**Part 3**

**From the Clinic to the Patients: HIV and Clinical Manifestations** 

370 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

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**15** 

*1Japan 2Russia* 

**Pathology of HIV/AIDS:** 

*2Smolensk Regional Institute of Pathology* 

**Lessons from Autopsy Series** 

*1Nagasaki University Graduate School of Biomedical Sciences* 

Andrey Bychkov1,2, Shunichi Yamashita1 and Alexander Dorosevich2

HIV infection is a global disease and despite considerable efforts of the international community it is a main cause of human mortality (UNAIDS, 2009). Morphological insights into HIV/AIDS are based on the study of clinical cases by means of biopsy and autopsy. Morphological changes during development of HIV infection and, especially, through AIDS progression are variable and specified mainly by characteristics of widespread secondary infections and tumors. Opportunistic infections account for approximately 80% of deaths in patients with AIDS and their spectrum is constantly changing, as a result of improvements in treatment options and prophylaxis along with the increasing life span of HIV-infected individuals. Postmortem examinations provide important diagnostic and epidemiological data and represent a most reliable source for estimation of the full spectrum of diseases in

Morphology of HIV/AIDS is manifested by wide range of indicative (secondary) diseases while specific changes caused by HIV are mainly detected in immune system at the early

Lymphadenopathy is the marked feature of acute HIV infection defined as generalized enlargement of lymph nodes. Histologically, this process passes through a series of changes: hyperplasia, involution, depletion, and sclerosis (Baroni & Uccini, 1993). In the stage of hyperplasia, the lymph nodes are characterized by disorderly grouped multiple follicles with 'starry sky' pattern due to arrangement of macrophages. Formation of multinuclear cells resembling symplasts is result of merging of lymphocytes infected by virus. With the progression of disease, lymphoid depletion becomes extensive and a fibrovascular carcass appears more evident along with increasing vascularity (angiomatosis). Finally, lymph nodes harbor 'burnt-out' appearance. Although profound depletion of lymphoid tissues is driven by cytotoxic effect of HIV but there is no histologic picture diagnostic of this

Large proportion of patients at different stages of disease has morphological proofs of HIVinduced brain damage (Kibayashi et al., 1996). HIV neuropathology is comprised of

**1. Introduction** 

individual patients and the general population.

stages of infection and in central nervous system.

**2. Pathomorphology of HIV/AIDS** 

condition (O'Murchadha et al., 1987).

## **Pathology of HIV/AIDS: Lessons from Autopsy Series**

Andrey Bychkov1,2, Shunichi Yamashita1 and Alexander Dorosevich2 *1Nagasaki University Graduate School of Biomedical Sciences 2Smolensk Regional Institute of Pathology 1Japan 2Russia* 

## **1. Introduction**

HIV infection is a global disease and despite considerable efforts of the international community it is a main cause of human mortality (UNAIDS, 2009). Morphological insights into HIV/AIDS are based on the study of clinical cases by means of biopsy and autopsy. Morphological changes during development of HIV infection and, especially, through AIDS progression are variable and specified mainly by characteristics of widespread secondary infections and tumors. Opportunistic infections account for approximately 80% of deaths in patients with AIDS and their spectrum is constantly changing, as a result of improvements in treatment options and prophylaxis along with the increasing life span of HIV-infected individuals. Postmortem examinations provide important diagnostic and epidemiological data and represent a most reliable source for estimation of the full spectrum of diseases in individual patients and the general population.

## **2. Pathomorphology of HIV/AIDS**

Morphology of HIV/AIDS is manifested by wide range of indicative (secondary) diseases while specific changes caused by HIV are mainly detected in immune system at the early stages of infection and in central nervous system.

Lymphadenopathy is the marked feature of acute HIV infection defined as generalized enlargement of lymph nodes. Histologically, this process passes through a series of changes: hyperplasia, involution, depletion, and sclerosis (Baroni & Uccini, 1993). In the stage of hyperplasia, the lymph nodes are characterized by disorderly grouped multiple follicles with 'starry sky' pattern due to arrangement of macrophages. Formation of multinuclear cells resembling symplasts is result of merging of lymphocytes infected by virus. With the progression of disease, lymphoid depletion becomes extensive and a fibrovascular carcass appears more evident along with increasing vascularity (angiomatosis). Finally, lymph nodes harbor 'burnt-out' appearance. Although profound depletion of lymphoid tissues is driven by cytotoxic effect of HIV but there is no histologic picture diagnostic of this condition (O'Murchadha et al., 1987).

Large proportion of patients at different stages of disease has morphological proofs of HIVinduced brain damage (Kibayashi et al., 1996). HIV neuropathology is comprised of

Pathology of HIV/AIDS: Lessons from Autopsy Series 375

exudation may extent from lobular up to sub-lobar area. Some alveoli contain accumulations of foamy macrophages that are characteristic for typical tuberculous inflammation. There is an increase in the thickness of the pleura caused by extensive hyperemia and edema. The intrathoracic lymph nodes are also affected, enlarged (3–4 cm in diameter), and aggregated. Partial or total caseous lymphadenitis is detected with the spread of inflammatory processes to the surrounding soft tissues. Evident reduction of follicular structures and lymphoid depletion is a characteristic feature of these lymph

*Extrapulmonary tuberculosis* is detected as a component of a generalized type of tuberculosis. Monomorphic miliary foci of caseous necrosis are found in various internal organs, more often in the spleen, kidneys, liver, and rarely in the meninges, peritoneum, exo- and endocrine glands (pancreas, adrenals, prostate, thyroid, ovaries). As a whole, in cases of generalized tuberculosis, *Mycobacteria* cause alterative and exudative reactions simultaneously in several organs with the mean number of organs involved is 5.4 (own data). Most of the foci are suspected to be spread via hematogenous dissemination from lungs. Histopathology of the parenchymatous organs reveals monomorphic miliary nodules of caseous necrosis with rare giant cells, as in the lungs. In many cases, tubercles are not visible by visual inspection. In the spleen, the foci of caseous necrosis have a tendency to

Tuberculous meningitis is characterized grossly by typical basilar localization with poorly detected gray-white exudates and tubercles in the subarachnoid space. Microscopic examination of the meninges reveals evident hyperemia and edema accompanied by alterative reactions. The latter is manifested as areas of caseous necrosis extensively infiltrated by polymorphs, lymphocytes, and macrophages. Various types of vasculitis such as endovasculitis, panvasculitis, thrombovasculitis, and perivasculitis are evident. Perivasculitis is more often present with edema and excessive mononuclear, neutrophilic, eosinophilic, and plasma cell infiltration in all layers of the vessel wall (Fig. 1c). Destructive process may extent into brain tissue with formation of localized

*Mycobacterium avium-intracellulare* (MAI) infection leads to massive necrotic destruction of lymph nodes with minor involvement of the lungs. Mostly granulomas are difficult to detect throughout the inner organs by naked eye. The only exception is spleen which is filled with miliary granulomas in roughly half of cases. Different groups of visceral lymph nodes are enlarged and show characteristic yellow tone of cut surface. Microscopically, proliferation of large round to elliptical striated pale blue macrophages is noted. Cytoplasm of these cells is packed with huge number of acid-fast bacilli. Well-formed granulomas with fibrosis, necrosis, and epithelioid histiocytes are present in less than one third of cases (Klatt et al.,

There is a broad spectrum of causative agents of pneumonia revealed by microbiology. Besides typical microflora, bacterial pneumonia can be caused by opportunistic agents, which are activated under immunodeficiency. The most common causative agents of pneumonia are *Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae* and *Escherichia coli* (Afessa et al., 1998).

nodes.

abscesses.

1987).

*Bacterial Pneumonia* 

fuse and may cover up to 50% of the cut surface.

**2.2 Morphology of bacterial infections** 

following patterns (in order of appearance): lymphocyte infiltration of the leptomeninges, microglial nodules formation and HIV encephalitis. The latter lesion consists of numerous foci with mononuclear cells typical of small macrophages, microglia, and multinucleated giant cells. The giant cells are the hallmark of HIV infection since viral antigens can be detected in their cytoplasm (Gyorkey et al., 1987).

Development of indicative diseases which include opportunistic infections and secondary neoplasms which reflects severe deficiency of immune system and in most of cases determines progression of the disease to full-blown AIDS. Morphological descriptions given below represent our common findings of infectious and neoplastic diseases in AIDS.

## **2.1 Morphology of mycobacterial Infections in HIV patients**

Tuberculosis in HIV-patients is characterized by a prevalence of its generalized form with extensive dissemination and acute progression of specific processes. Notable histological features are loss of granuloma formation and abundance of necrotic changes. Generally, all the forms of tuberculosis seen in the terminal stages are actively progressive. The main forms of tuberculosis are generalized, pulmonary (often disseminated) and extrapulmonary. Thus, various organs are affected, most often the lungs, lymph nodes, liver, kidneys, spleen, intestine, and central nervous system (Smith et al., 2000). Tissue reaction in the terminal stage shows typical tuberculous granulomas with giant and epithelioid cells in only 20% of lesions, whereas the remaining 80% demonstrates numerous foci of nonreactive caseous necrosis abundant of acid-fast bacilli (Parkhomenko et al., 2003).

*Pulmonary tuberculosis* is manifested as a bilateral disseminated type or polycavernous variant. In disseminated tuberculosis, foci of specific lesions (granulomas) comprise large central zones of caseous necrosis surrounded by a few inflammatory cells. Giant cells are uncommon. Ziehl-Neelsen staining shows numerous acid-fast bacteria in the foci of caseous necrosis. All these histological signs characterize tuberculosis as progressive and highly active. Macroscopic study of the lungs often reveals miliary disseminated tuberculosis, while macrofocal dissemination and caseous pneumonia are rare. The pattern of dissemination is bilateral, with a predominance of micronodular, miliary and submiliary types. Tubercles evenly spread to the whole organ or localized to one of the lobes. In a large proportion of cases, macroscopic detection of tuberculous changes in lungs is difficult, but histological examination reveals miliary and submiliary necrotic foci (Berdnikov et al., 2011). The characteristic microscopic picture is a predominance of alterative and exudative changes with the lack of a productive component of inflammation or its minimal manifestation (Fig. 1a). The latter is marked by the absence of signs of encapsulation and organization of inflammatory foci. Classic granulomas are infrequent and only few of them contain giant cells of Langhans (Fig. 1b). Initially, there is formation of colonies of *Mycobacteria* in the pulmonary parenchyma, which is accompanied by cellular infiltration with a significant predominance of polymorphonuclear leucocytes. The cells phagocytose the bacteria and this step is marked by karyorrhexis. Later, this process is associated with massive breakdown of leucocytes resulting in necrosis and microabscesses. Tissue sections stained by Ziehl–Neelsen showed numerous acid-fast bacteria in the foci of caseous necrosis. An exudative reaction in the form of serous-fibrinous pneumonia or fibrinous-purulent pneumonia with predominance of neutrophilic leucocytes is detected at the periphery of caseous foci. Such

following patterns (in order of appearance): lymphocyte infiltration of the leptomeninges, microglial nodules formation and HIV encephalitis. The latter lesion consists of numerous foci with mononuclear cells typical of small macrophages, microglia, and multinucleated giant cells. The giant cells are the hallmark of HIV infection since viral antigens can be

Development of indicative diseases which include opportunistic infections and secondary neoplasms which reflects severe deficiency of immune system and in most of cases determines progression of the disease to full-blown AIDS. Morphological descriptions given

Tuberculosis in HIV-patients is characterized by a prevalence of its generalized form with extensive dissemination and acute progression of specific processes. Notable histological features are loss of granuloma formation and abundance of necrotic changes. Generally, all the forms of tuberculosis seen in the terminal stages are actively progressive. The main forms of tuberculosis are generalized, pulmonary (often disseminated) and extrapulmonary. Thus, various organs are affected, most often the lungs, lymph nodes, liver, kidneys, spleen, intestine, and central nervous system (Smith et al., 2000). Tissue reaction in the terminal stage shows typical tuberculous granulomas with giant and epithelioid cells in only 20% of lesions, whereas the remaining 80% demonstrates numerous foci of nonreactive caseous necrosis abundant of acid-fast bacilli (Parkhomenko

*Pulmonary tuberculosis* is manifested as a bilateral disseminated type or polycavernous variant. In disseminated tuberculosis, foci of specific lesions (granulomas) comprise large central zones of caseous necrosis surrounded by a few inflammatory cells. Giant cells are uncommon. Ziehl-Neelsen staining shows numerous acid-fast bacteria in the foci of caseous necrosis. All these histological signs characterize tuberculosis as progressive and highly active. Macroscopic study of the lungs often reveals miliary disseminated tuberculosis, while macrofocal dissemination and caseous pneumonia are rare. The pattern of dissemination is bilateral, with a predominance of micronodular, miliary and submiliary types. Tubercles evenly spread to the whole organ or localized to one of the lobes. In a large proportion of cases, macroscopic detection of tuberculous changes in lungs is difficult, but histological examination reveals miliary and submiliary necrotic foci (Berdnikov et al., 2011). The characteristic microscopic picture is a predominance of alterative and exudative changes with the lack of a productive component of inflammation or its minimal manifestation (Fig. 1a). The latter is marked by the absence of signs of encapsulation and organization of inflammatory foci. Classic granulomas are infrequent and only few of them contain giant cells of Langhans (Fig. 1b). Initially, there is formation of colonies of *Mycobacteria* in the pulmonary parenchyma, which is accompanied by cellular infiltration with a significant predominance of polymorphonuclear leucocytes. The cells phagocytose the bacteria and this step is marked by karyorrhexis. Later, this process is associated with massive breakdown of leucocytes resulting in necrosis and microabscesses. Tissue sections stained by Ziehl–Neelsen showed numerous acid-fast bacteria in the foci of caseous necrosis. An exudative reaction in the form of serous-fibrinous pneumonia or fibrinous-purulent pneumonia with predominance of neutrophilic leucocytes is detected at the periphery of caseous foci. Such

below represent our common findings of infectious and neoplastic diseases in AIDS.

detected in their cytoplasm (Gyorkey et al., 1987).

et al., 2003).

**2.1 Morphology of mycobacterial Infections in HIV patients** 

exudation may extent from lobular up to sub-lobar area. Some alveoli contain accumulations of foamy macrophages that are characteristic for typical tuberculous inflammation. There is an increase in the thickness of the pleura caused by extensive hyperemia and edema. The intrathoracic lymph nodes are also affected, enlarged (3–4 cm in diameter), and aggregated. Partial or total caseous lymphadenitis is detected with the spread of inflammatory processes to the surrounding soft tissues. Evident reduction of follicular structures and lymphoid depletion is a characteristic feature of these lymph nodes.

*Extrapulmonary tuberculosis* is detected as a component of a generalized type of tuberculosis. Monomorphic miliary foci of caseous necrosis are found in various internal organs, more often in the spleen, kidneys, liver, and rarely in the meninges, peritoneum, exo- and endocrine glands (pancreas, adrenals, prostate, thyroid, ovaries). As a whole, in cases of generalized tuberculosis, *Mycobacteria* cause alterative and exudative reactions simultaneously in several organs with the mean number of organs involved is 5.4 (own data). Most of the foci are suspected to be spread via hematogenous dissemination from lungs. Histopathology of the parenchymatous organs reveals monomorphic miliary nodules of caseous necrosis with rare giant cells, as in the lungs. In many cases, tubercles are not visible by visual inspection. In the spleen, the foci of caseous necrosis have a tendency to fuse and may cover up to 50% of the cut surface.

Tuberculous meningitis is characterized grossly by typical basilar localization with poorly detected gray-white exudates and tubercles in the subarachnoid space. Microscopic examination of the meninges reveals evident hyperemia and edema accompanied by alterative reactions. The latter is manifested as areas of caseous necrosis extensively infiltrated by polymorphs, lymphocytes, and macrophages. Various types of vasculitis such as endovasculitis, panvasculitis, thrombovasculitis, and perivasculitis are evident. Perivasculitis is more often present with edema and excessive mononuclear, neutrophilic, eosinophilic, and plasma cell infiltration in all layers of the vessel wall (Fig. 1c). Destructive process may extent into brain tissue with formation of localized abscesses.

*Mycobacterium avium-intracellulare* (MAI) infection leads to massive necrotic destruction of lymph nodes with minor involvement of the lungs. Mostly granulomas are difficult to detect throughout the inner organs by naked eye. The only exception is spleen which is filled with miliary granulomas in roughly half of cases. Different groups of visceral lymph nodes are enlarged and show characteristic yellow tone of cut surface. Microscopically, proliferation of large round to elliptical striated pale blue macrophages is noted. Cytoplasm of these cells is packed with huge number of acid-fast bacilli. Well-formed granulomas with fibrosis, necrosis, and epithelioid histiocytes are present in less than one third of cases (Klatt et al., 1987).

#### **2.2 Morphology of bacterial infections**

#### *Bacterial Pneumonia*

There is a broad spectrum of causative agents of pneumonia revealed by microbiology. Besides typical microflora, bacterial pneumonia can be caused by opportunistic agents, which are activated under immunodeficiency. The most common causative agents of pneumonia are *Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae* and *Escherichia coli* (Afessa et al., 1998).

Pathology of HIV/AIDS: Lessons from Autopsy Series 377

(d) Pneumocystic pneumonia, foamy exudate. H&E, × 100

(e) Cytomegalovirus infection of lung, cell with 'owl-eye' appearance. H&E, × 1200

(f) Pulmonary aspergillosis,

branching hyphae of fungus. PAS, × 600

(a) Pulmonary tuberculosis,

(b) Pulmonary tuberculosis,

(c) Tuberculous meningitis,

panvasculitis with alteration. H&E, × 140

Fig. 1. Microscopic patterns of opportunistic infections in AIDS

granuloma with giant cell. H&E, × 140

foci of caseous necrosis. H&E, × 100

Hematoxylin and eosin together with Gram staining of sections of lungs helps in revealing nonspecific microflora. At autopsy, staining of smears of lung sections using Romanovskii– Giemsa and Gram stains is also useful in establishing the nonspecific character of microflora in cases of bacterial pneumonia. Bacteriological culture of lung tissue helps in revealing the nature of the causative agents of pneumonia most accurately. Grossly, patchy areas of red or grey consolidation involve more often the lower zones of the lungs. On cut surface, these patchy consolidated lesions are dry, granular, firm, red or grey in color, slightly elevated over the surface and are often located around a bronchiole. Histologically, suppurative exudate, consisting of neutrophils with admixture of fibrin, fills alveoli and alveolar septa are dilated by congested capillaries and leucocytic infiltration. Often, the course of pneumonia in HIV-infected patients has a tendency to form microabscesses, and in such cases, the microscopic changes resembles to microfocal dissemination in pulmonary tuberculosis. In microabscesses, purulent necrotic foci are found with expressed perifocal exudative reaction, which strengthened their resemblance to pulmonary tuberculosis in HIV-infected patients.

#### *Sepsis*

Pneumonia and primary bloodstream infections are the main sites of infections for almost all patients with sepsis, followed by angiogenic-related bacteremia originated from thrombophlebitis in intravenous drug users or from venous catheter in bedridden patients and urinary tract infections. Nosocomial infections compose the major part of etiology of severe sepsis. Microbiology of infections is comprised of different species, mostly *Pseudomonas aeruginosa*, *Klebsiella pneumoniae* and *Staphylococcus spp.*, while *Streptococcus spp.*, *Escherichia coli* and *Salmonella spp.* are detected with lower frequency (Japiassú et al., 2010). Microorganisms impact small vessels in the primary site and cause local injury both by obstructing the vessels and by releasing toxins. Subsequently a combination of necrosis, hemorrhage and suppuration occurs, with further formation of pyemic abscesses in the various organs and their distribution depends on the site of the original septic thrombosis. Microscopically, pyemic abscesses are typically surrounded by a zone of hemorrhage and an early lesion may show a central zone of necrosis often containing huge numbers of bacteria. This is surrounded by a zone of suppuration and an outermost zone of acutely inflamed and often hemorrhagic tissue. In septic thrombosis of major veins, larger fragments may be released into the circulation, and by impacting in arteries give rise to correspondingly larger foci of necrosis and suppuration (septic infarcts). In case if it involves heart, pyogenic bacteria may produce endocarditis and severely damage cardiac valves. The vegetations on valve are tend to break down and the valve cusps are largely covered by crumbling masses, which consist of layers of fibrin containing clumps of bacteria enclosed by a zone of leukocytes, macrophages and granulation tissue. The substance of the cusps may be extensively destroyed by suppuration.

#### **2.3 Invasive fungal infections**

*Pneumocystis jirovecii* (former *Pneumocystis carinii*) typically produces pneumonia that is widespread throughout the lungs with a chronic course of disease and rapid progression. Pulmonary pneumocystosis is a disease caused by intense multiplication of relatively pathogenic single-celled saprophyte *Pneumocystis jirovecii* in the human respiratory tract.

Hematoxylin and eosin together with Gram staining of sections of lungs helps in revealing nonspecific microflora. At autopsy, staining of smears of lung sections using Romanovskii– Giemsa and Gram stains is also useful in establishing the nonspecific character of microflora in cases of bacterial pneumonia. Bacteriological culture of lung tissue helps in revealing the nature of the causative agents of pneumonia most accurately. Grossly, patchy areas of red or grey consolidation involve more often the lower zones of the lungs. On cut surface, these patchy consolidated lesions are dry, granular, firm, red or grey in color, slightly elevated over the surface and are often located around a bronchiole. Histologically, suppurative exudate, consisting of neutrophils with admixture of fibrin, fills alveoli and alveolar septa are dilated by congested capillaries and leucocytic infiltration. Often, the course of pneumonia in HIV-infected patients has a tendency to form microabscesses, and in such cases, the microscopic changes resembles to microfocal dissemination in pulmonary tuberculosis. In microabscesses, purulent necrotic foci are found with expressed perifocal exudative reaction, which strengthened their resemblance to pulmonary tuberculosis in

Pneumonia and primary bloodstream infections are the main sites of infections for almost all patients with sepsis, followed by angiogenic-related bacteremia originated from thrombophlebitis in intravenous drug users or from venous catheter in bedridden patients and urinary tract infections. Nosocomial infections compose the major part of etiology of severe sepsis. Microbiology of infections is comprised of different species, mostly *Pseudomonas aeruginosa*, *Klebsiella pneumoniae* and *Staphylococcus spp.*, while *Streptococcus spp.*, *Escherichia coli* and *Salmonella spp.* are detected with lower frequency (Japiassú et al., 2010). Microorganisms impact small vessels in the primary site and cause local injury both by obstructing the vessels and by releasing toxins. Subsequently a combination of necrosis, hemorrhage and suppuration occurs, with further formation of pyemic abscesses in the various organs and their distribution depends on the site of the original septic thrombosis. Microscopically, pyemic abscesses are typically surrounded by a zone of hemorrhage and an early lesion may show a central zone of necrosis often containing huge numbers of bacteria. This is surrounded by a zone of suppuration and an outermost zone of acutely inflamed and often hemorrhagic tissue. In septic thrombosis of major veins, larger fragments may be released into the circulation, and by impacting in arteries give rise to correspondingly larger foci of necrosis and suppuration (septic infarcts). In case if it involves heart, pyogenic bacteria may produce endocarditis and severely damage cardiac valves. The vegetations on valve are tend to break down and the valve cusps are largely covered by crumbling masses, which consist of layers of fibrin containing clumps of bacteria enclosed by a zone of leukocytes, macrophages and granulation tissue. The substance of the cusps may be extensively destroyed by

*Pneumocystis jirovecii* (former *Pneumocystis carinii*) typically produces pneumonia that is widespread throughout the lungs with a chronic course of disease and rapid progression. Pulmonary pneumocystosis is a disease caused by intense multiplication of relatively pathogenic single-celled saprophyte *Pneumocystis jirovecii* in the human

HIV-infected patients.

*Sepsis* 

suppuration.

respiratory tract.

**2.3 Invasive fungal infections** 

(a) Pulmonary tuberculosis, foci of caseous necrosis. H&E, × 100

(b) Pulmonary tuberculosis, granuloma with giant cell. H&E, × 140

(d) Pneumocystic pneumonia, foamy exudate. H&E, × 100

(e) Cytomegalovirus infection of lung, cell with 'owl-eye' appearance. H&E, × 1200

(c) Tuberculous meningitis, panvasculitis with alteration. H&E, × 140

(f) Pulmonary aspergillosis, branching hyphae of fungus. PAS, × 600

Fig. 1. Microscopic patterns of opportunistic infections in AIDS

Pathology of HIV/AIDS: Lessons from Autopsy Series 379

'owl-eye' in the field of view) is accompanied with focal accumulations of serous fluid and protein masses in the alveolar cavities along with admixtures of macrophages and weak infiltration of interstitial tissue. If the lung changes consist of diffuse persisting alveolitis with CMV transformation (up to 20 cells per field of view), then this process is accompanied by extensive fibrosis, but uncommonly leads to the formation of a 'honeycomb-like' appearance of the lungs. The outcome of CMV infection of the lungs is peribronchial and widespread interstitial fibrosis with thickening and vast deformation of the interalveolar septa. Thus, heterogeneous patterns of CMV infection of the lung represent continuous progression of disease and include the following events as virus-induced transformation of the cells, pneumonias with cavity formation, productive granulomatous alveolitis and

*Toxoplasma gondii* is a protozoan parasite which is highly prevalent among humans and animals throughout the world. Immunocompromised patients are especially prone to develop disseminated toxoplasmosis, either from acute exposure to the organisms or from reactivation of latent infection. Multiple organ systems are often involved, including the CNS, heart, lungs and skeletal muscle. Damage to the CNS by *Toxoplasma gondii* is characterized by numerous foci of enlarging necrosis and microglia nodules. The former are often resolved with cyst formation or calcification. Presence of many brain abscesses with almost universal involvement of the cerebral hemispheres is the most characteristic feature of toxoplasmic encephalitis in AIDS patients. The diagnosis of toxoplasmosis is readily made from histologic analysis of tissue specimens by observing any of the three infectious stages of *T. gondii*: tachyzoites in groups, bradyzoites (parasitic tissue cysts) or sporozoites within oocysts. Tachyzoites and cysts are seen in and adjacent to necrotic foci near or in glial nodules, perivascular regions, and even in uninvolved cerebral tissue. Reactive

inflammatory reaction is comprised of mixed infiltrate distributed in patchy pattern.

epithelial or mesothelial surfaces, or near the capsules of organs.

*Kaposi's sarcoma* is a low-grade mesenchymal tumor which arises initially as an angioproliferative disorder caused by *Kaposi's sarcoma-associated herpes virus* (Du et al., 2007). Skin involvement is common and manifested by the presence of red to red-purple lesions ranging from flat patches to slightly raised plaques and nodules. Visceral involvement frequently includes the lung, lymph nodes, and gastrointestinal tract. Microscopically, Kaposi's sarcoma features clusters of tiny apparent capillaries budding off normal blood vessels. It grows as massed bundles of spindle cells, with red blood cells in slits between them. Hemosiderin pigmentation and hyaline globules usually accompany the spindle cell proliferation. Tumor has an ability to infiltrate around large vascular structures, near

*Non-Hodgkin lymphomas* (NHL) risk in AIDS patients is increased more than 70 times comparing with general population (Frisch et al., 2001). Malignant non-Hodgkin's lymphomas (mostly intermediate- to high-grade tumors) exhibit two major patterns which include systemic and CNS lymphomas. These lymphomas often show evidence of *Epstein-Barr virus* as etiologic agent (Fassone et al., 2002). AIDS-related lymphomas consistently determine a B-cell phenotype and are histogenetically related to germinal center or postgerminal center B-cells in the vast majority of cases. About 80% of NHL's in AIDS arise systemically, either nodally or extranodally, while 20% arise in the central nervous system. Almost any extranodal site can be involved with predominance of bone

eventually pulmonary fibrosis (Parkhomenko et al., 2004).

**2.5 HIV-associated neoplasia** 

The terminal period of pneumocystosis is pneumonia, manifested in the later stages of HIV infection, which often leads to death. The gross appearance resembles to pneumonic consolidation. The cut surface of the lung is pale pink with scattered areas of congestion and rarely hemorrhages. Microscopically, in the edematous stage, characteristic homogenous, foamy protein-containing eosinophilic exudate is found in the alveolar lumen (Fig. 1d). This is a pathognomonic sign of pneumocystic pneumonia. Neutrophils, macrophages and plasma cells are detected around the collections of *Pneumocystis jirovecii*.

*Cryptococcus neoformans* in immunocompromised hosts may spread from lungs, which is the site of primary infection, to distant organs anh most frequently affecting the central nervous system and causes meningitis. Pulmonary manifestations exhibit pneumonitis, pulmonary nodules or less commonly pleural effusions. Sometimes variably sized pale soft granulomas are grossly visible in the lungs. If fungi with capsules are numerous, a grossly apparent mucoid exudate may be seen in the cerebral ventricles or on the meninges. Microscopically, the yeast cells appear pale blue and ovoid while the capsule is round and clear. Inflammatory reaction is weak and represented by a few scattered lymphocytes or macrophages with phagocytized organisms. PAS stain is effective for detection of the capsule and nucleus of the organisms.

*Candida albicans* infection is one of the most prevalent in patients with AIDS, ranging from localized skin and mucosa lesions to widely disseminated disease. Characteristic gross findings of candidiasis are prominent in the pharynx, larynx, and trachea with invasion into principle bronchi, which includes a pseudomembranous form with white, elevated mucosal plaques. Bronchopulmonary aspergillosis and candidiasis are characterized by the collection of fungal mycelia in the lumen of small bronchi and invasion of fungus into the acini. *Candida* microabscesses are common and they had a typical polymorphonuclear leucocytes infiltration. Histologically, *Candida* organisms could be identified by their size, budding property, and pseudohyphae. The pseudohyphae could be distinguished from *Aspergillus* hyphae by the lack of branching, the smaller size, and frequent absence of true septations in the former. Histological diagnosis may be confirmed using the Romanovskii staining technique, which is helpful in differentiation between *Candida* and *Aspergillus*. Bronchopulmonary aspergillosis is characterized by the collection of branching mycelia of *Aspergillus* in the bronchial lumen with involvement of the bronchial wall and further invasion of the fungus into the acini (Fig. 1f).

#### **2.4 Viral and parasitic infections**

*Cytomegalovirus* (CMV) *infection* is one the most prevalent secondary diseases in AIDS. It is featured by multiple organs involvement, including lungs, digestive system, brain and eyes. CMV infection proceeds diversely from latent infection to severe acute generalization in the later stages of HIV infection. Microscopically, CMV lesions appear as characteristic metamorphosis of alveolar and bronchial epithelium (Fig. 1e). The persistence of viruses in the epithelial cells leads to cytomegalic giant cell formation. Alveolar cells increase in size up to 25–40 m. About 1–2 nuclear inclusions are detected containing viral particles in the chromatin in each cell and there is a thin perinuclear clear halo. The nucleus of each affected cell is usually eccentrically positioned and the cell border is not prominent. Additionally, the cytoplasm of affected cells may contain coarse dark basophilic bodies. Characteristic infiltrative changes and CMV transformations are numerous. Moderate cytomegalic transformation of alveolar and bronchial epithelial cells (2–3 typical cells in the form of an

The terminal period of pneumocystosis is pneumonia, manifested in the later stages of HIV infection, which often leads to death. The gross appearance resembles to pneumonic consolidation. The cut surface of the lung is pale pink with scattered areas of congestion and rarely hemorrhages. Microscopically, in the edematous stage, characteristic homogenous, foamy protein-containing eosinophilic exudate is found in the alveolar lumen (Fig. 1d). This is a pathognomonic sign of pneumocystic pneumonia. Neutrophils, macrophages and

*Cryptococcus neoformans* in immunocompromised hosts may spread from lungs, which is the site of primary infection, to distant organs anh most frequently affecting the central nervous system and causes meningitis. Pulmonary manifestations exhibit pneumonitis, pulmonary nodules or less commonly pleural effusions. Sometimes variably sized pale soft granulomas are grossly visible in the lungs. If fungi with capsules are numerous, a grossly apparent mucoid exudate may be seen in the cerebral ventricles or on the meninges. Microscopically, the yeast cells appear pale blue and ovoid while the capsule is round and clear. Inflammatory reaction is weak and represented by a few scattered lymphocytes or macrophages with phagocytized organisms. PAS stain is effective for detection of the

*Candida albicans* infection is one of the most prevalent in patients with AIDS, ranging from localized skin and mucosa lesions to widely disseminated disease. Characteristic gross findings of candidiasis are prominent in the pharynx, larynx, and trachea with invasion into principle bronchi, which includes a pseudomembranous form with white, elevated mucosal plaques. Bronchopulmonary aspergillosis and candidiasis are characterized by the collection of fungal mycelia in the lumen of small bronchi and invasion of fungus into the acini. *Candida* microabscesses are common and they had a typical polymorphonuclear leucocytes infiltration. Histologically, *Candida* organisms could be identified by their size, budding property, and pseudohyphae. The pseudohyphae could be distinguished from *Aspergillus* hyphae by the lack of branching, the smaller size, and frequent absence of true septations in the former. Histological diagnosis may be confirmed using the Romanovskii staining technique, which is helpful in differentiation between *Candida* and *Aspergillus*. Bronchopulmonary aspergillosis is characterized by the collection of branching mycelia of *Aspergillus* in the bronchial lumen with involvement of the bronchial wall and further

*Cytomegalovirus* (CMV) *infection* is one the most prevalent secondary diseases in AIDS. It is featured by multiple organs involvement, including lungs, digestive system, brain and eyes. CMV infection proceeds diversely from latent infection to severe acute generalization in the later stages of HIV infection. Microscopically, CMV lesions appear as characteristic metamorphosis of alveolar and bronchial epithelium (Fig. 1e). The persistence of viruses in the epithelial cells leads to cytomegalic giant cell formation. Alveolar cells increase in size up to 25–40 m. About 1–2 nuclear inclusions are detected containing viral particles in the chromatin in each cell and there is a thin perinuclear clear halo. The nucleus of each affected cell is usually eccentrically positioned and the cell border is not prominent. Additionally, the cytoplasm of affected cells may contain coarse dark basophilic bodies. Characteristic infiltrative changes and CMV transformations are numerous. Moderate cytomegalic transformation of alveolar and bronchial epithelial cells (2–3 typical cells in the form of an

plasma cells are detected around the collections of *Pneumocystis jirovecii*.

capsule and nucleus of the organisms.

invasion of the fungus into the acini (Fig. 1f).

**2.4 Viral and parasitic infections** 

'owl-eye' in the field of view) is accompanied with focal accumulations of serous fluid and protein masses in the alveolar cavities along with admixtures of macrophages and weak infiltration of interstitial tissue. If the lung changes consist of diffuse persisting alveolitis with CMV transformation (up to 20 cells per field of view), then this process is accompanied by extensive fibrosis, but uncommonly leads to the formation of a 'honeycomb-like' appearance of the lungs. The outcome of CMV infection of the lungs is peribronchial and widespread interstitial fibrosis with thickening and vast deformation of the interalveolar septa. Thus, heterogeneous patterns of CMV infection of the lung represent continuous progression of disease and include the following events as virus-induced transformation of the cells, pneumonias with cavity formation, productive granulomatous alveolitis and eventually pulmonary fibrosis (Parkhomenko et al., 2004).

*Toxoplasma gondii* is a protozoan parasite which is highly prevalent among humans and animals throughout the world. Immunocompromised patients are especially prone to develop disseminated toxoplasmosis, either from acute exposure to the organisms or from reactivation of latent infection. Multiple organ systems are often involved, including the CNS, heart, lungs and skeletal muscle. Damage to the CNS by *Toxoplasma gondii* is characterized by numerous foci of enlarging necrosis and microglia nodules. The former are often resolved with cyst formation or calcification. Presence of many brain abscesses with almost universal involvement of the cerebral hemispheres is the most characteristic feature of toxoplasmic encephalitis in AIDS patients. The diagnosis of toxoplasmosis is readily made from histologic analysis of tissue specimens by observing any of the three infectious stages of *T. gondii*: tachyzoites in groups, bradyzoites (parasitic tissue cysts) or sporozoites within oocysts. Tachyzoites and cysts are seen in and adjacent to necrotic foci near or in glial nodules, perivascular regions, and even in uninvolved cerebral tissue. Reactive inflammatory reaction is comprised of mixed infiltrate distributed in patchy pattern.

#### **2.5 HIV-associated neoplasia**

*Kaposi's sarcoma* is a low-grade mesenchymal tumor which arises initially as an angioproliferative disorder caused by *Kaposi's sarcoma-associated herpes virus* (Du et al., 2007). Skin involvement is common and manifested by the presence of red to red-purple lesions ranging from flat patches to slightly raised plaques and nodules. Visceral involvement frequently includes the lung, lymph nodes, and gastrointestinal tract. Microscopically, Kaposi's sarcoma features clusters of tiny apparent capillaries budding off normal blood vessels. It grows as massed bundles of spindle cells, with red blood cells in slits between them. Hemosiderin pigmentation and hyaline globules usually accompany the spindle cell proliferation. Tumor has an ability to infiltrate around large vascular structures, near epithelial or mesothelial surfaces, or near the capsules of organs.

*Non-Hodgkin lymphomas* (NHL) risk in AIDS patients is increased more than 70 times comparing with general population (Frisch et al., 2001). Malignant non-Hodgkin's lymphomas (mostly intermediate- to high-grade tumors) exhibit two major patterns which include systemic and CNS lymphomas. These lymphomas often show evidence of *Epstein-Barr virus* as etiologic agent (Fassone et al., 2002). AIDS-related lymphomas consistently determine a B-cell phenotype and are histogenetically related to germinal center or postgerminal center B-cells in the vast majority of cases. About 80% of NHL's in AIDS arise systemically, either nodally or extranodally, while 20% arise in the central nervous system. Almost any extranodal site can be involved with predominance of bone

Pathology of HIV/AIDS: Lessons from Autopsy Series 381

Since the first years of HIV/AIDS pathology has contributed significantly to study of new disease. Before mid-1990s various changes of organs and systems studied with different pathological techniques were described in numerous publications. The data taken from the study of autopsy series have shown that postmortem examination is extremely valuable for determining wide range of AIDS-related diseases. Diagnostic role of the autopsy is enhanced considerably by employment of histological examination of the organs. Such specimens can be further proceeded to staining with special techniques useful in detection of microorganisms or immunohistochemistry and even to molecular biological techniques. Thus, complete postmortem study allows determining the cause of death and contributed pathologies, it may identify diseases and etiological agents that were clinically unsuspected or undiagnosed. By providing these types of data, the autopsy serves as an important measure in monitoring the quality of care, basically comparing antemortem with postmortem findings. Autopsy remains established tool for obtaining epidemiological information about diseases and producing vital statistics, since systematic postmortem examination provides representative data on the main pathologies in distinct communities and permits evaluation of changes that may occur over time (Lanjewar, 2011; Lyon et al., 1996). Postmortem surveillance is vital for monitoring the course of HIV-infection and

However, over the past decades, autopsy rates have markedly declined all over the world due to various reasons (Table 1). Advances in laboratory and radiological diagnostics contribute in recognizing different AIDS-related diseases and diminish diagnostic value of

*Difficulties in obtaining consent* 


*Risk of infection for staff* 


*High costs* 


*High efficiency of clinical diagnostic tools:* 

*Choice of 'alternative autopsy' techniques:* 

**3.1 Value of autopsy** 

autopsy.

*Diagnostic value:*  - gross findings, - histological analysis,

*Epidemiological needs:*  - death records,

*Educational goals:*  - for students,

*Scientific potential:*  - case reports, - series reports,


promotes clinicians awareness (Sehonanda et al., 1996).

Benefits Limitations




Table 1. The AIDS autopsies today: *Pros & Cons* 

marrow, gastrointestinal tract and liver. NHLs appear as small infiltrates, focal nodular lesions, or larger tumor masses with accompanying necrosis and hemorrhage. Microscopically, tumors generally referred to diffuse large B-cell lymphomas or highgrade B-cell (small non-cleaved) Burkitt-like lymphomas, according to REAL classification. Immunohistochemistry is a routine diagnostic tool in typing of these lesions.

## **3. Autopsy series**

AIDS was recognized in 1981 for the first time, resulting in the deaths of more than 25 million people. Since the late 1990s approximately 2 million HIV-infected persons are reported to have died annually (UNAIDS, 2009). Distribution of the regions with the highest death tolls is determined by the prevalence of HIV infection. Countries of Sub-Saharan Africa are the worst-affected, followed by South and South-East Asia. Most countries with high rates of AIDS prevalence have published reports on autopsy series to date (Fig. 2). Currently, there is a global decline of autopsy rates as a consequence of improved patient management, introduction of etiologic therapy and preventive measures. However such advances are available only in developed countries, where postmortem examination has lost the status of routine diagnostic procedure. Concurrently only few recent reports from Sub-Saharan Africa are available while the pace of HIV epidemics is still very high. Moreover, some countries with high AIDS burden (more than 500,000 infected) including Thailand, China and Ukraine are yet to present large autopsy series.

Fig. 2. Worldwide representative autopsy series

## **3.1 Value of autopsy**

380 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

marrow, gastrointestinal tract and liver. NHLs appear as small infiltrates, focal nodular lesions, or larger tumor masses with accompanying necrosis and hemorrhage. Microscopically, tumors generally referred to diffuse large B-cell lymphomas or highgrade B-cell (small non-cleaved) Burkitt-like lymphomas, according to REAL classification. Immunohistochemistry is a routine diagnostic tool in typing of these

AIDS was recognized in 1981 for the first time, resulting in the deaths of more than 25 million people. Since the late 1990s approximately 2 million HIV-infected persons are reported to have died annually (UNAIDS, 2009). Distribution of the regions with the highest death tolls is determined by the prevalence of HIV infection. Countries of Sub-Saharan Africa are the worst-affected, followed by South and South-East Asia. Most countries with high rates of AIDS prevalence have published reports on autopsy series to date (Fig. 2). Currently, there is a global decline of autopsy rates as a consequence of improved patient management, introduction of etiologic therapy and preventive measures. However such advances are available only in developed countries, where postmortem examination has lost the status of routine diagnostic procedure. Concurrently only few recent reports from Sub-Saharan Africa are available while the pace of HIV epidemics is still very high. Moreover, some countries with high AIDS burden (more than 500,000 infected) including Thailand, China and Ukraine are yet to present large autopsy

lesions.

series.

Fig. 2. Worldwide representative autopsy series

**3. Autopsy series** 

Since the first years of HIV/AIDS pathology has contributed significantly to study of new disease. Before mid-1990s various changes of organs and systems studied with different pathological techniques were described in numerous publications. The data taken from the study of autopsy series have shown that postmortem examination is extremely valuable for determining wide range of AIDS-related diseases. Diagnostic role of the autopsy is enhanced considerably by employment of histological examination of the organs. Such specimens can be further proceeded to staining with special techniques useful in detection of microorganisms or immunohistochemistry and even to molecular biological techniques. Thus, complete postmortem study allows determining the cause of death and contributed pathologies, it may identify diseases and etiological agents that were clinically unsuspected or undiagnosed. By providing these types of data, the autopsy serves as an important measure in monitoring the quality of care, basically comparing antemortem with postmortem findings. Autopsy remains established tool for obtaining epidemiological information about diseases and producing vital statistics, since systematic postmortem examination provides representative data on the main pathologies in distinct communities and permits evaluation of changes that may occur over time (Lanjewar, 2011; Lyon et al., 1996). Postmortem surveillance is vital for monitoring the course of HIV-infection and promotes clinicians awareness (Sehonanda et al., 1996).

However, over the past decades, autopsy rates have markedly declined all over the world due to various reasons (Table 1). Advances in laboratory and radiological diagnostics contribute in recognizing different AIDS-related diseases and diminish diagnostic value of autopsy.


Table 1. The AIDS autopsies today: *Pros & Cons* 

Pathology of HIV/AIDS: Lessons from Autopsy Series 383

Table 2. Autopsy findings from the largest autopsy series.

Health care systems of developed countries offer high-quality diagnostic opportunities for HIV patients, while in developing countries such options have limited availability. Another one concern is that most relatives of died patients are not willing to provide consent for an autopsy because of cultural, traditional and other beliefs (Garcia-Jardon et al., 2010). It is important for clinicians to approach families for autopsy consent. From the other hand, some pathologists and technicians avoid to carry out autopsies on HIV infected cases, because of risk to be infected (Lanjewar, 2011). A major challenge in applying autopsy for AIDS cases is the rising trend of so-called 'alternative autopsy' techniques. Whereas incomplete autopsies such as examination of selected organs or needle autopsy may be accepted partially as being equivalent to a full autopsy, noninvasive procedures like virtual autopsy and echopsy cannot substitute for conventional necropsy techniques (Burton & Underwood, 2007). Verbal autopsy which appears to be gaining acceptance in developing countries (Bhattacharya & Neogi, 2008) is in no way an objective diagnostic technique. Postmortem examination should include collection of organs specimens for histological study; any exception to this rule will markedly decrease the value of autopsy.

#### **3.2 Results**

We have analyzed the largest autopsy series from different continents that covered the time period from 1982 to 2011 (Table 2). The main focus was on the prevalence of AIDS-indicative diseases and their distribution according to time periods and geography. Opportunistic infections were the most common autopsy findings, followed by less frequent secondary neoplasms.

Mycobacterial infections were detected in all the series with the lowest frequency around 20% (Afessa et al., 1998; Guerra et al., 2001; Soeiro et al., 2008). In developed countries such as Italy, Germany and Japan, the prevalence of tuberculosis in autopsies of patients with HIV/AIDS is 5-7%, whereas these rates were found to be 38-59% mostly in developing countries (Ansari et al., 2002; d'Arminio Monforte et al., 1992; Hsiao et al., 1997; Kaiser et al., 2000; Lucas et al., 1993; Ohtomo et al., 2000). Pulmonary lesions tend to hematogenous spread, thus the disseminated variant was described in 60-90% cases (Ansari et al., 2002; Cury et al., 2003; Parkhomenko et al., 2003; Rana et al., 2000; Soeiro et al., 2008). Extremely high rates of tuberculosis were reported in recent studies from Russia and India, 82% and 68%, respectively (Berdnikov et al., 2011; Lanjewar, 2011). Emergence of tuberculosis became obvious only in the last decade, when dramatic increase of this infection was implicated as a prime cause of death in AIDS patients. The main reason for such burden in Russia is the overlapping of prior independent epidemics of HIV and tuberculosis with subsequent merging and fast spread through neglected population groups like intravenous drug users, prisoners, alcoholics, homeless persons. Modern HIV-associated tuberculosis is a highly aggressive destructive process in the lungs caused by multidrug resistant strains of *Mycobacteria* and characterized by widespread dissemination and extrapulmonary involvement (Berdnikov et al., 2011).

Currently MAI infections are not of major significance, but they featured notably in the early series from USA and Europe (Guerra et al., 2001; Jellinger et al., 2000; Klatt et al., 1994; Masliah et al., 2000).


Table 2. Autopsy findings from the largest autopsy series.

Health care systems of developed countries offer high-quality diagnostic opportunities for HIV patients, while in developing countries such options have limited availability. Another one concern is that most relatives of died patients are not willing to provide consent for an autopsy because of cultural, traditional and other beliefs (Garcia-Jardon et al., 2010). It is important for clinicians to approach families for autopsy consent. From the other hand, some pathologists and technicians avoid to carry out autopsies on HIV infected cases, because of risk to be infected (Lanjewar, 2011). A major challenge in applying autopsy for AIDS cases is the rising trend of so-called 'alternative autopsy' techniques. Whereas incomplete autopsies such as examination of selected organs or needle autopsy may be accepted partially as being equivalent to a full autopsy, noninvasive procedures like virtual autopsy and echopsy cannot substitute for conventional necropsy techniques (Burton & Underwood, 2007). Verbal autopsy which appears to be gaining acceptance in developing countries (Bhattacharya & Neogi, 2008) is in no way an objective diagnostic technique. Postmortem examination should include collection of organs specimens for histological study; any exception to this rule will markedly decrease

We have analyzed the largest autopsy series from different continents that covered the time period from 1982 to 2011 (Table 2). The main focus was on the prevalence of AIDS-indicative diseases and their distribution according to time periods and geography. Opportunistic infections were the most common autopsy findings, followed by less frequent secondary

Mycobacterial infections were detected in all the series with the lowest frequency around 20% (Afessa et al., 1998; Guerra et al., 2001; Soeiro et al., 2008). In developed countries such as Italy, Germany and Japan, the prevalence of tuberculosis in autopsies of patients with HIV/AIDS is 5-7%, whereas these rates were found to be 38-59% mostly in developing countries (Ansari et al., 2002; d'Arminio Monforte et al., 1992; Hsiao et al., 1997; Kaiser et al., 2000; Lucas et al., 1993; Ohtomo et al., 2000). Pulmonary lesions tend to hematogenous spread, thus the disseminated variant was described in 60-90% cases (Ansari et al., 2002; Cury et al., 2003; Parkhomenko et al., 2003; Rana et al., 2000; Soeiro et al., 2008). Extremely high rates of tuberculosis were reported in recent studies from Russia and India, 82% and 68%, respectively (Berdnikov et al., 2011; Lanjewar, 2011). Emergence of tuberculosis became obvious only in the last decade, when dramatic increase of this infection was implicated as a prime cause of death in AIDS patients. The main reason for such burden in Russia is the overlapping of prior independent epidemics of HIV and tuberculosis with subsequent merging and fast spread through neglected population groups like intravenous drug users, prisoners, alcoholics, homeless persons. Modern HIV-associated tuberculosis is a highly aggressive destructive process in the lungs caused by multidrug resistant strains of *Mycobacteria* and characterized by widespread dissemination and extrapulmonary involvement

Currently MAI infections are not of major significance, but they featured notably in the early series from USA and Europe (Guerra et al., 2001; Jellinger et al., 2000; Klatt et al., 1994;

the value of autopsy.

(Berdnikov et al., 2011).

Masliah et al., 2000).

**3.2 Results** 

neoplasms.

Pathology of HIV/AIDS: Lessons from Autopsy Series 385

are chronic liver diseases, cardiovascular pathology and malignancies (d'Arminio Monforte, 2009; Friis-Møller et al., 2010; Lucas et al., 2008; Sackoff et al., 2006). Cases of hepatic involvement are extremely common in HIV-infected cohort of intravenous drug users with HCV co-infection which may die from liver cirrhosis or necrotizing liver failure (Guerra et

One of the important utilities of autopsy is the correlation between antemortem and postmortem diagnosis. A recent review from the UK spanning 23 years showed that the autopsy findings altered the primary diagnosis in 70% of cases, and that 36% of opportunistic infections were not diagnosed prior to death (Beadsworth et al., 2009). An Indian series showed discordance between antemortem and postmortem diagnosis in 42% cases (Lanjewar, 2011). Russian authors reported that in 7% of cases HIV infection (!) was detected only postmortem (Berdnikov et al., 2011). Both false positive as well as false negative antemortem diagnoses are described (Martinson et al., 2007). Infections such tuberculosis, *Cytomegalovirus* and invasive mycoses are missed with the highest rate (Antinori et al., 2009; Beadsworth et al.,

The most notable changes described in reviewed series are the rise of tuberculosis infection and bacterial pneumonias for last 10 years (Fig. 3). Tuberculosis is often represented by generalized and disseminated forms. Bacterial infections still occur more frequently than other opportunistic infections in patients with HIV. Multiple infections with involvement of

Abbreviations: PCP, pneumocystic pneumonia; CMV, *Cytomegalovirus* infection; MAI, *Mycobacterium avium-intracellulare* infection; TB, tuberculosis; IFI, invasive fungal infections; Toxo, toxoplasmosis

Lungs and central nervous system are the most common targets for pathological processes. The incidence of pneumocystic pneumonia has declined significantly as a result of antiretroviral therapy and chemoprophylaxis. Rates of CMV infection also had been

Fig. 3. Major changing patterns of AIDS reported in retrospective studies.

decreased, but not so markedly as pneumocystosis.

