitted HIV infection in both heterosexual and male who have sex with men populations but is highly dependent of the adherence to the medications. There are few promising agents that could be use over extended periods of time decreasing the need for daily medication.

**Microbicides:** Given the theoretical advantages of a microbicide (controlled by women, no need for male cooperation) the search for an effective product was elusive until investigators from CAPRISA 004 study reported at the World AIDS conference in 2010 in Vienna, that 1% tenofovir gel used with coitus reduced HIV risk by 39% among 889 South African women. Sub-analyses of the data showed that protection was more pronounced (54%) in women with higher adherence to the gel. Several studies are under way with other products and with alternative delivery systems that will alleviate the need for strict adherence to its use before and after sex.

### **2. Bio-medical interventions to prevent hiv sexually transmitted infection**

#### **2.1. Male circumcision**

acquisition of HIV infection in heterosexual men is circumcision, which has reduced HIV risk by 50-60% among heterosexual men in sub-Saharan Africa. The uptake of male circumcision in traditionally non-circumcision communities have been varied and influenced by different factor. In the US males from racial and ethnic minorities are less likely to be circumcised and also more likely to become infected with HIV so a recently published analyses showed that newborn circumcision resulted in lower expected HIV-related treatment costs and a slight

**Treatment of Positives:** Since the early years of the epidemic, it was demonstrated that the use of antiretrovirals in infected pregnant women decreased the likelihood of HIV infection in the new born. Additional studies demonstrated that the key factor in the transmission of the infection from the mother to the newborn was the maternal HIV viral load; and then the suppression of HIV by the administration of antiretrovirals became the standard of care in the management of HIV infected pregnant women. This practice led to the almost eradication of congenital HIV infection in communities with access to medications. Circumstantial evidence suggested that the same principle could be applied to the sexual transmission of HIV as in general there is correlation between the HIV viral load in blood and genital secretions. In 2011 a breakthrough study proved that treatment of HIV positive decreased the likelihood of sexual

**Pre-exposure prophylaxis (PrEP) in MSM and heterosexual men and women:** PrEP involves the use of antiretroviral medications before potential HIV exposure to prevent infection. In recent years several studies suggested the possible efficacy of the use of TDF/FTC as PrEP; but in the last six months, several controlled studies have provided definitive proof of its efficacy in certain populations: iPrEx was a study that randomized 2499 HIV-negative MSM or transgender women who have sex with men to take oral daily tenofovir and emtricitabine (FTC/TDF) or placebo. Overall, 100 subjects became infected during the study (36 in the FTC/ TDF group and 64 in the placebo group), indicating a 44% reduction in the HIV incidence. The Partners PrEP Study was a phase III, randomized, double blind, placebo-controlled, three arm trial of oral daily (FTC/TDF) PrEP for the prevention of HIV acquisition by HIV seronegative partner in HIV serodiscordant partnerships. The independent DSMB recommended that the results of the study be publically reported, nearly 2 years earlier than expected, and the placebo arm discontinued, because clear demonstration of HIV protection due to PrEP. The TDF2A was a double-blind, randomized, trial of daily oral FTC/TDF or placebo for prevention of HIV acquisition in young (18-39) women and men in Bostwana. A total of 1219 individuals were randomized, about 30% of the study population did not complete follow up. Adherence to PrEP overall was estimated to be approximately 84%. Overall 9 HIV infections occurred among those assigned to FTC/TDF compared to 24 among those assigned to placebo, translating to an efficacy for HIV protection of 63%. All these studies shown that PrEP is a viable biomedical intervention that can be use for the prevention of sexually transmitted HIV infection in both heterosexual and male who have sex with men populations but is highly dependent of the adherence to the medications. There are few promising agents that could be use over extended

transmission in more than 96% in discordant heterosexual couples.

periods of time decreasing the need for daily medication.

increase in quality-adjusted life years.

386 Current Perspectives in HIV Infection

Male circumcision is the surgical procedure that consists in the removal of some or all the foreskin of the penis [1]. The word "circumcision" comes from the Latin circum (meaning "around") and caedere (meaning "to cut") [2]. The foreskin is a continuation of the skin from the shaft of the penis, which covers the glans penis and the urethral meatus. The foreskin is attached to the glans by the frenulum, a highly vascularized tissue of the penis. Male circum‐ cision is one of the oldest surgical procedures known, traditionally undertaken as a mark of cultural identity or religious importance [3]. Rates of male circumcision are different around the word and related to cultural and religious beliefs [4]. Historically, male circumcision has been associated with religious practice and ethnic identity. Circumcision was practiced among ancient Semitic peoples including Egyptians and Jews, with the earliest records depicting the practice coming from Egyptian tomb artwork (from the Sixth Dynasty, 2345-2181 B.C.) and wall paintings dating from around 2300 BC [3]. Muslims are the largest religious group to practice male circumcision. As an Abrahamic faith, Muslims practice circumcision, as a confirmation of their relationship with God, and the practice is also known as tahera, meaning purification [3]. With the global spread of Islam from the 7th century AD, circumcision was widely adopted among previously non-circumcising peoples. In some regions, male circum‐ cision was already a cultural tradition prior to the arrival of Islam (for example among the Poro in West Africa, and in Timor in SE Asia). [5-7] Circumcision has also been practice for non-religious reasons for many thousand of years in sub-Saharan Africa, and in many ethnic groups around the world, including aboriginal Australasians, the Aztecs and Mayans in the Americas, inhabitants of the Philippines and eastern Indonesia and various pacific Islands, including Fiji and the Polynesian islands [3]. In the majority of these cultures, circumcision is an integral part of a rite of passage to manhood, although originally it may have been a test of bravery and endurance. Male circumcision traditionally has been done for medical and non medical reasons (including religious or cultural reasons). When it is practiced for non-medical reasons it is typically performed in the neonatal period or just before the adolescence. The practice of circumcision, in particular of neonatal circumcision remains highly controversial despite recent evidence of the medical benefits, including decreased risk of heterosexual acquisition of HIV infection by men, decreased risk of acquisition of several sexually trans‐ mitted infections, decreased risk of urinary tract infection and recent evidence of decreased risk of prostate cancer [8-10]. There are no reliable data of the rate of circumcision in many areas of the world in particular in regions where is not commonly practiced; but in general it is believed that rates of circumcision are very low in Latin-America including the Caribbean region, China, India and Europe [2], Fig 1.

Health (NIH) and the ARNS (French National Research Agency), three independent but similar randomized control trials were launched in three different communities in South Africa in 2002-2003 to address this question. The studies were performed in South Africa, Kenya, and Uganda, within peri-urban, urban, and rural communities respectively [20-22]. The study conducted in South Africa (Orange farm, bordering Johannesburg) included 3,128 men 18 to 24 years old. Eligible men were randomly allocated to undergo immediate or delayed (offered at the end of the follow up period) circumcision. Men were assessed at 3, 12 and 24 months for HIV acquisition, sexually transmitted infections, and changes in sexual behaviors. Interim analysis in 2004 revealed a 0.4 relative risk of HIV acquisition (95% CI, 0.24%-0.68%.; P < 0.001) among the circumcised compared to uncircumcised participants. This finding corresponds to a protective effect of circumcision of 60%, which is a level of protection similar many used vaccines. Given these striking results, the safety and monitoring board discontinued the trial early, and circumcision was offered to the control arm. The Orange Farm study results prompted ethical concerns about continuation of the two remaining studies. The World Health Organization (WHO) recommended continuation but mandated a previously unplanned, earlier interim evaluation. At the interim evaluation, the studies in Kenya and Uganda provided evidence of protection against HIV infection of 50% to 60%, remarkably similar to the results from the Orange Farm trial. These two trials were discontinued prematurely on December 12, 2006. Together, the three studies demonstrated a 50% to 60% reduction in HIV acquisition by medicalized circumcision. [20-22] In total, 10,908 uncircumcised, HIV-negative adult men were randomly assigned to intervention or control arms, and followed for up to 2 years. Overall retention rates were high (86-92% at the end of follow up, when men in the control arm were offered circumcision). Recent findings support the long-term benefit conveyed by MC, with the Kisumu, Kenya cohort maintaining/modestly increasing the earlier level of protection (60% to 64%) at 54 month follow up [23]. These studies, among others, provide "unequivocal evidence that circumcision plays a causal role in reducing the risk of

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

389

On the basis of the findings from the three clinical trials, a WHO and UNAIDS consultation in March 2007, recommended that circumcision should be recognized as an effective intervention for HIV prevention of heterosexual HIV acquisition in men [24]. WHO and UNAIDS also recommended that male circumcision should be offered HIV-negative men in addition, but not as a substitute, to other HIV risk-reduction strategies. The public-health effect of male circumcision will be largest in generalized epidemics. As such, WHO and UNAIDS recom‐ mend that countries with hyperendemic and generalized epidemics and low prevalence of male circumcision expand access to safe male circumcision services within the context of ensuring universal access to comprehensive HIV prevention, treatment, care, and support. [25]

The public health benefit of MC as a tool for HIV prevention, will depend of many factors. One of the most important is the acceptability and uptake of circumcision in traditionally noncircumcising societies. It can be expected that the benefit can spread beyond circumcised men because if sufficient number of males are circumcised, circumcision in the long range will also

HIV infection among men" [24].

**2.2. Acceptability of MC as a tool for HIV prevention**

Global map of male circumcision prevalence at country level, as of December 2006.

**Figure 1.** Worldwide prevalence of Male Circumcision.

#### *2.1.1. Studies addressing MC in the field of HIV prevention*

#### *2.1.1.1. Cohort studies*

The first paper suggesting a protective effect of MC against HIV infection was published in 1986 [11]. Since then, many observational studies have been published, some of which have observed that most men living in East and southern Africa, the regions with the highest prevalence of HIV are not circumcised [12-14]. More than 30 cross-sectional studies found the prevalence of HIV to be significantly higher in uncircumcised men than in those who are circumcised [15] and 14 prospective studies all showed a protective effect, ranging from 48% to 88% [16-18]. A systematic review and meta analyses of studies from sub-Saharan Africa reported an adjusted relative risk of 042 (95% CI 0.34-0.54) in all circumcised men, with a stronger adjusted relative risk of 0.29 (0.20 – 0.41) in circumcised men who were at higher risk of acquiring HIV [19].

#### *2.1.1.2. Randomized studies*

Given the compelling observational data of the potential protective role of male circumcision in the acquisition of heterosexually transmitted HIV infection and the growing crisis of HIV infection in sub-Saharan Africa; it was clear that only randomized studies could provide unequivocally evidence of this protection. Under the sponsorship of the National Institutes of Health (NIH) and the ARNS (French National Research Agency), three independent but similar randomized control trials were launched in three different communities in South Africa in 2002-2003 to address this question. The studies were performed in South Africa, Kenya, and Uganda, within peri-urban, urban, and rural communities respectively [20-22]. The study conducted in South Africa (Orange farm, bordering Johannesburg) included 3,128 men 18 to 24 years old. Eligible men were randomly allocated to undergo immediate or delayed (offered at the end of the follow up period) circumcision. Men were assessed at 3, 12 and 24 months for HIV acquisition, sexually transmitted infections, and changes in sexual behaviors. Interim analysis in 2004 revealed a 0.4 relative risk of HIV acquisition (95% CI, 0.24%-0.68%.; P < 0.001) among the circumcised compared to uncircumcised participants. This finding corresponds to a protective effect of circumcision of 60%, which is a level of protection similar many used vaccines. Given these striking results, the safety and monitoring board discontinued the trial early, and circumcision was offered to the control arm. The Orange Farm study results prompted ethical concerns about continuation of the two remaining studies. The World Health Organization (WHO) recommended continuation but mandated a previously unplanned, earlier interim evaluation. At the interim evaluation, the studies in Kenya and Uganda provided evidence of protection against HIV infection of 50% to 60%, remarkably similar to the results from the Orange Farm trial. These two trials were discontinued prematurely on December 12, 2006. Together, the three studies demonstrated a 50% to 60% reduction in HIV acquisition by medicalized circumcision. [20-22] In total, 10,908 uncircumcised, HIV-negative adult men were randomly assigned to intervention or control arms, and followed for up to 2 years. Overall retention rates were high (86-92% at the end of follow up, when men in the control arm were offered circumcision). Recent findings support the long-term benefit conveyed by MC, with the Kisumu, Kenya cohort maintaining/modestly increasing the earlier level of protection (60% to 64%) at 54 month follow up [23]. These studies, among others, provide "unequivocal evidence that circumcision plays a causal role in reducing the risk of HIV infection among men" [24].

On the basis of the findings from the three clinical trials, a WHO and UNAIDS consultation in March 2007, recommended that circumcision should be recognized as an effective intervention for HIV prevention of heterosexual HIV acquisition in men [24]. WHO and UNAIDS also recommended that male circumcision should be offered HIV-negative men in addition, but not as a substitute, to other HIV risk-reduction strategies. The public-health effect of male circumcision will be largest in generalized epidemics. As such, WHO and UNAIDS recom‐ mend that countries with hyperendemic and generalized epidemics and low prevalence of male circumcision expand access to safe male circumcision services within the context of ensuring universal access to comprehensive HIV prevention, treatment, care, and support. [25]

#### **2.2. Acceptability of MC as a tool for HIV prevention**

risk of prostate cancer [8-10]. There are no reliable data of the rate of circumcision in many areas of the world in particular in regions where is not commonly practiced; but in general it is believed that rates of circumcision are very low in Latin-America including the Caribbean

The first paper suggesting a protective effect of MC against HIV infection was published in 1986 [11]. Since then, many observational studies have been published, some of which have observed that most men living in East and southern Africa, the regions with the highest prevalence of HIV are not circumcised [12-14]. More than 30 cross-sectional studies found the prevalence of HIV to be significantly higher in uncircumcised men than in those who are circumcised [15] and 14 prospective studies all showed a protective effect, ranging from 48% to 88% [16-18]. A systematic review and meta analyses of studies from sub-Saharan Africa reported an adjusted relative risk of 042 (95% CI 0.34-0.54) in all circumcised men, with a stronger adjusted relative risk of 0.29 (0.20 – 0.41) in circumcised men who were at higher risk

Given the compelling observational data of the potential protective role of male circumcision in the acquisition of heterosexually transmitted HIV infection and the growing crisis of HIV infection in sub-Saharan Africa; it was clear that only randomized studies could provide unequivocally evidence of this protection. Under the sponsorship of the National Institutes of

region, China, India and Europe [2], Fig 1.

388 Current Perspectives in HIV Infection

**Figure 1.** Worldwide prevalence of Male Circumcision.

*2.1.1.1. Cohort studies*

of acquiring HIV [19].

*2.1.1.2. Randomized studies*

*2.1.1. Studies addressing MC in the field of HIV prevention*

Global map of male circumcision prevalence at country level, as of December 2006.

The public health benefit of MC as a tool for HIV prevention, will depend of many factors. One of the most important is the acceptability and uptake of circumcision in traditionally noncircumcising societies. It can be expected that the benefit can spread beyond circumcised men because if sufficient number of males are circumcised, circumcision in the long range will also protect women; effect similar to herd immunity [26]. In addition to the proportion of males who will become circumcised, the age at circumcision will be also a determinant of how rapidly the intervention results in reduction of HIV prevalence in the population. For example, if boys and young men before sexual debut are targeted, the measurable impact it is not likely to be realized for over 10 years; if older boys and men up to 30 years are prioritized a more rapid effect can be expected. On the other hand, circumcision of neonates, in whom the procedure is simpler and less risky, the impact of the strategy on HIV incidence would not be expected for at least 20 years. [25] Because acceptance of male circumcision by men and by parents of males in traditionally non-circumcising communities will be crucial to the success of a MC intervention for reducing HIV prevalence a significant number of studies have been conducted in different non-circumcising communities with high or increasing rates of HIV infection across the globe [26-29]. Across most of these studies, the most common barriers to the acceptability of male circumcision include the following factors: pain (apprehension about pain during and after the procedure has been reported to be the major barrier to MC accept‐ ability; culture and religion have also factors that have been consistently brought up in the discussions about acceptability of MC in diverse groups; cost of the procedure has been named as a significant barrier to MC acceptability and safety (potential for complications and adverse effects). Other potential barriers named in some but not in all studies include: lack of access to health care, required time away from work, the concern about loss of penile sensitivity, reduction in penis size, decreased ability to satisfy women, excessive sexual desire, increased promiscuity and the perception of circumcision as old-fashioned [28-29]. On the other hand, the most consistently named facilitators of MC include the following factors: hygiene, which has universally been recognized as a major benefit of MC; protection from sexually transmitted diseases and HIV (linked through hygiene) and improved sexual pleasure.

infected with HIV oral zidovudine from 14 weeks, intravenously at labor and delivery, and followed by six weeks of zidovudine prophylaxis to their newborns, could reduce transmission by 67.5% (95 percent confidence interval, 40.7 to 82.1 percent) [30]. Since this pivotal study proved the concept that antiretrovirals could be use to prevent HIV infection, significant progress has been accomplished in the prevention of mother to child transmission, to the point that current transmission rates are estimated at less than 2 percent with the use of triple antiretroviral drugs during pregnancy. [34, 35], Figure 2. Despite these major advances in the prevention of mother to child transmission of HIV-1, it was not until several years later that these ideas were extrapolated to the prevention of sexual transmission of HIV-1. A central idea was that the quantity of HIV-1 in plasma was a primary determinant of the risk of HIV-1 transmission [36]. By then it was already clear that antiretroviral therapy could reduce plasma HIV-1 to undetectable concentrations within 6 months of initiation in most patients [37, 38] and seminal and cervicovaginal HIV-1 concentrations could also be reduced to undetectable levels in most people on ART [39 – 41]. A meta-analyses of data from five studies reported only five cases of HIV-1 transmission from patients receiving antiretroviral therapy to sexual partners during 1098 person-years of follow up, which is consistent with an infection rate of 0.19 – 1.09 per 100 person-years [42]. Additional evidence was obtained from a pos-hoc analysis of the Partners in Prevention HSV/HIV Transmission study of acyclovir HSV-2 suppressive therapy versus placebo [43]. In this analysis of almost 3,400 HIV-1 serodiscordant heterosexual couples from seven African countries, ART use by the infected person was accompanied by a 92% reduction in the risk of HIV-1 transmission to their partner. Several other observational and some ecological studies added to the evidence and set the need for a randomized study to test the hypothesis if index individuals taking ART are less likely to transmit HIV infection than individuals not on ART. In 2007 the HIV Prevention Trials Network (HPTN) started to enroll participants in a multi-continent, randomized, controlled trial, called HPTN 052, to compare early versus delayed antiretroviral therapy for patients with HIV-1 infection who had CD4 counts between 350 and 550 cells per cubic millimeter and who were in a stable hetero‐ sexual relationship with a partner who was not infected [44]. A total of 1763 HIV-1 serodis‐ cordant couples were enrolled (886 couples were randomly assigned to the early therapy group and 877 to the delayed-therapy group). The study was slated to end in 2015, but an interim data review on April 26 2011, by an independent data and safety monitoring board (DSMB) found that of the total 28 cases of HIV infection among the previously uninfected partners, only one case occurred among those couples where the HIV-infected partner began immediate antiretroviral therapy. The DSMB, therefore, called for immediate public release of the study's findings on the basis of data collection through February 21, 2011. At that time, 90% of couples remained enrolled in the study, with a median follow up of 1.7 years. This study demonstrated the power of early antiretroviral treatment (ART) for almost completely preventing onward sexual HIV transmission in the clinical trial setting. This study offered proof of the concept that reduction of viral load through treatment could prevent HIV transmission, a concept that has served as the foundation for multiple modeling studies on treatment-as-prevention and one which was already held to be true by many. The data are incontrovertible, and although they resolve the question of whether this approach can prevent HIV transmission, they also lead to a more fully informed discussion of how ART might actually be used to prevent

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

391

In summary, the protective effect of adult male circumcision on HIV acquisition has been reported in a review of epidemiological studies and demonstrated by three randomized controlled trials conducted in Southern and Eastern Africa, which found that the risk of HIV acquisition among circumcised men was reduced by about 60%. Based on this evidence, in 2007 WHO/UNAIDS recommended adult male circumcision as an important, additional intervention which should be delivered as part of a comprehensive HIV prevention package in communities with generalized HIV epidemics and low male circumcision rates. Since then, a number of initiatives have taken place in different countries to role out adult male circum‐ cision services as an additional scientifically proven biomedical strategy to prevent HIV acquisition.

### **3. Treatment of positives**

The idea to use antiretrovirals to prevent the acquisition and transmission of the Human Immunodeficiency virus was tested early in the 90's after animal models of retroviral infection demonstrated that zidovudine could prevent or alter the course of maternally transmitted HIV infection [30 – 33]. The results of this initial US Pediatric AIDS Clinical Trials Group Protocol (PACTG) 076 clinical trial were announced in 1994, which showed that giving pregnant women infected with HIV oral zidovudine from 14 weeks, intravenously at labor and delivery, and followed by six weeks of zidovudine prophylaxis to their newborns, could reduce transmission by 67.5% (95 percent confidence interval, 40.7 to 82.1 percent) [30]. Since this pivotal study proved the concept that antiretrovirals could be use to prevent HIV infection, significant progress has been accomplished in the prevention of mother to child transmission, to the point that current transmission rates are estimated at less than 2 percent with the use of triple antiretroviral drugs during pregnancy. [34, 35], Figure 2. Despite these major advances in the prevention of mother to child transmission of HIV-1, it was not until several years later that these ideas were extrapolated to the prevention of sexual transmission of HIV-1. A central idea was that the quantity of HIV-1 in plasma was a primary determinant of the risk of HIV-1 transmission [36]. By then it was already clear that antiretroviral therapy could reduce plasma HIV-1 to undetectable concentrations within 6 months of initiation in most patients [37, 38] and seminal and cervicovaginal HIV-1 concentrations could also be reduced to undetectable levels in most people on ART [39 – 41]. A meta-analyses of data from five studies reported only five cases of HIV-1 transmission from patients receiving antiretroviral therapy to sexual partners during 1098 person-years of follow up, which is consistent with an infection rate of 0.19 – 1.09 per 100 person-years [42]. Additional evidence was obtained from a pos-hoc analysis of the Partners in Prevention HSV/HIV Transmission study of acyclovir HSV-2 suppressive therapy versus placebo [43]. In this analysis of almost 3,400 HIV-1 serodiscordant heterosexual couples from seven African countries, ART use by the infected person was accompanied by a 92% reduction in the risk of HIV-1 transmission to their partner. Several other observational and some ecological studies added to the evidence and set the need for a randomized study to test the hypothesis if index individuals taking ART are less likely to transmit HIV infection than individuals not on ART. In 2007 the HIV Prevention Trials Network (HPTN) started to enroll participants in a multi-continent, randomized, controlled trial, called HPTN 052, to compare early versus delayed antiretroviral therapy for patients with HIV-1 infection who had CD4 counts between 350 and 550 cells per cubic millimeter and who were in a stable hetero‐ sexual relationship with a partner who was not infected [44]. A total of 1763 HIV-1 serodis‐ cordant couples were enrolled (886 couples were randomly assigned to the early therapy group and 877 to the delayed-therapy group). The study was slated to end in 2015, but an interim data review on April 26 2011, by an independent data and safety monitoring board (DSMB) found that of the total 28 cases of HIV infection among the previously uninfected partners, only one case occurred among those couples where the HIV-infected partner began immediate antiretroviral therapy. The DSMB, therefore, called for immediate public release of the study's findings on the basis of data collection through February 21, 2011. At that time, 90% of couples remained enrolled in the study, with a median follow up of 1.7 years. This study demonstrated the power of early antiretroviral treatment (ART) for almost completely preventing onward sexual HIV transmission in the clinical trial setting. This study offered proof of the concept that reduction of viral load through treatment could prevent HIV transmission, a concept that has served as the foundation for multiple modeling studies on treatment-as-prevention and one which was already held to be true by many. The data are incontrovertible, and although they resolve the question of whether this approach can prevent HIV transmission, they also lead to a more fully informed discussion of how ART might actually be used to prevent

protect women; effect similar to herd immunity [26]. In addition to the proportion of males who will become circumcised, the age at circumcision will be also a determinant of how rapidly the intervention results in reduction of HIV prevalence in the population. For example, if boys and young men before sexual debut are targeted, the measurable impact it is not likely to be realized for over 10 years; if older boys and men up to 30 years are prioritized a more rapid effect can be expected. On the other hand, circumcision of neonates, in whom the procedure is simpler and less risky, the impact of the strategy on HIV incidence would not be expected for at least 20 years. [25] Because acceptance of male circumcision by men and by parents of males in traditionally non-circumcising communities will be crucial to the success of a MC intervention for reducing HIV prevalence a significant number of studies have been conducted in different non-circumcising communities with high or increasing rates of HIV infection across the globe [26-29]. Across most of these studies, the most common barriers to the acceptability of male circumcision include the following factors: pain (apprehension about pain during and after the procedure has been reported to be the major barrier to MC accept‐ ability; culture and religion have also factors that have been consistently brought up in the discussions about acceptability of MC in diverse groups; cost of the procedure has been named as a significant barrier to MC acceptability and safety (potential for complications and adverse effects). Other potential barriers named in some but not in all studies include: lack of access to health care, required time away from work, the concern about loss of penile sensitivity, reduction in penis size, decreased ability to satisfy women, excessive sexual desire, increased promiscuity and the perception of circumcision as old-fashioned [28-29]. On the other hand, the most consistently named facilitators of MC include the following factors: hygiene, which has universally been recognized as a major benefit of MC; protection from sexually transmitted

diseases and HIV (linked through hygiene) and improved sexual pleasure.

acquisition.

**3. Treatment of positives**

390 Current Perspectives in HIV Infection

In summary, the protective effect of adult male circumcision on HIV acquisition has been reported in a review of epidemiological studies and demonstrated by three randomized controlled trials conducted in Southern and Eastern Africa, which found that the risk of HIV acquisition among circumcised men was reduced by about 60%. Based on this evidence, in 2007 WHO/UNAIDS recommended adult male circumcision as an important, additional intervention which should be delivered as part of a comprehensive HIV prevention package in communities with generalized HIV epidemics and low male circumcision rates. Since then, a number of initiatives have taken place in different countries to role out adult male circum‐ cision services as an additional scientifically proven biomedical strategy to prevent HIV

The idea to use antiretrovirals to prevent the acquisition and transmission of the Human Immunodeficiency virus was tested early in the 90's after animal models of retroviral infection demonstrated that zidovudine could prevent or alter the course of maternally transmitted HIV infection [30 – 33]. The results of this initial US Pediatric AIDS Clinical Trials Group Protocol (PACTG) 076 clinical trial were announced in 1994, which showed that giving pregnant women

transmission in communities. The magnitude of protection against HIV infection demonstrat‐ ed in HPTN 052 has made the successful strategy of the clinical trial a key component of public health policies recently discussed by federal officials and others saying that achieving an end to the HIV/AIDS pandemic is now feasible with additional research and implementation efforts. Given the profound implications of HPTN 052's for the future response to the AIDS epidemic, the journal Science choose this study as its Breakthrough of the Year [45].

This graphic provides evidence of the impact at the population of an effective bio-medical

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

393

Pre-exposure prophylaxis (PrEP) involves the use of antiretroviral medications by HIV negative individuals before exposure to the HIV virus, to prevent HIV acquisition. The principle behind the use of antiretrovirals (ART) to prevent sexually acquisition of HIV lies on the success of HIV prevention in mother to Child transmission (PMTCT) and accidental exposure in healthcare workers. Early in the HIV epidemics, two large prevention trials (HIV Prevention Network Trial, HPTN 076 and HIVNET 012) showed that providing ART to infants born to HIV positive mothers significantly decreased the rates of HIV infection in newborns [30,46]. This is one of the greatest accomplishments in the field of HIV prevention, has been incorporated to PMTCT guidelines, and provided a starting ground for PrEP [30,46, 47]. In the area of health care related exposure to HIV, primarily needle sticks, the use of ART by the negative individual during the weeks after exposure reduces HIV acquisition by 80% [48, 49]. Following the human studies assessing PMTCT and prevention in the healthcare setting, animal studies to address PrEP demostrated that the administration of ART to macaque monkeys exposed to HIV prevented HIV infection [50,51]. All this data provided basis for

In recent years, tremendous advances in the field of PrEP in individuals at risk for HIV acquisition have led to landmark large randomized controlled studies using oral or topical agents. Results of the initial major studies addressing PrEP were somehow controversial, but recent data provides evidence that PrEP is an effective and safe alternative to prevent HIV

A major benefit of PrEP is its use by the individual at risk without involvement of sexual partners. Men who have sex with men (MSM) and women are especially vulnerable to HIV infection due to cultural, social and biological factors. Stigma associated with homosexuality, gender disparities, inability for women to negotiate condom use and fidelity, as well as frangibility of vaginal and rectal mucosa, predispose these populations to HIV infection and make them ideal candidates for such preventive method. PrEP is therefore emerging as a new powerful prevention method of especial importance in those populations at higher risk.

To date, most studies regarding PrEP have focused on two main modes of delivery: oral agents or topical microbidides. The two delivery modes will be presented separate in this chapter. Other forms of delivery such as subcutaneous or vaginal implants are under investigation and

While some studies addressing PrEP yielded important and relevant results, other studies are still undergoing and some are in the early stages of development. PrEP is therefore an evolving area in the field of HIV prevention and emerging data is likely to change the way we prevent

intervention to prevent HIV infection.

**4. Pre-exposure prophylaxis**

designing clinical trials to test PrEP in humans.

infection.

will be briefly mentioned.

sexually acquired HIV infection in the near future.

In summary, in 2011 it was scientifically demonstrated that treating individuals with HIV infection will prevent the transmission of HIV infection. However, the use of this strategy to the population level it is still not ready to fully achieve its potential because there are resource constraints and logistical hurdles, that limit its implementation.

**Figure 2.** AIDS Diagnoses among perinatally infected persons, 1985-2010. United States and 6 U.S. dependent areas.

This slide from the CDC presents trends from 1985 through 2010 in the estimated numbers of AIDS diagnoses among persons who were perinatally infected in the U.S. The blue line shows the annual numbers of perinatally infected children who were diagnosed with AIDS when they were less than 13 years of age; the pink line shows the annual numbers of persons who were infected with HIV perinatally and were diagnosed with AIDS at the age of 13 or older. This graphic provides evidence of the impact at the population of an effective bio-medical intervention to prevent HIV infection.

### **4. Pre-exposure prophylaxis**

transmission in communities. The magnitude of protection against HIV infection demonstrat‐ ed in HPTN 052 has made the successful strategy of the clinical trial a key component of public health policies recently discussed by federal officials and others saying that achieving an end to the HIV/AIDS pandemic is now feasible with additional research and implementation efforts. Given the profound implications of HPTN 052's for the future response to the AIDS

In summary, in 2011 it was scientifically demonstrated that treating individuals with HIV infection will prevent the transmission of HIV infection. However, the use of this strategy to the population level it is still not ready to fully achieve its potential because there are resource

**Figure 2.** AIDS Diagnoses among perinatally infected persons, 1985-2010. United States and 6 U.S. dependent areas.

This slide from the CDC presents trends from 1985 through 2010 in the estimated numbers of AIDS diagnoses among persons who were perinatally infected in the U.S. The blue line shows the annual numbers of perinatally infected children who were diagnosed with AIDS when they were less than 13 years of age; the pink line shows the annual numbers of persons who were infected with HIV perinatally and were diagnosed with AIDS at the age of 13 or older.

epidemic, the journal Science choose this study as its Breakthrough of the Year [45].

constraints and logistical hurdles, that limit its implementation.

392 Current Perspectives in HIV Infection

Pre-exposure prophylaxis (PrEP) involves the use of antiretroviral medications by HIV negative individuals before exposure to the HIV virus, to prevent HIV acquisition. The principle behind the use of antiretrovirals (ART) to prevent sexually acquisition of HIV lies on the success of HIV prevention in mother to Child transmission (PMTCT) and accidental exposure in healthcare workers. Early in the HIV epidemics, two large prevention trials (HIV Prevention Network Trial, HPTN 076 and HIVNET 012) showed that providing ART to infants born to HIV positive mothers significantly decreased the rates of HIV infection in newborns [30,46]. This is one of the greatest accomplishments in the field of HIV prevention, has been incorporated to PMTCT guidelines, and provided a starting ground for PrEP [30,46, 47]. In the area of health care related exposure to HIV, primarily needle sticks, the use of ART by the negative individual during the weeks after exposure reduces HIV acquisition by 80% [48, 49].

Following the human studies assessing PMTCT and prevention in the healthcare setting, animal studies to address PrEP demostrated that the administration of ART to macaque monkeys exposed to HIV prevented HIV infection [50,51]. All this data provided basis for designing clinical trials to test PrEP in humans.

In recent years, tremendous advances in the field of PrEP in individuals at risk for HIV acquisition have led to landmark large randomized controlled studies using oral or topical agents. Results of the initial major studies addressing PrEP were somehow controversial, but recent data provides evidence that PrEP is an effective and safe alternative to prevent HIV infection.

A major benefit of PrEP is its use by the individual at risk without involvement of sexual partners. Men who have sex with men (MSM) and women are especially vulnerable to HIV infection due to cultural, social and biological factors. Stigma associated with homosexuality, gender disparities, inability for women to negotiate condom use and fidelity, as well as frangibility of vaginal and rectal mucosa, predispose these populations to HIV infection and make them ideal candidates for such preventive method. PrEP is therefore emerging as a new powerful prevention method of especial importance in those populations at higher risk.

To date, most studies regarding PrEP have focused on two main modes of delivery: oral agents or topical microbidides. The two delivery modes will be presented separate in this chapter. Other forms of delivery such as subcutaneous or vaginal implants are under investigation and will be briefly mentioned.

While some studies addressing PrEP yielded important and relevant results, other studies are still undergoing and some are in the early stages of development. PrEP is therefore an evolving area in the field of HIV prevention and emerging data is likely to change the way we prevent sexually acquired HIV infection in the near future.


Table 1 summarizes the results of clinical trials on oral and topical agents addressing PrEP.

the chronic use of TDF for PrEP, include decline in kidney function and decrease in bone

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

395

Emtricitabine/tenofovir is a combination of nucleoside analogs approved for treatment of HIV. FTC/TDF is formulated as single day pill and is taken in combination with other agents for the treatment of HIV infection. Orally administered emtricitabine achieves good levels in plasma, lower female genital tract, and especially in the rectum making this combination a promise for PrEP [52]. The combination of FTC/TDF can cause those side effects listed above as well as those associated with FTC. Emtricitabine common side effects include nausea, vomiting, headaches, rash, abdominal pain, dizziness or abnormal dreams and occur in about 10% of the cases. Emtricitabine can also be associated with fatal lactic acidosis, liver or kidney toxicity.

Five studies have evaluated the use of oral agents to prevent HIV infection and will be described in this section. One study included only MSM (iPrEX), 2 included men and women (TDF2, PIP), and 2 included exclusively women (FEM-PrEP and VOICE). Two of these studies have validated the use of PrEP for HIV prevention, two have been prematurely stopped due to futility, and others are undergoing. Important to say is that all of these studies have addressed the use of PrEP in combination with intensive safer sex practices counseling.

iPREX was a randomized controlled study to evaluate the efficacy in reduction of new HIV infections using a daily tablet of fixed dose of FTC/TDF when compared to placebo. iPREX was funded by the National Institute of Allergy and Infectious Diseases and by the Bill and Melinda Gates Foundation. The study included 2499 young high-risk MSM in South America, Thailand and the US. The preliminary results of this study were released in 2010 and the study was the landmark for the use of oral PrEP. Results suggested for the first time that oral ART in combination with safe sex and condom use counseling could be used to reduce new HIV infections in MSM. The use of oral FTC/TDF was associated with a 42% reduction in HIV acquisition over 3 years (CI: 6%-60%). The study also analyzed the results according to selfreported adherence and reveal the importance of adhere to the prescribed drug. The incidence of new HIV cases was reduced to 68% when adherence was high (more than 90% of pills taken), to 50% if adherence was between 50% and 90%, and to 32% if adherence was low (less than 50%). In order to clarify if detectable drug levels were associated with protection against HIV infection a case control design was used to compare rates of infection in individuals with detectable blood levels with those without detectable levels. A relative risk reduction of 92% (CI: 40%-99%) in individuals with detectable study drug levels was found. This finding provided evidence that protection was directly related with drug levels, an indirect measure‐ ment of adherence. In addition, this study showed that FTC/TDF had a good safety profile with minimal gastrointestinal side effects. A minimal decrease in bone density in individuals taking the drug was also observed. Among the individuals that seroconvert, most of them were in the process of HIV seroconversion at enrollment and some developed a virus with resistant mutations. This finding reinforced the importance of excluding HIV infection when using FTC/

density [52].

*4.1.1. Studies addressing oral PrEP*

*4.1.1.1. iPREX (pre exposure prophylaxis initiative)*

**Table 1.** Summary of randomized controlled studies addressing the use of PrEP to prevent sexually transmitted HIV infection.

#### **4.1. PrEP using oral agents to prevent HIV infection in MSM and heterosexual men and women**

The oral agents evaluated or under evaluation for PrEP include anti HIV drugs currently approved for treatment of HIV infection. Such drugs are tenofovir (TDF) and a combination of emtricitabine/tenofovir FTC/ TDF.

Tenofovir is a nucleoside analog approved in combination with other ART for the treatment of HIV infection. As a nucleoside analog, the mechanism of action of TDF is to blocking HIV reverse transcriptase, which prevents HIV virus from replicating. In HIV infected individuals, as a result, TDF lowers HIV viral load in the blood. Tenofovir is a drug that achieves good drug levels in plasma as well as in female lower genital tract mucosa and rectal mucosa [52]. TDF is used orally and once a day, and is normally well tolerated, but as most drugs, could have potential side effects. The most common side effects of TDF are gastrointestinal (nausea and vomiting), rash or headaches, and occur in about 10% of the patients. The most serious risk factors of TDF are acute liver and kidney toxicity. Chronic risk factors of TDF, relevant to the chronic use of TDF for PrEP, include decline in kidney function and decrease in bone density [52].

Emtricitabine/tenofovir is a combination of nucleoside analogs approved for treatment of HIV. FTC/TDF is formulated as single day pill and is taken in combination with other agents for the treatment of HIV infection. Orally administered emtricitabine achieves good levels in plasma, lower female genital tract, and especially in the rectum making this combination a promise for PrEP [52]. The combination of FTC/TDF can cause those side effects listed above as well as those associated with FTC. Emtricitabine common side effects include nausea, vomiting, headaches, rash, abdominal pain, dizziness or abnormal dreams and occur in about 10% of the cases. Emtricitabine can also be associated with fatal lactic acidosis, liver or kidney toxicity.

### *4.1.1. Studies addressing oral PrEP*

Table 1 summarizes the results of clinical trials on oral and topical agents addressing PrEP.

Bostwana 1,219 heterosexual

**Table 1.** Summary of randomized controlled studies addressing the use of PrEP to prevent sexually transmitted HIV

**4.1. PrEP using oral agents to prevent HIV infection in MSM and heterosexual men and**

The oral agents evaluated or under evaluation for PrEP include anti HIV drugs currently approved for treatment of HIV infection. Such drugs are tenofovir (TDF) and a combination

Tenofovir is a nucleoside analog approved in combination with other ART for the treatment of HIV infection. As a nucleoside analog, the mechanism of action of TDF is to blocking HIV reverse transcriptase, which prevents HIV virus from replicating. In HIV infected individuals, as a result, TDF lowers HIV viral load in the blood. Tenofovir is a drug that achieves good drug levels in plasma as well as in female lower genital tract mucosa and rectal mucosa [52]. TDF is used orally and once a day, and is normally well tolerated, but as most drugs, could have potential side effects. The most common side effects of TDF are gastrointestinal (nausea and vomiting), rash or headaches, and occur in about 10% of the patients. The most serious risk factors of TDF are acute liver and kidney toxicity. Chronic risk factors of TDF, relevant to

4,758 serodiscordant couples

men and women

2,499 MSM FTC/TDF vs

2,210 women FTC/TDF vs

5,000 women TDF vs placebo

South Africa 1,341 women TDF gel vs placebo 39% reduction

placebo

FTC/TDF vs placebo

placebo

FTC vs placebo TDF gel vs placebo

TDF vs placebo FTC/TDF vs placebo

42% reduction (CI=6-60)

62% reduction (CI=21-83)

Study discontinued due to futility (2011)

TDF oral and gel discontinued due to futility (2011) FTC/TDF ongoing

TDF: 76% reduction (CI=42-81) FTC/TDF: 75% reduction (55-87)

**Study name Sponsor Country Participants Design Results**

South America Thailand USA

Sub Saharan African

Kenia, Tanzania South Africa

South Africa Uganda, Zambia Zimbabwe

countries

iPREX (Grant 2010) NIAID

394 Current Perspectives in HIV Infection

TDF2 (Thigpen 2012) CDC

Partners PrEP (Baeten

FemPrEP (van Damme

CAPRISA (Abdoul Karim 2010)

infection.

**women**

VOICE Microbicides

2012)

2012)

Gates Foundation

NIH

Gates Foundation

US Agency for International Development

Trial Network

NIH

of emtricitabine/tenofovir FTC/ TDF.

Multiple agencies Five studies have evaluated the use of oral agents to prevent HIV infection and will be described in this section. One study included only MSM (iPrEX), 2 included men and women (TDF2, PIP), and 2 included exclusively women (FEM-PrEP and VOICE). Two of these studies have validated the use of PrEP for HIV prevention, two have been prematurely stopped due to futility, and others are undergoing. Important to say is that all of these studies have addressed the use of PrEP in combination with intensive safer sex practices counseling.

#### *4.1.1.1. iPREX (pre exposure prophylaxis initiative)*

iPREX was a randomized controlled study to evaluate the efficacy in reduction of new HIV infections using a daily tablet of fixed dose of FTC/TDF when compared to placebo. iPREX was funded by the National Institute of Allergy and Infectious Diseases and by the Bill and Melinda Gates Foundation. The study included 2499 young high-risk MSM in South America, Thailand and the US. The preliminary results of this study were released in 2010 and the study was the landmark for the use of oral PrEP. Results suggested for the first time that oral ART in combination with safe sex and condom use counseling could be used to reduce new HIV infections in MSM. The use of oral FTC/TDF was associated with a 42% reduction in HIV acquisition over 3 years (CI: 6%-60%). The study also analyzed the results according to selfreported adherence and reveal the importance of adhere to the prescribed drug. The incidence of new HIV cases was reduced to 68% when adherence was high (more than 90% of pills taken), to 50% if adherence was between 50% and 90%, and to 32% if adherence was low (less than 50%). In order to clarify if detectable drug levels were associated with protection against HIV infection a case control design was used to compare rates of infection in individuals with detectable blood levels with those without detectable levels. A relative risk reduction of 92% (CI: 40%-99%) in individuals with detectable study drug levels was found. This finding provided evidence that protection was directly related with drug levels, an indirect measure‐ ment of adherence. In addition, this study showed that FTC/TDF had a good safety profile with minimal gastrointestinal side effects. A minimal decrease in bone density in individuals taking the drug was also observed. Among the individuals that seroconvert, most of them were in the process of HIV seroconversion at enrollment and some developed a virus with resistant mutations. This finding reinforced the importance of excluding HIV infection when using FTC/ TDF for PrEP. The study results were published in the New England Journal of Medicine in 2010 [53]

to address the effectiveness and safety of PrEP by gender. Incidence of new HIV infec‐ tions was 4.7% person-years in the treatment group and 5% person-years in the placebo group and this different was not statistically significant. This study was the first large study discontinued based on recommendations from the Data Safety Monitoring Board after interim results were unable to demonstrate efficacy of PrEP. In April of 2011 the study was stopped. As in prior studies, gastrointestinal side effects occurred more commonly in the treatment arm (nausea, vomiting and elevation of ALT) as well as renal laboratory abnormalities. Despite extensive counseling on adherence, less than 40% of the women in the treatment arm enrolled in the study had detectable drug levels raising once again the

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

397

importance of adherence to the prescribed regimen, perhaps lower in women [56].