2009; Eza et al., 2006; Tang et al., 2006; Wilkes et al., 1988).

al., 2001).

**3.3 Current trends** 

several organs are common.

Similarly, bacterial infections in the same way as tuberculosis showed a marked rise in the last decades and represent an important cause of mortality in AIDS patients. Bacterial pneumonias were identified in 21-36% of cases from low- and middle-income countries (Ansari et al., 2002; Garcia-Jardon et al., 2010; Lanjewar, 2011; Soeiro et al., 2008). Early American sets often not mentioned pneumonias apart from pyogenic infections like sepsis, because they were included in the list of AIDS criteria subsequently. HIV patients are prone to nosocomial pneumonias caused by bacterial associations which demonstrate relapsing course with complications such as abscess formation and pleural effusion (Parkhomenko et al., 2003).

The prevalence of *Cytomegalovirus* infection ranges from 13-19% in African, Indian and Brasilian series to 46-69% cases from USA and Europe (Jellinger et al., 2000; Klatt et al., 1994; Lyon et al., 1996; Masliah et al., 2000; Pillay et al. 1993; Walewska-Zielecka et al., 1996). The highest rates of 74-76% were described in Japan and Australia (Dore et al., 1995; Ohtomo et al., 2000). Among invasive fungal infections pneumocystosis exhibits most significant decline due to effective prophylaxis and introduction of highly active anti-retroviral therapy (HAART). Early reports described high prevalence of pneumocystic pneumonias in more than half of all patients (Klatt et al., 1994), however recent studies could reveal *Pneumocystis jirovecii* pneumonia in less than 10% cases (Parkhomenko et al., 2003). Low levels of pneumocystosis are also specific for African countries regardless time period (Garcia-Jardon et al., 2010; Lucas et al., 1993; Nelson et al., 1993). A large retrospective study of an Italian cohort showed that the prevalence of opportunistic mycoses decreased over time, owing mainly to a significant decrease in pneumocystosis and cryptococcosis, whereas the prevalence of aspergillosis and histoplasmosis remained relatively stable while that of candidiasis tended to increase in the last years (Antinori et al., 2009). Rates of toxoplasmosis showed no significant variation for decades and comprise 1-10% of cases (Cury et al., 2003; Guerra et al., 2001; Sehonanda et al., 1996). The levels of HIV-related neoplasms seem to be decreasing over time, which was demonstrated for both non-Hodgkin's lymphomas and Kaposi's sarcomas in reviewed series (Jones et al., 1999; Launay & Guillevin, 2003).

The main patterns of organ/system involvement in AIDS are pulmonary, generalized or system isolated (CNS, digestive system). In most autopsy series of HIV-infected patients, pulmonary pattern was the most common with an incidence of 60–88%, followed by the CNS (60–80%), and the gastrointestinal tract (Concepcion et al., 1996; Cox et al., 2010; Hofman et al., 1999; Jellinger et al., 2000; Mohar et al., 1992; Sehonanda et al., 1996). Opportunistic monoinfection was observed on the highest level only in 40% cases, while most postmortem studies detected several microbial agents (Rana et al., 2000; Soeiro et al., 2008).

Cases with advanced CNS alterations have a high frequency of opportunistic infections and neoplasms (Masliah et al., 2000). A generalized pattern may be caused by virtually all opportunistic agents, but the most disseminating microorganism today is *Mycobacterium tuberculosis* (Parkhomenko et al., 2003).

Not all deaths of AIDS patients are related to HIV. The percentage of deaths from AIDSrelated diseases has decreased, especially in those countries where highly active antiretroviral therapy is widely available. Non-AIDS causes in high-income countries account for at least a third of deaths, and include non-natural causes such as drug overdose, suicide, and violence along with various somatic diseases (Kohli et al., 2005; Krentz et al., 2005). Important non-HIV-related complications contributing to mortality of AIDS patients are chronic liver diseases, cardiovascular pathology and malignancies (d'Arminio Monforte, 2009; Friis-Møller et al., 2010; Lucas et al., 2008; Sackoff et al., 2006). Cases of hepatic involvement are extremely common in HIV-infected cohort of intravenous drug users with HCV co-infection which may die from liver cirrhosis or necrotizing liver failure (Guerra et al., 2001).

One of the important utilities of autopsy is the correlation between antemortem and postmortem diagnosis. A recent review from the UK spanning 23 years showed that the autopsy findings altered the primary diagnosis in 70% of cases, and that 36% of opportunistic infections were not diagnosed prior to death (Beadsworth et al., 2009). An Indian series showed discordance between antemortem and postmortem diagnosis in 42% cases (Lanjewar, 2011). Russian authors reported that in 7% of cases HIV infection (!) was detected only postmortem (Berdnikov et al., 2011). Both false positive as well as false negative antemortem diagnoses are described (Martinson et al., 2007). Infections such tuberculosis, *Cytomegalovirus* and invasive mycoses are missed with the highest rate (Antinori et al., 2009; Beadsworth et al., 2009; Eza et al., 2006; Tang et al., 2006; Wilkes et al., 1988).

## **3.3 Current trends**

384 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Similarly, bacterial infections in the same way as tuberculosis showed a marked rise in the last decades and represent an important cause of mortality in AIDS patients. Bacterial pneumonias were identified in 21-36% of cases from low- and middle-income countries (Ansari et al., 2002; Garcia-Jardon et al., 2010; Lanjewar, 2011; Soeiro et al., 2008). Early American sets often not mentioned pneumonias apart from pyogenic infections like sepsis, because they were included in the list of AIDS criteria subsequently. HIV patients are prone to nosocomial pneumonias caused by bacterial associations which demonstrate relapsing course with complications such as abscess formation and pleural effusion (Parkhomenko et

The prevalence of *Cytomegalovirus* infection ranges from 13-19% in African, Indian and Brasilian series to 46-69% cases from USA and Europe (Jellinger et al., 2000; Klatt et al., 1994; Lyon et al., 1996; Masliah et al., 2000; Pillay et al. 1993; Walewska-Zielecka et al., 1996). The highest rates of 74-76% were described in Japan and Australia (Dore et al., 1995; Ohtomo et al., 2000). Among invasive fungal infections pneumocystosis exhibits most significant decline due to effective prophylaxis and introduction of highly active anti-retroviral therapy (HAART). Early reports described high prevalence of pneumocystic pneumonias in more than half of all patients (Klatt et al., 1994), however recent studies could reveal *Pneumocystis jirovecii* pneumonia in less than 10% cases (Parkhomenko et al., 2003). Low levels of pneumocystosis are also specific for African countries regardless time period (Garcia-Jardon et al., 2010; Lucas et al., 1993; Nelson et al., 1993). A large retrospective study of an Italian cohort showed that the prevalence of opportunistic mycoses decreased over time, owing mainly to a significant decrease in pneumocystosis and cryptococcosis, whereas the prevalence of aspergillosis and histoplasmosis remained relatively stable while that of candidiasis tended to increase in the last years (Antinori et al., 2009). Rates of toxoplasmosis showed no significant variation for decades and comprise 1-10% of cases (Cury et al., 2003; Guerra et al., 2001; Sehonanda et al., 1996). The levels of HIV-related neoplasms seem to be decreasing over time, which was demonstrated for both non-Hodgkin's lymphomas and

Kaposi's sarcomas in reviewed series (Jones et al., 1999; Launay & Guillevin, 2003).

The main patterns of organ/system involvement in AIDS are pulmonary, generalized or system isolated (CNS, digestive system). In most autopsy series of HIV-infected patients, pulmonary pattern was the most common with an incidence of 60–88%, followed by the CNS (60–80%), and the gastrointestinal tract (Concepcion et al., 1996; Cox et al., 2010; Hofman et al., 1999; Jellinger et al., 2000; Mohar et al., 1992; Sehonanda et al., 1996). Opportunistic monoinfection was observed on the highest level only in 40% cases, while most postmortem studies detected several microbial agents (Rana et al., 2000; Soeiro et al.,

Cases with advanced CNS alterations have a high frequency of opportunistic infections and neoplasms (Masliah et al., 2000). A generalized pattern may be caused by virtually all opportunistic agents, but the most disseminating microorganism today is *Mycobacterium* 

Not all deaths of AIDS patients are related to HIV. The percentage of deaths from AIDSrelated diseases has decreased, especially in those countries where highly active antiretroviral therapy is widely available. Non-AIDS causes in high-income countries account for at least a third of deaths, and include non-natural causes such as drug overdose, suicide, and violence along with various somatic diseases (Kohli et al., 2005; Krentz et al., 2005). Important non-HIV-related complications contributing to mortality of AIDS patients

al., 2003).

2008).

*tuberculosis* (Parkhomenko et al., 2003).

The most notable changes described in reviewed series are the rise of tuberculosis infection and bacterial pneumonias for last 10 years (Fig. 3). Tuberculosis is often represented by generalized and disseminated forms. Bacterial infections still occur more frequently than other opportunistic infections in patients with HIV. Multiple infections with involvement of several organs are common.

Abbreviations: PCP, pneumocystic pneumonia; CMV, *Cytomegalovirus* infection; MAI, *Mycobacterium avium-intracellulare* infection; TB, tuberculosis; IFI, invasive fungal infections; Toxo, toxoplasmosis

Fig. 3. Major changing patterns of AIDS reported in retrospective studies.

Lungs and central nervous system are the most common targets for pathological processes. The incidence of pneumocystic pneumonia has declined significantly as a result of antiretroviral therapy and chemoprophylaxis. Rates of CMV infection also had been decreased, but not so markedly as pneumocystosis.

Pathology of HIV/AIDS: Lessons from Autopsy Series 387

Authors would like to thank Dr. Jimson W. D'Souza (Smolensk State Medical Academy), Dr. Florence Orim (Nagasaki University Graduate School of Biomedical Sciences), Dr. Jitender Singh (Sir Ganga Ram Hospital, New Delhi) and Dr. Larisa Skrobut (Smolensk Regional

This work was supported by Grant-in-Aid for Scientific Research by Ministry of Health, Labor and Welfare of Japan #H22-AIDS-nominated type-G009, "Patients' participated

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**5. Acknowledgment**

**6. References** 

The possible concern of described results is that early autopsy series from our set represent high-income developed countries and the most recent series are from low- and middleincome countries. Therefore, it is more correct to report about emergence of HIV-related tuberculosis in developing countries than all over the world. Actually, in Western world (high-income model) tuberculosis spreads through HIV-infected cohort, while in Russia and India social conditions drives tuberculosis in neglected population (alcoholics, imprisons, homeless), that is superimposed by HIV. Contribution of non-HIV-related pathology in AIDS mortality depends on availability of HAART and, consequently, economical development of the country.

Finally, we may suppose that current trends in AIDS mortality for low- and high-income countries are different. Emergence of tuberculosis and high prevalence of bacterial infections are typical for Sub-Saharan Africa, South-East Asia and Eastern Europe. Growth of non-AIDS-related diseases is observed in USA and Western Europe.

## **4. Conclusion**

Through the whole timeline of HIV epidemics significant differences in epidemiology contributed to evolution of disease. Thus, changing patterns of geographic distribution, modes of infection, spectrum of secondary diseases were widely described and explained. Since the first reports on AIDS autopsy has playing an important role in study of HIV infection. Autopsy series and case reports provided abundance of data on various aspects of AIDS. Soon after introduction of HAART large retrospective autopsy studies covering several thousand cases were published (Jellinger et al., 2000; Morgello et al., 2002; Neuenburg et al., 2002; Vago et al., 2002). Results of comprehensive post-mortem examinations were in concordance with data from numerous clinical studies declaring efficacy of therapy and marked reduction of mortality from AIDS (de Martino et al., 2000; Mocroft et al., 1998; Palella et al., 1998). HAART contributed the most important shift in the history of HIV epidemics. However, currently only 10% (roughly) of HIV patients globally are receiving ART (Brown et al., 2010). Moreover, rates of non-adherence to antiretroviral therapy has been shown to range from 33% to 88% (Mills et al., 2006). Access to antiretroviral therapy in developing high-burden countries is restricted and number of AIDS-related deaths in only Sub-Saharan Africa for the last 10 years has exceeded 10 million (UNAIDS, 2009).

The total number of HIV autopsies declined worldwide after the advent of combination therapy. It is thought, that recruiting of such sophisticated studies like autopsy series to analysis of morbidity and mortality trends is not reasonable. Instead of that new methods are established to assess mortality statistics in developing countries (Bhattacharaya & Neogi, 2008). Currently, the popularity of studies evaluating AIDS-related mortality by means of verbal autopsy is increasing (Bundhamcharoen et al., 2011; Lopman et al., 2010; Negin et al., 2010).

We believe that autopsy series represent most reliable sources in estimation of mortality trends. While in the early years of HIV epidemics autopsy function was largely scientific (e.g. recognizing and describing), nowadays the epidemiological data are of main value. Systematic retrospective study of autopsy series worldwide is a valuable tool that should contribute to the study of AIDS epidemics evolution.

### **5. Acknowledgment**

386 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

The possible concern of described results is that early autopsy series from our set represent high-income developed countries and the most recent series are from low- and middleincome countries. Therefore, it is more correct to report about emergence of HIV-related tuberculosis in developing countries than all over the world. Actually, in Western world (high-income model) tuberculosis spreads through HIV-infected cohort, while in Russia and India social conditions drives tuberculosis in neglected population (alcoholics, imprisons, homeless), that is superimposed by HIV. Contribution of non-HIV-related pathology in AIDS mortality depends on availability of HAART and, consequently, economical

Finally, we may suppose that current trends in AIDS mortality for low- and high-income countries are different. Emergence of tuberculosis and high prevalence of bacterial infections are typical for Sub-Saharan Africa, South-East Asia and Eastern Europe. Growth of non-

Through the whole timeline of HIV epidemics significant differences in epidemiology contributed to evolution of disease. Thus, changing patterns of geographic distribution, modes of infection, spectrum of secondary diseases were widely described and explained. Since the first reports on AIDS autopsy has playing an important role in study of HIV infection. Autopsy series and case reports provided abundance of data on various aspects of AIDS. Soon after introduction of HAART large retrospective autopsy studies covering several thousand cases were published (Jellinger et al., 2000; Morgello et al., 2002; Neuenburg et al., 2002; Vago et al., 2002). Results of comprehensive post-mortem examinations were in concordance with data from numerous clinical studies declaring efficacy of therapy and marked reduction of mortality from AIDS (de Martino et al., 2000; Mocroft et al., 1998; Palella et al., 1998). HAART contributed the most important shift in the history of HIV epidemics. However, currently only 10% (roughly) of HIV patients globally are receiving ART (Brown et al., 2010). Moreover, rates of non-adherence to antiretroviral therapy has been shown to range from 33% to 88% (Mills et al., 2006). Access to antiretroviral therapy in developing high-burden countries is restricted and number of AIDS-related deaths in only Sub-Saharan Africa for the last 10 years has exceeded 10 million

The total number of HIV autopsies declined worldwide after the advent of combination therapy. It is thought, that recruiting of such sophisticated studies like autopsy series to analysis of morbidity and mortality trends is not reasonable. Instead of that new methods are established to assess mortality statistics in developing countries (Bhattacharaya & Neogi, 2008). Currently, the popularity of studies evaluating AIDS-related mortality by means of verbal autopsy is increasing (Bundhamcharoen et al., 2011; Lopman et al., 2010; Negin et al.,

We believe that autopsy series represent most reliable sources in estimation of mortality trends. While in the early years of HIV epidemics autopsy function was largely scientific (e.g. recognizing and describing), nowadays the epidemiological data are of main value. Systematic retrospective study of autopsy series worldwide is a valuable tool that should

contribute to the study of AIDS epidemics evolution.

AIDS-related diseases is observed in USA and Western Europe.

development of the country.

**4. Conclusion** 

(UNAIDS, 2009).

2010).

Authors would like to thank Dr. Jimson W. D'Souza (Smolensk State Medical Academy), Dr. Florence Orim (Nagasaki University Graduate School of Biomedical Sciences), Dr. Jitender Singh (Sir Ganga Ram Hospital, New Delhi) and Dr. Larisa Skrobut (Smolensk Regional Institute of Pathology) for their help in preparation of manuscript.

This work was supported by Grant-in-Aid for Scientific Research by Ministry of Health, Labor and Welfare of Japan #H22-AIDS-nominated type-G009, "Patients' participated clinical research on long term therapy of HIV/HCV co-infected hemophiliacs".

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**16** 

*Japan* 

**HIV and Lung Cancer** 

Atsushi Ajisawa and Masahiko Shibuya

Yusuke Okuma, Naoki Yanagisawa, Yukio Hosomi,

*Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital* 

Lung cancer patients with HIV infection are expected to become an emerging issue with respect to morbidity and mortality, as the number of such patients is rapidly increasing. However, few reports or textbooks dealing with this issue have documented the details of these cases. Thus, in clinical settings, infectious disease physicians or medical oncologists occasionally hesitate to treat HIV-infected patients with lung cancer. Since 1996, the outcome of HIV-infected patients has improved, because CD4 cell counts and viral load are generally well controlled with the advent of highly active antiretroviral therapy (HAART), which strongly inhibits HIV viral proliferation and restores the patient's immunological status. Furthermore, the prognosis in the HIV population has improved significantly due to the prevention and treatment of opportunistic infections (OIs). As a result, HIV infection is chronically manageable. In the pre-HAART era, the median survival time in the HIV population was 10 years, while, at present,

In the pre-HAART era, most HIV-infected patients died of acquired immunodeficiency syndrome (AIDS). Recently, however, one-third of all such patients die of malignant tumor,(Bonnet *et al.*, 2009) and deaths due to AIDS-defining cancers (ADCs), such as Kaposi's sarcoma (KS), primary central nervous system lymphoma (PCNSL) and non-Hodgkin's lymphoma (NHL), and invasive cervical carcinoma, which were defined by the Centers for Disease Control and Prevention (CDC), are decreasing. On the other hand, the number of deaths due to non-AIDS-defining cancers (NADCs) is increasing.(Engels *et al.*, 2008, Silverberg *et al.*, 2009) At present, in the population with HIV infection, lung cancer accounts for 5% of all deaths and 15% of all deaths by malignant tumors.(Bonnet *et al.*, 2009) Of all of the NADCs, lung cancer is the most common,(Engels *et al.*, 2006, Lavole *et al.*, 2006, Patel *et al.*, 2008) followed by breast cancer, soft tissue sarcoma, Hodgkin's lymphoma (HL), penile cancer, lip cancer, and testicular seminoma.(Frisch *et al.*, 2001) In 1984, Irwin *et al*. reported the first case with simultaneous HIV infection and lung cancer,(Irwin *et al.*, 1984) and several dozen patients have since been reported in the United States and Europe. (Table. 1) The clinical demographics of lung cancer with HIV infection differ slightly from the general population and are characterized by younger age, advanced stage at diagnosis, and aggressive tumor extension. Thus, the prognosis of lung cancer in the HIV population is poorer than that of lung cancer in the general population.(Lavole *et al.*, 2006) Moreover, patient fragility to treatment needs to be considered. In the general population, lung cancer is the most common cause of cancer death worldwide. Furthermore, in the last decade, there has been progress in lung cancer

85% of patients survive more than 10 years.(Sepkowitz, 2001)

**1. Introduction** 


Yusuke Okuma, Naoki Yanagisawa, Yukio Hosomi, Atsushi Ajisawa and Masahiko Shibuya *Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital Japan* 

## **1. Introduction**

392 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Vago, L., Bonetto, S., Nebuloni, M., Duca, P., Carsana, L., Zerbi, P. & D'Arminio-Monforte,

Walewska-Zielecka, B., Kamiński, Z. & Nowosławski, A. (1996). AIDS Pathology: Infections

Autopsies. *AIDS*, Vol. 16, No. 14, pp. 1925-1928.

*Pathology*, Vol. 47, No. 4, pp. 163-170.

A. (2002). Pathological Findings in the Central Nervous System of AIDS Patients on Assumed Antiretroviral Therapeutic Regimens: Retrospective Study of 1597

and Neoplasms in 55 Fatal AIDS Cases. A Postmortem Study. *Polish Journal of* 

Lung cancer patients with HIV infection are expected to become an emerging issue with respect to morbidity and mortality, as the number of such patients is rapidly increasing. However, few reports or textbooks dealing with this issue have documented the details of these cases. Thus, in clinical settings, infectious disease physicians or medical oncologists occasionally hesitate to treat HIV-infected patients with lung cancer. Since 1996, the outcome of HIV-infected patients has improved, because CD4 cell counts and viral load are generally well controlled with the advent of highly active antiretroviral therapy (HAART), which strongly inhibits HIV viral proliferation and restores the patient's immunological status. Furthermore, the prognosis in the HIV population has improved significantly due to the prevention and treatment of opportunistic infections (OIs). As a result, HIV infection is chronically manageable. In the pre-HAART era, the median survival time in the HIV population was 10 years, while, at present, 85% of patients survive more than 10 years.(Sepkowitz, 2001)

In the pre-HAART era, most HIV-infected patients died of acquired immunodeficiency syndrome (AIDS). Recently, however, one-third of all such patients die of malignant tumor,(Bonnet *et al.*, 2009) and deaths due to AIDS-defining cancers (ADCs), such as Kaposi's sarcoma (KS), primary central nervous system lymphoma (PCNSL) and non-Hodgkin's lymphoma (NHL), and invasive cervical carcinoma, which were defined by the Centers for Disease Control and Prevention (CDC), are decreasing. On the other hand, the number of deaths due to non-AIDS-defining cancers (NADCs) is increasing.(Engels *et al.*, 2008, Silverberg *et al.*, 2009) At present, in the population with HIV infection, lung cancer accounts for 5% of all deaths and 15% of all deaths by malignant tumors.(Bonnet *et al.*, 2009) Of all of the NADCs, lung cancer is the most common,(Engels *et al.*, 2006, Lavole *et al.*, 2006, Patel *et al.*, 2008) followed by breast cancer, soft tissue sarcoma, Hodgkin's lymphoma (HL), penile cancer, lip cancer, and testicular seminoma.(Frisch *et al.*, 2001) In 1984, Irwin *et al*. reported the first case with simultaneous HIV infection and lung cancer,(Irwin *et al.*, 1984) and several dozen patients have since been reported in the United States and Europe. (Table. 1) The clinical demographics of lung cancer with HIV infection differ slightly from the general population and are characterized by younger age, advanced stage at diagnosis, and aggressive tumor extension. Thus, the prognosis of lung cancer in the HIV population is poorer than that of lung cancer in the general population.(Lavole *et al.*, 2006) Moreover, patient fragility to treatment needs to be considered.

In the general population, lung cancer is the most common cause of cancer death worldwide. Furthermore, in the last decade, there has been progress in lung cancer

must be considered, as they may increase or decrease efficacy by inhibiting cytochrome P450 (CYP450) induction, and the actual efficacy of and tolerance to therapy in such patients are

In this chapter, we discuss the epidemiology, frequency, risk factors, clinical management,

Between 2001 and 2006, 71% of deaths were due to malignant tumors, as compared to only 20% in the pre-HAART era.(Crum-Cianflone *et al.*, 2009) It is evident that the HIVinfected population has a higher risk for lung cancer. In many studies comparing the incidence of lung cancer in patients with HIV to that in the general population, the standardized incidence ratio (SIR), adjusted for age and sex, has been calculated. SIR is an estimate of the ratio of the incidence of cancer in a given patient subset compared with the projected cancer incidence in the population at large. For instance, an SIR > 1 would indicate that lung cancer occurs more frequently in HIV-infected patients than in the general population; in fact, the SIR was 1.4-4.5. In the period before the advent of HAART, the SIR was 6.5 (95% confidential interval (CI) 4.5-8.9),(Frisch & Hjalgrim, 1999, Parker *et al.*, 1998) from 1978-1996, the SIR was 4.5 with 808 patients,(Frisch *et al.*, 2001) and in most European studies, the SIR did not exceed 1.13.(Bower *et al.*, 2003, Herida *et al.*, 2003, Powles *et al.*, 2009) In the HAART era, the SIR was 2.27-3.3.(Powles *et al.*, 2009, Patel *et al.*, 2008) In a meta-analysis with seven observational studies of NADCs (n=1016), the SIR was 2.72 (95% CI 1.91-3.87).(Grulich *et al.*, 2007) In many studies, the number of lung cancer patients with HIV infection has been shown to increase from the HAART era to the post-HAART era. The incidence, however, has not changed. On the other hand, there are few data from Asian countries. The TAHOD study, a retrospective study of 617 patients between 2000 and 2008 in 10 Asian countries, reported that the number of patients with simultaneous HIV infection and NADCs is increasing, even in developing countries. Infection-unrelated NADCs (NADC-IURs), including lung cancer, account for 22%, with lung cancer being the most common (1.9%, 12 patients). In this study, the authors concluded that the Asian patient demographic differs from the Western

The risk factors for lung cancer in the HIV population are strongly associated with immunity and cigarette smoking. The higher risk for carcinogenesis in immunecompromised patients and the increased risk for lung cancer occurrence are particularly well known; kidney transplant patients have a significantly higher incidence of lung cancer than hemodialysis patients.(Vajdic *et al.*, 2006) Carcinogenesis in lung cancer is not directly associated with viral load and CD4 cell counts, and the mechanism of the increased risk for lung cancer is not fully understood. The reasons for the increased incidence of lung cancer

Cigarette smoking in the HIV population is a major contributing factor for carcinogenesis, as in the general population. The American Lung Association has reported that 87% of all lung

and treatment of HIV-infected lung cancer patients.

demographic.(Petoumenos *et al.*, 2010)

in HIV-infected patients therefore remain uncertain.

**3.1 Smoking exposure & other traditional risk factors** 

**3. Pathogenesis & risk factors** 

uncertain.

**2. Incidence** 

treatment modalities. The development of novel antitumor agents and molecular targeted drugs has increased the lines of chemotherapy, and new treatment strategies, such as maintenance therapy and biomarker-based therapy (personalized therapy), provide diverse options. At present, in front-line chemotherapy for lung cancer patients, platinum-doublet chemotherapy with the third-generation antitumor agent has been shown to prolong survival and contribute to symptom palliation. Before the 1990s, the median survival time with the best supportive care was 4-5 months, and the 1-year survival rate was 10% in Stage IV non-small cell lung cancer (NSCLC). In 1995, the benefits of chemotherapy for Stage IV NSCLC were confirmed, and the median survival time was prolonged to 8 months.(Nonsmall Cell Lung Cancer Collaborative Group, 1995) At present, median survival time is 12 months, and the 1-year survival rate has improved to 50-60% from 30-35% in 2002.(Azzoli *et al.*, 2009) Thus, the reported data dealing with lung cancer in HIV patients are not comparable. In addition, drug interactions between antiviralagents and antitumor agents


IVDU: intravenous drug user; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; PS: performance status

Table 1. Documented clinical demographics of lung cancer patients with HIV.

treatment modalities. The development of novel antitumor agents and molecular targeted drugs has increased the lines of chemotherapy, and new treatment strategies, such as maintenance therapy and biomarker-based therapy (personalized therapy), provide diverse options. At present, in front-line chemotherapy for lung cancer patients, platinum-doublet chemotherapy with the third-generation antitumor agent has been shown to prolong survival and contribute to symptom palliation. Before the 1990s, the median survival time with the best supportive care was 4-5 months, and the 1-year survival rate was 10% in Stage IV non-small cell lung cancer (NSCLC). In 1995, the benefits of chemotherapy for Stage IV NSCLC were confirmed, and the median survival time was prolonged to 8 months.(Nonsmall Cell Lung Cancer Collaborative Group, 1995) At present, median survival time is 12 months, and the 1-year survival rate has improved to 50-60% from 30-35% in 2002.(Azzoli *et al.*, 2009) Thus, the reported data dealing with lung cancer in HIV patients are not comparable. In addition, drug interactions between antiviralagents and antitumor agents

**Author** 

performance status

**No of patients** 

**Years** 

**Median age (y)** 

**Male (%)** 

**Smoking (%)** 

**Median pack-years** 

**IVDU (%)** 

**Homosexual (%)** 

*Sridhar et al. 19 86-91 47 100 94 60 21 32 95 42 31 5 121 53 - 37 79 3* 

*Trielli et al. 36 86-98 38 89 94 40 69 17 86 36 33 14 150 44 - 43 84 5* 

*Brock et al. 92 86-04 46 67 99 30 58 - 91 48 17 9 305 - 5.5 - 87 6.3* 

*Vyzula et al. 16 88-95 45 94 100 30 63 38 88 50 19 12 184 54 - 69 81 5.4* 

*Alshafie et al. 11 90-94 50 82 90 - 81 0 100 46 36 0 329 30 - - 90 3* 

*Spano et al. 22 93-02 45 86 95 40 23 45 95 36 50 5 364 30 - - 90 3* 

*Pakkala et al. 80 95-08 52 80 100 37 25 33 91 41 32 9 304 - - - - -* 

*Lavole et al. 49 96-07 46 67 99 33 17 18 100 67 17 0 350 - 8.6 71 84 8.1* 

*D'Jaen et al. 75 96-08 50 83 99 41 30 47 81 46 35 19 340 - 11 - 77 9* 

*Bertolaccini et al. 26 03-07 39 85 85 30 58 23 81 - - 19 143 - - - 76 23* 

IVDU: intravenous drug user; NSCLC: non-small cell lung cancer; SCLC: small cell lung cancer; PS:

Table 1. Documented clinical demographics of lung cancer patients with HIV.

**NSCLC (%)** 

**Adenocarcinoma** 

**Squamous cell carcinoma** 

**SCLC (%)** 

**Median CD4 (cells/µL)** 

**CD4 < 200 cells/µL** 

**Latency (y)** 

**PS > 2 (%)** 

**Stage III/IV** 

**Median Survival (mo)** 

must be considered, as they may increase or decrease efficacy by inhibiting cytochrome P450 (CYP450) induction, and the actual efficacy of and tolerance to therapy in such patients are uncertain.

In this chapter, we discuss the epidemiology, frequency, risk factors, clinical management, and treatment of HIV-infected lung cancer patients.

## **2. Incidence**

Between 2001 and 2006, 71% of deaths were due to malignant tumors, as compared to only 20% in the pre-HAART era.(Crum-Cianflone *et al.*, 2009) It is evident that the HIVinfected population has a higher risk for lung cancer. In many studies comparing the incidence of lung cancer in patients with HIV to that in the general population, the standardized incidence ratio (SIR), adjusted for age and sex, has been calculated. SIR is an estimate of the ratio of the incidence of cancer in a given patient subset compared with the projected cancer incidence in the population at large. For instance, an SIR > 1 would indicate that lung cancer occurs more frequently in HIV-infected patients than in the general population; in fact, the SIR was 1.4-4.5. In the period before the advent of HAART, the SIR was 6.5 (95% confidential interval (CI) 4.5-8.9),(Frisch & Hjalgrim, 1999, Parker *et al.*, 1998) from 1978-1996, the SIR was 4.5 with 808 patients,(Frisch *et al.*, 2001) and in most European studies, the SIR did not exceed 1.13.(Bower *et al.*, 2003, Herida *et al.*, 2003, Powles *et al.*, 2009) In the HAART era, the SIR was 2.27-3.3.(Powles *et al.*, 2009, Patel *et al.*, 2008) In a meta-analysis with seven observational studies of NADCs (n=1016), the SIR was 2.72 (95% CI 1.91-3.87).(Grulich *et al.*, 2007) In many studies, the number of lung cancer patients with HIV infection has been shown to increase from the HAART era to the post-HAART era. The incidence, however, has not changed. On the other hand, there are few data from Asian countries. The TAHOD study, a retrospective study of 617 patients between 2000 and 2008 in 10 Asian countries, reported that the number of patients with simultaneous HIV infection and NADCs is increasing, even in developing countries. Infection-unrelated NADCs (NADC-IURs), including lung cancer, account for 22%, with lung cancer being the most common (1.9%, 12 patients). In this study, the authors concluded that the Asian patient demographic differs from the Western demographic.(Petoumenos *et al.*, 2010)

## **3. Pathogenesis & risk factors**

The risk factors for lung cancer in the HIV population are strongly associated with immunity and cigarette smoking. The higher risk for carcinogenesis in immunecompromised patients and the increased risk for lung cancer occurrence are particularly well known; kidney transplant patients have a significantly higher incidence of lung cancer than hemodialysis patients.(Vajdic *et al.*, 2006) Carcinogenesis in lung cancer is not directly associated with viral load and CD4 cell counts, and the mechanism of the increased risk for lung cancer is not fully understood. The reasons for the increased incidence of lung cancer in HIV-infected patients therefore remain uncertain.

#### **3.1 Smoking exposure & other traditional risk factors**

Cigarette smoking in the HIV population is a major contributing factor for carcinogenesis, as in the general population. The American Lung Association has reported that 87% of all lung

Many cases of carcinogenesis in HIV-related carcinomas are related to viruses such as Epstein Barr virus or Human Herpes virus-8. The International Agency for Research on Cancer (IARC), an agency of the World Health Organization (WHO), is examining the relationship between viruses and carcinogenesis**,** including: Epstein Barr virus for HL, NHL, nasopharyngeal carcinoma, and Burkitt's lymphoma; human herpes virus-8 for KS and primary effusion lymphoma; human papilloma virus for cervical, vulvar, and vaginal carcinoma, penile carcinoma, anal carcinoma, oral cavity carcinoma, and oropharyngeal and tonsillar carcinoma; hepatitis C virus for hepatocellular carcinoma and NHL; hepatitis B virus for hepatocellular carcinoma; and HIV for cervical and conjunctival squamous cell carcinoma, NHL, PCNSL, KS, and HL (particularly mixed cellularity and lymphocyte depleted subtypes). Of these, HIV is not organ-specific and is unique in that carcinogenesis occurs indirectly through immune suppression. Considering immunological status and infection, carcinomas accompanying HIV infection are classified into three categories: first, KS, NHL, and head and neck cancer, including AIDS-defining disease; second, NADC-IRs (infection-related), related to infection, hepatocellular carcinoma, HL, leiomyosarcoma, anal cancer, bladder cancer, laryngeal cancer, oral cavity cancer, penile cancer, gastric cancer, tongue cancer, and tonsillar cancer; and lastly, NADC-IURs (infection-unrelated), not

Currently, carcinogenesis in lung cancer is considered not to be associated with HIV infection itself. On the other hand, microsatellite alternation resulting in genetic instability is seen in lung cancer patients with HIV infection.(Wistuba *et al.*, 1998) In another study, HIVinfected patients easily developed pulmonary disease because of decreased glutathione and antioxidant levels, as well as increased lysosome and chemokine ligand 5 (CCL5) levels in broncho-alveolar lavage fluid.(Agostini *et al.*, 1995, Allard *et al.*, 1998, Buhl *et al.*, 1989, Gordon *et al.*, 2005) Chronic inflammation is associated with carcinogenesis in lung cancer.(Buhl *et al.*, 1989) (Fig. 1) Furthermore, downregulation of HIV Tat-interacting protein

Fig. 1. Potential mechanisms for carcinogenesis in non-AIDS-defining cancer(Nguyen *et al.*)

related to infection, such as lung cancer and breast cancer.

**3.3 HIV as a risk factor** 

cancer is caused by smoking, and smoking cessation decreases the annual risk.(Samet *et al.*, 1988) The rate of smoking in the HIV population is 57%, higher than in the general population (33%),(Saves *et al.*, 2003) and a smoking history of 30-40 pack-years is seen in the HIV population.(Benard *et al.*, 2007, Friis-Moller *et al.*, 2003) In particular, in the Women's Interagency HIV Study (WIHS) cohort study in the HIV population in the United States, female lung cancer patients with HIV infection were significantly more common than in the general population, showing the increased risk for lung cancer.(Levine *et al.*, 2010) Thus, smoking cessation programs need to be directed to the HIV population when infection is diagnosed. On the other hand, smoking is reported to be an independent risk factor for carcinogenesis in lung cancer.(Kirk *et al.*, 2007)

Recently, the National Cancer Institute reported that an annual low-dose computed tomography (CT) scan in the general population decreased lung cancer death by 80% by detecting the early stages of lung cancer.(Aberle *et al.*, 2010) In a study at Johns Hopkins University and associated hospitals, most of the 92 lung cancer patients with HIV infection died of lung cancer. Overall, 60% of the 32 patients who underwent chest radiography were not diagnosed as having lung cancer within a year. With regard to CT, 1 out of 28 patients was not diagnosed.(James, 2006) Smoking cessation and low-dose CT scans to detect the early stages of lung cancer would therefore be beneficial for HIV population.

Among other behavioral risk factors, intravenous drug users had been considered as a higher risk for developing lung cancer. However, the higher rate of smoking among intravenous drug users may be a confounding factor in some studies.

#### **3.2 Immunosuppression as a risk factor**

Immunodeficiency is a significant risk factor for carcinogenesis in some types of cancer. However, there is no evidence that decreased CD4 cell counts are associated with carcinogenesis in NADCs.(Clifford & Franceschi, 2007) In many case-control studies, the incidence of NADCs was not associated with the CDC classification (Table 2).


CDC = U.S. Centers for Disease Control and Prevention; PGL = persistent generalized lymphadenopathy.

Table 2. CDC Classification System for HIV-Infected Adults and Adolescents

However, the incidence in HL, anal cancer, or hepatocellular carcinoma is affected by decreased CD4 cell counts. CD4 cell counts less than 200 cells/µL were associated with the incidence of NADCs (hazard ratio (HR), 1.67).(Powles *et al.*, 2009) CD4 cell counts increased by 100 cells/µL with the introduction of HAART, and the risk for NADCs decreased by 19%.(Bruyand *et al.*, 2009) However, carcinogenesis in lung cancer is not considered to be associated with immunological status (CD4 cell counts and viral load).(Kirk *et al.*, 2007, Spano *et al.*, 2004)

cancer is caused by smoking, and smoking cessation decreases the annual risk.(Samet *et al.*, 1988) The rate of smoking in the HIV population is 57%, higher than in the general population (33%),(Saves *et al.*, 2003) and a smoking history of 30-40 pack-years is seen in the HIV population.(Benard *et al.*, 2007, Friis-Moller *et al.*, 2003) In particular, in the Women's Interagency HIV Study (WIHS) cohort study in the HIV population in the United States, female lung cancer patients with HIV infection were significantly more common than in the general population, showing the increased risk for lung cancer.(Levine *et al.*, 2010) Thus, smoking cessation programs need to be directed to the HIV population when infection is diagnosed. On the other hand, smoking is reported to be an independent risk factor for

Recently, the National Cancer Institute reported that an annual low-dose computed tomography (CT) scan in the general population decreased lung cancer death by 80% by detecting the early stages of lung cancer.(Aberle *et al.*, 2010) In a study at Johns Hopkins University and associated hospitals, most of the 92 lung cancer patients with HIV infection died of lung cancer. Overall, 60% of the 32 patients who underwent chest radiography were not diagnosed as having lung cancer within a year. With regard to CT, 1 out of 28 patients was not diagnosed.(James, 2006) Smoking cessation and low-dose CT scans to detect the

Among other behavioral risk factors, intravenous drug users had been considered as a higher risk for developing lung cancer. However, the higher rate of smoking among

Immunodeficiency is a significant risk factor for carcinogenesis in some types of cancer. However, there is no evidence that decreased CD4 cell counts are associated with carcinogenesis in NADCs.(Clifford & Franceschi, 2007) In many case-control studies, the

**B** 

CDC = U.S. Centers for Disease Control and Prevention; PGL = persistent generalized

However, the incidence in HL, anal cancer, or hepatocellular carcinoma is affected by decreased CD4 cell counts. CD4 cell counts less than 200 cells/µL were associated with the incidence of NADCs (hazard ratio (HR), 1.67).(Powles *et al.*, 2009) CD4 cell counts increased by 100 cells/µL with the introduction of HAART, and the risk for NADCs decreased by 19%.(Bruyand *et al.*, 2009) However, carcinogenesis in lung cancer is not considered to be associated with immunological status (CD4 cell counts and viral load).(Kirk *et al.*, 2007,

Clinical Categories

Symptomatic

Conditions, not A or C

**C**  AIDS-Indicator Conditions

early stages of lung cancer would therefore be beneficial for HIV population.

incidence of NADCs was not associated with the CDC classification (Table 2).

>500/µL A1 B1 C1 200-500/µL A2 B2 C2 < 200/µL A3 B3 C3

Table 2. CDC Classification System for HIV-Infected Adults and Adolescents

intravenous drug users may be a confounding factor in some studies.

Asymptomatic, Acute

HIV, or PGL

carcinogenesis in lung cancer.(Kirk *et al.*, 2007)

**3.2 Immunosuppression as a risk factor** 

**A** 

CD4 Cell Categories

lymphadenopathy.

Spano *et al.*, 2004)

#### **3.3 HIV as a risk factor**

Many cases of carcinogenesis in HIV-related carcinomas are related to viruses such as Epstein Barr virus or Human Herpes virus-8. The International Agency for Research on Cancer (IARC), an agency of the World Health Organization (WHO), is examining the relationship between viruses and carcinogenesis**,** including: Epstein Barr virus for HL, NHL, nasopharyngeal carcinoma, and Burkitt's lymphoma; human herpes virus-8 for KS and primary effusion lymphoma; human papilloma virus for cervical, vulvar, and vaginal carcinoma, penile carcinoma, anal carcinoma, oral cavity carcinoma, and oropharyngeal and tonsillar carcinoma; hepatitis C virus for hepatocellular carcinoma and NHL; hepatitis B virus for hepatocellular carcinoma; and HIV for cervical and conjunctival squamous cell carcinoma, NHL, PCNSL, KS, and HL (particularly mixed cellularity and lymphocyte depleted subtypes). Of these, HIV is not organ-specific and is unique in that carcinogenesis occurs indirectly through immune suppression. Considering immunological status and infection, carcinomas accompanying HIV infection are classified into three categories: first, KS, NHL, and head and neck cancer, including AIDS-defining disease; second, NADC-IRs (infection-related), related to infection, hepatocellular carcinoma, HL, leiomyosarcoma, anal cancer, bladder cancer, laryngeal cancer, oral cavity cancer, penile cancer, gastric cancer, tongue cancer, and tonsillar cancer; and lastly, NADC-IURs (infection-unrelated), not related to infection, such as lung cancer and breast cancer.

Currently, carcinogenesis in lung cancer is considered not to be associated with HIV infection itself. On the other hand, microsatellite alternation resulting in genetic instability is seen in lung cancer patients with HIV infection.(Wistuba *et al.*, 1998) In another study, HIVinfected patients easily developed pulmonary disease because of decreased glutathione and antioxidant levels, as well as increased lysosome and chemokine ligand 5 (CCL5) levels in broncho-alveolar lavage fluid.(Agostini *et al.*, 1995, Allard *et al.*, 1998, Buhl *et al.*, 1989, Gordon *et al.*, 2005) Chronic inflammation is associated with carcinogenesis in lung cancer.(Buhl *et al.*, 1989) (Fig. 1) Furthermore, downregulation of HIV Tat-interacting protein

Fig. 1. Potential mechanisms for carcinogenesis in non-AIDS-defining cancer(Nguyen *et al.*)

SCLC is characterized by higher grade, rapid progression with proliferation, and ease of metastasis to lymph nodes/distant organs in the early stage. Untreated, the median survival time is between 2 and 4 months. The response rate and median survival time in limiteddisease SCLC are 70% and between 14 and 20 months, respectively. In extended-disease SCLC, chemotherapy is basic, and palliative radiotherapy is added according to the symptoms. The response rate in extended disease is 45-95%, and the median survival time is

In NSCLC, radiotherapy or chemotherapy is less sensitive than SCLC. Radical surgery is limited in Stage I-III NSCLC, and palliative chemotherapy is indicated in Stage IV NSCLC, while surgery alone is for Stage IA, and surgery-based multidisciplinary treatment is required in Stage IB-III. A decision on the treatment strategy should take into account histology, age, performance status (PS), and co-morbidities. In Stage IV patients with poor PS (≥ 3) best supportive care is recommended. The 5-year survival is 50% in Stage IA, 43% in Stage IB, 36% in Stage IIA, 25% in Stage IIB, 19% in Stage IIIA, 7% in Stage IIIB, and 2% in Stage IV. The median survival time is 14 months in Stage III and 10 months in Stage

In the period before the advent of HAART, HIV-infected patients were considered to have decreased immune competence of lymphocytes or CD4 cell counts because of accompanying complications or fragility to treatment. Toxicity and tolerance data in the treatment of other cancers are available. No fewer than 25% of advanced cancer patients with HIV infection were not treated,(Achenbach *et al.*) and among NSCLC patients with HIV infection, initial treatment consisted of chemotherapy in 31%, radiotherapy in 23%, and both in 15%.(D'Jaen

Surgery is a promising modality of treatment for Stage I and II NSCLC, and is the first-line choice of treatment for all operable patients. In previous reports, patients with CD4 cell counts of more than 500 cells/µL were considered operable, while in those with lower CD4 cell counts, the indication for surgery needed careful consideration. The treatment of HIVinfected lung cancer patients at present, however, should follow the standard of care for safety and efficacy, as their prognosis depends on their lung cancer, not their HIV status. Moreover, complications, such as cardiovascular diseases and interstitial pneumonia associated with cigarette smoking, need to be taken into account, because more of these

With surgery, a reported case series did not demonstrate an increased risk of postoperative complications because of CD4 cell counts or immunological status.(Massera *et al.*, 2000) Thus, the indication for surgery in HIV-infected lung cancer patients should be determined based on pulmonary function, PS, and staging, as in the general population. Furthermore, the prognosis of such patients is good.(Spano *et al.*, 2004) In addition, the clinician should consider the medical staff's perioperative risk for blood-borne infection and ensure that standard precautions are taken. The reported blood-borne infection rate associated with

In determining the clinical stage, 18F-fluorodeoxyglucose-positoron emission tomographycomputed tomography (PET-CT) scan is a highly sensitive and specific examination. However, prudent assessment with regard to lymph nodal diagnosis is needed in the HIV population because of potential false positive to lymph nodes and upstaging in anal

7-10 months.(El Maalouf *et al.*, 2007)

IV.(Goldstraw *et al.*, 2007)

patients have a history of smoking.(Aberg, 2009)

surgery ranges from 0.2-0.5%.(Bell, 1997)

cancer.(Cotter *et al.*, 2006)

*et al.*, 2010)

**5.1 Surgery** 

30 (TIP30) has been verified to promote metastasis of lung cancer *in vitro* and in nude mice.(Baker *et al.*, 2000, Tong *et al.*, 2009) Thus, lung cancer in the HIV population tends to be aggressive with poor prognosis. Inhibiting HIV appears to inhibit carcinogenesis in lung cancer; however, there is no clear evidence of decreased incidence of lung cancer with the use of HAART. HAART reconstitutes immunity and decreases the risk of OIs.

## **4. Clinical manifestations**

When compared to lung cancer in the general population, lung cancer in HIV-infected patients affects younger patients and is more aggressive. The median age of HIV-infected lung cancer patients is 45-50 years, while it is 62 years in the general population.(Spano *et al.*, 2004) With regard to the clinical stage of the lung cancer, 75-90% of all HIV-infected patients are advanced, 18-29% are in a locally advanced stage, and 50-68% are in the metastatic stage.(Lavole *et al.*, 2006) Adenocarcinoma is the most common (31-52%), followed by squamous cell carcinoma (17-39%), large cell carcinoma (3-16%), small cell carcinoma (SCLC) (1-14%), and bronchial alveolar carcinoma (less than 2%).(Tirelli *et al.*, 2000, Vyzula & Remick, 1996, Sridhar *et al.*, 1992, Alshafie *et al.*, 1997, D'Jaen *et al.*, 2010) This is similar to the distribution seen in the general population, as NSCLC accounts for 85% of all lung cancer patients in the general population. Comparing the pre-HAART era and the HAART era, the rate of adenocarcinoma was unchanged (48%), but the rate of squamous cell carcinoma was 21% in the pre-HAART era, as compared to 10% in the HAART era.(Brock *et al.*, 2006) Epidermal growth factor receptor (EGFR) mutation is a predictive factor for EGFRtyrosine kinase inhibitors (EGFR-TKIs), and the incidence of harboring EGFR mutation among Asians is 30-35%, while it is ~10% among Caucasians.(Maemondo *et al.*, 2010, Mitsudomi *et al.*, 2009, Rosell *et al.*, 2009) A lung cancer patient harboring EGFR mutations with HIV infection has been reported.(Erickson *et al.*, 2008) CD4 cell counts at diagnosis range between 120 and 360 cells/µL,(Spano *et al.*, 2004, Tirelli *et al.*, 2000, Vyzula & Remick, 1996, Sridhar *et al.*, 1992, Brock *et al.*, 2006, Bedimo *et al.*, 2009, Tenholder & Jackson, 1993) while median CD4 cell counts in the HAART era are more than 300 cells/µL.

Overall, 25-50% of lung cancer patients with HIV infection had AIDS,(Alshafie *et al.*, 1997, Lavole *et al.*, 2006, Spano *et al.*, 2004, Sridhar *et al.*, 1992, Tirelli *et al.*, 2000, Vyzula & Remick, 1996) and 55% underwent HAART. The latency from diagnosis of HIV infection to the diagnosis of lung cancer differs by sex, being 4.1 years in women and 7.7 years in men (p=0.02). However, the gender-based difference has not been discussed.(Pakkala *et al.*, 2010) The frequency of metastatic organ involvement is uncertain. Release of interleukin-1 by intracerebral gp-120 components with HIV promotes brain metastasis *in vivo*.(Hodgson *et al.*, 1998) In the clinical setting, a patient with two intracerebral hemorrhages has been reported (the incidence of intratumoral hemorrhage in NSCLC is 0.52%).(Okuma *et al.*, 2010) Of note, HIV-infected patients have a higher risk of intracranial events(d'Arminio Monforte *et al.*, 2004); thus, careful follow-up is required for HIV-infected patients in clinical settings.

#### **5. Multidisciplinary treatments & management**

The fundamental modalities of treatment for lung cancer are surgery, radiotherapy, and chemotherapy.

SCLC is sensitive to both chemotherapy and radiotherapy; thus, radical concurrent chemoradiotherapy is indicated for limited-disease SCLC. When compared to NSCLC,

30 (TIP30) has been verified to promote metastasis of lung cancer *in vitro* and in nude mice.(Baker *et al.*, 2000, Tong *et al.*, 2009) Thus, lung cancer in the HIV population tends to be aggressive with poor prognosis. Inhibiting HIV appears to inhibit carcinogenesis in lung cancer; however, there is no clear evidence of decreased incidence of lung cancer with the

When compared to lung cancer in the general population, lung cancer in HIV-infected patients affects younger patients and is more aggressive. The median age of HIV-infected lung cancer patients is 45-50 years, while it is 62 years in the general population.(Spano *et al.*, 2004) With regard to the clinical stage of the lung cancer, 75-90% of all HIV-infected patients are advanced, 18-29% are in a locally advanced stage, and 50-68% are in the metastatic stage.(Lavole *et al.*, 2006) Adenocarcinoma is the most common (31-52%), followed by squamous cell carcinoma (17-39%), large cell carcinoma (3-16%), small cell carcinoma (SCLC) (1-14%), and bronchial alveolar carcinoma (less than 2%).(Tirelli *et al.*, 2000, Vyzula & Remick, 1996, Sridhar *et al.*, 1992, Alshafie *et al.*, 1997, D'Jaen *et al.*, 2010) This is similar to the distribution seen in the general population, as NSCLC accounts for 85% of all lung cancer patients in the general population. Comparing the pre-HAART era and the HAART era, the rate of adenocarcinoma was unchanged (48%), but the rate of squamous cell carcinoma was 21% in the pre-HAART era, as compared to 10% in the HAART era.(Brock *et al.*, 2006) Epidermal growth factor receptor (EGFR) mutation is a predictive factor for EGFRtyrosine kinase inhibitors (EGFR-TKIs), and the incidence of harboring EGFR mutation among Asians is 30-35%, while it is ~10% among Caucasians.(Maemondo *et al.*, 2010, Mitsudomi *et al.*, 2009, Rosell *et al.*, 2009) A lung cancer patient harboring EGFR mutations with HIV infection has been reported.(Erickson *et al.*, 2008) CD4 cell counts at diagnosis range between 120 and 360 cells/µL,(Spano *et al.*, 2004, Tirelli *et al.*, 2000, Vyzula & Remick, 1996, Sridhar *et al.*, 1992, Brock *et al.*, 2006, Bedimo *et al.*, 2009, Tenholder & Jackson, 1993)

use of HAART. HAART reconstitutes immunity and decreases the risk of OIs.

while median CD4 cell counts in the HAART era are more than 300 cells/µL.

**5. Multidisciplinary treatments & management** 

chemotherapy.

Overall, 25-50% of lung cancer patients with HIV infection had AIDS,(Alshafie *et al.*, 1997, Lavole *et al.*, 2006, Spano *et al.*, 2004, Sridhar *et al.*, 1992, Tirelli *et al.*, 2000, Vyzula & Remick, 1996) and 55% underwent HAART. The latency from diagnosis of HIV infection to the diagnosis of lung cancer differs by sex, being 4.1 years in women and 7.7 years in men (p=0.02). However, the gender-based difference has not been discussed.(Pakkala *et al.*, 2010) The frequency of metastatic organ involvement is uncertain. Release of interleukin-1 by intracerebral gp-120 components with HIV promotes brain metastasis *in vivo*.(Hodgson *et al.*, 1998) In the clinical setting, a patient with two intracerebral hemorrhages has been reported (the incidence of intratumoral hemorrhage in NSCLC is 0.52%).(Okuma *et al.*, 2010) Of note, HIV-infected patients have a higher risk of intracranial events(d'Arminio Monforte *et al.*, 2004); thus, careful follow-up is required for HIV-infected patients in clinical settings.

The fundamental modalities of treatment for lung cancer are surgery, radiotherapy, and

SCLC is sensitive to both chemotherapy and radiotherapy; thus, radical concurrent chemoradiotherapy is indicated for limited-disease SCLC. When compared to NSCLC,

**4. Clinical manifestations** 

SCLC is characterized by higher grade, rapid progression with proliferation, and ease of metastasis to lymph nodes/distant organs in the early stage. Untreated, the median survival time is between 2 and 4 months. The response rate and median survival time in limiteddisease SCLC are 70% and between 14 and 20 months, respectively. In extended-disease SCLC, chemotherapy is basic, and palliative radiotherapy is added according to the symptoms. The response rate in extended disease is 45-95%, and the median survival time is 7-10 months.(El Maalouf *et al.*, 2007)

In NSCLC, radiotherapy or chemotherapy is less sensitive than SCLC. Radical surgery is limited in Stage I-III NSCLC, and palliative chemotherapy is indicated in Stage IV NSCLC, while surgery alone is for Stage IA, and surgery-based multidisciplinary treatment is required in Stage IB-III. A decision on the treatment strategy should take into account histology, age, performance status (PS), and co-morbidities. In Stage IV patients with poor PS (≥ 3) best supportive care is recommended. The 5-year survival is 50% in Stage IA, 43% in Stage IB, 36% in Stage IIA, 25% in Stage IIB, 19% in Stage IIIA, 7% in Stage IIIB, and 2% in Stage IV. The median survival time is 14 months in Stage III and 10 months in Stage IV.(Goldstraw *et al.*, 2007)

In the period before the advent of HAART, HIV-infected patients were considered to have decreased immune competence of lymphocytes or CD4 cell counts because of accompanying complications or fragility to treatment. Toxicity and tolerance data in the treatment of other cancers are available. No fewer than 25% of advanced cancer patients with HIV infection were not treated,(Achenbach *et al.*) and among NSCLC patients with HIV infection, initial treatment consisted of chemotherapy in 31%, radiotherapy in 23%, and both in 15%.(D'Jaen *et al.*, 2010)

## **5.1 Surgery**

Surgery is a promising modality of treatment for Stage I and II NSCLC, and is the first-line choice of treatment for all operable patients. In previous reports, patients with CD4 cell counts of more than 500 cells/µL were considered operable, while in those with lower CD4 cell counts, the indication for surgery needed careful consideration. The treatment of HIVinfected lung cancer patients at present, however, should follow the standard of care for safety and efficacy, as their prognosis depends on their lung cancer, not their HIV status. Moreover, complications, such as cardiovascular diseases and interstitial pneumonia associated with cigarette smoking, need to be taken into account, because more of these patients have a history of smoking.(Aberg, 2009)

With surgery, a reported case series did not demonstrate an increased risk of postoperative complications because of CD4 cell counts or immunological status.(Massera *et al.*, 2000) Thus, the indication for surgery in HIV-infected lung cancer patients should be determined based on pulmonary function, PS, and staging, as in the general population. Furthermore, the prognosis of such patients is good.(Spano *et al.*, 2004) In addition, the clinician should consider the medical staff's perioperative risk for blood-borne infection and ensure that standard precautions are taken. The reported blood-borne infection rate associated with surgery ranges from 0.2-0.5%.(Bell, 1997)

In determining the clinical stage, 18F-fluorodeoxyglucose-positoron emission tomographycomputed tomography (PET-CT) scan is a highly sensitive and specific examination. However, prudent assessment with regard to lymph nodal diagnosis is needed in the HIV population because of potential false positive to lymph nodes and upstaging in anal cancer.(Cotter *et al.*, 2006)

randomized studies, and chemotherapy showed a survival benefit with an HR of 0.73 (95% CI 0.71-0.83, p < 0.0001) again. On the other hand, the survival benefit is no different between 1995 and later studies (p = 0.77) (Non-small Cell Lung Cancer Collaborative Group, 2008). However, the survival time has gradually improved because of trials with novel antitumor drugs that were excluded from this meta-analysis and diversification of treatment strategies. As the population with HIV infection is excluded from clinical trials, information regarding the efficacy and safety of chemotherapy in these patients is limited to retrospective reports.

Chemotherapy is more frequently used for advanced lung cancer in HIV-infected patients because 75-90% of lung cancer patients with HIV infection have advanced disease.(Lavole *et al.*, 2006, Lavole *et al.*, 2009, Cadranel *et al.*, 2006) However, the benefit of chemotherapy is questionable, as the prospective clinical benefits and toxicities have not been realistically evaluated. In a phase II prospective study with carboplatin and gemcitabine combination chemotherapy followed by paclitaxel maintenance therapy involving 47 patients consisting mainly of lung cancer patients with poor PS (2 or 3) and immunologically fragile patients, including HIV infection and post-bone marrow transplantation, tolerance and efficacy were demonstrated to be adequate.(Bridges *et al.*, 2008) Previous reports have concluded that the benefit of chemotherapy was controversial, but the prognosis of NSCLC patients with HIV infection treated with chemotherapy was reported to be the same as the prognosis of the general population with NSCLC. D'Jean *et al.* reported that, among HIV-infected lung cancer patients, 81% (taxanes 45%, gemcitabine 26%, vinca alkaloid 10%) were treated with platinum-doublet chemotherapy in the front-line setting. Patients treated with singlet chemotherapy or oral antitumor agents outside of standard regimens were 3% each.(Previous study, 2010) Elderly lung cancer patients and lung cancer patients with poor PS in the general population have a poorer prognosis with chemotherapy and singlet chemotherapy, not platinum-doublet chemotherapy, is generally recommended.(D'Addario *et al.,* 2009) Among lung cancer patients with HIV infection, PS is poor (before 1996, 37~57% of patients had PS of more than 2; after 1996, this decreased to less than 30% of patients)(Spano *et al.*, 2004) Thus, for treatment of fragile patients, chemotherapy would be

Current standard chemotherapy for advanced NSCLC is based on platinum doublet (cisplatin or carboplatin) plus third-generation antitumor drugs (irinotecan, docetaxel, gemcitabine, vinorelbine, paclitaxel,(Schiller *et al.*, 2002, Kelly *et al.*, 2001, Ohe *et al.*, 2007) and pemetrexed(Scagliotti *et al.*, 2008)) or EGFR-TKIs; gefitinib(Maemondo *et al.*, 2010, Mitsudomi *et al.*, 2009) and erlotinib(Rosell *et al.*, 2009), and an antiangiogenic inhibitor (bevacizumab).(Sandler *et al.*, 2006) Maintenance therapy with pemetrexed(Ciuleanu *et al.*, 2009) and erlotinib(Cappuzzo *et al.*, 2010) is known to prolong survival. In SCLC, platinum and etoposide or irinotecan combination therapy is used.(Murray & Turrisi, 2006) For relapsed SCLC, amrubicin or topotecan is given. In locally advanced NSCLC and limited disease (LD) SCLC, thoracic irradiation is added. D'Jean *et al*. reported that, among HIVinfected lung cancer patients, the agents combined with platinum agents were topoisomerase in 67%, vinca alkaloid in 22%, and taxanes in 11%. The response rate to frontline chemotherapy was 39% in 41 patients. Of the treated patients, 63% had adverse events,

**5.3.1 Chemotherapy for metastatic stage in patients with HIV infection** 

applied to lung cancer patients with HIV infection.

**5.3.1.1 Front-line setting** 

With respect to adjuvant chemotherapy (postoperative chemotherapy) for patients with NSCLC, a 13% decrease in the risk of death was demonstrated with chemotherapy (HR 0.87, 95%CI 0.74-1.02, p=0.08) in 1995.(Non-small Cell Lung Cancer Collaborative Group, 1995) This rate is equivalent to a 5% improvement in the 5-year survival rate. In later studies, a 5- 15% improvement in the 5-year survival rate was demonstrated (HR 0.89, 95%CI 0.82-0.96, p=0.005) in NSCLC patients with Stage II-IIIA with cisplatin-based chemotherapy.(Pignon *et al.*, 2008) However, as described later, toxicity, efficacy and prognostic factors for HIVinfected lung cancer patients are uncertain.

#### **5.2 Radiotherapy**

The role of radiotherapy in HIV-infected lung cancer patients is uncertain. In general, radiation therapy for ether ADCs or NADCs leads to severe mucosal toxicity in acute phase and late-phase disturbances, even when low-dose radiation is used. In KS patients who undergo thoracic irradiation, esophagitis occurs frequently and is often severe.(Chak *et al.*, 1988, Cooper *et al.*, 1984) The mechanism of the more severe mucositis is considered to be related to decreased mucosal restoration due to a shortage of glutathione antioxidant(Buhl *et al.*, 1989, Vallis, 1991) or to be related to OIs (Fungi, Candida species, herpes, cytomegalovirus, and Cryptococcus infections).(Boal *et al.*, 1979, Rodriguez *et al.*, 1989)

In the patient with good PS or without weight loss, unresectable locoregionally advanced NSCLC or limited-disease SCLC, the standard of care is concurrent chemoradiotherapy. The 3-year survival rate in unresectable locoregionally advanced NSCLC is around 10% with radiotherapy alone, and at present, the 3-year survival rate improves by more than 25% with concurrent platinum-based chemoradiotherapy.(Blackstock & Govindan, 2007) Concurrent chemoradiotherapy is more effective but more toxic than sequential chemoradiotherapy. At present, it is recommended that HIV-infected lung cancer patients be treated with the same standard care as the general population. However, aggressive treatment requires consideration of the risk of interactions between antiretroviral agents and antitumor agents, and fragility to treatment and safety of chemoradiotherapy are uncertain. A reported case having locally advanced squamous cell lung cancer, concurrently treated with nelfinavir and 5 species of HAART and intensity modulated radiotherapy, died of massive hemoptysis because of bronchial perforation, whereas pathological complete response (CR) was achieved with intensity modulated radiotherapy at a dose of 20 Gy.(Chapman *et al.*, 2009) In a phase I study involving pancreatic cancer patients with HIV infection, a radiosensitizing effect with nelfinavir was reported.(Brunner *et al.*, 2008)

Conformal radiotherapy is appropriate, as in the general population, because of narrowing of the irradiation fields. Palliative radiotherapy is indicated according to symptoms in Stage IV.

#### **5.3 Chemotherapy**

With regard to chemotherapy, adjuvant chemotherapy is used for Stage IB-IIIA NSCLC, concomitant chemoradiotherapy is given in locoregionally advanced NSCLC, and palliative chemotherapy is given in Stage IV.(Azzoli *et al.*, 2009) In the meta-analysis of Stage IV NSCLC, which accounts for 40% of all lung cancer, platinum doublet chemotherapy prolonged the median survival to 1.5-2.8 months and improved the 1-year survival rate to 10%.(Non-small Cell Lung Cancer Collaborative Group, 2008, Grilli *et al.*, 1993, Marino *et al.*, 1994, Souquet *et al.*, 1993) Chemotherapy significantly improved survival, with a HR of 0.73 (p<0.0001) in 1995.(Kivisto *et al.*, 1995) In 2008, the same group reported the results of a meta-analysis of 16

With respect to adjuvant chemotherapy (postoperative chemotherapy) for patients with NSCLC, a 13% decrease in the risk of death was demonstrated with chemotherapy (HR 0.87, 95%CI 0.74-1.02, p=0.08) in 1995.(Non-small Cell Lung Cancer Collaborative Group, 1995) This rate is equivalent to a 5% improvement in the 5-year survival rate. In later studies, a 5- 15% improvement in the 5-year survival rate was demonstrated (HR 0.89, 95%CI 0.82-0.96, p=0.005) in NSCLC patients with Stage II-IIIA with cisplatin-based chemotherapy.(Pignon *et al.*, 2008) However, as described later, toxicity, efficacy and prognostic factors for HIV-

The role of radiotherapy in HIV-infected lung cancer patients is uncertain. In general, radiation therapy for ether ADCs or NADCs leads to severe mucosal toxicity in acute phase and late-phase disturbances, even when low-dose radiation is used. In KS patients who undergo thoracic irradiation, esophagitis occurs frequently and is often severe.(Chak *et al.*, 1988, Cooper *et al.*, 1984) The mechanism of the more severe mucositis is considered to be related to decreased mucosal restoration due to a shortage of glutathione antioxidant(Buhl *et al.*, 1989, Vallis, 1991) or to be related to OIs (Fungi, Candida species, herpes, cytomegalovirus, and Cryptococcus infections).(Boal *et al.*, 1979, Rodriguez *et al.*, 1989) In the patient with good PS or without weight loss, unresectable locoregionally advanced NSCLC or limited-disease SCLC, the standard of care is concurrent chemoradiotherapy. The 3-year survival rate in unresectable locoregionally advanced NSCLC is around 10% with radiotherapy alone, and at present, the 3-year survival rate improves by more than 25% with concurrent platinum-based chemoradiotherapy.(Blackstock & Govindan, 2007) Concurrent chemoradiotherapy is more effective but more toxic than sequential chemoradiotherapy. At present, it is recommended that HIV-infected lung cancer patients be treated with the same standard care as the general population. However, aggressive treatment requires consideration of the risk of interactions between antiretroviral agents and antitumor agents, and fragility to treatment and safety of chemoradiotherapy are uncertain. A reported case having locally advanced squamous cell lung cancer, concurrently treated with nelfinavir and 5 species of HAART and intensity modulated radiotherapy, died of massive hemoptysis because of bronchial perforation, whereas pathological complete response (CR) was achieved with intensity modulated radiotherapy at a dose of 20 Gy.(Chapman *et al.*, 2009) In a phase I study involving pancreatic cancer patients with HIV infection, a radiosensitizing

Conformal radiotherapy is appropriate, as in the general population, because of narrowing of the irradiation fields. Palliative radiotherapy is indicated according to symptoms in Stage IV.

With regard to chemotherapy, adjuvant chemotherapy is used for Stage IB-IIIA NSCLC, concomitant chemoradiotherapy is given in locoregionally advanced NSCLC, and palliative chemotherapy is given in Stage IV.(Azzoli *et al.*, 2009) In the meta-analysis of Stage IV NSCLC, which accounts for 40% of all lung cancer, platinum doublet chemotherapy prolonged the median survival to 1.5-2.8 months and improved the 1-year survival rate to 10%.(Non-small Cell Lung Cancer Collaborative Group, 2008, Grilli *et al.*, 1993, Marino *et al.*, 1994, Souquet *et al.*, 1993) Chemotherapy significantly improved survival, with a HR of 0.73 (p<0.0001) in 1995.(Kivisto *et al.*, 1995) In 2008, the same group reported the results of a meta-analysis of 16

infected lung cancer patients are uncertain.

effect with nelfinavir was reported.(Brunner *et al.*, 2008)

**5.2 Radiotherapy** 

**5.3 Chemotherapy** 

randomized studies, and chemotherapy showed a survival benefit with an HR of 0.73 (95% CI 0.71-0.83, p < 0.0001) again. On the other hand, the survival benefit is no different between 1995 and later studies (p = 0.77) (Non-small Cell Lung Cancer Collaborative Group, 2008). However, the survival time has gradually improved because of trials with novel antitumor drugs that were excluded from this meta-analysis and diversification of treatment strategies. As the population with HIV infection is excluded from clinical trials, information regarding the efficacy and safety of chemotherapy in these patients is limited to retrospective reports.

## **5.3.1 Chemotherapy for metastatic stage in patients with HIV infection**

## **5.3.1.1 Front-line setting**

Chemotherapy is more frequently used for advanced lung cancer in HIV-infected patients because 75-90% of lung cancer patients with HIV infection have advanced disease.(Lavole *et al.*, 2006, Lavole *et al.*, 2009, Cadranel *et al.*, 2006) However, the benefit of chemotherapy is questionable, as the prospective clinical benefits and toxicities have not been realistically evaluated. In a phase II prospective study with carboplatin and gemcitabine combination chemotherapy followed by paclitaxel maintenance therapy involving 47 patients consisting mainly of lung cancer patients with poor PS (2 or 3) and immunologically fragile patients, including HIV infection and post-bone marrow transplantation, tolerance and efficacy were demonstrated to be adequate.(Bridges *et al.*, 2008) Previous reports have concluded that the benefit of chemotherapy was controversial, but the prognosis of NSCLC patients with HIV infection treated with chemotherapy was reported to be the same as the prognosis of the general population with NSCLC. D'Jean *et al.* reported that, among HIV-infected lung cancer patients, 81% (taxanes 45%, gemcitabine 26%, vinca alkaloid 10%) were treated with platinum-doublet chemotherapy in the front-line setting. Patients treated with singlet chemotherapy or oral antitumor agents outside of standard regimens were 3% each.(Previous study, 2010) Elderly lung cancer patients and lung cancer patients with poor PS in the general population have a poorer prognosis with chemotherapy and singlet chemotherapy, not platinum-doublet chemotherapy, is generally recommended.(D'Addario *et al.,* 2009) Among lung cancer patients with HIV infection, PS is poor (before 1996, 37~57% of patients had PS of more than 2; after 1996, this decreased to less than 30% of patients)(Spano *et al.*, 2004) Thus, for treatment of fragile patients, chemotherapy would be applied to lung cancer patients with HIV infection.

Current standard chemotherapy for advanced NSCLC is based on platinum doublet (cisplatin or carboplatin) plus third-generation antitumor drugs (irinotecan, docetaxel, gemcitabine, vinorelbine, paclitaxel,(Schiller *et al.*, 2002, Kelly *et al.*, 2001, Ohe *et al.*, 2007) and pemetrexed(Scagliotti *et al.*, 2008)) or EGFR-TKIs; gefitinib(Maemondo *et al.*, 2010, Mitsudomi *et al.*, 2009) and erlotinib(Rosell *et al.*, 2009), and an antiangiogenic inhibitor (bevacizumab).(Sandler *et al.*, 2006) Maintenance therapy with pemetrexed(Ciuleanu *et al.*, 2009) and erlotinib(Cappuzzo *et al.*, 2010) is known to prolong survival. In SCLC, platinum and etoposide or irinotecan combination therapy is used.(Murray & Turrisi, 2006) For relapsed SCLC, amrubicin or topotecan is given. In locally advanced NSCLC and limited disease (LD) SCLC, thoracic irradiation is added. D'Jean *et al*. reported that, among HIVinfected lung cancer patients, the agents combined with platinum agents were topoisomerase in 67%, vinca alkaloid in 22%, and taxanes in 11%. The response rate to frontline chemotherapy was 39% in 41 patients. Of the treated patients, 63% had adverse events,

Platinum <sup>→</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> Hematological toxicity with ZDV,

Taxanes <sup>→</sup> <sup>↓</sup> <sup>↑</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> Hematological toxicity with ZDV

Etoposide → ↓ ↑ → → → Hematological toxicity with ZDV Gemcitabine <sup>→</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> Hematological toxicity with ZDV

Pemetrexed → → → → → → Hematological toxicity with ZDV Topotecan → → → → → → Hematological toxicity with ZDV Irinotecan → ↓ ↑ → → → Hematological toxicity with ZDV

INSTI: integrase strand transfar inhibitor; FI: fusion inhibitor; MVC: maraviroc; ZDV: zidovudine;

However, the available pharmacokinetic data for antiretroviral drugs and antitumor agents are not predictive: 1. available pharmacokinetic data are limited to case reports, and limited individual data cannot be generalized; 2. antitumor agents of a similar class can have variable pharmacokinetics; and 3. unexpected drug interactions can occur because

Antiretroviral agents are classified into six categories: nucleoside reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors (PIs); integrase inhibitors; fusion inhibitor enfuvirtide; and C-C chemokine receptor type 5 (CCR5) coreceptor antagonists. Interactions among these during treatment for ADCs, such as PCNSL or KS, enhance adverse toxicities. For instance, KS patients with CD4 cell counts greater than 200 cells/µL are reported to have a good response to paclitaxel

Drug interaction between antiretroviral agents and antitumor agents is assumed when the drug is metabolized by CYP450 pathway. Many PIs and NNRTIs are metabolized by this pathway, and competitive metabolism between antitumor drugs must be considered. (Table 3) Increases in toxicity between antiretroviral agents and antitumor agents have been reported. Among NNRTIs, efavirenz increases toxicity with concomitant use of vinka alkaloids and taxanes.(Makinson *et al.*, 2010) All NRTIs and most PIs have increased drug sensitivities *in vitro*, and this leads to increased toxicity. The NRTIs efavirenz, delavirdine, and nevirapine are primarily metabolized by CYP450.(Gulick, 1998, Flexner, 1998) In a study of patients with NHL undergoing treatment with concomitant antiretroviral agents and cyclophosphamide, doxorubicin, and etoposide, significantly lower nadir neutrophil counts were seen. As compared to the group with/without PIs, the group with PIs had greater toxicity (48% vs. 27%; *p*=0.0025). Drug interactions have also been confirmed *in vitro*; cultured cells that expressed Pglycoprotein (P-gp) accumulated increased concentrations of paclitaxel or vinblastine concomitant with PIs.(Washington *et al.*, 1998) PIs such as ritonavir and indinavir have a strong affinity for CYP450 and also strongly inhibit CYP3A4. These enzymes are used in metabolic pathways with ifosfamide, docetaxel, paclitaxel, irinotecan, vinca alkaloids, and

Table 3. Expected drug interactions between antiretroviral agents and antitumor agents

metabolism by CYP450 is associated with single nucleotide polymorphisms (SNPs).

treatment, with the same prognosis as patients with a normal immunological status.

HAART and chemotherapy NRTI NNRTI PI INSTI FI MVC

modifications based on antiretroviral drugs used Expected interactions between

Neuropathy, Nephropathy with TDF

Neuropathy with d4T and DDI

Nephropathy with TDF

Expected chemotherapeutic concentration

Erlotinib <sup>→</sup> <sup>↓</sup> <sup>↑</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> None Bevacizumab → → → → → → None

commonly used in NSCLC and SCLC.(Makinson *et al.*, 2010)

Gefitinib

TDF: tenofovir; ddI: didanosine

and 34% were Grade 3/4. Treatment-related deaths were seen in 2 patients (0.05%); 1 with pneumonitis, and 1 from an unknown cause.(Previous study, 2010)

#### **5.3.1.2 Second-line setting**

Overall, 60% of lung cancer patients treated with front-line chemotherapy proceed to second-line chemotherapy. In NSCLC patients with good PS, the standard of care is docetaxel (Shepherd *et al.*, 2001, Fossella *et al.*, 2000), pemetrexed(Hanna *et al.*, 2004) and erlotinib.(Shepherd *et al.*, 2005) Docetaxel is indicated for all histological types of NSCLC. Pemetrexed is expected to be active for non-squamous cell histology.(Scagliotti *et al.*, 2009) Erlotinib is effective for both patients harboring EGFR mutation and EGFR wildtype,(Ciuleanu *et al.*, 2010) although the response rate and survival time differ between them. Platinum doublet chemotherapy or non-platinum doublet chemotherapy is not anticipated to have efficacy in the second-line setting.(Azzoli *et al.*, 2009) For SCLC, intravenous or oral topotecan,(Eckardt *et al.*, 2007, von Pawel *et al.*, 1999) amrubicin,(Inoue *et al.*, 2008, Onoda *et al.*, 2006) and carboplatin and paclitaxel, re-treatment for sensitive-relapse cases are considered.(Giaccone *et al.*, 1987, Postmus *et al.*, 1987, Groen *et al.*, 1999) In the HIV population, details concerning second-line chemotherapy in Stage IV are uncertain. The rates of HIV-infected lung cancer patients treated with second-line chemotherapy in HIV population were 32% (17/53) in NSCLC and 10% (1/9) in SCLC. The response rate in this study was 11%, as in the general population.(D'Jaen *et al.*, 2010)

#### **5.3.1.3 Molecular targeted agents**

The understanding of cancer at the molecular level is profound, and proteins playing significant roles in tumor proliferation, invasion, and metastasis have been identified. As a result, molecular targeted inhibitors or antibodies for these proteins have recently been developed. Of these, drugs targeting EGFR, vascular endothelial growth factor (VEGF), and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase translocation (EML4-ALK)(Kwak *et al.*, 2010) have been shown to be efficacious. EGFRtargeted drugs have particularly strong evidence supporting their use. In NSCLC harboring EGFR mutation in the general population, use of EGFR-TKIs doubles survival.(Mitsudomi *et al.*, 2009, Maemondo *et al.*, 2010, Rosell *et al.*, 2009) Thus, despite the potential for drug interactions, use of EGFR-TKIs is indicated in HIV-infected patients. Though no drug interactions are expected, prudence is required from the perspective of cost and safety.

#### **5.3.2 Pharmacodynamic interactions between HAART & cytotoxic antitumor agents**

HAART reconstructs immunity and decreases risk of OIs to inhibit HIV viral load and increase CD4 cell counts for patients infected with HIV. The goal for HAART is to continuously suppress the viral load to undetectable and maintain CD4 cell counts above 500 cells/µL.(Silverberg *et al.*, 2007) However, decreases in antiretroviral agent concentrations can exacerbate clinical status, and increased/decreased concentrations of antitumor agents lead to severe toxicity or reduced antitumor effects. Both increases and decreases in serum concentrations can occur for either/both antiretroviral agents and/or cytotoxic antitumor agents.(Kivisto *et al.*, 1995) Therefore, decreased effectiveness and increased toxicity of chemotherapy must be considered. In addition, failure of virological treatment may occur. Interactions between antiretroviral agents and chemotherapeutic agents must always be considered and are a cause for concern for oncologists in clinical settings.

402 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

and 34% were Grade 3/4. Treatment-related deaths were seen in 2 patients (0.05%); 1 with

Overall, 60% of lung cancer patients treated with front-line chemotherapy proceed to second-line chemotherapy. In NSCLC patients with good PS, the standard of care is docetaxel (Shepherd *et al.*, 2001, Fossella *et al.*, 2000), pemetrexed(Hanna *et al.*, 2004) and erlotinib.(Shepherd *et al.*, 2005) Docetaxel is indicated for all histological types of NSCLC. Pemetrexed is expected to be active for non-squamous cell histology.(Scagliotti *et al.*, 2009) Erlotinib is effective for both patients harboring EGFR mutation and EGFR wildtype,(Ciuleanu *et al.*, 2010) although the response rate and survival time differ between them. Platinum doublet chemotherapy or non-platinum doublet chemotherapy is not anticipated to have efficacy in the second-line setting.(Azzoli *et al.*, 2009) For SCLC, intravenous or oral topotecan,(Eckardt *et al.*, 2007, von Pawel *et al.*, 1999) amrubicin,(Inoue *et al.*, 2008, Onoda *et al.*, 2006) and carboplatin and paclitaxel, re-treatment for sensitive-relapse cases are considered.(Giaccone *et al.*, 1987, Postmus *et al.*, 1987, Groen *et al.*, 1999) In the HIV population, details concerning second-line chemotherapy in Stage IV are uncertain. The rates of HIV-infected lung cancer patients treated with second-line chemotherapy in HIV population were 32% (17/53) in NSCLC and 10% (1/9) in SCLC. The response rate in this

The understanding of cancer at the molecular level is profound, and proteins playing significant roles in tumor proliferation, invasion, and metastasis have been identified. As a result, molecular targeted inhibitors or antibodies for these proteins have recently been developed. Of these, drugs targeting EGFR, vascular endothelial growth factor (VEGF), and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase translocation (EML4-ALK)(Kwak *et al.*, 2010) have been shown to be efficacious. EGFRtargeted drugs have particularly strong evidence supporting their use. In NSCLC harboring EGFR mutation in the general population, use of EGFR-TKIs doubles survival.(Mitsudomi *et al.*, 2009, Maemondo *et al.*, 2010, Rosell *et al.*, 2009) Thus, despite the potential for drug interactions, use of EGFR-TKIs is indicated in HIV-infected patients. Though no drug interactions are expected, prudence is required from the perspective of cost and safety.

**5.3.2 Pharmacodynamic interactions between HAART & cytotoxic antitumor agents**  HAART reconstructs immunity and decreases risk of OIs to inhibit HIV viral load and increase CD4 cell counts for patients infected with HIV. The goal for HAART is to continuously suppress the viral load to undetectable and maintain CD4 cell counts above 500 cells/µL.(Silverberg *et al.*, 2007) However, decreases in antiretroviral agent concentrations can exacerbate clinical status, and increased/decreased concentrations of antitumor agents lead to severe toxicity or reduced antitumor effects. Both increases and decreases in serum concentrations can occur for either/both antiretroviral agents and/or cytotoxic antitumor agents.(Kivisto *et al.*, 1995) Therefore, decreased effectiveness and increased toxicity of chemotherapy must be considered. In addition, failure of virological treatment may occur. Interactions between antiretroviral agents and chemotherapeutic agents must always be considered and are a cause for concern for oncologists in clinical

pneumonitis, and 1 from an unknown cause.(Previous study, 2010)

study was 11%, as in the general population.(D'Jaen *et al.*, 2010)

**5.3.1.2 Second-line setting** 

**5.3.1.3 Molecular targeted agents** 

settings.


INSTI: integrase strand transfar inhibitor; FI: fusion inhibitor; MVC: maraviroc; ZDV: zidovudine; TDF: tenofovir; ddI: didanosine

Table 3. Expected drug interactions between antiretroviral agents and antitumor agents commonly used in NSCLC and SCLC.(Makinson *et al.*, 2010)

However, the available pharmacokinetic data for antiretroviral drugs and antitumor agents are not predictive: 1. available pharmacokinetic data are limited to case reports, and limited individual data cannot be generalized; 2. antitumor agents of a similar class can have variable pharmacokinetics; and 3. unexpected drug interactions can occur because metabolism by CYP450 is associated with single nucleotide polymorphisms (SNPs).

Antiretroviral agents are classified into six categories: nucleoside reverse transcriptase inhibitors (NRTIs); non-nucleoside reverse transcriptase inhibitors (NNRTIs); protease inhibitors (PIs); integrase inhibitors; fusion inhibitor enfuvirtide; and C-C chemokine receptor type 5 (CCR5) coreceptor antagonists. Interactions among these during treatment for ADCs, such as PCNSL or KS, enhance adverse toxicities. For instance, KS patients with CD4 cell counts greater than 200 cells/µL are reported to have a good response to paclitaxel treatment, with the same prognosis as patients with a normal immunological status.

Drug interaction between antiretroviral agents and antitumor agents is assumed when the drug is metabolized by CYP450 pathway. Many PIs and NNRTIs are metabolized by this pathway, and competitive metabolism between antitumor drugs must be considered. (Table 3) Increases in toxicity between antiretroviral agents and antitumor agents have been reported. Among NNRTIs, efavirenz increases toxicity with concomitant use of vinka alkaloids and taxanes.(Makinson *et al.*, 2010) All NRTIs and most PIs have increased drug sensitivities *in vitro*, and this leads to increased toxicity. The NRTIs efavirenz, delavirdine, and nevirapine are primarily metabolized by CYP450.(Gulick, 1998, Flexner, 1998) In a study of patients with NHL undergoing treatment with concomitant antiretroviral agents and cyclophosphamide, doxorubicin, and etoposide, significantly lower nadir neutrophil counts were seen. As compared to the group with/without PIs, the group with PIs had greater toxicity (48% vs. 27%; *p*=0.0025). Drug interactions have also been confirmed *in vitro*; cultured cells that expressed Pglycoprotein (P-gp) accumulated increased concentrations of paclitaxel or vinblastine concomitant with PIs.(Washington *et al.*, 1998) PIs such as ritonavir and indinavir have a strong affinity for CYP450 and also strongly inhibit CYP3A4. These enzymes are used in metabolic pathways with ifosfamide, docetaxel, paclitaxel, irinotecan, vinca alkaloids, and

therapy. Interactions between morphine and some HAART drugs have been shown, but the benefit of morphine for palliation remains. In Stage IV NSCLC, early induction of palliative therapy after diagnosis significantly improves quality of life and mood, and prolongs survival by 2 months.(Temel *et al.*, 2010) As in patients from the general population, early palliative therapy is indicated for HIV-infected patients, as well as psychological support at the end-stage. As for the lung cancer patients with bone metastasis, zoledronic acid, a new bisphosphonate, is an appropriate palliative treatment for skeletal-related events (SREs) and symptoms associated with bone metastases.(Rosen *et al.*, 2003a, Rosen *et al.*, 2003b) The efficacy and safety of zoledronic acid given concomitantly with HAART for the osteoporosis that is associated with long-term HAART administration have been evaluated in a clinical trial and found to be advantageous.(Bolland *et al.*, 2008, Bolland *et al.*, 2007, Huang *et al.*, 2009) When SREs occur, they are associated with decreased activities of daily living and shorter survival.(Tsuya *et al.*, 2007) Thus, zoledronic acid should be given to patients with

Dexamethasone → ↓ ↓ → → → Lorazepam → ↓ ↑ → → →

antidepressants <sup>→</sup> <sup>→</sup> <sup>↑</sup> <sup>→</sup> <sup>→</sup> <sup>→</sup> Fentanyl → → ↑ → → → Carbamazepine → ↓ ↓ → → → Table 4. Expected drug interactions between antiretroviral agents and frequently used

Lung cancer patients with HIV infections are considered to have a poorer prognosis than the general population because of their younger age, immunodeficiency, aggressive extension, and more advanced stage at diagnosis. In a meta-analysis, the median survival time was 5-9 months.(Powles *et al.*, 2003, Karp *et al.*, 1993, Sridhar *et al.*, 1992, Tirelli *et al.*, 2000, Spano *et al.*, 2004, Alshafie *et al.*, 1997) The 1-year survival of HIV-infected lung cancer patients was 10% (0- 15%), as compared to 40% (20-50%) in the general population.(Cadranel *et al.*, 2006, Cinti *et al.*, 2008, Grubb *et al.*, 2006, Vyzula & Remick, 1996) Over the last 20 years, survival by histology was about 7 months in SCLC and 5 months in NSCLC.(Hakimian *et al.*, 2007) Favorable prognostic factors are reported to be good PS and early stage at diagnosis. The concomitant use of HAART is controversial as a prognostic factor. The reason for these patients' poor prognosis

CD4 cell count is sometimes considered to be a prognostic factor for chemotherapy. The prognosis for patients with a CD4 cell count greater than 200 cells/µL is 11.5 months, while that for patients with a CD4 cell count less than 200 cells/µL is 3.4 months.(Hakimian *et al.*, 2007) At present, patients with CD4 cell counts greater than 200 cells/µL can be given chemotherapy, and they have been demonstrated to have the comparable survival to non-

is considered to be their more advanced stage at diagnosis.(Lavole *et al.*, 2009)

Expected concentration modifications in drugs used supportive care based on antiretroviral drugs used NRTI NNRTI PI INSTI FI MVC

bone metastases of lung cancer, even asymptomatic.

supportive agents for chemotherapy.

HIV patients. (Hakimian *et al.*, 2007)

Tricyclic

**6. Prognosis** 

etoposide.(Rowinsky & Donehower, 1997, Stebbing & Bower, 2006) Severe myelosuppression with atazanavir(Richman *et al.*, 1987, Tan & Ratner, 1997) and peripheral neuropathy with didanosine, stavudine, and zalcitabine occur.(Rowinsky & Donehower, 1997) Thus, their combined use with platinum or paclitaxel leads to increased toxicities. Combination treatment with irinotecan and atazanavir is also contraindicated. Cisplatin, the key drug in lung cancer chemotherapy,(Azzoli *et al.*, 2009, Barlesi & Pujol, 2005) is not metabolized by the CYP450 enzyme pathway. Thus, drug interactions with HAART do not occur, but accumulating toxicity, such as nephrotoxicity and neurotoxicity, must be considered. In addition, patients on antiretroviral agents having nephrotoxicity such as tenofovir disoproxil require careful followup.

Of the molecular targeted agents, EGFR-TKIs have been poorly evaluated, but they are known to be metabolized by CYP3A4, and ritonavir should be avoided. Raltegravir is metabolized by UGT1A1 (uridine diphosphate glucuronosyl transferase isoform 1) and does not induce or inhibit hepatic enzymes; thus, drug interactions appear to be absent. Maraviroc, a CCR5 antagonist, also does not interact with CYP3A4. As for PIs, indinavir and sequinavir inhibit cell proliferation or invasion by acting through matrix metalloprotease.(Toschi *et al.*, 2011) Due to the increased toxicity of such drug interactions, the drugs that are better to apply in HAART regimens with antiretroviral drug are those not associated with CYP450, such as NRTI, raltegravir, or enfuvirtide.

In the future, dose adjustments will be used to investigate Pharmacokinetic data via a prospective study; however, the prognosis of lung cancer patients with HIV infection is anticipated to be similar to that in the general population. Thus, conventional doses and regimens are adequate.

#### **5.3.3 Prevention of opportunistic infections & potential complications**

An increased risk of OIs is considered to be a complication of chemotherapy because of the associated decrease in CD4 cell counts. In lung cancer patients, changes in CD4 cell counts with chemotherapy are unclear. However, previous reports on treatment for ADCs provide information about changes in CD4 cell counts. CD4 cell counts in NHL on chemotherapy decreased to 50% of baseline at the nadir and recovered within a month. CD4 cell counts and viral load do not change with chemotherapeutic treatment.(Powles *et al.*, 2002) In addition, in ADCs, CD4 cell counts in patients receiving concomitant HAART or HIV viral load-negative patients are considered to recover sooner.(Powles *et al.*, 2002, Hakim *et al.*, 1997) OIs on chemotherapy occurred in 8 of 25 patients (32%), and their CD4 cell counts were less than 150 cells/µL. These patients also had poor PS, and half of the patients developed Grade 3 or 4 hematological toxicity.(Tirelli *et al.*, 2000) Recent few reports have discussed the occurrence of OIs during chemotherapy. Primary prevention of OIs is adequate; no specific preventive therapies are necessary in patients with a well-controlled viral load. Generally, in patients with less than 200 cells/µL, trimethoprim-sulfamethoxazole or pentamidine inhalation is used for pneumocystis pneumonia prevention, and in patients with less than 50 cells/µL, a macrolide is used for Mycobacteriaum avium complex (MAC) prevention. Thus, a monthly CD4 cell count check is preferred during chemotherapy and one month after treatment.

#### **5.4 Supportive care**

In supportive care, drug interactions between antiretroviral agents and other agents must be considered (Table 4). However, in clinical settings, physicians must administer palliative

etoposide.(Rowinsky & Donehower, 1997, Stebbing & Bower, 2006) Severe myelosuppression with atazanavir(Richman *et al.*, 1987, Tan & Ratner, 1997) and peripheral neuropathy with didanosine, stavudine, and zalcitabine occur.(Rowinsky & Donehower, 1997) Thus, their combined use with platinum or paclitaxel leads to increased toxicities. Combination treatment with irinotecan and atazanavir is also contraindicated. Cisplatin, the key drug in lung cancer chemotherapy,(Azzoli *et al.*, 2009, Barlesi & Pujol, 2005) is not metabolized by the CYP450 enzyme pathway. Thus, drug interactions with HAART do not occur, but accumulating toxicity, such as nephrotoxicity and neurotoxicity, must be considered. In addition, patients on antiretroviral agents having nephrotoxicity such as tenofovir disoproxil require careful follow-

Of the molecular targeted agents, EGFR-TKIs have been poorly evaluated, but they are known to be metabolized by CYP3A4, and ritonavir should be avoided. Raltegravir is metabolized by UGT1A1 (uridine diphosphate glucuronosyl transferase isoform 1) and does not induce or inhibit hepatic enzymes; thus, drug interactions appear to be absent. Maraviroc, a CCR5 antagonist, also does not interact with CYP3A4. As for PIs, indinavir and sequinavir inhibit cell proliferation or invasion by acting through matrix metalloprotease.(Toschi *et al.*, 2011) Due to the increased toxicity of such drug interactions, the drugs that are better to apply in HAART regimens with antiretroviral drug are those not

In the future, dose adjustments will be used to investigate Pharmacokinetic data via a prospective study; however, the prognosis of lung cancer patients with HIV infection is anticipated to be similar to that in the general population. Thus, conventional doses and

An increased risk of OIs is considered to be a complication of chemotherapy because of the associated decrease in CD4 cell counts. In lung cancer patients, changes in CD4 cell counts with chemotherapy are unclear. However, previous reports on treatment for ADCs provide information about changes in CD4 cell counts. CD4 cell counts in NHL on chemotherapy decreased to 50% of baseline at the nadir and recovered within a month. CD4 cell counts and viral load do not change with chemotherapeutic treatment.(Powles *et al.*, 2002) In addition, in ADCs, CD4 cell counts in patients receiving concomitant HAART or HIV viral load-negative patients are considered to recover sooner.(Powles *et al.*, 2002, Hakim *et al.*, 1997) OIs on chemotherapy occurred in 8 of 25 patients (32%), and their CD4 cell counts were less than 150 cells/µL. These patients also had poor PS, and half of the patients developed Grade 3 or 4 hematological toxicity.(Tirelli *et al.*, 2000) Recent few reports have discussed the occurrence of OIs during chemotherapy. Primary prevention of OIs is adequate; no specific preventive therapies are necessary in patients with a well-controlled viral load. Generally, in patients with less than 200 cells/µL, trimethoprim-sulfamethoxazole or pentamidine inhalation is used for pneumocystis pneumonia prevention, and in patients with less than 50 cells/µL, a macrolide is used for Mycobacteriaum avium complex (MAC) prevention. Thus, a monthly CD4 cell count

In supportive care, drug interactions between antiretroviral agents and other agents must be considered (Table 4). However, in clinical settings, physicians must administer palliative

associated with CYP450, such as NRTI, raltegravir, or enfuvirtide.

**5.3.3 Prevention of opportunistic infections & potential complications** 

check is preferred during chemotherapy and one month after treatment.

up.

regimens are adequate.

**5.4 Supportive care** 

therapy. Interactions between morphine and some HAART drugs have been shown, but the benefit of morphine for palliation remains. In Stage IV NSCLC, early induction of palliative therapy after diagnosis significantly improves quality of life and mood, and prolongs survival by 2 months.(Temel *et al.*, 2010) As in patients from the general population, early palliative therapy is indicated for HIV-infected patients, as well as psychological support at the end-stage. As for the lung cancer patients with bone metastasis, zoledronic acid, a new bisphosphonate, is an appropriate palliative treatment for skeletal-related events (SREs) and symptoms associated with bone metastases.(Rosen *et al.*, 2003a, Rosen *et al.*, 2003b) The efficacy and safety of zoledronic acid given concomitantly with HAART for the osteoporosis that is associated with long-term HAART administration have been evaluated in a clinical trial and found to be advantageous.(Bolland *et al.*, 2008, Bolland *et al.*, 2007, Huang *et al.*, 2009) When SREs occur, they are associated with decreased activities of daily living and shorter survival.(Tsuya *et al.*, 2007) Thus, zoledronic acid should be given to patients with bone metastases of lung cancer, even asymptomatic.


Table 4. Expected drug interactions between antiretroviral agents and frequently used supportive agents for chemotherapy.

## **6. Prognosis**

Lung cancer patients with HIV infections are considered to have a poorer prognosis than the general population because of their younger age, immunodeficiency, aggressive extension, and more advanced stage at diagnosis. In a meta-analysis, the median survival time was 5-9 months.(Powles *et al.*, 2003, Karp *et al.*, 1993, Sridhar *et al.*, 1992, Tirelli *et al.*, 2000, Spano *et al.*, 2004, Alshafie *et al.*, 1997) The 1-year survival of HIV-infected lung cancer patients was 10% (0- 15%), as compared to 40% (20-50%) in the general population.(Cadranel *et al.*, 2006, Cinti *et al.*, 2008, Grubb *et al.*, 2006, Vyzula & Remick, 1996) Over the last 20 years, survival by histology was about 7 months in SCLC and 5 months in NSCLC.(Hakimian *et al.*, 2007) Favorable prognostic factors are reported to be good PS and early stage at diagnosis. The concomitant use of HAART is controversial as a prognostic factor. The reason for these patients' poor prognosis is considered to be their more advanced stage at diagnosis.(Lavole *et al.*, 2009)

CD4 cell count is sometimes considered to be a prognostic factor for chemotherapy. The prognosis for patients with a CD4 cell count greater than 200 cells/µL is 11.5 months, while that for patients with a CD4 cell count less than 200 cells/µL is 3.4 months.(Hakimian *et al.*, 2007) At present, patients with CD4 cell counts greater than 200 cells/µL can be given chemotherapy, and they have been demonstrated to have the comparable survival to non-HIV patients. (Hakimian *et al.*, 2007)

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## **7. Future directions**

Lung cancer has become common in HIV-infected patients and appears to be increasing in clinical settings, and NADCs have become the main cause of death. Thus, lung cancer has significant clinical meaning in the management of HIV-infected patients. Knowledge about its epidemiology, screening, risk factors, and intervention will reduce the incidence of lung cancer. In particular, aggressively promoting smoking cessation programs and screening for lung cancer for earlier detection will play important roles as strategies in preventing lung cancer.

HIV-infected patients should receive standard care for lung cancer, and it is anticipated that they will have the same prognosis as the general population. However, for these patients, we need to consider previously reported toxicities and fragility to treatment. In addition, increased intensity of treatment due to drug interactions and increased radiosensitization with HAART must be considered. As the clinical details of such patients have not been well reported, infectious disease physicians and oncologists must collaborate when treating HIVinfected lung cancer patients.

## **8. References**


Lung cancer has become common in HIV-infected patients and appears to be increasing in clinical settings, and NADCs have become the main cause of death. Thus, lung cancer has significant clinical meaning in the management of HIV-infected patients. Knowledge about its epidemiology, screening, risk factors, and intervention will reduce the incidence of lung cancer. In particular, aggressively promoting smoking cessation programs and screening for lung cancer for earlier detection will play important roles as strategies in preventing lung

HIV-infected patients should receive standard care for lung cancer, and it is anticipated that they will have the same prognosis as the general population. However, for these patients, we need to consider previously reported toxicities and fragility to treatment. In addition, increased intensity of treatment due to drug interactions and increased radiosensitization with HAART must be considered. As the clinical details of such patients have not been well reported, infectious disease physicians and oncologists must collaborate when treating HIV-

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patients treated for human immunodeficiency virus infection compared with the


**17** 

*Nigeria* 

**Infection and AIDS** 

Victor Obiajulu Olisah

**Neuropsychiatric Manifestations of HIV** 

*Department of Psychiatry, Ahmadu Bello University Teaching Hospital, Zaria,* 

Acquired Immune Deficiency Syndrome (AIDS) was first reported in the United States in 1981 and has since become a major worldwide epidemic. AIDS is caused by the human immunodeficiency virus (HIV). By killing or damaging cells of the body's immune system, HIV progressively destroys the body's ability to fight infections and certain cancers. The

Statistics on the world epidemic of HIV/AIDS indicates that 39.5 million people are living with HIV/AIDS worldwide. Of these, 24.7 million (63%) live in Sub-Saharan Africa, a region

HIV is a retrovirus, which is immunosuppressive, predisposing the individual to opportunistic infections and certain neoplasm (Wiley, 1994). In addition to impairment in immune functions, evidence has suggested that HIV is neurotropic. It should therefore be anticipated that neuropsychiatric complication might be common in HIV positive

Over the years, researchers have developed antiretroviral drugs to fight both HIV infection and its associated infections and cancers. Currently available drugs do not cure people with HIV infection or AIDS, and they all have side effects that can be severe. Because no vaccine for HIV is available, the only way to prevent infection is to avoid behaviours that put a

It is believed that neuropsychiatric disorders account for over 15% of the world's disease burden. Due to the recent advances in antiretroviral therapy, the life expectancy of people living with HIV has increased, and thus clinicians are more likely to encounter the neuropsychiatric manifestations of the disease. In as many as 20% of HIV infected individuals, neurologic or neuropsychiatric symptoms may be the presenting features, prior to other medical symptoms of AIDS. Despite improvement in and combination of antiretroviral therapy, neuropsychiatric complications still occur in as many as 50% of people living with HIV and are mostly undiagnosed and untreated. Assessment and management of mental disorders is integral to an effective HIV/AIDS intervention program. Mental health professionals will increasingly be called upon to assist in the management of people living with HIV/AIDS. Thus psychiatrists will need to be familiar with disorders that are prevalent in HIV infection. It is now estimated that 40–70% of patients with AIDS develop clinical neurologic abnormalities. The most common neurologic manifestations are minor cognitive motor disorder (MCMD) and HIV-associated dementia (HAD). On the other hand, depression is the most common psychiatric condition in people living with

that is home to just 10% of the world's population (UNAIDS/WHO report, 2006).

person at risk of infection, such as sharing needles and unprotected sex.

term AIDS applies to the most advanced stages of HIV infection.

individuals during all phases of HIV related illness.