VOICE is the largest clinical trial being conducted evaluating efficacy of PrEP in women. The study is sponsored by the Microbicide Trials Network and the National Institutes of Health. It enrolled over 5000 women in South Africa, Uganda, Zambia and Zimbabwe. Women were randomized to 3 arms: daily oral TDF, daily oral TDF/FTC, or topical TDF. Results of this trial resulted in the discontinuation of the oral TDF arm in September 2011 and the topical TDF arm in November 2011 because of inability to demonstrate efficacy. The topical arm of the study will be discussed under the microbicide section below and results of the TDF/FTC arm are

The Bangkok tenofovir study is an ongoing trial evaluating the efficacy of oral TDF in male injection drug users receiving direct observation therapy. Enrollment for this study is complete

Studies addressing oral PrEP have yielded conflicting results and although the use of oral PrEP appears to be beneficial in high risk MSM, the use in women still is under debate. Partners PrEP, TDF2 and iPrEx provided a proof of concepts for the use of oral antiretrovirals for HIV prevention. However, the results from VOICE and Fem-PrEP and other ongoing studies will provide further information on the efficacy and safety of oral PrEP, especially in women.

Efficacy of PrEP seems to be directly related to adherence, and detectable blood levels is a better marker of protection than self-reported adherence or pill count. Although in most studies, adherence measured by self reporting or by pill count was high, detectable blood drug

The highest levels of adherence were reported in Partner PrEP, where serodiscordant couples were enrolled and received extensive counseling. Tenofovir was detected in over 80% of participants in the treatment group and PrEP reduced by 70% new HIV infections. The results of Partner PrEP suggest that partner involvement is important, especially when addressing

In regards to decrease efficacy of PrEP in women the question of availability of drug at the exposure site has been raised. However, high drug levels are found in cervicovaginal lavages,

levels were found only in 50% of participants in the treatment arm of iPREX [53].

*4.1.1.5. VOICE (vaginal and oral interventions to control the epidemic)*

but no results are available at the time of this publication.

expected to be reported in 2013 [57].

HIV prevention in women [58,59].

*4.1.1.6. Bangkok TDF trial*

### *4.1.1.2. TDF2*

TDF2 was a randomized controlled study to evaluate the efficacy to reduce new HIV infection of a daily fixed dose of an oral combination pill of TDF/FTC when compared to placebo. This study was funded by the Centers for Disease Control and Prevention (CDC) and the division of AIDS at the National Institutes of Health. The study was conducted in Bostwana and included 1219 males and females, unmarried adults. This study had high rates of loss of follow up (30%) and due to low retention, enrollment was prematurely stopped and study closed. Enrolled participants were followed as planned and the last participant was followed until 2011. The results offered 62% (CI: 21%-83%) protection against HIV infection overall. This study also evaluated drug levels in individuals receiving the drug and revealed that plasma concentration were lower among the participants who seroconverted to HIV. Reported adherence was high and similar in the two groups (above 80%), although detectable drug levels in the drug arm suggested that adherence was lower that reported. Risky sexual behaviors were similar and did not change in the two groups during the study. Among the participants receiving the study drugs, there was and increase number of gastrointestinal side effects (nausea and vomiting) and dizziness as well as a significant decline in bone density. One participant was enrolled with unrecognized acute HIV infection and developed a resistant virus [54].

#### *4.1.1.3. Partners PrEP (partners in prevention)*

Partners in Prevention study is the largest trial evaluating PrEP in heterosexual discordant couples. It is an ongoing study with 3 study arms: daily TDF, daily TDF/FTC, and placebo. This study is supported by the Bill and Melinda Gates Foundation. The study enrolled 4758 serodiscordant couples in which the HIV infected partner was not eligible for ART according to country guidelines. This study in being conducted in sub Saharan Africa (Bostwana, Kenya, Rwanda, South Africa, Tanzania, Uganda and Zambia). Extensive counseling in safe sex and condom use was additionally provided to enrolled participants. TDF conferred a 67% (CI: 44%-81%) and FTC/TDF a 75% (CI: 55%-87%) reduction in new HIV infections. The difference in rates of HIV seroconversion among the two treatment groups was not statistically different. In July 2011 the DSMB recommended that the placebo group discontinued since the prede‐ termined criteria for stopping had already been made and a benefit in the treatment arms was achieved [55]. The study results followed iPREX in supporting the use of PrEP in high risk individuals.

#### *4.1.1.4. FEM-PrEP*

The FEM-PrEP study was a randomized controlled trial that included women in sub Saharan Africa (Kenya, South Africa and Tanzania). This study was supported by US Agency for International Development. Women were randomized to receive either oral daily FTC/TDF or placebo. This study evaluated 2120 women and was the first one designed

to address the effectiveness and safety of PrEP by gender. Incidence of new HIV infec‐ tions was 4.7% person-years in the treatment group and 5% person-years in the placebo group and this different was not statistically significant. This study was the first large study discontinued based on recommendations from the Data Safety Monitoring Board after interim results were unable to demonstrate efficacy of PrEP. In April of 2011 the study was stopped. As in prior studies, gastrointestinal side effects occurred more commonly in the treatment arm (nausea, vomiting and elevation of ALT) as well as renal laboratory abnormalities. Despite extensive counseling on adherence, less than 40% of the women in the treatment arm enrolled in the study had detectable drug levels raising once again the importance of adherence to the prescribed regimen, perhaps lower in women [56].

### *4.1.1.5. VOICE (vaginal and oral interventions to control the epidemic)*

VOICE is the largest clinical trial being conducted evaluating efficacy of PrEP in women. The study is sponsored by the Microbicide Trials Network and the National Institutes of Health. It enrolled over 5000 women in South Africa, Uganda, Zambia and Zimbabwe. Women were randomized to 3 arms: daily oral TDF, daily oral TDF/FTC, or topical TDF. Results of this trial resulted in the discontinuation of the oral TDF arm in September 2011 and the topical TDF arm in November 2011 because of inability to demonstrate efficacy. The topical arm of the study will be discussed under the microbicide section below and results of the TDF/FTC arm are expected to be reported in 2013 [57].

#### *4.1.1.6. Bangkok TDF trial*

TDF for PrEP. The study results were published in the New England Journal of Medicine in

TDF2 was a randomized controlled study to evaluate the efficacy to reduce new HIV infection of a daily fixed dose of an oral combination pill of TDF/FTC when compared to placebo. This study was funded by the Centers for Disease Control and Prevention (CDC) and the division of AIDS at the National Institutes of Health. The study was conducted in Bostwana and included 1219 males and females, unmarried adults. This study had high rates of loss of follow up (30%) and due to low retention, enrollment was prematurely stopped and study closed. Enrolled participants were followed as planned and the last participant was followed until 2011. The results offered 62% (CI: 21%-83%) protection against HIV infection overall. This study also evaluated drug levels in individuals receiving the drug and revealed that plasma concentration were lower among the participants who seroconverted to HIV. Reported adherence was high and similar in the two groups (above 80%), although detectable drug levels in the drug arm suggested that adherence was lower that reported. Risky sexual behaviors were similar and did not change in the two groups during the study. Among the participants receiving the study drugs, there was and increase number of gastrointestinal side effects (nausea and vomiting) and dizziness as well as a significant decline in bone density. One participant was enrolled with unrecognized acute HIV infection and developed a resistant

Partners in Prevention study is the largest trial evaluating PrEP in heterosexual discordant couples. It is an ongoing study with 3 study arms: daily TDF, daily TDF/FTC, and placebo. This study is supported by the Bill and Melinda Gates Foundation. The study enrolled 4758 serodiscordant couples in which the HIV infected partner was not eligible for ART according to country guidelines. This study in being conducted in sub Saharan Africa (Bostwana, Kenya, Rwanda, South Africa, Tanzania, Uganda and Zambia). Extensive counseling in safe sex and condom use was additionally provided to enrolled participants. TDF conferred a 67% (CI: 44%-81%) and FTC/TDF a 75% (CI: 55%-87%) reduction in new HIV infections. The difference in rates of HIV seroconversion among the two treatment groups was not statistically different. In July 2011 the DSMB recommended that the placebo group discontinued since the prede‐ termined criteria for stopping had already been made and a benefit in the treatment arms was achieved [55]. The study results followed iPREX in supporting the use of PrEP in high risk

The FEM-PrEP study was a randomized controlled trial that included women in sub Saharan Africa (Kenya, South Africa and Tanzania). This study was supported by US Agency for International Development. Women were randomized to receive either oral daily FTC/TDF or placebo. This study evaluated 2120 women and was the first one designed

2010 [53]

*4.1.1.2. TDF2*

396 Current Perspectives in HIV Infection

virus [54].

individuals.

*4.1.1.4. FEM-PrEP*

*4.1.1.3. Partners PrEP (partners in prevention)*

The Bangkok tenofovir study is an ongoing trial evaluating the efficacy of oral TDF in male injection drug users receiving direct observation therapy. Enrollment for this study is complete but no results are available at the time of this publication.

Studies addressing oral PrEP have yielded conflicting results and although the use of oral PrEP appears to be beneficial in high risk MSM, the use in women still is under debate. Partners PrEP, TDF2 and iPrEx provided a proof of concepts for the use of oral antiretrovirals for HIV prevention. However, the results from VOICE and Fem-PrEP and other ongoing studies will provide further information on the efficacy and safety of oral PrEP, especially in women.

Efficacy of PrEP seems to be directly related to adherence, and detectable blood levels is a better marker of protection than self-reported adherence or pill count. Although in most studies, adherence measured by self reporting or by pill count was high, detectable blood drug levels were found only in 50% of participants in the treatment arm of iPREX [53].

The highest levels of adherence were reported in Partner PrEP, where serodiscordant couples were enrolled and received extensive counseling. Tenofovir was detected in over 80% of participants in the treatment group and PrEP reduced by 70% new HIV infections. The results of Partner PrEP suggest that partner involvement is important, especially when addressing HIV prevention in women [58,59].

In regards to decrease efficacy of PrEP in women the question of availability of drug at the exposure site has been raised. However, high drug levels are found in cervicovaginal lavages, and even higher than in plasma or rectal mucosa, what would dispute this hypothesis [52,60]. Another possibility is a decrease of drug levels in women receiving hormonal contraceptives and it is under evaluation by the study team.

*4.1.2.3. Increased of high risk sexual behavior*

behavior needs to be further examined.

*4.1.2.4. Cost*

available [63].

prevention tools in the population at risk.

alternative for HIV prevention in women at risk.

In regards to increase of risky sexual risk behaviors, both iPREX and Partners PrEP revealed that all participants increased condom use, decrease number in sexual partners, unprotect‐ ed anal intercourse, and reduced rates for syphilis. This was likely due to the extensive counseling that both drug and placebo groups received and sustainability of sexual risk

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

399

The cost of providing PrEP to individuals at risk is of course under great debate due to both economical and ethical issues. ART are expensive medications and not available for all HIV infected patients in need for their own health. PrEP is an expensive approach and cost effectiveness will need to be justified prior to generalization to the population at risk. A costeffectiveness analysis of PrEP for HIV prevention in MSM published in 2012 in Annals of Internal Medicine revealed that although PrEP could have an important impact in the HIV epidemics, it will be an extremely expensive approach [63]. In a modeling analysis, Juusola recently showed that providing PrEp to all high-risk MSM for 20 years will cost \$75 billion in health care related cost, a non-insignificant amount [61]. An ethical concern is whether providing them to those HIV uninfected individuals will interfere with the treatment of HIV

The use of PrEP includes identification of high risk individuals, extensive risk counseling, provision of a drug and follow up risk assessments, HIV and laboratory tests. If PrEp is incorporated as part of primary care prevention activities, the primary care physician will need to become familiar with drugs normally prescribed for highly specialized physicians and will need to be aware of new research data and changes in the recommendations as they become

As summary, oral PrEP has demonstrated efficacy in certain populations at risk for HIV infection, especially in MSM. Studies assessing acceptability, long term efficacy, toxicity, risk of HIV resistance, cost and use in women are needed before including oral PrEP as part of HIV

Women are more vulnerable than men to acquire HIV during sex due to biological factors as well as difficulties in negotiating barrier methods and fidelity. Women can rarely negotiate condom use or faithfulness with their sexual partners and could greatly benefit of controlling their own risk of HIV infection without involvement of male partners. Studies addressing oral PrEP suggested lower efficacy of oral agents in women, which make microbicides an attractive

Microbicides are topical products applied to the rectum or the vagina to prevent HIV infection in HIV negative individuals. Research on microbicides has included primarily women but

infected patient in need for treatment, especially in poor resource settings.

*4.1.3. Feasibility of generalizing the use of oral PrEP to the population at risk.*

**4.2. Microbicides to prevent HIV infection in women and MSM**

Nevertheless, the possibility of low efficacy of oral PrEP in women suggest that microbicides or other delivery methods may be a better option in this population.

Following the positive results of daily ART use for HIV prevention, especially in MSM, newer studies are undergoing to evaluate the use of intermittent PrEP. These intermittent regimens could be more feasible in certain setting such as in non stable relationships. A large study in Kenia (ADAPT, Alternative Dosing to Augment PrEP Pill-Taking) is evaluating the safety and adherence to daily oral TDF/FTC versus intermittent TDF/FTC (Monday, Friday and within 2 hours after sex) or placebo. Another study (HPTN 067) is a study including MSM and heter‐ osexual women aiming to identify dosing regiments in people at high risk for HIV infection. Preliminary data demonstrated that although adherence may be decreased in intermittent dosing, it may still be appropriate for PrEP.

### *4.1.2. Potential problems associated with oral PrEP*

In July 2012, and based on the results of the mentioned trials, especially iPREX and Partners PrEP, the United States Food and Drug administration (US FDA) approved the use of daily TDF/FTC or Truvada® for prevention of sexually acquired HIV in individuals at risk for HIV infection. However, even if approval was granted, serious concerns have been raised by experts in the field of HIV prevention. The issues that need to be addressed before recommending PrEP as a generalized HIV prevention strategy are: development of drug resistance viruses, long term side effects, increase in sexual risk behaviors, cost, and incorporating PrEP as part of primary care prevention.

#### *4.1.2.1. Development of drug resistant viruses*

Development of drug resistance was identified in some of the participants who seroconvert in the mentioned studies but in most cases, occurred in individuals that enrolled with a new non identified HIV infection. Addressing this potential problem is difficult, since individuals at risk may have an early infection missed by routine antibody testing and routine viral load may not be easily available in high risk settings.

#### *4.1.2.2. Long term side toxicity*

As both TDF and FTC have potential serious long term side effects, it is important to determine if long use of FTC/TDF in HIV negative individuals will increase the risk of kidney failure or osteoporosis. In order to evaluate long term side effects, long term follow up is necessary to address if decline in renal function or bone density are clinically significant. However, as in HIV positive individuals using those agents, side effects may take many years to develop.

### *4.1.2.3. Increased of high risk sexual behavior*

In regards to increase of risky sexual risk behaviors, both iPREX and Partners PrEP revealed that all participants increased condom use, decrease number in sexual partners, unprotect‐ ed anal intercourse, and reduced rates for syphilis. This was likely due to the extensive counseling that both drug and placebo groups received and sustainability of sexual risk behavior needs to be further examined.

#### *4.1.2.4. Cost*

and even higher than in plasma or rectal mucosa, what would dispute this hypothesis [52,60]. Another possibility is a decrease of drug levels in women receiving hormonal contraceptives

Nevertheless, the possibility of low efficacy of oral PrEP in women suggest that microbicides

Following the positive results of daily ART use for HIV prevention, especially in MSM, newer studies are undergoing to evaluate the use of intermittent PrEP. These intermittent regimens could be more feasible in certain setting such as in non stable relationships. A large study in Kenia (ADAPT, Alternative Dosing to Augment PrEP Pill-Taking) is evaluating the safety and adherence to daily oral TDF/FTC versus intermittent TDF/FTC (Monday, Friday and within 2 hours after sex) or placebo. Another study (HPTN 067) is a study including MSM and heter‐ osexual women aiming to identify dosing regiments in people at high risk for HIV infection. Preliminary data demonstrated that although adherence may be decreased in intermittent

In July 2012, and based on the results of the mentioned trials, especially iPREX and Partners PrEP, the United States Food and Drug administration (US FDA) approved the use of daily TDF/FTC or Truvada® for prevention of sexually acquired HIV in individuals at risk for HIV infection. However, even if approval was granted, serious concerns have been raised by experts in the field of HIV prevention. The issues that need to be addressed before recommending PrEP as a generalized HIV prevention strategy are: development of drug resistance viruses, long term side effects, increase in sexual risk behaviors, cost, and incorporating PrEP as part

Development of drug resistance was identified in some of the participants who seroconvert in the mentioned studies but in most cases, occurred in individuals that enrolled with a new non identified HIV infection. Addressing this potential problem is difficult, since individuals at risk may have an early infection missed by routine antibody testing and routine viral load may

As both TDF and FTC have potential serious long term side effects, it is important to determine if long use of FTC/TDF in HIV negative individuals will increase the risk of kidney failure or osteoporosis. In order to evaluate long term side effects, long term follow up is necessary to address if decline in renal function or bone density are clinically significant. However, as in HIV positive individuals using those agents, side effects may take many years to develop.

or other delivery methods may be a better option in this population.

and it is under evaluation by the study team.

398 Current Perspectives in HIV Infection

dosing, it may still be appropriate for PrEP.

of primary care prevention.

*4.1.2.2. Long term side toxicity*

*4.1.2.1. Development of drug resistant viruses*

not be easily available in high risk settings.

*4.1.2. Potential problems associated with oral PrEP*

The cost of providing PrEP to individuals at risk is of course under great debate due to both economical and ethical issues. ART are expensive medications and not available for all HIV infected patients in need for their own health. PrEP is an expensive approach and cost effectiveness will need to be justified prior to generalization to the population at risk. A costeffectiveness analysis of PrEP for HIV prevention in MSM published in 2012 in Annals of Internal Medicine revealed that although PrEP could have an important impact in the HIV epidemics, it will be an extremely expensive approach [63]. In a modeling analysis, Juusola recently showed that providing PrEp to all high-risk MSM for 20 years will cost \$75 billion in health care related cost, a non-insignificant amount [61]. An ethical concern is whether providing them to those HIV uninfected individuals will interfere with the treatment of HIV infected patient in need for treatment, especially in poor resource settings.

### *4.1.3. Feasibility of generalizing the use of oral PrEP to the population at risk.*

The use of PrEP includes identification of high risk individuals, extensive risk counseling, provision of a drug and follow up risk assessments, HIV and laboratory tests. If PrEp is incorporated as part of primary care prevention activities, the primary care physician will need to become familiar with drugs normally prescribed for highly specialized physicians and will need to be aware of new research data and changes in the recommendations as they become available [63].

As summary, oral PrEP has demonstrated efficacy in certain populations at risk for HIV infection, especially in MSM. Studies assessing acceptability, long term efficacy, toxicity, risk of HIV resistance, cost and use in women are needed before including oral PrEP as part of HIV prevention tools in the population at risk.

#### **4.2. Microbicides to prevent HIV infection in women and MSM**

Women are more vulnerable than men to acquire HIV during sex due to biological factors as well as difficulties in negotiating barrier methods and fidelity. Women can rarely negotiate condom use or faithfulness with their sexual partners and could greatly benefit of controlling their own risk of HIV infection without involvement of male partners. Studies addressing oral PrEP suggested lower efficacy of oral agents in women, which make microbicides an attractive alternative for HIV prevention in women at risk.

Microbicides are topical products applied to the rectum or the vagina to prevent HIV infection in HIV negative individuals. Research on microbicides has included primarily women but studies addressing several rectal formulations in MSM are currently undergoing. Unfortu‐ nately, results on microbicide research have been conflicting and further research is needed. Topical vaginally applied TDF showed promising results in the CAPRISA trial. However, other agents have not been efficacious and research in this area is ongoing.

a coitally (before and after sex) related application of TDF vaginal gel when compared to placebo. 1341 women were enrolled. The incidence of HIV infections in the tenofovir arm was 5.6 (CI: 4.0-7.7) per 100 women-years and 9.1 (CI: 6.9-11.7) in the placebo arm. (IRR: 0.61; CI:0.4-0.94,p=0.017). Tenofovir gel reduced HIV acquisition by an estimate of 39% overall and by 54% in women with high adherence to the gel. This study did not find major side effects associated with the use of TDF and no TDF resistant virus were found in women who seroconverted. The results of this study were released in the Internation‐ al AIDS conference in Vienna in 2010 and provided a potential armamentum for women unable to negotiate fidelity and condom use. Caprisa also provided a reduction in HSV

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

401

VOICE as described in the oral PrEP section included one arm evaluating daily use of vaginal TDF gel. The gel arm enrolled approximately 1000 women. In September of 2011 this arm was discontinued as a recommendation from the DSMB due to no efficacy. No safety issues were identified [68]. In order to clarify if the differences between CAPRISA (39% reduction on new HIV infections) was found and VOICE (no effect of TDF gel), a new study will replicate CAPRISA (FACTS 001) and its results will help to clarify if TDF gel is useful and can be

The use of vaginal rings for prevention of HIV acquisition is under evaluation in several studies. Vaginal rings with antivirals could potentially be used in combination with contra‐ ceptives, and will release antiviral agent long term and independent of sexual intercourse. Dapivirine (TMC120) vaginal ring is currently evaluated under phase III studies as ASPIRE – A Study to Prevent Infection with a Ring for Extended study [69]. A combination of Dapivirine and Maraviroc is currently undergoing a phase 1 safety and pharmacokinetic study [70]. Other vaginal rings with maraviroc alone or in combination with tenofovir are also being developed.

The use of a long acting injectable agent that will provide protection for 3-9 months is a potential method that will increase adherence. Rilpivirine is under development for this

PrEP using oral or topical agents is a promising strategy in the field of HIV prevention. However, as single intervention may not be successful in controlling the HIV epidemics and the results obtained in controlled clinical trials are unlikely to persist overtime. The CDC recently published interim guidance for clinicians considering the use of PrEP for the prevention of HIV infection in heterosexually active adults [72]. This report addresses the remaining gap in knowledge regarding PrEP but provides a comprehensive evaluation of

acquisition [67].

*4.2.4.2. VOICE*

incorporated to the field of HIV prevention.

*4.2.5. Agents under development*

*4.2.5.2. Long acting injectables*

purpose [71].

*4.2.5.1. Vaginal rings*

In order for a microbicide to be successful it must fulfill the following characteristics: be biologically active, safe, and acceptable by the individual at risk. The principals mechanisms of action evaluated in microbide development are: buffer agents, surfactants, blockers and antiretrovirals.

#### *4.2.1. Buffers*

Buffers are supplements to the natural immune defenses of the vagina. Buffers maintain the vaginal pH favoring the persistence of the naturally protective vaginal lactobacilli. Alterations of the vaginal pH due to exposure to semen or vaginal infections such as bacterial vaginosis damage the vaginal microbiota and facilitate HIV infection. Buffergel ®, a buffer designed to maintain vaginal pH was tested in animals and in a phase III effectiveness trial; but unfortu‐ nately, did not prevent new HIV infections [63].

#### *4.2.2. Surfactants*

Surfactants act by inactivating infectious agents. Noxynol-9, a wide available microbicide with known activity against several infectious agents has been tested in multiple forms (film, sponge and gel) and was not effective in preventing new HIV infections [64]. SAVVY® (C31G) was a surfactant in a gel form tested in Ghana and Nigeria between 2004-2006 and not found to be effective [65]. Surfactants are no longer being considered as potential agents for microbicide use.

### *4.2.3. Blockers*

Blockers inhibit the fusion of the HIV virus to the cell membrane. Four compounds in this category have been tested to date: PRO2000®, Carrguard®, cellulose sulfate and dextrin 2 sulfate and have not demonstrated activity in clinical trials [66].

#### *4.2.4. Drugs with anti HIV activity*

Antiretroviral agents act by inhibiting the HIV replication cycle in the vaginal mucosa have been tested in two major clinical trials (CAPRISA and VOICE). Other agents acting as coreceptor blockers binding to chemokine co-receptors such as VVR5 or CxCR4 are also under investigation.

#### *4.2.4.1. CAPRISA*

The landmark study suggesting that the potential of microbicides as HIV prevention tools is CAPRISA, a two-arm randomized double blind placebo controlled trial conducted in South Africa between 2007 and 2010. The study evaluated the efficacy in HIV reduction of a coitally (before and after sex) related application of TDF vaginal gel when compared to placebo. 1341 women were enrolled. The incidence of HIV infections in the tenofovir arm was 5.6 (CI: 4.0-7.7) per 100 women-years and 9.1 (CI: 6.9-11.7) in the placebo arm. (IRR: 0.61; CI:0.4-0.94,p=0.017). Tenofovir gel reduced HIV acquisition by an estimate of 39% overall and by 54% in women with high adherence to the gel. This study did not find major side effects associated with the use of TDF and no TDF resistant virus were found in women who seroconverted. The results of this study were released in the Internation‐ al AIDS conference in Vienna in 2010 and provided a potential armamentum for women unable to negotiate fidelity and condom use. Caprisa also provided a reduction in HSV acquisition [67].

### *4.2.4.2. VOICE*

studies addressing several rectal formulations in MSM are currently undergoing. Unfortu‐ nately, results on microbicide research have been conflicting and further research is needed. Topical vaginally applied TDF showed promising results in the CAPRISA trial. However, other

In order for a microbicide to be successful it must fulfill the following characteristics: be biologically active, safe, and acceptable by the individual at risk. The principals mechanisms of action evaluated in microbide development are: buffer agents, surfactants, blockers and

Buffers are supplements to the natural immune defenses of the vagina. Buffers maintain the vaginal pH favoring the persistence of the naturally protective vaginal lactobacilli. Alterations of the vaginal pH due to exposure to semen or vaginal infections such as bacterial vaginosis damage the vaginal microbiota and facilitate HIV infection. Buffergel ®, a buffer designed to maintain vaginal pH was tested in animals and in a phase III effectiveness trial; but unfortu‐

Surfactants act by inactivating infectious agents. Noxynol-9, a wide available microbicide with known activity against several infectious agents has been tested in multiple forms (film, sponge and gel) and was not effective in preventing new HIV infections [64]. SAVVY® (C31G) was a surfactant in a gel form tested in Ghana and Nigeria between 2004-2006 and not found to be effective [65]. Surfactants are no longer being considered as potential agents for microbicide

Blockers inhibit the fusion of the HIV virus to the cell membrane. Four compounds in this category have been tested to date: PRO2000®, Carrguard®, cellulose sulfate and dextrin 2-

Antiretroviral agents act by inhibiting the HIV replication cycle in the vaginal mucosa have been tested in two major clinical trials (CAPRISA and VOICE). Other agents acting as coreceptor blockers binding to chemokine co-receptors such as VVR5 or CxCR4 are also under

The landmark study suggesting that the potential of microbicides as HIV prevention tools is CAPRISA, a two-arm randomized double blind placebo controlled trial conducted in South Africa between 2007 and 2010. The study evaluated the efficacy in HIV reduction of

sulfate and have not demonstrated activity in clinical trials [66].

agents have not been efficacious and research in this area is ongoing.

nately, did not prevent new HIV infections [63].

antiretrovirals.

400 Current Perspectives in HIV Infection

*4.2.2. Surfactants*

use.

*4.2.3. Blockers*

investigation.

*4.2.4.1. CAPRISA*

*4.2.4. Drugs with anti HIV activity*

*4.2.1. Buffers*

VOICE as described in the oral PrEP section included one arm evaluating daily use of vaginal TDF gel. The gel arm enrolled approximately 1000 women. In September of 2011 this arm was discontinued as a recommendation from the DSMB due to no efficacy. No safety issues were identified [68]. In order to clarify if the differences between CAPRISA (39% reduction on new HIV infections) was found and VOICE (no effect of TDF gel), a new study will replicate CAPRISA (FACTS 001) and its results will help to clarify if TDF gel is useful and can be incorporated to the field of HIV prevention.

#### *4.2.5. Agents under development*

#### *4.2.5.1. Vaginal rings*

The use of vaginal rings for prevention of HIV acquisition is under evaluation in several studies. Vaginal rings with antivirals could potentially be used in combination with contra‐ ceptives, and will release antiviral agent long term and independent of sexual intercourse. Dapivirine (TMC120) vaginal ring is currently evaluated under phase III studies as ASPIRE – A Study to Prevent Infection with a Ring for Extended study [69]. A combination of Dapivirine and Maraviroc is currently undergoing a phase 1 safety and pharmacokinetic study [70]. Other vaginal rings with maraviroc alone or in combination with tenofovir are also being developed.

#### *4.2.5.2. Long acting injectables*

The use of a long acting injectable agent that will provide protection for 3-9 months is a potential method that will increase adherence. Rilpivirine is under development for this purpose [71].

PrEP using oral or topical agents is a promising strategy in the field of HIV prevention. However, as single intervention may not be successful in controlling the HIV epidemics and the results obtained in controlled clinical trials are unlikely to persist overtime. The CDC recently published interim guidance for clinicians considering the use of PrEP for the prevention of HIV infection in heterosexually active adults [72]. This report addresses the remaining gap in knowledge regarding PrEP but provides a comprehensive evaluation of the available data and guidance to health care providers regarding the use of PrEP. However, HIV prevention guidelines are under development and 30 years of the history of HIV have shown the scientific community that a single intervention is unlikely to succeed.

**References**

((1999). Suppl. , 1, 1-12.

and acceptability. (2007).

J Med. (1986).

demiol (1990). , 19, 693-697.

[1] Alanis, M. C, & Lucidi, R. S. Neonatal circumcision: a review of the world's oldest and most controversial operation. Obstet Gynecol Surv. (2004). May; , 59(5), 379-95.

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

403

[3] Dunsmuir, W. D, & Gordon, E. M. The history of circumcision. BJU International

[4] UNAIDSMale circumcision: Global trends and determinants of prevalence, safety

[6] Hull, T. H, & Budiharsana, M. Male circumcision and penis enhacement in Southeast Asia: matters of pain and pleasure. Reprod Health Matters. (2001). , 9(18), 60-7.

[7] Mcwilliam, A. Case studies in dual classification as process: childbirth, headhunting

[8] Siegfried, N, Muller, M, & Volmink, J. Male circumcision for prevention of heterosex‐ ual acquisition of HIV in men. Cochrane Database Sust Rev. (2003). CD003362.

[9] Benatar, M, & Benatar, D. Between prophylaxis and child abuse: the ethics of neona‐

[10] Wright, J. L, Lin, D. W, & Stanford, J. L. Circumcision and the risk of prostate cancer.

[11] Fink, A. J. A possible explanation for heterosexual male infection with AIDS. N Engl

[12] Bongaarts, J, Reining, P, Way, P, & Conant, F. The relationship between male circum‐

[14] Moses, S, Bradley, J. E, Nagelkerke, N. J, Ronald, A. R, et al. Geographical patterns of male circumcision practices in Africa: Association with HIV seroprevalence. Int J Epi‐

[15] Bailey, R. C, Plummer, F. A, & Moses, S. Male circumcision and HIV prevention: cur‐ rent knowledge and future research directions. Lancet Infect Dis (2001). , 1, 223-31.

[16] Buchbinder, S. P, Vittinghoff, E, & Heagerty, P. J. Sexual risk, nitrite inhalant use and lack of circumcision associated with HIV seroconversion in men who have sex with

[17] MacDonald KSMalonza I, Chen DK. Vitamin A and risk of HIV-1 seroconversion

men in the United States. J Acquir Immune Def Syndr (2005). , 39, 82-89.

among Kenyan men with genital ulcers. AIDS (2001). , 15, 635-39.

cision and HIV infection in Africa population. AIDS (1989). , 3, 373-377.

[13] Caldwell, J. C, & Caldwell, P. The African AIDS epidemic. 1996 Sci Am (1996).

[2] Johnson, P. Israelities, in A History of the jews. (1993). Phoenix Press. , 37.

[5] Thomas, A. Circumcision: an ethnomedical study. (2003). The Gilgal Society.

and circumcision in West Timor, Oceania. (1994). , 65, 59-74.

tal male circumcision. Am J Bioeth. (2003). Spring; , 3(2), 35-48.

Cancer, (2012). published on line; doicncr.26653.

In summary, the science of HIV prevention has seen significant progress in recent years. After decades of frustration and lagging behind the spectacular progress brought up in the control of HIV disease by the use of antiretrovirals, the field of biomedical prevention of HIV has been revolutionized and energized by the scientific evidence produced in the last few years that supports the use of the four strategies discussed above: adult male circumcision, treatment of HIV infected people, pre-exposure prophylaxis and microbicides (Figure 3). However, although the foundations for successful HIV prevention programs are being laid out, there are still significant challenges ahead that will need to be solved before all these strategies can be fully scaled up, combined and delivered to the at risk individuals and communities. The field is also confident that the still elusive vaccine to prevent HIV infection can be unveiled in a not distant future.

Figure 3 lists currently proven biomedical interventions that prevent sexually transmitted HIV infection by gender.

**Figure 3.** Interventions to Prevent Sexually Transmited HIV Infection by Gender

### **Author details**

Jose G. Castro\* and Maria L. Alcaide

\*Address all correspondence to: Jcastro2@med.miami.edu

Division of Infectious Disease, Department of Medicine, Miller School of Medicine of the University of Miami, Miami, Florida, USA

### **References**

the available data and guidance to health care providers regarding the use of PrEP. However, HIV prevention guidelines are under development and 30 years of the history of HIV have shown the scientific community that a single intervention is unlikely to

In summary, the science of HIV prevention has seen significant progress in recent years. After decades of frustration and lagging behind the spectacular progress brought up in the control of HIV disease by the use of antiretrovirals, the field of biomedical prevention of HIV has been revolutionized and energized by the scientific evidence produced in the last few years that supports the use of the four strategies discussed above: adult male circumcision, treatment of HIV infected people, pre-exposure prophylaxis and microbicides (Figure 3). However, although the foundations for successful HIV prevention programs are being laid out, there are still significant challenges ahead that will need to be solved before all these strategies can be fully scaled up, combined and delivered to the at risk individuals and communities. The field is also confident that the still elusive vaccine to prevent HIV infection can be unveiled in a not

Figure 3 lists currently proven biomedical interventions that prevent sexually transmitted HIV

Division of Infectious Disease, Department of Medicine, Miller School of Medicine of the

**Figure 3.** Interventions to Prevent Sexually Transmited HIV Infection by Gender

and Maria L. Alcaide

University of Miami, Miami, Florida, USA

\*Address all correspondence to: Jcastro2@med.miami.edu

succeed.

402 Current Perspectives in HIV Infection

distant future.

infection by gender.

**Author details**

Jose G. Castro\*


[18] Reynolds, S. J, Shepherd, M. E, & Risbud, A. R. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet (2004). , 363, 1039-40.

[30] Connor, E. M, Sperling, R. S, Gelber, R, Kiselev, P, & Scott, W. Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine treat‐

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

405

[31] Shih, C-C, Kaneshima, H, & Rabin, L. Post exposure prophylaxis with zidovudine suppresses human immunodeficiency virus type 1 infection in SCID-hu mice in a

[32] Sharpe, A. H, Jaenisch, R, & Ruprecht, R. M. Retroviruses and mouse embryos: a rap‐ id model for neurovirulence and transplacental antiviral therapy. Science (1987). ,

[33] Sharpe, A. H, Hunter, J. J, Ruprecht, R. M, & Jaenisch, R. Maternal transmission of retroviral disease: transgenic mice as a rapid test system for evaluating perinatal and transplacental antiretroviral therapy. Proc Natl Acad U S A (1988). , 85, 9792-6. [34] Dorenbaum, A, Cunningham, C. K, & Gelber, R. Two-dose intrapartum/newborn ne‐ virapine and standard antiretroviral therapy to reduce perinatal HIV transmission: a

[35] Cooper, E. R, Charurat, M, & Mofenson, L. Combination antiretroviral strategies for the treatment of pregnant HIV-1 infected women and prevention of perinatal HIV-1

[36] Quinn, T. C, Wawer, M. J, & Sewankambo, N. Viral load and heterosexual transmis‐ sion of human immunodeficiency virus type 1. Rakai Project Study Group. N Eng J

[37] Chaisson, R. E, Keruly, J. C, & Moore, R. D. Association of initial CD4 cell count and viral load with response to highly active antiretroviral therapy. JAMA (2000). , 284,

[38] Phillips, A. N, Staszewski, S, & Weber, R. HIV viral load response to antiretroviral therapy according to the baseline CD4 cell count and viral load. JAMA (2001). , 286,

[39] Graham, S. M, Holte, S. E, & Peshu, N. M. Initiation of antiretroviral therapy leads to a rapid decline in cervical and vaginal HIV-1 shedding. AIDS (2007). , 21, 501-07. [40] Gupta, P, Mellors, J, & Kingsley, L. High viral load in semen of human immodefi‐ ciency virus type 1-infected men at all stages of disease and its reduction by therapy with protease and nonnucleoside reverse transcriptase inhibitors. J Virol (1997). , 71,

[41] Marcelin, A. G, & Tubiana, R. Lambert-Niclot. Detection of HIV-1 RNA in seminal plasma samples from treated patients with undetectable HIV-1 RNA in blood plas‐

transmission. J Acquir Immune Defic Syndr (2002). , 29(5), 484-94.

ment. N Eng J Med (1994). , 331, 1173-1180.

randomized trial. JAMA (2002). , 288(2), 189-98.

Med (2000). , 342, 921-929.

3128-29.

2560-67.

6271-75.

ma. AIDS (2008).

236, 1671-4.

time-dependent manner. J Infect Dis (1991). , 163, 625-627.


[30] Connor, E. M, Sperling, R. S, Gelber, R, Kiselev, P, & Scott, W. Reduction of maternalinfant transmission of human immunodeficiency virus type 1 with zidovudine treat‐ ment. N Eng J Med (1994). , 331, 1173-1180.

[18] Reynolds, S. J, Shepherd, M. E, & Risbud, A. R. Male circumcision and risk of HIV-1 and other sexually transmitted infections in India. Lancet (2004). , 363, 1039-40. [19] Weiss, H. A, Quigley, M. A, & Hayes, R. J. Male circumcision and risk of HIV infec‐ tion in sub-Saharan Africa: a systematic review and meta-analysis. AIDS (2000). , 14,

[20] Bailey, R. C, Moses, S, Parker, C. B, Agot, K, Maclean, I, Krieger, J. N, et al. Male cir‐ cumcision for HIV prevention in young men in Kisumu, Kenya: a randomized con‐

[21] Gray, R. H, Kigozi, G, Serwadda, D, Makumbi, F, Watya, S, Nalugoda, F, et al. Male circumcision for HIV prevention in men in Rikai, Uganda: a randomized trial. Lancet

[22] Auvert, B, Taljaard, D, Lagarde, E, Sobngwi-tambekou, J, Sitta, R, & Puren, A. Randomized, controlled intervention trial of male circumcision for reduction of HIV

[23] Riess, T. H, Achieng, M. M, Otieno, S, Ndinya-achola, J. O, & Bailey, R. C. (2010). When I Was Circumcised I Was Taught Certain Things": Risk Compensation and Protective Sexual Behavior among Circumcised Men in Kisumu, Kenya. PLoS ONE

[24] Byakika-TusiimeJayne. Circumcision and HIV Infection: Assessment of Causality.

[25] UNAIDS and WHONew data on male circumcision and HIV prevention: policy and programme implications; WHO/UNAIDS technical consultation male circumcision and HIV prevention: research implications for policy and programming Montreaux, Geneva: Joint United Nations Programme on HIV/AIDS and World Health Organiza‐

[26] Westercamp, N, & Bailet, R. C. Acceptability of male circumcision for prevention of HIV/AIDS in sub-Saharan Africa: A review. AIDS Behav (2007). , 11, 341-355.

[27] Castro, J. G, Jones, D. L, Lopez, M, Barradas, I, & Weiss, S. Making the case for cir‐ cumcision as a public health strategy: opening the dialogue. AIDS Patient Care and

[28] Madhivanan, P, Krupp, K, & Chandrasekaran, V. Acceptability of male circumcision among mothers with male children in Mysore, India. AIDS (2008). , 22, 983-988. [29] Castro, J. G, Jones, D. L, Lopez, M, Deeb, K, Barradas, I, & Weiss, S. Acceptability of neonatal circumcision by Hispanics in southern Florida. Journal of STD & AIDS

infection risk: the ANRS 1265 trial. PLoS Med (2005). e298.

AIDS and Behavior (2008). DOI:s10461-008-9453-6., 12(6)

5(8): e12366. doi:10.1371/journal.pone.0012366.

2361-70.

404 Current Perspectives in HIV Infection

(2007). , 369, 657-666.

tion, (2007).

STDs. (2010). , 24(6), 367-372.

(2010). , 21, 591-4.

trolled trial. Lancet (2007). , 369, 643-656.


[42] Attia, S, Egger, M, & Muller, M. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS (2009). , 23, 1397-404.

[55] Baeten, J. M, Donnell, D, Ndase, P, Mugo, N. R, Campbell, J. D, Wangisi, J, et al. Anti‐ retroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J

Prevention of Sexually Transmitted HIV Infection

http://dx.doi.org/10.5772/54168

407

[56] Van Damme, L, Corneli, A, Ahmed, K, Agot, K, Lombaard, J, Kapiga, S, et al. Preex‐ posure prophylaxis for HIV infection among African women. N Engl J Med. (2012).

[57] Microbicide Trials NetworkVOICE (MTN-003) study. Available from:http://

[58] Montgomery, E. T, Van Der Straten, A, Chidanyika, A, Chipato, T, Jaffar, S, & Padi‐ an, N. The importance of male partner involvement for women's acceptability and adherence to female initiated HIV prevention methods in Zimbabwe. AIDS Behav

[59] Montgomrery, E. T, Van Der Straten, A, & Torjesen, K. Male involvement in womens and children's HIV prevention: challenges in definition and interpretation. J Acqui

[60] Patterson, K, Prince, H, Kraft, E, Jenkings, A, Shaheen, N. J, Rooney, J. F, et al. Pene‐ tration of tenofovir and emtricitabine in mucosal tissues: implications for prevention

[61] Juusola, J, Brandeau, M, Owens, D, & Bendavid, E. The Cost-Effectiveness of Preex‐ posure Prophylaxis for HIV Prevention in the United States in Men Who Have Sex

[62] Krakower, D, & Mayer, K. H. What Primary Care Providers Need to Know About Preexposure Prophylaxis for HIV Prevention: A Narrative Review. (2012). epub

[63] Abdool Karim SSRichardson B, Ramjee G. Safety and effectiveness of BufferGel and 0.5% PRO2000 gel for the prevention of HIV infection in women. AIDS (2010). , 25,

[64] Van Damme, L, Ramjee, G, & Alary, M. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomized controlled

[65] Van Damme, L, Govinden, R, & Mirembe, F. M. Lack of Effectiveness of Cellulose Sulfate Gel for the Prevention of Vaginal HIV TransmissionInternational Partnership for Microbicides (2012). Available from: http://www.ipmglobal.org/our-work/ipm-

[66] 66. Skoler-karpoff, S, Ramjee, G, & Ahmed, K. Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-

Med. (2012). , 367(5), 399-410.

www.mtnstopshiv.org/news/studies/mtn003.

Immune Defic Syndr (2011). e , 114-116.

of HIV-1 transmission, Sci Transl Med (2011).

With Men. Ann Intern Med (2012). , 156, 541-550.

controlled trial. The Lancet (2008). , 372, 1977-1987.

Aug 2; , 367(5), 411-22.

(2011). , 15, 959-969.

ahead of print].

trial. Lancet (2002). , 360, 971-977.

product-pipeline/maraviroc.

957-966.


[55] Baeten, J. M, Donnell, D, Ndase, P, Mugo, N. R, Campbell, J. D, Wangisi, J, et al. Anti‐ retroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. (2012). , 367(5), 399-410.

[42] Attia, S, Egger, M, & Muller, M. Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis. AIDS (2009). , 23,

[43] Celum, C, Wald, A, & Lingappa, J. R. Acyclovir and transmission of HIV-1 from per‐

[44] Cohen, M. S, Chen, Y. Q, & Mccauley, M. Prevention of HIV-1 infection with early

[45] Cohen, J. Breakthrough of the year. HIV treatment as prevention, Science 23 Decem‐

[46] Guay, L. A, Musoke, P, Fleming, T, Bagenda, D, Allen, M, Nakabiito, C, et al. Intra‐ partum and neonatal single-dose nevirapine compared with zidovudine for preven‐ tion of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012

[47] World Health OrganizationUse of Antiretroviral Medication for Treating Pregnant Women and Preventing HIV infection in Infants (2012). Available from: http://

[48] Cardo, D, Culver, D. H, & Ciesielski, C. A. study of HIV seroconversion in health care worker after percutaneous exposure. New Eng J Med., , 337, 1485-90.