**1. Introduction** 


## **Neuropsychiatric Manifestations of HIV Infection and AIDS**

Victor Obiajulu Olisah

*Department of Psychiatry, Ahmadu Bello University Teaching Hospital, Zaria, Nigeria* 

## **1. Introduction**

414 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

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Acquired Immune Deficiency Syndrome (AIDS) was first reported in the United States in 1981 and has since become a major worldwide epidemic. AIDS is caused by the human immunodeficiency virus (HIV). By killing or damaging cells of the body's immune system, HIV progressively destroys the body's ability to fight infections and certain cancers. The term AIDS applies to the most advanced stages of HIV infection.

Statistics on the world epidemic of HIV/AIDS indicates that 39.5 million people are living with HIV/AIDS worldwide. Of these, 24.7 million (63%) live in Sub-Saharan Africa, a region that is home to just 10% of the world's population (UNAIDS/WHO report, 2006).

HIV is a retrovirus, which is immunosuppressive, predisposing the individual to opportunistic infections and certain neoplasm (Wiley, 1994). In addition to impairment in immune functions, evidence has suggested that HIV is neurotropic. It should therefore be anticipated that neuropsychiatric complication might be common in HIV positive individuals during all phases of HIV related illness.

Over the years, researchers have developed antiretroviral drugs to fight both HIV infection and its associated infections and cancers. Currently available drugs do not cure people with HIV infection or AIDS, and they all have side effects that can be severe. Because no vaccine for HIV is available, the only way to prevent infection is to avoid behaviours that put a person at risk of infection, such as sharing needles and unprotected sex.

It is believed that neuropsychiatric disorders account for over 15% of the world's disease burden. Due to the recent advances in antiretroviral therapy, the life expectancy of people living with HIV has increased, and thus clinicians are more likely to encounter the neuropsychiatric manifestations of the disease. In as many as 20% of HIV infected individuals, neurologic or neuropsychiatric symptoms may be the presenting features, prior to other medical symptoms of AIDS. Despite improvement in and combination of antiretroviral therapy, neuropsychiatric complications still occur in as many as 50% of people living with HIV and are mostly undiagnosed and untreated. Assessment and management of mental disorders is integral to an effective HIV/AIDS intervention program. Mental health professionals will increasingly be called upon to assist in the management of people living with HIV/AIDS. Thus psychiatrists will need to be familiar with disorders that are prevalent in HIV infection. It is now estimated that 40–70% of patients with AIDS develop clinical neurologic abnormalities. The most common neurologic manifestations are minor cognitive motor disorder (MCMD) and HIV-associated dementia (HAD). On the other hand, depression is the most common psychiatric condition in people living with

Neuropsychiatric Manifestations of HIV Infection and AIDS 417

infection of the nervous system and weakening of the host immune responses. HIV-1 is the form of the virus that causes disease in most part of the world. HIV-2 discovered in 1986, causes a relatively small proportion of cases clustered in West Africa. HIV has high affinity for CD4 T lymphocytes and monocytes. When HIV binds to CD4 cells, it becomes internalized. The virus replicates itself by generating a DNA copy using reverse transcriptase enzyme. Viral DNA becomes incorporated into the host DNA, enabling further replication (Green, 1991, Stebbing et al, 2004). HIV causes the lysis of CD4 lymphocytes. These cells are critical in cell-mediated immunity. The course of HIV infection is characterized by latency. Unfortunately, profound immune deficiency eventually develops, as CD4 cell count drops below 200cells per mm3. At this point, the patient becomes vulnerable to opportunistic infections and malignancies (Centers for Disease Control, 1982). Progression from HIV to AIDS occurs at a median of 11years after infection. In the recent past, most patients would not survive more than 1 to 2 years after diagnosis of AIDS. However, since the introduction of antiretroviral drugs and prophylaxis against

opportunistic pathogens, death rates from AIDS have begun to decline significantly.

Treatment is accomplished through numerous combinations of antiretroviral agents belonging to the following groups: Nucleoside analogue reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors and nucleoside analogues. In the mid-1990s, several investigators studied combination therapies of two reverse transcriptase inhibitors and a protease inhibitor. This therapy was later referred to as Highly Active Antiretroviral Therapy (HAART). HAART dramatically reduced viral load and often resulted in an increase in CD4 cell count. The current goal of treatment is to reduce viral load to undetectable levels and maintain such remission without interruption. Evidence suggests that the therapies suppress replication but do not eradicate HIV from all parts of the body, particularly lymphoid tissue and the brain. Not all patients who initiate antiretroviral therapy respond. The lack of clinical response is likely explained by problems with adherence, suboptimal antiretroviral treatment potency, and genetic mutation of HIV strains (Descamps et al, 2000). Many patients experience substantial side effects, and it is not uncommon for changes to be made in antiretroviral regimens because of such side effects. Adverse effects include lipodystrophy, hyperlipidemia, nephrotoxicity, bone marrow suppression, neuropathy and elevation of blood glucose to possibly diabetes mellitus levels (Deeks et al, 1997). Patients often experience nausea, vomiting, diarrhea, sleep disturbances and rashes. Adherence is of utmost concern with antiretroviral treatment because even minor deviations from the prescribed regimen can result in viral resistance and permanent loss of efficacy for existing medications (Practice guidelines for HIV treatment, 2000). Studies of antiretroviral treatment continue to indicate that a near-perfect adherence is needed to adequately repress

As the world HIV epidemic spreads increasingly among disadvantaged persons with limited resources who have multiple comorbid disorders, significantly more psychosocial stressors, and less access to ongoing primary or mental health care, these individuals are at risk of not receiving the recommended treatment for HIV infection. Services for HIV patients must balance medical interventions with the emotional, economic, and social supports required for good quality of life and prevention of further transmission (Practice

**3. Treatment of HIV infection** 

viral replication (Demasi et al, 2001).

guidelines for HIV treatment, 2000).

HIV/AIDS with estimated life time prevalence in the range of between 21% and 61% (Elliot et al, 1998). This category of psychiatric disorders presents diagnostic challenges because of the many neurovegetative confounding factors that are present in association with HIV illness. In both cases, the impact of these syndromes on seropositive patients is significant and appropriate intervention is required, the key to optimal treatment resting with early diagnosis and aggressive treatment.

Initially, the neuropsychiatric manifestations of HIV/AIDS were attributed to psychological reactions to a systemic illness, the effects of psychosocial stressors associated with the disease, or the consequences of opportunistic infections or neoplasms within the central nervous system (CNS). It is now recognized that the psychiatric sequelae of HIV infection and AIDS are numerous and have etiologies that involve neurobiological and psychosocial factors. These include the direct or primary effects of HIV on nervous tissue, the consequences of secondary viral and nonviral opportunistic infections, tumors, cerebrovascular disease, and the complications of systemic therapies for AIDS and associated disorders.

Some previous studies have indicated that Neuropsychiatric disorders in people living with HIV/AIDS are associated with disease progression, poor adherence to antiretroviral drugs, increased incidence of high risk sexual behavior with the potential for further HIV transmission, and deterioration in their quality of life.

Mental and neurological disorders have an intertwined relationship with HIV and AIDS, yet sadly are often overlooked when HIV interventions are planned and implemented. Several important aspects of HIV care and treatment place psychiatrists at the forefront of this epidemic, these include:


## **2. Biology and pathophysiology of HIV infection**

HIV is a lentivirus, a subgroup of retroviruses. As with other retroviruses, HIV has rapid rate of genetic mutation. This family of viruses is known for latency, persistent viremia,

HIV/AIDS with estimated life time prevalence in the range of between 21% and 61% (Elliot et al, 1998). This category of psychiatric disorders presents diagnostic challenges because of the many neurovegetative confounding factors that are present in association with HIV illness. In both cases, the impact of these syndromes on seropositive patients is significant and appropriate intervention is required, the key to optimal treatment resting with early

Initially, the neuropsychiatric manifestations of HIV/AIDS were attributed to psychological reactions to a systemic illness, the effects of psychosocial stressors associated with the disease, or the consequences of opportunistic infections or neoplasms within the central nervous system (CNS). It is now recognized that the psychiatric sequelae of HIV infection and AIDS are numerous and have etiologies that involve neurobiological and psychosocial factors. These include the direct or primary effects of HIV on nervous tissue, the consequences of secondary viral and nonviral opportunistic infections, tumors, cerebrovascular disease, and the

Some previous studies have indicated that Neuropsychiatric disorders in people living with HIV/AIDS are associated with disease progression, poor adherence to antiretroviral drugs, increased incidence of high risk sexual behavior with the potential for further HIV

Mental and neurological disorders have an intertwined relationship with HIV and AIDS, yet sadly are often overlooked when HIV interventions are planned and implemented. Several important aspects of HIV care and treatment place psychiatrists at the forefront of this

psychiatric disorders (including substance use) can increase an individual's risk of

pre-existing mental disorders (including substance use) can predate and/or complicate

neuropsychiatric complications and psychiatric illness can affect adherence to

new antiretroviral treatments and combination therapies can affect the CNS and/or

individuals with waning immunity and high viral loads may be at particular risk for the

 the proportion of mental health and/or substance abuse disorders among people living with HIV/AIDS is nearly 5 times greater than the proportion found in the general

persons living with a severe mental illness are disproportionately vulnerable (as high as

psychiatric syndromes can be especially challenging to recognize and accurately

 as HIV/AIDS becomes increasingly a chronic disorder with the improvement of treatments and longer survival times, the need for comprehensive psychiatric care and

HIV is a lentivirus, a subgroup of retroviruses. As with other retroviruses, HIV has rapid rate of genetic mutation. This family of viruses is known for latency, persistent viremia,

contribute to the development of psychiatric side effects/symptoms;

23%) to infection with HIV and other sexually transmitted diseases;

HIV-related CNS complications that can cause acute mental status changes;

complications of systemic therapies for AIDS and associated disorders.

acquiring sexually transmitted diseases, including HIV;

transmission, and deterioration in their quality of life.

diagnosis and aggressive treatment.

epidemic, these include:

HIV-related illness;

population;

antiretroviral therapy regimens;

diagnose in the medically ill; and

**2. Biology and pathophysiology of HIV infection** 

services is expected to rise.

infection of the nervous system and weakening of the host immune responses. HIV-1 is the form of the virus that causes disease in most part of the world. HIV-2 discovered in 1986, causes a relatively small proportion of cases clustered in West Africa. HIV has high affinity for CD4 T lymphocytes and monocytes. When HIV binds to CD4 cells, it becomes internalized. The virus replicates itself by generating a DNA copy using reverse transcriptase enzyme. Viral DNA becomes incorporated into the host DNA, enabling further replication (Green, 1991, Stebbing et al, 2004). HIV causes the lysis of CD4 lymphocytes. These cells are critical in cell-mediated immunity. The course of HIV infection is characterized by latency. Unfortunately, profound immune deficiency eventually develops, as CD4 cell count drops below 200cells per mm3. At this point, the patient becomes vulnerable to opportunistic infections and malignancies (Centers for Disease Control, 1982). Progression from HIV to AIDS occurs at a median of 11years after infection. In the recent past, most patients would not survive more than 1 to 2 years after diagnosis of AIDS. However, since the introduction of antiretroviral drugs and prophylaxis against opportunistic pathogens, death rates from AIDS have begun to decline significantly.

## **3. Treatment of HIV infection**

Treatment is accomplished through numerous combinations of antiretroviral agents belonging to the following groups: Nucleoside analogue reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors and nucleoside analogues. In the mid-1990s, several investigators studied combination therapies of two reverse transcriptase inhibitors and a protease inhibitor. This therapy was later referred to as Highly Active Antiretroviral Therapy (HAART). HAART dramatically reduced viral load and often resulted in an increase in CD4 cell count. The current goal of treatment is to reduce viral load to undetectable levels and maintain such remission without interruption. Evidence suggests that the therapies suppress replication but do not eradicate HIV from all parts of the body, particularly lymphoid tissue and the brain. Not all patients who initiate antiretroviral therapy respond. The lack of clinical response is likely explained by problems with adherence, suboptimal antiretroviral treatment potency, and genetic mutation of HIV strains (Descamps et al, 2000). Many patients experience substantial side effects, and it is not uncommon for changes to be made in antiretroviral regimens because of such side effects. Adverse effects include lipodystrophy, hyperlipidemia, nephrotoxicity, bone marrow suppression, neuropathy and elevation of blood glucose to possibly diabetes mellitus levels (Deeks et al, 1997). Patients often experience nausea, vomiting, diarrhea, sleep disturbances and rashes.

Adherence is of utmost concern with antiretroviral treatment because even minor deviations from the prescribed regimen can result in viral resistance and permanent loss of efficacy for existing medications (Practice guidelines for HIV treatment, 2000). Studies of antiretroviral treatment continue to indicate that a near-perfect adherence is needed to adequately repress viral replication (Demasi et al, 2001).

As the world HIV epidemic spreads increasingly among disadvantaged persons with limited resources who have multiple comorbid disorders, significantly more psychosocial stressors, and less access to ongoing primary or mental health care, these individuals are at risk of not receiving the recommended treatment for HIV infection. Services for HIV patients must balance medical interventions with the emotional, economic, and social supports required for good quality of life and prevention of further transmission (Practice guidelines for HIV treatment, 2000).

Neuropsychiatric Manifestations of HIV Infection and AIDS 419

associated cognitive disorders. Using synaptic density as an indicator of damage in postmortem brain samples from HIV-infected patients, Everall and colleagues found that reduced synaptic density correlated significantly with ante-mortem neuropsychological functioning, and stressed that early diagnosis and treatment could potentially reverse synaptic damage and prevent cognitive decline(Everall et al., 1999). Loss of subcortical neurons in the brain of

Evidence is accumulating to suggest roles for several HIV proteins, including glycoprotein 120 (gp120), HIV-1 negative factor (Nef), and transactivating protein (Tat), in HIV-induced neuropathogenesis. For example, the viral envelope protein gp120 appears to bind to rat dorsal root ganglia and human neuroblastoma cells (Apostolski et al., 1993), and in rats exposure to gp120 has been shown to cause swelling and increase tumor necrosis factor in the sciatic nerve trunk, induce astrocyte and microglial infiltration into the spinal cord, and cause neuropathic pain behaviours (Herzberg & Sagen, 2001). *In vitro*, studies have shown that Nef induces macrophage chemotaxis (Koedel et al., 1999) and acts as a potent neurotoxin (Trillo-Pazos et al., 2000). Astrocytes treated with Tat *in vitro* produced proinflammatory cytokines and chemokines that may contribute to neuronal injury (Galey et al., 2001). Tat also stimulates macrophage production of metalloproteinases, enzymes that are expressed at increased levels in certain neurologic diseases and in the brain tissues of patients with AIDS (Johnston et al.2000). Although the significance of these laboratory findings for patients with HIV or AIDS remains to be clarified, it is probable that many of these mechanisms combine to produce the neurologic and psychiatric changes seen with HIV infection and AIDS. Identifying and characterizing the mechanisms involved may open

The psychosocial stress associated with a socially stigmatizing terminal illness and frequent infections carries with it tremendous emotional upheaval in vulnerable individuals. There is usually a sense or loss of health, financial security, independence and relationships in HIV infected persons. This is made worse when relevant social support is missing (Katalan et al,

Specific crisis points and psychosocial factors can precipitate psychiatric disorders especially anxiety and depression in HIV-infected persons. These crisis points includes- learning of HIV positive status, disclosure of HIV status to family and friends, introduction of medication, occurrence of any physical illness, recognition of new symptoms/ progression of disease, necessity for hospitalization, death of a partner, diagnosis of AIDS, changes in major aspects of lifestyle, necessity for making end of life and permanency decisions (HIV

HIV is classified among the lentiviruses, a family of viruses characterized in part by their tendency to cause chronic neurologic disease in their animal hosts. It is not surprising, then, that neurologic complications of HIV infection are common and not confined to opportunistic infections. All levels of the neuraxis can be involved, including the brain, meninges, spinal cord, nerve, and muscle. Neurologic disease is the first manifestation of symptomatic HIV infection in roughly 10-20% of persons, while about 60% of patients with advanced HIV disease will have clinically evident neurologic dysfunction during the course

people infected with HIV may be associated with the experience of depression.

new avenues for prevention and treatment.

**5. Neurologic manifestations of HIV** 

**4.2 Psychosocial factors** 

clinical guidelines, 2000).

1989).

## **4. Etiology of the neuropsychiatric manifestations of HIV/AIDS**

#### **4.1 Impact of HIV on the Central Nervous System (CNS)**

Clinical evidence for direct infection of the CNS by HIV emerged in the mid- 1980s, when patients began to survive their presenting opportunistic infections but went on to develop neuropsychiatric syndromes that could not be attributed to CNS opportunistic infections and neoplasm. Additional evidence included signs of neuro-cognitive impairment in adults, loss or arrest of developmental milestones in children, ability to culture HIV from the cerebrospinal fluid, neuropathological lesions of the brain at autopsy, and abnormalities observed through brain imaging techniques, including cerebral atrophy (Deeks et al, 1997).

HIV invades the CNS early in the course of infection entering by way of macrophages, which along with microgial cells are largely responsible for HIV replication within the CNS. While HIV does not infect neurons in the CNS, it causes neuronal death by causing the elaboration of neurotoxins which in turn induce a variety of inflammatory factors that cause apoptosis, or programmed cell death of neurons (Swindells et al, 1999).

The pathogenesis of HIV infection within the brain and its relationship to neurologic and psychiatric complications remains obscure, but there is evidence that cellular and molecular components of the immune system are involved (Bloom & Rausch, 1997).

Several different mechanisms may explain the effects of HIV on the CNS. Researchers have hypothesized that pathogenesis begins with viral penetration of the CNS and associated loss of integrity of the blood-brain barrier. This may allow cellular and non-cellular inflammatory components of the immune system to enter the CNS, resulting in damage to neurons and non-neuronal support cells (Rabkin & Ferrando, 1997).

Some studies have examined viral load and CD4 cell counts, measures typically used to monitor immunologic function in patients with HIV infection, as potential markers of CNS injury and vulnerability to CNS complications. A study that followed viral loads and CD4 cell counts in a large cohort of HIV-infected men without AIDS found that relatively high plasma HIV RNA (> 3000 copies/ml) and low CD4 T-lymphocyte counts (< 500 x 106 cells/l) were predictive of both dementia and neuropathy (Childs et al., 1999).The authors suggested that effective suppression of HIV may reduce the risk of developing these neurological complications.

Based on evidence of basal ganglia dysfunction in HIV-associated dementia (Berger & Nath, 1997), some researchers proposed that microvascular abnormalities would be found in the basal ganglia of patients with this condition (Berger, 2000).Using time-course magnetic resonance imaging, these investigators observed increased enhancement, both immediate and late, in the basal ganglia of individuals with HIV infection and moderate-to-severe dementia, relative to HIV patients without dementia. These data suggested that increases in regional cerebral blood volume and disruption of the blood-brain barrier have an etiologic role in the development of HIV-associated dementia.

Most HIV DNA in the brain has been found in macrophages/microglia, often near apoptotic neurons, suggesting that cytokines produced by the infected cells might contribute to neuronal destruction (Shapshak et al., 1995). Macrophages may infiltrate the CNS by interacting with the endothelial cells that form the blood-brain barrier, causing endothelial cell damage and disrupting the barrier (Nottet, 1999). Chemokines (cytokines that act as macrophage attractants) and their receptors on neurons and glial cells appear to play a central role in HIV entry into the CNS and eventual cellular destruction (Gabuzda &Wang, 2000; Zheng, 1999).Synaptic damage, without neuronal loss, has been observed in patients with mild HIV-

Clinical evidence for direct infection of the CNS by HIV emerged in the mid- 1980s, when patients began to survive their presenting opportunistic infections but went on to develop neuropsychiatric syndromes that could not be attributed to CNS opportunistic infections and neoplasm. Additional evidence included signs of neuro-cognitive impairment in adults, loss or arrest of developmental milestones in children, ability to culture HIV from the cerebrospinal fluid, neuropathological lesions of the brain at autopsy, and abnormalities observed through brain imaging techniques, including cerebral atrophy (Deeks et al, 1997). HIV invades the CNS early in the course of infection entering by way of macrophages, which along with microgial cells are largely responsible for HIV replication within the CNS. While HIV does not infect neurons in the CNS, it causes neuronal death by causing the elaboration of neurotoxins which in turn induce a variety of inflammatory factors that cause

The pathogenesis of HIV infection within the brain and its relationship to neurologic and psychiatric complications remains obscure, but there is evidence that cellular and molecular

Several different mechanisms may explain the effects of HIV on the CNS. Researchers have hypothesized that pathogenesis begins with viral penetration of the CNS and associated loss of integrity of the blood-brain barrier. This may allow cellular and non-cellular inflammatory components of the immune system to enter the CNS, resulting in damage to

Some studies have examined viral load and CD4 cell counts, measures typically used to monitor immunologic function in patients with HIV infection, as potential markers of CNS injury and vulnerability to CNS complications. A study that followed viral loads and CD4 cell counts in a large cohort of HIV-infected men without AIDS found that relatively high plasma HIV RNA (> 3000 copies/ml) and low CD4 T-lymphocyte counts (< 500 x 106 cells/l) were predictive of both dementia and neuropathy (Childs et al., 1999).The authors suggested that effective suppression of HIV may reduce the risk of developing these

Based on evidence of basal ganglia dysfunction in HIV-associated dementia (Berger & Nath, 1997), some researchers proposed that microvascular abnormalities would be found in the basal ganglia of patients with this condition (Berger, 2000).Using time-course magnetic resonance imaging, these investigators observed increased enhancement, both immediate and late, in the basal ganglia of individuals with HIV infection and moderate-to-severe dementia, relative to HIV patients without dementia. These data suggested that increases in regional cerebral blood volume and disruption of the blood-brain barrier have an etiologic

Most HIV DNA in the brain has been found in macrophages/microglia, often near apoptotic neurons, suggesting that cytokines produced by the infected cells might contribute to neuronal destruction (Shapshak et al., 1995). Macrophages may infiltrate the CNS by interacting with the endothelial cells that form the blood-brain barrier, causing endothelial cell damage and disrupting the barrier (Nottet, 1999). Chemokines (cytokines that act as macrophage attractants) and their receptors on neurons and glial cells appear to play a central role in HIV entry into the CNS and eventual cellular destruction (Gabuzda &Wang, 2000; Zheng, 1999).Synaptic damage, without neuronal loss, has been observed in patients with mild HIV-

**4. Etiology of the neuropsychiatric manifestations of HIV/AIDS** 

apoptosis, or programmed cell death of neurons (Swindells et al, 1999).

components of the immune system are involved (Bloom & Rausch, 1997).

neurons and non-neuronal support cells (Rabkin & Ferrando, 1997).

role in the development of HIV-associated dementia.

neurological complications.

**4.1 Impact of HIV on the Central Nervous System (CNS)** 

associated cognitive disorders. Using synaptic density as an indicator of damage in postmortem brain samples from HIV-infected patients, Everall and colleagues found that reduced synaptic density correlated significantly with ante-mortem neuropsychological functioning, and stressed that early diagnosis and treatment could potentially reverse synaptic damage and prevent cognitive decline(Everall et al., 1999). Loss of subcortical neurons in the brain of people infected with HIV may be associated with the experience of depression.

Evidence is accumulating to suggest roles for several HIV proteins, including glycoprotein 120 (gp120), HIV-1 negative factor (Nef), and transactivating protein (Tat), in HIV-induced neuropathogenesis. For example, the viral envelope protein gp120 appears to bind to rat dorsal root ganglia and human neuroblastoma cells (Apostolski et al., 1993), and in rats exposure to gp120 has been shown to cause swelling and increase tumor necrosis factor in the sciatic nerve trunk, induce astrocyte and microglial infiltration into the spinal cord, and cause neuropathic pain behaviours (Herzberg & Sagen, 2001). *In vitro*, studies have shown that Nef induces macrophage chemotaxis (Koedel et al., 1999) and acts as a potent neurotoxin (Trillo-Pazos et al., 2000). Astrocytes treated with Tat *in vitro* produced proinflammatory cytokines and chemokines that may contribute to neuronal injury (Galey et al., 2001). Tat also stimulates macrophage production of metalloproteinases, enzymes that are expressed at increased levels in certain neurologic diseases and in the brain tissues of patients with AIDS (Johnston et al.2000). Although the significance of these laboratory findings for patients with HIV or AIDS remains to be clarified, it is probable that many of these mechanisms combine to produce the neurologic and psychiatric changes seen with HIV infection and AIDS. Identifying and characterizing the mechanisms involved may open new avenues for prevention and treatment.

## **4.2 Psychosocial factors**

The psychosocial stress associated with a socially stigmatizing terminal illness and frequent infections carries with it tremendous emotional upheaval in vulnerable individuals. There is usually a sense or loss of health, financial security, independence and relationships in HIV infected persons. This is made worse when relevant social support is missing (Katalan et al, 1989).

Specific crisis points and psychosocial factors can precipitate psychiatric disorders especially anxiety and depression in HIV-infected persons. These crisis points includes- learning of HIV positive status, disclosure of HIV status to family and friends, introduction of medication, occurrence of any physical illness, recognition of new symptoms/ progression of disease, necessity for hospitalization, death of a partner, diagnosis of AIDS, changes in major aspects of lifestyle, necessity for making end of life and permanency decisions (HIV clinical guidelines, 2000).

## **5. Neurologic manifestations of HIV**

HIV is classified among the lentiviruses, a family of viruses characterized in part by their tendency to cause chronic neurologic disease in their animal hosts. It is not surprising, then, that neurologic complications of HIV infection are common and not confined to opportunistic infections. All levels of the neuraxis can be involved, including the brain, meninges, spinal cord, nerve, and muscle. Neurologic disease is the first manifestation of symptomatic HIV infection in roughly 10-20% of persons, while about 60% of patients with advanced HIV disease will have clinically evident neurologic dysfunction during the course

Neuropsychiatric Manifestations of HIV Infection and AIDS 421

brain. Activated macrophages, whether infected with HIV or not, are capable of secreting potent neurotoxins, inducing pro-inflammatory cytokines, and generating oxygen free radicals that can damage cells and lead to neuronal dysfunction or death (Glass et al., 1995). A particular subtype of monocyte/macrophages derived from the peripheral blood was found to be greatly increased among patients with AIDS dementia compared with both HIV infected and uninfected controls. Soluble factors from these macrophages were found to be highly neurotoxic--that is, they killed human brain cells in culture (Pulliam et al., 1997). Although the incidence of nearly all nervous system opportunistic infections has declined dramatically in the era of potent antiretroviral therapy, the impact on the incidence and prevalence of HIV-associated cognitive impairment including frank ADC--has been low. The prevalence of ADC in HIV-infected individuals with higher CD4 counts (200-350 cells/µL) actually appears to have increased since 1996. Pathologically, the prevalence of HIV-associated brain disease, or encephalopathy, is rising despite suppressive antiretroviral therapy (Neuenburg et al., 2002). Poor penetration of the blood-brain barrier by many of the antiretroviral drugs, particularly the protease inhibitors, has been suggested as a reason for

There is some evidence that, despite the poor CNS penetration of most antiretrovirals, effective antiretroviral therapy may attenuate the neurotoxicity of circulating monocytes/macrophages. Among individuals with ADC receiving effective antiretroviral regimens, macrophage-derived soluble factors were found to be less neurotoxic than observed prior to the availability of combination antiretroviral therapy (Pulliam et al.,

The major difference between "HIV associated dementia complex" and "HIV associated minor cognitive/ motor disorder" is the severity of impairment in activities of daily living. That is, by definition, dementia must have cognitive impairment severe enough to interfere with occupational or social functioning. In "HIV associated minor cognitive/motor disorder," activities of daily living are generally intact with the possible exception of mild

The initial features of HIV associated dementia include an overall slowing in cognition (i.e., bradyphrenia) and movement (i.e., bradykinesia) as well as difficulties in motor dexterity and coordination, forgetfulness, poor concentration, and marked apathy. Although dysphoric mood is not a common feature, the pronounced slowing and apathy may appear as if the patient is depressed. Furthermore, assessing other aspects of depression (e.g., weight loss, cognitive disturbance and insomnia) is difficult for patients with this disorder due to shared symptomatology that may be indistinguishable from the psychiatric

Later in the course of HIV associated dementia, the patient may exhibit myoclonus, bowel and bladder incontinence, and, eventually, mutism and a vegetative state. Once these

Because the above initial symptoms are similar to those seen in other patient groups with subcortical impairment (e.g., Parkinson's disease, progressive supranuclear palsy, multiple sclerosis) and because of the neuroimaging findings of subcortical neuropathology, HIV associated dementia was originally described as a subcortical dementia. However, in light of the more recent findings of cortical atrophy and higher cortical function deficits in AIDS patients, this characterization may not fully describe the spectrum of neuropsychiatric

the persistence of ADC.

difficulties in the most demanding activities.

advanced features are present, death is typically imminent.

deficits associated with HIV infection and AIDS.

1997).

symptoms.

of their illness (Koppel et al., 1985). The incidence of subclinical neurologic disease is even higher: autopsy studies of patients with advanced HIV disease have demonstrated pathologic abnormalities of the nervous system in 75-90% of cases (De la Monte et al., 1987). HIV has been cultured from brain, nerve, and cerebrospinal fluid (CSF) from persons at all stages of the disease, including those without neurologic signs or symptoms. Positive HIV cultures in CSF do not predict the presence or development of neurologic signs or symptoms later on. The development of neurologic manifestations of AIDS depends on a number of factors, such as antiretroviral treatment history, degree of immunosuppression, and the molecular biology of the viral strain, particularly its neurovirulence(McGuire & Greene, 1996) Host factors, including genetic makeup, undoubtedly play a role in selective vulnerability to neurologic manifestations.

The initial infection of the nervous system by HIV is usually asymptomatic, although acute aseptic meningitis, encephalitis, and inflammatory polyneuropathy have all occurred in this setting. Despite its potential to cause disease at all levels of the nervous system, HIV does not directly infect central or peripheral neurons, astrocytes, or oligodendroglial cells. Latent or low level HIV infection in the CNS is maintained by virus-infected cells of the monocyte/macrophage lineage. "Indirect effects" of macrophage activation--such as dysregulation of cytokines and chemokines, free-radical (oxidative stress) injury, and secretion of soluble factors that are potently neurotoxic, have been implicated as effectors of nervous Minor Cognitive system injury in HIV.

#### **5.1 Minor cognitive impairment**

Despite evidence of early infection of the CNS, symptoms of cognitive impairment typically occur late in symptomatic HIV disease, usually in the setting of severe immunosuppression (Miller et al., 1990).

Cognitive impairment has long been recognized as part of manifestation of human immune deficiency virus infection. These changes include loss of cognitive flexibility, difficulty in problem solving, mental slowness and difficulty in concentration. There are also difficulties in memory which manifest as delayed recall. Despite the wide spread use of highly active antiretroviral therapy (HAART), at least in developed nations and some developing nations, cognitive impairment and other neurological complications of HIV infection persist with devastating personal and socioeconomic consequences. Even though neurons are rarely infected by human immunodeficiency virus especially at early stage of the infection, neuronal loss is quite common in patient with HIV infection.

Although as many as 40% of patients with HIV/AIDS will have some form of cognitive impairment even before the development of full dementia, only a small percentage (5-10%) may go on to develop dementia itself. Various type of cognitive impairment in HIV infection has been documented and the American academy of Neurology (AAN) published a diagnostic criteria for HIV associated dementia (HAD) and minor cognitive motor disorder (MCMD); which include motor, affective and behavioural abnormalities, consistent with the early description of AIDS dementia complex.

#### **5.2 AIDS Dementia Complex (ADC)**

Some investigators hold that increased HIV proliferation in the brain is necessary for the development of ADC. Others propose that a macrophage-initiated cascade of events can lead to brain dysfunction and clinical dementia, even in the absence of high viral load in the

of their illness (Koppel et al., 1985). The incidence of subclinical neurologic disease is even higher: autopsy studies of patients with advanced HIV disease have demonstrated pathologic abnormalities of the nervous system in 75-90% of cases (De la Monte et al., 1987). HIV has been cultured from brain, nerve, and cerebrospinal fluid (CSF) from persons at all stages of the disease, including those without neurologic signs or symptoms. Positive HIV cultures in CSF do not predict the presence or development of neurologic signs or symptoms later on. The development of neurologic manifestations of AIDS depends on a number of factors, such as antiretroviral treatment history, degree of immunosuppression, and the molecular biology of the viral strain, particularly its neurovirulence(McGuire & Greene, 1996) Host factors, including genetic makeup, undoubtedly play a role in selective

The initial infection of the nervous system by HIV is usually asymptomatic, although acute aseptic meningitis, encephalitis, and inflammatory polyneuropathy have all occurred in this setting. Despite its potential to cause disease at all levels of the nervous system, HIV does not directly infect central or peripheral neurons, astrocytes, or oligodendroglial cells. Latent or low level HIV infection in the CNS is maintained by virus-infected cells of the monocyte/macrophage lineage. "Indirect effects" of macrophage activation--such as dysregulation of cytokines and chemokines, free-radical (oxidative stress) injury, and secretion of soluble factors that are potently neurotoxic, have been implicated as effectors of

Despite evidence of early infection of the CNS, symptoms of cognitive impairment typically occur late in symptomatic HIV disease, usually in the setting of severe immunosuppression

Cognitive impairment has long been recognized as part of manifestation of human immune deficiency virus infection. These changes include loss of cognitive flexibility, difficulty in problem solving, mental slowness and difficulty in concentration. There are also difficulties in memory which manifest as delayed recall. Despite the wide spread use of highly active antiretroviral therapy (HAART), at least in developed nations and some developing nations, cognitive impairment and other neurological complications of HIV infection persist with devastating personal and socioeconomic consequences. Even though neurons are rarely infected by human immunodeficiency virus especially at early stage of the infection,

Although as many as 40% of patients with HIV/AIDS will have some form of cognitive impairment even before the development of full dementia, only a small percentage (5-10%) may go on to develop dementia itself. Various type of cognitive impairment in HIV infection has been documented and the American academy of Neurology (AAN) published a diagnostic criteria for HIV associated dementia (HAD) and minor cognitive motor disorder (MCMD); which include motor, affective and behavioural abnormalities, consistent with the

Some investigators hold that increased HIV proliferation in the brain is necessary for the development of ADC. Others propose that a macrophage-initiated cascade of events can lead to brain dysfunction and clinical dementia, even in the absence of high viral load in the

vulnerability to neurologic manifestations.

nervous Minor Cognitive system injury in HIV.

neuronal loss is quite common in patient with HIV infection.

early description of AIDS dementia complex.

**5.2 AIDS Dementia Complex (ADC)** 

**5.1 Minor cognitive impairment** 

(Miller et al., 1990).

brain. Activated macrophages, whether infected with HIV or not, are capable of secreting potent neurotoxins, inducing pro-inflammatory cytokines, and generating oxygen free radicals that can damage cells and lead to neuronal dysfunction or death (Glass et al., 1995). A particular subtype of monocyte/macrophages derived from the peripheral blood was found to be greatly increased among patients with AIDS dementia compared with both HIV infected and uninfected controls. Soluble factors from these macrophages were found to be highly neurotoxic--that is, they killed human brain cells in culture (Pulliam et al., 1997).

Although the incidence of nearly all nervous system opportunistic infections has declined dramatically in the era of potent antiretroviral therapy, the impact on the incidence and prevalence of HIV-associated cognitive impairment including frank ADC--has been low. The prevalence of ADC in HIV-infected individuals with higher CD4 counts (200-350 cells/µL) actually appears to have increased since 1996. Pathologically, the prevalence of HIV-associated brain disease, or encephalopathy, is rising despite suppressive antiretroviral therapy (Neuenburg et al., 2002). Poor penetration of the blood-brain barrier by many of the antiretroviral drugs, particularly the protease inhibitors, has been suggested as a reason for the persistence of ADC.

There is some evidence that, despite the poor CNS penetration of most antiretrovirals, effective antiretroviral therapy may attenuate the neurotoxicity of circulating monocytes/macrophages. Among individuals with ADC receiving effective antiretroviral regimens, macrophage-derived soluble factors were found to be less neurotoxic than observed prior to the availability of combination antiretroviral therapy (Pulliam et al., 1997).

The major difference between "HIV associated dementia complex" and "HIV associated minor cognitive/ motor disorder" is the severity of impairment in activities of daily living. That is, by definition, dementia must have cognitive impairment severe enough to interfere with occupational or social functioning. In "HIV associated minor cognitive/motor disorder," activities of daily living are generally intact with the possible exception of mild difficulties in the most demanding activities.

The initial features of HIV associated dementia include an overall slowing in cognition (i.e., bradyphrenia) and movement (i.e., bradykinesia) as well as difficulties in motor dexterity and coordination, forgetfulness, poor concentration, and marked apathy. Although dysphoric mood is not a common feature, the pronounced slowing and apathy may appear as if the patient is depressed. Furthermore, assessing other aspects of depression (e.g., weight loss, cognitive disturbance and insomnia) is difficult for patients with this disorder due to shared symptomatology that may be indistinguishable from the psychiatric symptoms.

Later in the course of HIV associated dementia, the patient may exhibit myoclonus, bowel and bladder incontinence, and, eventually, mutism and a vegetative state. Once these advanced features are present, death is typically imminent.

Because the above initial symptoms are similar to those seen in other patient groups with subcortical impairment (e.g., Parkinson's disease, progressive supranuclear palsy, multiple sclerosis) and because of the neuroimaging findings of subcortical neuropathology, HIV associated dementia was originally described as a subcortical dementia. However, in light of the more recent findings of cortical atrophy and higher cortical function deficits in AIDS patients, this characterization may not fully describe the spectrum of neuropsychiatric deficits associated with HIV infection and AIDS.

Neuropsychiatric Manifestations of HIV Infection and AIDS 423

Apart from dementia, HIV-infected patients are at risk for a wide range of neurologic diseases. Cerebral signs and symptoms are the most common. Global cerebral disease can present with altered mental status or generalized seizures, whereas focal disease often produces hemiparesis, hemisensory loss, visual field cuts, or disturbances in language use. Fungal, viral, and mycobacterial meningoencephalitides are the most common causes of global cerebral dysfunction, and progressive multifocal leukoencephalopathy (PML), primary CNS lymphoma, and toxoplasmosis account for the majority of focal presentations. As the epidemic has progressed, the epidemiology of CNS complications has changed. In general, availability of effective antiretroviral regimens has been associated with a dramatic decline in incidence and severity of opportunistic infections of the CNS. Even before the availability of these regimens, the incidence of CNS toxoplasmosis had declined among patients receiving trimethoprimsulfamethoxazole prophylaxis against Pneumocystis. Unfortunately, antiretroviral regimens have not demonstrably decreased the prevalence of PML, and the incidence among individuals with higher CD4 counts may be increasing. However, the prognosis of this once uniformly fatal disease has improved dramatically, with long-term remissions now fairly common among

Viral and, rarely, fungal and parasitic opportunistic infections can affect the spinal cord. Systemic lymphoma can infiltrate nerve roots and meninges, occasionally causing a mass lesion within the cord. In addition, HIV itself is associated with a spastic paraparesis similar to that seen with vitamin B12 deficiency. Peripheral nerve injury is very common, particularly a painful distal neuropathy seen late in HIV infection. About 35% of hospitalized patients with

Although myalgias or muscle pains are a frequent complaint, frank muscle disease is less common. Both inflammatory myopathies and a toxic myopathy secondary to zidovudine have been observed. More recently, a syndrome of acute neuromuscular weakness, often associated with lactic acidosis, has been described in association with several nucleoside analogue reverse transcriptase inhibitors, including zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), either alone or in combination. Any patient on antiretroviral therapy presenting with a "Guillain-Barré-type" picture of ascending neuromuscular weakness should be tested for lactic acidosis and evaluated with

Among patients infected with HIV, serious neurologic disease may present with relatively trivial symptoms and signs. Therefore, a high index of suspicion must be maintained to detect disease early in these patients. A careful neurologic examination to attempt anatomic localization is necessary to guide further laboratory and imaging studies. Because multiple neurologic diseases often coexist in patients, close follow-up is needed even if a presumptive diagnosis has been made. A change in clinical condition often necessitates a

There is growing awareness that pain from a variety of etiologies commonly complicates HIV disease. In general, patients with AIDS have pain comparable in prevalence and intensity to

**5.3 Overview of clinical neurologic disease** 

patients receiving antiretroviral therapy (Berger et al., 1998).

**5.3.2 Syndromes affecting cord, nerve roots, and muscle** 

advanced HIV disease have peripheral neuropathy (Hall et al., 1991).

electromyography and nerve conduction studies.

thorough reevaluation.

**5.3.3 Pain** 

**5.3.1 Cerebral symptoms and signs** 

Antiretroviral therapy may be helpful in treating Minor Cognitive /Motor Disorder and HIV associated dementia and should be recommended for all patients, unless there are contraindications. The ability of particular antiretroviral drugs to penetrate the blood-brain barrier may be less important to treatment success than the overall potency of the regimen and the ability of the patient to adhere to it.

Studies from the 1980s showed that zidovudine monotherapy was beneficial in patients with HAD, so some clinicians include it in the ART regimen for anyone with neurocognitive impairment. Others suggest using at least 2 drugs that cross the blood-brain barrier (eg, zidovudine, stavudine, abacavir, lamivudine, and nevirapine). Efavirenz, didanosine, and lamivudine cross to a lesser degree. As a class, protease inhibitors (PIs) have poor bloodbrain barrier penetration. Nevertheless, patients have shown neurocognitive improvement while taking PI-containing regimens, perhaps because of indirect effects on HIV activity in the CNS.

When present, depressive symptoms should be treated with low dosages of selective serotonin reuptake inhibitors (SSRIs).

Antipsychotic medications may be useful in treating agitation and hallucinations, but patients with these conditions are often extremely sensitive to anticholinergic adverse effects and extrapyramidal symptoms. Newer neuroleptic or antipsychotic agents, such as olanzapine and risperidone, have lower rates of significant side effects compared with older drugs. The starting dosage of olanzapine is 2.5 mg orally at bedtime; that for risperidone is 0.5-1 mg orally at bedtime. Note that these drugs may interact with antiretroviral medications, especially ritonavir, and can cause weight gain and other metabolic adverse effects. Avoid benzodiazepines, which tend to increase confusion and decrease concentration.

Psychostimulants such as methylphenidate (Ritalin) and dextroamphetamine (Dexedrine) have been used to improve attention, concentration, and psychomotor function. Dosages of methylphenidate start at 5 mg for a test dose, then 2.5-5.0 mg twice daily, increasing by doses of 5 mg every other day until the desired effect is achieved. Usual dosages are in the range of 20-30 mg per day. Monitor blood pressure, heart rate, and symptoms of restlessness, agitation, nausea, and psychosis.

For a patient who is knowledgeable about HIV, a dementia workup or diagnosis often precipitates a crisis, with an increased risk of suicide. Carefully screen for depression and suicidality, and treat these if they develop.

Behavioral management strategies may assist the patient with early manifestations of dementia to continue living with some degree of independence and safety in the home. Memory aids such as posted notes, calendars, alarmed pill-boxes, and other environmental cues may help.

It is critical to enlist the support of family members and significant others at an early stage of the illness. Because the disease is frightening and may be progressive, the patient and members of the support system need assistance in anticipating and planning for the future. Plans for assisted living or other in-home custodial care should be made early. Severe or late dementia causes fear, misunderstanding, and frustration for both the patient and care givers. All involved will require help from visiting nurses, social workers, hospice workers, and physicians. Recommend the preparation of an advance directive for the patient with early manifestations of dementia.

#### **5.3 Overview of clinical neurologic disease 5.3.1 Cerebral symptoms and signs**

422 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Antiretroviral therapy may be helpful in treating Minor Cognitive /Motor Disorder and HIV associated dementia and should be recommended for all patients, unless there are contraindications. The ability of particular antiretroviral drugs to penetrate the blood-brain barrier may be less important to treatment success than the overall potency of the regimen

Studies from the 1980s showed that zidovudine monotherapy was beneficial in patients with HAD, so some clinicians include it in the ART regimen for anyone with neurocognitive impairment. Others suggest using at least 2 drugs that cross the blood-brain barrier (eg, zidovudine, stavudine, abacavir, lamivudine, and nevirapine). Efavirenz, didanosine, and lamivudine cross to a lesser degree. As a class, protease inhibitors (PIs) have poor bloodbrain barrier penetration. Nevertheless, patients have shown neurocognitive improvement while taking PI-containing regimens, perhaps because of indirect effects on HIV activity in

When present, depressive symptoms should be treated with low dosages of selective

Antipsychotic medications may be useful in treating agitation and hallucinations, but patients with these conditions are often extremely sensitive to anticholinergic adverse effects and extrapyramidal symptoms. Newer neuroleptic or antipsychotic agents, such as olanzapine and risperidone, have lower rates of significant side effects compared with older drugs. The starting dosage of olanzapine is 2.5 mg orally at bedtime; that for risperidone is 0.5-1 mg orally at bedtime. Note that these drugs may interact with antiretroviral medications, especially ritonavir, and can cause weight gain and other metabolic adverse effects. Avoid benzodiazepines, which tend to increase confusion and decrease

Psychostimulants such as methylphenidate (Ritalin) and dextroamphetamine (Dexedrine) have been used to improve attention, concentration, and psychomotor function. Dosages of methylphenidate start at 5 mg for a test dose, then 2.5-5.0 mg twice daily, increasing by doses of 5 mg every other day until the desired effect is achieved. Usual dosages are in the range of 20-30 mg per day. Monitor blood pressure, heart rate, and symptoms of

For a patient who is knowledgeable about HIV, a dementia workup or diagnosis often precipitates a crisis, with an increased risk of suicide. Carefully screen for depression and

Behavioral management strategies may assist the patient with early manifestations of dementia to continue living with some degree of independence and safety in the home. Memory aids such as posted notes, calendars, alarmed pill-boxes, and other environmental

It is critical to enlist the support of family members and significant others at an early stage of the illness. Because the disease is frightening and may be progressive, the patient and members of the support system need assistance in anticipating and planning for the future. Plans for assisted living or other in-home custodial care should be made early. Severe or late dementia causes fear, misunderstanding, and frustration for both the patient and care givers. All involved will require help from visiting nurses, social workers, hospice workers, and physicians. Recommend the preparation of an advance directive for the patient with

and the ability of the patient to adhere to it.

serotonin reuptake inhibitors (SSRIs).

restlessness, agitation, nausea, and psychosis.

suicidality, and treat these if they develop.

early manifestations of dementia.

the CNS.

concentration.

cues may help.

Apart from dementia, HIV-infected patients are at risk for a wide range of neurologic diseases. Cerebral signs and symptoms are the most common. Global cerebral disease can present with altered mental status or generalized seizures, whereas focal disease often produces hemiparesis, hemisensory loss, visual field cuts, or disturbances in language use. Fungal, viral, and mycobacterial meningoencephalitides are the most common causes of global cerebral dysfunction, and progressive multifocal leukoencephalopathy (PML), primary CNS lymphoma, and toxoplasmosis account for the majority of focal presentations. As the epidemic has progressed, the epidemiology of CNS complications has changed. In general, availability of effective antiretroviral regimens has been associated with a dramatic decline in incidence and severity of opportunistic infections of the CNS. Even before the availability of these regimens, the incidence of CNS toxoplasmosis had declined among patients receiving trimethoprimsulfamethoxazole prophylaxis against Pneumocystis. Unfortunately, antiretroviral regimens have not demonstrably decreased the prevalence of PML, and the incidence among individuals with higher CD4 counts may be increasing. However, the prognosis of this once uniformly fatal disease has improved dramatically, with long-term remissions now fairly common among patients receiving antiretroviral therapy (Berger et al., 1998).

#### **5.3.2 Syndromes affecting cord, nerve roots, and muscle**

Viral and, rarely, fungal and parasitic opportunistic infections can affect the spinal cord. Systemic lymphoma can infiltrate nerve roots and meninges, occasionally causing a mass lesion within the cord. In addition, HIV itself is associated with a spastic paraparesis similar to that seen with vitamin B12 deficiency. Peripheral nerve injury is very common, particularly a painful distal neuropathy seen late in HIV infection. About 35% of hospitalized patients with advanced HIV disease have peripheral neuropathy (Hall et al., 1991).

Although myalgias or muscle pains are a frequent complaint, frank muscle disease is less common. Both inflammatory myopathies and a toxic myopathy secondary to zidovudine have been observed. More recently, a syndrome of acute neuromuscular weakness, often associated with lactic acidosis, has been described in association with several nucleoside analogue reverse transcriptase inhibitors, including zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), either alone or in combination. Any patient on antiretroviral therapy presenting with a "Guillain-Barré-type" picture of ascending neuromuscular weakness should be tested for lactic acidosis and evaluated with electromyography and nerve conduction studies.

Among patients infected with HIV, serious neurologic disease may present with relatively trivial symptoms and signs. Therefore, a high index of suspicion must be maintained to detect disease early in these patients. A careful neurologic examination to attempt anatomic localization is necessary to guide further laboratory and imaging studies. Because multiple neurologic diseases often coexist in patients, close follow-up is needed even if a presumptive diagnosis has been made. A change in clinical condition often necessitates a thorough reevaluation.

#### **5.3.3 Pain**

There is growing awareness that pain from a variety of etiologies commonly complicates HIV disease. In general, patients with AIDS have pain comparable in prevalence and intensity to

Neuropsychiatric Manifestations of HIV Infection and AIDS 425

centers. A secondary myopathy attributable to the muscle toxicity of AZT emerged in the latter half of the 1980s with widespread use of the drug. The hallmark of myopathy is diffuse, symmetric weakness of "proximal" muscles, hip or shoulder girdle muscles, with a sparing of sensory and autonomic functions. Difficulty with squatting, rising from a chair, or walking upstairs is often the presenting symptom of myopathy. Some patients have myalgia and muscle tenderness, but these complaints are also common in patients without myopathy. In patients receiving AZT, discontinuation of the drug may result in clinical improvement of myopathy. Muscle pain and serum creatine kinase levels decrease first, followed by a more delayed improvement in strength. Some patients may tolerate rechallenging with lower doses of AZT, although the use of other antiretroviral therapy is probably preferable (Dalakas et al., 1990).

Clinically significant spinal cord disorders are less common in HIV disease than are peripheral nervous system diseases. The neurologic signs of myelopathy such as increased tone and hyperreflexia in the legs and Babinski signs (extensor plantar responses) may be elicited even in the absence of subjective complaints. In most cases, such asymptomatic signs reflect mild HIV-associated spinal cord disease that may or may not progress. Patients with symptomatic myelopathy usually complain first of clumsy gait and urinary hesitancy. The clinical course is typically one of slow progression, and most patients remain ambulatory. A more fulminant course may be seen with wheelchair dependence within a few months. Upper extremities are affected very late, if at all. Baclofen (10-30 mg three times daily) or tizanidine (4 mg three times daily) may attenuate leg spasticity and reduce leg cramps. Painful dysesthesias may be treated

The CNS disorders in the setting of HIV disease can be divided into four general categories: a) primary infection of the brain by HIV; b) opportunistic infections by parasitic, fungal, viral, and bacterial organisms; b) CNS neoplasms; and d) complications of systemic

Primary HIV Infection of the Brain: HIV Associated Dementia Complex has already been

CNS toxoplasmosis has been the most common cause of intracerebral mass lesion in HIVinfected patients. Its incidence has declined dramatically among patients receiving PCP prophylaxis, and further declined among patients treated with effective antiretroviral therapy. Earlier reports described frequencies of 3-40%, reflecting the considerable regional variation in exposure to the parasite. CT scan of the brain usually shows multiple ringenhancing lesions with predilection for cortex and deep gray-matter structures such as the basal ganglia. The cerebellum and brain stem are less commonly involved. Radiologic appearance can vary markedly; single lesions and lesions with diffuse enhancement, as well

Patients with aseptic meningitis often present initially with headache and occasionally with altered mental status or cranial neuropathies. Many patients with this syndrome probably

with "neuropathic pain" adjuvants, such as lamotrigine or desipramine.

**5.4.3 Spinal cord disorders** 

**5.4.4 Intracranial disorders** 

**5.4.5 Intracranial opportunistic infections** 

as nonenhancing lesions can appear.

**5.4.6 Aseptic meningitis** 

disorders.

discussed above.

pain in patients with cancer, with similar mixtures of neuropathic and visceral-somatic etiologies. However, although efforts to improve malignant pain management have benefited many patients with cancer, pain in patients with AIDS is dramatically undertreated.

Aggressive pain treatment can be the single most important and most challenging intervention in the care of patients with HIV disease. In a recent U.S. study, only 15% of ambulatory AIDS patients with severe pain received adequate pain management. The principles of pain assessment and treatment in the patient with HIV/AIDS are not fundamentally different from those in the patient with cancer and should be followed.

These principles are described in the WHO analgesic ladder (WHO clinical guidelines, 1994), a well-validated, stepwise approach to pain management related to pain severity. Therapy ranges from nonopioid analgesics and adjuvants to systemic weak and strong opioids to intraspinal drug delivery for refractory severe pain. Opioids, except in quite high doses, can be ineffective in neuropathic pain; adjuvants (namely, tricyclics, anticonvulsants) are often more successful. Where neuropathic pain is refractory to such therapies, pain management specialists should be consulted.

#### **5.4 Specific neurologic conditions**

#### **5.4.1 Neuromuscular disorders**

A wide range of peripheral nervous system disorders develop in patients with HIV infection, leading to pain, sensory symptoms, and muscle weakness. Both "primary" HIV associated nerve disorders, and those secondary to opportunistic processes are well described. In addition, certain antiretroviral drugs may cause or exacerbate peripheral neuropathies.

Classification of Neuromuscular Disorders

Four types of neuropathy are important to recognize in clinical practice, either because of their high prevalence or their therapeutic implications, or both. They are:


The incidence of neuropathy increases with declining CD4 cell count and advancing systemic HIV disease. Familiar causes of neuropathy, such as nutritional deficiency and diabetes mellitus, account for only a small percentage of the neuropathy in these patients. Toxicity of therapeutic drugs, notably zalcitabine (ddC) is responsible for some cases of neuropathy, or for progression; however, antiretroviral toxicity is probably overdiagnosed as a primary cause of HIV-associated neuropathy.

Proper recognition of the different types of peripheral nerve dysfunction is essential for patient management. Except for the few neuropathies with known causes, most of these disorders are characterized on the basis of clinical features alone. The rate of symptom progression, the degree of weakness relative to sensory loss, and the severity of immunosuppression guide the differential diagnosis. The electrophysiologic features of nerve conduction and electromyographic studies remain the gold standard for diagnosis, and may lead to different therapeutic options.

#### **5.4.2 Myopathy**

Symptomatic primary muscle disease is uncommon in patients with HIV infection. A polymyositislike syndrome occurs rarely, with few cases encountered even in large referral centers. A secondary myopathy attributable to the muscle toxicity of AZT emerged in the latter half of the 1980s with widespread use of the drug. The hallmark of myopathy is diffuse, symmetric weakness of "proximal" muscles, hip or shoulder girdle muscles, with a sparing of sensory and autonomic functions. Difficulty with squatting, rising from a chair, or walking upstairs is often the presenting symptom of myopathy. Some patients have myalgia and muscle tenderness, but these complaints are also common in patients without myopathy. In patients receiving AZT, discontinuation of the drug may result in clinical improvement of myopathy. Muscle pain and serum creatine kinase levels decrease first, followed by a more delayed improvement in strength. Some patients may tolerate rechallenging with lower doses of AZT, although the use of other antiretroviral therapy is probably preferable (Dalakas et al., 1990).

## **5.4.3 Spinal cord disorders**

424 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

pain in patients with cancer, with similar mixtures of neuropathic and visceral-somatic etiologies. However, although efforts to improve malignant pain management have benefited

Aggressive pain treatment can be the single most important and most challenging intervention in the care of patients with HIV disease. In a recent U.S. study, only 15% of ambulatory AIDS patients with severe pain received adequate pain management. The principles of pain assessment and treatment in the patient with HIV/AIDS are not fundamentally different from those in the patient with cancer and should be followed. These principles are described in the WHO analgesic ladder (WHO clinical guidelines, 1994), a well-validated, stepwise approach to pain management related to pain severity. Therapy ranges from nonopioid analgesics and adjuvants to systemic weak and strong opioids to intraspinal drug delivery for refractory severe pain. Opioids, except in quite high doses, can be ineffective in neuropathic pain; adjuvants (namely, tricyclics, anticonvulsants) are often more successful. Where neuropathic pain is refractory to such therapies, pain

A wide range of peripheral nervous system disorders develop in patients with HIV infection, leading to pain, sensory symptoms, and muscle weakness. Both "primary" HIV associated nerve disorders, and those secondary to opportunistic processes are well described. In

Four types of neuropathy are important to recognize in clinical practice, either because of

The incidence of neuropathy increases with declining CD4 cell count and advancing systemic HIV disease. Familiar causes of neuropathy, such as nutritional deficiency and diabetes mellitus, account for only a small percentage of the neuropathy in these patients. Toxicity of therapeutic drugs, notably zalcitabine (ddC) is responsible for some cases of neuropathy, or for progression; however, antiretroviral toxicity is probably overdiagnosed

Proper recognition of the different types of peripheral nerve dysfunction is essential for patient management. Except for the few neuropathies with known causes, most of these disorders are characterized on the basis of clinical features alone. The rate of symptom progression, the degree of weakness relative to sensory loss, and the severity of immunosuppression guide the differential diagnosis. The electrophysiologic features of nerve conduction and electromyographic studies remain the gold standard for diagnosis,

Symptomatic primary muscle disease is uncommon in patients with HIV infection. A polymyositislike syndrome occurs rarely, with few cases encountered even in large referral

addition, certain antiretroviral drugs may cause or exacerbate peripheral neuropathies.

their high prevalence or their therapeutic implications, or both. They are:

many patients with cancer, pain in patients with AIDS is dramatically undertreated.

management specialists should be consulted.

Classification of Neuromuscular Disorders

2. Mononeuropathy multiplex

1. Distal symmetric polyneuropathy (DSPN)

4. Progressive lumbosacral polyradiculopathy

as a primary cause of HIV-associated neuropathy.

and may lead to different therapeutic options.

**5.4.2 Myopathy** 

3. Chronic inflammatory demyelinating polyneuropathy

**5.4 Specific neurologic conditions 5.4.1 Neuromuscular disorders** 

Clinically significant spinal cord disorders are less common in HIV disease than are peripheral nervous system diseases. The neurologic signs of myelopathy such as increased tone and hyperreflexia in the legs and Babinski signs (extensor plantar responses) may be elicited even in the absence of subjective complaints. In most cases, such asymptomatic signs reflect mild HIV-associated spinal cord disease that may or may not progress. Patients with symptomatic myelopathy usually complain first of clumsy gait and urinary hesitancy. The clinical course is typically one of slow progression, and most patients remain ambulatory. A more fulminant course may be seen with wheelchair dependence within a few months. Upper extremities are affected very late, if at all. Baclofen (10-30 mg three times daily) or tizanidine (4 mg three times daily) may attenuate leg spasticity and reduce leg cramps. Painful dysesthesias may be treated with "neuropathic pain" adjuvants, such as lamotrigine or desipramine.

#### **5.4.4 Intracranial disorders**

The CNS disorders in the setting of HIV disease can be divided into four general categories: a) primary infection of the brain by HIV; b) opportunistic infections by parasitic, fungal, viral, and bacterial organisms; b) CNS neoplasms; and d) complications of systemic disorders.

Primary HIV Infection of the Brain: HIV Associated Dementia Complex has already been discussed above.

#### **5.4.5 Intracranial opportunistic infections**

CNS toxoplasmosis has been the most common cause of intracerebral mass lesion in HIVinfected patients. Its incidence has declined dramatically among patients receiving PCP prophylaxis, and further declined among patients treated with effective antiretroviral therapy. Earlier reports described frequencies of 3-40%, reflecting the considerable regional variation in exposure to the parasite. CT scan of the brain usually shows multiple ringenhancing lesions with predilection for cortex and deep gray-matter structures such as the basal ganglia. The cerebellum and brain stem are less commonly involved. Radiologic appearance can vary markedly; single lesions and lesions with diffuse enhancement, as well as nonenhancing lesions can appear.

#### **5.4.6 Aseptic meningitis**

Patients with aseptic meningitis often present initially with headache and occasionally with altered mental status or cranial neuropathies. Many patients with this syndrome probably

Neuropsychiatric Manifestations of HIV Infection and AIDS 427

study, this incidence is less than that among age-matched young adults with other terminal illnesses. Among patients with advanced HIV disease, cerebral ischemic disease is more

Recognizing the psychiatric manifestations of HIV disease can be complicated by the complex biologic, psychologic and social circumstances associated with this illness, and psychiatric symptoms often go unrecognized and untreated(Evans et al., 1999). The significance of these findings is magnified by emerging evidence that certain symptoms, such as depression, may be associated with an increase in mortality rate among HIV-

The psychiatric sequelae of HIV infection and AIDS are numerous and have etiologies that involve neurobiological and psychosocial factors. These include the natural and expected grief response to being diagnosed with a terminal illness, later reactions to disability and illness, exacerbation of preexisting psychiatric illness, development of new primary psychiatric symptoms and syndromes, and the neuropsychiatric manifestations of HIV

It is understandable that individuals who receive notification of positive HIV test results will be emotionally distressed as they adjust to the knowledge of their HIV serostatus. The severity of the acute distress will vary from individual to individual. Whereas some individuals may react with little distress, others may be at increased risk of suicide. Thus, it appears that although individuals are often distraught after receiving positive HIV test results, after an adjustment period lasting weeks to a few months, most will cope well and will show a reduction in anxiety and depressive symptoms. Consequently, it appears that symptoms of depression and anxiety should not be considered "normal" in asymptomatic HIV infection. Rather, significant symptoms should warrant careful clinical evaluation.

Depressive symptoms are the commonest psychiatric complication of chronic medical illnesses (Practice guidelines for HIV treatment, 2000). Studies have shown that the prevalence of depression in people living with HIV/AIDS is 2 to 3 times higher than that in the general population (Bing et al, 2001). Depressive disorder is the most common psychiatric condition in people living with HIV/AIDS with estimated life time prevalence in the range of between 21% and 61% (Elliot et al, 1998). A recent meta-analysis of data from ten studies examining the prevalence of depression among HIV-infected individuals reveal a two-fold increase in rates of depression compared with HIV-negative individuals (Ciesla et al, 2001).The current estimates may represent an underestimation as there is evidence that depression may be under diagnosed in the context of HIV medical care (Steven et al, 2003). Previous research has also shown that depression in patients with HIV/AIDS may be associated with disease progression (Cook et al, 2004), reduced compliance with antiretroviral treatment (Rabkin et al, 2002), and as a result of additional illness burden, lead to a reduction in the quality of life (Sherbourne et al, 2000). Depressed individuals with HIV use significantly more health care and related services (Williams et al, 2005). Despite all of these important evidences, depression remains underrecognized, underdiagnosed and undertreated in medical clinics. Thus, recognizing and treating depression is important

seropositive women and with disease progression in HIV-seropositive men.

common than hemorrhagic stroke.

associated neurological illness.

**6. Psychiatric manifestations of HIV infection** 

**6.1 Depressive disorder in patients with HIV/AIDS** 

have primary HIV meningoencephalitis. In investigating symptoms such as headache, altered mental status, and cranial neuropathy, aseptic meningitis must be a diagnosis of exclusion.

## **5.4.7 Viral encephalitis**

Among the opportunistic viral infections of the CNS, the most important are the herpes viruses: herpes simplex types 1 and 2 (HSV-1 and -2), herpes varicella-zoster (VZV), and CMV. Each can cause a meningoencephalitis with mental status changes and focal neurologic findings. Diagnosis is complicated by the low yield of CSF viral cultures in herpesvirus encephalitis in general. In general, the onset of headache, fever, and seizures should, in the absence of other clear etiologies, prompt empiric treatment for herpes simplex encephalitis with acyclovir (10.0 to 12.5 mg/kg intravenously every 8 hours).

## **5.4.8 Fungal encephalitis**

Candida Albicans, which commonly infects the oral mucosa of patients with HIV disease, can cause a meningoencephalitis, usually in the setting of fungemia. Microabscesses are the usual pathologic findings in the brain. Mucormycosis, especially among injection drug users, and aspergillosis have been reported causes of meningoencephalitis in patients with advanced HIV disease.

## **5.4.9 Systemic neoplasms**

Although Kaposi sarcoma (KS) is the most common systemic neoplasm in HIV disease, it rarely spreads to the CNS. Among the systemic cancers, non-Hodgkin lymphoma is the most important cause of neurologic dysfunction in HIV disease and invades the CNS by spreading along the leptomeninges. Common signs and symptoms include cranial nerve palsies and polyradiculopathy and less commonly, myelopathy due to epidural metastasis with spinal cord compression.

## **5.4.10 Central nervous system lymphoma**

Primary CNS lymphoma (PCNSL) is a fairly common cause of cerebral mass lesions in patients with advanced HIV disease. The most common signs and symptoms are confusion, lethargy, and personality changes, usually with focal deficits, such as hemiparesis, hemisensory loss, ataxia, and aphasia. Seizures are less common, but not rare.

#### **5.4.11 Metabolic encephalopathy**

Metabolic encephalopathy occurs frequently in patients with advanced HIV disease. Adverse reactions to therapeutic drugs, hypoxia, electrolyte imbalance, and multiorgan failure are common etiologies. Efavirenz can cause a transient encephalopathy for a few weeks after initiation of therapy. In the cachectic patient or in patients with significant liver disease or history of protracted vomiting, Wernicke encephalopathy due to thiamine deficiency should be considered.

#### **5.4.12 Stroke**

Cerebral infarction and transient ischaemic attacks are seen infrequently in HIV infected patients, with a reported incidence ranging from 0.5% to 8.0%. Based on a case control

have primary HIV meningoencephalitis. In investigating symptoms such as headache, altered mental status, and cranial neuropathy, aseptic meningitis must be a diagnosis of

Among the opportunistic viral infections of the CNS, the most important are the herpes viruses: herpes simplex types 1 and 2 (HSV-1 and -2), herpes varicella-zoster (VZV), and CMV. Each can cause a meningoencephalitis with mental status changes and focal neurologic findings. Diagnosis is complicated by the low yield of CSF viral cultures in herpesvirus encephalitis in general. In general, the onset of headache, fever, and seizures should, in the absence of other clear etiologies, prompt empiric treatment for herpes simplex

Candida Albicans, which commonly infects the oral mucosa of patients with HIV disease, can cause a meningoencephalitis, usually in the setting of fungemia. Microabscesses are the usual pathologic findings in the brain. Mucormycosis, especially among injection drug users, and aspergillosis have been reported causes of meningoencephalitis in patients with

Although Kaposi sarcoma (KS) is the most common systemic neoplasm in HIV disease, it rarely spreads to the CNS. Among the systemic cancers, non-Hodgkin lymphoma is the most important cause of neurologic dysfunction in HIV disease and invades the CNS by spreading along the leptomeninges. Common signs and symptoms include cranial nerve palsies and polyradiculopathy and less commonly, myelopathy due to epidural metastasis

Primary CNS lymphoma (PCNSL) is a fairly common cause of cerebral mass lesions in patients with advanced HIV disease. The most common signs and symptoms are confusion, lethargy, and personality changes, usually with focal deficits, such as hemiparesis,

Metabolic encephalopathy occurs frequently in patients with advanced HIV disease. Adverse reactions to therapeutic drugs, hypoxia, electrolyte imbalance, and multiorgan failure are common etiologies. Efavirenz can cause a transient encephalopathy for a few weeks after initiation of therapy. In the cachectic patient or in patients with significant liver disease or history of protracted vomiting, Wernicke encephalopathy due to thiamine

Cerebral infarction and transient ischaemic attacks are seen infrequently in HIV infected patients, with a reported incidence ranging from 0.5% to 8.0%. Based on a case control

hemisensory loss, ataxia, and aphasia. Seizures are less common, but not rare.

encephalitis with acyclovir (10.0 to 12.5 mg/kg intravenously every 8 hours).

exclusion.

**5.4.7 Viral encephalitis** 

**5.4.8 Fungal encephalitis** 

advanced HIV disease.

**5.4.9 Systemic neoplasms** 

with spinal cord compression.

**5.4.11 Metabolic encephalopathy** 

deficiency should be considered.

**5.4.12 Stroke** 

**5.4.10 Central nervous system lymphoma** 

study, this incidence is less than that among age-matched young adults with other terminal illnesses. Among patients with advanced HIV disease, cerebral ischemic disease is more common than hemorrhagic stroke.

## **6. Psychiatric manifestations of HIV infection**

Recognizing the psychiatric manifestations of HIV disease can be complicated by the complex biologic, psychologic and social circumstances associated with this illness, and psychiatric symptoms often go unrecognized and untreated(Evans et al., 1999). The significance of these findings is magnified by emerging evidence that certain symptoms, such as depression, may be associated with an increase in mortality rate among HIVseropositive women and with disease progression in HIV-seropositive men.

The psychiatric sequelae of HIV infection and AIDS are numerous and have etiologies that involve neurobiological and psychosocial factors. These include the natural and expected grief response to being diagnosed with a terminal illness, later reactions to disability and illness, exacerbation of preexisting psychiatric illness, development of new primary psychiatric symptoms and syndromes, and the neuropsychiatric manifestations of HIV associated neurological illness.

It is understandable that individuals who receive notification of positive HIV test results will be emotionally distressed as they adjust to the knowledge of their HIV serostatus. The severity of the acute distress will vary from individual to individual. Whereas some individuals may react with little distress, others may be at increased risk of suicide. Thus, it appears that although individuals are often distraught after receiving positive HIV test results, after an adjustment period lasting weeks to a few months, most will cope well and will show a reduction in anxiety and depressive symptoms. Consequently, it appears that symptoms of depression and anxiety should not be considered "normal" in asymptomatic HIV infection. Rather, significant symptoms should warrant careful clinical evaluation.

### **6.1 Depressive disorder in patients with HIV/AIDS**

Depressive symptoms are the commonest psychiatric complication of chronic medical illnesses (Practice guidelines for HIV treatment, 2000). Studies have shown that the prevalence of depression in people living with HIV/AIDS is 2 to 3 times higher than that in the general population (Bing et al, 2001). Depressive disorder is the most common psychiatric condition in people living with HIV/AIDS with estimated life time prevalence in the range of between 21% and 61% (Elliot et al, 1998). A recent meta-analysis of data from ten studies examining the prevalence of depression among HIV-infected individuals reveal a two-fold increase in rates of depression compared with HIV-negative individuals (Ciesla et al, 2001).The current estimates may represent an underestimation as there is evidence that depression may be under diagnosed in the context of HIV medical care (Steven et al, 2003). Previous research has also shown that depression in patients with HIV/AIDS may be associated with disease progression (Cook et al, 2004), reduced compliance with antiretroviral treatment (Rabkin et al, 2002), and as a result of additional illness burden, lead to a reduction in the quality of life (Sherbourne et al, 2000). Depressed individuals with HIV use significantly more health care and related services (Williams et al, 2005). Despite all of these important evidences, depression remains underrecognized, underdiagnosed and undertreated in medical clinics. Thus, recognizing and treating depression is important

Neuropsychiatric Manifestations of HIV Infection and AIDS 429

illness on social status, friends, family and work, as well as existential concerns all may

Psychosis is a recognized, but relative to the mood disorders, an uncommon psychiatric manifestation of AIDS. Even less commonly, antiretroviral therapy may precipitate psychosis. For example, there have been anecdotal reports of psychosis associated with ganciclovir and efavirenz. Paranoid delusions, and auditory hallucination have been reported most frequently and manic symptoms and catatonia have also been described. Psychosis has been found more frequently in patients with AIDS-related neurocognitive impairments and can be a manifestation of psychiatric conditions such as delirium, affective disorders, or schizophrenia, but it also may occur in the absence of these conditions. Estimates of the prevalence of new-onset psychosis in patients with HIV range from 0.5 to 15% (which is considerably higher than would be expected in the general population).

Delirium is a frequent consequence of the severe medical illnesses or treatment that occurs over the course of AIDS. Behavioural manifestations include agitation, psychosis, aggressive behaviour, mutism and marked withdrawal. The delirium in AIDS is usually indistinguishable from the delirium resulting from any other serious acute medical illness.

Abuse of variety of substances, including alcohol, and other illicit drugs may be common in groups at high risk of HIV infection. Continued abuse of substances may have many adverse consequences, including interference with patients adherence to needed medical treatment, increased risk of behaviour that could result in further transmission of HIV (such as unsafe sex while intoxicated, sharing needles etc.), as well as morbidity related directly to the use of the substance. It is therefore necessary to do a careful assessment for an existing

Several epidemiological studies suggest that AIDS patients are at increased risk of death by suicide. The relative prevalence is estimated to range from 7 to 36 times the rate in demographically similar control populations. Other studies, however, have not found patients with AIDS to have higher suicidal ideation, especially when comparing persons

HIV infection may exacerbate psychiatric conditions, including major depression, bipolar disorder, and schizophrenia. One study of patients who had schizophrenia before they were diagnosed with HIV infection found that the patients had more severe depressive episodes and reduced tolerance to psychopharmacologic medications (including benzodiazepines and neuroleptics) after infection than before. Although methodological issues make such studies difficult, more research is needed to understand better the role of HIV infection in

Various complications of HIV infection including opportunistic infections of the CNS, tumors, systemic disease, and adverse effects of medications may mimic psychiatric illnesses, producing symptoms that resemble mania, depression, psychosis, or drug

result in significant anxiety.

**6.4 Psychosis** 

**6.5 Delirium** 

**6.7 Suicide** 

**6.6 Substance abuse** 

substance use disorder in HIV positive patients.

worsening pre-existing psychiatric disorders.

with AIDS to other medically or neuropsychiatrically ill patients.

because of its association with poor self-care and worse health outcomes in those with HIV (Paterson et al, 2000).

The relationship between depression and HIV/AIDS may be complex. Firstly, populations at risk for HIV infection have elevated rates of major depression. High rates of major depression have been found in homosexual men (Sittirai et al, 1993) and patients with substance use disorders (Mc Kinon et al, 1996). Secondly, major depression is a risk factor for HIV infection by virtue of its impact on behavior, intensification of substance abuse, exacerbation of self-destructive behaviors, and promotion of poor partner choice in relationships. In this way, depression can be seen as a vector of HIV transmission. Patients with depression have also been shown to be at increased risk for disease progression and mortality. Thirdly, HIV increases the risk of developing major depression through a variety of mechanisms, including direct injury to subcortical areas of the brain, chronic stress, stigma, worsening social isolation, bereavement, debilitation and intense demoralization (Zisook et al, 1998). Although direct evidence for a relationship between worsening HIV disease and the development of depression is limited, there are several studies that support this link, particularly the study based on the Multicenter AIDS Cohort Study showing that there is a two and half fold increase in rates of depression as patients CD4 cell count falls below 200cells per mm3.

Symptoms of depression include persistent sadness, loss of interest, decreased energy and appetite, low concentration, sleep problems, guilt/worthlessness feelings, psychomotor retardation or agitation, and suicidal ideations. In addition to significant distress, symptoms of depression can also cause other health-related functional and quality of life impairments.

#### **6.2 Mania**

Higher rates of mania have also been noted with progression of HIV infection. In early HIV infection, 1%–2% of patients experience manic episodes (Lyketsos &Treisman, 2001), which is only slightly higher than the rate in the general population. However, after the onset of AIDS, 4%–8% of patients appear to experience mania (Lyketsos et al., 1993). This increased frequency of mania around the time of onset of AIDS has been closely associated with cognitive changes or dementia and is thought to be a secondary manic syndrome due to HIV infection of the CNS. In a 17-month chart review, among the 8% of patients with manic episodes, counts of helper/inducer lymphocyte (CD3+/CD4+) cells were significantly higher in those with a history of mood disorder, suggesting that mania may be a direct effect of HIV on the CNS (Lyketsos et al., 1993).In a case–control study of 19 patients with HIVassociated mania and 57 HIV-seropositive controls, AIDS dementia was significantly more common in patients with mania, which suggests a strong association between HIV neuropathology and manic symptoms(Mijch et al., 1999). Sometimes referred to as "AIDS mania," this condition is phenomenologically different from the typical manic syndrome of bipolar disorder in both its symptom profile and severity, and it is often characterized by irritability rather than euphoria.

#### **6.3 Anxiety**

Anxiety is common in patients with HIV seropositivity. Individuals with pre-existing disorder may be at increased risk for exacerbation of symptoms, due to the numerous stresses of HIV positivity. Concern over possible progression of HIV disease, the impact of illness on social status, friends, family and work, as well as existential concerns all may result in significant anxiety.

#### **6.4 Psychosis**

428 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

because of its association with poor self-care and worse health outcomes in those with HIV

The relationship between depression and HIV/AIDS may be complex. Firstly, populations at risk for HIV infection have elevated rates of major depression. High rates of major depression have been found in homosexual men (Sittirai et al, 1993) and patients with substance use disorders (Mc Kinon et al, 1996). Secondly, major depression is a risk factor for HIV infection by virtue of its impact on behavior, intensification of substance abuse, exacerbation of self-destructive behaviors, and promotion of poor partner choice in relationships. In this way, depression can be seen as a vector of HIV transmission. Patients with depression have also been shown to be at increased risk for disease progression and mortality. Thirdly, HIV increases the risk of developing major depression through a variety of mechanisms, including direct injury to subcortical areas of the brain, chronic stress, stigma, worsening social isolation, bereavement, debilitation and intense demoralization (Zisook et al, 1998). Although direct evidence for a relationship between worsening HIV disease and the development of depression is limited, there are several studies that support this link, particularly the study based on the Multicenter AIDS Cohort Study showing that there is a two and half fold increase in rates of depression as patients CD4 cell count falls

Symptoms of depression include persistent sadness, loss of interest, decreased energy and appetite, low concentration, sleep problems, guilt/worthlessness feelings, psychomotor retardation or agitation, and suicidal ideations. In addition to significant distress, symptoms of depression can also cause other health-related functional and quality of life

Higher rates of mania have also been noted with progression of HIV infection. In early HIV infection, 1%–2% of patients experience manic episodes (Lyketsos &Treisman, 2001), which is only slightly higher than the rate in the general population. However, after the onset of AIDS, 4%–8% of patients appear to experience mania (Lyketsos et al., 1993). This increased frequency of mania around the time of onset of AIDS has been closely associated with cognitive changes or dementia and is thought to be a secondary manic syndrome due to HIV infection of the CNS. In a 17-month chart review, among the 8% of patients with manic episodes, counts of helper/inducer lymphocyte (CD3+/CD4+) cells were significantly higher in those with a history of mood disorder, suggesting that mania may be a direct effect of HIV on the CNS (Lyketsos et al., 1993).In a case–control study of 19 patients with HIVassociated mania and 57 HIV-seropositive controls, AIDS dementia was significantly more common in patients with mania, which suggests a strong association between HIV neuropathology and manic symptoms(Mijch et al., 1999). Sometimes referred to as "AIDS mania," this condition is phenomenologically different from the typical manic syndrome of bipolar disorder in both its symptom profile and severity, and it is often characterized by

Anxiety is common in patients with HIV seropositivity. Individuals with pre-existing disorder may be at increased risk for exacerbation of symptoms, due to the numerous stresses of HIV positivity. Concern over possible progression of HIV disease, the impact of

(Paterson et al, 2000).

below 200cells per mm3.

irritability rather than euphoria.

**6.3 Anxiety** 

impairments.

**6.2 Mania** 

Psychosis is a recognized, but relative to the mood disorders, an uncommon psychiatric manifestation of AIDS. Even less commonly, antiretroviral therapy may precipitate psychosis. For example, there have been anecdotal reports of psychosis associated with ganciclovir and efavirenz. Paranoid delusions, and auditory hallucination have been reported most frequently and manic symptoms and catatonia have also been described. Psychosis has been found more frequently in patients with AIDS-related neurocognitive impairments and can be a manifestation of psychiatric conditions such as delirium, affective disorders, or schizophrenia, but it also may occur in the absence of these conditions. Estimates of the prevalence of new-onset psychosis in patients with HIV range from 0.5 to 15% (which is considerably higher than would be expected in the general population).

## **6.5 Delirium**

Delirium is a frequent consequence of the severe medical illnesses or treatment that occurs over the course of AIDS. Behavioural manifestations include agitation, psychosis, aggressive behaviour, mutism and marked withdrawal. The delirium in AIDS is usually indistinguishable from the delirium resulting from any other serious acute medical illness.

## **6.6 Substance abuse**

Abuse of variety of substances, including alcohol, and other illicit drugs may be common in groups at high risk of HIV infection. Continued abuse of substances may have many adverse consequences, including interference with patients adherence to needed medical treatment, increased risk of behaviour that could result in further transmission of HIV (such as unsafe sex while intoxicated, sharing needles etc.), as well as morbidity related directly to the use of the substance. It is therefore necessary to do a careful assessment for an existing substance use disorder in HIV positive patients.

#### **6.7 Suicide**

Several epidemiological studies suggest that AIDS patients are at increased risk of death by suicide. The relative prevalence is estimated to range from 7 to 36 times the rate in demographically similar control populations. Other studies, however, have not found patients with AIDS to have higher suicidal ideation, especially when comparing persons with AIDS to other medically or neuropsychiatrically ill patients.

HIV infection may exacerbate psychiatric conditions, including major depression, bipolar disorder, and schizophrenia. One study of patients who had schizophrenia before they were diagnosed with HIV infection found that the patients had more severe depressive episodes and reduced tolerance to psychopharmacologic medications (including benzodiazepines and neuroleptics) after infection than before. Although methodological issues make such studies difficult, more research is needed to understand better the role of HIV infection in worsening pre-existing psychiatric disorders.

Various complications of HIV infection including opportunistic infections of the CNS, tumors, systemic disease, and adverse effects of medications may mimic psychiatric illnesses, producing symptoms that resemble mania, depression, psychosis, or drug

Neuropsychiatric Manifestations of HIV Infection and AIDS 431

The impact of depression on the course of HIV has initiated the application of specific psychosocial and pharmacologic treatments targeting individuals with HIV and comorbid depression. Pharmacotherapy is the mainstay of treatment of moderate to severe depression. Several studies have demonstrated efficacy of various antidepressant agents in HIV patients, but no single antidepressant has been found superior in treating HIV-infected patients as a

Aside from how well the pharmacology of the antidepressant matches a patient's disease, the engine that drives effectiveness is patient adherence. The general rule is to start at low doses of any medication and titrate up to a therapeutic dose slowly, so as to minimize early side effects that may act as obstacles to adherence. Patients who show partial response to antidepressant after adequate dosage and duration should be offered an augmentation strategy. The choice of an antidepressant is largely based on their side effect profile. Some of the antidepressant drugs that are useful in treatment of depression in patients with HIV/AIDS include Amitriptyline, Imipramine, Clomipramine, Fluoxetine, Paroxetine, Sertraline, Fluvoxamine and Venlafaxine (Elliot et al, 1998). The use of psychostimulants such as Methylphenidate and Dextroamphetamine has also been found effective (Wagner et

Some clinicians often wonder about the interaction of antidepressants and HAART. Some interactions may occur but two points deserve emphasis. Firstly, because depression is associated with reduction in adherence to HAART, untreated depression may be equally or more detrimental to disease progression than any medication interaction. Secondly, experience in working with comorbid HIV and depression has not shown clinical

Psychosocial intervention is an integral part of treatment for depression in patients with HIV/AIDS. A combination of psychosocial intervention and medication was shown to be more effective for patients than either modality alone. Among the individual psychotherapies, interpersonal psychotherapy, cognitive-behavioral psychotherapy and supportive psychotherapy are effective in treatment of depression in patients with HIV/AIDS (Markowitz et al, 1995). A social intervention such as social support group

Identifying and treating depression in patients with HIV/AIDS could result in substantial improvement in quality of life and potentially increase medication adherence, which would

Treatment of anxiety disorders in HIV/AIDS also requires a combination of psychosocial intervention and medication. Adequate counseling and relaxation techniques are sufficient to treat mild anxiety associated with the various crisis points in the course of HIV/AIDS. For the more severe anxiety disorders, antidepressants and cognitive behavioural

Every patient with HIV/AIDS presenting with psychiatric disorder must also be assessed for suicidal risk and cases where risk is high, patients should be hospitalized for detailed

Substance abuse is a common problem in patients with HIV/AIDS. Physicians should have a high index of suspicion while assessing patients. When present, motivational interviews are important. Patients with severe problems who are motivated should be hospitalized for

detoxification and appropriate pharmacological and psychosocial treatment.

group (Olatunji et al, 2006).

significance to antidepressant-HAART interaction.

therapy is also effective (Kelly et al, 1993).

evaluation and appropriate treatment.

techniques are useful.

in turn affect illness severity and progression.

al, 2000).

intoxication. In all cases, any underlying medical problem should be addressed. The acute onset of psychiatric symptoms in a patient with no such prior history should prompt a complete neuropsychiatric evaluation, toxicology and laboratory screens, and when appropriate, neuroimaging studies and lumbar puncture to help identify possible causes.

## **7. Assessment and treatment of psychiatric disorders in people living with HIV/AIDS**

A comprehensive history from the patient and/or caregiver is needed. There should be special focus on the history of the current complaint, past psychiatric history, past and present substance abuse history, full medical history and sexual risk history and the patient's adherence to previous treatment regimens. Of equal importance is identification of social support systems.

A mental status examination (MSE) of the patient's level of cognitive (knowledge-related) ability, appearance, emotional mood, and thought patterns at the time of evaluation should be conducted. In the psychotic patient one needs to focus specifically on the behaviour and appearance of the patient. His or her speech and speed of thoughts should be assessed, and mood symptoms, affect, suicidality and neuro-vegetative symptoms evaluated. Perceptual disturbances, thought form, thought content and finally insight and judgment also need to be assessed.

A comprehensive and meticulous physical and neurological examination should be performed to exclude any organic causes for the presenting psychiatric symptoms. One should first examine for signs of delirium and rule out HIV-associated cognitive disorders. Medical diagnoses should first be considered and only after that should a psychiatric diagnosis be entertained.

Differential diagnosis needs to consider the presence of a pre-existing psychiatric illness, use of illicit substances and the presence of cognitive impairment.

Assessment and treatment of psychotic disorders in people living with HIV/AIDS (PLWHA) can be very challenging. A useful delineation may be to divide psychosis in the PLWHA into: (i) psychiatric disorders predating HIV infection; (ii) new-onset psychotic disorders; and (iii) disorders associated with medical conditions (delirium) or substance intoxication or withdrawal, and those that are likely to be complications of treatment (i.e. antiretrovirals or antituberculosis drugs). A good history, mental state and physical examination is usually important in making this delineation. Laboratory investigations are crucial in the assessment of delirium and substance intoxication.

The choice of antipsychotic drugs depends largely on the patient, presenting symptoms, past response, potential side-effect profile, possible drug interactions, cost, and pill burden of the chronically ill patient. Many patients with new-onset psychosis or psychosis associated with various medical conditions may only require short-term treatment with antipsychotic medication. However, some patients may require long-term maintenance treatment with antipsychotic agents, and here special attention must be paid to the following factors. The typical antipsychotics are commonly used in resource-constrained settings. Here low doses of haloperidol or chlorpromazine can be used. Vigilance is required with regard to extrapyramidal side effects. Newer atypical antipsychotics such as Risperidone or Olanzepine are now widely used in the treatment of psychotic disorders in HIV/AIDS. They have lower propensity to cause extrapyramidal side effects.

intoxication. In all cases, any underlying medical problem should be addressed. The acute onset of psychiatric symptoms in a patient with no such prior history should prompt a complete neuropsychiatric evaluation, toxicology and laboratory screens, and when appropriate, neuroimaging studies and lumbar puncture to help identify possible causes.

**7. Assessment and treatment of psychiatric disorders in people living with** 

A comprehensive history from the patient and/or caregiver is needed. There should be special focus on the history of the current complaint, past psychiatric history, past and present substance abuse history, full medical history and sexual risk history and the patient's adherence to previous treatment regimens. Of equal importance is identification of

A mental status examination (MSE) of the patient's level of cognitive (knowledge-related) ability, appearance, emotional mood, and thought patterns at the time of evaluation should be conducted. In the psychotic patient one needs to focus specifically on the behaviour and appearance of the patient. His or her speech and speed of thoughts should be assessed, and mood symptoms, affect, suicidality and neuro-vegetative symptoms evaluated. Perceptual disturbances, thought form, thought content and finally insight and judgment also need to

A comprehensive and meticulous physical and neurological examination should be performed to exclude any organic causes for the presenting psychiatric symptoms. One should first examine for signs of delirium and rule out HIV-associated cognitive disorders. Medical diagnoses should first be considered and only after that should a psychiatric

Differential diagnosis needs to consider the presence of a pre-existing psychiatric illness, use

Assessment and treatment of psychotic disorders in people living with HIV/AIDS (PLWHA) can be very challenging. A useful delineation may be to divide psychosis in the PLWHA into: (i) psychiatric disorders predating HIV infection; (ii) new-onset psychotic disorders; and (iii) disorders associated with medical conditions (delirium) or substance intoxication or withdrawal, and those that are likely to be complications of treatment (i.e. antiretrovirals or antituberculosis drugs). A good history, mental state and physical examination is usually important in making this delineation. Laboratory investigations are

The choice of antipsychotic drugs depends largely on the patient, presenting symptoms, past response, potential side-effect profile, possible drug interactions, cost, and pill burden of the chronically ill patient. Many patients with new-onset psychosis or psychosis associated with various medical conditions may only require short-term treatment with antipsychotic medication. However, some patients may require long-term maintenance treatment with antipsychotic agents, and here special attention must be paid to the following factors. The typical antipsychotics are commonly used in resource-constrained settings. Here low doses of haloperidol or chlorpromazine can be used. Vigilance is required with regard to extrapyramidal side effects. Newer atypical antipsychotics such as Risperidone or Olanzepine are now widely used in the treatment of psychotic disorders in

of illicit substances and the presence of cognitive impairment.

crucial in the assessment of delirium and substance intoxication.

HIV/AIDS. They have lower propensity to cause extrapyramidal side effects.

**HIV/AIDS** 

be assessed.

social support systems.

diagnosis be entertained.

The impact of depression on the course of HIV has initiated the application of specific psychosocial and pharmacologic treatments targeting individuals with HIV and comorbid depression. Pharmacotherapy is the mainstay of treatment of moderate to severe depression. Several studies have demonstrated efficacy of various antidepressant agents in HIV patients, but no single antidepressant has been found superior in treating HIV-infected patients as a group (Olatunji et al, 2006).

Aside from how well the pharmacology of the antidepressant matches a patient's disease, the engine that drives effectiveness is patient adherence. The general rule is to start at low doses of any medication and titrate up to a therapeutic dose slowly, so as to minimize early side effects that may act as obstacles to adherence. Patients who show partial response to antidepressant after adequate dosage and duration should be offered an augmentation strategy. The choice of an antidepressant is largely based on their side effect profile. Some of the antidepressant drugs that are useful in treatment of depression in patients with HIV/AIDS include Amitriptyline, Imipramine, Clomipramine, Fluoxetine, Paroxetine, Sertraline, Fluvoxamine and Venlafaxine (Elliot et al, 1998). The use of psychostimulants such as Methylphenidate and Dextroamphetamine has also been found effective (Wagner et al, 2000).

Some clinicians often wonder about the interaction of antidepressants and HAART. Some interactions may occur but two points deserve emphasis. Firstly, because depression is associated with reduction in adherence to HAART, untreated depression may be equally or more detrimental to disease progression than any medication interaction. Secondly, experience in working with comorbid HIV and depression has not shown clinical significance to antidepressant-HAART interaction.

Psychosocial intervention is an integral part of treatment for depression in patients with HIV/AIDS. A combination of psychosocial intervention and medication was shown to be more effective for patients than either modality alone. Among the individual psychotherapies, interpersonal psychotherapy, cognitive-behavioral psychotherapy and supportive psychotherapy are effective in treatment of depression in patients with HIV/AIDS (Markowitz et al, 1995). A social intervention such as social support group therapy is also effective (Kelly et al, 1993).

Identifying and treating depression in patients with HIV/AIDS could result in substantial improvement in quality of life and potentially increase medication adherence, which would in turn affect illness severity and progression.

Treatment of anxiety disorders in HIV/AIDS also requires a combination of psychosocial intervention and medication. Adequate counseling and relaxation techniques are sufficient to treat mild anxiety associated with the various crisis points in the course of HIV/AIDS. For the more severe anxiety disorders, antidepressants and cognitive behavioural techniques are useful.

Every patient with HIV/AIDS presenting with psychiatric disorder must also be assessed for suicidal risk and cases where risk is high, patients should be hospitalized for detailed evaluation and appropriate treatment.

Substance abuse is a common problem in patients with HIV/AIDS. Physicians should have a high index of suspicion while assessing patients. When present, motivational interviews are important. Patients with severe problems who are motivated should be hospitalized for detoxification and appropriate pharmacological and psychosocial treatment.

Neuropsychiatric Manifestations of HIV Infection and AIDS 433

episodes in association with zidovudine treatment, even in patients with no previous psychiatric history. In some patients, mania was severe enough to necessitate hospitalization. In recent years, fewer problems have been reported, in part because zidovudine is now used in lower doses‹approximately of 600 mg/day (or 300 mg twice a

The mechanisms involved in zidovudine-associated psychiatric effects are unknown. For some patients, dose reduction is beneficial, but for others, discontinuation may be necessary. Discontinuing zidovudine treatment has been shown to rapidly reduce manic symptoms (and symptoms returned upon reintroduction of the drug, suggesting a causal relationship). However, patients have been able to resume zidovudine treatment if they also received

Other adverse neurologic effects of zidovudine treatment are insomnia, myalgia, and severe headaches. Zidovudine also has been associated with seizures, particularly in cases of overdose, which have on rare occasions been fatal. Because HIV infection is associated with similar neurological problems, it is important to exclude other causes before attributing them to zidovudine treatment. However, the severity of these side-effects suggests the need

Neurologic symptoms associated with other NRTI may include headache, malaise, and fatigue; for most patients, these symptoms are not severe enough to discontinue HAART. A more serious side-effect is peripheral neuropathy and may be seen with didanosine, zalcitabine, or stavudine treatment but not with zidovudine treatment. The mechanism is unknown, but in vitro studies have shown that zalcitabine, stavudine, and didanosine but not zidovudine - inhibit nerve growth factor (NGF)-stimulated differentiation of a neuronal

For patients with peripheral neuropathy, symptomatic treatment with ibuprofen or topical analgesic creams can sometimes be effective. Tricyclic antidepressants have been used to manage pain in patients with HIV-associated peripheral neuropathy. In clinical practice, we have found that Tricyclic antidepressants can be partially effective, but for many patients, the pain of neuropathy can be severe, irreversible, and debilitating. Therefore, patients with HIV who develop neuropathy require careful evaluation to determine the risks and benefits of continuing NRTI treatment. In some cases, decreasing dosage may help, but in others, the

Three NNRTIs - efavirenz, delavirdine, and nevirapine - are currently available for the treatment of HIV infection. They are usually prescribed in combination with NRTI. Clinical trials of delavirdine and nevirapine revealed few adverse events affecting the CNS; therefore, the relatively more substantial CNS side-effects seen in clinical trials of efavirenz

CNS side-effects observed with efavirenz include dizziness, headache, confusion, stupor, impaired concentration, agitation, amnesia, depersonalization, hallucinations, insomnia, and abnormal or vivid dreams. For most patients, these side-effects resolve within 6-10 weeks of starting treatment, but for some patients, symptoms seem to wax and wane over a long term. For most patients, these disturbances diminished or resolved within 2 months. Neither

Psychiatric effects also have been noted with efavirenz, though they occur less frequently than neurologic effects.When efavirenz-associated psychiatric effects occur, they may be

dose reduction nor dose splitting shortened or reduced the intensity of symptoms.

serious and may include anxiety, depression, and suicidal ideation.

day) versus the up to 2000 mg/day doses used in the pre-HAART era.

treatment for mania.

cell line.

were unexpected.

to closely monitor patients taking this drug.

contributing drug must be discontinued.

## **8. Neurologic and psychiatric complications of antiretroviral drugs**

Much progress has been made in treating HIV infection in the last several years and people infected with HIV are now living longer, healthier lives. What was once considered a progressive, ultimately fatal disease has become, in developed countries, a chronic condition that often can be managed long term.

In large part, this change has resulted from the introduction of protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) in highly active antiretroviral treatment (HAART) regimen. Now, carefully selected combinations of these agents can bring viral loads below detectable levels, increase CD4 T-lymphocyte counts, and improve immune function.

Investigators have realized that HIV cannot be completely eradicated with the treatments that are currently available and that long-term HAART may have side-effects that are severe or health- complicating enough to require modification or temporary cessation of treatment. Even when the virus is virtually undetectable in the blood, it appears to remain sequestered in host reservoirs that are inaccessible to HAART and may provide a source for viral rebound if therapy is withdrawn. With the treatments currently available, HAART will probably need to continue for the patient's lifetime, and clinicians need a thorough understanding of the health implications associated with long-term HAART, the potential complications of HIV infection even in the absence of overt illness, and the strategies for maintaining treatment adherence and minimizing treatment side-effects.

Unfortunately, complications of HAART and complications of HIV infection, particularly in patients with advanced disease and AIDS, overlap significantly. Among health risks that may be associated with HIV or HAART are neurologic complications (such as myelopathy, neuropathy and neuropathic pain, changes in cognition, and dementia), and psychiatric complications (such as mania, depression, schizophrenia, and substance abuse and dependence). CNS complications in patients with HIV, including psychiatric syndromes, delirium, seizures, and cognitive impairment, may in some cases reflect consequences of treatment with antiretroviral drugs that penetrate the CNS. For example, zidovudine and efavirenz, both considered attractive choices for patients with CNS complications because they have good CNS penetration, are themselves associated with potentially significant neuropsychiatric complications. Peripheral neurologic complications including neuropathic pain, neuropathic weakness, and denervation syndromes have been attributed to various toxic and metabolic factors in association with antiretroviral treatment. In managing neurologic complications, it is important to distinguish, when possible, between symptoms related to the HIV disease process and side-effects of HAART. To make such distinctions, clinicians need to understand which antiretroviral agents may cause neurologic and psychiatric symptoms.

Zidovudine, a nucleoside analogue that inhibits replication of HIV by interfering with viral reverse transcriptase, was the first agent to significantly reduce mortality and opportunistic infections in HIV-infected patients. Zidovudine has been found effective at high doses in slowing the progression of AIDS dementia, and can penetrate the blood-brain barrier. Zidovudine is therefore an attractive choice in HAART regimens targeting dementia and other CNS complications of HIV. However, its CNS penetration may also explain the confusion, agitation, and insomnia in up to 5% of people who took zidovudine for one year. In addition, there are anecdotal reports of psychiatric symptoms, including mania and depression, in patients treated with zidovudine. Several case reports document manic

Much progress has been made in treating HIV infection in the last several years and people infected with HIV are now living longer, healthier lives. What was once considered a progressive, ultimately fatal disease has become, in developed countries, a chronic condition

In large part, this change has resulted from the introduction of protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI) in highly active antiretroviral treatment (HAART) regimen. Now, carefully selected combinations of these agents can bring viral loads below detectable levels,

Investigators have realized that HIV cannot be completely eradicated with the treatments that are currently available and that long-term HAART may have side-effects that are severe or health- complicating enough to require modification or temporary cessation of treatment. Even when the virus is virtually undetectable in the blood, it appears to remain sequestered in host reservoirs that are inaccessible to HAART and may provide a source for viral rebound if therapy is withdrawn. With the treatments currently available, HAART will probably need to continue for the patient's lifetime, and clinicians need a thorough understanding of the health implications associated with long-term HAART, the potential complications of HIV infection even in the absence of overt illness, and the strategies for

Unfortunately, complications of HAART and complications of HIV infection, particularly in patients with advanced disease and AIDS, overlap significantly. Among health risks that may be associated with HIV or HAART are neurologic complications (such as myelopathy, neuropathy and neuropathic pain, changes in cognition, and dementia), and psychiatric complications (such as mania, depression, schizophrenia, and substance abuse and dependence). CNS complications in patients with HIV, including psychiatric syndromes, delirium, seizures, and cognitive impairment, may in some cases reflect consequences of treatment with antiretroviral drugs that penetrate the CNS. For example, zidovudine and efavirenz, both considered attractive choices for patients with CNS complications because they have good CNS penetration, are themselves associated with potentially significant neuropsychiatric complications. Peripheral neurologic complications including neuropathic pain, neuropathic weakness, and denervation syndromes have been attributed to various toxic and metabolic factors in association with antiretroviral treatment. In managing neurologic complications, it is important to distinguish, when possible, between symptoms related to the HIV disease process and side-effects of HAART. To make such distinctions, clinicians need to understand which antiretroviral agents may cause neurologic and

Zidovudine, a nucleoside analogue that inhibits replication of HIV by interfering with viral reverse transcriptase, was the first agent to significantly reduce mortality and opportunistic infections in HIV-infected patients. Zidovudine has been found effective at high doses in slowing the progression of AIDS dementia, and can penetrate the blood-brain barrier. Zidovudine is therefore an attractive choice in HAART regimens targeting dementia and other CNS complications of HIV. However, its CNS penetration may also explain the confusion, agitation, and insomnia in up to 5% of people who took zidovudine for one year. In addition, there are anecdotal reports of psychiatric symptoms, including mania and depression, in patients treated with zidovudine. Several case reports document manic

**8. Neurologic and psychiatric complications of antiretroviral drugs** 

increase CD4 T-lymphocyte counts, and improve immune function.

maintaining treatment adherence and minimizing treatment side-effects.

that often can be managed long term.

psychiatric symptoms.

episodes in association with zidovudine treatment, even in patients with no previous psychiatric history. In some patients, mania was severe enough to necessitate hospitalization. In recent years, fewer problems have been reported, in part because zidovudine is now used in lower doses‹approximately of 600 mg/day (or 300 mg twice a day) versus the up to 2000 mg/day doses used in the pre-HAART era.