[49] Garcia-lerma, J. G, Otten, R. A, & Qari, S. H. (2008). Prevention of rectal SHIV trans‐ mission in macaques by daily or intermittent prophylaxis with emtricitabine and te‐

[50] Van Rompay, K. K, Mcchesney, M. B, & Aguirre, N. L. (2001). Two low doses of teno‐ fovir protect new-born macaques against oral simian immunodeficiency virus infec‐

[51] Anderson, P. L, Kiser, J. J, Gardner, E. M, Rower, J. E, Meditz, A, & Grant, R. M. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infec‐

[52] Gilead laboratoriesTenofovir disoproxil fumarate. Updated August (2012). Available

[53] Gant, R, Lama, J, Anderson, P, Mcmahan, V, Liu, A, & Vargas, L. el al. IPrEX study team. Peexposure Chemoprophylaxis for HIV Prevention in Men Who Have Sex

[54] Thigpen, M. C, Kebaabetswe, P. M, Paxton, L. A, Smith, D. K, Rose, C. E, Segolodi, T. M, et al. TDF2 Study Group. Antiretroviral preexposure prophylaxis for heterosexual

HIV transmission in Botswana. N Engl J Med. (2012). , 367(5), 423-34.

sons infected with HIV-1 and HSV-2. N Engl J Med (2010). , 362, 427-39.

antiretroviral therapy. N Engl J Med (2011). , 365, 493-505.

randomised trial. Lancet. (1999). Sep 4; , 354(9181), 795-802.

1397-404.

406 Current Perspectives in HIV Infection

ber (2011). , 334(6063), 1628.

www.who.int/hiv/PMTCT\_update.pdf

nofovir. PLOS medicine, e , 28, 0291-0299.

tion. J Antimicrob Chemother. (2011). , 66(2), 240-50.

from: http://www.gilead.com/pdf/viread\_pi.pdf.

with Men. NEngl J Med (2010). , 363(27), 2587-2599.

tion. J Infect Dis. 2001; , 184, 429-438.


[67] Abdool Karim QAbdool Karim S, Frohlich J, Grobler A, Baxter C, Mansoor L et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the pre‐ vention of HIV infection in women. Science; , 329(5996), 1168-1174.

**Section 6**

**Recent Advances**


**Section 6**

**Recent Advances**

[67] Abdool Karim QAbdool Karim S, Frohlich J, Grobler A, Baxter C, Mansoor L et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the pre‐

[68] Microbicide Trials NetworkVOICE (MTN-003) study. Available from: http://

[69] International Partnership for Microbicides (2012). Available from: http://ipmglo‐

[70] International Partnership for Microbicides (2012). Available from: http://

[71] Van'Klooster, t, Hoeben, G, Borghys, E, Looszova, H, Bouche, A, Van Velsen, M, et al. Pharmacokinetics and disposition of rilpivirine (TMC 278) nanosuspension as a long-acting injectable antiretroviral formulation. Antimicrob Agents Chemother

[72] Smith, D, Thigpen, M, Nesheim, S, Lampe, M, Pazton, L, Fenton, M, et al. Interim Guidance for Clinicians Considering the Use of Preexposure Prophylaxis for the Pre‐ vention of HIV Infection in Heterosexually Active Adults. MMWR (2012). Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6131a2.htm?

vention of HIV infection in women. Science; , 329(5996), 1168-1174.

www.mtnstopshiv.org/node/3909.Accessed September 10th (2012).

www.ipmglobal.org/our-work/ipm-product-pipeline/maraviroc.

bal.org/node/532

408 Current Perspectives in HIV Infection

(2010). , 54, 2042-2050.

s\_cid=mm6131a2\_w , 586-589.

**Chapter 18**

countries sharing economical-social links with them

Scarce data but less efficiently transmitted than

Naturally resistant to non-nucleoside analogous targeting reverse transcriptase. Scarce and sometimes conflicting results regarding susceptibility to other anti-retroviral drugs

HIV-1

© 2013 Azevedo-Pereira; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**HIV-2 Interaction with Target Cell Receptors,**

Although sharing identical transmission routes as well as structural and genomic properties, human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2, respectively) show different pathogenic abilities in human host. Despite both HIV-1 and HIV-2 lead to immunological failure and Acquired Immunodeficiency Syndrome (AIDS), a slower rate of disease progres‐ sion with a longer asymptomatic period and lower levels of viremia in general characterize HIV-2 infection (Table 1). Comparative studies measuring the progression rates of both HIV-1 and HIV-2 infections provided clear evidence that the majority of HIV-2 infected individuals

*HIV-1 HIV-2* **Geographic distribution** Worldwide Restricted to West African countries and to

Usually less than 10 years Usually decades

and reproduction in any medium, provided the original work is properly cited.

**Viral load** Usually moderate to high Usually undetectable

all anti-retroviral drugs. Resistance-conferring mutations well established and defined

**Table 1.** Comparison between epidemiologic and clinical data of HIV-1 and HIV-2 infections

**or Why HIV-2 is Less Pathogenic than HIV-1**

José Miguel Azevedo-Pereira

http://dx.doi.org/10.5772/53201

**1. Introduction**

**Duration of asymptomatic**

**stage**

Additional information is available at the end of the chapter

fit in a definition of long-term non-progressors [1-3].

**Transmission** By sexual route is usually inefficient, requiring multiple exposures

**Treatment** Plenty of data regarding viral susceptibility to

## **HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic than HIV-1**

José Miguel Azevedo-Pereira

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53201

### **1. Introduction**

Although sharing identical transmission routes as well as structural and genomic properties, human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2, respectively) show different pathogenic abilities in human host. Despite both HIV-1 and HIV-2 lead to immunological failure and Acquired Immunodeficiency Syndrome (AIDS), a slower rate of disease progres‐ sion with a longer asymptomatic period and lower levels of viremia in general characterize HIV-2 infection (Table 1). Comparative studies measuring the progression rates of both HIV-1 and HIV-2 infections provided clear evidence that the majority of HIV-2 infected individuals fit in a definition of long-term non-progressors [1-3].


**Table 1.** Comparison between epidemiologic and clinical data of HIV-1 and HIV-2 infections

© 2013 Azevedo-Pereira; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

All these findings support the notion that in HIV-2 infected individuals several factors (e.g. virologic and immunologic) should account for a best fitted response that ultimately leads to a better control of HIV-2 infection compared to HIV-1. Deciphering these factors should provide crucial information about the mechanisms underlying the delayed disease progression and may help explain how a retroviruses infection could be coped for such a long time without causing disease. This knowledge is important to clarify AIDS pathogenesis and to identify the correlates of protection crucial to develop an efficient HIV vaccine.

to the preintegration complex (PIC) composed by several cellular and viral components, e.g. viral DNA, RT, integrase (IN), matrix (MA) and Vpr proteins (reviewed in [12]). This PIC allows the reverse transcribed viral DNA to enter the nucleus through the nuclear

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

413

After integration, the HIV-2 proviral DNA is transcribed into several mRNAs by cellular RNA polymerase II, a process initiated through the binding of cellular activation factors to the viral LTR, culminating in the synthesis of viral proteins and in the production of new progeny virions. The function of each HIV-2 protein has been inferred from HIV-1 counterparts and

Compared to HIV-1, HIV-2 lacks the *vpu* gene while has the *vpx* gene. The Vpu protein has been associated with two main functions in HIV-1 replication: induces a rapid degradation of CD4 molecules (see below the role of CD4 as viral receptor) in endoplasmic reticulum through the ubiquitin-proteasome system [14]; and enhancing the budding and release of viral particles [15] by counteracting the activity of Tetherin/BST2, a cellular factor that restricts the egress of enveloped viruses (e.g. HIV, Ebola virus), thereby reducing viral production and cell-free virus propagation [16, 17]. In HIV-2, this latter role in viral replication seems to be assumed by the membrane-anchored subunit and the extracellular domain of transmembrane (TM) envelope

Vpx is a protein only present in HIV-2 and SIVsm lineage. Sequence analysis suggests that the *vpx* gene is a duplication of *vpr* gene but despite amino acid sequence similarities between both proteins, their functions are clearly distinct. While Vpr is mainly involved in cell cycle arrest in G2/M phase [20], the Vpx protein has been recently linked to the enhancement of HIV-1 infection of dendritic cells and an essential factor in innate response to HIV infection [21]. The obvious importance of Vpx in the pathogenesis of human lentiviral infection will be further

As in all zoonosis, the emergence of HIV-1 and HIV-2, as successful new human pathogens, involved not only a close contact with animal reservoirs but also the capability of the crossspecies viruses to: encounter and efficiently infect human host cells, and to be able to be

Although HIV-1 and HIV-2 shared common transmission routes, they show a clear distinct epidemiology. While HIV-1, particularly group M, has spread literally worldwide, HIV-2 infection reveal a much more confined geographic distribution: West Africa and countries that maintained social-economic links to this region (e.g. Portugal, France and their former colonies). Since both viruses had begun to spread nearly at the same time, somewhere between 1950 and 1970, this limited expansion of HIV-2 indicates a less efficient human transmission. Heterosexual spread of HIV-2 is remarkably lower than in HIV-1: it seems that HIV-2 is five to nine times less efficiently transmitted than HIV-1 by sexual route [22]. Likewise, mother-to-

pore and to be integrated into the genome of target cell.

reviewed in [13].

glycoprotein [18, 19].

discussed in subchapters 4 and 5.

**4. HIV-2 as a limited spreading virus**

effectively transmitted within the human population.

Despite the potential importance of HIV-2 as a model to address those issues, it has been mostly neglected and very few data exists regarding HIV-2 interaction with target cells. In this chapter I will focus on these interactions, particularly those concerning early events. Distinguishing features between HIV-1 and HIV-2 will be highlighted and their implications in viral fitness and pathogenic differences between the two viruses will be discussed.

### **2. Origin of HIV-2**

HIV-2, as HIV-1, belongs to Family *Retroviridae*, Subfamily *Orthoretrovirinae*, Genus *Lentivi‐ rus* [4]. It was first isolated from a symptomatic patient from Guinea-Bissau [5] and subse‐ quently associated with immunological failure and clinical manifestations typically observed in AIDS patients infected with HIV-1 [6].

HIV-1 and HIV-2 were introduced into human population as a consequence of multiple crossspecies transmissions from simian immunodeficiency virus (SIV)-infected non-human primates. The genetic relatedness between HIV-1, HIV-2 and SIV strains, and the coincidence of natural habitats of specific simian species and geographic regions where HIV-1 and HIV-2 had probably emerged, allowed the identification of SIVcpz (infecting the chimpanzee subspecies *Pan troglodytes troglodytes*) and SIVsm (infecting sooty mangabey subspecies *Cercocebus atys*) as viral ancestors of HIV-1 and HIV-2, respectively [7-9]. Through a combina‐ tion of phylogenetic and molecular clock analysis it was estimated that the date of the most recent common ancestor of HIV-1 group M was 1930 ± 15, and that of "HIV-2 group A was 1940 ± 16 [8, 10]. These cross-species transmission events was then fuelled-up by social, sexual and iatrogenic factors during colonial period in Africa [11], converting a restricted zoonotic disease into an epidemic (HIV-2) and pandemic (HIV-1) infections.

### **3. Genomic organization of HIV-2**

The genomic information of HIV-2 is comprised in two identical copies of 9.2 kb single strand RNA. HIV-2 genome encodes nine open reading frames (i.e. *gag, pol, vif, vpr, tat, rev, vpx, env* and *nef*), flanked by two long terminal repeats (5'LTR and 3'LTR). Soon af‐ ter entry into target cell the genomic RNA is converted to a double-stranded DNA mole‐ cule, a reaction catalized by reverse transcriptase (RT) enzyme, that occurs in a cytoplasmic complex, named reverse transcriptase complex (RTC). The RTC transforms to the preintegration complex (PIC) composed by several cellular and viral components, e.g. viral DNA, RT, integrase (IN), matrix (MA) and Vpr proteins (reviewed in [12]). This PIC allows the reverse transcribed viral DNA to enter the nucleus through the nuclear pore and to be integrated into the genome of target cell.

After integration, the HIV-2 proviral DNA is transcribed into several mRNAs by cellular RNA polymerase II, a process initiated through the binding of cellular activation factors to the viral LTR, culminating in the synthesis of viral proteins and in the production of new progeny virions. The function of each HIV-2 protein has been inferred from HIV-1 counterparts and reviewed in [13].

Compared to HIV-1, HIV-2 lacks the *vpu* gene while has the *vpx* gene. The Vpu protein has been associated with two main functions in HIV-1 replication: induces a rapid degradation of CD4 molecules (see below the role of CD4 as viral receptor) in endoplasmic reticulum through the ubiquitin-proteasome system [14]; and enhancing the budding and release of viral particles [15] by counteracting the activity of Tetherin/BST2, a cellular factor that restricts the egress of enveloped viruses (e.g. HIV, Ebola virus), thereby reducing viral production and cell-free virus propagation [16, 17]. In HIV-2, this latter role in viral replication seems to be assumed by the membrane-anchored subunit and the extracellular domain of transmembrane (TM) envelope glycoprotein [18, 19].

Vpx is a protein only present in HIV-2 and SIVsm lineage. Sequence analysis suggests that the *vpx* gene is a duplication of *vpr* gene but despite amino acid sequence similarities between both proteins, their functions are clearly distinct. While Vpr is mainly involved in cell cycle arrest in G2/M phase [20], the Vpx protein has been recently linked to the enhancement of HIV-1 infection of dendritic cells and an essential factor in innate response to HIV infection [21]. The obvious importance of Vpx in the pathogenesis of human lentiviral infection will be further discussed in subchapters 4 and 5.

### **4. HIV-2 as a limited spreading virus**

All these findings support the notion that in HIV-2 infected individuals several factors (e.g. virologic and immunologic) should account for a best fitted response that ultimately leads to a better control of HIV-2 infection compared to HIV-1. Deciphering these factors should provide crucial information about the mechanisms underlying the delayed disease progression and may help explain how a retroviruses infection could be coped for such a long time without causing disease. This knowledge is important to clarify AIDS pathogenesis and to identify the

Despite the potential importance of HIV-2 as a model to address those issues, it has been mostly neglected and very few data exists regarding HIV-2 interaction with target cells. In this chapter I will focus on these interactions, particularly those concerning early events. Distinguishing features between HIV-1 and HIV-2 will be highlighted and their implications in viral fitness

HIV-2, as HIV-1, belongs to Family *Retroviridae*, Subfamily *Orthoretrovirinae*, Genus *Lentivi‐ rus* [4]. It was first isolated from a symptomatic patient from Guinea-Bissau [5] and subse‐ quently associated with immunological failure and clinical manifestations typically observed

HIV-1 and HIV-2 were introduced into human population as a consequence of multiple crossspecies transmissions from simian immunodeficiency virus (SIV)-infected non-human primates. The genetic relatedness between HIV-1, HIV-2 and SIV strains, and the coincidence of natural habitats of specific simian species and geographic regions where HIV-1 and HIV-2 had probably emerged, allowed the identification of SIVcpz (infecting the chimpanzee subspecies *Pan troglodytes troglodytes*) and SIVsm (infecting sooty mangabey subspecies *Cercocebus atys*) as viral ancestors of HIV-1 and HIV-2, respectively [7-9]. Through a combina‐ tion of phylogenetic and molecular clock analysis it was estimated that the date of the most recent common ancestor of HIV-1 group M was 1930 ± 15, and that of "HIV-2 group A was 1940 ± 16 [8, 10]. These cross-species transmission events was then fuelled-up by social, sexual and iatrogenic factors during colonial period in Africa [11], converting a restricted zoonotic

The genomic information of HIV-2 is comprised in two identical copies of 9.2 kb single strand RNA. HIV-2 genome encodes nine open reading frames (i.e. *gag, pol, vif, vpr, tat, rev, vpx, env* and *nef*), flanked by two long terminal repeats (5'LTR and 3'LTR). Soon af‐ ter entry into target cell the genomic RNA is converted to a double-stranded DNA mole‐ cule, a reaction catalized by reverse transcriptase (RT) enzyme, that occurs in a cytoplasmic complex, named reverse transcriptase complex (RTC). The RTC transforms

correlates of protection crucial to develop an efficient HIV vaccine.

and pathogenic differences between the two viruses will be discussed.

disease into an epidemic (HIV-2) and pandemic (HIV-1) infections.

**2. Origin of HIV-2**

412 Current Perspectives in HIV Infection

in AIDS patients infected with HIV-1 [6].

**3. Genomic organization of HIV-2**

As in all zoonosis, the emergence of HIV-1 and HIV-2, as successful new human pathogens, involved not only a close contact with animal reservoirs but also the capability of the crossspecies viruses to: encounter and efficiently infect human host cells, and to be able to be effectively transmitted within the human population.

Although HIV-1 and HIV-2 shared common transmission routes, they show a clear distinct epidemiology. While HIV-1, particularly group M, has spread literally worldwide, HIV-2 infection reveal a much more confined geographic distribution: West Africa and countries that maintained social-economic links to this region (e.g. Portugal, France and their former colonies). Since both viruses had begun to spread nearly at the same time, somewhere between 1950 and 1970, this limited expansion of HIV-2 indicates a less efficient human transmission. Heterosexual spread of HIV-2 is remarkably lower than in HIV-1: it seems that HIV-2 is five to nine times less efficiently transmitted than HIV-1 by sexual route [22]. Likewise, mother-tochild transmission rate of HIV-2 is 0-4%, while in HIV-1 this transmission occurs in 15-40% of untreated pregnancies [23].

susceptible cells such as T lymphocytes, macrophages, Langerhans cells and dendritic cells. Mucus, particularly abundant in upper female genital tract, provides the first barrier to HIV infection. Mucus protective role of underlying epithelial cells is provided by the presence of soluble factors (e.g. chemokines produced by epithelial cells) that decrease viral infectivity and by mechanical trapping of virions in the dense protein mesh that constitutes the cervical mucus [33]. By slowing viral diffusion, mucus reduces the probability of infectious virus reach the

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

415

Virions that successfully crossed the mucus encounters the epithelial cells layer that line the different compartments of the female genital tract. These different compartments show remarkable differences in the structure of epithelial layer. The mucosa from the lower female genital tract (i.e. exocervix and vagina) consists of stratified squamous epithelium, several layers thick. In contrast, in the upper reproductive compartment (i.e. endocervix and endo‐ metrium) the mucosal lining is composed of a single layer of columnar epithelium over the basement membrane and is characterized by the presence of tight junctions between cells.

As expected by their different composition, the lower female genital epithelium is much more robust and provides a more effective physical barrier than the fragile single columnar layer of upper genital epithelium. Furthermore, the junction between the exocervix and the endocervix, where the structure of the epithelium abruptly changes from stratified to single layer (called the transitional or transformational zone), is characterized by an intense immunologic activity and thus enriched with abundant lymphocytes and antigen presenting cells (e.g. dendritic cells and macrophages), particularly during inflammatory processes [34]. The physical vulnerabil‐ ity and the presence of abundant target cells in transitional zone, make this region highly

Even the thicker vaginal epithelial barrier could quickly expose susceptible cells in the submucosa to HIV. In fact, the stratified squamous epithelium changes markedly through the menstrual cycle, in response to progesterone [36], leading to a thinning of this physical barrier. Additionally, breaches could occur because of microulcerations and breaks in the epithelium due to sexual intercourse, inflammatory processes, sexually transmitted infections, and other

Additionally, the mere exposure of genital mucosa to semen induces local alterations that could potentiate the transmission of HIV-1 and (probably) HIV-2. These include the neutrali‐ zation of the acidic pH of the cervicovaginal secretions, the regulation of inflammatory cytokines in genital tract epithelial cells, and the promotion of leukocyte infiltration and the attraction of Langerhans cells in cervical and vaginal mucosae [40, 41]. Semen could also directly promote HIV infection of epithelial target cells through the formation of amyloid fibrils that capture HIV particles and enhances virus-cell attachment and fusion [42]. This amyloi‐ dogenic activity of human semen seems to be related with fragments of prostatic acidic phosphatase [42]. Apparently this enhancement is semen donor-dependent but independent

In contrast to female genital tract, HIV transmission through male genital tract is poorly understood. Despite the presence of CD4+ T lymphocytes, Langerhans cells, dendritic cells

genital infections, increasing the likelihood of establishing an HIV infection [37-39].

surface of underlying cells.

susceptible to HIV entry and infection [35].

of HIV strain or cell type used [43].

This poor capability to infect new hosts could lead HIV-2 to a dead end. Viral ecology imposes two ideal conditions: maintain the host alive as long as possible while being efficiently transmitted within host population. HIV-2 only fulfils the first condition leading to a decline in HIV-2 prevalence even in regions (i.e. West Africa) where, in the early stages of AIDS epidemic, a clear predominance of HIV-2 infections existed compared to HIV-1 [24].

### **4.1. Viral load and transmission**

Many different factors account for a successful transmission of HIV by sexual route. One of the most critical is the amount of infectious viral particles present in the transmitting body fluid (e.g. blood, semen or cervicovaginal secretion). Higher concentrations are more likely associated with transmission events. Apparently, in HIV-1, the cutoff of 1500 copies of viral RNA per ml of plasma is required for efficient transmission [25].

Not surprisingly, plasma and semen viral loads are significantly lower in patients infected with HIV-2 compared to those infected with HIV-1 [26, 27], providing a likely explanation for the reduced transmission rate and spread within human population. This lower viral load is observed throughout the infection and persists until late in the course of the disease, but is remarkably important during asymptomatic stage. During this stage, which in HIV-2 could last for several decades, an undetectable viremia is a hallmark of almost every HIV-2 patients. However, a similar proviral burden is detected in both HIV-1 and HIV-2-infected individuals [28, 29]. This apparent paradox suggests that the lower plasma viral load observed in HIV-2 infection may be due to lower levels of infectious virus production, or a better host-driven suppression of viral replication, or both.

### **4.2. The mucosal barrier**

Besides viral load, numerous barriers decrease the efficiency of mucosal transmission. The foundations of this important notion emanates from studies of couples discordant for HIV-1 infection, which demonstrated that heterosexual transmission is very inefficient requiring multiple exposures for a successful transmission [30, 31]. A detailed understanding of the events surrounding transmission should provide important clues how HIV establishes a new infection and what additional vulnerabilities HIV-2 has, at this stage, that can help explain its lower spread.

Although HIV-1 and HIV-2 (as well as SIV) are commonly referred as "lentivirus" based on the long incubation period and slow onset of disease, it is now clear from data using rhesus macaque model infected with SIV, that initial virus-host interactions, crucial to establishing systemic infection, take place in a rapid succession of related events, soon after mucosal transmission (recently reviewed in [32]). In sexual transmission, the most common form of HIV transmission, these events involve the interactions with cells present in cervical/vaginal mucosa epithelial surfaces. To establish infection, HIV present in semen must go through mucus that covers female genital epithelia and penetrate through the epithelial layer to access susceptible cells such as T lymphocytes, macrophages, Langerhans cells and dendritic cells. Mucus, particularly abundant in upper female genital tract, provides the first barrier to HIV infection. Mucus protective role of underlying epithelial cells is provided by the presence of soluble factors (e.g. chemokines produced by epithelial cells) that decrease viral infectivity and by mechanical trapping of virions in the dense protein mesh that constitutes the cervical mucus [33]. By slowing viral diffusion, mucus reduces the probability of infectious virus reach the surface of underlying cells.

child transmission rate of HIV-2 is 0-4%, while in HIV-1 this transmission occurs in 15-40% of

This poor capability to infect new hosts could lead HIV-2 to a dead end. Viral ecology imposes two ideal conditions: maintain the host alive as long as possible while being efficiently transmitted within host population. HIV-2 only fulfils the first condition leading to a decline in HIV-2 prevalence even in regions (i.e. West Africa) where, in the early stages of AIDS

Many different factors account for a successful transmission of HIV by sexual route. One of the most critical is the amount of infectious viral particles present in the transmitting body fluid (e.g. blood, semen or cervicovaginal secretion). Higher concentrations are more likely associated with transmission events. Apparently, in HIV-1, the cutoff of 1500 copies of viral

Not surprisingly, plasma and semen viral loads are significantly lower in patients infected with HIV-2 compared to those infected with HIV-1 [26, 27], providing a likely explanation for the reduced transmission rate and spread within human population. This lower viral load is observed throughout the infection and persists until late in the course of the disease, but is remarkably important during asymptomatic stage. During this stage, which in HIV-2 could last for several decades, an undetectable viremia is a hallmark of almost every HIV-2 patients. However, a similar proviral burden is detected in both HIV-1 and HIV-2-infected individuals [28, 29]. This apparent paradox suggests that the lower plasma viral load observed in HIV-2 infection may be due to lower levels of infectious virus production, or a better host-driven

Besides viral load, numerous barriers decrease the efficiency of mucosal transmission. The foundations of this important notion emanates from studies of couples discordant for HIV-1 infection, which demonstrated that heterosexual transmission is very inefficient requiring multiple exposures for a successful transmission [30, 31]. A detailed understanding of the events surrounding transmission should provide important clues how HIV establishes a new infection and what additional vulnerabilities HIV-2 has, at this stage, that can help explain its

Although HIV-1 and HIV-2 (as well as SIV) are commonly referred as "lentivirus" based on the long incubation period and slow onset of disease, it is now clear from data using rhesus macaque model infected with SIV, that initial virus-host interactions, crucial to establishing systemic infection, take place in a rapid succession of related events, soon after mucosal transmission (recently reviewed in [32]). In sexual transmission, the most common form of HIV transmission, these events involve the interactions with cells present in cervical/vaginal mucosa epithelial surfaces. To establish infection, HIV present in semen must go through mucus that covers female genital epithelia and penetrate through the epithelial layer to access

epidemic, a clear predominance of HIV-2 infections existed compared to HIV-1 [24].

RNA per ml of plasma is required for efficient transmission [25].

untreated pregnancies [23].

414 Current Perspectives in HIV Infection

**4.1. Viral load and transmission**

suppression of viral replication, or both.

**4.2. The mucosal barrier**

lower spread.

Virions that successfully crossed the mucus encounters the epithelial cells layer that line the different compartments of the female genital tract. These different compartments show remarkable differences in the structure of epithelial layer. The mucosa from the lower female genital tract (i.e. exocervix and vagina) consists of stratified squamous epithelium, several layers thick. In contrast, in the upper reproductive compartment (i.e. endocervix and endo‐ metrium) the mucosal lining is composed of a single layer of columnar epithelium over the basement membrane and is characterized by the presence of tight junctions between cells.

As expected by their different composition, the lower female genital epithelium is much more robust and provides a more effective physical barrier than the fragile single columnar layer of upper genital epithelium. Furthermore, the junction between the exocervix and the endocervix, where the structure of the epithelium abruptly changes from stratified to single layer (called the transitional or transformational zone), is characterized by an intense immunologic activity and thus enriched with abundant lymphocytes and antigen presenting cells (e.g. dendritic cells and macrophages), particularly during inflammatory processes [34]. The physical vulnerabil‐ ity and the presence of abundant target cells in transitional zone, make this region highly susceptible to HIV entry and infection [35].

Even the thicker vaginal epithelial barrier could quickly expose susceptible cells in the submucosa to HIV. In fact, the stratified squamous epithelium changes markedly through the menstrual cycle, in response to progesterone [36], leading to a thinning of this physical barrier. Additionally, breaches could occur because of microulcerations and breaks in the epithelium due to sexual intercourse, inflammatory processes, sexually transmitted infections, and other genital infections, increasing the likelihood of establishing an HIV infection [37-39].

Additionally, the mere exposure of genital mucosa to semen induces local alterations that could potentiate the transmission of HIV-1 and (probably) HIV-2. These include the neutrali‐ zation of the acidic pH of the cervicovaginal secretions, the regulation of inflammatory cytokines in genital tract epithelial cells, and the promotion of leukocyte infiltration and the attraction of Langerhans cells in cervical and vaginal mucosae [40, 41]. Semen could also directly promote HIV infection of epithelial target cells through the formation of amyloid fibrils that capture HIV particles and enhances virus-cell attachment and fusion [42]. This amyloi‐ dogenic activity of human semen seems to be related with fragments of prostatic acidic phosphatase [42]. Apparently this enhancement is semen donor-dependent but independent of HIV strain or cell type used [43].

In contrast to female genital tract, HIV transmission through male genital tract is poorly understood. Despite the presence of CD4+ T lymphocytes, Langerhans cells, dendritic cells and macrophages in the foreskin and glans of the penis [44, 45], the mechanisms underlying the transmission across these mucosae are not completed elucidated. Foreskin seems to play a crucial role in female-to-male transmission of HIV-1, since several randomized controlled clinical trials have shown that circumcision reduce this route of transmission by approximately 60% [46]. One plausible mechanism for greater susceptibility to HIV-1 infection in uncircum‐ cised men could be the increased risk for sexually transmitted infections and consequent inflammation of the foreskin (reviewed in [47]). This predisposition to local infection and inflammatory reactions will lead to the recruitment of activated target cells that facilitates the early events of HIV transmission and provides a local environment suitable for productive HIV systemic infection.

be released to extracellular milieu and fuse with target-cell membranes allowing the transfer

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

417

Alternatively, HIV can directly infect the dendritic cell subset, present in submucosal tissues (*cis-*infection), using the natural expression of the main HIV cellular receptors (i.e. CD4 and CCR5; see bellow) at dendritic cell surface [56, 58, 59]. Despite the susceptibility of dendritic cells, conferred by the presence of these major receptors, HIV replication in dendritic cells is in general less productive, compared with CD4+ T lymphocytes [60]. The reasons for the decreased viral production in dendritic cells include: (i) lower expression levels of HIV receptors; (ii) degradation of internalized virions, soon after infection; and (iii) presence of

Interestingly, although HIV can infect dendritic cells, extensive viral replication only takes place after dendritic cells come into contact with CD4+ T lymphocytes in lymphoid tissue [61]. The dendritic cell-T lymphocyte interaction provides activation signaling to the latter, allowing HIV to be presented to a population of highly activated and susceptible T-lymphocytes. This further indicates that the infection of dendritic cells by HIV-1 is a double-edged sword: dendritic cells must deliver appropriate signals to T lymphocytes in order to induce an HIVspecific immune response; however, this interaction imposes a close contact between dendritic cells and T lymphocytes (immunological synapse) leaving the latter susceptible to infection by

In conclusion, dendritic cell-mediated virus transfer occurs in two distinct phases: in the first phase (*trans*-infection), dendritic cell capture and internalize virus within endosomal com‐ partments which are relocated at the dendritic cell/CD4+ T-lymphocyte contact zone (virolog‐ ical synapse); alternatively, a fraction of the endocytosed particles may be targeted for exocytosis, associated with exosomes [62]. Both processes occur without dendritic cell productive infection. In the second phase, the direct infection of dendritic cell (*cis*-infection) contributes to the spread of newly synthesized progeny virus to CD4+ T-lymphocytes [63]. In this regard, several studies have provided important data defining entry-enhancement factors on dendritic cells, such as DC-SIGN, and other C-type lectins receptors (mannose receptor, langerin, syndecan-3, and dendritic cell immunoreceptor - DCIR) [63]. The role of C-type lectin receptors seems to be crucial in both *trans*- and *cis*-infection modes. For example, HIV-1 bound to DC-SIGN is rapidly taken up within endolysosomal vacuoles and protected from degrada‐ tion while remaining infectious for 1–3 days [64]. Interestingly, suppression of DC-SIGN expression has been shown to impair the viral synapse formation, and to inhibit *trans*-infection

All the data reviewed until now was obtained almost exclusively using HIV-1 model (and in some instances SIV). As referred earlier in this chapter, HIV-2 is a lentivirus that shows a decreased capacity to spread between humans, and probably with additional vulnerabilities during transmission, compared with HIV-1. Besides the lower viral load both in plasma and semen referred previously, little is know about HIV-2 interaction with mucosal cells and how the described physical barriers counteract effective HIV-2 transmission to a new host. For example, very few data exists about HIV-2 interaction with DC-SIGN or the way HIV-2 uses *trans*-infection mechanisms to spread to T-lymphocytes. Apparently the T-cell line adapted

intracellular restriction factors that inhibited post-entry events of replication cycle.

of HIV to them [57].

the HIV-1 carried by dendritic cells.

of HIV-1 to CD4+ T-lymphocytes [65].

The vaginal flora could in some circumstances also favour female-to-male HIV transmission. The predominance of potential pathogenic bacteria instead of normal *Lactobacillus* species, observed during bacterial vaginosis, seems to be related not only with increased risk of HIV-1 acquisition by women (as referred above) but also with higher concentrations of HIV-1 in cervicovaginal secretions, due to a bacterial-driven augmentation of HIV-1 replication and shedding [48-50]. Thus, women with bacterial vaginosis are more infectious and the proba‐ bility of female-to-male HIV-1 transmission during sexual intercourse is greater than in women with normal vaginal flora [51].

#### **4.3. Crossing the intact mucosal barrier**

Although infection of mucosal epithelial cells could happen, HIV must gain access to permis‐ sive host cells present in underlying submucosa tissue (e.g. dendritic cells macrophages and CD4+ T-lymphocytes) to facilitate virus production and dissemination. The mechanisms for crossing intact stratified squamous epithelium of the vagina or the simple columnar epithelium of the cervix could be one (or more) of the following: (i) transcytosis by a vesicular pathway [52] – an apparently rare but possible event [53]; (ii) capture or infection of dendritic cells resident in the stratified squamous epithelium of the vaginal mucosa and in the underlying tissues of the vagina and cervix [54]; and (iii) direct infection of intraepithelial lymphocytes in the endocervical mucosa [55].

Regardless the pathway used by cell-free HIV virions to penetrate the epithelial cell barrier, they ultimately lead to viral exposure of dendritic cells, macrophages and CD4+ T-lymphocytes present in underlying submucosal tissues, allowing the initiation of infection. Dendritic cells can capture HIV virions through C-type lectin receptors (CLRs) present at cell membrane (e.g. DC-SIGN, DCIR), and internalize the captured virus without being infected. This internalized virus, as well as those bound to dendritic cell membrane, remains full infectious and able to be transmitted to surrounding CD4+ T-lymphocytes through a structure analogous to the immunological synapse, named "virological synapse". This tight adhesive junction between an HIV-exposed dendritic cell and an uninfected CD4+ T-lymphocyte allows the virus to be efficiently transferred from one cell to the other, in a process named *trans-*infection (for a review in HIV interactions with dendritic cells see [56]). Besides trans-infection through virological synapse, dendritic cells could also transfer HIV to CD4+ T lymphocytes by cell-free exosomes. These endosomal multivesicular bodies (MVB), containing endocytosed HIV particles, could be released to extracellular milieu and fuse with target-cell membranes allowing the transfer of HIV to them [57].

and macrophages in the foreskin and glans of the penis [44, 45], the mechanisms underlying the transmission across these mucosae are not completed elucidated. Foreskin seems to play a crucial role in female-to-male transmission of HIV-1, since several randomized controlled clinical trials have shown that circumcision reduce this route of transmission by approximately 60% [46]. One plausible mechanism for greater susceptibility to HIV-1 infection in uncircum‐ cised men could be the increased risk for sexually transmitted infections and consequent inflammation of the foreskin (reviewed in [47]). This predisposition to local infection and inflammatory reactions will lead to the recruitment of activated target cells that facilitates the early events of HIV transmission and provides a local environment suitable for productive

The vaginal flora could in some circumstances also favour female-to-male HIV transmission. The predominance of potential pathogenic bacteria instead of normal *Lactobacillus* species, observed during bacterial vaginosis, seems to be related not only with increased risk of HIV-1 acquisition by women (as referred above) but also with higher concentrations of HIV-1 in cervicovaginal secretions, due to a bacterial-driven augmentation of HIV-1 replication and shedding [48-50]. Thus, women with bacterial vaginosis are more infectious and the proba‐ bility of female-to-male HIV-1 transmission during sexual intercourse is greater than in women

Although infection of mucosal epithelial cells could happen, HIV must gain access to permis‐ sive host cells present in underlying submucosa tissue (e.g. dendritic cells macrophages and CD4+ T-lymphocytes) to facilitate virus production and dissemination. The mechanisms for crossing intact stratified squamous epithelium of the vagina or the simple columnar epithelium of the cervix could be one (or more) of the following: (i) transcytosis by a vesicular pathway [52] – an apparently rare but possible event [53]; (ii) capture or infection of dendritic cells resident in the stratified squamous epithelium of the vaginal mucosa and in the underlying tissues of the vagina and cervix [54]; and (iii) direct infection of intraepithelial lymphocytes in

Regardless the pathway used by cell-free HIV virions to penetrate the epithelial cell barrier, they ultimately lead to viral exposure of dendritic cells, macrophages and CD4+ T-lymphocytes present in underlying submucosal tissues, allowing the initiation of infection. Dendritic cells can capture HIV virions through C-type lectin receptors (CLRs) present at cell membrane (e.g. DC-SIGN, DCIR), and internalize the captured virus without being infected. This internalized virus, as well as those bound to dendritic cell membrane, remains full infectious and able to be transmitted to surrounding CD4+ T-lymphocytes through a structure analogous to the immunological synapse, named "virological synapse". This tight adhesive junction between an HIV-exposed dendritic cell and an uninfected CD4+ T-lymphocyte allows the virus to be efficiently transferred from one cell to the other, in a process named *trans-*infection (for a review in HIV interactions with dendritic cells see [56]). Besides trans-infection through virological synapse, dendritic cells could also transfer HIV to CD4+ T lymphocytes by cell-free exosomes. These endosomal multivesicular bodies (MVB), containing endocytosed HIV particles, could

HIV systemic infection.

416 Current Perspectives in HIV Infection

with normal vaginal flora [51].

the endocervical mucosa [55].

**4.3. Crossing the intact mucosal barrier**

Alternatively, HIV can directly infect the dendritic cell subset, present in submucosal tissues (*cis-*infection), using the natural expression of the main HIV cellular receptors (i.e. CD4 and CCR5; see bellow) at dendritic cell surface [56, 58, 59]. Despite the susceptibility of dendritic cells, conferred by the presence of these major receptors, HIV replication in dendritic cells is in general less productive, compared with CD4+ T lymphocytes [60]. The reasons for the decreased viral production in dendritic cells include: (i) lower expression levels of HIV receptors; (ii) degradation of internalized virions, soon after infection; and (iii) presence of intracellular restriction factors that inhibited post-entry events of replication cycle.

Interestingly, although HIV can infect dendritic cells, extensive viral replication only takes place after dendritic cells come into contact with CD4+ T lymphocytes in lymphoid tissue [61]. The dendritic cell-T lymphocyte interaction provides activation signaling to the latter, allowing HIV to be presented to a population of highly activated and susceptible T-lymphocytes. This further indicates that the infection of dendritic cells by HIV-1 is a double-edged sword: dendritic cells must deliver appropriate signals to T lymphocytes in order to induce an HIVspecific immune response; however, this interaction imposes a close contact between dendritic cells and T lymphocytes (immunological synapse) leaving the latter susceptible to infection by the HIV-1 carried by dendritic cells.

In conclusion, dendritic cell-mediated virus transfer occurs in two distinct phases: in the first phase (*trans*-infection), dendritic cell capture and internalize virus within endosomal com‐ partments which are relocated at the dendritic cell/CD4+ T-lymphocyte contact zone (virolog‐ ical synapse); alternatively, a fraction of the endocytosed particles may be targeted for exocytosis, associated with exosomes [62]. Both processes occur without dendritic cell productive infection. In the second phase, the direct infection of dendritic cell (*cis*-infection) contributes to the spread of newly synthesized progeny virus to CD4+ T-lymphocytes [63]. In this regard, several studies have provided important data defining entry-enhancement factors on dendritic cells, such as DC-SIGN, and other C-type lectins receptors (mannose receptor, langerin, syndecan-3, and dendritic cell immunoreceptor - DCIR) [63]. The role of C-type lectin receptors seems to be crucial in both *trans*- and *cis*-infection modes. For example, HIV-1 bound to DC-SIGN is rapidly taken up within endolysosomal vacuoles and protected from degrada‐ tion while remaining infectious for 1–3 days [64]. Interestingly, suppression of DC-SIGN expression has been shown to impair the viral synapse formation, and to inhibit *trans*-infection of HIV-1 to CD4+ T-lymphocytes [65].

All the data reviewed until now was obtained almost exclusively using HIV-1 model (and in some instances SIV). As referred earlier in this chapter, HIV-2 is a lentivirus that shows a decreased capacity to spread between humans, and probably with additional vulnerabilities during transmission, compared with HIV-1. Besides the lower viral load both in plasma and semen referred previously, little is know about HIV-2 interaction with mucosal cells and how the described physical barriers counteract effective HIV-2 transmission to a new host. For example, very few data exists about HIV-2 interaction with DC-SIGN or the way HIV-2 uses *trans*-infection mechanisms to spread to T-lymphocytes. Apparently the T-cell line adapted strain HIV-2ROD is able to bind to DC-SIGN [66], however data from primary isolates (more closely related to circulating viral variants) are still missing.

within a median time of 10 years. However, in contrast to the aforementioned typical pro‐ gression, virtually all HIV-2 and a small percentage [75] of HIV-1 infections (appropriately referred as "long-term nonprogressors" or "elite controllers") remain healthy for several decades without any antiretroviral therapy, with undetectable plasma viral load and CD4+

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

419

A longer asymptomatic phase and slower progression to AIDS are indeed hallmarks of the natural course of HIV-2 infection [1-3]. A clear demonstration of both features was provided by a prospective study conducted with untreated Senegalese sex workers, where 67% of HIV-1 infected women remain AIDS-free 5 years after seroconversion, in contrast with 100% for HIV-2-infected women [3]. The rate of developing CD4+ lymphocyte counts bellow 400 cells/ µl was also reduced in HIV-2 participants [3]. Thus, as a rule, HIV-2-infection has no effect on

The mechanisms responsible for this less pathogenic course of HIV-2 infection are still poorly understood but surely result from a combination of distinct factors involving the virus, the infected cell and the equilibrium established between viral replication and host immunologic response. This equilibrium is clearly much well preserved in HIV-2 than in HIV-1 infection and it is paradoxical that the study of HIV-2 interaction with host cells remains poorly explored and sometimes neglected. Interestingly, a recent report indicates that a pre-existing infection by HIV-2 appears to inhibit the rate of HIV-1 disease progression [76], together with higher CD4+ T-cell counts and lower viral diversity of HIV-1. This apparent protective effect of HIV-2 may be explained by several viral and immunological mechanisms, namely the higher immunosupression of surface glycoprotein of HIV-2 compared to HIV-1 counterpart [77], or the ability of HIV-2 Nef protein to promote the downmodulation of TCR-CD3 from the surface of CD4+ T-cells [78] and thus the impairment of immunological synapse, established between these lymphocytes and antigen presenting cells (i.e. dendritic cells and macrophages). Both mechanisms have direct impact on immune activation and may help explain the better

HIV replication cycle begins by a specific interaction between viral envelope glycoproteins and cellular receptors allowing the binding of virion to target cell. Further sequential interac‐ tions eventually lead to viral envelope and cell membrane fusion. The cellular receptors involved in these early events are the CD4 molecule [79, 80] and a member of seven-trans‐ membrane, G-protein-coupled, receptors' family (GPCRs), referred as coreceptor. According to the proposed model, the specific binding of SU envelope glycoprotein to CD4 induces structural changes in this glycoprotein that expose, create or stabilize the coreceptor-binding regions, enabling the SU to engage the coreceptor molecule. This second binding event causes further conformational changes in SU that allows the disclosure of an amino-terminal hydro‐ phobic region (fusion peptide) of the TM envelope glycoprotein subunit. The insertion of the fusion peptide in the cell surface leads to the fusion of viral envelope with the cell membrane and the release of viral nucleocapside into the cell cytoplasm (reviewed in [81, 82]). This fusion process as long been assumed to occur at the cell surface through a direct fusion mechanism

outcome of HIV-2 infection alone or after superinfection with HIV-1.

**5.1. HIV-2 entry into target cells — Early events**

cell counts above 500 cells/µL.

survival in adults [2].

Early reports referred that dendritic cells derived from hematopoietic progenitor cells or from peripheral blood monocytes are less susceptible to productive infection by HIV-2 compared with HIV-1 [67, 68]. Paradoxically, recent data have disclosed a cellular protein (SAMHD1) that inhibits HIV-1 replication in immature monocytes-derived dendritic cells, in dendritic cells derived from PMA-differentiated THP-1 monocytic cell line [69] and in macrophages [70]. This restriction factor affects the efficiency of reverse transcription leading to a reduced amount of viral cDNA [71]. SAMHD1 is counteracted by the HIV-2/SIV Vpx protein and its inhibitory mechanism, in the absence of Vpx, helps to explain the different permissivity of these nondividing cells to lentiviral infection [21]. In this scenario, the non-permissiveness of dendritic cells to HIV-1 infection favours viral dissemination by *trans*-infection pathway, enabling more virions being delivered to CD4+ T-lymphocytes through virological synapse and eventually enhancing the depletion of these latter cells [72]. More importantly, HIV-2 avoiding the effect of SAMHD1 is more prone to trigger host innate immune responses through type I interferon, mediated by viral DNA-exposed dendritic cells [73, 74]. Also, productive infection of dendritic cells by HIV-2 may lead to a different spectrum of presented antigens that ultimately could lead to a different adaptive immune response [74].