The mechanisms involved in zidovudine-associated psychiatric effects are unknown. For some patients, dose reduction is beneficial, but for others, discontinuation may be necessary. Discontinuing zidovudine treatment has been shown to rapidly reduce manic symptoms (and symptoms returned upon reintroduction of the drug, suggesting a causal relationship). However, patients have been able to resume zidovudine treatment if they also received treatment for mania.

Other adverse neurologic effects of zidovudine treatment are insomnia, myalgia, and severe headaches. Zidovudine also has been associated with seizures, particularly in cases of overdose, which have on rare occasions been fatal. Because HIV infection is associated with similar neurological problems, it is important to exclude other causes before attributing them to zidovudine treatment. However, the severity of these side-effects suggests the need to closely monitor patients taking this drug.

Neurologic symptoms associated with other NRTI may include headache, malaise, and fatigue; for most patients, these symptoms are not severe enough to discontinue HAART. A more serious side-effect is peripheral neuropathy and may be seen with didanosine, zalcitabine, or stavudine treatment but not with zidovudine treatment. The mechanism is unknown, but in vitro studies have shown that zalcitabine, stavudine, and didanosine but not zidovudine - inhibit nerve growth factor (NGF)-stimulated differentiation of a neuronal cell line.

For patients with peripheral neuropathy, symptomatic treatment with ibuprofen or topical analgesic creams can sometimes be effective. Tricyclic antidepressants have been used to manage pain in patients with HIV-associated peripheral neuropathy. In clinical practice, we have found that Tricyclic antidepressants can be partially effective, but for many patients, the pain of neuropathy can be severe, irreversible, and debilitating. Therefore, patients with HIV who develop neuropathy require careful evaluation to determine the risks and benefits of continuing NRTI treatment. In some cases, decreasing dosage may help, but in others, the contributing drug must be discontinued.

Three NNRTIs - efavirenz, delavirdine, and nevirapine - are currently available for the treatment of HIV infection. They are usually prescribed in combination with NRTI. Clinical trials of delavirdine and nevirapine revealed few adverse events affecting the CNS; therefore, the relatively more substantial CNS side-effects seen in clinical trials of efavirenz were unexpected.

CNS side-effects observed with efavirenz include dizziness, headache, confusion, stupor, impaired concentration, agitation, amnesia, depersonalization, hallucinations, insomnia, and abnormal or vivid dreams. For most patients, these side-effects resolve within 6-10 weeks of starting treatment, but for some patients, symptoms seem to wax and wane over a long term. For most patients, these disturbances diminished or resolved within 2 months. Neither dose reduction nor dose splitting shortened or reduced the intensity of symptoms.

Psychiatric effects also have been noted with efavirenz, though they occur less frequently than neurologic effects.When efavirenz-associated psychiatric effects occur, they may be serious and may include anxiety, depression, and suicidal ideation.

Neuropsychiatric Manifestations of HIV Infection and AIDS 435

and mortality (Lesserman et al., 1997). Some studies found that HIV-sero-positive gay men who reported depressive symptoms demonstrated immunological changes associated with

Some studies have compared pattern of neuropsychiatric disorder especially the neurocognitive impairment at various level of CD4 cell counts namely 200, 250, 300, 350 and 400 cells /ml and found that there is generally worsening trend of neurocognitive impairment as the CD4 cell count decreases and therefore recommended the serial determination of CD4 cell count in HIV infected patient and screening for neuropsychiatric syndromes in those with CD4 count values of less than 350 cell/ml( Bornstein et al., 1992;

Research has shown that neuropsychiatric disorders in patients with HIV/AIDS complicates help seeking, diagnosis, quality of care provided, treatment and its outcome and adherence(World Health Organization report, 2008). Regardless of aetiology, the co morbidity of mental illness and HIV poses special challenge for HIV care. Individual with these co morbidity face even greater barriers to care than those with HIV alone. Once in care, their treatment is more complex (Francine et al., 2009). Mental and substance use disorders in HIV/AIDS affects help seeking behaviour or uptake of diagnostic and

People with alcohol use disorders are more likely than the general population to contract HIV. Similarly, rates of alcohol problems are high among HIV/AIDS patients (Petry, 1999). Lifetime prevalence rates of alcohol use disorders ranging from 29% to 60% have been found among HIV positive populations (Bryant, 1998). This is 2 to 4 times higher than in the general population. Alcohol use is associated with high-risk sexual behaviors and

In persons already infected, the combination of heavy drinking and HIV has been associated with increased medical and psychiatric complications, delays in seeking treatment (Samet et al., 1998), difficulties with HIV medication adherence (Cook et al., 2001; Wagner et al., 2001), and poorer HIV treatment outcomes (Lucas et al., 2002). Decreasing alcohol use in people who have HIV or who are at risk for becoming infected reduces the spread of HIV and the

People who abuse alcohol are more likely to engage in behaviors that place them at risk for contracting or transmitting HIV. A history alcohol use has been correlated with a lifetime tendency toward high-risk sexual behaviors, including multiple sex partners, unprotected intercourse, sex with high-risk partners (e.g., injection drug users, prostitutes), and the exchange of sex for money or drugs (Avins et al., 1994; Boscarino et al., 1995; Malow et al., 2001; Windle, 1997).There may be many reasons for this association. For example, alcohol can act directly on the brain to reduce inhibitions and diminish risk perception (Cooper,

Decreasing alcohol use among HIV patients not only reduces the medical and psychiatric consequences associated with alcohol consumption but also decreases other drug use and risky sexual behavior and hence reduces HIV transmission (Lucas et al., 2002). Thus, alcohol and other drug abuse treatment can be considered primary HIV prevention as well (Metzger

With improved treatments and longer survival times for persons with HIV infection, the maintenance and improvement of their functioning and well-being (collectively referred to as "health-related quality of life") have become major goals of treatment. The World Health

intravenous drug use which are two major modes of HIV transmission.

HIV activity and progression, for example CD4, CD8 cell count proliferate.

Heaton et al., 1995; Miller et al., 1990).

treatment services for HIV and AIDS.

diseases associated with it.

et al., 1998).

2002; Fromme et al., 1999; MacDonald et al., 2000).

Clinicians should advise patients of possible CNS effects of efavirenz, and should watch for changes in behavior, cognition, or mood. If side-effects persist or patients find them intolerable, a switch in HAART regimen may be appropriate. Although efavirenz is often a first-line treatment, many patients receive it after experiencing treatment failure on earlier HAART regimens. Therefore, patients who switch to efavirenz and then experience neurologic or psychiatric side-effects may have limited options for future antiretroviral treatment. It is important to carefully consider risks and treatment alternatives for these patients.

The combination of HIV Protease Inhibitor with the older antiretroviral agents brought about substantial decreases in viral loads and opportunistic infections with concomitant increases in CD4 T-cell counts. As a result, HIV-associated morbidity and mortality has declined dramatically in recent years.

Although PI may have neurologic side-effects, they tend to be variable and less prominent than those seen with NRTI or NNRTI. Neurologic symptoms may occur more often with ritonavir or ritonavir/saquinavir combination treatments than with indinavir treatment.

## **9. Consequences of neuropsychiatric problems in patients with HIV/AIDS**

Some previous studies have indicated that Neuropsychiatric disorders in people living with HIV/AIDS are associated with disease progression, poor adherence to antiretroviral drugs, increased incidence of high risk sexual behavior with the potential for further HIV transmission, and deterioration in their quality of life. Thus, the place of psychiatrists in the treatment and care of patients with HIV/AIDS is crucial.

There is a consistently strong evidence from high income countries that adherence to Highly Active Antiretroviral Therapy is lowered by depression, cognitive impairment, alcohol use and substance use disorders. A study in Ethiopia showed that depression was associated with less than 95% self reported adherence (Ambebir et al., 2008). Previous research has also shown that depression in patients with HIV/AIDS may be associated with reduced adherence with antiretroviral treatment (Byakika-Tusuiime et al., 2009; Dimatteo et al., 2000; Mugavero et al., 2000; Phyllips et al., 2002; Rabkin & Goetz 2002)and disease progression(Cook 2004; Paterson 2000).They concluded that identifying and treating depression in these patients may improve medication adherence.

In a study of women who were medically eligible to receive Highly Active Antiretroviral Therapy (HAART), its non receipt was associated with substance use. Furthermore, other epidemiological studies indicate that the presence of drug use disorder can complicate the management of HIV illness and compromise adherence to HIV medication and secondary preventive efforts (HIV clinical resource 2009).

HIV-infected subjects in several studies reported "forgetting" as one of the most common reasons for poor adherence to antiretroviral drugs. It is also possible that HIV-associated neurocognitive disturbances, which are common and more prominent as the disease advances, might be responsible for some of the cases of poor medication adherence. Other studies have reported a significantly greater risk of poor adherence to HAART in HIVinfected persons with neurocognitive impairment (Hinkin et al. 2002).

Depression has been associated with immune suppression and other health outcomes in studies of individual with and without chronic disease (; Herbert & Cohen 1993; Rover et al., 1991). Studies have documented association between depression and HIV progression (Lesserman et al., 1997; Lesserman et al, 1999), HIV-related symptoms (Leketsos et al., 1993)

Clinicians should advise patients of possible CNS effects of efavirenz, and should watch for changes in behavior, cognition, or mood. If side-effects persist or patients find them intolerable, a switch in HAART regimen may be appropriate. Although efavirenz is often a first-line treatment, many patients receive it after experiencing treatment failure on earlier HAART regimens. Therefore, patients who switch to efavirenz and then experience neurologic or psychiatric side-effects may have limited options for future antiretroviral treatment. It is important to carefully consider risks and treatment alternatives for these

The combination of HIV Protease Inhibitor with the older antiretroviral agents brought about substantial decreases in viral loads and opportunistic infections with concomitant increases in CD4 T-cell counts. As a result, HIV-associated morbidity and mortality has

Although PI may have neurologic side-effects, they tend to be variable and less prominent than those seen with NRTI or NNRTI. Neurologic symptoms may occur more often with ritonavir or ritonavir/saquinavir combination treatments than with indinavir treatment.

Some previous studies have indicated that Neuropsychiatric disorders in people living with HIV/AIDS are associated with disease progression, poor adherence to antiretroviral drugs, increased incidence of high risk sexual behavior with the potential for further HIV transmission, and deterioration in their quality of life. Thus, the place of psychiatrists in the

There is a consistently strong evidence from high income countries that adherence to Highly Active Antiretroviral Therapy is lowered by depression, cognitive impairment, alcohol use and substance use disorders. A study in Ethiopia showed that depression was associated with less than 95% self reported adherence (Ambebir et al., 2008). Previous research has also shown that depression in patients with HIV/AIDS may be associated with reduced adherence with antiretroviral treatment (Byakika-Tusuiime et al., 2009; Dimatteo et al., 2000; Mugavero et al., 2000; Phyllips et al., 2002; Rabkin & Goetz 2002)and disease progression(Cook 2004; Paterson 2000).They concluded that identifying and treating

In a study of women who were medically eligible to receive Highly Active Antiretroviral Therapy (HAART), its non receipt was associated with substance use. Furthermore, other epidemiological studies indicate that the presence of drug use disorder can complicate the management of HIV illness and compromise adherence to HIV medication and secondary

HIV-infected subjects in several studies reported "forgetting" as one of the most common reasons for poor adherence to antiretroviral drugs. It is also possible that HIV-associated neurocognitive disturbances, which are common and more prominent as the disease advances, might be responsible for some of the cases of poor medication adherence. Other studies have reported a significantly greater risk of poor adherence to HAART in HIV-

Depression has been associated with immune suppression and other health outcomes in studies of individual with and without chronic disease (; Herbert & Cohen 1993; Rover et al., 1991). Studies have documented association between depression and HIV progression (Lesserman et al., 1997; Lesserman et al, 1999), HIV-related symptoms (Leketsos et al., 1993)

**9. Consequences of neuropsychiatric problems in patients with HIV/AIDS** 

patients.

declined dramatically in recent years.

treatment and care of patients with HIV/AIDS is crucial.

depression in these patients may improve medication adherence.

infected persons with neurocognitive impairment (Hinkin et al. 2002).

preventive efforts (HIV clinical resource 2009).

and mortality (Lesserman et al., 1997). Some studies found that HIV-sero-positive gay men who reported depressive symptoms demonstrated immunological changes associated with HIV activity and progression, for example CD4, CD8 cell count proliferate.

Some studies have compared pattern of neuropsychiatric disorder especially the neurocognitive impairment at various level of CD4 cell counts namely 200, 250, 300, 350 and 400 cells /ml and found that there is generally worsening trend of neurocognitive impairment as the CD4 cell count decreases and therefore recommended the serial determination of CD4 cell count in HIV infected patient and screening for neuropsychiatric syndromes in those with CD4 count values of less than 350 cell/ml( Bornstein et al., 1992; Heaton et al., 1995; Miller et al., 1990).

Research has shown that neuropsychiatric disorders in patients with HIV/AIDS complicates help seeking, diagnosis, quality of care provided, treatment and its outcome and adherence(World Health Organization report, 2008). Regardless of aetiology, the co morbidity of mental illness and HIV poses special challenge for HIV care. Individual with these co morbidity face even greater barriers to care than those with HIV alone. Once in care, their treatment is more complex (Francine et al., 2009). Mental and substance use disorders in HIV/AIDS affects help seeking behaviour or uptake of diagnostic and treatment services for HIV and AIDS.

People with alcohol use disorders are more likely than the general population to contract HIV. Similarly, rates of alcohol problems are high among HIV/AIDS patients (Petry, 1999). Lifetime prevalence rates of alcohol use disorders ranging from 29% to 60% have been found among HIV positive populations (Bryant, 1998). This is 2 to 4 times higher than in the general population. Alcohol use is associated with high-risk sexual behaviors and intravenous drug use which are two major modes of HIV transmission.

In persons already infected, the combination of heavy drinking and HIV has been associated with increased medical and psychiatric complications, delays in seeking treatment (Samet et al., 1998), difficulties with HIV medication adherence (Cook et al., 2001; Wagner et al., 2001), and poorer HIV treatment outcomes (Lucas et al., 2002). Decreasing alcohol use in people who have HIV or who are at risk for becoming infected reduces the spread of HIV and the diseases associated with it.

People who abuse alcohol are more likely to engage in behaviors that place them at risk for contracting or transmitting HIV. A history alcohol use has been correlated with a lifetime tendency toward high-risk sexual behaviors, including multiple sex partners, unprotected intercourse, sex with high-risk partners (e.g., injection drug users, prostitutes), and the exchange of sex for money or drugs (Avins et al., 1994; Boscarino et al., 1995; Malow et al., 2001; Windle, 1997).There may be many reasons for this association. For example, alcohol can act directly on the brain to reduce inhibitions and diminish risk perception (Cooper, 2002; Fromme et al., 1999; MacDonald et al., 2000).

Decreasing alcohol use among HIV patients not only reduces the medical and psychiatric consequences associated with alcohol consumption but also decreases other drug use and risky sexual behavior and hence reduces HIV transmission (Lucas et al., 2002). Thus, alcohol and other drug abuse treatment can be considered primary HIV prevention as well (Metzger et al., 1998).

With improved treatments and longer survival times for persons with HIV infection, the maintenance and improvement of their functioning and well-being (collectively referred to as "health-related quality of life") have become major goals of treatment. The World Health

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Organization (WHO) defined quality of life (QOL) as an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns. It is a broad-ranging concept affected in a complex way by the person's physical health, psychological state, level of independence, social relationships and their relationship to salient features of their environment (WHOQOL Group, 1995).

We know from studies of patients and general populations that mood disorders, particularly depression, have a substantial negative impact on a person's health-related quality of life (Jia et al, 2004). In fact, for most domains of functioning and well-being, depression is more debilitating than most medical conditions (Sherbourne et al, 2000). In a study conducted by Sherbourne et al (2000) to assess the impact of psychiatric conditions on health related quality of life, they recruited a national probability sample of persons with HIV, receiving medical care in the United States. Subjects were screened for psychiatric conditions and their health-related quality of life was assessed. They found that 36% of subjects screened positive for a current depressive disorder and 26% for dysthymia. Subjects with a probable diagnosis of any mood disorder had significantly worse functioning and well-being than those without a mood disorder diagnosis on all health-related quality of life measures, including the physical and mental health composites. These findings substantiate the considerable additional illness burden associated with mood disorders in HIV infected people.

This chapter is intended to help create awareness about mental health problems and its consequences in patients with HIV/AIDS, so as to facilitate routine screening of mental disorders and mental health integration in the comprehensive care

of people living with HIV/AIDS.

#### **10. References**


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We know from studies of patients and general populations that mood disorders, particularly depression, have a substantial negative impact on a person's health-related quality of life (Jia et al, 2004). In fact, for most domains of functioning and well-being, depression is more debilitating than most medical conditions (Sherbourne et al, 2000). In a study conducted by Sherbourne et al (2000) to assess the impact of psychiatric conditions on health related quality of life, they recruited a national probability sample of persons with HIV, receiving medical care in the United States. Subjects were screened for psychiatric conditions and their health-related quality of life was assessed. They found that 36% of subjects screened positive for a current depressive disorder and 26% for dysthymia. Subjects with a probable diagnosis of any mood disorder had significantly worse functioning and well-being than those without a mood disorder diagnosis on all health-related quality of life measures, including the physical and mental health composites. These findings substantiate the considerable

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**18** 

**AIDS and Trauma** 

*University of Cape Town* 

*South Africa* 

Erik Vakil, Caroline Zabiegaj-Zwick and AB (Sebastian) van As

Trauma is a significant cause of mortality (10%) worldwide and is responsible for 15% of all disability-adjusted life years (DALYs) (Murray & Lopez, 1997). Seven of the top 30 contributors to the global burden of disease are due to injury, including motor vehicle accidents, falls, war injuries, self-inflicted injuries, violence, drowning and burns. All of these injuries are seen in the trauma setting and places trauma workers at risk of exposure to blood and other body fluids. The relevance of HIV and trauma is increasing as the global prevalence of HIV continues to rise. Sixty million have been infected with HIV since the beginning of the epidemic and 25 million have died of HIV-related causes (UNAIDS, 2009). Of those newly infected, 40% were young people - the group most likely to be involved in

In general, the risk of transmission of any infectious disease may be minimised in the trauma setting by implementing universal precautions. The World Health Organization (WHO) has developed universal precaution guidelines which are summarised below

Wearing a mask, eye protection and a gown if blood or other body fluids might splash

In addition, the WHO advocates Hepatitis B virus (HBV) vaccination of healthcare workers, development of post exposure protocols for those at risk of contact with infected body fluids, adequate provision of personal protective equipment (PPE) with appropriate means

Historically, trauma workers have generally had poor compliance with universal precaution guidelines. In a Jamaican study, where health care workers were interviewed to determine the reason for not adhering to universal precautions, numerous reason were provided including: (1) increase in workload made adherence difficult, (2) a perceived reduction in dexterity when wearing gloves, (3) insufficient supply of PPE and (4) lack of penalties for

Gloves for contact with body fluids, non intact skin and mucous membranes

**1. Introduction** 

trauma.

(WHO, 2007).

**2. Universal precaution** 

Hand wash after any direct contact with patients

 Cleaning of spills of blood and other bodily fluids Safe system for hospital waste management and disposal

of disposal, and monitoring of staff training and use of PPE.

Safe collection and disposal of sharps

Covering cuts and abrasions

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## **AIDS and Trauma**

Erik Vakil, Caroline Zabiegaj-Zwick and AB (Sebastian) van As *University of Cape Town South Africa* 

## **1. Introduction**

442 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Zisook S, Peterkin J, Goggin KJ, Sledge P, Atkinson JH, Cotter RL, Thylin MR, Epstein L,

73:8256-8267.

for human immunodeficiency virus type 1-associated dementia. *Journal of Virology*,

Swartz JM, Shepard RB, Liu X, Nukuna A & Gendelman HE. (1998). Treatment of major depression in HIV positive men. *Journal of Clinical Psychiatry,* 59: 217 – 24.

> Trauma is a significant cause of mortality (10%) worldwide and is responsible for 15% of all disability-adjusted life years (DALYs) (Murray & Lopez, 1997). Seven of the top 30 contributors to the global burden of disease are due to injury, including motor vehicle accidents, falls, war injuries, self-inflicted injuries, violence, drowning and burns. All of these injuries are seen in the trauma setting and places trauma workers at risk of exposure to blood and other body fluids. The relevance of HIV and trauma is increasing as the global prevalence of HIV continues to rise. Sixty million have been infected with HIV since the beginning of the epidemic and 25 million have died of HIV-related causes (UNAIDS, 2009). Of those newly infected, 40% were young people - the group most likely to be involved in trauma.

## **2. Universal precaution**

In general, the risk of transmission of any infectious disease may be minimised in the trauma setting by implementing universal precautions. The World Health Organization (WHO) has developed universal precaution guidelines which are summarised below (WHO, 2007).


In addition, the WHO advocates Hepatitis B virus (HBV) vaccination of healthcare workers, development of post exposure protocols for those at risk of contact with infected body fluids, adequate provision of personal protective equipment (PPE) with appropriate means of disposal, and monitoring of staff training and use of PPE.

Historically, trauma workers have generally had poor compliance with universal precaution guidelines. In a Jamaican study, where health care workers were interviewed to determine the reason for not adhering to universal precautions, numerous reason were provided including: (1) increase in workload made adherence difficult, (2) a perceived reduction in dexterity when wearing gloves, (3) insufficient supply of PPE and (4) lack of penalties for

AIDS and Trauma 445

Sexual contact in cases where a condom was not used, broke or fell off during

**Exposure between body fluids suspected of, or confirmed to be, HIV positive and:** 

Exposure to non-infectious body fluids such as saliva, faeces, urine, and sweat

The risk of non-occupational exposure depends on the nature of contact with contaminated fluids. In cases of sexual assault, the method of assault, the condition of genital or oral mucosa, the circumcision status, and the level of HIV virulence all play a role. Risk is increased in cases of rape, where there is decreased lubrication and may be associate with violent penetration. Children, especially small children, are also at an increased risk for anatomical reasons. Generalised risk from a single sexual contact depends on the method of exposure. Published estimates of HIV transmission for receptive anal intercourse are 1-30%, insertive anal intercourse 0.1-10%, receptive vaginal intercourse 0.1-10%, and insertive vaginal intercourse 0.1-1% (Boily et al., 2009). Case studies have also reported transmission

PEP should be offered to all victims of sexual assault attending the trauma service where the act occurred within 72 hours. In many cases, particularly with children, the assault may be on a background of chronic abuse, in which case PEP is not indicated. However, special care should be taken to distinguish between cases of chronic abuse and cases of acute-on-chronic abuse where a different perpetrator is responsible for the most recent assault. In such cases,

1 The risk for oral transmission is considered very low but PEP may be offered in cases where the exposure is in association with significat oral disease such as ulceration or dysplasia 2 Adapted from: WHO. Post-exposure prophylaxis to prevent HIV infection: Joint WHO/ILO guidelines on post-exposure prophylaxis (PEP) to prevent HIV infection. *HIV/AIDS Programme: Strengthening health services to fight HIV/AIDS.* 2007 3 Chronic exposure should be distinguished from episodic exposure where PEP may still be effective.

from oral sex with ejaculation (Lifson et al., 1990; Rozenbaum et al., 1988).

 Non-intact skin (needlestick, sharp injury, skin abrasion) Mucous membranes (oral cavity, nasal cavity, eyes)

Patient is already HIV positive from previous exposure

Sexual contact with condom use that remains intact

Greater than 72 hours have elapsed since exposure

Exposure to HIV negative body fluids

**3.2 Exposure as a result of sexual assault** 

intercourse

Oral sex with ejaculation1

 Exposure has been chronic3 Exposure through intact skin

Table 2. Contraindications to PEP2

PEP should be offered.

This distinction may be challenging.

Table 1. Indications for PEP2

not adhering to universal precautions (Vaz et al., 2010). Other studies in the United States have reached similar conclusions and also highlighted that trauma workers have a poor knowledge of infection risk (Kelen et al. 1990; Kim et al., 1999)

## **3. Post-exposure prophylaxis**

Post-exposure prophylaxis (PEP) is the collection of measures taken after exposure to a pathogen in order to prevent or reduce the risk of transmission. In the case of HIV, such measures should include, but are not limited to, first-aid, appropriate HIV testing, counselling, anti-retroviral (ARV) chemotherapy, and follow-up. The risk of occupational exposure to healthcare workers in the trauma setting depends on the relative prevalence of HIV in the trauma population and the level of exposure. The use of PEP in patients attending the trauma service should also be considered in cases of sexual assault and other forms of acute non-occupational exposure. It is strongly recommended that all trauma services have well established PEP protocols, sufficient resources and necessary training for effective implementation.

The only direct evidence supporting the prophylactic use of ARV chemotherapy (zidovudine) for healthcare associated HIV exposure comes from a single case-control study involving patients from the United States, United Kingdom, France and Italy (Cardo et al., 1997). Healthcare workers were 81% less likely to seroconvert if they received zidovudine after a needlestick injury and the risk of seroconversion was linked to the volume of blood transmitted and the HIV blood titre level. Indirect evidence supporting the prophylactic use of ARVs include reduced rates of vertical transmission in HIV positive mothers who received zidovudine and the success of ARVs in raising CD4+ counts, reducing viral titres, and decreasing morbidity and mortality in HIV positive patients (Connor et al., 1996).

#### **3.1 Occupational exposure**

The risk of HIV transmission through needlestick injury is 0.3%. The risk of transmission from contact of contaminated fluids with mucous membranes or damaged skin is approximately 0.09%. However, the risk of occupational exposure in trauma may be higher than in other hospital settings. This is because the HIV status of patients is usually unknown, the prevalence of HIV in the trauma population is generally greater than the community, the mechanism of injury is often violent and may increase the level of exposure, and the emergent nature of trauma increases the situational stress and may lead to riskier practice.

PEP is only indicated in cases where there is a risk of transmission (Table 1) and contraindicated in cases where there is no appreciable benefit (Table 2). For occupational exposure, this includes contact between body fluids at risk of HIV contamination and nonintact skin or mucous membranes. Indirect evidence from animal studies suggest that initiation of PEP after 72 hours following exposure is not effective at reducing rates of seroconversion. PEP should therefore not be offered in such cases and strategies should exist to offer PEP as soon as possible after exposure (Martin et al., 1993). Starter packs are wellsuited to the emergency department as they offer quick access to ARVs, may result in less wasted medication if PEP is not continued, requires the patient to attend follow-up to obtain additional ARVs ensuring appropriate testing and counselling, and can easily be placed in small or under-serviced departments. Theoretical risk of HIV resistance may develop if starter packs are inappropriately used or ARV courses are not routinely completed.

not adhering to universal precautions (Vaz et al., 2010). Other studies in the United States have reached similar conclusions and also highlighted that trauma workers have a poor

Post-exposure prophylaxis (PEP) is the collection of measures taken after exposure to a pathogen in order to prevent or reduce the risk of transmission. In the case of HIV, such measures should include, but are not limited to, first-aid, appropriate HIV testing, counselling, anti-retroviral (ARV) chemotherapy, and follow-up. The risk of occupational exposure to healthcare workers in the trauma setting depends on the relative prevalence of HIV in the trauma population and the level of exposure. The use of PEP in patients attending the trauma service should also be considered in cases of sexual assault and other forms of acute non-occupational exposure. It is strongly recommended that all trauma services have well established PEP protocols, sufficient resources and necessary training for

The only direct evidence supporting the prophylactic use of ARV chemotherapy (zidovudine) for healthcare associated HIV exposure comes from a single case-control study involving patients from the United States, United Kingdom, France and Italy (Cardo et al., 1997). Healthcare workers were 81% less likely to seroconvert if they received zidovudine after a needlestick injury and the risk of seroconversion was linked to the volume of blood transmitted and the HIV blood titre level. Indirect evidence supporting the prophylactic use of ARVs include reduced rates of vertical transmission in HIV positive mothers who received zidovudine and the success of ARVs in raising CD4+ counts, reducing viral titres, and decreasing morbidity and mortality in HIV positive patients (Connor et al., 1996).

The risk of HIV transmission through needlestick injury is 0.3%. The risk of transmission from contact of contaminated fluids with mucous membranes or damaged skin is approximately 0.09%. However, the risk of occupational exposure in trauma may be higher than in other hospital settings. This is because the HIV status of patients is usually unknown, the prevalence of HIV in the trauma population is generally greater than the community, the mechanism of injury is often violent and may increase the level of exposure, and the emergent nature of

PEP is only indicated in cases where there is a risk of transmission (Table 1) and contraindicated in cases where there is no appreciable benefit (Table 2). For occupational exposure, this includes contact between body fluids at risk of HIV contamination and nonintact skin or mucous membranes. Indirect evidence from animal studies suggest that initiation of PEP after 72 hours following exposure is not effective at reducing rates of seroconversion. PEP should therefore not be offered in such cases and strategies should exist to offer PEP as soon as possible after exposure (Martin et al., 1993). Starter packs are wellsuited to the emergency department as they offer quick access to ARVs, may result in less wasted medication if PEP is not continued, requires the patient to attend follow-up to obtain additional ARVs ensuring appropriate testing and counselling, and can easily be placed in small or under-serviced departments. Theoretical risk of HIV resistance may develop if

starter packs are inappropriately used or ARV courses are not routinely completed.

trauma increases the situational stress and may lead to riskier practice.

knowledge of infection risk (Kelen et al. 1990; Kim et al., 1999)

**3. Post-exposure prophylaxis** 

effective implementation.

**3.1 Occupational exposure** 

**Exposure between body fluids suspected of, or confirmed to be, HIV positive and:** 


Table 1. Indications for PEP2


Table 2. Contraindications to PEP2

#### **3.2 Exposure as a result of sexual assault**

The risk of non-occupational exposure depends on the nature of contact with contaminated fluids. In cases of sexual assault, the method of assault, the condition of genital or oral mucosa, the circumcision status, and the level of HIV virulence all play a role. Risk is increased in cases of rape, where there is decreased lubrication and may be associate with violent penetration. Children, especially small children, are also at an increased risk for anatomical reasons. Generalised risk from a single sexual contact depends on the method of exposure. Published estimates of HIV transmission for receptive anal intercourse are 1-30%, insertive anal intercourse 0.1-10%, receptive vaginal intercourse 0.1-10%, and insertive vaginal intercourse 0.1-1% (Boily et al., 2009). Case studies have also reported transmission from oral sex with ejaculation (Lifson et al., 1990; Rozenbaum et al., 1988).

PEP should be offered to all victims of sexual assault attending the trauma service where the act occurred within 72 hours. In many cases, particularly with children, the assault may be on a background of chronic abuse, in which case PEP is not indicated. However, special care should be taken to distinguish between cases of chronic abuse and cases of acute-on-chronic abuse where a different perpetrator is responsible for the most recent assault. In such cases, PEP should be offered.

<sup>1</sup> The risk for oral transmission is considered very low but PEP may be offered in cases where the

exposure is in association with significat oral disease such as ulceration or dysplasia 2 Adapted from: WHO. Post-exposure prophylaxis to prevent HIV infection: Joint WHO/ILO guidelines on post-exposure prophylaxis (PEP) to prevent HIV infection. *HIV/AIDS Programme: Strengthening health* 

*services to fight HIV/AIDS.* 2007 3 Chronic exposure should be distinguished from episodic exposure where PEP may still be effective. This distinction may be challenging.

AIDS and Trauma 447

population sub-groups such as children and victims of sexual assault should also be made

The function of a trauma unit is to stabilise and treat life threatening injuries. It has been shown that HIV alone is not responsible for mortality in trauma but rather the patient's ability to mount an immune response (Allard & Meintjies, 2005). It is also unethical to not treat life-threatening conditions based on a patient's HIV status (Smit 2010). In fact, a number of studies have suggested that HIV positive patients have the same mortality rate as non-infected patients, especially if they are in the early stages of the disease (Smit, 2010). With regard to surgical outcomes, early views were often pessimistic. It was felt that HIV positive patients were prone to poor wound healing, high post-operative complication rates, a prolonged post-operative period and higher mortality rates. This helped trigger a number of studies investigating the morbidity and complication rates among HIV positive patients

Many such studies have produced conflicting results. Duane et al conducted a retrospective study comparing outcomes of HIV positive and HIV negative patients over a 5-year period in the trauma unit. They found no difference in infection rates or overall complications based on CD4+ count alone (Duane et al., 2008). Conversely, Karpelowsky et al showed that in children who were HIV positive or exposed to HIV had increased rates of poor wound healing and breakdown of reconstruction sites (Karpelowsky et al., 2009). Other postoperative complications cited in the study were likely due to non-HIV related factors. For example, a large proportion of the children studied underwent emergency surgery, which is known to have higher rates of post-operative complications since the children tend to be sicker at presentation. This is true for both HIV positive and HIV negative patients. It was also found that up to 79% of children included in the study were undernourished and 36% had other co-morbid diseases including major respiratory and nutritional problems prior to

Stawicki et al found that HIV positive patients had both longer length of hospital stay as well as longer length of stay in ICU (Stawicki et al., 2005). They noted however, that HIV positive patients had more pulmonary, infectious and renal complications than the control group and suggested that the mortality of HIV positive patients was likely linked to these co-morbid processes. They also found that HIV positive patients needed greater numbers of surgical procedures but failed to state what the indication for these procedures were. Studies by Morrison et al and Horberg et al found similar findings to Stawicki et al, stating that HIV positive patients had higher post-operative complication rates, especially

Studies comparing complication rates in orthopaedic surgeries have been small and only tentative conclusions can be drawn. It has been shown that HIV positive patients with an open fracture (depending on the contamination of the wound) have a higher rate of infection, especially deep infection. There is also a higher rate of late sepsis with procedures that need internal instrumentation, but sepsis may have been avoided with improved medical management including prophylactic antibiotic use before invasive procedures as well as early evaluation and treatment of possible infections (Luck Jr, 1994; Van Aardt,

respiratory complications (Horberg et al., 2006; Morrison et al., 2010).

**4. Management and outcome of HIV positive patients in trauma** 

available.

both in general and orthopaedic surgery.

undergoing surgery.

2010).

#### **3.3 Other types of exposure**

Routine PEP after community-acquired needlestick injury is controversial and administration should be based on risk assessment. At risk populations include children, security workers and cleaners (Celenza et al., 2011). Children from communities with low prevalence of HIV may not warrant PEP (Makwana & Riordan, 2005). Care should also be taken to ensure exposure was within 72 hours as presentation to the emergency department may be delayed (Johnston & O'Conor, 2005).

The risk associated with needle-sharing is approximately 0.67%. PEP for needle-sharing may also be offered if presented within 72 hours and where exposure is likely to be acute rather than chronic.

### **3.4 PEP regimens**

When indicated, the ARV regimen used depends on various factors including national policy, institutional policy, level of resources, toxicity and side-effects, daily pill burden, drug contra-indications and compliance. Although a single drug regimen using zidovudine has shown to be effective, multi-drug regimens are now more commonly used in order to cover drug-resistant HIV clones. The use of two drugs must be weighed against cost, toxicity and availability. A third drug may be considered in cases where the background prevalence of ARV resistance is greater than 15%.

Two drug regimens include fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) therapy with combination zidovudine-lamivudine or combination tenofoviremtricitabine. A protease inhibitor (PI), usually in combination with ritonavir, which increases PI plasma levels, are usually added if a third drug is necessary. Combination ritonavir-lopinavir, -atazanavir, -darunavir have all been used. All PEP regimens are given for 28 days post exposure.

## **3.5 Testing, follow-up and counselling**

Testing of the source patient, in cases where HIV status is unknown, should include rapid-ELISA testing for HIV as well as testing for HBV (surface antigen - HBsAg) and Hepatitis C virus (HCV). In cases where HIV or HCV infection has occurred within the last 2-4 weeks, HIV or HCV RNA PCR may be indicated.

Testing of the exposed patient should be carried out as soon as possible to establish a baseline for follow-up testing. Tests should include a rapid-ELISA for HIV, HBV immunity status (anti-HB antibodies), HBsAg and HCV antibodies. Baseline full blood count, liver enzymes and creatinine should also be obtained to monitor for PEP side-effects and sequelae from hepatitis infection. Screening for other sexually transmitted infections may be warranted in cases of sexual assault or in patients with high risk behaviour.

At the minimum, follow-up testing at 6 months should be performed to document HIV negative status. Seroconversion after 6 months in those receiving PEP has been reported but is extremely rare (Ippolito et al., 1999). More intensive follow-up can include HIV and HCV antibody testing at 4-6 weeks, 3 months, and 6 months. Relevant additional testing should be offered in patients who become symptomatic or experience drug toxicity.

Post-exposure counselling should form an integral part of the PEP protocol. Services should be available to address HIV testing, follow-up testing, ARV treatment, legal issues and compensation claims should they arise. In the event that HIV is contracted, services should be available to address relevant needs. Counselling to address special needs of certain

Routine PEP after community-acquired needlestick injury is controversial and administration should be based on risk assessment. At risk populations include children, security workers and cleaners (Celenza et al., 2011). Children from communities with low prevalence of HIV may not warrant PEP (Makwana & Riordan, 2005). Care should also be taken to ensure exposure was within 72 hours as presentation to the emergency department

The risk associated with needle-sharing is approximately 0.67%. PEP for needle-sharing may also be offered if presented within 72 hours and where exposure is likely to be acute

When indicated, the ARV regimen used depends on various factors including national policy, institutional policy, level of resources, toxicity and side-effects, daily pill burden, drug contra-indications and compliance. Although a single drug regimen using zidovudine has shown to be effective, multi-drug regimens are now more commonly used in order to cover drug-resistant HIV clones. The use of two drugs must be weighed against cost, toxicity and availability. A third drug may be considered in cases where the background

Two drug regimens include fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) therapy with combination zidovudine-lamivudine or combination tenofoviremtricitabine. A protease inhibitor (PI), usually in combination with ritonavir, which increases PI plasma levels, are usually added if a third drug is necessary. Combination ritonavir-lopinavir, -atazanavir, -darunavir have all been used. All PEP regimens are given

Testing of the source patient, in cases where HIV status is unknown, should include rapid-ELISA testing for HIV as well as testing for HBV (surface antigen - HBsAg) and Hepatitis C virus (HCV). In cases where HIV or HCV infection has occurred within the last 2-4 weeks,

Testing of the exposed patient should be carried out as soon as possible to establish a baseline for follow-up testing. Tests should include a rapid-ELISA for HIV, HBV immunity status (anti-HB antibodies), HBsAg and HCV antibodies. Baseline full blood count, liver enzymes and creatinine should also be obtained to monitor for PEP side-effects and sequelae from hepatitis infection. Screening for other sexually transmitted infections may be

At the minimum, follow-up testing at 6 months should be performed to document HIV negative status. Seroconversion after 6 months in those receiving PEP has been reported but is extremely rare (Ippolito et al., 1999). More intensive follow-up can include HIV and HCV antibody testing at 4-6 weeks, 3 months, and 6 months. Relevant additional testing should

Post-exposure counselling should form an integral part of the PEP protocol. Services should be available to address HIV testing, follow-up testing, ARV treatment, legal issues and compensation claims should they arise. In the event that HIV is contracted, services should be available to address relevant needs. Counselling to address special needs of certain

warranted in cases of sexual assault or in patients with high risk behaviour.

be offered in patients who become symptomatic or experience drug toxicity.

**3.3 Other types of exposure** 

rather than chronic.

**3.4 PEP regimens** 

for 28 days post exposure.

**3.5 Testing, follow-up and counselling** 

HIV or HCV RNA PCR may be indicated.

may be delayed (Johnston & O'Conor, 2005).

prevalence of ARV resistance is greater than 15%.

population sub-groups such as children and victims of sexual assault should also be made available.

#### **4. Management and outcome of HIV positive patients in trauma**

The function of a trauma unit is to stabilise and treat life threatening injuries. It has been shown that HIV alone is not responsible for mortality in trauma but rather the patient's ability to mount an immune response (Allard & Meintjies, 2005). It is also unethical to not treat life-threatening conditions based on a patient's HIV status (Smit 2010). In fact, a number of studies have suggested that HIV positive patients have the same mortality rate as non-infected patients, especially if they are in the early stages of the disease (Smit, 2010).

With regard to surgical outcomes, early views were often pessimistic. It was felt that HIV positive patients were prone to poor wound healing, high post-operative complication rates, a prolonged post-operative period and higher mortality rates. This helped trigger a number of studies investigating the morbidity and complication rates among HIV positive patients both in general and orthopaedic surgery.

Many such studies have produced conflicting results. Duane et al conducted a retrospective study comparing outcomes of HIV positive and HIV negative patients over a 5-year period in the trauma unit. They found no difference in infection rates or overall complications based on CD4+ count alone (Duane et al., 2008). Conversely, Karpelowsky et al showed that in children who were HIV positive or exposed to HIV had increased rates of poor wound healing and breakdown of reconstruction sites (Karpelowsky et al., 2009). Other postoperative complications cited in the study were likely due to non-HIV related factors. For example, a large proportion of the children studied underwent emergency surgery, which is known to have higher rates of post-operative complications since the children tend to be sicker at presentation. This is true for both HIV positive and HIV negative patients. It was also found that up to 79% of children included in the study were undernourished and 36% had other co-morbid diseases including major respiratory and nutritional problems prior to undergoing surgery.

Stawicki et al found that HIV positive patients had both longer length of hospital stay as well as longer length of stay in ICU (Stawicki et al., 2005). They noted however, that HIV positive patients had more pulmonary, infectious and renal complications than the control group and suggested that the mortality of HIV positive patients was likely linked to these co-morbid processes. They also found that HIV positive patients needed greater numbers of surgical procedures but failed to state what the indication for these procedures were. Studies by Morrison et al and Horberg et al found similar findings to Stawicki et al, stating that HIV positive patients had higher post-operative complication rates, especially respiratory complications (Horberg et al., 2006; Morrison et al., 2010).

Studies comparing complication rates in orthopaedic surgeries have been small and only tentative conclusions can be drawn. It has been shown that HIV positive patients with an open fracture (depending on the contamination of the wound) have a higher rate of infection, especially deep infection. There is also a higher rate of late sepsis with procedures that need internal instrumentation, but sepsis may have been avoided with improved medical management including prophylactic antibiotic use before invasive procedures as well as early evaluation and treatment of possible infections (Luck Jr, 1994; Van Aardt, 2010).

AIDS and Trauma 449

Increased Lamivudine levels?

Increased diazepam levels (increased sedation, respireatory depression)

levels

Fentanyl

Increased

ketamine

levels

effects

Increased

(increased sedation,

dilitiazem effects

Increased effects of

Increased effects of

haloperidol effects

Decreased effects of ARVs if recently ingested due to induced vomiting

Possibly increased methylprednisone

midazolam effects

confusion, respireatory depression)

Unknown at present

adjustment necessary for either drug

Do not co-administer Alternative agents: Lorazepam, oxazepam, temazepam

Monitor digoxin levels closely

Titrate dilitiazem to clinical effect

Close monitoring

Monitor and adjust dosage as indicated

Avoid concurrent use

Monitor and adjust dose as necessary

Monitor and adjust lidocaine dose

Monitor while using

Single dose IV midazolam may be used; chronic midazolam administration should be avoided

necessary

reaction Do not co-administer

ARVS? Use with caution

but no dose

Beta-blockers Use with caution

 **Drugs ARV interaction Clinical Effects Management** 

Beta- Blockers Protease inhibitors Increased effects of

Zidovudine, Protease inhibitors,

Digoxin Protease inhibitor Increased digoxin

Protease inhibitors

Protease inhibitors Lamivudine

**<sup>K</sup>**Ketamine NNRTIs Reduced effects of

**<sup>L</sup>**Lidocaine Protease Inhibitors Increased lidocaine

Protease Inhibitors

Protease inhibitors

NNRTIs

NNRTI

Flagyl Protease Inhibitors Disulfiram-like

NNRTI

PIs

Efavirenz

Dilitiazem Efavirenz Decreased

**B** Bactrim Lamivudine

**<sup>F</sup>**Fentanyl NNRTI

**<sup>H</sup>**Haloperidol NNRTIs

**I** Ipecac All

**D** Diazepam

Furosemide

**M** Methyl-

Midazolam

prednisone

The overwhelming conclusion in all these studies however, has been that there is not enough evidence to properly evaluate the relationship between HIV and outcomes after trauma. There is a significant deficiency in research in this particular area and often available data is extrapolated from studies determining the effect of HIV on patients undergoing surgical procedures, either emergency or elective. Unfortunately, researchers face an ethical challenge when testing for HIV in the trauma setting and it is unlikely that sufficiently powered studies with adequate controls are possible in the current medical climate.

## **5. Drug interference between ARVs and commonly used trauma drugs**

Currently available ARVs inhibit the reverse transcriptase and protease enzymes of the human immunodeficiency virus. These drugs are associated with many side-effects and close monitoring is mandatory. It is also important in the trauma setting to recognise a patient's HIV status and the possible concurrent use of ARVs since administration of drugs with potential for interaction may to lead to adverse outcomes.

First-line treatment of HIV involves the use of 2 NRTIs and a non-nucleoside transcriptase inhibitor (NNRTI). Protease inhibitors are used as second line therapies (Town, 2003). Common side effects of NRTIs include lactic acidosis, hypersensitivity reactions, pancreatitis, peripheral neuropathy and hepatic dysfunction (as most are metabolised in the liver). NNRTIs are known inducers or inhibitors of other drugs due to their effect on the hepatic cytochrome systems, and hypersensitivity reactions are common. Protease inhibitors undergo hepatic cytochrome P450 (CYP450) metabolism and many in this class are potent hepatic inhibitors.

Table 3 outlines the drug interactions between NNRTIs or protease inhibitors and other drugs that are dependent on CYP450 metabolism. Many potential interactions of other commonly used drugs remain unknown and have not been included. It is important to take a drug history to ensure that potential side effects can be avoided or closely monitored. In cases where drugs must be administratered, dose adjustment may limit side-effects.


The overwhelming conclusion in all these studies however, has been that there is not enough evidence to properly evaluate the relationship between HIV and outcomes after trauma. There is a significant deficiency in research in this particular area and often available data is extrapolated from studies determining the effect of HIV on patients undergoing surgical procedures, either emergency or elective. Unfortunately, researchers face an ethical challenge when testing for HIV in the trauma setting and it is unlikely that sufficiently powered studies with adequate controls are possible in the current medical

**5. Drug interference between ARVs and commonly used trauma drugs** 

with potential for interaction may to lead to adverse outcomes.

Currently available ARVs inhibit the reverse transcriptase and protease enzymes of the human immunodeficiency virus. These drugs are associated with many side-effects and close monitoring is mandatory. It is also important in the trauma setting to recognise a patient's HIV status and the possible concurrent use of ARVs since administration of drugs

First-line treatment of HIV involves the use of 2 NRTIs and a non-nucleoside transcriptase inhibitor (NNRTI). Protease inhibitors are used as second line therapies (Town, 2003). Common side effects of NRTIs include lactic acidosis, hypersensitivity reactions, pancreatitis, peripheral neuropathy and hepatic dysfunction (as most are metabolised in the liver). NNRTIs are known inducers or inhibitors of other drugs due to their effect on the hepatic cytochrome systems, and hypersensitivity reactions are common. Protease inhibitors undergo hepatic cytochrome P450 (CYP450) metabolism and many in this class are potent

Table 3 outlines the drug interactions between NNRTIs or protease inhibitors and other drugs that are dependent on CYP450 metabolism. Many potential interactions of other commonly used drugs remain unknown and have not been included. It is important to take a drug history to ensure that potential side effects can be avoided or closely monitored. In cases where drugs must be administratered, dose adjustment may limit

> Decreased theophylline effects

Increased

amiodarone effects (hypotension, bradycardia, cardiac arrhythmias

Monitor and adjust theophylline levels as

Monitor and adjust amiodarone as indicated, with reduction of

amiodarone dose as

Should not be coadministered with

indicated

needed

PIs

 **Drugs ARV interaction Clinical Effects Management** 

Protease inhibitors

climate.

hepatic inhibitors.

side-effects.

**A** Aminophylline Protease inhibitors

Amiodarone NNRTI


AIDS and Trauma 451

Celenza, A.; D'Orsogna, L. J.; Tosif, S. H.; Bateman, S. M.; O'Brien, D.; French, M. A. &

*of Medicine*, Vol.331, No.18, (November 1994), pp. 1173-1180, ISSN 0028-4793 Duane, T. M.; Sekel, S.; Wolfe, L. G.; Malhotra, A. K.; Aboutanos, M. B. & Ivatury, R. R.

Horberg, M. A.; Hurley, L. B.; Klein, D. B.; Follansbee, S. E.; Quesenberry, C.; Flamm, J. A.;

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Johnston, J.J. & O'Conor, E. (2005). Neddlestick Injuries, Management and Education: A Role

Karpelowsky, J. S.; Leva, S. E.; Kelley, B.; Numanoglu, A.; Rode, H. & Millar, A. J. W. (2009).

Kelen, G.D.; DiGiovanna, T.A.; Celentano, D.D.; Kalainov, D.; Bisson, L.; Junkins, E.; Stein,

Kim, L. E.; Evanoff, B. A.; Parks, R. L.; Jeffe, D. B.; Mutha, S.; Haase, C. & Fraser, V. J. (1999).

Lifson, A. R.; O'Malley, P. M.; Hessol, N.A.; Buchbinder, S.P.; Cannon, L. & Rutherford, G.

Luck Jr., J.V. (1994). Orthopaedic Surgery on the HIV-Positive Patient: Complications and Outcomes. *Instructional Course Lectures*, Vol.43, pp. 543-549, ISSN 0065-6895

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1509-1511, ISSN 0090-0036

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R.; Bey, M.; Shearer, W.; Jacobson, R. L.; Jimenez, E.; O'Neill, E.; Bazin, B.; Delfraissy, J. F.; Culnane, M.; Coombs, R.; Elkins, M.; Moye, J.; Stratton, P. & Balsley, J. (1994). Reduction of Maternal-Infant Transmission of Human Immunodeficiency Virus Type 1 with Zidovudine Treatment. *New England Journal* 

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Compliance with Universal Precautions Among Emergency Department Personnel: Implications for Prevention Programs. *American Journal of Infection Control*, Vol.27,

W. (1990). HIV Seroconversion in Two Homosexual Men After Receptive Oral Intercourse with Ejaculation: Implications for Counseling Concerning Safe Sexual Practices. *American Journal of Public Health*, Vol.80, No.12, (December 1990), pp.


Table 3. Commonly used drugs in the trauma unit and possible complications (McNicholl 2011; University of Cape Town 2003; University of Liverpool 2010)

## **6. Conclusion**

It is likely that trauma units will see an increasing number of HIV positive patients in the years to come. In an area still lacking adequate research, trauma workers need to be diligent to approach the HIV positive patient in the context of their presentation. They must also stay vigilant to protect themselves against transmission. It is hoped that as HIV prevention and treatment improve, HIV patients will no longer represent a unique cohort and their management, and most importantly, their outcomes, will be as good as those without HIV.

## **7. References**


Increased morphine levels (increased sedation and respir-atory depression)

Possible increase in effects of nitroglycerine

Decreased NNRTI and PI levels

Decreased NNRTI and PI levels

Possibly increased

Possible prolongation of effects of succinylcholine

Table 3. Commonly used drugs in the trauma unit and possible complications (McNicholl

It is likely that trauma units will see an increasing number of HIV positive patients in the years to come. In an area still lacking adequate research, trauma workers need to be diligent to approach the HIV positive patient in the context of their presentation. They must also stay vigilant to protect themselves against transmission. It is hoped that as HIV prevention and treatment improve, HIV patients will no longer represent a unique cohort and their management, and most importantly, their outcomes, will be as good as those without HIV.

Allard, D. & Meintjies, G. (2005). HIV and Trauma, In: *Handbook of Trauma for Southern* 

Boily, M.; Baggaley R. F.; Wang L.; Masse, B.; White, R. G.; Hayes, R. J. & Alary M. (2009).

Cardo, D. M.; Culver, D. H.; Ciesielski, C. A.; Srivastava, P. U.; Marcus, R.; Abiteboul, D.;

*Africa*, A. Nicol, (Ed.), pp. 374-380, Oxford University Press, ISBN 978-019-5780-80-

Heterosexual Risk of HIV-1 Infection Per Sexual Act: Systematic Review and Meta-Analysis of Observational Studies. *The Lancet Infectious Diseases*, Vol.9, No.2,

Heptonstall, J.; Ippolito, G.; Lot, F.; McKibben, P. S. & Bell, D. M. (1997). A Case–

Monitor closely when using together

Not known- but monitor for hypotension

Monitor closely in used concurrently for

Avoid combination if

Avoid combination if

Use with caution

side effects

possible

possible

prednisone effects Close monitoring

 **Drugs ARV interaction Clinical Effects Management** 

Protease inhibitors Unknown

Protease inhibitors

Protease inhibitors

Protease Inhibitors

Protease inhibitors

2011; University of Cape Town 2003; University of Liverpool 2010)

Morphine Protease inhibitors

**N** Nitroglycerine Protease inhibitors

**<sup>P</sup>**Phenergan NNRTIs

Phenobarbitol NNRTIs,

Phenytoin NNRTIs

Prednisone NNRTIs

**<sup>S</sup>**Succinylcholine NNRTI

**6. Conclusion** 

**7. References** 

2, Cape Town, South Africa

(February 2009), pp. 118-129, ISSN 1473-3099

Control Study of HIV Seroconversion in Health Care Workers after Percutaneous Exposure. *New England Journal of Medicine*, Vol.337, No.21, (November 1997), pp. 1485-1490, ISSN 0028-4793


**19** 

*Nigeria* 

**Sub-Sahara African** 

**Cutaneous Manifestations of HIV/AIDS in** 

Innocent Ocheyana George1 and Dasetima Dandison Altraide2

*1Department of Paediatrics, University of Port Harcourt Teaching Hospital,Port Harcourt, 2Department of Medicine, University of Port Harcourt Teaching Hospital, Port Harcourt,* 

The burden of skin disease is high in developing countries particularly the sub-Saharan Africa. The HIV/AIDS epidemic does not make it any better. More than 90% of HIV positive patients may develop mucocutaneous problems at one stage of the disease or the other with

The aim is to highlight common cutaneous manifestations of HIV/AIDS in sub-Sahara Africa. A good knowledge of these cutaneous lesions may aid in early diagnosis and

Cutaneous manifestations are common in patients with HIV infection in the sub-Saharan Africa and can be broadly classified into infection/infestation, malignancy, and cutaneous hypersensitivity. It may be the sentinel event that brings the patient to the physician. Majority of HIV-infected patients will have dermatologic problem at some time during their illness. This may provide a more accurate measure of the disease progression than other

Skin disorders are mostly attributable to the alterations in immune function. Some of the skin diseases are unique to HIV infection, while some are really not new diseases (Aftergut and Cockerell , 1999; Olumide, 2002). The later diseases may be more widespread, have an unusual character or a more prolonged course and may be resistant to therapy. The affected individuals have a significantly increased incidence of skin complaints which rises as HIV infection progresses (Wiwanitkit, 2004). In the asymptomatic stage of HIV infection, cutaneous manifestations are non-specific. Common cutaneous disorders present with atypical features for instance, shingles (VZV) may be severe, recurrent, haemorrhagic or affect more than one dermatome; warts may be multiple and large. Seborrhoeic dermatitis, pityrosorum folliculitis, eosinophilic pustulosis and bacilliary angiomatosis are all well recognized. In the later symptomatic stages, in addition to those infections mentioned above, the following should also be remembered: mycobacterium tuberculosis and atypical mycobacteria, candida species; *Trichophyton rubrum, Malassezia furfur*, chronic herpes simplex, florid molluscum contagiosum. Neoplastic processes, especially Kaposi's sarcoma

**1. Introduction** 

significant morbidity and mortality.

make their appearance at this time.

appropriate treatment of HIV infection.

**2. Cutaneous manifestations of HIV/AIDS** 

organs because the skin is much accessible (Johnson, 1999).

	- http://www.hiv-druginteractions.org/PrintableCharts.aspx

http://www.who.int/csr/resources/publications/standardprecautions/en/index. html

## **Cutaneous Manifestations of HIV/AIDS in Sub-Sahara African**

Innocent Ocheyana George1 and Dasetima Dandison Altraide2 *1Department of Paediatrics, University of Port Harcourt Teaching Hospital,Port Harcourt, 2Department of Medicine, University of Port Harcourt Teaching Hospital, Port Harcourt, Nigeria* 

## **1. Introduction**

452 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Makwana, N. & Riordan, F. A. (2005). Prospective Study of Community Needlestick Injuries. *Archives of Disease in* Childhood, Vol.90, No.5, (May 2005), pp. 523-524, ISSN 1468-2044 Martin, L. N.; Murphy-Corb, M.; Soike, K. F.; Davison-Fairburn, B. & Baskin, G. B. (1993). Effects

*Infectious Diseases*, Vol.168, No.4, (October 1993), pp. 825-835, ISSN 0022-1899 McNicholl, I. R. (Ed.) (2011). Database of Antiretroviral Drug Interaction, In: *HIV InSite,* 

Morrison, C. A.; Wyatt, M. M. & Carrick, M. M. (2010). Effects of Human Immunodeficiency

*Surgical Infections*, Vol.11, No.1, (February 2010) pp. 41-47, ISSN 1557-8674 Murray, C. J. L. & Lopez, A. D. (1997). Global Mortality, Disability, and the Contribution of

Rozenbaum, W.; Gharakhanian, S.; Duval, C. E. & Coulard, J. P. (1988). HIV Transmission By Oral Sex. *The Lancet*, Vol.331, No.8599, (June 1988), pp. 1395-1395, ISSN 0140-6736 Smit, S. (2010). Guidelines For Surgery in the HIV Patient. *CME*, Vol.28, No.8, (August 2010)

Sperling, R. S.; Shapiro, D.; Coombs, R. W.; Todd, J. A.; Herman, S. A.; McSherry, G. D.;

Stawicki, S. P.; Hoff, W. S.; Hoey, B. A.; Grossman, M. D.; Scoll, B. & Reed 3rd, J. F. (2005).

*The Journal of Trauma*, Vol.58, No.1, (January 2005), pp. 88-93, ISSN 0022-5282 University of Cape Town. (2003). *South African Medical Formulary*, South African Medical

UNAIDS. (2009). Global Facts and Figures, In: *Data and Analysis*, 06.05.2011, Available from

University of Liverpool. (July 2010). HIV Drug Interactions, In: *HIV Drug Interactions*,

Van Aardt, P. (2010). The Impact of HIV/AIDS on Orthopedic Surgery. *CME* Vol.28,

Vaz, K.; McGrowder, D.; Alexander-Lindo, R.; Gordon, L.; Brown, P. & Irving, R. (2010).

WHO. (2007). Standard Precautions in Healthcare, In: *Global Alert and Response*. 06.05.2011,

Knowledge, Awareness and Compliance with Universal Precautions Among Health Care Workers at the University Hospital of the West Indies, Jamaica. *The International Journal of Occupational and Environmental Medicine*, Vol.1, No.1,

http://www.who.int/csr/resources/publications/standardprecautions/en/index.

http://data.unaids.org/pub/GlobalReport/2006/200605-

http://www.hiv-druginteractions.org/PrintableCharts.aspx

(October 2010), pp. 171-181, ISSN 2008-6814

http://hivinsite.ucsf.edu/insite?page=ar-00-02

1997), pp. 1436-1442, ISSN 0140-6736

pp. 356-358

Town, South Africa.

fs\_globalfactsfigures\_en.pdf.

06.05.2011, Available from

(August 2010), pp. 384

Available from

html

of Initiation of 3′-Azido,3′-Deoxythymidine (Zidovudine) Treatment at Different Times after Infection of Rhesus Monkeys with Simian Immunodeficiency Virus. *Journal of* 

*University of California San Francisco*, 06.05.2011, Available from

Virus Status on Trauma Outcomes: A Review of the National Trauma Database.

Risk Factors: Global Burden of Disease Study. *The Lancet*, Vol.349, No.9063 (May

O'Sullivan, M. J.; VanDyke, R. B.; Jimenez, E.; Rouzioux, C.; Flynn, P. M.; Sullivan, J. L.; Spector, S. A.; Diaz, C.; Rooney, J.; Balsley, J.; Gelber, R. D. & Connor, E. M. (1996). Maternal Viral Load, Zidovudine Treatment, and the Risk of Transmission of Human Immunodeficiency Virus Type 1 from Mother to Infant. *New England Journal of Medicine*, Vol.335, No.22, (November 1996), pp. 1621-1629, ISSN 0028-4793

Human Immunodeficiency Virus Infection in Trauma Patients: Where Do We Stand?"

Association: Health and Medical Publishing Group, ISBN 1-875098-39-9 , Cape

The burden of skin disease is high in developing countries particularly the sub-Saharan Africa. The HIV/AIDS epidemic does not make it any better. More than 90% of HIV positive patients may develop mucocutaneous problems at one stage of the disease or the other with significant morbidity and mortality.

The aim is to highlight common cutaneous manifestations of HIV/AIDS in sub-Sahara Africa. A good knowledge of these cutaneous lesions may aid in early diagnosis and appropriate treatment of HIV infection.

## **2. Cutaneous manifestations of HIV/AIDS**

Cutaneous manifestations are common in patients with HIV infection in the sub-Saharan Africa and can be broadly classified into infection/infestation, malignancy, and cutaneous hypersensitivity. It may be the sentinel event that brings the patient to the physician. Majority of HIV-infected patients will have dermatologic problem at some time during their illness. This may provide a more accurate measure of the disease progression than other organs because the skin is much accessible (Johnson, 1999).

Skin disorders are mostly attributable to the alterations in immune function. Some of the skin diseases are unique to HIV infection, while some are really not new diseases (Aftergut and Cockerell , 1999; Olumide, 2002). The later diseases may be more widespread, have an unusual character or a more prolonged course and may be resistant to therapy. The affected individuals have a significantly increased incidence of skin complaints which rises as HIV infection progresses (Wiwanitkit, 2004). In the asymptomatic stage of HIV infection, cutaneous manifestations are non-specific. Common cutaneous disorders present with atypical features for instance, shingles (VZV) may be severe, recurrent, haemorrhagic or affect more than one dermatome; warts may be multiple and large. Seborrhoeic dermatitis, pityrosorum folliculitis, eosinophilic pustulosis and bacilliary angiomatosis are all well recognized. In the later symptomatic stages, in addition to those infections mentioned above, the following should also be remembered: mycobacterium tuberculosis and atypical mycobacteria, candida species; *Trichophyton rubrum, Malassezia furfur*, chronic herpes simplex, florid molluscum contagiosum. Neoplastic processes, especially Kaposi's sarcoma make their appearance at this time.

Cutaneous Manifestations of HIV/AIDS in Sub-Sahara African 455

Unusual courses of syphilis have been reported in HIV infections. Not only may the serological response to *T. pallidum* be impaired but also syphilis may progress much more rapidly to advanced stages than in individuals without HIV. Moreover syphilis in patients with HIV infection may not respond to conventional treatment. Skin signs of syphilis in HIV infected patients are usually similar to that of HIV – negative patients but are often

A severe form of secondary syphilis or lues, 'syphilis maligna' can occur in HIV patients with papular, papulovesicular, pustular and necrotizing lesions which may form thick crusts and painful ulcers accompanying severe systemic symptoms . Tertiary gummata and

Recommended treatment is benzathine penicilin 2.4 million units intramuscularly in a single dose given as 1.2 million units in each buttock. The treatment is repeated in a week. If there is central nervous system involvement 2.4 million units of aqueous penicillin is given intravenously every 4 hours for 10 – 14 days. This is because intramuscular benzathine

Skin infections with *Staph aureus* are quite common in HIV infected patients and the frequency increases with progression of immune-deficiency. Not only is *Staph aureus* the most common bacterial pathogen in HIV infected patients but also a large percentage of patients become chronic carriers. Apart from the types of skin lesions commonly associated with *Staph aureus* in patients without HIV such as folliculitis, impetigo, ecthyma, abscesses and cellulitis, more unusual manifestations such as atypical plaque – like folliculitis,

Botryomycosis is characterized by chronic, Suppurating, granulomatous lesions which may present as inflammatory nodules, discharging ulcers, sinuses and fistulae. The lesions usually solitary can occur in the skin, liver, bones, etc, and on gross examination of the pus, pinhead – sized whitish yellow granules are evident. The granules simply contain a central mass of bacteria surrounded by a capsule and can be demonstrated on biopsy or smear of the purulent focus. The capsule is usually periodic – Acid – Schiff (PAS) positive. Botryomycosis is caused by bacteria with *Staph aureus* usually the major causal agent and *Pseudomonas aeruginosa* ranking second in frequency. The therapy of choice is surgical

These angioma-like lesions may affect skin, mucosal surfaces and internal organs, Cutaneous lesions typically begin as tiny pinpoint papules, resembling Campbel de Morgan sports, often in large numbers and very widespread. They enlarge rapidly both outwards and inwards, looking like pyogenic granulomas and subcutaneous nodules. They may resemble some forms of AIDS-related Kaposi's sarcoma (and indeed the two may coexist but can generally be distinguished by their faster growth, bright red color and rounder shape, with no elongation along skin crease). If injured, lesions bleed profusely. Visceral lesions may occur and deaths from laryngeal obstruction and disseminated intravascular obstruction are recorded. Bacillary angiomatosis has been seen mainly in HIV disease, but also in other immunodeficient patients and rarely in the otherwise healthy. It is caused by *Bartonella henselae* or occassional *B. quintana*, argyrophilic bacilli. Confirmation of diagnosis

pyomyositis or botryomycosis are frequently encountered during HIV diseases.

extensive and atypical.

**2.3 Staphylococcus aureus** 

excision in conjunction with antibiotics.

**2.4 Bacillary angiomatosis** 

neurosyphilis also appear more common.

penicillin does not give therapeutic levels in the CSF.

## **2.1 Mycobacteria**

These organisms are important causes of systemic infection in HIV disease, but cutaneous lesions have also been recognized, both direct infection and papulonecrotic tuberculide. Cutaneous lesions of mycobacterium avium complex (MAC) include nodules (Fig 1), ulcerations, pustules abscesses, folliculitis and lymph adenitis. Cutaneous lesions of mycobacterium tuberculosis (TB) include scrofuloderma, papules, vesicles, necrotic ulcerations, subcutaneous nodules and pustules. Bacillus calmette – Guerin (BCG) vaccine may cause local and systemic infection in HIV patients especially after signs of defective immunity have appeared, it is regarded as contra-indicated except for children as yet asymptomatic in areas of high risk for tuberculosis.

Fig. 1. Cutaneous nodule of Tuberculosis in HIV

The treatment of mycobacterium tuberculosis is the conventional DOTS using rifampicin, isonazid, ethambutol and pyrazinamide. It is recommended that for MAC treatment regimen should include at least 2 agents, with ethambutol being one of the agents.

#### **2.2 Syphilis**

Syphilis is a sexually transmitted disease due to infection with *Treponema pallidum*. Both syphilis and HIV infection are sexually transmitted diseases and so could occur concurrently (Olumide; 2002).

Unusual courses of syphilis have been reported in HIV infections. Not only may the serological response to *T. pallidum* be impaired but also syphilis may progress much more rapidly to advanced stages than in individuals without HIV. Moreover syphilis in patients with HIV infection may not respond to conventional treatment. Skin signs of syphilis in HIV infected patients are usually similar to that of HIV – negative patients but are often extensive and atypical.

A severe form of secondary syphilis or lues, 'syphilis maligna' can occur in HIV patients with papular, papulovesicular, pustular and necrotizing lesions which may form thick crusts and painful ulcers accompanying severe systemic symptoms . Tertiary gummata and neurosyphilis also appear more common.

Recommended treatment is benzathine penicilin 2.4 million units intramuscularly in a single dose given as 1.2 million units in each buttock. The treatment is repeated in a week. If there is central nervous system involvement 2.4 million units of aqueous penicillin is given intravenously every 4 hours for 10 – 14 days. This is because intramuscular benzathine penicillin does not give therapeutic levels in the CSF.

#### **2.3 Staphylococcus aureus**

454 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

These organisms are important causes of systemic infection in HIV disease, but cutaneous lesions have also been recognized, both direct infection and papulonecrotic tuberculide. Cutaneous lesions of mycobacterium avium complex (MAC) include nodules (Fig 1), ulcerations, pustules abscesses, folliculitis and lymph adenitis. Cutaneous lesions of mycobacterium tuberculosis (TB) include scrofuloderma, papules, vesicles, necrotic ulcerations, subcutaneous nodules and pustules. Bacillus calmette – Guerin (BCG) vaccine may cause local and systemic infection in HIV patients especially after signs of defective immunity have appeared, it is regarded as contra-indicated except for children as yet

The treatment of mycobacterium tuberculosis is the conventional DOTS using rifampicin, isonazid, ethambutol and pyrazinamide. It is recommended that for MAC treatment

Syphilis is a sexually transmitted disease due to infection with *Treponema pallidum*. Both syphilis and HIV infection are sexually transmitted diseases and so could occur

regimen should include at least 2 agents, with ethambutol being one of the agents.

**2.1 Mycobacteria** 

asymptomatic in areas of high risk for tuberculosis.

Fig. 1. Cutaneous nodule of Tuberculosis in HIV

**2.2 Syphilis** 

concurrently (Olumide; 2002).

Skin infections with *Staph aureus* are quite common in HIV infected patients and the frequency increases with progression of immune-deficiency. Not only is *Staph aureus* the most common bacterial pathogen in HIV infected patients but also a large percentage of patients become chronic carriers. Apart from the types of skin lesions commonly associated with *Staph aureus* in patients without HIV such as folliculitis, impetigo, ecthyma, abscesses and cellulitis, more unusual manifestations such as atypical plaque – like folliculitis, pyomyositis or botryomycosis are frequently encountered during HIV diseases.

Botryomycosis is characterized by chronic, Suppurating, granulomatous lesions which may present as inflammatory nodules, discharging ulcers, sinuses and fistulae. The lesions usually solitary can occur in the skin, liver, bones, etc, and on gross examination of the pus, pinhead – sized whitish yellow granules are evident. The granules simply contain a central mass of bacteria surrounded by a capsule and can be demonstrated on biopsy or smear of the purulent focus. The capsule is usually periodic – Acid – Schiff (PAS) positive. Botryomycosis is caused by bacteria with *Staph aureus* usually the major causal agent and *Pseudomonas aeruginosa* ranking second in frequency. The therapy of choice is surgical excision in conjunction with antibiotics.

#### **2.4 Bacillary angiomatosis**

These angioma-like lesions may affect skin, mucosal surfaces and internal organs, Cutaneous lesions typically begin as tiny pinpoint papules, resembling Campbel de Morgan sports, often in large numbers and very widespread. They enlarge rapidly both outwards and inwards, looking like pyogenic granulomas and subcutaneous nodules. They may resemble some forms of AIDS-related Kaposi's sarcoma (and indeed the two may coexist but can generally be distinguished by their faster growth, bright red color and rounder shape, with no elongation along skin crease). If injured, lesions bleed profusely. Visceral lesions may occur and deaths from laryngeal obstruction and disseminated intravascular obstruction are recorded. Bacillary angiomatosis has been seen mainly in HIV disease, but also in other immunodeficient patients and rarely in the otherwise healthy. It is caused by *Bartonella henselae* or occassional *B. quintana*, argyrophilic bacilli. Confirmation of diagnosis

Cutaneous Manifestations of HIV/AIDS in Sub-Sahara African 457

persons. 8-13% of patients with AIDS have experienced at least one episode of herpes zoster and recurrent herpes zoster is observed more frequently in HIV-1 seropositive patients than in sero-negative individuals. However, herpes zoster is not a reliable sign of profound immunodeficiency because it can occur at any state of HIV infection. Clinical manifestations range from an uneventful vesicular eruption in a dermatomal pattern, similar to that in non-HIV-1 infected individuals, to severe haemorrhagic and necrotic lesions that may extend over several dermatomes, followed by cutaneous dissemination. In contrast to the high frequency of systemic dissemination associated with primary VZV infection, dissemination is infrequent in conventional herpes zoster. Nevertheless, chronic verrucous or ecthymatous VZV infections may persist for

Poxvirus infection causing Molluscum contagiosum is ordinarily self-limited in immunocompetent individuals, occurring mainly in children. However, during HIV-1 disease molluscum contagiosum is seen in up to 20% of patients, and is usually associated

Characteristics lesions, which appear commonly on the face and in the genital regions, include skin-coloured umbilicated papules with one or more central hyperkeratotic pores. Individual lesions can grow to more than 1 cm in size and, if located on the face, may be disfiguring. If multiple nodular lesions become confluent they are difficult to treat, commonly recurring after conventional local destruction. The differential diagnosis includes basal-cell carcinoma, common warts, keratacanthoma, atypical mycobacterial infections, and, especially, cutaneous manifestations of systemic infections with *Cyptococcus neoformans*, *Histoplasma capsulatum*, or *Penicillium marneffei*. Since differentiation of molluscum contagiosum from these important fungal infections is often uncertain clinically,

**Human Papilloma virus**- Common warts may occur in unusual locations, with unusual severity, and with high frequency in HIV-1 infected patients but they are seldom serious. With respect to genital involvement in women (Fig2), both frequency of human papilloma virus (HPV) infection and the progression of HPV-associated cervical lesions correlate with the level of immune suppression. Moderate to severe cervical dysplasia and carcinoma-insitu are part of category B symptomatic conditions in the revised classification system for HIV infection. In men, the rate of anogenital HPV infection is high in HIV-1 sero-positive and sero-negative homosexuals. However, as for women, HPV prevalence and symptoms

Tinea infections of varying sites do occur and may be chronic and widespread in HIV positive patient (Fig 3). The overall frequency is higher in non-infected control population. Nail involvement is common and can cause diffuse whitening. Proximal nail whitening or proximal subungual onychomycosis, unusual in immunocompetent individuals is regarded

Treatment is standard with the use of topical and systemic anti-fungal agents.

months.

**2.9 Molluscum contagiosum** 

with established immunodeficiency.

histopathological confirmation should always be sought.

by some as characteristic of HIV-associated nail infection.

tend to increase with disease progression.

**3. Fungal infections** 

**3.1 Dematophyte Infection** 

is by recognition of histological features or by PCR amplification of the organism's nucleic acid obtained from biopsy tissue.

Treatment – the recommended treatment for bacillary angiomatosis is erythromycin 500mg qds. If the patient has severe disease or can not tolerate orally, intravenous erythromycin can be given. Alternative to erythromycin include doxycline 100mg bid; minocycline 100mg bid or tetracycline 50mg qid, treatment should continue for 8-12 weeks and in case of systematic disease 3-4 months.

## **2.5 Demodicidosis**

Folliculitis due to *Demodex folliculorum* may cause an itchy papular eruption in HIV patients. Affected areas include head and neck, and trunk and arms Microscopy of smears or scrapings, or histology confirms the presence of numerous mites. There is a rapid response to topical treatment with insecticides such as y-benzene hexachloride.

## **2.6 Viral infection**

Viruses other than HIV-1 are common pathogens in HIV-1 disease and are probably important infectious co-factors for disease progression (Sterling and Kurtz, 1998). These opportunistic infections range from relatively benign disorder such as cosmetically disfiguring molluscum contagiosum to severe infections of the skin and mucus membranes such as ulcerating herpes simplex and oral hairy leukoplakia, which is attributed to Epstein Barr virus infection.

## **2.7 Herpes simplex**

Chronic painful, non-healing ulcers found in herpes simplex virus (HDV) infections are commonly located at the junction between skin and mucous membranes, mainly in the perioral and perianal areas. Chronic ulcerating herpes simplex must first be differentiated from conventional recurrent HSV infection. Whereas the latter can occur at any stage of HIV-1 disease and is clinically and morphologically indistinguishable from the blistering eruptions commonly seen in patients without HIV-1 infection, the former heralds profound immunodeficiency. Chronic ulcerating herpes simplex is one of the AIDS-defining opportunistic infection according to Centers for Disease Control and Prevention. Systemic antiviral treatment is essential since these lesions show no tendency to resolve spontaneously. The differential diagnosis, which depends on the location of the lesions, includes pyoderma gangrenosum, bacterial and fungal infection, and cutaneous manifestation of lymphomas.

The recommended treatment for primary or recurrent HSV injection is oral acyclovir. In severe infections, intravenous acyclovir can be used. Other alternatives include famciclovir and fascarnet.

#### **2.8 Varicella-zoster**

Clinical manifestation of infection with the varicella-zoster virus (VZV), another member of the herpes virus family, depends largely on the age of the patient. Primary VZV infection in HIV-1 infected children is often severe, with dissemination and pneumoina, encephalitis, or pancreatitis. As with adult patients, epidemiological studies indicate that the frequency of reactivation of latent VZV, leading to herpes zoster, is greatly increased, with a relative risk in one study of 16.9 for HIV-1 infected person over non-infected persons. 8-13% of patients with AIDS have experienced at least one episode of herpes zoster and recurrent herpes zoster is observed more frequently in HIV-1 seropositive patients than in sero-negative individuals. However, herpes zoster is not a reliable sign of profound immunodeficiency because it can occur at any state of HIV infection. Clinical manifestations range from an uneventful vesicular eruption in a dermatomal pattern, similar to that in non-HIV-1 infected individuals, to severe haemorrhagic and necrotic lesions that may extend over several dermatomes, followed by cutaneous dissemination. In contrast to the high frequency of systemic dissemination associated with primary VZV infection, dissemination is infrequent in conventional herpes zoster. Nevertheless, chronic verrucous or ecthymatous VZV infections may persist for months.

#### **2.9 Molluscum contagiosum**

456 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

is by recognition of histological features or by PCR amplification of the organism's nucleic

Treatment – the recommended treatment for bacillary angiomatosis is erythromycin 500mg qds. If the patient has severe disease or can not tolerate orally, intravenous erythromycin can be given. Alternative to erythromycin include doxycline 100mg bid; minocycline 100mg bid or tetracycline 50mg qid, treatment should continue for 8-12 weeks and in case of

Folliculitis due to *Demodex folliculorum* may cause an itchy papular eruption in HIV patients. Affected areas include head and neck, and trunk and arms Microscopy of smears or scrapings, or histology confirms the presence of numerous mites. There is a rapid response

Viruses other than HIV-1 are common pathogens in HIV-1 disease and are probably important infectious co-factors for disease progression (Sterling and Kurtz, 1998). These opportunistic infections range from relatively benign disorder such as cosmetically disfiguring molluscum contagiosum to severe infections of the skin and mucus membranes such as ulcerating herpes simplex and oral hairy leukoplakia, which is attributed to Epstein

Chronic painful, non-healing ulcers found in herpes simplex virus (HDV) infections are commonly located at the junction between skin and mucous membranes, mainly in the perioral and perianal areas. Chronic ulcerating herpes simplex must first be differentiated from conventional recurrent HSV infection. Whereas the latter can occur at any stage of HIV-1 disease and is clinically and morphologically indistinguishable from the blistering eruptions commonly seen in patients without HIV-1 infection, the former heralds profound immunodeficiency. Chronic ulcerating herpes simplex is one of the AIDS-defining opportunistic infection according to Centers for Disease Control and Prevention. Systemic antiviral treatment is essential since these lesions show no tendency to resolve spontaneously. The differential diagnosis, which depends on the location of the lesions, includes pyoderma gangrenosum, bacterial and fungal infection, and cutaneous

The recommended treatment for primary or recurrent HSV injection is oral acyclovir. In severe infections, intravenous acyclovir can be used. Other alternatives include famciclovir

Clinical manifestation of infection with the varicella-zoster virus (VZV), another member of the herpes virus family, depends largely on the age of the patient. Primary VZV infection in HIV-1 infected children is often severe, with dissemination and pneumoina, encephalitis, or pancreatitis. As with adult patients, epidemiological studies indicate that the frequency of reactivation of latent VZV, leading to herpes zoster, is greatly increased, with a relative risk in one study of 16.9 for HIV-1 infected person over non-infected

to topical treatment with insecticides such as y-benzene hexachloride.

acid obtained from biopsy tissue.

systematic disease 3-4 months.

**2.5 Demodicidosis** 

**2.6 Viral infection** 

Barr virus infection.

**2.7 Herpes simplex** 

manifestation of lymphomas.

and fascarnet.

**2.8 Varicella-zoster** 

Poxvirus infection causing Molluscum contagiosum is ordinarily self-limited in immunocompetent individuals, occurring mainly in children. However, during HIV-1 disease molluscum contagiosum is seen in up to 20% of patients, and is usually associated with established immunodeficiency.

Characteristics lesions, which appear commonly on the face and in the genital regions, include skin-coloured umbilicated papules with one or more central hyperkeratotic pores. Individual lesions can grow to more than 1 cm in size and, if located on the face, may be disfiguring. If multiple nodular lesions become confluent they are difficult to treat, commonly recurring after conventional local destruction. The differential diagnosis includes basal-cell carcinoma, common warts, keratacanthoma, atypical mycobacterial infections, and, especially, cutaneous manifestations of systemic infections with *Cyptococcus neoformans*, *Histoplasma capsulatum*, or *Penicillium marneffei*. Since differentiation of molluscum contagiosum from these important fungal infections is often uncertain clinically, histopathological confirmation should always be sought.

**Human Papilloma virus**- Common warts may occur in unusual locations, with unusual severity, and with high frequency in HIV-1 infected patients but they are seldom serious. With respect to genital involvement in women (Fig2), both frequency of human papilloma virus (HPV) infection and the progression of HPV-associated cervical lesions correlate with the level of immune suppression. Moderate to severe cervical dysplasia and carcinoma-insitu are part of category B symptomatic conditions in the revised classification system for HIV infection. In men, the rate of anogenital HPV infection is high in HIV-1 sero-positive and sero-negative homosexuals. However, as for women, HPV prevalence and symptoms tend to increase with disease progression.

## **3. Fungal infections**

#### **3.1 Dematophyte Infection**

Tinea infections of varying sites do occur and may be chronic and widespread in HIV positive patient (Fig 3). The overall frequency is higher in non-infected control population. Nail involvement is common and can cause diffuse whitening. Proximal nail whitening or proximal subungual onychomycosis, unusual in immunocompetent individuals is regarded by some as characteristic of HIV-associated nail infection.

Treatment is standard with the use of topical and systemic anti-fungal agents.

Cutaneous Manifestations of HIV/AIDS in Sub-Sahara African 459

This is common in all stages of HIV infection affecting the skin, nail, genitals and oral mucosa.Cutaneous lesions are often located in the intertriginous areas/ skin folds as highly pruritic inflamed areas with satellite lesions and/or follicular pustules. In addition to HIV, other risk factors are diabetes mellitus, obesity, malignancy, use of immunosuppressive therapy and cytotoxic drugs, use of systemic and topical corticosteroids and antibiotic therapy, hot humid environment, occlusion e.g. diapers, casts and dressings, blood malignancies and neutropenia and skin disease which disturb the cutaneous barrier e.g.

Nail lesions affect the proximal nail fold and nail plate. Nail fold lesions (paronychia) present as painful, erythematous swellings which may discharge purulent material. Genital lesions present as pruritic vulvo-vaginitis with discharge of a creamy white material. There may be involvement of the perineum with erythematous and satellite lesions. In severe cases, the oral mucosa may show extensive white plagues or widespread erythema, and

Standard topical therapy will suffice but in severe cases and nail involvement systemic therapy may be needed. Fluconazole (50mg daily) has a higher cure rate than ketoconazole (20mg daily) and intermittent administration of fluconazole (150mg) also proved effective.

Persons infected with Human Immunodeficiency Virus (HIV) are at higher risk for the development of certain types of cancers. The AIDS was first reported in the summer of 1981 in Los Angeles among young homosexuals who were observed to have had a disseminated

Kaposi's sarcoma (KS), the most common tumor in patients with AIDS, is strongly associated with immunosuppression (Schwartz et al., 2008). KS is a vascular neoplasm affecting the endothelial cell and that affects the skin, and the mucosa, less commonly involves other organs like the gastrointestinal tracts, lungs and lymph nodes. KS can occur in HIV-negative patients where it typically has a chronic indolent course. In HIV infected

Epidemiological data suggest that the cause is a sexually transmitted infectious agent and this has recently been supported by the finding of herpes virus nucleic acid in Kaposi's sarcoma lesions (Schwartz et al., 2008) .However, this virus called Kaposi's sarcoma associated herpes virus (or human herpes virus type 8) has also been detected in classical KS; Gut lymphomas and other skin lesions of AIDS patients. The role of HHV-8 in the

The mucocutaneous lesions of KS are usually asymptomatic vary from the earliest pink macules to the thickened papules and plaques which later develop to nodules. Diffuse lesions may manifest mainly as oedema. The lesions initially may appear benign-looking and may be misdiagnosed as pigmented naevi, Spitz naevi, dermatofibroma, bruises, pyogenic granulomas, malignant melanoma, ecchymosis, molluscum contagiosum or lichen planus. The lesions may appear any where on the skin but the tip of the nose and the hard palate are common sites. Lesions in the feet may occasionally become warty. Lesions may

patients KS has a more aggressive course and may have systemic involvement.

esophageal involvement may give rise to dysphagia and retrosternal pain.

type of Kaposi's sarcoma and pneumocystis carini infection.

pathogenesis of Kaposi's sarcoma is yet to be clearly defined.

develop at the site of trauma (Kobner Phenomenon).

**3.2 Candidiasis** 

psoriasis and contact dermatitis.

**3.3 Cutaneous malignancies** 

**3.4 Kaposi's sarcoma** 

Fig. 2. Genital warts in HIV

Fig. 3. Extensive tinea cruris and corporis

## **3.2 Candidiasis**

458 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Fig. 2. Genital warts in HIV

Fig. 3. Extensive tinea cruris and corporis

This is common in all stages of HIV infection affecting the skin, nail, genitals and oral mucosa.Cutaneous lesions are often located in the intertriginous areas/ skin folds as highly pruritic inflamed areas with satellite lesions and/or follicular pustules. In addition to HIV, other risk factors are diabetes mellitus, obesity, malignancy, use of immunosuppressive therapy and cytotoxic drugs, use of systemic and topical corticosteroids and antibiotic therapy, hot humid environment, occlusion e.g. diapers, casts and dressings, blood malignancies and neutropenia and skin disease which disturb the cutaneous barrier e.g. psoriasis and contact dermatitis.

Nail lesions affect the proximal nail fold and nail plate. Nail fold lesions (paronychia) present as painful, erythematous swellings which may discharge purulent material. Genital lesions present as pruritic vulvo-vaginitis with discharge of a creamy white material. There may be involvement of the perineum with erythematous and satellite lesions. In severe cases, the oral mucosa may show extensive white plagues or widespread erythema, and esophageal involvement may give rise to dysphagia and retrosternal pain.

Standard topical therapy will suffice but in severe cases and nail involvement systemic therapy may be needed. Fluconazole (50mg daily) has a higher cure rate than ketoconazole (20mg daily) and intermittent administration of fluconazole (150mg) also proved effective.

#### **3.3 Cutaneous malignancies**

Persons infected with Human Immunodeficiency Virus (HIV) are at higher risk for the development of certain types of cancers. The AIDS was first reported in the summer of 1981 in Los Angeles among young homosexuals who were observed to have had a disseminated type of Kaposi's sarcoma and pneumocystis carini infection.

#### **3.4 Kaposi's sarcoma**

Kaposi's sarcoma (KS), the most common tumor in patients with AIDS, is strongly associated with immunosuppression (Schwartz et al., 2008). KS is a vascular neoplasm affecting the endothelial cell and that affects the skin, and the mucosa, less commonly involves other organs like the gastrointestinal tracts, lungs and lymph nodes. KS can occur in HIV-negative patients where it typically has a chronic indolent course. In HIV infected patients KS has a more aggressive course and may have systemic involvement.

Epidemiological data suggest that the cause is a sexually transmitted infectious agent and this has recently been supported by the finding of herpes virus nucleic acid in Kaposi's sarcoma lesions (Schwartz et al., 2008) .However, this virus called Kaposi's sarcoma associated herpes virus (or human herpes virus type 8) has also been detected in classical KS; Gut lymphomas and other skin lesions of AIDS patients. The role of HHV-8 in the pathogenesis of Kaposi's sarcoma is yet to be clearly defined.

The mucocutaneous lesions of KS are usually asymptomatic vary from the earliest pink macules to the thickened papules and plaques which later develop to nodules. Diffuse lesions may manifest mainly as oedema. The lesions initially may appear benign-looking and may be misdiagnosed as pigmented naevi, Spitz naevi, dermatofibroma, bruises, pyogenic granulomas, malignant melanoma, ecchymosis, molluscum contagiosum or lichen planus. The lesions may appear any where on the skin but the tip of the nose and the hard palate are common sites. Lesions in the feet may occasionally become warty. Lesions may develop at the site of trauma (Kobner Phenomenon).

Cutaneous Manifestations of HIV/AIDS in Sub-Sahara African 461

the course of the illness. The cause of the lesion is not known but most people think that it is

Treatment with antihistamines, phototherapy and photochemotherapy may be used but of

Seborrheic dermatitis (SD) is a chronic papulosquamous disorder characterized by distinctive morphology (red, sharply marginated lesion covered with greasy looking scales and hypopigmentation which is usually seen in dark skinned people) and a distinctive distribution in areas with a rich supply of sebaceous glands namely the scalp, forehead, eyebrows, lashline, nasolabial folds, beard and post auricular skin. Other areas include

The prevalence of seborrheic dermatitis is around 1-3% in the general population and 40-

The aetiology of SD is unclear. It has been suggested that the yeast *Pityrosporum ovale* is important in the aetiology of SD. Clinically, a wide spectrum of lesions exist but characteristic distribution; hypopigmented nummular patches which may coalesce to form polycyclic lesion on the back and presternal area; diffuse erythematous hypopigmented macules involving the scalp margins and butterfly areas of the face and trunk; scalp and

presternal region, inter scapular area, axillae, groin and gluteal crease.

a hypersensitivity reaction to antigens or a direct effect of the HIV.

Fig. 4. Pruritic papular of HIV infection

**3.9 Seborrheic Dermatitis** 

83% in HIV/AIDS patients.

limited success.Patient education as to the cause of the illness is important.

Unlike the metastatic behavior of other malignant tumors, KS is a multifocal neoplasm in which each lesion seems to develop de novo from endothelial cells that line lymphatic or blood vessels into skin or visceral.

Progression of lesions depends upon the immune status. If the CD4+ cell count rises, either with or without treatment lesion may regress at least temporary.

**Treatment:** This is not curative. Palliative therapy is indicated for lesions that are disfiguring, causing pains or with systemic symptoms.

Local therapy would include:


Systemic therapy would include the following:


#### **3.5 Other malignancies**

AIDS-related lymphomas are not uncommon and are usually high grade of the immunoblastic or small-cell type.

#### **3.6 Cutaneous hypersensitivity**

This is a group of eruptions in patients with HIV disease. The pathophysiology of some of them is not well defined and therapeutic responses have been disappointing. However, some explanations have been advised based on some immunologic findings. Monocytes, macrophages, epidermal langerhans cells and dendritic cells of the dermis have CD4 antigen and are potential targets for infection by HIV. The decrease in langerhans cells as in AIDS may lead to altered cell mediated immunity.

#### **3.7 Xeroderma**

Dry skin is common in HIV/AIDS especially if chronic diarrhea is a masked feature and may be related to malabsorption. There is associated prutitus. In more severe cases with changes you have acquired ichthyosis. Icythuosis is a disorder of keratinization characterized clinically by dry scaly skin. It should be noted that acquired ichthyosis can also be found in lymphomas, lepromatous leprosy and sarcoidosis which are conditions with reduced immunity. Treatment is the use of emollients.

#### **3.8 Pruritic Papular Eruption (PPE) of HIV**

PPE of HIV is a unique manifestation of HIV which has not been seen in seronegative patients (Eisman, 2006, Machtinger et al., 2004). Clinically, the lesions are red or skin coloured papules that are symmetrically disseminated in the trunk, buttocks and extremities (Fig 4). The lesions are extremely pruritic. The lesions heal with post inflammatory hypopigmentation with new hyperpigmented lesions. The eruptions wax and wane during

Unlike the metastatic behavior of other malignant tumors, KS is a multifocal neoplasm in which each lesion seems to develop de novo from endothelial cells that line lymphatic or

Progression of lesions depends upon the immune status. If the CD4+ cell count rises, either

**Treatment:** This is not curative. Palliative therapy is indicated for lesions that are

b. Biology response modifiers which include IFN-a, interleukin-2 and intravenous

AIDS-related lymphomas are not uncommon and are usually high grade of the

This is a group of eruptions in patients with HIV disease. The pathophysiology of some of them is not well defined and therapeutic responses have been disappointing. However, some explanations have been advised based on some immunologic findings. Monocytes, macrophages, epidermal langerhans cells and dendritic cells of the dermis have CD4 antigen and are potential targets for infection by HIV. The decrease in langerhans cells as in AIDS

Dry skin is common in HIV/AIDS especially if chronic diarrhea is a masked feature and may be related to malabsorption. There is associated prutitus. In more severe cases with changes you have acquired ichthyosis. Icythuosis is a disorder of keratinization characterized clinically by dry scaly skin. It should be noted that acquired ichthyosis can also be found in lymphomas, lepromatous leprosy and sarcoidosis which are conditions

PPE of HIV is a unique manifestation of HIV which has not been seen in seronegative patients (Eisman, 2006, Machtinger et al., 2004). Clinically, the lesions are red or skin coloured papules that are symmetrically disseminated in the trunk, buttocks and extremities (Fig 4). The lesions are extremely pruritic. The lesions heal with post inflammatory hypopigmentation with new hyperpigmented lesions. The eruptions wax and wane during

a. Surgery for large lesions. This would include the use of excision and laser.

with or without treatment lesion may regress at least temporary.

a. Chemotherapy including vinblastine, bleomycin, Doxorubicin

disfiguring, causing pains or with systemic symptoms.

c. Intralesional chemotherapy using vinblastine d. The tumor is sensitive to radiotherapy. Systemic therapy would include the following:

blood vessels into skin or visceral.

Local therapy would include:

immunoglobulin c. Antiretroviral therapy d. Photodynamic therapy.

**3.5 Other malignancies** 

**3.7 Xeroderma** 

immunoblastic or small-cell type.

**3.6 Cutaneous hypersensitivity** 

may lead to altered cell mediated immunity.

**3.8 Pruritic Papular Eruption (PPE) of HIV** 

with reduced immunity. Treatment is the use of emollients.

b. Cryosurgery

the course of the illness. The cause of the lesion is not known but most people think that it is a hypersensitivity reaction to antigens or a direct effect of the HIV.

Treatment with antihistamines, phototherapy and photochemotherapy may be used but of limited success.Patient education as to the cause of the illness is important.

Fig. 4. Pruritic papular of HIV infection

### **3.9 Seborrheic Dermatitis**

Seborrheic dermatitis (SD) is a chronic papulosquamous disorder characterized by distinctive morphology (red, sharply marginated lesion covered with greasy looking scales and hypopigmentation which is usually seen in dark skinned people) and a distinctive distribution in areas with a rich supply of sebaceous glands namely the scalp, forehead, eyebrows, lashline, nasolabial folds, beard and post auricular skin. Other areas include presternal region, inter scapular area, axillae, groin and gluteal crease.

The prevalence of seborrheic dermatitis is around 1-3% in the general population and 40- 83% in HIV/AIDS patients.

The aetiology of SD is unclear. It has been suggested that the yeast *Pityrosporum ovale* is important in the aetiology of SD. Clinically, a wide spectrum of lesions exist but characteristic distribution; hypopigmented nummular patches which may coalesce to form polycyclic lesion on the back and presternal area; diffuse erythematous hypopigmented macules involving the scalp margins and butterfly areas of the face and trunk; scalp and

**20** 

*Canada* 

**Benign and Malignant Lymphoproliferative** 

Owing to the striking lymphotropsism exhibited by the human immunodeficiency virus, HIV/AIDS patients demonstrate a wide breadth of both benign and malignant lymphoproliferative disorders. These disorders span the spectrum from viral lymphadenopathy to lymphocentric opportunistic infections to proliferations of uncertain and frankly malignant potential. This chapter explores a number of the many possible HIV/AIDS associated disorders from the perspective of the lymphoid system. Notably, some of these disorders are themselves AIDS defining illnesses while others are entities known to occur frequently in the HIV/AIDS population but not directly influenced by HIV infection. In most cases, HIV-associated lymphoproliferative disorders are thought to result from an aberrant host immune response in the context of chronic inflammatory stimulation

The human immunodeficiency virus is a member of the lentivirus genus (lenti- , *latin*  "slow"), a group of viruses in the retrovirus family characterized by tropism for immune cells (Norkin, 2010). HIV demonstrates strong affinity for a specific cohort of human T-cells, the CD4 "Helper" T-cell; this is accomplished by means of the viral gp120 protein's strong affinity for the CD4 molecule (Wain-Hobson, 1996). HIV infects cells with CD4 cell-surface receptor molecules, using them to gain entry into the cell (Verani, et al., 2005). In early infection, HIV is widely disseminated by way of its interaction with antigen presenting cells (e.g. Langerhans and dendritic cells) which direct antigen obtained from mucous membranes toward the tissues of the adaptive immune system (namely the lymph nodes); HIV can accomplish this both by means of CD4 receptor binding but also by exploiting the immune response itself by allowing phagocytosis into these antigen presenting cells through either interations with complement or Fc receptors (Verani, et al., 2005). The result is a systemic dissemination of HIV infection to lymphoid tissues (Pantaleo, et al., 1993). Once gained access to the lymphoid tissues of the body, HIV may engage in a latent infection of Tcells by way of viral integration into resting or memory T-cells; these cells may then serve

A number of studies have explored the biological influences that HIV may have on lymphomagenesis. The primary role of the CD4 T-cell is played out in the adaptive immune

**1. Introduction** 

**1.1 Pathogenesis** 

rather than as a direct consequence of HIV infection.

another reservoir of infection (Sierra, et al., 2005).

**Disorders in HIV/AIDS** 

Etienne Mahe and Monalisa Sur *McMaster University, Hamilton, Ontario* 

facial involvement presenting as dandruff and blepharitis; flexural, petaloid and pityrosporum folliculitis.

In Africa, hypopigmentation is a prominent feature which has been explained as a result of dicarboxylic acids produced by malassezia causing competitive inhibition of tyrosinase and perhaps a direct cytotoxic effect on hyperactive melanocytes (Altraide et al., 2010).

Seborrheic dermatitis in HIV/AIDS patients occur in varying severity (Altraide et al; 2010). It is usually characterized by thick micaceous scales and usually hyperkeratotic and inflammatory and more widespread and generalized.

Conclusion: Skin disorders are common in sub-Saharan African and may present with early, severe, unusual and atypical manifestations in the course of HIV infection. Awareness of the varied pattern of these manifestations would help in the early diagnosis and management of HIV infection, which would in turn decrease the morbidity and improve the quality of life of HIV-infected patients.

#### **4. References**


## **Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS**

Etienne Mahe and Monalisa Sur *McMaster University, Hamilton, Ontario Canada* 

## **1. Introduction**

462 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

facial involvement presenting as dandruff and blepharitis; flexural, petaloid and

In Africa, hypopigmentation is a prominent feature which has been explained as a result of dicarboxylic acids produced by malassezia causing competitive inhibition of tyrosinase and

Seborrheic dermatitis in HIV/AIDS patients occur in varying severity (Altraide et al; 2010). It is usually characterized by thick micaceous scales and usually hyperkeratotic and

Conclusion: Skin disorders are common in sub-Saharan African and may present with early, severe, unusual and atypical manifestations in the course of HIV infection. Awareness of the varied pattern of these manifestations would help in the early diagnosis and management of HIV infection, which would in turn decrease the morbidity and improve the quality of life of

Aftergut K., Cockerell CJ (1999). Update on the cutaneous manifestations of HIV infection. Clinical and pathologic features. Dermatol. Clin. Vol.17, No.3, pp. 445-71. Altraide DD, Olumide YM, Mohammed TT (2010). Predictive value of seborrheic dermatitis for HIV infection in Lagos Nigeria. Port Harcourt Medical Journal. 5(1): 30-36.

Johnson RA (1999). Cutaneous manifestations of human immunodeficiency virus disease.In:

Machtinger EL, Van Beek M, Furmanski L, et al(2004).Etiology of pruritic papular eruption

Olumide YM (2002). A self–instructed textbook of acquired immune deficiency syndrome

Schwartz RA, Micali G, Nasca MR, Scuderi L (2008). Kaposi sarcoma: a continuing

Sterling JC, Kurtz JB. Viral infections: In. Champion RH, Burton JL, Burns DA, Breathnach

Tschachler E, Bergstresser PR, Stingl G(1996). HIV-related skin diseases. *Lancet* Vol. 348,

Wiwanitkit V. Prevalence of dermatological disorders in Thai HIV-infected patients

Friedberg IM, Eisen AZ, Wolf K, *et al*., eds . *Fitzpatrick's Dermatology.* McGraw- Hill,

(HIV/AIDS) for medical students, resident doctors and medical practioners.

SM eds Rookwdkinson/Ebling, Textbook of dermatology 6th edition. London 1998:

correlated with different CD4 lymphocyte count statuses: a note on 120 cases. *Int* 

Eisman S (2006). Pruritic papular eruption in HIV. *Dermatol. Clin*. Vol.24, pp.449-457.

with HIV infection in Uganda. *JAMA*. ; vol292, pp.2614-2621.

conundrum. J Am Acad Dermatol. Vol.59, No. 2, pp. 179-206.

perhaps a direct cytotoxic effect on hyperactive melanocytes (Altraide et al., 2010).

inflammatory and more widespread and generalized.

pityrosporum folliculitis.

HIV-infected patients.

pp. 2138-2150.

pp. 659-63.

Longman Nigeria PLC pp.22-80.

Blackwell science LTD 2: 1057-1079.

*JDermatol* 2004; 43 (4): 265-8.