### **5. HIV-2 chronic infection in human host: a natural long-term non progressive infection**

The long-term non-progressive infection that characterizes the HIV-2 infection in humans is determined by several host-virus interactions that, in contrast to HIV-1, enable the control and the confinement of HIV-2 pathogenic potential.

As referred above, the different pathogenic outcome observed in HIV-2 infection compared to HIV-1 seems to be dictated as early as the initial interactions with dendritic cells and macro‐ phages present at mucosae surfaces. The expression of Vpx by HIV-2, allowing the bypass of SAMHD1 restriction and the consequent productive infection of dendritic cells and macro‐ phages (*cis*-infection), may result in reduced *trans*-infection to CD4+ T-lymphocytes, a more appropriate innate and adaptive immune response and thus to a more limited infection.

Noteworthy, and despite the described mechanisms that could lead to a hindrance in HIV-2 dissemination at early stages during acute infection, a similar proviral load is ob‐ served in HIV-2 and HIV-1 infected patients. These observations suggest that HIV-2, like HIV-1, is able to disseminate and an equal number of target cells are infected during acute and chronic phase or, alternatively, that in HIV-1 a greater number of infected CD4+ T-cells are destroyed in the course of the disease, leading to a similar number of cells containing integrated HIV-1 or HIV-2 genomes.

Typically, infection with HIV-1 is characterized by a gradual and irreversible depletion of CD4+ T-lymphocytes, leading to severe immune dysfunction and the development of AIDS within a median time of 10 years. However, in contrast to the aforementioned typical pro‐ gression, virtually all HIV-2 and a small percentage [75] of HIV-1 infections (appropriately referred as "long-term nonprogressors" or "elite controllers") remain healthy for several decades without any antiretroviral therapy, with undetectable plasma viral load and CD4+ cell counts above 500 cells/µL.

A longer asymptomatic phase and slower progression to AIDS are indeed hallmarks of the natural course of HIV-2 infection [1-3]. A clear demonstration of both features was provided by a prospective study conducted with untreated Senegalese sex workers, where 67% of HIV-1 infected women remain AIDS-free 5 years after seroconversion, in contrast with 100% for HIV-2-infected women [3]. The rate of developing CD4+ lymphocyte counts bellow 400 cells/ µl was also reduced in HIV-2 participants [3]. Thus, as a rule, HIV-2-infection has no effect on survival in adults [2].

The mechanisms responsible for this less pathogenic course of HIV-2 infection are still poorly understood but surely result from a combination of distinct factors involving the virus, the infected cell and the equilibrium established between viral replication and host immunologic response. This equilibrium is clearly much well preserved in HIV-2 than in HIV-1 infection and it is paradoxical that the study of HIV-2 interaction with host cells remains poorly explored and sometimes neglected. Interestingly, a recent report indicates that a pre-existing infection by HIV-2 appears to inhibit the rate of HIV-1 disease progression [76], together with higher CD4+ T-cell counts and lower viral diversity of HIV-1. This apparent protective effect of HIV-2 may be explained by several viral and immunological mechanisms, namely the higher immunosupression of surface glycoprotein of HIV-2 compared to HIV-1 counterpart [77], or the ability of HIV-2 Nef protein to promote the downmodulation of TCR-CD3 from the surface of CD4+ T-cells [78] and thus the impairment of immunological synapse, established between these lymphocytes and antigen presenting cells (i.e. dendritic cells and macrophages). Both mechanisms have direct impact on immune activation and may help explain the better outcome of HIV-2 infection alone or after superinfection with HIV-1.

#### **5.1. HIV-2 entry into target cells — Early events**

strain HIV-2ROD is able to bind to DC-SIGN [66], however data from primary isolates (more

Early reports referred that dendritic cells derived from hematopoietic progenitor cells or from peripheral blood monocytes are less susceptible to productive infection by HIV-2 compared with HIV-1 [67, 68]. Paradoxically, recent data have disclosed a cellular protein (SAMHD1) that inhibits HIV-1 replication in immature monocytes-derived dendritic cells, in dendritic cells derived from PMA-differentiated THP-1 monocytic cell line [69] and in macrophages [70]. This restriction factor affects the efficiency of reverse transcription leading to a reduced amount of viral cDNA [71]. SAMHD1 is counteracted by the HIV-2/SIV Vpx protein and its inhibitory mechanism, in the absence of Vpx, helps to explain the different permissivity of these nondividing cells to lentiviral infection [21]. In this scenario, the non-permissiveness of dendritic cells to HIV-1 infection favours viral dissemination by *trans*-infection pathway, enabling more virions being delivered to CD4+ T-lymphocytes through virological synapse and eventually enhancing the depletion of these latter cells [72]. More importantly, HIV-2 avoiding the effect of SAMHD1 is more prone to trigger host innate immune responses through type I interferon, mediated by viral DNA-exposed dendritic cells [73, 74]. Also, productive infection of dendritic cells by HIV-2 may lead to a different spectrum of presented antigens that ultimately could

**5. HIV-2 chronic infection in human host: a natural long-term non**

The long-term non-progressive infection that characterizes the HIV-2 infection in humans is determined by several host-virus interactions that, in contrast to HIV-1, enable the control and

As referred above, the different pathogenic outcome observed in HIV-2 infection compared to HIV-1 seems to be dictated as early as the initial interactions with dendritic cells and macro‐ phages present at mucosae surfaces. The expression of Vpx by HIV-2, allowing the bypass of SAMHD1 restriction and the consequent productive infection of dendritic cells and macro‐ phages (*cis*-infection), may result in reduced *trans*-infection to CD4+ T-lymphocytes, a more appropriate innate and adaptive immune response and thus to a more limited infection.

Noteworthy, and despite the described mechanisms that could lead to a hindrance in HIV-2 dissemination at early stages during acute infection, a similar proviral load is ob‐ served in HIV-2 and HIV-1 infected patients. These observations suggest that HIV-2, like HIV-1, is able to disseminate and an equal number of target cells are infected during acute and chronic phase or, alternatively, that in HIV-1 a greater number of infected CD4+ T-cells are destroyed in the course of the disease, leading to a similar number of

Typically, infection with HIV-1 is characterized by a gradual and irreversible depletion of CD4+ T-lymphocytes, leading to severe immune dysfunction and the development of AIDS

closely related to circulating viral variants) are still missing.

lead to a different adaptive immune response [74].

the confinement of HIV-2 pathogenic potential.

cells containing integrated HIV-1 or HIV-2 genomes.

**progressive infection**

418 Current Perspectives in HIV Infection

HIV replication cycle begins by a specific interaction between viral envelope glycoproteins and cellular receptors allowing the binding of virion to target cell. Further sequential interac‐ tions eventually lead to viral envelope and cell membrane fusion. The cellular receptors involved in these early events are the CD4 molecule [79, 80] and a member of seven-trans‐ membrane, G-protein-coupled, receptors' family (GPCRs), referred as coreceptor. According to the proposed model, the specific binding of SU envelope glycoprotein to CD4 induces structural changes in this glycoprotein that expose, create or stabilize the coreceptor-binding regions, enabling the SU to engage the coreceptor molecule. This second binding event causes further conformational changes in SU that allows the disclosure of an amino-terminal hydro‐ phobic region (fusion peptide) of the TM envelope glycoprotein subunit. The insertion of the fusion peptide in the cell surface leads to the fusion of viral envelope with the cell membrane and the release of viral nucleocapside into the cell cytoplasm (reviewed in [81, 82]). This fusion process as long been assumed to occur at the cell surface through a direct fusion mechanism independent of the pH [83]. However, more recent data describe HIV-1 entry and fusion occurs following endocytosis [84, 85].

population of transmitted viruses are favored, these two reports support the idea that non-R5 viruses could indeed be transmitted. This warrants reconsidering the dogma of exclusive R5 variants transmission and should lead us to the following question: is there actually any biological filter at mucosae environment (including physical or chemical barriers, epithelial cells and immune cells present at mucosal surface or in the submucosal layer) that suppresses the invasion and/or dissemination of non-R5 variants; and why in these cases (and other cases?) they were not selected? In other words, are there sufficient and conclusive data to discard the hypothesis of random transmission in favor of a gatekeeper or bottleneck theory [108]? Perhaps the preferential transmission of R5 variants are solely a consequence of their higher proportion in body fluids involved in transmission, either in acute or during most of chronic infection. Further studies are warranted in order to elucidate if X4 or R5X4 variants (and other biotypes,

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

421

In HIV-2 no data exists regarding transmitted/founder viruses, or the characteristics or the viral evolution during primary infection. The mechanisms described for HIV-1 and SIV should also be present in HIV-2 infection. However, the identification of HIV-2 isolates unable to infect target cells using the CCR5 or CXCR4 coreceptors [96, 109] obtained from individuals at asymptomatic stage of infection and immunologically competent [96], raises the possibility that, at least in some patients, CCR5 usage is acquired *in vivo* as a result of HIV-2 evolution

Identification of the biochemical processes required for HIV fusion and the engagement of chemokine receptors as critical step for HIV entry, has also unveiled several important aspects on envelope glycoproteins structure crucial to the fusion process. HIV-1 and HIV-2 SU glycoprotein contain five conserved regions (C1 to C5), separated by an equal number of variable regions (V1 to V5). The variable regions are limited by cysteine residues forming flexible loops on the outer domain of SU glycoprotein [110-112]. HIV coreceptor usage seems to be largely determined by variable regions of the SU subunit. In HIV-1, the most studied model, the third variable (V3) region has been referred as the major determinant of coreceptor engagement [113-117]. Higher positive net charge (above +5) in V3 region of HIV-1 has been associated with CXCR4 usage (or usage of both CXCR4 and CCR5) [118, 119]. Structural models of SU bound to CD4 and chemokine receptor have provided further information about the functional roles played by several regions of SU, revealing that the V1V2 region is also involved

In HIV-2, structural and functional studies of the envelope glycoproteins regions are much more scarce and in some aspects contradictory. The genetic characterization of HIV-2 SU has revealed a limited variability, probably as a result of the lower replication rate within the infected individual. Noteworthy, in contrast to HIV-1, the V3 region of HIV-2 SU glycoprotein appears to be highly conserved. Conversely, the V1V2 region is much more prone to genetic variation [125], suggesting that either this region is more exposed and under a stronger selective pressure, or that the lack of V3 loop variation is related to some functional constraints

including CCR8-using viruses) are less transmissible.

**5.2. Molecular determinants of coreceptor usage**

from an initial population of CCR5- and CXCR4-independent viruses.

in coreceptor binding, by a direct cooperation with the V3 region [120-124].

After the initial identification of CXCR4 and CCR5 in 1996 [86, 87], several other GPCRs have been described as being able to act as coreceptors for HIV-1, HIV-2 and SIV: CCR1, CCR2b, CCR3, CCR4, CCR5, CCR8, CCR9, CCR10, CXCR2, CXCR4, CXCR5, CXCR6, CX3CR1, XCR1, FPRL1, GPR1, GPR15, APJ, ChemR23, CXCR7/ RDC1, D6, BLTR and US28 [88-92]. Despite this extensive array of potential HIV entry coreceptors, only CCR5 and CXCR4 have been consid‐ ered important for HIV-1 infection *in vivo* [93, 94]. This notion stems from studies reporting: (i) the apparent selection of CCR5-using (R5) variants during mucosal transmission; (ii) the predominance of R5 population during asymptomatic stage of infection; and (iii) the arise and eventual predominance of CXCR4-using (X4) variants in late stages of HIV-1 infection. However, several exceptions to this simplistic R5/X4 dichotomy have been reported [89, 91, 95-104], revealing that some HIV-1 and HIV-2 isolates can exploit other coreceptors *in vitro*, raising the possibility that these alternate molecules can *in vivo* contribute to HIV infection of natural target cells, at least under certain circumstances.

Genetic studies of HIV-1 variants present soon after sexual transmission have shown that only R5, and occasionally dual tropic R5X4, are transmitted regardless the diversity of viral population present in initial inoculum. During chronic infection HIV genetic diversity increases due to viral replication based on an error-prone reverse transcriptase. The resulting viral population (or *quasiespecies*) provides the substrate for natural selection exerted by host immune response and local environment, leading to continuous viral adaptation and persis‐ tence within HIV infected patient. However, during mucosal transmission this diversity is severely reduced suggesting a "bottleneck" or "gatekeeper" effect (reviewed in [105]), probably as a result of the biology of mucosal transmission and the kind of cells encountered by HIV (discussed above).

The analysis by single-genome amplification, together with full-length cloning of transmitted/ founder variants, has provided remarkable data on HIV transmission and viral evolution during acute infection. Based on this data, the selection of transmitted/founder viruses encompasses three main signatures: usage of CCR5, high replication rate in CD4+ T-lympho‐ cytes and lack of macrophage tropism (reviewed in [106]). The deficient replication in mono‐ cyte-derived macrophages observed in HIV-1 transmitted viruses, although requiring confirmation using tissue macrophages, is consistent with data obtained in nonhuman primates infected with SIV, indicating that CD4+ T-lymphocytes are the predominant cellular substrate for viral replication soon after transmission.

However, a recent and unprecedented observation, regarding HIV coreceptor usage and transmission, revealed that a transmitted/founder HIV-1 was unable to efficiently use either CCR5 or CXCR4 to infect CD4+ cell lines or peripheral blood mononuclear cells [95]. Alternate GPCRs (GPR15, APJ, and FPRL-1) were efficiently used, further emphasizing the notion that "rare" coreceptors could be used *in vivo* in some circumstances or in some cell populations by HIV-1 and HIV-2 alike. Additionally, Chalmet *et al*. [107] have recently provided important data showing that the transmitted viruses could be X4 or R5X4. Considering the established concept, stating that during mucosal transmission the R5 variants present in initial inoculum

population of transmitted viruses are favored, these two reports support the idea that non-R5 viruses could indeed be transmitted. This warrants reconsidering the dogma of exclusive R5 variants transmission and should lead us to the following question: is there actually any biological filter at mucosae environment (including physical or chemical barriers, epithelial cells and immune cells present at mucosal surface or in the submucosal layer) that suppresses the invasion and/or dissemination of non-R5 variants; and why in these cases (and other cases?) they were not selected? In other words, are there sufficient and conclusive data to discard the hypothesis of random transmission in favor of a gatekeeper or bottleneck theory [108]? Perhaps the preferential transmission of R5 variants are solely a consequence of their higher proportion in body fluids involved in transmission, either in acute or during most of chronic infection. Further studies are warranted in order to elucidate if X4 or R5X4 variants (and other biotypes, including CCR8-using viruses) are less transmissible.

In HIV-2 no data exists regarding transmitted/founder viruses, or the characteristics or the viral evolution during primary infection. The mechanisms described for HIV-1 and SIV should also be present in HIV-2 infection. However, the identification of HIV-2 isolates unable to infect target cells using the CCR5 or CXCR4 coreceptors [96, 109] obtained from individuals at asymptomatic stage of infection and immunologically competent [96], raises the possibility that, at least in some patients, CCR5 usage is acquired *in vivo* as a result of HIV-2 evolution from an initial population of CCR5- and CXCR4-independent viruses.

#### **5.2. Molecular determinants of coreceptor usage**

independent of the pH [83]. However, more recent data describe HIV-1 entry and fusion occurs

After the initial identification of CXCR4 and CCR5 in 1996 [86, 87], several other GPCRs have been described as being able to act as coreceptors for HIV-1, HIV-2 and SIV: CCR1, CCR2b, CCR3, CCR4, CCR5, CCR8, CCR9, CCR10, CXCR2, CXCR4, CXCR5, CXCR6, CX3CR1, XCR1, FPRL1, GPR1, GPR15, APJ, ChemR23, CXCR7/ RDC1, D6, BLTR and US28 [88-92]. Despite this extensive array of potential HIV entry coreceptors, only CCR5 and CXCR4 have been consid‐ ered important for HIV-1 infection *in vivo* [93, 94]. This notion stems from studies reporting: (i) the apparent selection of CCR5-using (R5) variants during mucosal transmission; (ii) the predominance of R5 population during asymptomatic stage of infection; and (iii) the arise and eventual predominance of CXCR4-using (X4) variants in late stages of HIV-1 infection. However, several exceptions to this simplistic R5/X4 dichotomy have been reported [89, 91, 95-104], revealing that some HIV-1 and HIV-2 isolates can exploit other coreceptors *in vitro*, raising the possibility that these alternate molecules can *in vivo* contribute to HIV infection of

Genetic studies of HIV-1 variants present soon after sexual transmission have shown that only R5, and occasionally dual tropic R5X4, are transmitted regardless the diversity of viral population present in initial inoculum. During chronic infection HIV genetic diversity increases due to viral replication based on an error-prone reverse transcriptase. The resulting viral population (or *quasiespecies*) provides the substrate for natural selection exerted by host immune response and local environment, leading to continuous viral adaptation and persis‐ tence within HIV infected patient. However, during mucosal transmission this diversity is severely reduced suggesting a "bottleneck" or "gatekeeper" effect (reviewed in [105]), probably as a result of the biology of mucosal transmission and the kind of cells encountered

The analysis by single-genome amplification, together with full-length cloning of transmitted/ founder variants, has provided remarkable data on HIV transmission and viral evolution during acute infection. Based on this data, the selection of transmitted/founder viruses encompasses three main signatures: usage of CCR5, high replication rate in CD4+ T-lympho‐ cytes and lack of macrophage tropism (reviewed in [106]). The deficient replication in mono‐ cyte-derived macrophages observed in HIV-1 transmitted viruses, although requiring confirmation using tissue macrophages, is consistent with data obtained in nonhuman primates infected with SIV, indicating that CD4+ T-lymphocytes are the predominant cellular

However, a recent and unprecedented observation, regarding HIV coreceptor usage and transmission, revealed that a transmitted/founder HIV-1 was unable to efficiently use either CCR5 or CXCR4 to infect CD4+ cell lines or peripheral blood mononuclear cells [95]. Alternate GPCRs (GPR15, APJ, and FPRL-1) were efficiently used, further emphasizing the notion that "rare" coreceptors could be used *in vivo* in some circumstances or in some cell populations by HIV-1 and HIV-2 alike. Additionally, Chalmet *et al*. [107] have recently provided important data showing that the transmitted viruses could be X4 or R5X4. Considering the established concept, stating that during mucosal transmission the R5 variants present in initial inoculum

following endocytosis [84, 85].

420 Current Perspectives in HIV Infection

by HIV (discussed above).

natural target cells, at least under certain circumstances.

substrate for viral replication soon after transmission.

Identification of the biochemical processes required for HIV fusion and the engagement of chemokine receptors as critical step for HIV entry, has also unveiled several important aspects on envelope glycoproteins structure crucial to the fusion process. HIV-1 and HIV-2 SU glycoprotein contain five conserved regions (C1 to C5), separated by an equal number of variable regions (V1 to V5). The variable regions are limited by cysteine residues forming flexible loops on the outer domain of SU glycoprotein [110-112]. HIV coreceptor usage seems to be largely determined by variable regions of the SU subunit. In HIV-1, the most studied model, the third variable (V3) region has been referred as the major determinant of coreceptor engagement [113-117]. Higher positive net charge (above +5) in V3 region of HIV-1 has been associated with CXCR4 usage (or usage of both CXCR4 and CCR5) [118, 119]. Structural models of SU bound to CD4 and chemokine receptor have provided further information about the functional roles played by several regions of SU, revealing that the V1V2 region is also involved in coreceptor binding, by a direct cooperation with the V3 region [120-124].

In HIV-2, structural and functional studies of the envelope glycoproteins regions are much more scarce and in some aspects contradictory. The genetic characterization of HIV-2 SU has revealed a limited variability, probably as a result of the lower replication rate within the infected individual. Noteworthy, in contrast to HIV-1, the V3 region of HIV-2 SU glycoprotein appears to be highly conserved. Conversely, the V1V2 region is much more prone to genetic variation [125], suggesting that either this region is more exposed and under a stronger selective pressure, or that the lack of V3 loop variation is related to some functional constraints that impairs its evolution. Accordingly, the role of HIV-2 V3 region as a target for neutralizing antibodies has been controversial [126-132].

The evolution that was observed in viral phenotype has now an explanation based on the coreceptors used: isolates obtained during asymptomatic stage are R5 (formerly NSI, M-tropic and slow/low) while in later stages of infection, coincident with immunodeficiency and opportunistic infections, the predominant variants are X4 (formerly SI, T-tropic and rapid/ high). This shift from predominance of R5 variants to X4, during disease progression, occurs in about 40% of the patients and could be seen as an additional consequence of an already deteriorated immune response, which contributes to an accelerated depletion of T-lympho‐

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

423

In HIV-2, the usage of cell receptors seems to be much more complex and the correlation between disease stage and receptors usage is apparently less clear-cut than in HIV-1. The key notions about cell receptors engagement by HIV-2 are: (i) non-usage of CCR5 or CXCR4 as coreceptors; (ii) a broader coreceptor usage compared to HIV-1; and (iii) the CD4-independent

Although CCR5 or CXCR4 usage seems to be an absolute requirement for HIV to fuse its envelope with target-cell membrane, we and others have identified HIV-2 variants that *in vitro* do not use those chemokine receptors (or use it inefficiently) as cofactors for viral entry. These reports indicate that other coreceptors could replace CCR5 and CXCR4 as key players in HIV infection, not just "in addition to" but also "instead of" these coreceptors, clearly suggesting that they have an important role in HIV-2 infection and pathogenesis. Furthermore, we demonstrated that these variants have lower replicative capacity *in vitro* [96, 125], an

The main inference made from studies addressing coreceptors usage by HIV is that the acquisition of CCR5 usage is crucial for HIV pathogenesis. And why CCR5 usage is so important and provides a clear selective advantage *in vivo*? One of the reasons is because CCR5 usage confers HIV the ability to infect stimulated, full-permissive cells, leading to the produc‐ tion of a significantly more infectious viral population. While CXCR4 is expressed in both resting and stimulated T-lymphocytes [142], CCR5 expression is higher in memory CD4+ Tcells (CD45RO+) than in naïve (non-activated) CD4+ T-lymphocyte subset (CD45RA+) [143, 144]. Remarkably, the former are highly permissive to HIV replication, while productive infection of CD45RA+ lymphocytes requires cellular activation soon after viral entry; other‐

In addition, the persistence of R5 viruses throughout the asymptomatic stage and in some cases even in individuals with clinical symptoms, suggests that they may escape immune surveil‐ lance mechanisms (e.g. neutralization by specific antibodies) or that they could infect longlived cell reservoirs, such as macrophages and dendritic cells, thus providing long-lasting R5

Interestingly, the described CCR5/CXCR4-independent HIV-2 variants were obtained during asymptomatic stage of infection [96, 109]. As referred, HIV-1 and HIV-2 infections are strikingly different during this period: a longer asymptomatic period with higher CD4+ T-cell

cytes and disease progression.

*5.3.1. Non-usage of CCR5 or CXCR4 as coreceptors*

observation later confirmed by others [141].

wise, an abortive infection is observed [145].

viruses production.

infection of target cells.

Similar to neutralization data, molecular determinants of coreceptor usage by HIV-2 is also controversial. Some studies had claimed an association between V3 loop sequence and CCR5 or CXCR4 usage [133-137], while others had found no genetic signature underlying coreceptors usage [138-140]. Particularly, the C-terminal region of the V3 loop, a global net charge above +6 and the presence of mutations in amino acids 18 and 19, appear to dictate the ability to use CXCR4 alone or in addition to CCR5 [134, 137]. However, those studies have some limitations due to the low number of X4 or R5X4 strains and because they restricted the coreceptors usage to the dichotomy R5 vs. X4, without considering the concomitant or alternative use of other coreceptors. We have shown in the molecular characterization of the *env* gene of two CCR5/ CXCR4-independent isolates that, although this phenotype is determined by the SU glyco‐ protein [125], no genetic signature could be clearly found in the V3 region of those strains [125]. Noteworthy and considering that the ability to use a certain coreceptor is solely determined by the V3 loop, the absence of a significant variability in this region is hardly concealed with the broad and "exotic" coreceptor usage observed in HIV-2. Obviously, different regions beside V3 cooperate during envelope glycoproteins interaction with cellular receptors, playing a role in coreceptor choice by a particular virus. One of the strongest candidates is the V1V2 region, where an outstanding genetic variability was observed [140], including length variation and loss of potential glycosilation sites. Moreover, some unique sequence signatures were also founded in the central ectodomain and in the second heptad repeat (HR2) of the TM glycoprotein [140]. All these mutations may affect the conformation of the envelope glyco‐ proteins complex, leading to a more open structure. This will affect not only the dynamics of HIV-2 interaction with cellular receptors, but also the way neutralizing epitopes are exposed and recognized by host immune response, leading to decreased viral fitness, lower replication rate and increased susceptibility to neutralization.

#### **5.3. Evolution of coreceptor usage during HIV-2 chronic infection**

Earlier studies addressing the correlation between HIV infection stages (i.e. acute/primary infection, asymptomatic stage and AIDS) and *in vitro* biological characteristics of HIV, gave rise to three distinct classifications according to: (i) the efficiency of replication (rapid/high, slow/low); (ii) the capacity to induce syncytia formation in T-cells (syncytium-inducing/non syncytium-inducing; SI/NSI); and (iii) the ability to replicate in primary macrophages vs. Tcell lines (M-tropic/T-tropic). From these earlier studies it was also clear that, during the course of infection, selection might occur for variants more cytopathic (i.e. able to induce syncytia), with faster replication kinetics (rapid/high) and with tropism for T-cell lines (T-tropic).

Identification of the biochemical processes required for HIV fusion and the engagement of chemokine receptors, clarified the determinants of HIV tropism. Consistent with the proposed model, HIV cell tropism is largely determined by the expression patterns of the appropriate coreceptor molecule at the target-cell membrane. T-tropic viruses (in general with rapid/high and SI phenotype) required the presence of CXCR4 coreceptor (X4 strains) while M-tropic (associated generally with slow/low and NSI phenotype) use CCR5 as coreceptor (R5 strains). The evolution that was observed in viral phenotype has now an explanation based on the coreceptors used: isolates obtained during asymptomatic stage are R5 (formerly NSI, M-tropic and slow/low) while in later stages of infection, coincident with immunodeficiency and opportunistic infections, the predominant variants are X4 (formerly SI, T-tropic and rapid/ high). This shift from predominance of R5 variants to X4, during disease progression, occurs in about 40% of the patients and could be seen as an additional consequence of an already deteriorated immune response, which contributes to an accelerated depletion of T-lympho‐ cytes and disease progression.

In HIV-2, the usage of cell receptors seems to be much more complex and the correlation between disease stage and receptors usage is apparently less clear-cut than in HIV-1. The key notions about cell receptors engagement by HIV-2 are: (i) non-usage of CCR5 or CXCR4 as coreceptors; (ii) a broader coreceptor usage compared to HIV-1; and (iii) the CD4-independent infection of target cells.

#### *5.3.1. Non-usage of CCR5 or CXCR4 as coreceptors*

that impairs its evolution. Accordingly, the role of HIV-2 V3 region as a target for neutralizing

Similar to neutralization data, molecular determinants of coreceptor usage by HIV-2 is also controversial. Some studies had claimed an association between V3 loop sequence and CCR5 or CXCR4 usage [133-137], while others had found no genetic signature underlying coreceptors usage [138-140]. Particularly, the C-terminal region of the V3 loop, a global net charge above +6 and the presence of mutations in amino acids 18 and 19, appear to dictate the ability to use CXCR4 alone or in addition to CCR5 [134, 137]. However, those studies have some limitations due to the low number of X4 or R5X4 strains and because they restricted the coreceptors usage to the dichotomy R5 vs. X4, without considering the concomitant or alternative use of other coreceptors. We have shown in the molecular characterization of the *env* gene of two CCR5/ CXCR4-independent isolates that, although this phenotype is determined by the SU glyco‐ protein [125], no genetic signature could be clearly found in the V3 region of those strains [125]. Noteworthy and considering that the ability to use a certain coreceptor is solely determined by the V3 loop, the absence of a significant variability in this region is hardly concealed with the broad and "exotic" coreceptor usage observed in HIV-2. Obviously, different regions beside V3 cooperate during envelope glycoproteins interaction with cellular receptors, playing a role in coreceptor choice by a particular virus. One of the strongest candidates is the V1V2 region, where an outstanding genetic variability was observed [140], including length variation and loss of potential glycosilation sites. Moreover, some unique sequence signatures were also founded in the central ectodomain and in the second heptad repeat (HR2) of the TM glycoprotein [140]. All these mutations may affect the conformation of the envelope glyco‐ proteins complex, leading to a more open structure. This will affect not only the dynamics of HIV-2 interaction with cellular receptors, but also the way neutralizing epitopes are exposed and recognized by host immune response, leading to decreased viral fitness, lower replication

antibodies has been controversial [126-132].

422 Current Perspectives in HIV Infection

rate and increased susceptibility to neutralization.

**5.3. Evolution of coreceptor usage during HIV-2 chronic infection**

Earlier studies addressing the correlation between HIV infection stages (i.e. acute/primary infection, asymptomatic stage and AIDS) and *in vitro* biological characteristics of HIV, gave rise to three distinct classifications according to: (i) the efficiency of replication (rapid/high, slow/low); (ii) the capacity to induce syncytia formation in T-cells (syncytium-inducing/non syncytium-inducing; SI/NSI); and (iii) the ability to replicate in primary macrophages vs. Tcell lines (M-tropic/T-tropic). From these earlier studies it was also clear that, during the course of infection, selection might occur for variants more cytopathic (i.e. able to induce syncytia), with faster replication kinetics (rapid/high) and with tropism for T-cell lines (T-tropic).

Identification of the biochemical processes required for HIV fusion and the engagement of chemokine receptors, clarified the determinants of HIV tropism. Consistent with the proposed model, HIV cell tropism is largely determined by the expression patterns of the appropriate coreceptor molecule at the target-cell membrane. T-tropic viruses (in general with rapid/high and SI phenotype) required the presence of CXCR4 coreceptor (X4 strains) while M-tropic (associated generally with slow/low and NSI phenotype) use CCR5 as coreceptor (R5 strains). Although CCR5 or CXCR4 usage seems to be an absolute requirement for HIV to fuse its envelope with target-cell membrane, we and others have identified HIV-2 variants that *in vitro* do not use those chemokine receptors (or use it inefficiently) as cofactors for viral entry. These reports indicate that other coreceptors could replace CCR5 and CXCR4 as key players in HIV infection, not just "in addition to" but also "instead of" these coreceptors, clearly suggesting that they have an important role in HIV-2 infection and pathogenesis. Furthermore, we demonstrated that these variants have lower replicative capacity *in vitro* [96, 125], an observation later confirmed by others [141].

The main inference made from studies addressing coreceptors usage by HIV is that the acquisition of CCR5 usage is crucial for HIV pathogenesis. And why CCR5 usage is so important and provides a clear selective advantage *in vivo*? One of the reasons is because CCR5 usage confers HIV the ability to infect stimulated, full-permissive cells, leading to the produc‐ tion of a significantly more infectious viral population. While CXCR4 is expressed in both resting and stimulated T-lymphocytes [142], CCR5 expression is higher in memory CD4+ Tcells (CD45RO+) than in naïve (non-activated) CD4+ T-lymphocyte subset (CD45RA+) [143, 144]. Remarkably, the former are highly permissive to HIV replication, while productive infection of CD45RA+ lymphocytes requires cellular activation soon after viral entry; other‐ wise, an abortive infection is observed [145].

In addition, the persistence of R5 viruses throughout the asymptomatic stage and in some cases even in individuals with clinical symptoms, suggests that they may escape immune surveil‐ lance mechanisms (e.g. neutralization by specific antibodies) or that they could infect longlived cell reservoirs, such as macrophages and dendritic cells, thus providing long-lasting R5 viruses production.

Interestingly, the described CCR5/CXCR4-independent HIV-2 variants were obtained during asymptomatic stage of infection [96, 109]. As referred, HIV-1 and HIV-2 infections are strikingly different during this period: a longer asymptomatic period with higher CD4+ T-cell counts and undetectable viremia is observed in HIV-2. The host and viral factors that contrib‐ utes for this high level of control remain poorly understood, but we hypothesized that one of the viral factors that could be involved is the existence of a less fitted viral population, during a variable period of the asymptomatic stage. This population has lower replicative capacity and, at least in some cases, they do not efficiently use CCR5 and/or CXCR4 coreceptors.

the existence of HIV-2 unable to use CCR5 or CXCR4 as coreceptors to infect primary CD4+ lymphocytes or CD4-expressing cell lines [96, 125]. CCR8, formerly known as TER1, ChemR1 and CKR-L1, is the receptor for the chemokine CCL1/I-309 [156, 157]. It is expressed in a wide range of cells; some of them are primary targets for HIV infection *in vivo*, e.g. monocytes, thymocytes and peripheral blood CD4+ T-lymphocytes [157-159]. Its tissue distribution and the significant proportion of HIV-1 isolates able to use CCR8, deserves a deeper discussion. If in HIV-2, due to the well-known promiscuous usage of chemokine receptors as coreceptors, the usage of this GPCR was expected, in HIV-1, this was completely unpredicted. As I pointed before, identification of viruses able to use other coreceptors besides CCR5 and CXCR4 seems to be an abnormality in HIV-1. Yet, the findings presented in the cited report [89] together with previous data [91, 100, 103, 160], indicating the efficient use of CCR8 as coreceptor by distinct HIV-1 isolates, either in indicator cell lines or in primary cells, highlight the potential relevance

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

*receptors HIV interaction\*\*\* with CCR5 or CXCR4 coreceptors*

Activation of lipid kinase PI3K

Activation of guanine nucleotide exchange factors specific for Rho family GTPases

Transcriptional activation.

http://dx.doi.org/10.5772/53201

425

Modulation of cytoskeleton: actin rearrangement

Cell migration

Cell adhesion. Cell survival

Activation of phospholipase C-γ

of this molecule for viral transmission and pathogenesis, including HIV-1.

Transcriptional activation. Cell migration (chemotaxis)

Transcriptional activation.

Modulation of cytoskeleton: actin rearrangement; myosin light-chain phosphorilation and microtubule rearrangement

\* Ligand: SDF-1α; \*\* Ligands: MIP-1α, MIP-1β, and RANTES; \*\*\* by the surface envelope glycoprotein

**Table 2.** Major chemokine receptor signalling pathways triggered after binding of chemokines or HIV envelope

It is widely recognized that during later stages of HIV-1 infection, a significant proportion of viral variants that constitute the *quasispecies* within an infected individual, evolve in order to efficiently use CXCR4 (and probably other chemokine receptors) in addition to, or instead of, CCR5-using variants, which predominate during early stages of infection [161]. These X4 variants are characterized by increased replicative capacity, a more cytopathic phenotype and the ability to infect a broader range of cells [162]. Accordingly, the emergence of X4 variants is associated with accelerated disease progression and increased CD4+ T-lymphocytes depletion [161]. The infection of naive T-cells by X4 strains is likely to occur early in Tlymphocyte ontogeny and may thus contribute to the described enhancement of T-cells depletion by X4 strains. Studies of thymocyte development demonstrated that CXCR4 is highly expressed on immature T-cell progenitors resident to thymic cortex. As a result, infection of

Cell adhesion. Cell survival

**Primary activation Downstream outcome Primary activation Downstream outcome**

*Chemokine interaction with CXCR4\* or CCR5\*\**

Activation of phospholipase C-γ

Activation of lipid kinase PI3K

Activation of guanine nucleotide exchange factors specific for Rho family GTPases

surface glycoprotein (for more details see [149])

#### *5.3.2. Broad coreceptor usage*

A hallmark of earlier studies addressing the coreceptors usage by HIV-2 primary isolates was that HIV-2 entry into target cells could be mediated by an array of different GPCRs *in vitro* (reviewed in [146, 147]). In contrast, HIV-1 isolates with coreceptor usage biotype other than R5 and/or X4 have been rarely described. Furthermore, HIV-2 isolates can exploit these alternative coreceptors as efficiently as they use CCR5 or CXCR4, even those rarely used by HIV-1. However, it should be noted that most of the viruses used in these studies were obtained from patients in advanced disease stages, were more pathogenic variants could be present, presumably leading to a bias in the viral population that was preferentially isolated.

The ability to use a larger set of coreceptors should constitute an advantage for HIV-2, since it contributes to a potentially broader cell tropism, with the inherent ability to infect different cell types in different compartments [98, 135, 148]. Yet, as referred in R5-to-X4 evolution (see above) this could lead to the infection of non-activated cells, and thus to abortive cycles. Moreover, the engagement of alternative GPCRs, although being sufficient to mediate HIV-2 entry, could be inadequate to trigger appropriate intracellular signaling required for produc‐ tive infection. Several studies have shown a direct correlation between the capacity of envelope glycoproteins to elicit appropriate signaling and the ability to perform a productive infection in several cell types (reviewed in [149]). Such signalling events affect multiple intracellular pathways (in a process mimicking chemokine signaling through binding to their receptors) and include: actin depolymerization, cytoskeleton rearrangement, migration of cells and activation of kinases and transcription factors associated with cell activation (Table 2). Although the relevance of coreceptor signaling in HIV pathogenesis has not been clearly defined, it seems that HIV takes advantage of the chemokine signaling network to create an intracellular environment suitable to accomplish a productive infection [149].

Another factor that may account for the apparent paradox of HIV-2 broad coreceptor usage and low virus production *in vivo*, could be the relative concentration of appropriate viral receptors and their co-localization in plasma membrane of specific cell types [150-153]. Moreover, their expression levels could change during activation/differentiation of T lym‐ phocytes and macrophages, as referred for CD4, CCR5 and CXCR4 [144, 154, 155]. Thus, the availability of target cells expressing CD4 and the appropriate coreceptor *in vivo* could be a limiting factor for HIV-2 infection and spread.

Recently we have studied the contribution of CCR8 as an effective coreceptor for HIV-1 and HIV-2 primary isolates [89]. A major and interesting finding arise from this report: a minor coreceptor such as CCR8 was used much more frequently by HIV-1 than by HIV-2 primary isolates, regardless the clinical stage, the plasma viral load or the CD4+ T-cell counts of patients. The rationale for revisiting CCR8 as coreceptor was based on our earlier findings, revealing the existence of HIV-2 unable to use CCR5 or CXCR4 as coreceptors to infect primary CD4+ lymphocytes or CD4-expressing cell lines [96, 125]. CCR8, formerly known as TER1, ChemR1 and CKR-L1, is the receptor for the chemokine CCL1/I-309 [156, 157]. It is expressed in a wide range of cells; some of them are primary targets for HIV infection *in vivo*, e.g. monocytes, thymocytes and peripheral blood CD4+ T-lymphocytes [157-159]. Its tissue distribution and the significant proportion of HIV-1 isolates able to use CCR8, deserves a deeper discussion. If in HIV-2, due to the well-known promiscuous usage of chemokine receptors as coreceptors, the usage of this GPCR was expected, in HIV-1, this was completely unpredicted. As I pointed before, identification of viruses able to use other coreceptors besides CCR5 and CXCR4 seems to be an abnormality in HIV-1. Yet, the findings presented in the cited report [89] together with previous data [91, 100, 103, 160], indicating the efficient use of CCR8 as coreceptor by distinct HIV-1 isolates, either in indicator cell lines or in primary cells, highlight the potential relevance of this molecule for viral transmission and pathogenesis, including HIV-1.

counts and undetectable viremia is observed in HIV-2. The host and viral factors that contrib‐ utes for this high level of control remain poorly understood, but we hypothesized that one of the viral factors that could be involved is the existence of a less fitted viral population, during a variable period of the asymptomatic stage. This population has lower replicative capacity and, at least in some cases, they do not efficiently use CCR5 and/or CXCR4 coreceptors.

A hallmark of earlier studies addressing the coreceptors usage by HIV-2 primary isolates was that HIV-2 entry into target cells could be mediated by an array of different GPCRs *in vitro* (reviewed in [146, 147]). In contrast, HIV-1 isolates with coreceptor usage biotype other than R5 and/or X4 have been rarely described. Furthermore, HIV-2 isolates can exploit these alternative coreceptors as efficiently as they use CCR5 or CXCR4, even those rarely used by HIV-1. However, it should be noted that most of the viruses used in these studies were obtained from patients in advanced disease stages, were more pathogenic variants could be present,

presumably leading to a bias in the viral population that was preferentially isolated.

intracellular environment suitable to accomplish a productive infection [149].

limiting factor for HIV-2 infection and spread.

Another factor that may account for the apparent paradox of HIV-2 broad coreceptor usage and low virus production *in vivo*, could be the relative concentration of appropriate viral receptors and their co-localization in plasma membrane of specific cell types [150-153]. Moreover, their expression levels could change during activation/differentiation of T lym‐ phocytes and macrophages, as referred for CD4, CCR5 and CXCR4 [144, 154, 155]. Thus, the availability of target cells expressing CD4 and the appropriate coreceptor *in vivo* could be a

Recently we have studied the contribution of CCR8 as an effective coreceptor for HIV-1 and HIV-2 primary isolates [89]. A major and interesting finding arise from this report: a minor coreceptor such as CCR8 was used much more frequently by HIV-1 than by HIV-2 primary isolates, regardless the clinical stage, the plasma viral load or the CD4+ T-cell counts of patients. The rationale for revisiting CCR8 as coreceptor was based on our earlier findings, revealing

The ability to use a larger set of coreceptors should constitute an advantage for HIV-2, since it contributes to a potentially broader cell tropism, with the inherent ability to infect different cell types in different compartments [98, 135, 148]. Yet, as referred in R5-to-X4 evolution (see above) this could lead to the infection of non-activated cells, and thus to abortive cycles. Moreover, the engagement of alternative GPCRs, although being sufficient to mediate HIV-2 entry, could be inadequate to trigger appropriate intracellular signaling required for produc‐ tive infection. Several studies have shown a direct correlation between the capacity of envelope glycoproteins to elicit appropriate signaling and the ability to perform a productive infection in several cell types (reviewed in [149]). Such signalling events affect multiple intracellular pathways (in a process mimicking chemokine signaling through binding to their receptors) and include: actin depolymerization, cytoskeleton rearrangement, migration of cells and activation of kinases and transcription factors associated with cell activation (Table 2). Although the relevance of coreceptor signaling in HIV pathogenesis has not been clearly defined, it seems that HIV takes advantage of the chemokine signaling network to create an

*5.3.2. Broad coreceptor usage*

424 Current Perspectives in HIV Infection


**Table 2.** Major chemokine receptor signalling pathways triggered after binding of chemokines or HIV envelope surface glycoprotein (for more details see [149])

It is widely recognized that during later stages of HIV-1 infection, a significant proportion of viral variants that constitute the *quasispecies* within an infected individual, evolve in order to efficiently use CXCR4 (and probably other chemokine receptors) in addition to, or instead of, CCR5-using variants, which predominate during early stages of infection [161]. These X4 variants are characterized by increased replicative capacity, a more cytopathic phenotype and the ability to infect a broader range of cells [162]. Accordingly, the emergence of X4 variants is associated with accelerated disease progression and increased CD4+ T-lymphocytes depletion [161]. The infection of naive T-cells by X4 strains is likely to occur early in Tlymphocyte ontogeny and may thus contribute to the described enhancement of T-cells depletion by X4 strains. Studies of thymocyte development demonstrated that CXCR4 is highly expressed on immature T-cell progenitors resident to thymic cortex. As a result, infection of immature thymocytes by X4 strains may disrupt thymopoiesis leading to an impairment of Tcell development and to an accelerated T-cell depletion [163-165].

formed or exposed allowing the virus to circumvent the need for prior CD4 interaction. The conformation of envelope glycoproteins allowing the direct interaction with coreceptor (as well as the interaction with different coreceptors) might elicit neutralizing antibodies targeting these critical regions, favoring the host immunological control in HIV-2 infection. Consistent with this notion, sera from HIV-2 infected individuals have higher and broader neutralizing

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

427

Studies conducted with HIV-2 CD4-independent strains clearly demonstrated a less fitted interaction and a reduced replication rate *in vitro*. This suggests that the coreceptor-binding site is only partially formed (or exposed) affecting the stability/affinity of the complex formed between coreceptor and the envelope glycoproteins. In turn, this may also indicate that prior CD4 interaction is important to assure the infection of more permissive cells, enabling a more productive infection. The intracellular factors that dictate this "friendly" environment for viral replication in CD4+ cells remain unknown but may be related to some unidentified restriction factors that could be present in CD4 negative cells. Conversely, the interaction with CD4 may induce cell-signaling events that could account for optimal viral replication conditions, as I

Two lentiviruses infect humans with different outcomes. HIV-1 and HIV-2, both a result of cross-species transmission, have similar genomic and structural characteristics, and yet they distinctively affect human host. While HIV-1 infection leads to severe immune dysfunction and the development of AIDS within a median time of 10 years, HIV-2 usually takes decades

Through this chapter, I have provided several data that help to explain this different patho‐ genic potential of HIV-1 and HIV-2 (see Table 3 for a brief summary). I have focused on those

**•** Avoidance of SAMHD1 degradation of viral cDNA during infection of dendritic cells,

**•** Inability to use CCR5 or CXCR4 that severely affects viral fitness during asymptomatic

**•** A less common acquisition of CXCR4 usage during the course of infection and the conse‐ quent maintenance of a predominant less cytopathic R5 population, which may help to better preserve CD4+ lymphocyte repertoire and immune system functionality in HIV-2

**•** Usage of alternate coreceptors that ultimately could lead to inappropriate cell signalling and/or infection of cell populations unable to fully support the HIV-2 replication cycle.

viral characteristics that determines different virus-host interactions and outcomes:

**•** Lower viral load in body fluids directly involved in HIV-2 transmission.

leading to sensing and stronger innate immune response by HIV-2.

discussed earlier about coreceptor engagement by envelope glycoproteins.

capacity compared to those of HIV-1 [126, 190].

**6. Concluding remarks**

to accomplish that.

phase of infection.

infected individuals.

However, in HIV-2 the correlation between disease progression and coreceptor usage was not consistently observed and a clear pattern of R5-to-X4 evolution, along with disease progres‐ sion, has been difficult to establish. Even so, R5 viruses are mainly observed in asymptomatic or early symptomatic patients, and strains showing a restricted CXCR4 usage are only observed in late symptomatic individuals [96, 166-168]. In a study comparing CCR5, CXCR4 and CCR8 usage by HIV-1 and HIV-2, an interesting observation was withdrawn pointing to a more frequent usage of CXCR4 by HIV-1 than by HIV-2 primary isolates [89]. Conversely, CCR5 use was significantly more common in HIV-2 isolates than in HIV-1. According to the described enhancement of T-cell depletion by X4 variants, the predominance of a non-X4 viral population, mostly observed in HIV-2 cohort, may contribute to better preserve CD4+ lymphocyte repertoire and immune system functionality and help explain the slower disease progression, generally observed in HIV-2 infected patients compared with HIV-1.

#### *5.3.3. CD4-independent infection*

Despite the potential advantage of broader cell tropism associated with lower CD4 depend‐ ency, CD4-independent HIV-1 variants, although readily derived *in vitro* [169-172], have been rarely described *in vivo* [173-175]. In contrast, several primary HIV-2 and SIV isolates have been shown to enter cells in a CD4-independent way [81, 148, 168, 176-179].

The ability to entry cells through direct interaction with the coreceptor molecule, bypassing the requirement of prior CD4 engagement, may enable viruses to infect a broader range of cells CD4 negative/coreceptor positive, or cells where CD4 expression is lower and thus limiting. This notion is consistent with studies showing that neutopathogenic HIV-1 variants show reduced CD4 dependence and the ability to infect CD4-negative cells. Viruses with a CD4 independent phenotype could infect cells in different tissue compartments within an infected individual, besides haematopoietic CD4+ cells, such as the brain, testes, lymphoid tissue, kidneys or lungs, further suggesting that CD4-independence could constitute an advantage and might play an important role in some particular tissue settings [148, 173-175, 180, 181]. Interestingly, the CD4-independent phenotype not only appears to be a potential advantage but it can be easily acquired as a consequence of very few amino acids changes in viral envelope glycoproteins [169-172, 182, 183]. Therefore, a central question may arise: why CD4-independ‐ ent HIV-1 variants are so rare, or why the occurrence of such variants in HIV-2 is not associated with an increased pathogenic outcome?

The infrequent detection of CD4-independent HIV-1 isolates should reflect the selective advantage of CD4 interaction prior to coreceptor engagement. One of the reasons could be the high affinity of CD4-SU envelope glycoprotein binding, stabilizing virion attachment to target cell. However, many other surface molecules have been described to interact with HIV-1 (reviewed in [184]) and thus capable of mediate a stabilizing interaction with virions. Another possible explanation for CD4 dependency could be the shielding of coreceptor binding sites from neutralizing antibodies [170, 182, 185-189]. Considering the proposed mechanism for HIV fusion, the CD4-independent infection imposes that the coreceptor-binding site is already formed or exposed allowing the virus to circumvent the need for prior CD4 interaction. The conformation of envelope glycoproteins allowing the direct interaction with coreceptor (as well as the interaction with different coreceptors) might elicit neutralizing antibodies targeting these critical regions, favoring the host immunological control in HIV-2 infection. Consistent with this notion, sera from HIV-2 infected individuals have higher and broader neutralizing capacity compared to those of HIV-1 [126, 190].

Studies conducted with HIV-2 CD4-independent strains clearly demonstrated a less fitted interaction and a reduced replication rate *in vitro*. This suggests that the coreceptor-binding site is only partially formed (or exposed) affecting the stability/affinity of the complex formed between coreceptor and the envelope glycoproteins. In turn, this may also indicate that prior CD4 interaction is important to assure the infection of more permissive cells, enabling a more productive infection. The intracellular factors that dictate this "friendly" environment for viral replication in CD4+ cells remain unknown but may be related to some unidentified restriction factors that could be present in CD4 negative cells. Conversely, the interaction with CD4 may induce cell-signaling events that could account for optimal viral replication conditions, as I discussed earlier about coreceptor engagement by envelope glycoproteins.

### **6. Concluding remarks**

immature thymocytes by X4 strains may disrupt thymopoiesis leading to an impairment of T-

However, in HIV-2 the correlation between disease progression and coreceptor usage was not consistently observed and a clear pattern of R5-to-X4 evolution, along with disease progres‐ sion, has been difficult to establish. Even so, R5 viruses are mainly observed in asymptomatic or early symptomatic patients, and strains showing a restricted CXCR4 usage are only observed in late symptomatic individuals [96, 166-168]. In a study comparing CCR5, CXCR4 and CCR8 usage by HIV-1 and HIV-2, an interesting observation was withdrawn pointing to a more frequent usage of CXCR4 by HIV-1 than by HIV-2 primary isolates [89]. Conversely, CCR5 use was significantly more common in HIV-2 isolates than in HIV-1. According to the described enhancement of T-cell depletion by X4 variants, the predominance of a non-X4 viral population, mostly observed in HIV-2 cohort, may contribute to better preserve CD4+ lymphocyte repertoire and immune system functionality and help explain the slower disease

progression, generally observed in HIV-2 infected patients compared with HIV-1.

been shown to enter cells in a CD4-independent way [81, 148, 168, 176-179].

Despite the potential advantage of broader cell tropism associated with lower CD4 depend‐ ency, CD4-independent HIV-1 variants, although readily derived *in vitro* [169-172], have been rarely described *in vivo* [173-175]. In contrast, several primary HIV-2 and SIV isolates have

The ability to entry cells through direct interaction with the coreceptor molecule, bypassing the requirement of prior CD4 engagement, may enable viruses to infect a broader range of cells CD4 negative/coreceptor positive, or cells where CD4 expression is lower and thus limiting. This notion is consistent with studies showing that neutopathogenic HIV-1 variants show reduced CD4 dependence and the ability to infect CD4-negative cells. Viruses with a CD4 independent phenotype could infect cells in different tissue compartments within an infected individual, besides haematopoietic CD4+ cells, such as the brain, testes, lymphoid tissue, kidneys or lungs, further suggesting that CD4-independence could constitute an advantage and might play an important role in some particular tissue settings [148, 173-175, 180, 181]. Interestingly, the CD4-independent phenotype not only appears to be a potential advantage but it can be easily acquired as a consequence of very few amino acids changes in viral envelope glycoproteins [169-172, 182, 183]. Therefore, a central question may arise: why CD4-independ‐ ent HIV-1 variants are so rare, or why the occurrence of such variants in HIV-2 is not associated

The infrequent detection of CD4-independent HIV-1 isolates should reflect the selective advantage of CD4 interaction prior to coreceptor engagement. One of the reasons could be the high affinity of CD4-SU envelope glycoprotein binding, stabilizing virion attachment to target cell. However, many other surface molecules have been described to interact with HIV-1 (reviewed in [184]) and thus capable of mediate a stabilizing interaction with virions. Another possible explanation for CD4 dependency could be the shielding of coreceptor binding sites from neutralizing antibodies [170, 182, 185-189]. Considering the proposed mechanism for HIV fusion, the CD4-independent infection imposes that the coreceptor-binding site is already

cell development and to an accelerated T-cell depletion [163-165].

*5.3.3. CD4-independent infection*

426 Current Perspectives in HIV Infection

with an increased pathogenic outcome?

Two lentiviruses infect humans with different outcomes. HIV-1 and HIV-2, both a result of cross-species transmission, have similar genomic and structural characteristics, and yet they distinctively affect human host. While HIV-1 infection leads to severe immune dysfunction and the development of AIDS within a median time of 10 years, HIV-2 usually takes decades to accomplish that.

Through this chapter, I have provided several data that help to explain this different patho‐ genic potential of HIV-1 and HIV-2 (see Table 3 for a brief summary). I have focused on those viral characteristics that determines different virus-host interactions and outcomes:


**•** CD4-independent infection of target cells, providing the potential to infect cells in different compartments but also exposing critical regions of coreceptor binding site to host neutral‐ izing immune response.

**Author details**

**References**

José Miguel Azevedo-Pereira

(1997). , 349(9056), 911-914.

ence. (1986). , 233(4761), 343-346.

265(5178), 1587-1590.

313(5786), 523-526.

of Pharmacy, University of Lisbon (FFUL), Lisbon, Portugal

line.org/virusTaxonomy.asp?version=2009&bhcp=1.

England Journal of Medicine. (1987). , 316(19), 1180-1185.

Molecular Pathogenesis Centre, Retrovirus and Related Infections Unit (CPM-URIA), Faculty

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

429

[1] Whittle, H, Morris, J, Todd, J, Corrah, T, Sabally, S, Bangali, J, et al. HIV-2-infected patients survive longer than HIV-1-infected patients. AIDS. (1994). , 8(11), 1617-1620.

[2] Poulsen, A. G, Aaby, P, Larsen, O, Jensen, H, Naucler, A, Lisse, I. M, et al. year HIV-2-associated mortality in an urban community in Bissau, west Africa. Lancet.

[3] Marlink, R, Kanki, P, Thior, I, Travers, K, Eisen, G, Siby, T, et al. Reduced rate of dis‐ ease development after HIV-2 infection as compared to HIV-1. Science. (1994). ,

[4] Virus Taxonomy: (2009). Release [database on the Internet]International Comittee on Taxonomy of Viruses (ICTV). [cited 19 June 2012]. Available from: http://ictvon‐

[5] Clavel, F, Guetard, D, Brun-vezinet, F, Chamaret, S, Rey, M. A, Santos-ferreira, M. O, et al. Isolation of a new human retrovirus from West African patients with AIDS. Sci‐

[6] Clavel, F, Mansinho, K, Chamaret, S, Guetard, D, Favier, V, Nina, J, et al. Human im‐ munodeficiency virus type 2 infection associated with AIDS in West Africa. New

[7] Keele, B. F, Van Heuverswyn, F, Li, Y, Bailes, E, Takehisa, J, Santiago, M. L, et al. Chimpanzee reservoirs of pandemic and nonpandemic HIV-1. Science. (2006). ,

[8] Lemey, P, Pybus, O. G, Wang, B, Saksena, N. K, Salemi, M, & Vandamme, A. M. Tracing the origin and history of the HIV-2 epidemic. Proceedings of the National Academy of Sciences of the United States of America. (2003). , 100(11), 6588-6592.

[9] Hahn, B. H, Shaw, G. M, De Cock, K. M, & Sharp, P. M. AIDS as a zoonosis: scientific

[10] Korber, B, Muldoon, M, Theiler, J, Gao, F, Gupta, R, Lapedes, A, et al. Timing the an‐ cestor of the HIV-1 pandemic strains. Science. (2000). , 288(5472), 1789-1796.

and public health implications. Science. (2000). , 287(5453), 607-614.

**•** A more relaxed envelope glycoproteins structure that could modulate HIV-2 interaction with cellular receptors, helping explaining the exotic coreceptor usage and CD4-independ‐ ency but also a less fitted interaction with those receptors and thus to an inappropriate cell signalling.

Much more data is needed to fully comprehend the way human host is able to cope with HIV-2 but not with HIV-1 infection. Further studies addressing HIV-2-cell interactions are warranted as they could reveal undisclosed mechanisms and pathways that may help to clarify the underlying causes for the different pathogenic potential observed between HIV-2 and HIV-1, en route to assist in HIV vaccine development and new therapeutic strategies.


**Table 3.** Differences between HIV-1 and HIV-2 regarding virus-host interaction (see text for further details)

### **Acknowledgements**

The author wish to acknowledge bioMérieux Portugal for the financial support in the article processing charge of this chapter.

### **Author details**

**•** CD4-independent infection of target cells, providing the potential to infect cells in different compartments but also exposing critical regions of coreceptor binding site to host neutral‐

**•** A more relaxed envelope glycoproteins structure that could modulate HIV-2 interaction with cellular receptors, helping explaining the exotic coreceptor usage and CD4-independ‐ ency but also a less fitted interaction with those receptors and thus to an inappropriate cell

Much more data is needed to fully comprehend the way human host is able to cope with HIV-2 but not with HIV-1 infection. Further studies addressing HIV-2-cell interactions are warranted as they could reveal undisclosed mechanisms and pathways that may help to clarify the underlying causes for the different pathogenic potential observed between HIV-2 and HIV-1,

en route to assist in HIV vaccine development and new therapeutic strategies.

Conflicting results. Susceptible to antiviral activity of cellular factor SAMHD1

Less efficiently triggered due to several factors, namely to the restricted infection

efficiently use CCR5 and CXCR4

Mostly the V3 region of SU envelope

**Table 3.** Differences between HIV-1 and HIV-2 regarding virus-host interaction (see text for further details)

of dendritic cells

**Coreceptor usage** Generally described has only being able to

glycoprotein

*HIV-1 HIV-2*

Conflicting results. Resistant to antiviral activity of cellular factor SAMHD1 (by Vpx

More robust than in HIV-1 namely because infection of dendritic cells could trigger IFN-I mediated response

Generally described has being able to efficiently use other coreceptors besides

Conflicting data. Probably V1/V2 region and, to a lesser extend, V3 region

protein)

CCR5 and CXCR4

Rarely described Several primary isolates reported

Reduced Higher and broader

The author wish to acknowledge bioMérieux Portugal for the financial support in the article

izing immune response.

428 Current Perspectives in HIV Infection

signalling.

**Infection of dendritic**

**Innate immune response**

**CD4-independent**

**Neutralization capacity of serum antibodies**

**Acknowledgements**

processing charge of this chapter.

**infection**

**Molecular determinants of coreceptor usage**

**cells**

José Miguel Azevedo-Pereira

Molecular Pathogenesis Centre, Retrovirus and Related Infections Unit (CPM-URIA), Faculty of Pharmacy, University of Lisbon (FFUL), Lisbon, Portugal

### **References**


[11] Sharp, P. M, & Hahn, B. H. The evolution of HIV-1 and the origin of AIDS. Philo‐ sophical Transactions of the Royal Society of London Series B, Biological sciences. (2010). , 365(1552), 2487-2494.

French Perinatal Cohort EPF-CO1. Clinical Infectious Diseases. (2010). , 51(7),

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

431

[24] Van Tienen, C, Van Der Loeff, M. S, Zaman, S. M, Vincent, T, Sarge-njie, R, Peterson, I, et al. Two Distinct Epidemics: The Rise of HIV-1 and Decline of HIV-2 Infection Be‐ tween 1990 and 2007 in Rural Guinea-Bissau. Journal of Acquired Immune Deficien‐

[25] Quinn, T. C, Wawer, M. J, Sewankambo, N, Serwadda, D, Li, C, Wabwire-mangen, F, et al. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. New England Journal of Medicine. (2000). ,

[26] Gottlieb, G. S, Hawes, S. E, Agne, H. D, Stern, J. E, Critchlow, C. W, Kiviat, N. B, et al. Lower levels of HIV RNA in semen in HIV-2 compared with HIV-1 infection: impli‐

[27] Popper, S. J, Sarr, A. D, Travers, K. U, Gueye-ndiaye, A, Mboup, S, Essex, M. E, et al. Lower human immunodeficiency virus (HIV) type 2 viral load reflects the difference in pathogenicity of HIV-1 and HIV-2. Journal of Infectious Diseases. (1999). , 180(4),

[28] Gomes, P, Taveira, N. C, Pereira, J. M, Antunes, F, Ferreira, M. O, & Lourenco, M. H. Quantitation of human immunodeficiency virus type 2 DNA in peripheral blood mononuclear cells by using a quantitative-competitive PCR assay. Journal of Clinical

[29] Popper, S. J, Sarr, A. D, Gueye-ndiaye, A, Mboup, S, Essex, M. E, & Kanki, P. J. Low plasma human immunodeficiency virus type 2 viral load is independent of proviral load: low virus production in vivo. Journal of Virology. (2000). , 74(3), 1554-1557. [30] Wawer, M. J, Gray, R. H, Sewankambo, N. K, Serwadda, D, Li, X, Laeyendecker, O, et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai,

[31] Gray, R. H, Wawer, M. J, Brookmeyer, R, Sewankambo, N. K, Serwadda, D, Wab‐ wire-mangen, F, et al. Probability of HIV-1 transmission per coital act in monoga‐ mous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet. (2001). ,

[32] Haase, A. T. Early events in sexual transmission of HIV and SIV and opportunities

[33] Lai, S. K, Hida, K, Shukair, S, Wang, Y. Y, Figueiredo, A, Cone, R, et al. Human im‐ munodeficiency virus type 1 is trapped by acidic but not by neutralized human cer‐

Uganda. Journal of Infectious Diseases. (2005). , 191(9), 1403-1409.

for interventions. Annual Review of Medicine. (2011). , 62-127.

vicovaginal mucus. Journal of Virology. (2009). , 83(21), 11196-11200.

cations for differences in transmission. AIDS. (2006). , 20(6), 895-900.

833-843.

342(13), 921-929.

1116-1121.

357(9263), 1149-1153.

cy Syndromes. (2009). , 53(5), 640-647.

Microbiology. (1999). , 37(2), 453-456.


French Perinatal Cohort EPF-CO1. Clinical Infectious Diseases. (2010). , 51(7), 833-843.

[24] Van Tienen, C, Van Der Loeff, M. S, Zaman, S. M, Vincent, T, Sarge-njie, R, Peterson, I, et al. Two Distinct Epidemics: The Rise of HIV-1 and Decline of HIV-2 Infection Be‐ tween 1990 and 2007 in Rural Guinea-Bissau. Journal of Acquired Immune Deficien‐ cy Syndromes. (2009). , 53(5), 640-647.

[11] Sharp, P. M, & Hahn, B. H. The evolution of HIV-1 and the origin of AIDS. Philo‐ sophical Transactions of the Royal Society of London Series B, Biological sciences.

[12] Suzuki, Y, & Craigie, R. The road to chromatin- nuclear entry of retroviruses. Nature

[13] Frankel, A. D, & Young, J. A. HIV-1: fifteen proteins and an RNA. Annual Review of

[14] Schubert, U, Anton, L. C, Bacik, I, Cox, J. H, Bour, S, Bennink, J. R, et al. CD4 glyco‐ protein degradation induced by human immunodeficiency virus type 1 Vpu protein requires the function of proteasomes and the ubiquitin-conjugating pathway. Journal

[15] Varthakavi, V, Smith, R. M, Bour, S. P, Strebel, K, & Spearman, P. Viral protein U counteracts a human host cell restriction that inhibits HIV-1 particle production. Pro‐ ceedings of the National Academy of Sciences of the United States of America.

[16] Perez-caballero, D, Zang, T, Ebrahimi, A, Mcnatt, M. W, Gregory, D. A, Johnson, M. C, et al. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell.

[17] Neil, S. J, Zang, T, & Bieniasz, P. D. Tetherin inhibits retrovirus release and is antago‐

[18] Abada, P, Noble, B, & Cannon, P. M. Functional domains within the human immu‐ nodeficiency virus type 2 envelope protein required to enhance virus production.

[19] Bour, S. P, Schubert, U, Peden, K, & Strebel, K. The envelope glycoprotein of human immunodeficiency virus type 2 enhances viral particle release: a Vpu-like factor?

[20] Andersen, J. L, & Planelles, V. The role of Vpr in HIV-1 pathogenesis. Current HIV

[21] Goujon, C, Rivière, L, Jarrosson-wuilleme, L, Bernaud, J, Rigal, D, Darlix, J-L, et al. SIVSM/HIV-2 Vpx proteins promote retroviral escape from a proteasome-dependent

[22] Kanki, P, Boup, M, Marlink, S, Travers, R, Hsieh, K, & Gueye, C. C. A, et al. Preva‐ lence and risk determinants of human immunodeficiency virus type 2 (HIV-2) and human immunodeficiency virus type 1 (HIV-1) in west African female prostitutes.

[23] Burgard, M, Jasseron, C, Matheron, S, Damond, F, Hamrene, K, Blanche, S, et al. Mother-to-child transmission of HIV-2 infection from 1986 to 2007 in the ANRS

restriction pathway present in human dendritic cells. Retrovirology. (2007).

American Journal of Epidemiology. (1992). , 136(7), 895-907.

nized by HIV-1 Vpu. Nature. (2008). , 451(7177), 425-430.

Journal of Virology. (2005). , 79(6), 3627-3638.

Journal of Virology. (1996). , 70(2), 820-829.

Research. (2005). , 3(1), 43-51.

(2010). , 365(1552), 2487-2494.

430 Current Perspectives in HIV Infection

Biochemistry. (1998). , 67-1.

(2003). , 100(25), 15154-15159.

(2009). , 139(3), 499-511.

of Virology. (1998). , 72(3), 2280-2288.

Reviews Microbiology. (2007). , 5(3), 187-196.


[34] Pudney, J, Quayle, A. J, & Anderson, D. J. Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone. Biology of Reproduction. (2005). , 73(6), 1253-1263.

[46] Auvert, B, Taljaard, D, Lagarde, E, Sobngwi-tambekou, J, Sitta, R, & Puren, A. Randomized, controlled intervention trial of male circumcision for reduction of HIV

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

433

[47] Edwards, S. Balanitis and balanoposthitis: a review. Genitourinary Medicine. (1996). ,

[48] Sha, B. E, Zariffard, M. R, Wang, Q. J, Chen, H. Y, Bremer, J, Cohen, M. H, et al. Fe‐ male genital-tract HIV load correlates inversely with Lactobacillus species but posi‐ tively with bacterial vaginosis and Mycoplasma hominis. Journal of Infectious

[49] Hashemi, F. B, Ghassemi, M, Faro, S, Aroutcheva, A, & Spear, G. T. Induction of hu‐ man immunodeficiency virus type 1 expression by anaerobes associated with bacteri‐

[50] Simoes, J. A, Hashemi, F. B, Aroutcheva, A. A, Heimler, I, Spear, G. T, Shott, S, et al. Human immunodeficiency virus type 1 stimulatory activity by Gardnerella vagina‐ lis: relationship to biotypes and other pathogenic characteristics. Journal of Infectious

[51] Cohen, C. R, Lingappa, J. R, Baeten, J. M, Ngayo, M. O, Spiegel, C. A, Hong, T, et al. Bacterial Vaginosis Associated with Increased Risk of Female-to-Male HIV-1 Trans‐ mission: A Prospective Cohort Analysis among African Couples. PLoS Medicine.

[52] Bomsel, M. Transcytosis of infectious human immunodeficiency virus across a tight

[53] Bobardt, M. D, Chatterji, U, Selvarajah, S, Van Der Schueren, B, David, G, Kahn, B, et al. Cell-free human immunodeficiency virus type 1 transcytosis through primary

[54] Frank, I, & Pope, M. The enigma of dendritic cell-immunodeficiency virus interplay.

[55] Zhang, Z, Schuler, T, Zupancic, M, Wietgrefe, S, Staskus, K. A, Reimann, K. A, et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4+

[56] Wu, L. KewalRamani VN. Dendritic-cell interactions with HIV: infection and viral

[57] Wiley, R. D, & Gummuluru, S. Immature dendritic cell-derived exosomes can medi‐ ate HIV-1 trans infection. Proceedings of the National Academy of Sciences of the

dissemination. Nature Reviews Immunology. (2006). , 6(11), 859-868.

human epithelial cell line barrier. Nature Medicine. (1997). , 3(1), 42-47.

genital epithelial cells. Journal of Virology. (2007). , 81(1), 395-405.

Current Molecular Medicine. (2002). , 2(3), 229-248.

T cells. Science. (1999). , 286(5443), 1353-1357.

United States of America. (2006). , 103(3), 738-743.

al vaginosis. Journal of Infectious Diseases. (2000). , 181(5), 1574-1580.

infection risk: the ANRS 1265 Trial. PLoS Medicine. (2005). e298.

72(3), 155-159.

Diseases. (2005). , 191(1), 25-32.

Diseases. (2001). , 184(1), 22-27.

(2012). e1001251.


[46] Auvert, B, Taljaard, D, Lagarde, E, Sobngwi-tambekou, J, Sitta, R, & Puren, A. Randomized, controlled intervention trial of male circumcision for reduction of HIV infection risk: the ANRS 1265 Trial. PLoS Medicine. (2005). e298.

[34] Pudney, J, Quayle, A. J, & Anderson, D. J. Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone. Biology of Reproduction. (2005). , 73(6), 1253-1263. [35] Moss, G. B, Clemetson, D, Costa, D, Plummer, L, Ndinya-achola, F. A, & Reilly, J. O. M, et al. Association of cervical ectopy with heterosexual transmission of human im‐ munodeficiency virus: results of a study of couples in Nairobi, Kenya. Journal of In‐

[36] Marx, P. A, Spira, A. I, Gettie, A, Dailey, P. J, Veazey, R. S, Lackner, A. A, et al. Pro‐ gesterone implants enhance SIV vaginal transmission and early virus load. Nature

[37] Norvell, M. K, Benrubi, G. I, & Thompson, R. J. Investigation of microtrauma after sexual intercourse. Journal of Reproductive Medicine. (1984). , 29(4), 269-271.

[38] Sewankambo, N, Gray, R. H, Wawer, M. J, Paxton, L, Mcnaim, D, Wabwire-mangen, F, et al. HIV-1 infection associated with abnormal vaginal flora morphology and bac‐

[39] Cohn, M. A, Frankel, S. S, Rugpao, S, Young, M. A, Willett, G, Tovanabutra, S, et al. Chronic inflammation with increased human immunodeficiency virus (HIV) RNA expression in the vaginal epithelium of HIV-infected Thai women. Journal of Infec‐

[40] Sharkey, D. J, Macpherson, A. M, Tremellen, K. P, & Robertson, S. A. Seminal plasma differentially regulates inflammatory cytokine gene expression in human cervical and vaginal epithelial cells. Molecular Human Reproduction. (2007). , 13(7), 491-501.

[41] Berlier, W, Cremel, M, Hamzeh, H, Levy, R, Lucht, F, Bourlet, T, et al. Seminal plas‐ ma promotes the attraction of Langerhans cells via the secretion of CCL20 by vaginal epithelial cells: involvement in the sexual transmission of HIV. Human Reproduc‐

[42] Münch, J, Rücker, E, Ständker, L, Adermann, K, Goffinet, C, Schindler, M, et al. Se‐ men-derived amyloid fibrils drastically enhance HIV infection. Cell. (2007). , 131(6),

[43] Kim, K-A, Yolamanova, M, Zirafi, O, Roan, N. R, Staendker, L, Forssmann, W-G, et al. Semen-mediated enhancement of HIV infection is donor-dependent and corre‐

[44] Mccoombe, S. G, & Short, R. V. Potential HIV-1 target cells in the human penis.

[45] Patterson, B. K, Landay, A, Siegel, J. N, Flener, Z, Pessis, D, Chaviano, A, et al. Sus‐ ceptibility to human immunodeficiency virus-1 infection of human foreskin and cer‐ vical tissue grown in explant culture. American Journal of Pathology. (2002). , 161(3),

fectious Diseases. (1991). , 164(3), 588-591.

terial vaginosis. Lancet. (1997). , 350(9077), 546-550.

lates with the levels of SEVI. Retrovirology. (2010).

Medicine. (1996). , 2(10), 1084-1089.

432 Current Perspectives in HIV Infection

tious Diseases. (2001). , 184(4), 410-417.

tion. (2006). , 21(5), 1135-1142.

AIDS. (2006). , 20(11), 1491-1495.

1059-1071.

867-873.


[58] Rubbert, A, Combadiere, C, Ostrowski, M, Arthos, J, Dybul, M, Machado, E, et al. Dendritic cells express multiple chemokine receptors used as coreceptors for HIV en‐ try. Journal of Immunology. (1998). , 160(8), 3933-3941.

[70] Hrecka, K, Hao, C, Gierszewska, M, Swanson, S. K, Kesik-brodacka, M, Srivastava, S, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

435

[71] Goldstone, D. C, Ennis-adeniran, V, Hedden, J. J, Groom, H. C, Rice, G. I, Christo‐ doulou, E, et al. HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate

[72] Altfeld, M, Fadda, L, Frleta, D, & Bhardwaj, N. DCs and NK cells: critical effectors in the immune response to HIV-1. Nature Reviews Immunology. (2011). , 11(3), 176-186.

[73] Manel, N, Hogstad, B, Wang, Y, Levy, D. E, Unutmaz, D, & Littman, D. R. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature.

[74] Manel, N, & Littman, D. R. Hiding in plain sight: how HIV evades innate immune

[75] Lambotte, O, Boufassa, F, Madec, Y, Nguyen, A, Goujard, C, Meyer, L, et al. HIV controllers: a homogeneous group of HIV-1-infected patients with spontaneous con‐

[76] Esbjornsson, J, Mansson, F, Kvist, A, Isberg, P-E, Nowroozalizadeh, S, Biague, A. J, et al. Inhibition of HIV-1 disease progression by contemporaneous HIV-2 infection. The

[77] Cavaleiro, R, Sousa, A. E, Loureiro, A, & Victorino, R. M. Marked immunosuppres‐ sive effects of the HIV-2 envelope protein in spite of the lower HIV-2 pathogenicity.

[78] Arhel, N, Lehmann, M, Clau, K, Nienhaus, G. U, Piguet, V, & Kirchhoff, F. The in‐ ability to disrupt the immunological synapse between infected human T cells and APCs distinguishes HIV-1 from most other primate lentiviruses. Journal of Clinical

[79] Dalgleish, A. G, Beverley, P. C, Clapham, P. R, Crawford, D. H, Greaves, M. F, Weiss, R. A, & The, C. D. T4) antigen is an essential component of the receptor for the AIDS

[80] Klatzmann, D, Champagne, E, Chamaret, S, Gruest, J, Guetard, D, Hercend, T, et al. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV. Na‐

[81] Clapham, P. R, & Mcknight, A. Cell surface receptors, virus entry and tropism of pri‐

[82] Doms, R. W, & Trono, D. The plasma membrane as a combat zone in the HIV battle‐

[83] Marsh, M, & Helenius, A. Virus entry: open sesame. Cell. (2006). , 124(4), 729-740.

mate lentiviruses. Journal of General Virology. (2002). Pt 8) 1809-1829.

field. Genes and Development. (2000). , 14(21), 2677-2688.

trol of viral replication. Clinical Infectious Diseases. (2005). , 41(7), 1053-1056.

SAMHD1 protein. Nature. (2011). , 474(7353), 658-661.

triphosphohydrolase. Nature. (2011). , 480(7377), 379-382.

New England journal of medicine. (2012). , 367(3), 224-232.

(2010). , 467(7312), 214-217.

responses. Cell. (2011). , 147(2), 271-274.

AIDS. (2000). , 14(17), 2679-2686.

ture. (1984). , 312(5996), 767-768.

Investigation. (2009). , 119(10), 2965-2975.

retrovirus. Nature. (1984). , 312(5996), 763-767.


[70] Hrecka, K, Hao, C, Gierszewska, M, Swanson, S. K, Kesik-brodacka, M, Srivastava, S, et al. Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein. Nature. (2011). , 474(7353), 658-661.

[58] Rubbert, A, Combadiere, C, Ostrowski, M, Arthos, J, Dybul, M, Machado, E, et al. Dendritic cells express multiple chemokine receptors used as coreceptors for HIV en‐

[59] Granelli-piperno, A, Moser, B, Pope, M, Chen, D, Wei, Y, Isdell, F, et al. Efficient in‐ teraction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors.

[60] Canque, B, Bakri, Y, Camus, S, Yagello, M, Benjouad, A, & Gluckman, J. C. The sus‐ ceptibility to X4 and R5 human immunodeficiency virus-1 strains of dendritic cells derived in vitro from CD34(+) hematopoietic progenitor cells is primarily determined

[61] Granelli-piperno, A, Finkel, V, Delgado, E, & Steinman, R. M. Virus replication be‐ gins in dendritic cells during the transmission of HIV-1 from mature dendritic cells

[62] Izquierdo-useros, N, Naranjo-gómez, M, Erkizia, I, Puertas, M. C, Borràs, F. E, Blan‐ co, J, et al. HIV and mature dendritic cells: Trojan exosomes riding the Trojan horse?

[63] Turville, S, Wilkinson, J, Cameron, P, Dable, J, & Cunningham, A. L. The role of den‐ dritic cell C-type lectin receptors in HIV pathogenesis. Journal of Leukocyte Biology.

[64] Freer, G, & Matteucci, D. Influence of dendritic cells on viral pathogenicity. PLoS

[65] Arrighi, J. F, Pion, M, Wiznerowicz, M, Geijtenbeek, T. B, Garcia, E, Abraham, S, et al. Lentivirus-mediated RNA interference of DC-SIGN expression inhibits human im‐ munodeficiency virus transmission from dendritic cells to T cells. Journal of Virolo‐

[66] Pohlmann, S, Baribaud, F, Lee, B, Leslie, G. J, Sanchez, M. D, Hiebenthal-millow, K, et al. DC-SIGN interactions with human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus. Journal of Virology. (2001). , 75(10), 4664-4672. [67] Vanham, G, Van Tendeloo, V, Willems, B, Penne, L, Kestens, L, Beirnaert, E, et al. The HIV-2 genotype and the HIV-1 syncytium-inducing phenotype are associated with a lower virus replication in dendritic cells. Journal of Medical Virology. (2000). ,

[68] Duvall, M. G, Loré, K, Blaak, H, Ambrozak, D. A, Adams, W. C, Santos, K, et al. Den‐ dritic cells are less susceptible to human immunodeficiency virus type 2 (HIV-2) in‐ fection than to HIV-1 infection. Journal of Virology. (2007). , 81(24), 13486-13498. [69] Laguette, N, Sobhian, B, Casartelli, N, Ringeard, M, Chable-bessia, C, Ségéral, E, et al. SAMHD1 is the dendritic- and myeloid-cell-specific HIV-1 restriction factor counter‐

try. Journal of Immunology. (1998). , 160(8), 3933-3941.

Journal of Experimental Medicine. (1996). , 184(6), 2433-2438.

by their maturation stage. Blood. (1999). , 93(11), 3866-3875.

to T cells. Current Biology. (1999). , 9(1), 21-29.

PLoS Pathogens. (2010). e1000740.

(2003). , 74(5), 710-718.

434 Current Perspectives in HIV Infection

60(3), 300-312.

Pathogens. (2009). e1000384.

gy. (2004). , 78(20), 10848-10855.

acted by Vpx. Nature. (2011). , 474(7353), 654-657.


[84] Daecke, J, Fackler, O. T, Dittmar, M. T, & Krausslich, H. G. Involvement of clathrinmediated endocytosis in human immunodeficiency virus type 1 entry. Journal of Vi‐ rology. (2005). , 79(3), 1581-1594.

[95] Jiang, C, Parrish, N. F, Wilen, C. B, Li, H, Chen, Y, Pavlicek, J. W, et al. Primary infec‐ tion by a human immunodeficiency virus with atypical coreceptor tropism. Journal

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

437

[96] Azevedo-pereira, J. M, Santos-costa, Q, Mansinho, K, & Moniz-pereira, J. Identifica‐ tion and characterization of HIV-2 strains obtained from asymptomatic patients that

[97] Xiao, L, Rudolph, D. L, Owen, S. M, Spira, T. J, & Lal, R. B. Adaptation to promiscu‐ ous usage of CC and CXC-chemokine coreceptors in vivo correlates with HIV-1 dis‐

[98] Willey, S. J, Reeves, J. D, Hudson, R, Miyake, K, Dejucq, N, Schols, D, et al. Identifica‐ tion of a subset of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus strains able to exploit an alternative coreceptor on untrans‐ formed human brain and lymphoid cells. Journal of Virology. (2003). , 77(11),

[99] Pohlmann, S, Krumbiegel, M, & Kirchhoff, F. Coreceptor usage of BOB/GPR15 and Bonzo/STRL33 by primary isolates of human immunodeficiency virus type 1. Journal

[100] Lee, S, Tiffany, H. L, King, L, Murphy, P. M, Golding, H, & Zaitseva, M. B. CCR8 on human thymocytes functions as a human immunodeficiency virus type 1 coreceptor.

[101] Edinger, A. L, Hoffman, T. L, Sharron, M, Lee, B, Dowd, O, & Doms, B. RW. Use of GPR1, GPR15, and STRL33 as coreceptors by diverse human immunodeficiency vi‐ rus type 1 and simian immunodeficiency virus envelope proteins. Virology. (1998). ,

[102] Deng, H. K, & Unutmaz, D. KewalRamani VN, Littman DR. Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature.

[103] Cilliers, T, Willey, S, Sullivan, W. M, Patience, T, Pugach, P, Coetzer, M, et al. Use of alternate coreceptors on primary cells by two HIV-1 isolates. Virology. (2005). ,

[104] Gharu, L, Ringe, R, & Bhattacharya, J. Evidence of extended alternate coreceptor us‐ age by HIV-1 clade C envelope obtained from an Indian patient. Virus Research.

[105] Grivel, J-C, Shattock, R. J, & Margolis, L. B. Selective transmission of R5 HIV-1 var‐ iants: where is the gatekeeper? Journal of Translational Medicine. (2011). Suppl 1 S6.

[106] Keele, B. F, & Estes, J. D. Barriers to mucosal transmission of immunodeficiency vi‐

do not use CCR5 or CXCR4 coreceptors. Virology. (2003). , 313(1), 136-146.

of Virology. (2011). , 85(20), 10669-10681.

ease progression. AIDS. (1998). F, 137-143.

of General Virology. (1999). Pt 5) 1241-1251.

Journal of Virology. (2000). , 74(15), 6946-6952.

6138-6152.

249(2), 367-378.

339(1), 136-144.

(1997). , 388(6639), 296-300.

(2012). , 163(1), 410-414.

ruses. Blood. (2011). , 118(4), 839-846.


[95] Jiang, C, Parrish, N. F, Wilen, C. B, Li, H, Chen, Y, Pavlicek, J. W, et al. Primary infec‐ tion by a human immunodeficiency virus with atypical coreceptor tropism. Journal of Virology. (2011). , 85(20), 10669-10681.

[84] Daecke, J, Fackler, O. T, Dittmar, M. T, & Krausslich, H. G. Involvement of clathrinmediated endocytosis in human immunodeficiency virus type 1 entry. Journal of Vi‐

[85] Miyauchi, K, Kim, Y, Latinovic, O, Morozov, V, & Melikyan, G. B. HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes. Cell. (2009). ,

[86] Alkhatib, G, Combadiere, C, Broder, C. C, Feng, Y, Kennedy, P. E, Murphy, P. M, et al. CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for

[87] Feng, Y, Broder, C. C, Kennedy, P. E, & Berger, E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science.

[88] Broder, C. C, & Jones-trower, A. Coreceptor use by primate Lentiviruses. In: Kuiken C, Foley BT, Hahn B, Korber B, McCutchan F, Marx PA, et al., (eds.) Human Retrovi‐ ruses and AIDS: A Compilation and Analysis of Nucleic Acid and Amino Acid Se‐ quences. Los Alamos, NM: Theoretical Biology and Biophysics Group, Los Alamos

[89] Calado, M, Matoso, P, Santos-costa, Q, Espirito-santo, M, Machado, J, Rosado, L, et al. Coreceptor usage by HIV-1 and HIV-2 primary isolates: the relevance of CCR8 chemokine receptor as an alternative coreceptor. Virology. (2010). , 408(2), 174-182.

[90] Neil, S. J, Aasa-chapman, M. M, Clapham, P. R, Nibbs, R. J, Mcknight, A, & Weiss, R. A. The promiscuous CC chemokine receptor D6 is a functional coreceptor for pri‐ mary isolates of human immunodeficiency virus type 1 (HIV-1) and HIV-2 on astro‐

[91] Shimizu, N, Tanaka, A, Oue, A, Mori, T, Ohtsuki, T, Apichartpiyakul, C, et al. Broad usage spectrum of G protein-coupled receptors as coreceptors by primary isolates of

[92] Simmons, G, Reeves, J, Hibbitts, S, Stine, J, Gray, P, Proudfoot, A, et al. Co-receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands. Immuno‐

[93] Zhang, Y. J, Dragic, T, Cao, Y, Kostrikis, L, Kwon, D. S, Littman, D. R, et al. Use of coreceptors other than CCR5 by non-syncytium-inducing adult and pediatric isolates of human immunodeficiency virus type 1 is rare in vitro. Journal of Virology. (1998). ,

[94] Moore, J. P, Kitchen, S. G, Pugach, P, & Zack, J. A. The CCR5 and CXCR4 corecep‐ tors--central to understanding the transmission and pathogenesis of human immuno‐ deficiency virus type 1 infection. AIDS Research and Human Retroviruses. (2004). ,

macrophage-tropic HIV-1. Science. (1996). , 272(5270), 1955-1958.

rology. (2005). , 79(3), 1581-1594.

(1996). , 272(5263), 872-877.

National Laboratory; (1999). , 517-541.

HIV. AIDS. (2009). , 27(7), 761-769.

logical Reviews. (2000). , 177-112.

72(11), 9337-9344.

20(1), 111-126.

cytes. Journal of Virology. (2005). , 79(15), 9618-9624.

137(3), 433-444.

436 Current Perspectives in HIV Infection


[107] Chalmet, K, Dauwe, K, Foquet, L, Baatz, F, Seguin-devaux, C, Van Der Gucht, B, et al. Presence of CXCR4-Using HIV-1 in Patients With Recently Diagnosed Infection: Correlates and Evidence for Transmission. Journal of Infectious Diseases. (2012). , 205(2), 174-184.

[118] Briggs, D. R, Tuttle, D. L, Sleasman, J. W, Goodenow, M. M, & Envelope, V. amino acid sequence predicts HIV-1 phenotype (co-receptor usage and tropism for macro‐

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

439

[119] Delobel, P, Nugeyre, M. T, Cazabat, M, Pasquier, C, Marchou, B, Massip, P, et al. Population-based sequencing of the region of env for predicting the coreceptor usage of human immunodeficiency virus type 1 quasispecies. Journal of Clinical Microbiol‐

[120] Kwong, P. D, Wyatt, R, Robinson, J, Sweet, R. W, Sodroski, J, & Hendrickson, W. A. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor

[121] Labrosse, B, Treboute, C, Brelot, A, & Alizon, M. Cooperation of the V2 and V3 do‐ mains of human immunodeficiency virus type 1 gp120 for interaction with the

[122] Nabatov, A. A, Pollakis, G, Linnemann, T, Kliphius, A, Chalaby, M. I, & Paxton, W. A. Intrapatient alterations in the human immunodeficiency virus type 1 gp120 and V3 regions differentially modulate coreceptor usage, virus inhibition by CC/CXC chemokines, soluble CD4, and the b12 and 2G12 monoclonal antibodies. Journal of

[123] Pollakis, G, Kang, S, Kliphuis, A, Chalaby, M. I, & Goudsmit, J. Paxton WA. N-linked glycosylation of the HIV type-1 gp120 envelope glycoprotein as a major determinant of CCR5 and CXCR4 coreceptor utilization. Journal of Biological Chemistry. (2001). ,

[124] Wyatt, R, Moore, J, Accola, M, Desjardin, E, Robinson, J, & Sodroski, J. Involvement of the V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding. Journal of Virology. (1995). , 1

[125] Santos-costa, Q, Mansinho, K, Moniz-pereira, J, & Azevedo-pereira, J. M. Characteri‐ zation of HIV-2 chimeric viruses unable to use CCR5 and CXCR4 coreceptors. Virus

[126] De Silva, T. I, Aasa-chapman, M, Cotten, M, Hué, S, Robinson, J, Bibollet-ruche, F, et al. Potent Autologous and Heterologous Neutralizing Antibody Responses Occur in HIV-2 Infection across a Broad Range of Infection Outcomes. Journal of Virology.

[127] Kong, R, Li, H, Bibollet-ruche, F, Decker, J. M, Zheng, N. N, Gottlieb, G. S, et al. Broad and Potent Neutralizing Antibody Responses Elicited in Natural HIV-2 Infec‐

[128] Marcelino, J. M, Borrego, P, Rocha, C, Barroso, H, Quintas, A, Novo, C, et al. Potent and Broadly Reactive HIV-2 Neutralizing Antibodies Elicited by a Vaccinia Virus

and a neutralizing human antibody. Nature. (1998). , 393(6686), 648-659.

phages). AIDS. (2000). , 14(18), 2937-2939.

CXCR4 receptor. Journal of Virology. (2001). , 1

ogy. (2007). , 3

Virology. (2004). , 1V2

276(16), 13433-13441.

Research. (2009).

(2012). , 86(2), 930-946.

tion. Journal of Virology. (2012). , 86(2), 947-960.


[118] Briggs, D. R, Tuttle, D. L, Sleasman, J. W, Goodenow, M. M, & Envelope, V. amino acid sequence predicts HIV-1 phenotype (co-receptor usage and tropism for macro‐ phages). AIDS. (2000). , 14(18), 2937-2939.

[107] Chalmet, K, Dauwe, K, Foquet, L, Baatz, F, Seguin-devaux, C, Van Der Gucht, B, et al. Presence of CXCR4-Using HIV-1 in Patients With Recently Diagnosed Infection: Correlates and Evidence for Transmission. Journal of Infectious Diseases. (2012). ,

[108] Hedskog, C, Mild, M, & Albert, J. Transmission of the X4 Phenotype of HIV-1: Is There Evidence Against the "Random Transmission" Hypothesis? Journal of Infec‐

[109] Sol, N, Ferchal, F, Braun, J, Pleskoff, O, Treboute, C, Ansart, I, et al. Usage of the core‐ ceptors CCR-5, CCR-3, and CXCR-4 by primary and cell line-adapted human immu‐

[110] Mcknight, A, Shotton, C, Cordell, J, Jones, I, Simmons, G, & Clapham, P. R. Location, exposure, and conservation of neutralizing and nonneutralizing epitopes on human immunodeficiency virus type 2 SU glycoprotein. Journal of Virology. (1996). , 70(7),

[111] Starcich, B. R, Hahn, B. H, Shaw, G. M, Mcneely, P. D, Modrow, S, Wolf, H, et al. Identification and characterization of conserved and variable regions in the envelope

[112] Willey, R. L, Rutledge, R. A, Dias, S, Folks, T, Theodore, T, Buckler, C. E, et al. Identi‐ fication of conserved and divergent domains within the envelope gene of the ac‐ quired immunodeficiency syndrome retrovirus. Proceedings of the National Academy of Sciences of the United States of America. (1986). , 83(14), 5038-5042. [113] Cho, M. W, Lee, M. K, Carney, M. C, Berson, J. F, Doms, R. W, & Martin, M. A. Iden‐ tification of determinants on a dualtropic human immunodeficiency virus type 1 en‐ velope glycoprotein that confer usage of CXCR4. Journal of Virology. (1998). , 72(3),

[114] Hoffman, T. L, & Doms, R. W. HIV-1 envelope determinants for cell tropism and che‐ mokine receptor use. Molecular Membrane Biology. (1999). , 16(1), 57-65.

[115] Hoffman, T. L, Stephens, E. B, Narayan, O, & Doms, R. W. HIV type I envelope de‐ terminants for use of the CCR2b, CCR3, STRL33, and APJ coreceptors. Proceedings of the National Academy of Sciences of the United States of America. (1998). , 95(19),

[116] Hu, Q, Trent, J. O, Tomaras, G. D, Wang, Z, Murray, J. L, Conolly, S. M, et al. Identifi‐ cation of ENV determinants in that influence the molecular anatomy of CCR5 utiliza‐

[117] Smyth, R. J, Yi, Y, Singh, A, & Collman, R. G. Determinants of entry cofactor utiliza‐ tion and tropism in a dualtropic human immunodeficiency virus type 1 primary iso‐

gene of HTLV-III/LAV, the retrovirus of AIDS. Cell. (1986). , 45(5), 637-648.

nodeficiency virus type 2. Journal of Virology. (1997). , 71(11), 8237-8244.

205(2), 174-184.

438 Current Perspectives in HIV Infection

4598-4606.

2509-2515.

11360-11365.

tion. Journal of Molecular Biology. (2000). , 3

late. Journal of Virology. (1998). , 72(5), 4478-4484.

tious Diseases. (2012). , 205(2), 163-165.


Vector Prime-C2Polypeptide Boost Immunization Strategy. Journal of Virology. (2010). , 3C3

[140] Santos-costa, Q, Parreira, R, Moniz-pereira, J, & Azevedo-pereira, J. M. Molecular characterization of the env gene of two CCR5/CXCR4-independent human immuno‐ deficiency 2 primary isolates. Journal of Medical Virology. (2009). , 81(11), 1869-1881.

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

441

[141] Blaak, H, Van Der Ende, M. E, Boers, P. H, Schuitemaker, H, & Osterhaus, A. D. In vitro replication capacity of HIV-2 variants from long-term aviremic individuals. Vi‐

[142] Baggiolini, M, Dewald, B, & Moser, B. Human chemokines: an update. Annual Re‐

[143] Bleul, C. C, Wu, L, Hoxie, J. A, Springer, T. A, & Mackay, C. R. The HIV coreceptors CXCR4 and CCR5 are differentially expressed and regulated on human T lympho‐ cytes. Proceedings of the National Academy of Sciences of the United States of Amer‐

[144] Wu, L, Paxton, W. A, Kassam, N, Ruffing, N, Rottman, J. B, Sullivan, N, et al. CCR5 levels and expression pattern correlate with infectability by macrophage-tropic

HIV-1, in vitro. Journal of Experimental Medicine. (1997). , 185(9), 1681-1691.

[145] Woods, T. C, Roberts, B. D, Butera, S. T, & Folks, T. M. Loss of inducible virus in CD45RA naive cells after human immunodeficiency virus-1 entry accounts for pref‐ erential viral replication in CD45RO memory cells. Blood. (1997). , 89(5), 1635-1641.

[146] Azevedo-pereira, J. M, Santos-costa, Q, & Moniz-pereira, J. HIV-2 infection and che‐ mokine receptors usage- clues to reduced virulence of HIV-2. Current HIV Research.

[147] Reeves, J. D, & Doms, R. W. Human immunodeficiency virus type 2. Journal of Gen‐

[148] Willey, S, Roulet, V, Reeves, J. D, Kergadallan, M. L, Thomas, E, Mcknight, A, et al. Human Leydig cells are productively infected by some HIV-2 and SIV strains but not

[149] Wu, Y, & Yoder, A. Chemokine coreceptor signaling in HIV-1 infection and patho‐

[150] Kozak, S. L, Platt, E. J, Madani, N, & Ferro, F. E. Jr, Peden K, Kabat D. CD4, CXCR-4, and CCR-5 dependencies for infections by primary patient and laboratory-adapted isolates of human immunodeficiency virus type 1. Journal of Virology. (1997). , 71(2),

[151] Kuhmann, S. E, Platt, E. J, Kozak, S. L, & Kabat, D. Cooperation of multiple CCR5 coreceptors is required for infections by human immunodeficiency virus type 1. Jour‐

[152] Lee, B, Sharron, M, Montaner, L. J, Weissman, D, & Doms, R. W. Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differen‐

rology. (2006). , 353(1), 144-154.

ica. (1997). , 94(5), 1925-1930.

(2005). , 3(1), 3-16.

873-882.

eral Virology. (2002). Pt 6) 1253-1265.

by HIV-1. AIDS. (2003). , 17(2), 183-188.

genesis. PLoS Pathogens. (2009). e1000520.

nal of Virology. (2000). , 74(15), 7005-7015.

view of Immunology. (1997). , 15-675.


[140] Santos-costa, Q, Parreira, R, Moniz-pereira, J, & Azevedo-pereira, J. M. Molecular characterization of the env gene of two CCR5/CXCR4-independent human immuno‐ deficiency 2 primary isolates. Journal of Medical Virology. (2009). , 81(11), 1869-1881.

Vector Prime-C2Polypeptide Boost Immunization Strategy. Journal of Virology.

[129] Ozkaya Sahin GHolmgren B, da Silva Z, Nielsen J, Nowroozalizadeh S, Esbjörnsson J, et al. Potent Intratype Neutralizing Activity Distinguishes Human Immunodefi‐ ciency Virus Type 2 (HIV-2) from HIV-1. Journal of Virology. (2012). , 86(2), 961-971.

[130] Bjorling, E, Broliden, K, Bernardi, D, Utter, G, Thorstensson, R, Chiodi, F, et al. Hy‐ perimmune antisera against synthetic peptides representing the glycoprotein of hu‐ man immunodeficiency virus type 2 can mediate neutralization and antibodydependent cytotoxic activity. Proceedings of the National Academy of Sciences of the

[131] Bjorling, E, Chiodi, F, Utter, G, & Norrby, E. Two neutralizing domains in the region in the envelope glycoprotein gp125 of HIV type 2. Journal of Immunology. (1994). , 3

[132] Matsushita, S, Matsumi, S, Yoshimura, K, Morikita, T, Murakami, T, & Takatsuki, K. Neutralizing monoclonal antibodies against human immunodeficiency virus type 2

[133] Albert, J, Stalhandske, P, Marquina, S, Karis, J, Fouchier, R. A, Norrby, E, et al. Bio‐ logical phenotype of HIV type 2 isolates correlates with genotype. AIDS Research

[134] Isaka, Y, Sato, A, Miki, S, Kawauchi, S, Sakaida, H, Hori, T, et al. Small amino acid changes in the loop of human immunodeficiency virus type 2 determines the core‐

[135] Morner, A, Thomas, J. A, Bjorling, E, Munson, P. J, Lucas, S. B, & Mcknight, A. Pro‐ ductive HIV-2 infection in the brain is restricted to macrophages/microglia. AIDS.

[136] Shi, Y, Brandin, E, Vincic, E, Jansson, M, Blaxhult, A, Gyllensten, K, et al. Evolution of human immunodeficiency virus type 2 coreceptor usage, autologous neutraliza‐ tion, envelope sequence and glycosylation. Journal of General Virology. (2005). Pt 12)

[137] Visseaux, B, Hurtado-nedelec, M, Charpentier, C, Collin, G, Storto, A, Matheron, S, et al. Molecular Determinants of HIV-2 R5-X4 Tropism in the Loop: Development of a

[138] Kulkarni, S, Tripathy, S, Agnihotri, K, Jatkar, N, Jadhav, S, Umakanth, W, et al. Indi‐ an primary HIV-2 isolates and relationship between genotype, biological phenotype

[139] Owen, S. M, Ellenberger, D, Rayfield, M, Wiktor, S, Michel, P, Grieco, M. H, et al. Ge‐ netically divergent strains of human immunodeficiency virus type 2 use multiple

coreceptors for viral entry. Journal of Virology. (1998). , 72(7), 5425-5432.

New Genotypic Tool. Journal of Infectious Diseases. (2012). , 3

and coreceptor usage. Virology. (2005). , 3

United States of America. (1991). , 88(14), 6082-6086.

gp120. Journal of Virology. (1995). , 69(6), 3333-3340.

ceptor usage for CXCR4 and CCR5. Virology. (1999). , 3

and Human Retroviruses. (1996). , 3

(2003). , 17(10), 1451-1455.

3385-3396.

(2010). , 3C3

440 Current Perspectives in HIV Infection


tially conditioned monocyte-derived macrophages. Proceedings of the National Academy of Sciences of the United States of America. (1999). , 96(9), 5215-5220.

[164] Kitchen, S. G, & Zack, J. A. CXCR4 expression during lymphopoiesis: implications for human immunodeficiency virus type 1 infection of the thymus. Journal of Virolo‐

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

443

[165] Taylor, J. R. Jr., Kimbrell KC, Scoggins R, Delaney M, Wu L, Camerini D. Expression and function of chemokine receptors on human thymocytes: implications for infec‐ tion by human immunodeficiency virus type 1. Journal of Virology. (2001). , 75(18),

[166] Guillon, C, Van Der Ende, M. E, Boers, P. H, Gruters, R. A, Schutten, M, & Osterhaus, A. D. Coreceptor usage of human immunodeficiency virus type 2 primary isolates and biological clones is broad and does not correlate with their syncytium-inducing

[167] Mcknight, A, Dittmar, M. T, Moniz-periera, J, Ariyoshi, K, Reeves, J. D, Hibbitts, S, et al. A broad range of chemokine receptors are used by primary isolates of human im‐ munodeficiency virus type 2 as coreceptors with CD4. Journal of Virology. (1998). ,

[168] Reeves, J. D, Hibbitts, S, Simmons, G, Mcknight, A, Azevedo-pereira, J. M, Monizpereira, J, et al. Primary human immunodeficiency virus type 2 (HIV-2) isolates in‐ fect CD4-negative cells via CCR5 and CXCR4: comparison with HIV-1 and simian immunodeficiency virus and relevance to cell tropism in vivo. Journal of Virology.

[169] Dumonceaux, J, Nisole, S, Chanel, C, Quivet, L, Amara, A, Baleux, F, et al. Spontane‐ ous mutations in the env gene of the human immunodeficiency virus type 1 NDK isolate are associated with a CD4-independent entry phenotype. Journal of Virology.

[170] Hoffman, T. L. LaBranche CC, Zhang W, Canziani G, Robinson J, Chaiken I, et al. Stable exposure of the coreceptor-binding site in a CD4-independent HIV- 1 enve‐ lope protein. Proceedings of the National Academy of Sciences of the United States

[171] Kolchinsky, P, Mirzabekov, T, Farzan, M, Kiprilov, E, Cayabyab, M, Mooney, L. J, et al. Adaptation of a CCR5-using, primary human immunodeficiency virus type 1 iso‐ late for CD4-independent replication. Journal of Virology. (1999). , 73(10), 8120-8126.

[172] LaBranche CCHoffman TL, Romano J, Haggarty BS, Edwards TG, Matthews TJ, et al. Determinants of CD4 independence for a human immunodeficiency virus type 1 var‐ iant map outside regions required for coreceptor specificity. Journal of Virology.

[173] Xiao, P, Usami, O, Suzuki, Y, Ling, H, Shimizu, N, Hoshino, H, et al. Characterization of a CD4-independent clinical HIV-1 that can efficiently infect human hepatocytes

through chemokine (C-X-C motif) receptor 4. AIDS. (2008). , 22(14), 1749-1757.

capacities. Journal of Virology. (1998). , 72(7), 6260-6263.

gy. (1997). , 71(9), 6928-6934.

8752-8760.

72(5), 4065-4071.

(1999). , 73(9), 7795-7804.

(1998). , 72(1), 512-519.

of America. (1999). , 96(11), 6359-6364.

(1999). , 73(12), 10310-10319.


[164] Kitchen, S. G, & Zack, J. A. CXCR4 expression during lymphopoiesis: implications for human immunodeficiency virus type 1 infection of the thymus. Journal of Virolo‐ gy. (1997). , 71(9), 6928-6934.

tially conditioned monocyte-derived macrophages. Proceedings of the National Academy of Sciences of the United States of America. (1999). , 96(9), 5215-5220.

[153] Platt, E. J, Wehrly, K, Kuhmann, S. E, Chesebro, B, & Kabat, D. Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human

immunodeficiency virus type 1. Journal of Virology. (1998). , 72(4), 2855-2864.

[154] Naif, H. M, Li, S, Alali, M, Sloane, A, Wu, L, Kelly, M, et al. CCR5 expression corre‐ lates with susceptibility of maturing monocytes to human immunodeficiency virus

[155] Tuttle, D. L, Harrison, J. K, Anders, C, Sleasman, J. W, & Goodenow, M. M. Expres‐ sion of CCR5 increases during monocyte differentiation and directly mediates mac‐ rophage susceptibility to infection by human immunodeficiency virus type 1. Journal

[156] Roos, R. S, Loetscher, M, Legler, D. F, Clark-lewis, I, Baggiolini, M, & Moser, B. Iden‐ tification of CCR8, the receptor for the human CC chemokine I-309. Journal of Biolog‐

[157] Tiffany, H. L, Lautens, L. L, Gao, J. L, Pease, J, Locati, M, Combadiere, C, et al. Identi‐ fication of CCR8: a human monocyte and thymus receptor for the CC chemokine

[158] Ambrosio, D, Iellem, D, Bonecchi, A, Mazzeo, R, Sozzani, D, & Mantovani, S. A, et al. Selective up-regulation of chemokine receptors CCR4 and CCR8 upon activation of polarized human type 2 Th cells. Journal of Immunology. (1998). , 161(10), 5111-5115.

[159] Zingoni, A, Soto, H, Hedrick, J. A, Stoppacciaro, A, Storlazzi, C. T, Sinigaglia, F, et al. The chemokine receptor CCR8 is preferentially expressed in Th2 but not Th1 cells.

[160] Horuk, R, Hesselgesser, J, Zhou, Y, Faulds, D, Halks-miller, M, Harvey, S, et al. The CC chemokine I-309 inhibits CCR8-dependent infection by diverse HIV-1 strains.

[161] Connor, R. I, Sheridan, K. E, Ceradini, D, Choe, S, & Landau, N. R. Change in core‐ ceptor use coreceptor use correlates with disease progression in HIV-1--infected indi‐

[162] van'Wout, t, Blaak, A. B, Ran, H, Brouwer, L. J, Kuiken, M, & Schuitemaker, C. H. Evolution of syncytium-inducing and non-syncytium-inducing biological virus clones in relation to replication kinetics during the course of human immunodefi‐

[163] Berkowitz, R. D, Beckerman, K. P, Schall, T. J, & Mccune, J. M. CXCR4 and CCR5 ex‐ pression delineates targets for HIV-1 disruption of T cell differentiation. Journal of

ciency virus type 1 infection. Journal of Virology. (1998). , 72(6), 5099-5107.

viduals. Journal of Experimental Medicine. (1997). , 185(4), 621-628.

I-309. Journal of Experimental Medicine. (1997). , 186(1), 165-170.

type 1 infection. Journal of Virology. (1998). , 72(1), 830-836.

of Virology. (1998). , 72(6), 4962-4969.

442 Current Perspectives in HIV Infection

ical Chemistry. (1997). , 272(28), 17251-17254.

Journal of Immunology. (1998). , 161(2), 547-551.

Immunology. (1998). , 161(7), 3702-3710.

Journal of Biological Chemistry. (1998). , 273(1), 386-391.


[174] Zerhouni, B, Nelson, J. A, & Saha, K. Isolation of CD4-independent primary human immunodeficiency virus type 1 isolates that are syncytium inducing and acutely cy‐ topathic for CD8+ lymphocytes. Journal of Virology. (2004). , 78(3), 1243-1255.

[185] Bhattacharya, J, Peters, P. J, & Clapham, P. R. CDindependent infection of HIV and SIV: implications for envelope conformation and cell tropism in vivo. AIDS. (2003).

HIV-2 Interaction with Target Cell Receptors, or Why HIV-2 is Less Pathogenic Than HIV-1

http://dx.doi.org/10.5772/53201

445

[186] Kolchinsky, P, Kiprilov, E, & Sodroski, J. Increased neutralization sensitivity of CD4 independent human immunodeficiency virus variants. Journal of Virology. (2001). ,

[187] Puffer, B. A, Pohlmann, S, Edinger, A. L, Carlin, D, Sanchez, M. D, Reitter, J, et al. CD4 independence of simian immunodeficiency virus Envs is associated with macro‐ phage tropism, neutralization sensitivity, and attenuated pathogenicity. Journal of

[188] Thomas, E. R, Shotton, C, Weiss, R. A, Clapham, P. R, Mcknight, A, & Hiv-2, C. D4-d. e. p. e. n. d. e. n. t a. n. d C. D4-i. n. d. e. p. e. n. d. e. n. t. consequences for neutraliza‐

[189] Zhang, P. F, Bouma, P, Park, E. J, Margolick, J. B, Robinson, J. E, Zolla-pazner, S, et al. A variable region 3 (mutation determines a global neutralization phenotype and CD4-independent infectivity of a human immunodeficiency virus type 1 envelope associated with a broadly cross-reactive, primary virus-neutralizing antibody re‐

[190] Bjorling, E, Scarlatti, G, Von Gegerfelt, A, Albert, J, Biberfeld, G, Chiodi, F, et al. Au‐ tologous neutralizing antibodies prevail in HIV-2 but not in HIV-1 infection. Virolo‐

Suppl 4 S35-43., 4.

75(5), 2041-2050.

Virology. (2002). , 76(6), 2595-2605.

tion. AIDS. (2003). , 17(3), 291-300.

sponse. Journal of Virology. (2002). , 3

gy. (1993). , 193(1), 528-530.


[185] Bhattacharya, J, Peters, P. J, & Clapham, P. R. CDindependent infection of HIV and SIV: implications for envelope conformation and cell tropism in vivo. AIDS. (2003). Suppl 4 S35-43., 4.

[174] Zerhouni, B, Nelson, J. A, & Saha, K. Isolation of CD4-independent primary human immunodeficiency virus type 1 isolates that are syncytium inducing and acutely cy‐

topathic for CD8+ lymphocytes. Journal of Virology. (2004). , 78(3), 1243-1255. [175] Saha, K, Zhang, J, Gupta, A, Dave, R, Yimen, M, & Zerhouni, B. Isolation of primary HIV-1 that target CD8+ T lymphocytes using CD8 as a receptor. Nature Medicine.

[176] Azevedo-pereira, J. M, Santos-costa, Q, Taveira, N, Verissimo, F, & Moniz-pereira, J. Construction and characterization of CD4-independent infectious recombinant

[177] Edinger, A. L, Mankowski, J. L, Doranz, B. J, Margulies, B. J, Lee, B, Rucker, J, et al. CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain. Proceedings of the National Academy of Sciences of the United States of America. (1997). , 94(26), 14742-14747.

[178] Endres, M. J, Clapham, P. R, Marsh, M, Ahuja, M, Turner, J. D, Mcknight, A, et al. CD4-independent infection by HIV-2 is mediated by fusin/CXCR4. Cell. (1996). ,

[179] Liu, H. Y, Soda, Y, Shimizu, N, Haraguchi, Y, Jinno, A, Takeuchi, Y, et al. CD4-De‐ pendent and CD4-independent utilization of coreceptors by human immunodeficien‐ cy viruses type 2 and simian immunodeficiency viruses. Virology. (2000). , 278(1),

[180] Gorry, P. R, Taylor, J, Holm, G. H, Mehle, A, Morgan, T, Cayabyab, M, et al. In‐ creased CCR5 affinity and reduced CCR5/CD4 dependence of a neurovirulent pri‐ mary human immunodeficiency virus type 1 isolate. Journal of Virology. (2002). ,

[181] Marras, D, Bruggeman, L. A, Gao, F, Tanji, N, Mansukhani, M. M, Cara, A, et al. Rep‐ lication and compartmentalization of HIV-1 in kidney epithelium of patients with

[182] Edwards, T. G, Hoffman, T. L, Baribaud, F, & Wyss, S. LaBranche CC, Romano J, et al. Relationships between CD4 independence, neutralization sensitivity, and expo‐ sure of a CD4-induced epitope in a human immunodeficiency virus type 1 envelope

[183] Reeves, J. D, Schulz, T. F, & The, C. D. independent tropism of human immunodefi‐ ciency virus type 2 involves several regions of the envelope protein and correlates with a reduced activation threshold for envelope-mediated fusion. Journal of Virolo‐

[184] Ugolini, S, Mondor, I, & Sattentau, Q. J. HIV-1 attachment: another look. Trends in

HIV-associated nephropathy. Nature Medicine. (2002). , 8(5), 522-526.

protein. Journal of Virology. (2001). , 75(11), 5230-5239.

HIV-2 molecular clones. Virus Research. (2003). , 97(2), 159-163.

(2001). , 7(1), 65-72.

444 Current Perspectives in HIV Infection

87(4), 745-756.

76(12), 6277-6292.

gy. (1997). , 71(2), 1453-1465.

Microbiology. (1999). , 7(4), 144-149.

276-288.


**Chapter 19**

**Interaction of FIV with Heterologous Microbes in the**

Since the emergence of the acquired immune deficiency syndrome (AIDS), there has been a great deal of interest in identifying cofactors that accelerate progression of the disease elicit‐ ed by human immunodeficiency virus types 1 or 2 (HIV-1, HIV-2). Beside inherent factors and environmental agents, speculations led to the conclusion that infectious diseases fre‐ quently occur in HIV infected persons, might augment HIV replication, and consequently facilitate AIDS progression. HIV infection is followed by a long disease-free period, during which a low number of CD4+ immune cells contains transcriptionally silent provirus. Acti‐ vation of CD4+ cells by external factors, including heterologous viruses, terminates latency forcing towards a productive HIV infection. Transactivation of the HIV long terminal repeat (LTR) by cellular, nuclear transcriptional factors (e.g. NF-κB, Sp1) induced by mitogens, cy‐ tokines, chemokines, simultaneous virus infections is followed by gene expression including the synthesis of the HIV transactivator protein (TAT), which binds to the transactivating re‐ sponse (TAR) element of the genome, ultimately leading to large scale production of HIV and death of infected cells through apoptosis [1,2]. *In vitro* studies showed that products of immediate early (IE) or early (E) genes of several DNA viruses such as human herpesviruses (HHV) -1, 2, 3, 4, 5, 6A, 8, adenoviruses, as well as hepatitis B virus (HBV) X gene, human T lymphotropic virus type I (HTLV-I) *tax* gene upregulated production of these transcriptional factors and activate HIV-1 or HIV-2 in the same cells. Simultaneous infection in a single cell is relatively rare event *in vivo*; therefore such type of biological effects in nature could be minimal. On the contrary, cross-talk between immune cells carrying different viruses via cy‐ tokines, chemokines is more common. Heterologous viruses infect many types of cells, which are not targets of HIV, but release several immunomodulatory mediators, usually in

> © 2013 Ongrádi et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

**Feline AIDS Model**

http://dx.doi.org/10.5772/52767

**1. Introduction**

Nagy Károly and Pistello Mauro

Joseph Ongrádi, Stercz Balázs, Kövesdi Valéria,

Additional information is available at the end of the chapter

### **Interaction of FIV with Heterologous Microbes in the Feline AIDS Model**

Joseph Ongrádi, Stercz Balázs, Kövesdi Valéria, Nagy Károly and Pistello Mauro

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/52767

### **1. Introduction**

Since the emergence of the acquired immune deficiency syndrome (AIDS), there has been a great deal of interest in identifying cofactors that accelerate progression of the disease elicit‐ ed by human immunodeficiency virus types 1 or 2 (HIV-1, HIV-2). Beside inherent factors and environmental agents, speculations led to the conclusion that infectious diseases fre‐ quently occur in HIV infected persons, might augment HIV replication, and consequently facilitate AIDS progression. HIV infection is followed by a long disease-free period, during which a low number of CD4+ immune cells contains transcriptionally silent provirus. Acti‐ vation of CD4+ cells by external factors, including heterologous viruses, terminates latency forcing towards a productive HIV infection. Transactivation of the HIV long terminal repeat (LTR) by cellular, nuclear transcriptional factors (e.g. NF-κB, Sp1) induced by mitogens, cy‐ tokines, chemokines, simultaneous virus infections is followed by gene expression including the synthesis of the HIV transactivator protein (TAT), which binds to the transactivating re‐ sponse (TAR) element of the genome, ultimately leading to large scale production of HIV and death of infected cells through apoptosis [1,2]. *In vitro* studies showed that products of immediate early (IE) or early (E) genes of several DNA viruses such as human herpesviruses (HHV) -1, 2, 3, 4, 5, 6A, 8, adenoviruses, as well as hepatitis B virus (HBV) X gene, human T lymphotropic virus type I (HTLV-I) *tax* gene upregulated production of these transcriptional factors and activate HIV-1 or HIV-2 in the same cells. Simultaneous infection in a single cell is relatively rare event *in vivo*; therefore such type of biological effects in nature could be minimal. On the contrary, cross-talk between immune cells carrying different viruses via cy‐ tokines, chemokines is more common. Heterologous viruses infect many types of cells, which are not targets of HIV, but release several immunomodulatory mediators, usually in

© 2013 Ongrádi et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

an abnormal pattern. High level of tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and low level of IL-2, IL-12 were frequently observed in the blood of AIDS patients, only to mention the most important ones. Abundant pro-inflammatory cytokines bind to HIV carri‐ er cells and through consequently activated secondary messenger systems activate the same transcriptional factors for HIV activation. This category of interaction has a more significant impact on HIV infection. This phenomenon called as transcellular transactivation can last lifetime, its intensity may vary depending on the host, the other transiently or chronically coinfecting microbes, etc. [3]. These external confounding factors act in a pleiotropic man‐ ner, which is impossible to study *in vitro*. Animal studies are ideal to establish their role in AIDS progression [4].

particular felid species that carries a specific strain of FIV. Typical examples have been re‐ ported recently. A highly virulent FeLV outbreak in FIV*Pco* infected free ranging Florida pu‐ mas (*Puma concolor coryi*) threatened this endangered species [12]. In another outbreak in the Serengeti, FIV*Ple* B infected lions (*Panthera leo*) were twice as likely to survive CDV infection compared to lions infected with FIV*Ple* A or FIV*Ple* C [34]. These cases clearly demonstrate that specificities of both microbes might express increased risk for severe synergistic patho‐ genicity. Recent surveys on coinfections mentioned above were carried out for descriptive epidemiological purposes. In the majority of studies, occurrence of heterologous microbes were judged as opportunistic infections, but some of the investigators have come to the con‐ clusion that FIV and heterologous microbes might mutually aggravate immunosuppression at the level of the organism [12,17]. Both FIV and FeLV independently might predispose ani‐ mals for toxoplasma infection [21]. In spite of similar clinical manifestations by FIV or FeLV, they might specifically predispose the host for different heterologous microbial pathogens: FIV predisposes to Leishmania [12,16], mycoplasma [25,27,33,35], fungal [26], FCoV [12] in‐ fections, while FeLVsensitises the organism to BH infection [36]. Others found that the rate of toxoplasma [16,30,32] or FCV [24] infections occur independently of FIV status. These re‐ sult, even some of them are contradictory, clearly show that each retrovirus must have its specific way to interact with other microbes at molecular or immunological level. It is con‐ ceivable that HIV and human microbes have similar ways for interactions. Both direct trans‐ activation of FIV in the simultaneously infected cells (Figure 1) or cross-talk between cells infected by FIV, and other cells infected by heterologous microbes (Figure 2) can take place

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

449

in the body of cats.

**Figure 1.** Scheme of intracellular virus transactivation

### **2. The feline AIDS model**

Feline AIDS (FAIDS) induced by feline immunodeficiency virus (FIV) is the only natural small animal model of human AIDS [4,5-8 ]. FIV shares many genetic, structural and biologi‐ cal characteristics with HIV. FIV also shows tropism for CD4+ immune cells, but its receptor is the CD134 molecule with the CXCR4 coreceptor. FIV LTR accommodates multiple en‐ hancer or promoter protein-binding sites (e.g. NF-κB, AP-1). Although FIV lacks TAT and the TAR element, its Orf-2 (also designated as Orf-A) acts as a transactivator gene to some degree and is necessary for productive FIV replication [7,9]. The similarities in the clinical course of infection between HIV and FIV are striking [6,8,10]. Male gender and adult age are known risk factors for both HIV and FIV transmission [6,7,11,12]. Domestic cats infected with FIV develop progressive immune dysfunction characterised by depletion of CD4+ T cells, wasting, cachexia, gingivostomatitis, neuropathological disorders, opportunistic infec‐ tions, unusual malignancies such as B cell lymphomas, fibrosarcomas [13]. CD4+CD25+hi‐ FoxP3+ immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modu‐ lating virus-specific and inflammatory immune responses. Influence of Treg cell suppres‐ sion during FIV and HIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection [10]. It is important to remember that increased ac‐ tivity of Treg cells promotes immunosenescence in the normal elderly, and AIDS is regarded as an extremely rapid ageing process [14]. Disease progression occurs over a similar time scale to HIV-1 infection in humans [6]. FIV is distributed worldwide; it has several subtypes similarly to HIV [12,15]. Species-specific strains of FIV circulate in many members of *Felidae* family, including endangered big cats in which also induce AIDS-like illnesses [6,12]. Some opportunistic infections in cats also occur worldwide such as feline leukaemia virus (FeLV), feline herpesvirus type 1 (FHV-1), *Toxoplasma gondii* (TG), feline coronavirus (FCoV), *Barto‐ nella henselae* (BH), canine distemper virus (CDV), fungal pathogens or mycoplasmas. Their incidence depends on geographical regions, cat subpopulations (pet, indoor, stray, feral, free-roaming, etc.), gender and age [11,12,16-28]. Incidence of other opportunistic microbes depends on endemic geographical areas and local vectors (e.g. haemoplasma or Leishmania species, different helminths) [16,18,29-33]. Some of these microbes establish coinfection in a particular felid species that carries a specific strain of FIV. Typical examples have been re‐ ported recently. A highly virulent FeLV outbreak in FIV*Pco* infected free ranging Florida pu‐ mas (*Puma concolor coryi*) threatened this endangered species [12]. In another outbreak in the Serengeti, FIV*Ple* B infected lions (*Panthera leo*) were twice as likely to survive CDV infection compared to lions infected with FIV*Ple* A or FIV*Ple* C [34]. These cases clearly demonstrate that specificities of both microbes might express increased risk for severe synergistic patho‐ genicity. Recent surveys on coinfections mentioned above were carried out for descriptive epidemiological purposes. In the majority of studies, occurrence of heterologous microbes were judged as opportunistic infections, but some of the investigators have come to the con‐ clusion that FIV and heterologous microbes might mutually aggravate immunosuppression at the level of the organism [12,17]. Both FIV and FeLV independently might predispose ani‐ mals for toxoplasma infection [21]. In spite of similar clinical manifestations by FIV or FeLV, they might specifically predispose the host for different heterologous microbial pathogens: FIV predisposes to Leishmania [12,16], mycoplasma [25,27,33,35], fungal [26], FCoV [12] in‐ fections, while FeLVsensitises the organism to BH infection [36]. Others found that the rate of toxoplasma [16,30,32] or FCV [24] infections occur independently of FIV status. These re‐ sult, even some of them are contradictory, clearly show that each retrovirus must have its specific way to interact with other microbes at molecular or immunological level. It is con‐ ceivable that HIV and human microbes have similar ways for interactions. Both direct trans‐ activation of FIV in the simultaneously infected cells (Figure 1) or cross-talk between cells infected by FIV, and other cells infected by heterologous microbes (Figure 2) can take place in the body of cats.

**Figure 1.** Scheme of intracellular virus transactivation

an abnormal pattern. High level of tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and low level of IL-2, IL-12 were frequently observed in the blood of AIDS patients, only to mention the most important ones. Abundant pro-inflammatory cytokines bind to HIV carri‐ er cells and through consequently activated secondary messenger systems activate the same transcriptional factors for HIV activation. This category of interaction has a more significant impact on HIV infection. This phenomenon called as transcellular transactivation can last lifetime, its intensity may vary depending on the host, the other transiently or chronically coinfecting microbes, etc. [3]. These external confounding factors act in a pleiotropic man‐ ner, which is impossible to study *in vitro*. Animal studies are ideal to establish their role in

Feline AIDS (FAIDS) induced by feline immunodeficiency virus (FIV) is the only natural small animal model of human AIDS [4,5-8 ]. FIV shares many genetic, structural and biologi‐ cal characteristics with HIV. FIV also shows tropism for CD4+ immune cells, but its receptor is the CD134 molecule with the CXCR4 coreceptor. FIV LTR accommodates multiple en‐ hancer or promoter protein-binding sites (e.g. NF-κB, AP-1). Although FIV lacks TAT and the TAR element, its Orf-2 (also designated as Orf-A) acts as a transactivator gene to some degree and is necessary for productive FIV replication [7,9]. The similarities in the clinical course of infection between HIV and FIV are striking [6,8,10]. Male gender and adult age are known risk factors for both HIV and FIV transmission [6,7,11,12]. Domestic cats infected with FIV develop progressive immune dysfunction characterised by depletion of CD4+ T cells, wasting, cachexia, gingivostomatitis, neuropathological disorders, opportunistic infec‐ tions, unusual malignancies such as B cell lymphomas, fibrosarcomas [13]. CD4+CD25+hi‐ FoxP3+ immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modu‐ lating virus-specific and inflammatory immune responses. Influence of Treg cell suppres‐ sion during FIV and HIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection [10]. It is important to remember that increased ac‐ tivity of Treg cells promotes immunosenescence in the normal elderly, and AIDS is regarded as an extremely rapid ageing process [14]. Disease progression occurs over a similar time scale to HIV-1 infection in humans [6]. FIV is distributed worldwide; it has several subtypes similarly to HIV [12,15]. Species-specific strains of FIV circulate in many members of *Felidae* family, including endangered big cats in which also induce AIDS-like illnesses [6,12]. Some opportunistic infections in cats also occur worldwide such as feline leukaemia virus (FeLV), feline herpesvirus type 1 (FHV-1), *Toxoplasma gondii* (TG), feline coronavirus (FCoV), *Barto‐ nella henselae* (BH), canine distemper virus (CDV), fungal pathogens or mycoplasmas. Their incidence depends on geographical regions, cat subpopulations (pet, indoor, stray, feral, free-roaming, etc.), gender and age [11,12,16-28]. Incidence of other opportunistic microbes depends on endemic geographical areas and local vectors (e.g. haemoplasma or Leishmania species, different helminths) [16,18,29-33]. Some of these microbes establish coinfection in a

AIDS progression [4].

448 Current Perspectives in HIV Infection

**2. The feline AIDS model**

pesviruses have been implicated as cofactors for AIDS progression, possible interaction of feline herpesvirus 1 (FHV-1, subfamily *Betaherpesvirinae,* a homologue of human cytomega‐ lovirus /CMV/), with FIV has been studied *in vivo* and *in vitro*. FHV-1 might spread in some captive felids with higher frequency than in their free-ranging counterparts demonstrating the importance of human intervention in natural epidemiology [11,29,38]. Single or simulta‐ neous infection by FHV-1 and TG or BH have been implicated as causative agents of feline uveitis [20]. It is of note, that FHV-1 homologue human CMV induces very severe retinitis in HIV infected humans [12], and human CMV was found one of the clinically most frequent and strongest transactivator of HIV. On the contrary to human experience with HSV-1 and adenoviruses [39], FHV-1 could not be implicated in the multifactorial aetiology of gingivitis [24]. FHV-1 also infects T lymphocytes. FHV-1 is a significant pathogen limited to the family *Felidae*, causing an upper respiratory disease in cats. Interaction of acute FHV-1 infection in chronically, experimentally FIV infected specific pathogen-free (SPF) animals results in sev‐ eral immunological abnormalities. FIV infected cats produce less FHV-1 neutralising IgM antibodies during the first 3 weeks of infection than non-FIV infected animals, whereas the IgG antibody response remains unaffected. The ongoing IgG antibody response to FIV is not affected by FHV-1 infection. Lymphocyte blastogenic response to concanavalin A (Con-A) is depressed in FIV-infected and non-infected cats, but response to pokeweed mitogen (PWM) takes longer to return to normal in FIV infected animals. Lymphocytes from FIV infected cats have a greater and more sustained proliferative response to FHV-1 antigen than noninfected cats [40]. Cats with pre-existing FIV infection have more severe signs of disease af‐ ter exposure to FHV-1 or TG, than FIV-free counterparts. Primary immune responses to all heterologous pathogens are delayed or diminished in FIV infected compared with non-FIVinfected animals. Repeated infections have no significant effect on the level of FIV-specific antibodies or on the production of peripheral blood mononuclear cells (PBMC) containing FIV proviral DNA. FIV infected cats exposed to cofactors have normal levels of IL-2R and major histocompatibility complex (MHC)-II antigen expression on PBMCs, while only-FIVinfected animals have upregulated IL-2R and down-regulated MHC-II expression [41]. By transfection of a recombinant plasmid containing the FIV LTR linked to the chloramphenicol acetyltransferase (CAT) gene, followed by infection of FHV-1 into Crandell feline kidney (CrFK) or *Felis catus* whole fetus 4 (fcwf-4) cells enhancement of CAT activity was demon‐ strated. Both immunofluorescence and electron microscopy showed productive coinfection of individual T lymphocytes [42]. A series of FIV LTR deletion mutants were constructed and cotransfected with FHV-1 to identify the regions that are responsible for transactivation. It was demonstrated that sequences between -124 and -79, and between -21 and -32 (relative to the cap site) are essential of FIV replication in fcwf-4 cells and that the sequence between -63 and -23 responds to transactivation of FIV LTR by FHV-1 [43]. FHV-1 infected-cell-pro‐ tein 4 (ICP4) was found to down-regulate FIV LTR directed gene expression via the C/EBP site in the LTR, but after introduction of a site-specific mutation of this site, ICP4 significant‐ ly stimulated LTR. These results indicate that FHV-1 ICP4 possesses both abilities to transac‐ tivate or down-regulate FIV-directed gene expression. C/EBP and AP-1 regulatory sequences are known to act as both positive and negative regulators [44]. Interestingly enough, plasmids expressing ICP4 homologues of Alphaherpesviruses, namely pseudora‐

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

451

**Figure 2.** Scheme of transcellular transactivation

Comparison of human clinical observations on opportunistic infections in HIV infected pa‐ tients and *in vitro* transactivation studies unambiguously demonstrate that several viruses can cause both opportunistic infection and transactivate HIV. The domestic cat is afflicted with multiple microbes that also induce human diseases (e.g. TG, Leishmania, fungi, myco‐ bacteria). Furthermore, domestic cats harbour several feline virus species that are homolo‐ gous to human viruses: FIV, FeLV, FHV, FCV, FCoV, as well as feline sarcoma virus, feline parvovirus, feline morbillivirus [12]. These feline microbe species provide a panoply of in‐ fectious disease models for many devastating human diseases including for studies on the possible interaction between retroviruses and heterologous microbes among natural condi‐ tions of FAIDS at molecular, immunological, cellular level in any organ or the whole body of infected cats by any available methodology.

### **3. Simultaneous infections: Both opportunists and transactivators**

#### **3.1. Feline herpesvirus**

Simultaneous infection by retroviruses and heterogenous microbes and their association with a variety of diseases have come into focus recently. The very sensitive methods to de‐ tect nucleic acids of microbes have promoted our understanding that microbial interaction may result in the synergistic induction of more severe disease course. Retroviruses and her‐ pesviruses might be associated with a variety of diseases in animals. Coinfection of chickens with Marek's disease virus (*Gammaherpesvirinae*) and retrovirus (avian leukosis virus) in‐ crease the incidence of retrovirus associated tumours [37]. As several species of human her‐

pesviruses have been implicated as cofactors for AIDS progression, possible interaction of feline herpesvirus 1 (FHV-1, subfamily *Betaherpesvirinae,* a homologue of human cytomega‐ lovirus /CMV/), with FIV has been studied *in vivo* and *in vitro*. FHV-1 might spread in some captive felids with higher frequency than in their free-ranging counterparts demonstrating the importance of human intervention in natural epidemiology [11,29,38]. Single or simulta‐ neous infection by FHV-1 and TG or BH have been implicated as causative agents of feline uveitis [20]. It is of note, that FHV-1 homologue human CMV induces very severe retinitis in HIV infected humans [12], and human CMV was found one of the clinically most frequent and strongest transactivator of HIV. On the contrary to human experience with HSV-1 and adenoviruses [39], FHV-1 could not be implicated in the multifactorial aetiology of gingivitis [24]. FHV-1 also infects T lymphocytes. FHV-1 is a significant pathogen limited to the family *Felidae*, causing an upper respiratory disease in cats. Interaction of acute FHV-1 infection in chronically, experimentally FIV infected specific pathogen-free (SPF) animals results in sev‐ eral immunological abnormalities. FIV infected cats produce less FHV-1 neutralising IgM antibodies during the first 3 weeks of infection than non-FIV infected animals, whereas the IgG antibody response remains unaffected. The ongoing IgG antibody response to FIV is not affected by FHV-1 infection. Lymphocyte blastogenic response to concanavalin A (Con-A) is depressed in FIV-infected and non-infected cats, but response to pokeweed mitogen (PWM) takes longer to return to normal in FIV infected animals. Lymphocytes from FIV infected cats have a greater and more sustained proliferative response to FHV-1 antigen than noninfected cats [40]. Cats with pre-existing FIV infection have more severe signs of disease af‐ ter exposure to FHV-1 or TG, than FIV-free counterparts. Primary immune responses to all heterologous pathogens are delayed or diminished in FIV infected compared with non-FIVinfected animals. Repeated infections have no significant effect on the level of FIV-specific antibodies or on the production of peripheral blood mononuclear cells (PBMC) containing FIV proviral DNA. FIV infected cats exposed to cofactors have normal levels of IL-2R and major histocompatibility complex (MHC)-II antigen expression on PBMCs, while only-FIVinfected animals have upregulated IL-2R and down-regulated MHC-II expression [41]. By transfection of a recombinant plasmid containing the FIV LTR linked to the chloramphenicol acetyltransferase (CAT) gene, followed by infection of FHV-1 into Crandell feline kidney (CrFK) or *Felis catus* whole fetus 4 (fcwf-4) cells enhancement of CAT activity was demon‐ strated. Both immunofluorescence and electron microscopy showed productive coinfection of individual T lymphocytes [42]. A series of FIV LTR deletion mutants were constructed and cotransfected with FHV-1 to identify the regions that are responsible for transactivation. It was demonstrated that sequences between -124 and -79, and between -21 and -32 (relative to the cap site) are essential of FIV replication in fcwf-4 cells and that the sequence between -63 and -23 responds to transactivation of FIV LTR by FHV-1 [43]. FHV-1 infected-cell-pro‐ tein 4 (ICP4) was found to down-regulate FIV LTR directed gene expression via the C/EBP site in the LTR, but after introduction of a site-specific mutation of this site, ICP4 significant‐ ly stimulated LTR. These results indicate that FHV-1 ICP4 possesses both abilities to transac‐ tivate or down-regulate FIV-directed gene expression. C/EBP and AP-1 regulatory sequences are known to act as both positive and negative regulators [44]. Interestingly enough, plasmids expressing ICP4 homologues of Alphaherpesviruses, namely pseudora‐

**Figure 2.** Scheme of transcellular transactivation

450 Current Perspectives in HIV Infection

infected cats by any available methodology.

**3.1. Feline herpesvirus**

Comparison of human clinical observations on opportunistic infections in HIV infected pa‐ tients and *in vitro* transactivation studies unambiguously demonstrate that several viruses can cause both opportunistic infection and transactivate HIV. The domestic cat is afflicted with multiple microbes that also induce human diseases (e.g. TG, Leishmania, fungi, myco‐ bacteria). Furthermore, domestic cats harbour several feline virus species that are homolo‐ gous to human viruses: FIV, FeLV, FHV, FCV, FCoV, as well as feline sarcoma virus, feline parvovirus, feline morbillivirus [12]. These feline microbe species provide a panoply of in‐ fectious disease models for many devastating human diseases including for studies on the possible interaction between retroviruses and heterologous microbes among natural condi‐ tions of FAIDS at molecular, immunological, cellular level in any organ or the whole body of

**3. Simultaneous infections: Both opportunists and transactivators**

Simultaneous infection by retroviruses and heterogenous microbes and their association with a variety of diseases have come into focus recently. The very sensitive methods to de‐ tect nucleic acids of microbes have promoted our understanding that microbial interaction may result in the synergistic induction of more severe disease course. Retroviruses and her‐ pesviruses might be associated with a variety of diseases in animals. Coinfection of chickens with Marek's disease virus (*Gammaherpesvirinae*) and retrovirus (avian leukosis virus) in‐ crease the incidence of retrovirus associated tumours [37]. As several species of human her‐

bies virus (PRV) and equine herpesvirus type 1 (EHV-1) could significantly inhibit FIV LTRdirected gene expression in CrFK and fcwf-4 cells. Moreover, the ICP4 homologues also exhibited a marked suppressive effect on FIV replication in CrFK cells cotransfected with an infectious clone of FIV [45]. These experiments drow attention to the role of other herpesvi‐ ruses, among them Roseoloviruses [46], which might exist in cats. Similarities and differen‐ ces between the human or feline AIDS could help elucidating their devastating role in human and feline patients.

sion [12,28]. There are four naturally occurring exogenous FeLV strains: FeLV-A, -B, -C, and –T. FeLV-A is the predominant subgroup circulating in feral cats. Its integrated proviral se‐ quences are transmitted vertically through the germ line. Recombination might occur be‐ tween FeLV-A and other subgroups. The outcome after exposure depends on several host and environmental factors, but the clinical course is more aggressive than seen with FIV. In approximately one third of exposed cats, viraemia is persistent and eventually results in clinical disorders such as immunosuppression, bone marrow suppression (mainly anaemia), and neoplasm (mainly lymphoma) [12,19]. Like FIV, FeLV infection alone also renders the animals more susceptible to infection, persistence and disease elicited by heterologous mi‐ crobes [19,28,33] such as TG [21] or BH [36]. Mortality among persistently FeLV infected cats is high as 83% die within 3.5 years [references in 12]. About 10 to 15% of the cats that are clinically ill with FIV infection are coinfected with FeLV worldwide [59,60]. Upon superin‐ fection with FIV, asymptomatic cats with persistent FeLV infection manifest a more acceler‐ ate and exacerbated FIV disease, anticipated death and show a higher FIV load in lymphoid tissues than did naive cats under both natural and experimental conditions, while the blood level of FeLV p27 antigen was not elevated. Interestingly, the synergy between FIV and FeLV is bidirectional: doubly infected cats develop FeLV induced tumours more frequently than did cats infected with either virus alone [61]. Dually infected cats remain more leuko‐ penic than cats infected with FIV or FeLV alone, and their CD4+/CD8+ T lymphocyte ratios become rapidly inverted [62]. This interrelationship is similar to what has been described for

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

453

Scarce data are available on the possible effect on FIV and FAIDS exerted by feline bacterial infections. *Listeria monocytogenes* (LM) can infect both humans and cats, and its profound im‐ munomodulatory capabilities are well known. Beside HIV, both FIV and LM impair the in‐ nate immune response that fails to gain control of their replication prior to the adaptive immune response. These effects might be additive or synergistic in simultaneously infected individuals. In a series of recent experiments, chronically FIV infected and SPF control cats were challenged with LM, then their whole blood and lymph nodes were collected 3 days after challenge. The number and functions of natural killer (NK) cells (CD3-CD56+), NKT cells (CD3+CD56+), CD4 (CD3+CD4+), CD8 (CD3+CD8+), regulatory T cells (CD4+CD25+Fox3+) and Langerhans cells (CD1a) were evaluated. NK, NKT, CD4+ and CD8+ T cells in the LM challenged lymph node of FIV-infected cats did not increase in num‐ ber, NK cells did not increase their proliferation, apoptosis was elevated, and perforin ex‐ pression was not upregulated when compared to SPF control animals. No difference in Treg cell number was found. Delayed control and clearance of opportunistic LM was also ob‐ served. In the blood compartment of LM challenged cats, CD4+ T cell proliferation did not differ in SPF-control and FIV positive cats, while CD8+ T cell proliferation increased in FIVpositive animals. The number of Langerhans cells did not decrease in FIV and LM infected animals, but their ability to produce NK-activating IL-15 and other mediators became im‐ paired. Although it is concluded that FIV-infected cats are more vulnerable to LM superin‐ fection [2], it is conceivable that precedent or ongoing Listeria infection diminishes the

HIV and HTLV-I [63].

**3.4. Simultaneous Listeria and FIV infection**

### **3.2. Feline adenovirus**

Among other DNA viruses, adenovirus (AdV) also might enhance AIDS progression in cats. So far, the only feline adenovirus (FeAdV) isolate (also the first one from the family *Felidae*) was obtained from a fecal sample of a cat with AdV PCR positivity [47] and unknown FIV serostatus [48]. Its hexon [49], fiber [50], and nucleotide sequences published so far suggest that it might be related to human AdV type 1 (HAdV-1). Similar nucleotide sequences have been shown in the feces of a small child suffering with gastroenteritis and her cat in Japan [51], and in one nasopharyngeal aspirate sample of a 468 member cohort of children present‐ ing acute respiratory disease in Brazil [52]. This virus might be widespread all over the world and one can speculate that it could transactivate both HIV and FIV, e.g. in pet owners. Seroepidemiological studies show that approx. 10-20% of free roaming cats are seropositive in Hungary and Europe [53,54]. In a series of consecutive transfer of FIV by intravenous in‐ oculation of experimental SPF casts, four were AdV seropositive, but their serostatus before FIV inoculation remained unknown. One can speculate that accidental transfer of AdV along with FIV occurred [55]. FeAdV would be ideal to compare its unique clinical and mo‐ lecular effects in the human and the cat both *in vivo* and *in vitro* similarly to studies on the interaction of HHV-6 and SIV in humans and pig-tailed macaques [56,57]. As it was isolated from cat feces, one could use FeAdV and FIV to model intestinal molecular interaction of HAdVs and HIV.

#### **3.3. Feline leukaemia virus**

Another common interaction in nature is between FIV infection and FeLV. FeLV is of partic‐ ular significance because it can also induce immunodeficiency [58]. FeLV is a homologue of human T lymphotropic virus (HTLV). It displays a prevalence of 1-8% worldwide [16,24,33,38], but in some geographical areas much higher prevalence of FeLV antigen has been detected (14.2% in Iran, [21], 24.5% in Thailand, [18], 26% in Portugal, [28]). In catteries its prevalence could be much lower or up to zero [17,26,30,32]. Its prevalence has been de‐ creasing in most countries and is regarded as a less important deadly infectious agent in the last 20 years compared to FIV [19]. In confined geographical regions or among captive ani‐ mals in different facilities, simultaneous decline in the seroprevalence of both FeLV and FIV has also been observed [29,33]. Seroprevalence is higher in intact males than females, and increases with age [17,18]. Transmission is usually by direct contact or saliva wounds. FeLV infection among non-domestic cats of the *Felidae* family is rare, but FeLV has been shown to cross species barriers, especially in case of prior or simultaneous microbial immunosuppres‐ sion [12,28]. There are four naturally occurring exogenous FeLV strains: FeLV-A, -B, -C, and –T. FeLV-A is the predominant subgroup circulating in feral cats. Its integrated proviral se‐ quences are transmitted vertically through the germ line. Recombination might occur be‐ tween FeLV-A and other subgroups. The outcome after exposure depends on several host and environmental factors, but the clinical course is more aggressive than seen with FIV. In approximately one third of exposed cats, viraemia is persistent and eventually results in clinical disorders such as immunosuppression, bone marrow suppression (mainly anaemia), and neoplasm (mainly lymphoma) [12,19]. Like FIV, FeLV infection alone also renders the animals more susceptible to infection, persistence and disease elicited by heterologous mi‐ crobes [19,28,33] such as TG [21] or BH [36]. Mortality among persistently FeLV infected cats is high as 83% die within 3.5 years [references in 12]. About 10 to 15% of the cats that are clinically ill with FIV infection are coinfected with FeLV worldwide [59,60]. Upon superin‐ fection with FIV, asymptomatic cats with persistent FeLV infection manifest a more acceler‐ ate and exacerbated FIV disease, anticipated death and show a higher FIV load in lymphoid tissues than did naive cats under both natural and experimental conditions, while the blood level of FeLV p27 antigen was not elevated. Interestingly, the synergy between FIV and FeLV is bidirectional: doubly infected cats develop FeLV induced tumours more frequently than did cats infected with either virus alone [61]. Dually infected cats remain more leuko‐ penic than cats infected with FIV or FeLV alone, and their CD4+/CD8+ T lymphocyte ratios become rapidly inverted [62]. This interrelationship is similar to what has been described for HIV and HTLV-I [63].

#### **3.4. Simultaneous Listeria and FIV infection**

bies virus (PRV) and equine herpesvirus type 1 (EHV-1) could significantly inhibit FIV LTRdirected gene expression in CrFK and fcwf-4 cells. Moreover, the ICP4 homologues also exhibited a marked suppressive effect on FIV replication in CrFK cells cotransfected with an infectious clone of FIV [45]. These experiments drow attention to the role of other herpesvi‐ ruses, among them Roseoloviruses [46], which might exist in cats. Similarities and differen‐ ces between the human or feline AIDS could help elucidating their devastating role in

Among other DNA viruses, adenovirus (AdV) also might enhance AIDS progression in cats. So far, the only feline adenovirus (FeAdV) isolate (also the first one from the family *Felidae*) was obtained from a fecal sample of a cat with AdV PCR positivity [47] and unknown FIV serostatus [48]. Its hexon [49], fiber [50], and nucleotide sequences published so far suggest that it might be related to human AdV type 1 (HAdV-1). Similar nucleotide sequences have been shown in the feces of a small child suffering with gastroenteritis and her cat in Japan [51], and in one nasopharyngeal aspirate sample of a 468 member cohort of children present‐ ing acute respiratory disease in Brazil [52]. This virus might be widespread all over the world and one can speculate that it could transactivate both HIV and FIV, e.g. in pet owners. Seroepidemiological studies show that approx. 10-20% of free roaming cats are seropositive in Hungary and Europe [53,54]. In a series of consecutive transfer of FIV by intravenous in‐ oculation of experimental SPF casts, four were AdV seropositive, but their serostatus before FIV inoculation remained unknown. One can speculate that accidental transfer of AdV along with FIV occurred [55]. FeAdV would be ideal to compare its unique clinical and mo‐ lecular effects in the human and the cat both *in vivo* and *in vitro* similarly to studies on the interaction of HHV-6 and SIV in humans and pig-tailed macaques [56,57]. As it was isolated from cat feces, one could use FeAdV and FIV to model intestinal molecular interaction of

Another common interaction in nature is between FIV infection and FeLV. FeLV is of partic‐ ular significance because it can also induce immunodeficiency [58]. FeLV is a homologue of human T lymphotropic virus (HTLV). It displays a prevalence of 1-8% worldwide [16,24,33,38], but in some geographical areas much higher prevalence of FeLV antigen has been detected (14.2% in Iran, [21], 24.5% in Thailand, [18], 26% in Portugal, [28]). In catteries its prevalence could be much lower or up to zero [17,26,30,32]. Its prevalence has been de‐ creasing in most countries and is regarded as a less important deadly infectious agent in the last 20 years compared to FIV [19]. In confined geographical regions or among captive ani‐ mals in different facilities, simultaneous decline in the seroprevalence of both FeLV and FIV has also been observed [29,33]. Seroprevalence is higher in intact males than females, and increases with age [17,18]. Transmission is usually by direct contact or saliva wounds. FeLV infection among non-domestic cats of the *Felidae* family is rare, but FeLV has been shown to cross species barriers, especially in case of prior or simultaneous microbial immunosuppres‐

human and feline patients.

**3.2. Feline adenovirus**

452 Current Perspectives in HIV Infection

HAdVs and HIV.

**3.3. Feline leukaemia virus**

Scarce data are available on the possible effect on FIV and FAIDS exerted by feline bacterial infections. *Listeria monocytogenes* (LM) can infect both humans and cats, and its profound im‐ munomodulatory capabilities are well known. Beside HIV, both FIV and LM impair the in‐ nate immune response that fails to gain control of their replication prior to the adaptive immune response. These effects might be additive or synergistic in simultaneously infected individuals. In a series of recent experiments, chronically FIV infected and SPF control cats were challenged with LM, then their whole blood and lymph nodes were collected 3 days after challenge. The number and functions of natural killer (NK) cells (CD3-CD56+), NKT cells (CD3+CD56+), CD4 (CD3+CD4+), CD8 (CD3+CD8+), regulatory T cells (CD4+CD25+Fox3+) and Langerhans cells (CD1a) were evaluated. NK, NKT, CD4+ and CD8+ T cells in the LM challenged lymph node of FIV-infected cats did not increase in num‐ ber, NK cells did not increase their proliferation, apoptosis was elevated, and perforin ex‐ pression was not upregulated when compared to SPF control animals. No difference in Treg cell number was found. Delayed control and clearance of opportunistic LM was also ob‐ served. In the blood compartment of LM challenged cats, CD4+ T cell proliferation did not differ in SPF-control and FIV positive cats, while CD8+ T cell proliferation increased in FIVpositive animals. The number of Langerhans cells did not decrease in FIV and LM infected animals, but their ability to produce NK-activating IL-15 and other mediators became im‐ paired. Although it is concluded that FIV-infected cats are more vulnerable to LM superin‐ fection [2], it is conceivable that precedent or ongoing Listeria infection diminishes the activity of NK cells, helps promote FIV replication and dissemination in the body of ani‐ mals. In HIV-infected patients, dysfunction of NK cells with low perforin expression, aner‐ gy, furthermore, abnormal antigen presentation and low level of IL-15, IL-12 levels are also known [2]. In humans, infection by LM or other bacteria with immunosuppressive potential might augment impaired immunosurveillance, consequently increase HIV load, and ulti‐ mately facilitate AIDS progression.

**3.6. Feline mycobacteria**

other lymphoid cultures [3].

ideal models to study such aspects.

Mycobacteria are important opportunistic infections in HIV infected patients worldwide. Es‐ pecially in Sub-Saharan Africa very aggressive forms of tuberculosis occur in the immuno‐ compromised population induced by several mycobacterium species. Mycobacteria severely suppress activities of the cellular immune reactions but due to the difficulties in their culti‐ vation and the chronic nature of the disease, it is extremely difficult to study their mutual effects on the immune system. Several mycobacterium species that infect the human and are prevalent in HIV infected patients (*e.g. M. bovis, M. avium, M. microti*), induce disease in cats [23]. This finding raises the idea that FAIDS would be an appropriate model to study inti‐

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

455

Repeated exposure of FIV positive cats to bacterial lipopolysaccharide endotoxin (LPS) re‐ sulted in lower plasma and brain viremia. In HIV infected humans and FIV infected cats, macrophages produce elevated amount of specific chemokine CXCL10, which in turn dam‐ ages brain cells. LPS treatment of infected macrophages release IL-10 counteracting CXCL10 expression of brain cells. Suppressed CXCL10 level in the brain of FIV-positive cats and en‐ suing T cell infiltration is concomitant with reduction in neurovirulence [71]. This observa‐ tion is in correlation with earlier results, namely that LPS treatment of HHV-6A infected lymphoid cells decrease expression of such soluble mediators that transactivate HIV-1 in

Humans and cats can be infected by several common fungal pathogens, such as Cryptococ‐ cus [22], Malassezia, Microsporum [26] and others [28]. Dermatophyte fungi were isolated in 29.4% from stray cats in Portugal [28]. *Microsporum gypseum* and, occasionally, *M. canis* were found in an equal ratio of FIV negative and positive cats (8 and 8.5%, respectively). In con‐ trast, Malassezia species were more frequently isolated from FIV infected cats than FIV-un‐ infected cats (84% vs. 28.6%) thus showing a closer biological relationship in the effect of FIV and certain fungal species. The CD4:CD8 ratio for FIV infected cats with cutaneous overall fungal infection was significantly lower than the CD4:CD8 ratio in the FIV infected cats but without cutaneous fungal infection. It is obvious that worsening cellular immunity repre‐ sents a risk factor to cutaneous fungal colonisation in cats [26], but existence of a cutaneous or systematic fungal infection due to insufficient activity of the cellular immunity acquired by inherent or environmental effects might also make easier to acquire FIV infection. Dam‐ aged local immunity in the skin in case of wound FIV infection could be one of the most frequent examples. Cats having human or human homologues of fungal species would be

Cats having access to the outdoor world, very easily acquire parasitic infections. Feral cats can serve as a direct or indirect source of infectious diseases for pet cats. Contact with ani‐ mals of other species, conditions of breeding, food supply and age are considered significant for infections. A recent study conducted in a Brazilian cat colony free from FIV, FeLV and *Neospora caninum* infection, clearly showed these differences. Of cats from urban and rural areas, 10.4% and 27.2% were seropositive for TG, respectively. Cats having access to streets

mate relationship between mycobacteria and feline retroviruses *in vivo*.

**3.7. Fungal and parasitic infections in FIV infected cats**

#### **3.5. Feline haemotropic mycoplasmas (haemoplasmas)**

Epidemiological surveys on simultaneous infections by FIV and feline haemophilic myco‐ plasmas suggest that opportunistic infections also promote FIV progression. Feline haemo‐ philic mycoplasmas (*Mycoplasma haemofelis, Candidatus Mycoplasma haemominutus*) collectively called haemoplasmas can cause anaemia and severe clinical disease of affected cats. *Candidatus Mycoplasma haemominutus* (CMH) is usually not associated with clinical dis‐ ease, but typically causes anaemia in cats carrying pre-existing FIV or FeLV infection [29,64,65]. Chronic FIV infection appears to modify the acute phase response to feline hae‐ motropic mycoplasmas, which varies with the infecting haemoplasma species, namely CMH and *M. haemofelis* (MH), respectively [64]. A recent study in a Canadian feral cat population found that CMH positive cats were significantly more likely to be concurrently retrovirus positive than were CMH negative animals [33]. Another recent study in Spain found that, FIV seropositivity and male sex were significantly associated with MH, CMH and *Ca. M. tu‐ ricensis* infection [27]. It is of note, that mycoplasmas in HIV infected patients have been re‐ garded as AIDS promoting factors for a long time, and this phenomenon was proved *in vitro*, either [66]. A meta-analysis of former studies unambiguously demonstrated that geni‐ tal infection by *M. genitalium* poses high risk for acquisition of HIV. Testing and treatment of *M. genitalium*-positive individuals in high risk groups is recommended as a potential HIV prevention strategy [67]. Bacterial vaginosis-associated microflora in the female genital tract also predisposes for HIV infection. Among flora members, *M. hominis* was shown to activate NF-κB and AP-1. Through mediation of a soluble HIV inducing factor (HIF), these transcrip‐ tional factors may subsequently increase genital tract viral load and potentially contribute to HIV transmission [68]. MH infection along with BH infection has been verified by PCR in an HIV infected person [69]. The 34 year old man owned several cats. Haemoplasma DNA is present in saliva and feces of cats, which suggests that aggressive interactions among cats and humans involving biting may lead to transmission of the organism. So far, haemotropic mycoplasma infections have been reported in a patient with systemic lupus erythematosus (SLE) and in an anaemic patient showing that some forms of immunosuppression are re‐ quired for acquisition of an unusual pathogen [70]. Increasing number of human patients with compromised immune systems living near cats increases the possibility that haemo‐ plasma infections may emerge in this population [69]. Haemoplasma positive cats like my‐ coplasma positive humans ought to be regarded at increased risk for retrovirus infection. Testing would also be appropriate prior to relocation of felids [29]. Feline mycoplasmas could provide a unique model to clarify the exact role of mycoplasmas in AIDS progression.

#### **3.6. Feline mycobacteria**

activity of NK cells, helps promote FIV replication and dissemination in the body of ani‐ mals. In HIV-infected patients, dysfunction of NK cells with low perforin expression, aner‐ gy, furthermore, abnormal antigen presentation and low level of IL-15, IL-12 levels are also known [2]. In humans, infection by LM or other bacteria with immunosuppressive potential might augment impaired immunosurveillance, consequently increase HIV load, and ulti‐

Epidemiological surveys on simultaneous infections by FIV and feline haemophilic myco‐ plasmas suggest that opportunistic infections also promote FIV progression. Feline haemo‐ philic mycoplasmas (*Mycoplasma haemofelis, Candidatus Mycoplasma haemominutus*) collectively called haemoplasmas can cause anaemia and severe clinical disease of affected cats. *Candidatus Mycoplasma haemominutus* (CMH) is usually not associated with clinical dis‐ ease, but typically causes anaemia in cats carrying pre-existing FIV or FeLV infection [29,64,65]. Chronic FIV infection appears to modify the acute phase response to feline hae‐ motropic mycoplasmas, which varies with the infecting haemoplasma species, namely CMH and *M. haemofelis* (MH), respectively [64]. A recent study in a Canadian feral cat population found that CMH positive cats were significantly more likely to be concurrently retrovirus positive than were CMH negative animals [33]. Another recent study in Spain found that, FIV seropositivity and male sex were significantly associated with MH, CMH and *Ca. M. tu‐ ricensis* infection [27]. It is of note, that mycoplasmas in HIV infected patients have been re‐ garded as AIDS promoting factors for a long time, and this phenomenon was proved *in vitro*, either [66]. A meta-analysis of former studies unambiguously demonstrated that geni‐ tal infection by *M. genitalium* poses high risk for acquisition of HIV. Testing and treatment of *M. genitalium*-positive individuals in high risk groups is recommended as a potential HIV prevention strategy [67]. Bacterial vaginosis-associated microflora in the female genital tract also predisposes for HIV infection. Among flora members, *M. hominis* was shown to activate NF-κB and AP-1. Through mediation of a soluble HIV inducing factor (HIF), these transcrip‐ tional factors may subsequently increase genital tract viral load and potentially contribute to HIV transmission [68]. MH infection along with BH infection has been verified by PCR in an HIV infected person [69]. The 34 year old man owned several cats. Haemoplasma DNA is present in saliva and feces of cats, which suggests that aggressive interactions among cats and humans involving biting may lead to transmission of the organism. So far, haemotropic mycoplasma infections have been reported in a patient with systemic lupus erythematosus (SLE) and in an anaemic patient showing that some forms of immunosuppression are re‐ quired for acquisition of an unusual pathogen [70]. Increasing number of human patients with compromised immune systems living near cats increases the possibility that haemo‐ plasma infections may emerge in this population [69]. Haemoplasma positive cats like my‐ coplasma positive humans ought to be regarded at increased risk for retrovirus infection. Testing would also be appropriate prior to relocation of felids [29]. Feline mycoplasmas could provide a unique model to clarify the exact role of mycoplasmas in AIDS progression.

mately facilitate AIDS progression.

454 Current Perspectives in HIV Infection

**3.5. Feline haemotropic mycoplasmas (haemoplasmas)**

Mycobacteria are important opportunistic infections in HIV infected patients worldwide. Es‐ pecially in Sub-Saharan Africa very aggressive forms of tuberculosis occur in the immuno‐ compromised population induced by several mycobacterium species. Mycobacteria severely suppress activities of the cellular immune reactions but due to the difficulties in their culti‐ vation and the chronic nature of the disease, it is extremely difficult to study their mutual effects on the immune system. Several mycobacterium species that infect the human and are prevalent in HIV infected patients (*e.g. M. bovis, M. avium, M. microti*), induce disease in cats [23]. This finding raises the idea that FAIDS would be an appropriate model to study inti‐ mate relationship between mycobacteria and feline retroviruses *in vivo*.

Repeated exposure of FIV positive cats to bacterial lipopolysaccharide endotoxin (LPS) re‐ sulted in lower plasma and brain viremia. In HIV infected humans and FIV infected cats, macrophages produce elevated amount of specific chemokine CXCL10, which in turn dam‐ ages brain cells. LPS treatment of infected macrophages release IL-10 counteracting CXCL10 expression of brain cells. Suppressed CXCL10 level in the brain of FIV-positive cats and en‐ suing T cell infiltration is concomitant with reduction in neurovirulence [71]. This observa‐ tion is in correlation with earlier results, namely that LPS treatment of HHV-6A infected lymphoid cells decrease expression of such soluble mediators that transactivate HIV-1 in other lymphoid cultures [3].

### **3.7. Fungal and parasitic infections in FIV infected cats**

Humans and cats can be infected by several common fungal pathogens, such as Cryptococ‐ cus [22], Malassezia, Microsporum [26] and others [28]. Dermatophyte fungi were isolated in 29.4% from stray cats in Portugal [28]. *Microsporum gypseum* and, occasionally, *M. canis* were found in an equal ratio of FIV negative and positive cats (8 and 8.5%, respectively). In con‐ trast, Malassezia species were more frequently isolated from FIV infected cats than FIV-un‐ infected cats (84% vs. 28.6%) thus showing a closer biological relationship in the effect of FIV and certain fungal species. The CD4:CD8 ratio for FIV infected cats with cutaneous overall fungal infection was significantly lower than the CD4:CD8 ratio in the FIV infected cats but without cutaneous fungal infection. It is obvious that worsening cellular immunity repre‐ sents a risk factor to cutaneous fungal colonisation in cats [26], but existence of a cutaneous or systematic fungal infection due to insufficient activity of the cellular immunity acquired by inherent or environmental effects might also make easier to acquire FIV infection. Dam‐ aged local immunity in the skin in case of wound FIV infection could be one of the most frequent examples. Cats having human or human homologues of fungal species would be ideal models to study such aspects.

Cats having access to the outdoor world, very easily acquire parasitic infections. Feral cats can serve as a direct or indirect source of infectious diseases for pet cats. Contact with ani‐ mals of other species, conditions of breeding, food supply and age are considered significant for infections. A recent study conducted in a Brazilian cat colony free from FIV, FeLV and *Neospora caninum* infection, clearly showed these differences. Of cats from urban and rural areas, 10.4% and 27.2% were seropositive for TG, respectively. Cats having access to streets (17.1%), cats cohabiting with rats (19.6%), and cats feeding on homemade food and raw milk (27.2%) were positive for this protozoon. In addition, 4.2% of cats were positive for *Leishma‐ nia spp.* [30]. In several countries, parasitic infections, especially intestinal parasites, of cats are more frequent than infections with FIV or FeLV. In Italy, comparison of FIV, FeLV and TG IgG seropositivity resulted in the same ratio: 6.6%, 3.8% and 30.5%, respectively [11]. Ep‐ idemiological studies in Portugal found 24.2% TG seropositivity, 31% carrier state of intesti‐ nal parasites (*Toxocara cati, Isospora felis, Ankylostoma stenocephala, Toxascaris leonina*) as compared to FIV and FeLV infection (10.2% and 7.1%, respectively) in the same stray cat population [28]. In a confined region of Canada, 29.8% of cats had TG antibodies, 1.3% ex‐ creted oocysts in their feces, while FIV and FeLV seropositivity was significantly lower (5.2% and 3.1%, respectively [33]. In Thailand, although the ratio between retroviral and parasitic infections were different (FIV, FeLV, heartworm (*Dirofilaria immitis*) and TG IgG (20.1%, 24.5%, 4.6% and 10.1%, respectively) from the other data mentioned above, of the 348 cats sampled for all four pathogens, 3.1%, 2.8% and 0.28% were positive for TG antibod‐ ies and FIV antibodies, FeLV antigen or *D. immitis* antigen, respectively. Of the 35 TG sero‐ positive cats, 42.9% were coinfected with at least one of the other three pathogens [18]. Feral cats from Cairo, Egypt exhibited an extremely high ratio of TG infestation as compared to FIV, FeLV of heartworm seroprevalence: 95.5%, 33.9%, 4.6% and 3.4%, respectively. It is of interest that 57.4% of TG positive cats had very high antibody titre (>1:640) [31]. Oocyst shedding was found to be accompanied by high level antibodies: cats shedding TG had high antibody level (>1:256). In the same cat cohort, *Toxocara cati* eggs were identified in 37%, *Cys‐ toisospora felis* oocysts in 14%, *Taenia sp*. segments in 15% of animals. Most of the fecal sam‐ ples showed evidence of at least one intestinal parasite, while many samples contained evidence of multiple intestinal parasites. High prevalence of antibodies reflects latent infec‐ tions. However, it must be emphasized that cats with latent infection can pose a considera‐ ble zoonotic risk with respect to the shedding of intestinal parasites in their feces. Stress conditions induce shedding. Intercurrent retroviral infections (FIV or FeLV or both) with consequent declination in systemic and mucosal immunity are regarded as important stress factors [33]. Result of the multivariate logistic regression analysis of another recent survey on simultaneous virus and parasite seropositivity (FIV, FeLV and TG was 19.2%, 14.2% and 32.1%, respectively) in Iran showed that retroviral-associated immunosuppression is a risk factor for activation of toxoplasmosis in cats [21]. Beside toxoplasmosis, Leishmania infec‐ tion is frequent in many countries. Cellular immunity of normal cats effectively controls *Leishmania infantum* (syn. *L. chagasi*). However, feline immunosuppressive diseases such as FIV and FeLV infection impair the normal response to infection and expose cats to reactiva‐ tion or new infections by other pathogens, among them Leishmania. Although no statistical evidence of association between TG and Leishmania was found, but in cats coinfected with FIV, a strong statistical association for the triple coinfection was found [16]. One can con‐ clude from these epidemiological surveys, that parasites cause not only opportunistic infec‐ tions in retrovirus infected cats, but activation of their latent infection by retroviruses suggests existence of a closer relationship between phylogenetically distant two groups of foreign agents at molecular or immunological level.

Following infection of FIV carrier cats with a secondary pathogen, cytokine dysregulation is more pronounced. TG increases both IFN-γ and IL-10, but fails to increase IL-2, IL-12, while TG infected FIV negative cats show an increase in IFN-γ, IL-2 and IL-12 [72]. A similar dys‐ regulation has been reported in cats challenged with LM [73]. The increase in IL-10 to IL-12 ratio predicts the loss of cellular immunity in FIV infected cats [72,74]. These *in vivo* studies are in good correlation with *in vitro* experiments. Latent infection in HIV or FIV infected lymphocytes and macrophages can be reactivated and virus production can be increased by chemical immune activators such as phorbol myristate acetate [75], concanavalin A [5], granulocyte macrophage-colony stimulating factor [76]. Both HIV and FIV induce apoptosis not only in the infected cells, but in the vicinity of infected cells as well. Programmed cell death of infected cells is mediated mainly by TNF-α released from infected cells [77]. Cyto‐ kine dysregulation affects not only the FIV carrier animal, but damages the fetus by causing a pro-inflammatory placental microenvironment at early pregnancy: increased expression of IL-6, IL-12, decreased expression of IL-1β, SDF-1α. Similarly to AIDS patients, IL-6 expres‐ sion correlated with FIV load [78]. The exact role of cytokines and chemokines in the process

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

457

**4. Diagnosis, treatment and prevention of simultaneous infections**

Preventing exposure of healthy cats to FIV or FeLV infected cats by tests and removal or iso‐ lation is an important measure, and is not alternative to vaccination. The most common method for diagnosis of FIV infection is screening for antibodies (typically against p24 and p15) using an ELISA. Several commercial kits are available worldwide. Confirmatory testing for cats with positive results is strongly recommended, Western-blot and immunofluores‐ cent antibody assays (IFA) are used. Infection from queens can be transmitted to kittens, testing for newly acquired cats and kittens is strongly recommended. Vaccinated cats also produce antibodies that cannot be distinguished, by any commercially available antibody test [79], from antibodies due to natural infection, and queens might transmit these antibod‐ ies to the litter via colostrum. FIV vaccine induces fewer antibodies for non-structural pro‐ teins compared to natural infection. There are tests to discriminate this pattern, but these are unsuitable for routine use. Polymerase chain reaction (PCR) has promoted by some com‐ mercial laboratories as a method to determine a cat's true infection status. The test detects FIV RNA or proviral DNA. A real-time PCR assay for FIV quantification of proviral DNA in PBMC has high sensitivity and specificity. This and reverse transcriptase (RT)-PCR are methods to quantitate viral load and dissemination in the body after activation of latent FIV infection. Due to genetically heterologous nature of FIV, tests with concurrent determination of subtype differentiation are recommended. Serological diagnosis of FeLV relies on detec‐ tion of the core antigen p27 in PBMC using an ELISA. IFA test is also used but discordant results might occur. PCR is offered by a number of commercial laboratories, it can be per‐ formed on blood, saliva, bone marrow and tissues. Kittens can be tested for FeLV at any age, as passively acquired maternal antibody does not interfere with testing for viral antigen.

of simultaneous infections waits for clarification.

Following infection of FIV carrier cats with a secondary pathogen, cytokine dysregulation is more pronounced. TG increases both IFN-γ and IL-10, but fails to increase IL-2, IL-12, while TG infected FIV negative cats show an increase in IFN-γ, IL-2 and IL-12 [72]. A similar dys‐ regulation has been reported in cats challenged with LM [73]. The increase in IL-10 to IL-12 ratio predicts the loss of cellular immunity in FIV infected cats [72,74]. These *in vivo* studies are in good correlation with *in vitro* experiments. Latent infection in HIV or FIV infected lymphocytes and macrophages can be reactivated and virus production can be increased by chemical immune activators such as phorbol myristate acetate [75], concanavalin A [5], granulocyte macrophage-colony stimulating factor [76]. Both HIV and FIV induce apoptosis not only in the infected cells, but in the vicinity of infected cells as well. Programmed cell death of infected cells is mediated mainly by TNF-α released from infected cells [77]. Cyto‐ kine dysregulation affects not only the FIV carrier animal, but damages the fetus by causing a pro-inflammatory placental microenvironment at early pregnancy: increased expression of IL-6, IL-12, decreased expression of IL-1β, SDF-1α. Similarly to AIDS patients, IL-6 expres‐ sion correlated with FIV load [78]. The exact role of cytokines and chemokines in the process of simultaneous infections waits for clarification.

(17.1%), cats cohabiting with rats (19.6%), and cats feeding on homemade food and raw milk (27.2%) were positive for this protozoon. In addition, 4.2% of cats were positive for *Leishma‐ nia spp.* [30]. In several countries, parasitic infections, especially intestinal parasites, of cats are more frequent than infections with FIV or FeLV. In Italy, comparison of FIV, FeLV and TG IgG seropositivity resulted in the same ratio: 6.6%, 3.8% and 30.5%, respectively [11]. Ep‐ idemiological studies in Portugal found 24.2% TG seropositivity, 31% carrier state of intesti‐ nal parasites (*Toxocara cati, Isospora felis, Ankylostoma stenocephala, Toxascaris leonina*) as compared to FIV and FeLV infection (10.2% and 7.1%, respectively) in the same stray cat population [28]. In a confined region of Canada, 29.8% of cats had TG antibodies, 1.3% ex‐ creted oocysts in their feces, while FIV and FeLV seropositivity was significantly lower (5.2% and 3.1%, respectively [33]. In Thailand, although the ratio between retroviral and parasitic infections were different (FIV, FeLV, heartworm (*Dirofilaria immitis*) and TG IgG (20.1%, 24.5%, 4.6% and 10.1%, respectively) from the other data mentioned above, of the 348 cats sampled for all four pathogens, 3.1%, 2.8% and 0.28% were positive for TG antibod‐ ies and FIV antibodies, FeLV antigen or *D. immitis* antigen, respectively. Of the 35 TG sero‐ positive cats, 42.9% were coinfected with at least one of the other three pathogens [18]. Feral cats from Cairo, Egypt exhibited an extremely high ratio of TG infestation as compared to FIV, FeLV of heartworm seroprevalence: 95.5%, 33.9%, 4.6% and 3.4%, respectively. It is of interest that 57.4% of TG positive cats had very high antibody titre (>1:640) [31]. Oocyst shedding was found to be accompanied by high level antibodies: cats shedding TG had high antibody level (>1:256). In the same cat cohort, *Toxocara cati* eggs were identified in 37%, *Cys‐ toisospora felis* oocysts in 14%, *Taenia sp*. segments in 15% of animals. Most of the fecal sam‐ ples showed evidence of at least one intestinal parasite, while many samples contained evidence of multiple intestinal parasites. High prevalence of antibodies reflects latent infec‐ tions. However, it must be emphasized that cats with latent infection can pose a considera‐ ble zoonotic risk with respect to the shedding of intestinal parasites in their feces. Stress conditions induce shedding. Intercurrent retroviral infections (FIV or FeLV or both) with consequent declination in systemic and mucosal immunity are regarded as important stress factors [33]. Result of the multivariate logistic regression analysis of another recent survey on simultaneous virus and parasite seropositivity (FIV, FeLV and TG was 19.2%, 14.2% and 32.1%, respectively) in Iran showed that retroviral-associated immunosuppression is a risk factor for activation of toxoplasmosis in cats [21]. Beside toxoplasmosis, Leishmania infec‐ tion is frequent in many countries. Cellular immunity of normal cats effectively controls *Leishmania infantum* (syn. *L. chagasi*). However, feline immunosuppressive diseases such as FIV and FeLV infection impair the normal response to infection and expose cats to reactiva‐ tion or new infections by other pathogens, among them Leishmania. Although no statistical evidence of association between TG and Leishmania was found, but in cats coinfected with FIV, a strong statistical association for the triple coinfection was found [16]. One can con‐ clude from these epidemiological surveys, that parasites cause not only opportunistic infec‐ tions in retrovirus infected cats, but activation of their latent infection by retroviruses suggests existence of a closer relationship between phylogenetically distant two groups of

456 Current Perspectives in HIV Infection

foreign agents at molecular or immunological level.

### **4. Diagnosis, treatment and prevention of simultaneous infections**

Preventing exposure of healthy cats to FIV or FeLV infected cats by tests and removal or iso‐ lation is an important measure, and is not alternative to vaccination. The most common method for diagnosis of FIV infection is screening for antibodies (typically against p24 and p15) using an ELISA. Several commercial kits are available worldwide. Confirmatory testing for cats with positive results is strongly recommended, Western-blot and immunofluores‐ cent antibody assays (IFA) are used. Infection from queens can be transmitted to kittens, testing for newly acquired cats and kittens is strongly recommended. Vaccinated cats also produce antibodies that cannot be distinguished, by any commercially available antibody test [79], from antibodies due to natural infection, and queens might transmit these antibod‐ ies to the litter via colostrum. FIV vaccine induces fewer antibodies for non-structural pro‐ teins compared to natural infection. There are tests to discriminate this pattern, but these are unsuitable for routine use. Polymerase chain reaction (PCR) has promoted by some com‐ mercial laboratories as a method to determine a cat's true infection status. The test detects FIV RNA or proviral DNA. A real-time PCR assay for FIV quantification of proviral DNA in PBMC has high sensitivity and specificity. This and reverse transcriptase (RT)-PCR are methods to quantitate viral load and dissemination in the body after activation of latent FIV infection. Due to genetically heterologous nature of FIV, tests with concurrent determination of subtype differentiation are recommended. Serological diagnosis of FeLV relies on detec‐ tion of the core antigen p27 in PBMC using an ELISA. IFA test is also used but discordant results might occur. PCR is offered by a number of commercial laboratories, it can be per‐ formed on blood, saliva, bone marrow and tissues. Kittens can be tested for FeLV at any age, as passively acquired maternal antibody does not interfere with testing for viral antigen. Compliance of cat owners with FIV and FeLV testing is low, in spite of using combined test kits, and professional recommendations by veterinarians (Table 1).

ing in endemic areas of certain parasites are significantly more likely to be co-infected with FIV and/or FeLV, which may present confounding clinical signs and therefore cats in such areas should be always carefully screened for coinfections [16]. Occasionally, knowing the cat's geographical location can be helpful, while the nature of the clinical presentation might be less informative [23]. Informations concerning risk assessment of viral pathogens to other animal populations are currently an important issue [28]. Screening for multiple infections is appropriate prior to relocation of cats and other felids to prevent introduction of pathogens in host colonies (households, catteries, zoos, national parks, etc.) [29]. As with HIV, careful consideration should also be given to systematic testing and treatment of individuals in high-risk populations, and this may prove to be a potential strategy to prevent FIV transmis‐ sion [67]. Preventive measures are important, because transmission of pathogens in cluster conditions may occur between asymptomatic cats and immunocompromised animals [25,32]. Furthermore, certain FIV or FeLV strains are able to emerge in new host species. Do‐ mestic cat strains of viruses can cross species barriers with potentially devastating conse‐ quences to fragile populations of large felids [12]. As seen with feline haemoplasma, it could infect even the immunocompromised human cat owner [69] so; cat owners ought to be pro‐

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

459

While testing and identification of infected cats is necessary for prevention and transmis‐ sion, vaccination is also an important tool. Various independent bodies, including the Inter‐ national Vaccination Guidelines Group (IVGG), the European Advisory Board on Cat Diseases (ABCD), the World Small Animal Veterinary Association (WSAVA), or the Ameri‐ can Association of Feline Practitioners (AAFP) have developed and regularly issues recom‐ mendations for vaccination protocols for cats and kittens. The guidelines encompass the types of antigens used, the types of vaccines available, the frequency of vaccination and the anatomical site used for administration. These guidelines differ from each other and also from the manufacturer's datasheets or recommendations of national authorities. General as‐ pects and details of vaccination of cats are far beyond the scope of recent review; in this re‐ gard see a recent publication by Dean et al. 2012. Core vaccines are defined as those vaccines which all cats, regardless of circumstances, should receive to protect animals from severe, life threatening diseases which have global distribution. Only to emphasize those in context with microbes with transactivating and opportunistic potential, FHV-1 vaccination of kittens seems to be important. Vaccination against FCV, FPV also belongs to core vaccines. These vaccinations are recommended to start as early as vaccination with FeLV, applying revacci‐ nations up to 16-20 weeks of age. Most practices routinely give the commonly used antigens annually, although with the exception of the FHV, the FCV and FIV vaccination is recom‐ mended every 3 years [80]. Non-core vaccines are those that are required by only those ani‐ mals whose geographic location, local environment or lifestyle place them at risk of contracting specific infections. This moment, both FIV and FeLV vaccines are regarded as non-core. FIV vaccine development was initiated as a model for HIV vaccination. Vaccina‐ tion against HIV started with experiments to trigger a specific, potent and long-lasting im‐ munity in a surrogate animal model. Later, several novel approaches were tested in the feline model. Although the quest for a truly effective AIDS vaccine is years away [81], vacci‐ nation against FIV became available [82]. This vaccine (Fel-O-Vax FIV®) is marketed in many

tected from common zoonotic infections.


**Table 1.** Major recommendations for FIV and FeLV testing of cats

The owner must also consider the cost of immunisation, fecal parasite testing, de-worming, or blood screening to reveal and eliminate concomitant infections [17]. Further commercially available kits for serological screening, and/or antigen detection including FHV-1 and the most pathogens are widely available for domestic and large cats. These kits used separately depending on the clinical course of the animal can be combined in definitively. Well estab‐ lished, cheap but somewhat laborious and time consuming classical methods have been used for direct detection of common bacteria, fungi and parasites (cultivation, biochemistry, microscopy, etc.). For feline pathogens causing infection in humans, the same methods and kits can be used as in human medicine. With technological advances quantitative real-time or RT-PCR assays have been used subsequently their products are sequenced to determine species or variants. Load of viruses in body fluids can be determined by quantitative molec‐ ular methods [5,7,24,36]. Simultaneous detection of nucleic acids of coinfecting microbes would be ideal by using multiple PCR [20, 29]. Development of easily available panels is a financial interest of biotechnology companies. Gene arrays capable of detecting even hun‐ dreds of microbes at nucleic acid level could also be marketed in near future.

Aims of detecting simultaneous infection in cats and large felids are very variable. As retro‐ viral infection might represent a considerable risk factor to several bacterial, fungal and par‐ asitic opportunistic infections and activating potential of their latency, demonstration of retroviruses ought to be followed by screening for other pathogens [21]. Vice versa, cats liv‐ ing in endemic areas of certain parasites are significantly more likely to be co-infected with FIV and/or FeLV, which may present confounding clinical signs and therefore cats in such areas should be always carefully screened for coinfections [16]. Occasionally, knowing the cat's geographical location can be helpful, while the nature of the clinical presentation might be less informative [23]. Informations concerning risk assessment of viral pathogens to other animal populations are currently an important issue [28]. Screening for multiple infections is appropriate prior to relocation of cats and other felids to prevent introduction of pathogens in host colonies (households, catteries, zoos, national parks, etc.) [29]. As with HIV, careful consideration should also be given to systematic testing and treatment of individuals in high-risk populations, and this may prove to be a potential strategy to prevent FIV transmis‐ sion [67]. Preventive measures are important, because transmission of pathogens in cluster conditions may occur between asymptomatic cats and immunocompromised animals [25,32]. Furthermore, certain FIV or FeLV strains are able to emerge in new host species. Do‐ mestic cat strains of viruses can cross species barriers with potentially devastating conse‐ quences to fragile populations of large felids [12]. As seen with feline haemoplasma, it could infect even the immunocompromised human cat owner [69] so; cat owners ought to be pro‐ tected from common zoonotic infections.

Compliance of cat owners with FIV and FeLV testing is low, in spite of using combined test

known exposure to retrovirus infected cats

kits, and professional recommendations by veterinarians (Table 1).

458 Current Perspectives in HIV Infection

**At risk of infection**

cats access to outdoors

multicat environment

**Cats entering new homes, shelters**

**Newly acquired cats and kittens about to be**

The owner must also consider the cost of immunisation, fecal parasite testing, de-worming, or blood screening to reveal and eliminate concomitant infections [17]. Further commercially available kits for serological screening, and/or antigen detection including FHV-1 and the most pathogens are widely available for domestic and large cats. These kits used separately depending on the clinical course of the animal can be combined in definitively. Well estab‐ lished, cheap but somewhat laborious and time consuming classical methods have been used for direct detection of common bacteria, fungi and parasites (cultivation, biochemistry, microscopy, etc.). For feline pathogens causing infection in humans, the same methods and kits can be used as in human medicine. With technological advances quantitative real-time or RT-PCR assays have been used subsequently their products are sequenced to determine species or variants. Load of viruses in body fluids can be determined by quantitative molec‐ ular methods [5,7,24,36]. Simultaneous detection of nucleic acids of coinfecting microbes would be ideal by using multiple PCR [20, 29]. Development of easily available panels is a financial interest of biotechnology companies. Gene arrays capable of detecting even hun‐

**Cats used for blood or tissue donation**

dreds of microbes at nucleic acid level could also be marketed in near future.

Aims of detecting simultaneous infection in cats and large felids are very variable. As retro‐ viral infection might represent a considerable risk factor to several bacterial, fungal and par‐ asitic opportunistic infections and activating potential of their latency, demonstration of retroviruses ought to be followed by screening for other pathogens [21]. Vice versa, cats liv‐

bite wounds

oral disease

**vaccinated for FIV or FeLV**

**Sick cats**

**Table 1.** Major recommendations for FIV and FeLV testing of cats

While testing and identification of infected cats is necessary for prevention and transmis‐ sion, vaccination is also an important tool. Various independent bodies, including the Inter‐ national Vaccination Guidelines Group (IVGG), the European Advisory Board on Cat Diseases (ABCD), the World Small Animal Veterinary Association (WSAVA), or the Ameri‐ can Association of Feline Practitioners (AAFP) have developed and regularly issues recom‐ mendations for vaccination protocols for cats and kittens. The guidelines encompass the types of antigens used, the types of vaccines available, the frequency of vaccination and the anatomical site used for administration. These guidelines differ from each other and also from the manufacturer's datasheets or recommendations of national authorities. General as‐ pects and details of vaccination of cats are far beyond the scope of recent review; in this re‐ gard see a recent publication by Dean et al. 2012. Core vaccines are defined as those vaccines which all cats, regardless of circumstances, should receive to protect animals from severe, life threatening diseases which have global distribution. Only to emphasize those in context with microbes with transactivating and opportunistic potential, FHV-1 vaccination of kittens seems to be important. Vaccination against FCV, FPV also belongs to core vaccines. These vaccinations are recommended to start as early as vaccination with FeLV, applying revacci‐ nations up to 16-20 weeks of age. Most practices routinely give the commonly used antigens annually, although with the exception of the FHV, the FCV and FIV vaccination is recom‐ mended every 3 years [80]. Non-core vaccines are those that are required by only those ani‐ mals whose geographic location, local environment or lifestyle place them at risk of contracting specific infections. This moment, both FIV and FeLV vaccines are regarded as non-core. FIV vaccine development was initiated as a model for HIV vaccination. Vaccina‐ tion against HIV started with experiments to trigger a specific, potent and long-lasting im‐ munity in a surrogate animal model. Later, several novel approaches were tested in the feline model. Although the quest for a truly effective AIDS vaccine is years away [81], vacci‐ nation against FIV became available [82]. This vaccine (Fel-O-Vax FIV®) is marketed in many countries, but it might not protect cats against all field strains of subtypes A or B. Lifespan of infected cats appears similar to that of uninfected cats, but exposure to other infectious dis‐ eases drastically reduces survival of FIV positive animals [17]. Historically, FeLV vaccina‐ tion has been used for decades, well before FIV vaccination. The combined use of testing and vaccination programs is assumed to have decreased the prevalence of FeLV over the last 20 years [17,19]. Administering the first vaccine to kittens is at 8-10 weeks of age, with regular revaccinations usually every year. Several practitioners stopped revaccinating in‐ door and older cats, once they reached a certain age (≥ 6 years) assuming that they would not have close contact with a persistently infected cat, or elder cats are less easily infected with FeLV than younger animals. As persistently infected cats have been diagnosed at all ages, due to the decreased susceptibility to FeLV infection, vaccinating at 2-3 years intervals rather than annually seems to be acceptable. For free-roaming cats, annual FeLV vaccination is recommended. To increase revaccination interval assuming the presence of high level an‐ tibodies is not feasible because quantitative assays to measure serum FeLV antibodies are commercially available in few countries [80]. A marked difference in vaccination efficacy ex‐ ists, and suggests that only inactivated whole virus or canarypox-vectored recombinant vac‐ cines should be used. Cats with access to outdoors should be vaccinated, but should have at least one negative FeLV ELISA test before vaccination. Several studies showed that the mean survival time of FeLV positive cats are significantly shorter than that of FeLV-negative cats including vaccinated ones (references in 17). Aspecific measures to prevent FIV and FeLV transmission were set according to the biological characteristics of these viruses. Al‐ though retroviruses become inactivated within a few hours on dry surfaces, they may re‐ main viable in dried biological deposits for more than a week. Both viruses are inactivated by common detergents and hospital disinfectants. Spreading via body fluids is best prevent‐ ed by single set of instruments in clinical practice. To prevent infections by other microbes, including those with transactivation or opportunistic potential, hospitalised cats should not be allowed to have direct contact with one another. It is important not to keep retrovirusinfected cats in contagious disease ward as they are potentially immunosuppressed and car‐ ry or acquire other pathogens [17]. A recent survey in the UK showed that several veterinarians are not aware of the guidelines, or they do not adhere to them. Similarly to guidelines in human healthcare, other barriers included lack of agreement or lack of ability to follow guidelines, lack of motivation to follow them, and lack to perceive benefits to pa‐ tients. The frequency, combination and selection of antigens routinely given to cats by veter‐ inarians remain unknown, as are the anatomical sites to inject cats. Therefore, the impact of the published guidelines on practitioners working also remains unknown [80]. Further work is required to elicit why following guidelines may reduce occurrence and severity of both opportunistic infections and halt onset and slow progression of FAIDS by eliminating infec‐ tion by other microbes.

**5. Conclusions**

**Author details**

**References**

Joseph Ongrádi1\*, Stercz Balázs1

relevant to both FIV- and HIV-related diseases.

\*Address all correspondence to: ongjos@hotmail.com

2 Retrovirus Centre, University of Pisa, Pisa, Italy

, Kövesdi Valéria1

1 Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary

[1] Folkl A, Wen X, Kuczynski E, Clark ME, Bienzle D. Feline programmed death and its ligand: characterization and changes with feline immunodeficiency virus infection.

The Veterinary Immunology and Immunopathology 2010;134(1-2) 107-114.

, Nagy Károly1

and Pistello Mauro2

Descriptive epidemiological surveys on the simultaneous infection by feline retroviruses, namely FIV and/or FeLV, and heterologous microbes clearly show that progression of FAIDS is facilitated by certain viruses, bacteria and other parasites that also induce oppor‐ tunistic infections in a vicious circle. Scarce experimental data suggest that FIV transactivat‐ ing potential of heterologous microbes might increase FIV load, facilitate FAIDS course, and help induce malignancies resulting in considerably impaired quality of life and shorter life span of afflicted domestic cats. Simultaneous cross-species transmission of infection by par‐ ticular FIV and FeLV strains in endangered big cats may also occur. Emerging infections by FIV transactivating and opportunistic feline microbes in immunocompromised humans have already been described. Additive or synergistic impairing effects on the native immune reactions, activation of negatively affecting Treg cells, depression of cytotoxic T cell activi‐ ties, and abnormal cytokine pattern exerted by heterologous microbes demonstrate striking similarities between AIDS and FAIDS. Regular vaccination against transactivating microbes (e.g. FeLV, FHV-1) and transactivated microbe (FIV) starting at early age prevents and dis‐ rupts deleterious microbial interactions. These result in a complete halt or a significant slow‐ down of acquired immunodeficiency states. Experience verified in the feline model enables us to continue studying microbial interactions at molecular, cellular, immunological or clini‐ cal levels. Further experiments are warranted to better delineate the role of putative cofac‐ tors in FIV infection. Further studies should examine concurrent infections as contributing factors in the development and progression of neoplasia in FIV-positive cats. Determination of viral cooperative mechanisms that promote cancer during co-infection would be highly

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

461

The FIV/cat model has provided a unique opportunity to test novel therapeutic interven‐ tions aimed at eradicating latent virus, but the use of antiretroviral drugs in FIV infected cats and other felids has not gained grounds in the routine veterinary practice [7,8]. Several conventional microbial coinfections are treated with routine medication.

### **5. Conclusions**

countries, but it might not protect cats against all field strains of subtypes A or B. Lifespan of infected cats appears similar to that of uninfected cats, but exposure to other infectious dis‐ eases drastically reduces survival of FIV positive animals [17]. Historically, FeLV vaccina‐ tion has been used for decades, well before FIV vaccination. The combined use of testing and vaccination programs is assumed to have decreased the prevalence of FeLV over the last 20 years [17,19]. Administering the first vaccine to kittens is at 8-10 weeks of age, with regular revaccinations usually every year. Several practitioners stopped revaccinating in‐ door and older cats, once they reached a certain age (≥ 6 years) assuming that they would not have close contact with a persistently infected cat, or elder cats are less easily infected with FeLV than younger animals. As persistently infected cats have been diagnosed at all ages, due to the decreased susceptibility to FeLV infection, vaccinating at 2-3 years intervals rather than annually seems to be acceptable. For free-roaming cats, annual FeLV vaccination is recommended. To increase revaccination interval assuming the presence of high level an‐ tibodies is not feasible because quantitative assays to measure serum FeLV antibodies are commercially available in few countries [80]. A marked difference in vaccination efficacy ex‐ ists, and suggests that only inactivated whole virus or canarypox-vectored recombinant vac‐ cines should be used. Cats with access to outdoors should be vaccinated, but should have at least one negative FeLV ELISA test before vaccination. Several studies showed that the mean survival time of FeLV positive cats are significantly shorter than that of FeLV-negative cats including vaccinated ones (references in 17). Aspecific measures to prevent FIV and FeLV transmission were set according to the biological characteristics of these viruses. Al‐ though retroviruses become inactivated within a few hours on dry surfaces, they may re‐ main viable in dried biological deposits for more than a week. Both viruses are inactivated by common detergents and hospital disinfectants. Spreading via body fluids is best prevent‐ ed by single set of instruments in clinical practice. To prevent infections by other microbes, including those with transactivation or opportunistic potential, hospitalised cats should not be allowed to have direct contact with one another. It is important not to keep retrovirusinfected cats in contagious disease ward as they are potentially immunosuppressed and car‐ ry or acquire other pathogens [17]. A recent survey in the UK showed that several veterinarians are not aware of the guidelines, or they do not adhere to them. Similarly to guidelines in human healthcare, other barriers included lack of agreement or lack of ability to follow guidelines, lack of motivation to follow them, and lack to perceive benefits to pa‐ tients. The frequency, combination and selection of antigens routinely given to cats by veter‐ inarians remain unknown, as are the anatomical sites to inject cats. Therefore, the impact of the published guidelines on practitioners working also remains unknown [80]. Further work is required to elicit why following guidelines may reduce occurrence and severity of both opportunistic infections and halt onset and slow progression of FAIDS by eliminating infec‐

The FIV/cat model has provided a unique opportunity to test novel therapeutic interven‐ tions aimed at eradicating latent virus, but the use of antiretroviral drugs in FIV infected cats and other felids has not gained grounds in the routine veterinary practice [7,8]. Several

conventional microbial coinfections are treated with routine medication.

tion by other microbes.

460 Current Perspectives in HIV Infection

Descriptive epidemiological surveys on the simultaneous infection by feline retroviruses, namely FIV and/or FeLV, and heterologous microbes clearly show that progression of FAIDS is facilitated by certain viruses, bacteria and other parasites that also induce oppor‐ tunistic infections in a vicious circle. Scarce experimental data suggest that FIV transactivat‐ ing potential of heterologous microbes might increase FIV load, facilitate FAIDS course, and help induce malignancies resulting in considerably impaired quality of life and shorter life span of afflicted domestic cats. Simultaneous cross-species transmission of infection by par‐ ticular FIV and FeLV strains in endangered big cats may also occur. Emerging infections by FIV transactivating and opportunistic feline microbes in immunocompromised humans have already been described. Additive or synergistic impairing effects on the native immune reactions, activation of negatively affecting Treg cells, depression of cytotoxic T cell activi‐ ties, and abnormal cytokine pattern exerted by heterologous microbes demonstrate striking similarities between AIDS and FAIDS. Regular vaccination against transactivating microbes (e.g. FeLV, FHV-1) and transactivated microbe (FIV) starting at early age prevents and dis‐ rupts deleterious microbial interactions. These result in a complete halt or a significant slow‐ down of acquired immunodeficiency states. Experience verified in the feline model enables us to continue studying microbial interactions at molecular, cellular, immunological or clini‐ cal levels. Further experiments are warranted to better delineate the role of putative cofac‐ tors in FIV infection. Further studies should examine concurrent infections as contributing factors in the development and progression of neoplasia in FIV-positive cats. Determination of viral cooperative mechanisms that promote cancer during co-infection would be highly relevant to both FIV- and HIV-related diseases.

### **Author details**

Joseph Ongrádi1\*, Stercz Balázs1 , Kövesdi Valéria1 , Nagy Károly1 and Pistello Mauro2

\*Address all correspondence to: ongjos@hotmail.com

1 Institute of Medical Microbiology, Semmelweis University, Budapest, Hungary

2 Retrovirus Centre, University of Pisa, Pisa, Italy

#### **References**

[1] Folkl A, Wen X, Kuczynski E, Clark ME, Bienzle D. Feline programmed death and its ligand: characterization and changes with feline immunodeficiency virus infection. The Veterinary Immunology and Immunopathology 2010;134(1-2) 107-114.

[2] Simões RD, Howard KE, Dean GA. In Vivo assessment of natural killer cell responses during chronic feline immunodeficiency virus infection. PLoS One 2012;7(5) 3760-3766.

[14] Ongrádi J, Stercz B, Kövesdi V, Vértes L. Immunosenescence and vaccination of the elderly. Part I. Age-related immune impairment. Acta Microbiologica et Immunolog‐

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

463

[15] Steinrigl A, Ertl R, Langbei, I, Klein D. Phylogenetic analysis suggests independent introduction of feline immunodeficiency virus clades A and B to Central Europe and identifies diverse variants of clade B. The Veterinary Immunology and Immunopa‐

[16] Sobrinho LS, Rossi CN. Vides JP, Braga ET, Gomes AA, de Lima VM, Perri SH, Gen‐ eroso D, Langoni H, Leutenegger C, Biondo AW, Laurenti MD, Marcondes M. Coin‐ fection of Leishmania chagasi with Toxoplasma gondii, Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV) in cats from an endemic area of zoo‐

[17] Little S, Bienzle D, Carioto L, Chisholm H, O'Brien E, Scherk M. Feline leukemia vi‐ rus and feline immunodeficiency virus in Canada: recommendations for testing and

[18] Sukhumavasi W, Bellosa ML, Lucio-Forster A, Liotta JL, Lee AC, Pornmingmas P, Chungpivat S., Mohammed HO, Lorentzen L, Dubey JP, Bowman DD. Serological survey of Toxoplasma gondii, Dirofilaria immitis, Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV) infections in pet cats in Bangkok and vicini‐

[19] Hartmann K. Clinical aspects of feline immunodeficiency and feline leukemia virus infection. Veterinary Immunology and Immunopathology2011;143(3-4) 190-201.

[20] Powell CC, McInni, CL, Fontenelle JP, Lappin MR. Bartonella species, feline herpes‐ virus-1, and Toxoplasma gondii PCR assay results from blood and aqueous humor samples from 104 cats with naturally occurring endogenous uveitis. Journal of Feline

[21] Akhtardanesh B, Ziaal, N, Sharifi H, Rezaei S. Feline immunodeficiency virus, feline leukemia virus and Toxoplasma gondii in stray and household cats in Kerman-Iran: seroprevalence and correlation with clinical and laboratory findings. Research in Vet‐

[22] Sykes JE. Immunodeficiencies caused by infectious diseases. Veterinary Clinics of

[23] Gunn-Moore DA, McFarland SE, Brewer JI, Crawshaw TR, Clifton-Hadley RS, Kova‐ lik M, Shaw DJ. Mycobacterial disease in cats in Great Britain: I. Culture results, geo‐ graphical distribution and clinical presentation of 339 cases. Journal of Feline

[24] Belgard S, Truyen U, Thibault JC, Sauter-Louis C, Hartmann K. Relevance of feline calicivirus, feline immunodeficiency virus, feline leukemia virus, feline herpesvirus

notic visceral leishmaniasis. Veterinary Parasitology 2012;187(1-2) 302-306.

management. The Canadian Veterinary Journal 2011;52(8), 849-855.

ties, Thailand. Veterinary Parasitology,2012;188(1-2) 25-30.

North America: Small Animal Practice 2010; 40(3) 409-423.

Medicine and Surgery 210;12(12) 923-928.

Medicine and Surgery 2011;12(12) 934-944.

erinary Science 2010;89(2) 306-310.

ica Hungarica 2009;56(3) 199-210.

thology 2010;134(1-2) 82-89.


[14] Ongrádi J, Stercz B, Kövesdi V, Vértes L. Immunosenescence and vaccination of the elderly. Part I. Age-related immune impairment. Acta Microbiologica et Immunolog‐ ica Hungarica 2009;56(3) 199-210.

[2] Simões RD, Howard KE, Dean GA. In Vivo assessment of natural killer cell responses during chronic feline immunodeficiency virus infection. PLoS One 2012;7(5)

[3] Ongrádi J, Ceccherini-Nelli L, Soldaini E , Bendinelli M, Conaldi PG, Specter S, Fried‐ man H. Endotoxin suppresses indirect activation of HIV-1 by human herpesvirus 6. In: Nowotny A, Spitzer J J, Ziegler EJ. (eds.) Cellular and molecular aspects of endo‐

[4] Ongrádi J, Kövesdi V, Nagy K, Matteoli B, Ceccherini-Nelli L, Ablashi D. In vitro and in vivo transactivation of HIV by HHV-6. In: Chang TL. (ed.) HIV-Host Interactions. Vienna: InTech; 2011. p257-298. ISBN: 978-953-307-442-9. Available from www.inte‐ chopen.com/books/hiv-host-interactions/in-vitro-and-in-vivo-transactivation-of-

[5] Murphy B, Vapniarsky N, Hillman C, Castillo D, McDonnel S, Moore P, Luciw PA, Sparger EE. FIV establishes a latent infection in feline peripheral blood CD4+ T lym‐ phocytes in vivo during the asymptomatic phase of infection. Retrovirology 2012;

[6] Kenyon JC, Lever AM. The molecular biology of feline immunodeficiency virus

[7] Elder JH, Lin YC, Fink E, Grant CK. Feline immunodeficiency virus (FIV) as a model for study of lentivirus infections: parallels with HIV. Current HIV Research 2010; 8(1)

[8] McDonnel SJ, Sparger EE, Luciw PA, Murphy BG. Transcriptional regulation of la‐ tent feline immunodeficiency virus in peripheral CD4+ T-lymphocytes. Viruses

[9] Gemeniano MC, Sawai ET, Leutenegger CM, Sparger EE. Feline immunodeficiency virus ORF-A is required for virus particle formation and virus infectivity. The Jour‐

[10] Mikkelsen SR, Long JM, Zhang L, Galemore ER, VandeWoude S, Dean GA. Partial regulatory T cell depletion prior to acute feline immunodeficiency virus infection

[11] Spada E, Proverbio D, della Pepa A, Perego R, Baggiani L, DeGiorgi GB, Domenichi‐ ni G, Ferro E, Cremonesi F. Seroprevalence of feline immunodeficiency virus, feline leukaemia virus and Toxoplasma gondii in stray cat colonies in Northern Italy and correlation with clinical and laboratory data. Journal of Feline Medicine and Surgery

[12] O'Brien SJ, Troyer JL, Brown MA, Johnson WE, Antunes A, Roelke ME, Pecon-Slat‐ tery J. Emerging viruses in the Felidae: shifting paradigms. Viruses 2012;4(2) 236-257.

[13] Magden, E, Quackenbush SL, VandeWou de S. FIV associated neoplasms: a mini-re‐ view. The Veterinary Immunology and Immunopathology 2011; 143(3-4) 227-234.

does not alter disease pathogenesis. PLoS One 2011;6(2) 17181723.

toxin reactions. Amsterdam: Elsevier Science Publishers B.V; 1990. p387-394.

hiv-1-by-human-herpesvirus-6 (accessed 1 October 2012)

9(12) doi10.1186/1742-4690-9-12

(FIV). Viruses 2011;3(11) 2192-2193.

nal of Virology 2003;77(16) 8819-8830.

3760-3766.

462 Current Perspectives in HIV Infection

73-80.

2012;4(5) 878-888.

2012;14(6) 369-377.


and Bartonella henselae in cats with chronic gingivostomatitis. Berliner und Münch‐ ener Tierärztliche Wochenschrift 2010;123(9-10) 369-376.

may influence disease outcome in African lions. The Veterinary Immunology and

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

465

[35] Korman RM, Cerón JJ, Knowles TG, Barker EN, Eckersall PD, Tasker S. Acute phase response to Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' infection in FIV-infected and non-FIV-infected cats. The Veterinary Journal 2012;

[36] Buchmann AU, Kershaw O, Kempf VA, Gruber AD. Does a feline leukemia virus in‐ fection pave the way for Bartonella henselae infection in cats? Journal of Clinical Mi‐

[37] Bacon LD, Witter RL, FadlyAM. Augmentation of retrovirus-induced lymphoid leu‐ kosis by Marek's disease herpesviruses in White Leghorn chickens. Journal of Virolo‐

[38] Thalwitzer S, Wachter B, Robert N, Wibbelt G, Müller T, Lonzer J, Meli ML, Bay G, Hofer H. Lutz H. Seroprevalences to viral pathogens in free-ranging and captive cheetahs (Acinonyx jubatus) on Namibian Farmland. Clinical and Vaccine Immunol‐

[39] Ongrádi J, Sallay K, Kulcsár G. The decreased antibacterial activity of oral polymor‐ phonuclear leukocytes coincides with the occurence of virus-carrying oral lympho‐

[40] Reubel GH, George JW, Barlough JE, Higgins J, Grant CK, Pedersen NC. Interaction of acute feline herpesvirus-1 and chronic feline immunodeficiency virus infections in experimentally infected specific pathogen free cats. The Veterinary Immunology and

[41] Reubel GH, Dean GA, George JW, Barlough, JE, Pedersen NC. Effects of incidental infections and immune activation on disease progression in experimentally feline im‐ munodeficiency virus-infected cats. Journal of Acquired Immune Deficiency Syn‐

[42] Kawaguchi Y, Miyazawa T, Horimoto T, Itagaki S, Fukasawa M, Takahashi E, Mika‐ mi T. Activation of feline immunodeficiency virus long terminal repeat by feline her‐

[43] Kawaguchi Y, Norimine J, Miyazawa T, Kai C, Mikami T. Sequences within the feline immunodeficiency virus long terminal repeat that regulate gene expression and re‐

spond to activation by feline herpesvirus type 1. Virology 1992;190(1) 465-468.

[44] Kawaguchi Y, Maeda K, Pecoraro MR, Inoshima Y, Jang HK, Kohmoto M, Iwatsuki K, Ikeda Y, Shimojima M, Tohya Y, et al. The feline herpesvirus type 1 ICP4 downregulates feline immunodeficiency virus long terminal repeat (LTR)-directed gene expression via the C/EBP site in the LTR. Journal of Veterinary Medical Science

cytes and epithelial cells. Folia microbiologica 1987;32(5) 438-447.

Immunopathology 2011;143(3-4) 338-346.

http://dx.doi.org/10.1016/j.tvjl.2011.12.009

crobiology 2010;48(9) 3295-3300.

gy 1989;63(2) 504-512.

ogy, 2010;7(2) 232-238.

Immunpathology 1992;35(1-2) 95-119.

pesvirus type 1. Virology 1991;184(1) 449-454.

dromes, 1994;7(10) 1003-1015.

1995;57(6) 1129-1131.


may influence disease outcome in African lions. The Veterinary Immunology and Immunopathology 2011;143(3-4) 338-346.

[35] Korman RM, Cerón JJ, Knowles TG, Barker EN, Eckersall PD, Tasker S. Acute phase response to Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' infection in FIV-infected and non-FIV-infected cats. The Veterinary Journal 2012; http://dx.doi.org/10.1016/j.tvjl.2011.12.009

and Bartonella henselae in cats with chronic gingivostomatitis. Berliner und Münch‐

[25] Tanahara M, Miyamoto S, Nishio T, Yoshii Y, Sakuma M, Sakata Y, Nishigaki K, Tsu‐ jimoto H, Setoguchi A, Endo Y. An epidemiological survey of feline hemoplasma in‐

[26] Reche A Jr, Daniel AG, Lazaro Strauss TC, Taborda CP, Vieira Marques SA, Haipek K, Oliveira LJ, Monteiro JM, Kfoury JR Jr. Cutaneous mycoflora and CD4:CD8 ratio of cats infected with feline immunodeficiency virus. Journal of Feline Medicine and

[27] Roura X, Peter, IR, Alte, L, Tabar MD, Barker EN, Planellas M, Helps CR, Francino O, Shaw SE, Tasker S. Prevalence of hemotropic mycoplasmas in healthy and unhealthy cats and dogs in Spain. Journal of Veterinary Diagnostic Investigation 2010;22(2)

[28] Duarte A, Castr, I, Pereira da Fonseca IM, Almeida V, Madeira de Carvalho LM, Meireles J, Fazendeiro MI, Tavares L, Vaz Y. Survey of infectious and parasitic dis‐ eases in stray cats at the Lisbon Metropolitan Area, Portugal. Journal of Feline Medi‐

[29] Filoni C, Catão-Dias JL, Cattori V, Willi B, Meli ML, Corrêa SH, Marques MC,Adania CH, Silva JC, Marvulo MF, Ferreira Neto JS, Durigon EL, de Carvalho VM,Coutinh, SD, Lutz H, Hofmann-Lehmann R. Surveillance using serological and molecular methods for the detection of infectious agents in captive Brazilian neotropic and

exotic felids. Journal of Veterinary Diagnostic Investigation 2012;24(1)166-173.

[30] Coelho WM, do Amarante AF, Apolinário Jde C, Coelho NM, de Lima VM, Perri SH, Bresciani, KD. Seroepidemiology of Toxoplasma gondii, Neospora caninum, and Leishmania spp. infections and risk factors for cats from Brazil. Parasitology Re‐

[31] Al-Kappany YM, Lappin MR, Kwok OC, Abu-Elwafa SA, Hilali M, Dubey JP. Sero‐ prevalence of Toxoplasma gondii and concurrent Bartonella spp., feline immunodefi‐ ciency virus, feline leukemia virus, and Dirofilaria immitis infections in Egyptian

[32] Miró G, Hernández, Montoya A, Arranz-Solís D, Dado D, Rojo-Montejo S, Mendoza-Ibarra JA, Ortega-Mora LM, Pedraza-Díaz S. First description of naturally acquired Tritrichomonas foetus infection in a Persian cattery in Spain. Parasitology Research

[33] Stojanovic V, Foley P. Infectious disease prevalence in a feral cat population on Prince Edward Island, Canada. The Canadian Veterinary Journal 2011;52(9) 979-982.

[34] Troyer JL, Roelke ME, Jespersen JM, Baggett N, Buckley-Beason V, MacNulty D,Craft M, Packer C, Pecon-Slattery J, O'Brien SJ. FIV diversity: FIVPle subtype composition

fection in Japan. Journal of Veterinary Medical Science 2010;72(12) 1575-1581.

ener Tierärztliche Wochenschrift 2010;123(9-10) 369-376.

Surgery 2010;12(4) 355-358.

cine and Surgery 2010;12(6) 441-446.

search 2011;109(4) 1009-1013.

2011;109(4) 1151-1154.

cats. Journal of Parasitology 2011;97(2) 256-258.

270-274.

464 Current Perspectives in HIV Infection


[45] Kawaguchi Y, Maeda K, Miyazawa T, Ono M, Tsubota K, Tomonaga K, Mikami T. Inhibition of feline immunodeficiency virus gene expression and replication by al‐ phaherpesvirus ICP4 homologues. Journal of General Virology 1994;75(10) 2783-2787.

Proceedings of National Academy of Sciences of the United States of America

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

467

[58] Rojko JL, Olsen RG. The immunobiology of the feline leukemia virus. The Veterinary

[59] Ishida T, Washizu T, Toriyabe K, Motoyoshi S, Tomoda I, Pedersen NC. Feline im‐ munodeficiency virus infection in cats of Japan. Journal of theAmerican Veterinary

[60] Yamamoto JK, Hansen H, Ho EW, Morishita TY, Okuda T, Sawa TR, Nakamura RM. Pedersen NC. Epidemiologic and clinical aspects of feline immunodeficiency virus infection in cats from the continental United States and Canada and possible mode of transmission. Journal of the American Veterinary Medical Association 1989; 194(2)

[61] Shelton GH, Grant CK, Cotter SM, Gardner MB, Hardy WD Jr. DiGiacomo RF. Feline immunodeficiency virus and feline leukemia virus infections and their relationships to lymphoid malignancies in cats: a retrospective study (1968-1988). Journal of Ac‐

[62] Pedersen NC, Torten M, Rideout B, Sparger E, Tonachini T, Luciw PA, Ackley C, Levy N, Yamamoto J. Feline leukemia virus infection as a potentiating cofactor for the primary and secondary stages of experimentally induced feline immunodeficien‐

[63] Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Re‐

[64] Korman RM, Cerón JJ, Knowles TG, Barker EN, Eckersall PD, Tasker S. Acute phase response to Mycoplasma haemofelis and 'Candidatus Mycoplasma haemominutum' infection in FIV-infected and non-FIV-infected cats. The Veterinary Journal 2012;

[65] George JW, DVM, PhD Bruce A, Rideout, DVM, PhD Stephen M. Griffey, DVM, PhD Niels C. Pedersen, DVM, PhD Effect of preexisting FeLV infection or FeLV and feline immunodeficiency virus coinfection on pathogenicity of the small variant of Haemo‐ bartonella felis in cats. American Journal of Veterinary Research 2002;63(8)

[66] Chowdhury MI, Munakata T, Koyanagi Y, Arai S, Yamamoto N. Mycoplasmastimu‐ lates HIV-1 expression from acutely- and dormantly-infected promonocyte/mono‐

[67] Mavedzenge SN, Van Der Pol B, Weiss HA, Kwok C, Mambo F, Chipato T, Van der‐ Straten A, Salata R, Morrison C. The association between Mycoplasma genitalium

[68] Al-Harthi L, Spear GT, Hashemi FB, Landay A, Sha BE, Roebuck KA. A human im‐ munodeficiency virus (HIV)-inducing factor from the female genital tract activates

blastoid cell lines. Archives of Virology 1994;139(3-4) 431-438.

and HIV-1 acquisition in African women. AIDS 2012;26(5) 617-24.

Immunology and Immunpathology 1984; 6(1-2) 107-165.

quired Immune Deficiency Syndromes 1990;3(6) 623-630.

cy virus infection. Journal of Virology 1990;64(2) 598-606.

Medical Association 1989;194(2) 221-225.

2007;104(12) 5067-5072.

view 1993;57(1) 183-289.

193(2) 433-438.

1172-1178.

213-210.


Proceedings of National Academy of Sciences of the United States of America 2007;104(12) 5067-5072.

[58] Rojko JL, Olsen RG. The immunobiology of the feline leukemia virus. The Veterinary Immunology and Immunpathology 1984; 6(1-2) 107-165.

[45] Kawaguchi Y, Maeda K, Miyazawa T, Ono M, Tsubota K, Tomonaga K, Mikami T. Inhibition of feline immunodeficiency virus gene expression and replication by al‐ phaherpesvirus ICP4 homologues. Journal of General Virology 1994;75(10)

[46] Ongrádi J, Maródi CL, Nagy K., Csiszár A, Bánhegyi D, Horváth A. HHV-6A pri‐ mary infections at risk and recurrent infections during the course of AIDS. Journal of Acquired Immune Deficiency Syndrome and Human Retroviruses 1999;22(3)

[47] Lakatos B, Farkas J, Egberink HF, Vennema H, Horzinek MC, van Vliet A, Rossen, J, Benkő M, Ongrádi J. PCR detection of adenovirus in a cat. Hungarian Veterinary

[48] Ongrádi J. Identification of a feline adenovirus isolate that replicates in monkey and human cells in vitro American Journal of Veterinary Research 1999;60(12) 1463. [49] Pring-Akerblom P, Ongrádi J. Feline adenovirus hexon. GenBank Accession Number

[50] Pring-Akerblom P, Ongrádi J. Feline adenovirus fiber. GenBank Accession Number

[51] Phan TG, Shimizu H, Nishimura S, Okitsu S, Maneekarn N, Ushijima H. Human ade‐ novirus type 1 related to feline adenovirus: evidence of interspecies transmission.

[52] Luiz LN, Leite JP, Yokosawa J, Carneiro BM, Pereira Filho E, Oliveira TF, Freitas GR, Costa LF, Paula NT, Silveira HL, Nepomuceno JC, Queiróz DA. Molecular character‐ ization of adenoviruses from children presenting with acute respiratory disease in Uberlândia, Minas Gerais, Brazil, and detection of an isolate genetically related to fe‐

[53] Lakatos B, Farkas J, Ádám É, Jarrett O, Egberink HF, Bendinelli M, Nász I, Ongrádi J. Data to the adenovirus infection of European cats. Hungarian Veterinary Journal

[54] Lakatos B, Farkas J, Ádám É, Dobay O, Jeney Cs, Nász I, Ongrádi J. Serological evi‐ dence of adenovirus infection in cats. Archieves of Virology 2000;145(5) 1029-1033. [55] Ongrádi J, Pistello M, Mazzetti P, Bendinelli M. The effect of cytokines on the early events of feline immunodeficiency virus (FIV) infection of macrophages Annual Meeting of the International Society for Interferon and Cytokine Research, Budapest, Hungary, 2-7 October, 1994. Journal of Interferon Research 14 (Suppl.1), 137, 1994. [56] Biancotto A, Grivel JC, Lisco A, Vanpouille C, Markham PD, Gallo RC, Margolis LB, Lusso P. Evolution of SIV toward RANTES resistance in macaques rapidly progress‐

ing to AIDS upon coinfection with HHV-6A. Retrovirology 2009;2(6), 61.

[57] Lusso P, Crowley RW, Malnati MS, Di Serio C, Ponzoni M, Biancotto A, Markham PD, Gallo RC. Human herpesvirus 6A accelerates AIDS progression in macaques.

line adenovirus. Memórias do Instituto Oswaldo Cruz 2010;105(5) 712-716.

2783-2787.

466 Current Perspectives in HIV Infection

311-312.

AY512566

AY 518270

1996; 51,543-545.

Journal 1997;119, 517-519.

Clinical Laboratory 2006;52(9-10) 515-518.


HIV-1 gene expression through the kappaB enhancer. Journal of Infectious Diseases. 1998;178(5) 1343-1351.

[81] Pistello M, Conti F,Vannucci L, Freer G. Novel approaches to vaccination against the feline immunodeficiency virus. Veterinary Immunology and Immunopathology

Interaction of FIV with Heterologous Microbes in the Feline AIDS Model

http://dx.doi.org/10.5772/52767

469

[82] Yamamoto JK, Pu R, Sato E, Hohdatsu T. Feline immunodeficiency virus pathogene‐ sis and development of a dual-subtype feline-immunodeficiency-virus vaccine. AIDS

2010;134(1-2) 48-53.

2007;21(5) 547-563.


[81] Pistello M, Conti F,Vannucci L, Freer G. Novel approaches to vaccination against the feline immunodeficiency virus. Veterinary Immunology and Immunopathology 2010;134(1-2) 48-53.

HIV-1 gene expression through the kappaB enhancer. Journal of Infectious Diseases.

[69] dos Santos AP, dos Santos RP, Biondo AW, Dora JM, Goldani LZ, de Oliveira ST, de Sá Guimarães AM, Timenetsky J, de Morais HA, González FH, Messick JB.Hemo‐ plasma infection in HIV-positive patient, Brazil. Emerging Infectious Diseases

[70] Kallick CA, Levin S, Reddi KT, Landau WL. Systemic lupus erythematosus associat‐ ed with haemobartonella-like organisms. Nature New Biology 1972;236(66) 145-146.

[71] Maingat F, Viappiani S, Zhu Y, Vivithanapor, P, Ellestad KK, Holden J, Silva, C, Power C. Regulation of lentivirus neurovirulence by lipopolysaccharide condition‐ ing: suppression of CXCL10 in the brain by IL-10. Journal of Immunology2010;184(3)

[72] Levy JA, Hsueh F, Blackbourn DJ, Wara D, Weintrub PS. CD8 cell noncytotoxic anti‐ viral activity in human immunodeficiency virus-infected and -uninfected children.

[73] Dean GA, Higgins J, LaVoy A, Fan Z, Pedersen NC. Measurement of feline cytokine gene expression by quantitative-competitive RT-PCR. The Veterinary Immunology

[74] Dean GA, Pedersen NC. Cytokine response in multiple lymphoid tissues during the primary phase of feline immunodeficiency virus infection. Journal of Virology

[75] Tochikura, TS, Naito Y, Kozutsumi Y, Hohdatsu T. Induction of feline immunodefi‐ ciency virus from a chronically infected feline T-lymphocyte cell line. Research in

[76] Ongrádi, J.Report on the feline AIDS model study of the University of Pisa. Medical

[77] Ongrádi J, Sheikh JM, Austen B, Pistello M, Bendinelli M, Dalgleish AG. Program‐ med cell death of cultured immune cells induced by HIV-1 or FIV. Acta Microbiolog‐

[78] Scott VL, Boudreaux CE, Lockett NN, Clay BT, Coats KS. Cytokine dysregulation in early- and late-term placentas from feline immunodeficiency virus (FIV)-infected

[79] Levy J, Crawford C, Hartmann K, Hofmann-Lehmann R, Little S, Sundahl E, Thayer V. 2008 American Association of Feline Practitioners' feline retrovirus management

[80] Dean RS, Pfeiffer DU, Adams VJ. Feline vaccination practices and protocols used by veterinarians in the United Kingdom. The Veterinary Journal. 2012; http://dx.doi.org/

cats. American Journal of Reproductive Immunology 2011;65(5) 480-491.

guidelines. Journal of Feline Medicine and Surgery 2008;10(3) 300-316.

Journal of Infectious Diseases. 1998;177(2) 470-472.

and Immunpathology 1998;63(1-2) 73-82.

Veterinary Science 2012;92(2) 327-332.

Journal/OrvosiHetilap 1993;134(47) 2621-2622.

ica et Immunologica Hungarica 1997;44(1) 48-49.

1998;178(5) 1343-1351.

468 Current Perspectives in HIV Infection

2008;14(12) 1922-1924.

1998;72,(12) 9436-9440.

10.1016/j.tvjl.2012.02.024

1566-1574.

[82] Yamamoto JK, Pu R, Sato E, Hohdatsu T. Feline immunodeficiency virus pathogene‐ sis and development of a dual-subtype feline-immunodeficiency-virus vaccine. AIDS 2007;21(5) 547-563.

*Edited by Shailendra K. Saxena*

This book gives a comprehensive overview of HIV and AIDS including NeuroAIDS, as well as general concepts of pathology, immunity and immunopathology, diagnosis, treatment, epidemiology and etiology to current clinical recommendations in management of HIV/AIDS including NeuroAIDS, highlighting the ongoing issues, recent advances and future directions in diagnostic approaches and therapeutic strategies.

Photo by Vichly44 / iStock

Current Perspectives in HIV Infection

Current Perspectives in

HIV Infection