**4. References** 

Owing to the striking lymphotropsism exhibited by the human immunodeficiency virus, HIV/AIDS patients demonstrate a wide breadth of both benign and malignant lymphoproliferative disorders. These disorders span the spectrum from viral lymphadenopathy to lymphocentric opportunistic infections to proliferations of uncertain and frankly malignant potential. This chapter explores a number of the many possible HIV/AIDS associated disorders from the perspective of the lymphoid system. Notably, some of these disorders are themselves AIDS defining illnesses while others are entities known to occur frequently in the HIV/AIDS population but not directly influenced by HIV infection. In most cases, HIV-associated lymphoproliferative disorders are thought to result from an aberrant host immune response in the context of chronic inflammatory stimulation rather than as a direct consequence of HIV infection.

#### **1.1 Pathogenesis**

The human immunodeficiency virus is a member of the lentivirus genus (lenti- , *latin*  "slow"), a group of viruses in the retrovirus family characterized by tropism for immune cells (Norkin, 2010). HIV demonstrates strong affinity for a specific cohort of human T-cells, the CD4 "Helper" T-cell; this is accomplished by means of the viral gp120 protein's strong affinity for the CD4 molecule (Wain-Hobson, 1996). HIV infects cells with CD4 cell-surface receptor molecules, using them to gain entry into the cell (Verani, et al., 2005). In early infection, HIV is widely disseminated by way of its interaction with antigen presenting cells (e.g. Langerhans and dendritic cells) which direct antigen obtained from mucous membranes toward the tissues of the adaptive immune system (namely the lymph nodes); HIV can accomplish this both by means of CD4 receptor binding but also by exploiting the immune response itself by allowing phagocytosis into these antigen presenting cells through either interations with complement or Fc receptors (Verani, et al., 2005). The result is a systemic dissemination of HIV infection to lymphoid tissues (Pantaleo, et al., 1993). Once gained access to the lymphoid tissues of the body, HIV may engage in a latent infection of Tcells by way of viral integration into resting or memory T-cells; these cells may then serve another reservoir of infection (Sierra, et al., 2005).

A number of studies have explored the biological influences that HIV may have on lymphomagenesis. The primary role of the CD4 T-cell is played out in the adaptive immune

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 465

protein-1 was capable of inducing a Hodgkin-like state in non-previously transformed

Less commonly, HIV-associated lymphomas demonstrate co-infection with the Kaposi sarcoma herpes virus, HHV-8. A number of HHV-8 viral proteins have been implicated in lymphomagenesis: the HHV-8 latency-associated nuclear antigen has been shown to interfere with normal p53 and Rb gene protein functions; the K13 viral protein interferes with host cell Fas-mediated apoptosis pathways; and the Kaposin B viral protein has been shown to prevent the normal degeneration of stimulatory cytokines (Wen & Damania, 2010). The combined influence of these and other HHV-8 encoded proteins, especially within the context of an already abnormal immunomodulation from HIV infection, places infected B-

Lymphadenopathy is a characteristic (though certainly not specific) finding in HIV/AIDS patients. Variable definitions of lymphadenopathy exist in the medical literature, typically making reference to enlarged, swollen or painful lymph nodes as definitive. Size cut-offs have been proposed in some definitions and many clinicians will investigate lymph nodes exceeding 1 cm in size. Ioachim notes that lymph nodes larger than 3 cm should raise suspicion of neoplasia (Ioachim & Medeiros, 2009b). Often lymphadenopathy will come to clinical attention as rapidly enlarging lymph nodes; unfortunately, there is little data to suggest how the rapidity of lymph node enlargement pertains to the presence of absence of a neoplastic proliferation. Other features of clinical concern include matting or adherence of multiple nodes to one another, as well as enlargement of several nodes in a given nodal chain (Ioachim & Medeiros, 2009b). Most frequently, due to the frequent clinical concern that an enlarged lymph node may admonish, biopsy and pathological examination of lymph nodes is necessary, especially in the at risk HIV/AIDS community. For our purposes, HIV-associated lymphadenopathy refers to enlarged lymph nodes attributable strictly to a non-neoplastic viral process excluding other opportunistic

Lymphadenopathy was identified as one of the earliest clinical signs in early epidemiologic studies of patients with AIDS; the closely studied 1982 Vancouver cohort of at risk homosexual men demonstrated a prevalence of 50% of post-seroconversion lymphadenopathy (Boyko, et al., 1987). Similar values were noted in other cohorts, including heterosexual males and females, such as the Zimbabwean cohort of Latif, et al. (Latif, et al., 1989). Lymphadenopathy is also more commonly identified in HIV positive children than in non-HIV infected children (Bakaki, et al., 2001; Nielsen, et al., 1997). HIVassociated lymphadenopathy demonstrates preponderance for the head and neck area, often presenting as cervical lymphadenopathy (Prasad, et al., 2006). Other radiologic studies have also demonstrated frequent (typically occult) intra-abdominal lymphadenopathy in HIV positive patients, most commonly as a result of opportunistic infection but also due to lymphomas (Jasmer, et al., 2002). Concern over the latter not infrequently results in invasive

HIV-associated lymphadenopathy follows a consistent histological pattern of progression (see Figure 2). Lymphadenopathy typically begins with the onset of HIV viremia; this acute phase of HIV infection (the acute retroviral syndrome) is typically described as a

germinal centre B-cells (Vockerodt, et al., 2008).

cells at high risk of malignant transformation.

**2.1 HIV-associated lymphadenopathy** 

pathogens (discussed later).

**2. Non-neoplastic lymphoid disorders in HIV/AIDS** 

abdominal lymph node biopsies for diagnostic purposes.

response. More specifically, non-infected CD4 T-cells function as immune system modulators through interactions with a multitude of other cells of both the adaptive immune system (i.e. B-cells) as well as the innate immune system (e.g. macrophages and monocytes)(Robbins, et al., 2010). HIV infected CD4 cells cannot execute these normal immunomodulatory functions: HIV replication within CD4 cells is directly cytopathic (Hazenberg, et al., 2000); non-infected CD4 cells will be reduced in number due to activation-induced cell death under the influence of both HIV infection as well as other concomitant infections (McCune, 2001); HIV tropism for CD4 cells will result in colonization and persistent immunostimulation in lymphoid tissues; HIV will also infect immature CD4 positive precursor T-cells thereby further reducing the effective CD4 T-cell pool (Robbins, et al., 2010).

#### Fig. 1. HIV receptor-specific pathogenesis

In contrast to other viruses associated with neoplasms, HIV is not regarded as a directly transforming virus (i.e. its effect on the host cell genome does not directly initiate neoplastic transformation). This is evidenced by a number of observations regarding HIV-associated lymphomas: there is a wide etiologic range of possible HIV-associated lymphomas; there is frequent association of HIV-associated lymphomas with "super-infecting" known oncogenic pathogens (e.g. Kaposi-sarcoma virus and Epstein-Barr virus); and most HIV-associated lymphomas are lymphomas of B-cells (and not of T-cells, which one would expect if HIV were a uniformly transformative virus). Molecular studies have also noted a propensity for viral genomic integration at random active gene sites; while this may theoretically lead to an insertion at a transformative locus, HIV does not show consistent insertion at a transformative site (Mitchell, et al., 2004).

EBV has been shown to contribute to lymphomagenesis in a number of ways; the latent membrane proteins, in particular, have garnered much research interest in this vein. In the 1980s it was recognized that EBV latent membrane protein-1 gene was able to transform mouse cell models (Wang, et al., 1985). EBV-LMP has also been shown to activate the tumor necrosis factor and p38 mitogenic pathways (Mosialos, et al., 1995; Eliopoulos, et al., 1999); activation of these pathways may contribute to the ability of EBV-infected (and potentially transformed) cells to evade host defense mechanisms. Another EBV encoded protein, latent membrane protein A2 has been shown to stimulate lymphocyte development and proliferation in mouse models outside of the normal immunologic milieu (Caldwell, et al., 1998). Finally, Vockerodt and colleague recently demonstrated that latent membrane

response. More specifically, non-infected CD4 T-cells function as immune system modulators through interactions with a multitude of other cells of both the adaptive immune system (i.e. B-cells) as well as the innate immune system (e.g. macrophages and monocytes)(Robbins, et al., 2010). HIV infected CD4 cells cannot execute these normal immunomodulatory functions: HIV replication within CD4 cells is directly cytopathic (Hazenberg, et al., 2000); non-infected CD4 cells will be reduced in number due to activation-induced cell death under the influence of both HIV infection as well as other concomitant infections (McCune, 2001); HIV tropism for CD4 cells will result in colonization and persistent immunostimulation in lymphoid tissues; HIV will also infect immature CD4 positive precursor T-cells thereby further reducing the effective CD4 T-cell pool (Robbins, et

In contrast to other viruses associated with neoplasms, HIV is not regarded as a directly transforming virus (i.e. its effect on the host cell genome does not directly initiate neoplastic transformation). This is evidenced by a number of observations regarding HIV-associated lymphomas: there is a wide etiologic range of possible HIV-associated lymphomas; there is frequent association of HIV-associated lymphomas with "super-infecting" known oncogenic pathogens (e.g. Kaposi-sarcoma virus and Epstein-Barr virus); and most HIV-associated lymphomas are lymphomas of B-cells (and not of T-cells, which one would expect if HIV were a uniformly transformative virus). Molecular studies have also noted a propensity for viral genomic integration at random active gene sites; while this may theoretically lead to an insertion at a transformative locus, HIV does not show consistent insertion at a

EBV has been shown to contribute to lymphomagenesis in a number of ways; the latent membrane proteins, in particular, have garnered much research interest in this vein. In the 1980s it was recognized that EBV latent membrane protein-1 gene was able to transform mouse cell models (Wang, et al., 1985). EBV-LMP has also been shown to activate the tumor necrosis factor and p38 mitogenic pathways (Mosialos, et al., 1995; Eliopoulos, et al., 1999); activation of these pathways may contribute to the ability of EBV-infected (and potentially transformed) cells to evade host defense mechanisms. Another EBV encoded protein, latent membrane protein A2 has been shown to stimulate lymphocyte development and proliferation in mouse models outside of the normal immunologic milieu (Caldwell, et al., 1998). Finally, Vockerodt and colleague recently demonstrated that latent membrane

al., 2010).

Fig. 1. HIV receptor-specific pathogenesis

transformative site (Mitchell, et al., 2004).

protein-1 was capable of inducing a Hodgkin-like state in non-previously transformed germinal centre B-cells (Vockerodt, et al., 2008).

Less commonly, HIV-associated lymphomas demonstrate co-infection with the Kaposi sarcoma herpes virus, HHV-8. A number of HHV-8 viral proteins have been implicated in lymphomagenesis: the HHV-8 latency-associated nuclear antigen has been shown to interfere with normal p53 and Rb gene protein functions; the K13 viral protein interferes with host cell Fas-mediated apoptosis pathways; and the Kaposin B viral protein has been shown to prevent the normal degeneration of stimulatory cytokines (Wen & Damania, 2010). The combined influence of these and other HHV-8 encoded proteins, especially within the context of an already abnormal immunomodulation from HIV infection, places infected Bcells at high risk of malignant transformation.

## **2. Non-neoplastic lymphoid disorders in HIV/AIDS**

## **2.1 HIV-associated lymphadenopathy**

Lymphadenopathy is a characteristic (though certainly not specific) finding in HIV/AIDS patients. Variable definitions of lymphadenopathy exist in the medical literature, typically making reference to enlarged, swollen or painful lymph nodes as definitive. Size cut-offs have been proposed in some definitions and many clinicians will investigate lymph nodes exceeding 1 cm in size. Ioachim notes that lymph nodes larger than 3 cm should raise suspicion of neoplasia (Ioachim & Medeiros, 2009b). Often lymphadenopathy will come to clinical attention as rapidly enlarging lymph nodes; unfortunately, there is little data to suggest how the rapidity of lymph node enlargement pertains to the presence of absence of a neoplastic proliferation. Other features of clinical concern include matting or adherence of multiple nodes to one another, as well as enlargement of several nodes in a given nodal chain (Ioachim & Medeiros, 2009b). Most frequently, due to the frequent clinical concern that an enlarged lymph node may admonish, biopsy and pathological examination of lymph nodes is necessary, especially in the at risk HIV/AIDS community. For our purposes, HIV-associated lymphadenopathy refers to enlarged lymph nodes attributable strictly to a non-neoplastic viral process excluding other opportunistic pathogens (discussed later).

Lymphadenopathy was identified as one of the earliest clinical signs in early epidemiologic studies of patients with AIDS; the closely studied 1982 Vancouver cohort of at risk homosexual men demonstrated a prevalence of 50% of post-seroconversion lymphadenopathy (Boyko, et al., 1987). Similar values were noted in other cohorts, including heterosexual males and females, such as the Zimbabwean cohort of Latif, et al. (Latif, et al., 1989). Lymphadenopathy is also more commonly identified in HIV positive children than in non-HIV infected children (Bakaki, et al., 2001; Nielsen, et al., 1997). HIVassociated lymphadenopathy demonstrates preponderance for the head and neck area, often presenting as cervical lymphadenopathy (Prasad, et al., 2006). Other radiologic studies have also demonstrated frequent (typically occult) intra-abdominal lymphadenopathy in HIV positive patients, most commonly as a result of opportunistic infection but also due to lymphomas (Jasmer, et al., 2002). Concern over the latter not infrequently results in invasive abdominal lymph node biopsies for diagnostic purposes.

HIV-associated lymphadenopathy follows a consistent histological pattern of progression (see Figure 2). Lymphadenopathy typically begins with the onset of HIV viremia; this acute phase of HIV infection (the acute retroviral syndrome) is typically described as a

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 467

order that the correct diagnosis be made and that the correct treatment regimen be instituted. The vascular proliferation noted in Grade 2 and 3 may also be misconstrued for Kaposi's sarcoma (see later for the lymph node features of Kaposi's sarcoma); immunohistochemistry for the Kaposi's sarcoma virus is now a commonplace tool to avoid this diagnostic confusion. Other more aggressive lymphoproliferative disorders need to be ruled out in lymph nodes sampled in the context of HIV; the key feature in HIV-associated lymphadenopathy of any Grade is the relative preservation of lymph node architecture

EBV seropositivity is widespread in HIV positive patients and in the context of lymphadenopathy EBV infection can confuse the histopathologic diagnosis (see Figure 3). More specifically, EBV infection may produce reactive cells demonstrating a striking resemblance to the Reed-Sternberg cells of Hodgkin's lymphoma. In such cases, immunohistochemistry is essential. In order to rule out Hodgkin's lymphoma, the atypical Reed-Sternberg like cells seen in lymphadenitis will typically stain positive for CD20, CD45, and may stain positive for CD30 (an activation marker); these cells, unlike true Reed-

Fig. 3. HIV Lymphadenopathy with EBV related changes: A: Loss of normal lymph node architecture; B: Reed-sternberg-like cells present in EBV-related HIV Lymphadenopathy; C:

Treatment for HIV-associated lymphadenopathy is focused around optimizing antiretroviral therapy, treated other concomitant infections as needed and clinical follow-up. The latter point is emphasized in order that lymphoid neoplasia not be missed. Studies have explored the outcomes of patients diagnosed with HIV-associated lymphadenopathy and graded according to the above scheme. In their cohort of HIV patients with lymphadenopathy, Ioachim and colleagues noted that most cases of HIV-associated lymphadenopathy began as Grade 1; many cases subsequently progressed from Grade 1 to 2 and from Grade 2 to 3; most cases with Grade 3 lymphadenopathy subsequently developed AIDS defining illnesses (Ioachim & Medeiros, 2009; Ioachim, et al., 1990). Ioachim et al also noted a distinct survival difference between the various grades of HIV-associated lymphadenopathy (Ioachim & Medeiros, 2009; Ioachim, et al., 1990). Grade 3 HIV-associated lymphadenopathy is also strongly associated with development of Kaposi's sarcoma

which is often lost in lymphoid malignancies.

Sternberg cells, should not stain for CD15.

Corresponding EBV Stain

(Ioachim & Medeiros, 2009c).

mononucleosis-like cluster of symptoms. Acute retroviral syndrome typically begins 2-6 weeks post-infection and may last for several weeks. Typical symptoms include fever, headache, malaise, pharyngitis and lymphadenopathy (Carpenter, et al., 2004). The lymphadenopathy, however, often persists beyond this acute phase. The histological features of early HIV-associated lymphadenopathy typically demonstrate exuberant hyperplastic changes: large lymphoid follicles with irregular serpiginous shapes are characteristic; irregular enlargement of germinal centres is noted; these large germinal centres typically demonstrate prominent apoptotic bodies and tingible body macrophages; and there may be expansion of the interfollicular zones by numerous transformed B lymphocytes (these have a monocytoid appearance and correspond to antigenically stimulated B-cells). These features are typical of the so-called Grade 1 HIV-associated lymphadenopathy.

Fig. 2. HIV Lymphadenopathy: A: Early HIV Lymphadenopathy (Grade 1); B: BCL2 stain demonstrating benign follicle staining pattern (negative in follicles and positive in interfollicular zones); C: Ki67 demonstrating benign follicle staining pattern (high index nuclear staining in follicles with low index in interfollicular zones); D: Grade 2 HIV Lymphadenopathy demonstrating early follicular-lysis; E: Corresponding CD21 stain demonstrating hyperplastic moth-eaten follicular dendritic cell meshwork (replaced by fibrosis); F: Grade 3 HIV Lymphadenopathy demonstrating marked fibrosis and loss of follicles; G: Corresponding CD21 stain demonstrating near absence of follicular dendritic meshwork

As HIV infection progresses, the antigenic stimulation within the lymph node begins to wane. This leads to a Grade 2 pattern of HIV-associated lymphadenopathy characterized by a reduction in the number of lymphoid follicles, an increase in the number of plasma cells and a proliferation of perifollicular blood vessels. At the extreme of HIV-associated lymphadenopathy is the Grade 3 pattern in which the residual follicles begin to display sclerosis of their germinal centres.

Although consistent, none of the histologic features noted above are specific to HIV. The Grade 1 pattern, for example, is frequently observed in non-HIV viral lymphadenitides. The Grade 2 and 3 patterns show a significant overlap with those of Castleman's disease (see later). In such cases, a clinical history of known or suspected HIV infection is essential in

mononucleosis-like cluster of symptoms. Acute retroviral syndrome typically begins 2-6 weeks post-infection and may last for several weeks. Typical symptoms include fever, headache, malaise, pharyngitis and lymphadenopathy (Carpenter, et al., 2004). The lymphadenopathy, however, often persists beyond this acute phase. The histological features of early HIV-associated lymphadenopathy typically demonstrate exuberant hyperplastic changes: large lymphoid follicles with irregular serpiginous shapes are characteristic; irregular enlargement of germinal centres is noted; these large germinal centres typically demonstrate prominent apoptotic bodies and tingible body macrophages; and there may be expansion of the interfollicular zones by numerous transformed B lymphocytes (these have a monocytoid appearance and correspond to antigenically stimulated B-cells). These features are typical of the so-called Grade 1 HIV-associated

Fig. 2. HIV Lymphadenopathy: A: Early HIV Lymphadenopathy (Grade 1); B: BCL2 stain demonstrating benign follicle staining pattern (negative in follicles and positive in interfollicular zones); C: Ki67 demonstrating benign follicle staining pattern (high index nuclear staining in follicles with low index in interfollicular zones); D: Grade 2 HIV Lymphadenopathy demonstrating early follicular-lysis; E: Corresponding CD21 stain demonstrating hyperplastic moth-eaten follicular dendritic cell meshwork (replaced by fibrosis); F: Grade 3 HIV Lymphadenopathy demonstrating marked fibrosis and loss of follicles; G: Corresponding CD21 stain demonstrating near absence of follicular dendritic

As HIV infection progresses, the antigenic stimulation within the lymph node begins to wane. This leads to a Grade 2 pattern of HIV-associated lymphadenopathy characterized by a reduction in the number of lymphoid follicles, an increase in the number of plasma cells and a proliferation of perifollicular blood vessels. At the extreme of HIV-associated lymphadenopathy is the Grade 3 pattern in which the residual follicles begin to display

Although consistent, none of the histologic features noted above are specific to HIV. The Grade 1 pattern, for example, is frequently observed in non-HIV viral lymphadenitides. The Grade 2 and 3 patterns show a significant overlap with those of Castleman's disease (see later). In such cases, a clinical history of known or suspected HIV infection is essential in

lymphadenopathy.

meshwork

sclerosis of their germinal centres.

order that the correct diagnosis be made and that the correct treatment regimen be instituted. The vascular proliferation noted in Grade 2 and 3 may also be misconstrued for Kaposi's sarcoma (see later for the lymph node features of Kaposi's sarcoma); immunohistochemistry for the Kaposi's sarcoma virus is now a commonplace tool to avoid this diagnostic confusion. Other more aggressive lymphoproliferative disorders need to be ruled out in lymph nodes sampled in the context of HIV; the key feature in HIV-associated lymphadenopathy of any Grade is the relative preservation of lymph node architecture which is often lost in lymphoid malignancies.

EBV seropositivity is widespread in HIV positive patients and in the context of lymphadenopathy EBV infection can confuse the histopathologic diagnosis (see Figure 3). More specifically, EBV infection may produce reactive cells demonstrating a striking resemblance to the Reed-Sternberg cells of Hodgkin's lymphoma. In such cases, immunohistochemistry is essential. In order to rule out Hodgkin's lymphoma, the atypical Reed-Sternberg like cells seen in lymphadenitis will typically stain positive for CD20, CD45, and may stain positive for CD30 (an activation marker); these cells, unlike true Reed-Sternberg cells, should not stain for CD15.

Fig. 3. HIV Lymphadenopathy with EBV related changes: A: Loss of normal lymph node architecture; B: Reed-sternberg-like cells present in EBV-related HIV Lymphadenopathy; C: Corresponding EBV Stain

Treatment for HIV-associated lymphadenopathy is focused around optimizing antiretroviral therapy, treated other concomitant infections as needed and clinical follow-up. The latter point is emphasized in order that lymphoid neoplasia not be missed. Studies have explored the outcomes of patients diagnosed with HIV-associated lymphadenopathy and graded according to the above scheme. In their cohort of HIV patients with lymphadenopathy, Ioachim and colleagues noted that most cases of HIV-associated lymphadenopathy began as Grade 1; many cases subsequently progressed from Grade 1 to 2 and from Grade 2 to 3; most cases with Grade 3 lymphadenopathy subsequently developed AIDS defining illnesses (Ioachim & Medeiros, 2009; Ioachim, et al., 1990). Ioachim et al also noted a distinct survival difference between the various grades of HIV-associated lymphadenopathy (Ioachim & Medeiros, 2009; Ioachim, et al., 1990). Grade 3 HIV-associated lymphadenopathy is also strongly associated with development of Kaposi's sarcoma (Ioachim & Medeiros, 2009c).

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 469

(Maguina, et al., 2009). In a notable number of cases of BA, lymphadenopathy may be identified as the inciting event (Gasquet, et al., 1998). *B. henselae* BA, in particular, tends to demonstrate lymphadenoapthy, both with and without skin lesions (Ioachim & Medeiros, 2009a). Aggressive cases of bacillary angiomatosis may demonstrate splenic or hepatic

The histologic features of bacillary angiomatosis in lymph nodes are similar to those seen in skin lesions and elsewhere (see Figure 4). Bacillary angiomatosis typically forms richly vascular nodules. Proliferating endothelial cells are evident, forming variably sized bloodfilled vascular spaces into which their nuclei protrude. There may be notable anisonucleosis, multiple nucleoli and numerous mitoses; these features may suggest a malignant entity. Ancillary staining with Warthin-Starry silver stain invariably demonstrates numerous bacilli, 0.2-0.3 m in size, often noted in clumps (Maguina, et al., 2009; Ioachim & Medeiros, 2009a). Electron microscopy will demonstrate a trilaminar bacillus in association with an obvious proliferation of endothelial cells with characteristic Weibel-Palade bodies (Kostianovsky & Greco, 1994). Modern attempts at developing reliable immunohistochemical markers to aid in the diagnosis of bacillary angiomatosis have been as yet unsuccessful; PCR techniques may be relied upon to confirm the presence of *Bartonella*

infection in cases that may be diagnostically equivocal (Caponetti, et al., 2009).

Fig. 4. Bacillary Angiomatosis: A: Low-power view demonstrating proliferating venules; B:

The differential diagnosis of bacillary angiomatosis may include a number of entities, especially if the HIV/AIDS status of the patient is unknown. On hematoxylin & eosin staining alone, bacillary angiomatosis may resemble a hemangioma. Gram staining may help distinguish bacillary angiomatosis from pyogenic granuloma (the former being invariably negative). Bacillary angiomatosis may sometimes be difficult to discern from Kaposi's sarcoma. Histologically, Kaposi's cells are more characteristically spindled and there is a predominance of slit-like vascular spaces. Nonetheless, most authories recommend using an immunohistochemical stain against HHV-8, the causal virus of Kaposi's sarcoma, in order to rule out this more serious condition. Another malignant condition that may be mimicked by bacillary angiomatosis is typical angiosarcoma; this entity is highly aggressive

Although the clinical course of bacillary angiomatosis is variable, the treatment of choice is antibiotics (typically a course of erythromycin or doxycycline); some cases may also resolve spontaneously even without treatment, however (Wolff, et al., 2005). Care should be taken in HIV/AIDS patients with very low CD4 counts; these patients not only require quick accurate diagnosis to define the appropriate treatment regimen, but further preventative

Warthin-starry stain demonstrating extracellular clump of bacteria (arrow)

action may also be beneficial, such as prevention of exposure to animals.

and demonstrates an infiltrative architecture.

involvement as bacillary peliosis, often with fatal outcomes.

#### **2.2 Bacillary angiomatosis**

Bacillary Angiomatosis is a lesion of proliferating endothelial cells caused by *Bartonella* species occuring in immunocompromised patients, almost exclusively in patients with AIDS. The first documented case of HIV/AIDS associated bacillary angiomatosis was reported by Stoler and colleagues in 1983 (Cotell & Noskin, 1994; Stoler, et al., 1983); they reported a peculiar case of a young AIDS patient with multiple cutaneous nodules found to consist of proliferating endothelial cells forming lobular networks of small caliber blood vessels. Interspersed within this network were small gram-negative bacillary forms visible only on Warthin-Starry staining. For many years, efforts to speciate the organism observed histologically were unsuccessful; initial attempts at culturing the organism with a range of media produced no results (Cotell & Noskin, 1994; Stoler, et al., 1983). Finally, with the dawning of PCR based techniques, the organism believed to be the causal agent in bacillary angiomatosis was found to be genomically comparable to the species known to cause Cat Scratch Disease, the organism known today as *Bartonella henselae* (Relman, et al., 1990).

It is now known that bacillary angiomatosis may be associated with a number of *Bartonella* species, most common *B. henselae* and *B. quintana* (Maguina, et al., 2009). Interestingly, studies have shown high seroprevalence for *Bartonella* species in the population overall (Lamas, et al., 2010). Furthermore, clinically silent *Bartonella* seroprevalence has been observed in the HIV population, rarely with very high titres (Pape, et al., 2005; Yousif, et al., 1996). These laboratory data mirror the clinically evident divergence of *Bartonella* infection observed in the immunocompromised and immunocompetent populations. In immunocompetent individuals, *Bartonella* infection, if clinically evident, typically manifests as the so-called "cat-scratch disease," characterized by lymphadenopathy demonstrating caseating granuloma formation. In immunocompromised patients, on the other hand, the infection manifests as vascular lesions, sometimes progressing to a potentially fatal systemic infection. This stark contrast has spawned a number of studies demonstrating the importance of an intact adaptive immune system.

*Bartonella* infection is transmitted either by means of an insect vector (e.g. mites, lice) or by means of trauma by an animal vector (the namesake "cat-scratch" is evident) (Minnick, et al., 2003; Ioachim & Medeiros, 2009a; Wolff, et al., 2005). Studies exploring the comparative genomics of *Bartonella* infections in HIV patients and their pet cats have confirmed this long suspected epidemiologic link (Chang, et al., 2002). After inoculation, *Bartonella* species home to erythrocytes and endothelial cells, thereby allowing it access to multiple sites in the body (Minnick, et al., 2003). *Bartonella* then exploits a number of molecular pathways to evade its host's immune system (Minnick, et al., 2003); this evasion may explain the clinically observed propensity of *Bartonella* to produce granulomatous lymphadenitis. In immunocompromised patients, exploiting an already weakened immune system, *Bartonella*  stimulates angiogenesis; *Bartonella* infection stimulates the production of hypoxia-induced factor and other cytokines, thereby upregulating angiogenesis (Minnick, et al., 2003).

Bacillary angiomatosis typically occurs in AIDS patients with low CD4 counts (typically less than 100/mm3) (Maguina, et al., 2009). Most patients present with skin lesions, characteristically as multiple violaceous or red papules; these lesions may be painful, typically progress over days to weeks and may resemble cherry hemangiomas or pyogenic granulomas (Wolff, 2005). In most cases a combination of clinical history, known HIV/AIDS status and clinical assessment will result in the correct diagnosis; the differential diagnosis, however, may include Kaposi's sarcoma thereby mandating histopathological assessment

Bacillary Angiomatosis is a lesion of proliferating endothelial cells caused by *Bartonella* species occuring in immunocompromised patients, almost exclusively in patients with AIDS. The first documented case of HIV/AIDS associated bacillary angiomatosis was reported by Stoler and colleagues in 1983 (Cotell & Noskin, 1994; Stoler, et al., 1983); they reported a peculiar case of a young AIDS patient with multiple cutaneous nodules found to consist of proliferating endothelial cells forming lobular networks of small caliber blood vessels. Interspersed within this network were small gram-negative bacillary forms visible only on Warthin-Starry staining. For many years, efforts to speciate the organism observed histologically were unsuccessful; initial attempts at culturing the organism with a range of media produced no results (Cotell & Noskin, 1994; Stoler, et al., 1983). Finally, with the dawning of PCR based techniques, the organism believed to be the causal agent in bacillary angiomatosis was found to be genomically comparable to the species known to cause Cat Scratch Disease, the organism known today as *Bartonella henselae* (Relman, et al., 1990). It is now known that bacillary angiomatosis may be associated with a number of *Bartonella* species, most common *B. henselae* and *B. quintana* (Maguina, et al., 2009). Interestingly, studies have shown high seroprevalence for *Bartonella* species in the population overall (Lamas, et al., 2010). Furthermore, clinically silent *Bartonella* seroprevalence has been observed in the HIV population, rarely with very high titres (Pape, et al., 2005; Yousif, et al., 1996). These laboratory data mirror the clinically evident divergence of *Bartonella* infection observed in the immunocompromised and immunocompetent populations. In immunocompetent individuals, *Bartonella* infection, if clinically evident, typically manifests as the so-called "cat-scratch disease," characterized by lymphadenopathy demonstrating caseating granuloma formation. In immunocompromised patients, on the other hand, the infection manifests as vascular lesions, sometimes progressing to a potentially fatal systemic infection. This stark contrast has spawned a number of studies demonstrating the

*Bartonella* infection is transmitted either by means of an insect vector (e.g. mites, lice) or by means of trauma by an animal vector (the namesake "cat-scratch" is evident) (Minnick, et al., 2003; Ioachim & Medeiros, 2009a; Wolff, et al., 2005). Studies exploring the comparative genomics of *Bartonella* infections in HIV patients and their pet cats have confirmed this long suspected epidemiologic link (Chang, et al., 2002). After inoculation, *Bartonella* species home to erythrocytes and endothelial cells, thereby allowing it access to multiple sites in the body (Minnick, et al., 2003). *Bartonella* then exploits a number of molecular pathways to evade its host's immune system (Minnick, et al., 2003); this evasion may explain the clinically observed propensity of *Bartonella* to produce granulomatous lymphadenitis. In immunocompromised patients, exploiting an already weakened immune system, *Bartonella*  stimulates angiogenesis; *Bartonella* infection stimulates the production of hypoxia-induced

factor and other cytokines, thereby upregulating angiogenesis (Minnick, et al., 2003).

Bacillary angiomatosis typically occurs in AIDS patients with low CD4 counts (typically less than 100/mm3) (Maguina, et al., 2009). Most patients present with skin lesions, characteristically as multiple violaceous or red papules; these lesions may be painful, typically progress over days to weeks and may resemble cherry hemangiomas or pyogenic granulomas (Wolff, 2005). In most cases a combination of clinical history, known HIV/AIDS status and clinical assessment will result in the correct diagnosis; the differential diagnosis, however, may include Kaposi's sarcoma thereby mandating histopathological assessment

**2.2 Bacillary angiomatosis** 

importance of an intact adaptive immune system.

(Maguina, et al., 2009). In a notable number of cases of BA, lymphadenopathy may be identified as the inciting event (Gasquet, et al., 1998). *B. henselae* BA, in particular, tends to demonstrate lymphadenoapthy, both with and without skin lesions (Ioachim & Medeiros, 2009a). Aggressive cases of bacillary angiomatosis may demonstrate splenic or hepatic involvement as bacillary peliosis, often with fatal outcomes.

The histologic features of bacillary angiomatosis in lymph nodes are similar to those seen in skin lesions and elsewhere (see Figure 4). Bacillary angiomatosis typically forms richly vascular nodules. Proliferating endothelial cells are evident, forming variably sized bloodfilled vascular spaces into which their nuclei protrude. There may be notable anisonucleosis, multiple nucleoli and numerous mitoses; these features may suggest a malignant entity. Ancillary staining with Warthin-Starry silver stain invariably demonstrates numerous bacilli, 0.2-0.3 m in size, often noted in clumps (Maguina, et al., 2009; Ioachim & Medeiros, 2009a). Electron microscopy will demonstrate a trilaminar bacillus in association with an obvious proliferation of endothelial cells with characteristic Weibel-Palade bodies (Kostianovsky & Greco, 1994). Modern attempts at developing reliable immunohistochemical markers to aid in the diagnosis of bacillary angiomatosis have been as yet unsuccessful; PCR techniques may be relied upon to confirm the presence of *Bartonella* infection in cases that may be diagnostically equivocal (Caponetti, et al., 2009).

Fig. 4. Bacillary Angiomatosis: A: Low-power view demonstrating proliferating venules; B: Warthin-starry stain demonstrating extracellular clump of bacteria (arrow)

The differential diagnosis of bacillary angiomatosis may include a number of entities, especially if the HIV/AIDS status of the patient is unknown. On hematoxylin & eosin staining alone, bacillary angiomatosis may resemble a hemangioma. Gram staining may help distinguish bacillary angiomatosis from pyogenic granuloma (the former being invariably negative). Bacillary angiomatosis may sometimes be difficult to discern from Kaposi's sarcoma. Histologically, Kaposi's cells are more characteristically spindled and there is a predominance of slit-like vascular spaces. Nonetheless, most authories recommend using an immunohistochemical stain against HHV-8, the causal virus of Kaposi's sarcoma, in order to rule out this more serious condition. Another malignant condition that may be mimicked by bacillary angiomatosis is typical angiosarcoma; this entity is highly aggressive and demonstrates an infiltrative architecture.

Although the clinical course of bacillary angiomatosis is variable, the treatment of choice is antibiotics (typically a course of erythromycin or doxycycline); some cases may also resolve spontaneously even without treatment, however (Wolff, et al., 2005). Care should be taken in HIV/AIDS patients with very low CD4 counts; these patients not only require quick accurate diagnosis to define the appropriate treatment regimen, but further preventative action may also be beneficial, such as prevention of exposure to animals.

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 471

atypical mycobacteria or the *Mycobacterium avium complex* can be challenging, often requiring molecular testing for speciation (which can fortunately be performed off formalinfixed and paraffin-embedded tissues). The presence of the so-called Langhans giant cells (with peripherally rimmed nuclei) may hint at the presence of *Mycobacteria tuberculosis* but is by no means specific. Another advantage to molecular testing when acid-fast bacteria are encountered is the ability to test for antimicrobial resistant strains by PCR; this may be an invaluable aid given the burgeoning cohort of multidrug resistant TB cases encountered in

Fig. 5. Tuberculous Lymphadenitis: Granuloma with eosinophilic necrotic centre; inset: characteristics Langhans giant cell (top left) with adjacent necrosis (bottom right)

*Toxoplasma gondii* is the causative agent of toxoplasmosis, a parasitic infection believed to be one of the worlds most prevalent. *Toxoplasma gondii* seropositivity in the at-large population has previously been reported as high as 70-90%, though modern estimates in the range of 10-40% seem reasonable (Shin, et al., 2009; Kamani, et al., 2009; Fromont, et al., 2009). Not unexpectedly, the overall seroprevalence of *Toxoplasma gondii* is also high; while the estimates may be lower in North American and Europe, one recent Nigerian cohort demonstrated a seroprevalence of over 50% with active parasitism in the blood detected in over 20% (Lindstrom, et al., 2006). *Toxoplasma gondii* demonstrates parasitism of a number of animal hosts, most commonly of felines (the definitive host). Humans are typically infected by way of consumption of contaminated foods or exposure to contaminated soil or animal droppings. Vertical transmission is also possible, producing a dangerous congenital toxoplasmosis. One of the most frequent presentations of toxoplasmosis in the HIV population is toxoplasma encephalitis (Ioachim & Medeiros, 2009e); a histologically characteristic infection of lymph nodes is also common, however. Toxoplasmosis lymphadenopathy typically affects the lymph nodes of the head and neck; these are typically slightly enlarged and tender to palpation. The most frequently encountered histologic features are nodal follicular hyperplasia with interspersed aggregates and sheets of monocytoid lymphocytes and scattered clusters of epithelioid cells (see Figure 6). The monocytoid cells are immunoglobin producing B-cells (which will stain positive for B-cell markers) and can most typically be found in the subcapsular and paratrabecular locations while the epithelioid cells are histiocytes and are characteristically seen to encroach upon follicles but do not form true granulomas. Many HIV positive cases of toxoplasma

HIV/AIDS.

**2.3.3 Toxoplasmosis** 

## **2.3 Other common infectious lymphadenitides in HIV/AIDS**

While a complete review of the opportunistic and co-infectious agents encountered in HIV/AIDS is beyond the scope of this book, any discussion of the lymph node based disease entities encountered in HIV/AIDS would be remiss if not for a discussion of the commonest node-based co-infections. The following is a brief discussion of the most common opportunistic infections encountered in HIV/AIDS patients from the perspective of lymph node disease.

#### **2.3.1 Pneumocystis**

*Pneumocystis jiroveci* is a ubiquitous organism in nature manifesting as a disease-causing organism only in the immunocompromised. This fungus first came to broad clinical attention in the early 1980s when it was noted in 70-80%of AIDS patients, most commonly manifest as pneumonia. Rarely, however, pneumocystosis does involve the lymph nodes. Anderson and Barrie were probably the first to report pneumocystis in a lymph node, two decades prior to the first identified cases of HIV/AIDS (ANDERSON & BARRIE, 1960). Of the reported extra-pulmonary cases of pneumocystis, the lymphoreticular system is probably the most common (Grimes, et al., 1987; Ioachim & Medeiros, 2009d). When involving lymph nodes, pneumocystis most commonly involves the mediastinum and retroperitoneal lymph nodes (Ioachim & Medeiros, 2009d). The gross features typically reflect the presence of necrotizing granuloma: lymph nodes are typically enlarged with central areas of purulent material. Microscopically, granulomata with central necrotic eosinophilic material will be noted (see Figure 5). The causal microorganisms are generally not overtly evident on routine histologic stains but can be readily identified on fungal silver stains as helmet-shaped organisms within the necrotic foci. Immunohistochemical stains for *Pneumocystis jiroveci* are available, though a combination of clinical history of HIV infection and morphologic features identified on silver staining are often sufficient. The current treatment of choice is trimethoprim-sulfamethoxazole antibiotics; the US centres for disease control also recommend that all HIV-positive patients diagnosed with pneumocystosis be maintained on indefinite prophylactic anti-fungal agents provided that CD4 count remains below 200 cells/L (Kaplan, et al., 2009).

## **2.3.2 Mycobacteria**

Globally the risk of co-infection with *Mycobacteria tuberculosis* is 20-37 times higher in patients with HIV than those without (WHO Department of HIV/AIDS Stop TB Department, 2010). The WHO also estimates that 25% of HIV-positive patients will die due to concomitant tuberculosis (WHO Department of HIV/AIDS Stop TB Department, 2010). Other non-tuberculous infections are also frequent in (and many are characteristic of) HIV infection. In addition to their primary involvement of the lungs, mycobacteria are also frequently encountered in lymph nodes, especially in the context of HIV infection. Mycobacterial lymphadenitis, regardless of the underlying species, will characteristically produce lymph node enlargement with foci of necrosis. The histologic features are often characteristic, namely central eosinophilic necrosis surrounded by a rim of pallisading histiocytes and giant cells (see Figure 5). In this peripheral rim of histiocytes, mycobacteria may be identified, often few and far between, on acid fast staining (pathologists often use a Ziehl-Neelsen stain for this purpose). Positivity on acid-fast staining does not equate to tuberculosis, however, and in many cases distinguishing between *Mycobacteria tuberculosis*, atypical mycobacteria or the *Mycobacterium avium complex* can be challenging, often requiring molecular testing for speciation (which can fortunately be performed off formalinfixed and paraffin-embedded tissues). The presence of the so-called Langhans giant cells (with peripherally rimmed nuclei) may hint at the presence of *Mycobacteria tuberculosis* but is by no means specific. Another advantage to molecular testing when acid-fast bacteria are encountered is the ability to test for antimicrobial resistant strains by PCR; this may be an invaluable aid given the burgeoning cohort of multidrug resistant TB cases encountered in HIV/AIDS.

Fig. 5. Tuberculous Lymphadenitis: Granuloma with eosinophilic necrotic centre; inset: characteristics Langhans giant cell (top left) with adjacent necrosis (bottom right)

## **2.3.3 Toxoplasmosis**

470 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

While a complete review of the opportunistic and co-infectious agents encountered in HIV/AIDS is beyond the scope of this book, any discussion of the lymph node based disease entities encountered in HIV/AIDS would be remiss if not for a discussion of the commonest node-based co-infections. The following is a brief discussion of the most common opportunistic infections encountered in HIV/AIDS patients from the perspective

*Pneumocystis jiroveci* is a ubiquitous organism in nature manifesting as a disease-causing organism only in the immunocompromised. This fungus first came to broad clinical attention in the early 1980s when it was noted in 70-80%of AIDS patients, most commonly manifest as pneumonia. Rarely, however, pneumocystosis does involve the lymph nodes. Anderson and Barrie were probably the first to report pneumocystis in a lymph node, two decades prior to the first identified cases of HIV/AIDS (ANDERSON & BARRIE, 1960). Of the reported extra-pulmonary cases of pneumocystis, the lymphoreticular system is probably the most common (Grimes, et al., 1987; Ioachim & Medeiros, 2009d). When involving lymph nodes, pneumocystis most commonly involves the mediastinum and retroperitoneal lymph nodes (Ioachim & Medeiros, 2009d). The gross features typically reflect the presence of necrotizing granuloma: lymph nodes are typically enlarged with central areas of purulent material. Microscopically, granulomata with central necrotic eosinophilic material will be noted (see Figure 5). The causal microorganisms are generally not overtly evident on routine histologic stains but can be readily identified on fungal silver stains as helmet-shaped organisms within the necrotic foci. Immunohistochemical stains for *Pneumocystis jiroveci* are available, though a combination of clinical history of HIV infection and morphologic features identified on silver staining are often sufficient. The current treatment of choice is trimethoprim-sulfamethoxazole antibiotics; the US centres for disease control also recommend that all HIV-positive patients diagnosed with pneumocystosis be maintained on indefinite prophylactic anti-fungal agents provided that CD4 count remains

Globally the risk of co-infection with *Mycobacteria tuberculosis* is 20-37 times higher in patients with HIV than those without (WHO Department of HIV/AIDS Stop TB Department, 2010). The WHO also estimates that 25% of HIV-positive patients will die due to concomitant tuberculosis (WHO Department of HIV/AIDS Stop TB Department, 2010). Other non-tuberculous infections are also frequent in (and many are characteristic of) HIV infection. In addition to their primary involvement of the lungs, mycobacteria are also frequently encountered in lymph nodes, especially in the context of HIV infection. Mycobacterial lymphadenitis, regardless of the underlying species, will characteristically produce lymph node enlargement with foci of necrosis. The histologic features are often characteristic, namely central eosinophilic necrosis surrounded by a rim of pallisading histiocytes and giant cells (see Figure 5). In this peripheral rim of histiocytes, mycobacteria may be identified, often few and far between, on acid fast staining (pathologists often use a Ziehl-Neelsen stain for this purpose). Positivity on acid-fast staining does not equate to tuberculosis, however, and in many cases distinguishing between *Mycobacteria tuberculosis*,

**2.3 Other common infectious lymphadenitides in HIV/AIDS** 

of lymph node disease.

**2.3.1 Pneumocystis** 

below 200 cells/L (Kaplan, et al., 2009).

**2.3.2 Mycobacteria** 

*Toxoplasma gondii* is the causative agent of toxoplasmosis, a parasitic infection believed to be one of the worlds most prevalent. *Toxoplasma gondii* seropositivity in the at-large population has previously been reported as high as 70-90%, though modern estimates in the range of 10-40% seem reasonable (Shin, et al., 2009; Kamani, et al., 2009; Fromont, et al., 2009). Not unexpectedly, the overall seroprevalence of *Toxoplasma gondii* is also high; while the estimates may be lower in North American and Europe, one recent Nigerian cohort demonstrated a seroprevalence of over 50% with active parasitism in the blood detected in over 20% (Lindstrom, et al., 2006). *Toxoplasma gondii* demonstrates parasitism of a number of animal hosts, most commonly of felines (the definitive host). Humans are typically infected by way of consumption of contaminated foods or exposure to contaminated soil or animal droppings. Vertical transmission is also possible, producing a dangerous congenital toxoplasmosis. One of the most frequent presentations of toxoplasmosis in the HIV population is toxoplasma encephalitis (Ioachim & Medeiros, 2009e); a histologically characteristic infection of lymph nodes is also common, however. Toxoplasmosis lymphadenopathy typically affects the lymph nodes of the head and neck; these are typically slightly enlarged and tender to palpation. The most frequently encountered histologic features are nodal follicular hyperplasia with interspersed aggregates and sheets of monocytoid lymphocytes and scattered clusters of epithelioid cells (see Figure 6). The monocytoid cells are immunoglobin producing B-cells (which will stain positive for B-cell markers) and can most typically be found in the subcapsular and paratrabecular locations while the epithelioid cells are histiocytes and are characteristically seen to encroach upon follicles but do not form true granulomas. Many HIV positive cases of toxoplasma

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 473

tumour necrosis factor (Jones, et al., 2001). Another study demonstrated that HHV-8 produces an interleukin-6 homologue (Osborne, et al., 1999). These factors together may account for the pathogenesis of the plasma cell variant, especially the multicentric form. The hyaline vascular variant, however, does not demonstrate as strong an association with HHV-8 and is most common in non-HIV patients, some with no evident immune

The hyaline vascular variant is the most common variant of the unicentric form, representing 80-90% of cases (Ioachim & Medeiros, 2009f). This variant typically presents as enlargement of a lymph node or lymph node group, often in the mediastinal region. This variant is also is more common than the plasma cell variant to affect younger patients. Few systemic symptoms are present in the hyaline vascular variant and most symptoms are related to mass effect. The classical histological features demonstrate preservation of overall lymph node architecture with an abundance of follicles (see Figure 7). In these follicles are one or two (sometime conjoined) germinal centres demonstrating prominent sclerosis and paucicellularity. The mantle/marginal cells of these follicles can be seen to form concentric layers (termed "onion-skinning") around the sclerosed germinal centres. The classic form also demonstrates a hyalinized penetrating vessel passing into the sclerotic germinal centre from the exterior of the follicle (forming so called "lollipop" lesions). Other interfollicular zone changes may be noted including extensive proliferation of small vascular channels (termed "high endothelial venules"). Sclerosis of the lymph node capsule is also a common finding. As noted previously, similar features may also be noted in cases of high-grade HIVassociated lymphadenopathy. The latter usually lack the classical lollipop lesions and the mantle/marginal zone onion-skinning is usually far less prominent. Ancillary tests for

The plasma cell variant is the less common of the unicentric forms (Ioachim & Medeiros, 2009f). As in the hyaline vascular variant, the unicentric plasma cell variant may present as an enlarging mass. Patients with this histological variant, however, are more prone to systemic clinical symptoms than those patients with the hyaline vascular variant. Typical symptoms include fevers, night sweats, malaise, and weight loss (these symptoms, in conjunction with enlarged lymph nodes often arouse suspicions of a lymphoproliferative disorder; biopsy for diagnosis is generally recommended). The plasma cell variant demonstrates the similar features of onion skinning and lollipop lesions, though the degree of hyalinization of the germinal centres is markedly reduced relative to the hyaline vascular

dysregulation; in these cases, the pathogenesis has yet to be elucidated.

HHV-8 may be helpful but typically the diagnosis is made histologically.

Fig. 7. Hyaline Vascular Variant of Castleman's Disease

lymphadenopathy will demonstrate free or engulfed trophozoites (which may be seen staining hook-like organisms H&E, either free floating or within macrophages); they are rarely observed in immunocompetent patients, however. The giemsa special stain can be used to highlight the organisms and some labs use immunohistochemistry with *Toxoplasma gondii* antibodies; PCR testing is the gold-standard, however. The histologic differential diagnosis is long—as would be expected in most cases with prominent collections of histiocytes. For this reason, it is advisable to use ancillary testing or special stains when examining lymph nodes with prominent collections of histiocytes. In addition to antibiotics for treatment of acute toxoplasmosis (such as pyrimethamine, sulfadiazine or clindamycin), the centres for disease control and prevention also currently recommend antibiotic prophylaxis for HIV patients with low CD4 counts (less than 200 cells/µL) (Kaplan, et al., 2009). Routine serologic testing of HIV positive patients is also recommended (Kaplan, et al., 2009).

Fig. 6. Toxoplasma Lymphadenitis: Hyperplastic follicle with moth-eaten appearance infiltrated by epithelioid histiocytes (arrow) with adjacent collection of monocytoid B-cells (arrowhead)

#### **2.4 Castleman's disease**

Castleman's disease, also known as angiofollicular lymphadenopathy, was first described by Castleman and colleagues in the 1950's. The first studies of Castleman's disease predated the recongnition of HIV and it was not until decades later that its connection to HIV and HHV-8 was recognized. We now recognize two distinct histological forms, the hyalinevascular and plasma variants. The plasma cell variant may further be categorized into unicentric and multicentric forms, the latter characteristically HIV-associated and of poorer prognosis.

The pathogenetic mechanisms leading to the development of Castleman's disease remain debated. Evidence supports HHV-8 as the etiologic agent in at least some cases; in one study, 50% of the unicentric plasma cell variant cases and nearly all cases of the mulcentric form were noted to be positive for HHV-8 (Soulier, et al., 1995). Further evidence in support of HIV and HHV-8 viral pathogens as etiologic agents stems from studies indicating a response of HIV associated multicentric Castleman's disease to antiviral agents (Casper, et al., 2004). Other studies have identified the lymphokine interleukin-6 (IL-6) as a potential contributor to the development of the plasma cell variant (Oksenhendler, et al., 2002). Interleukin-6 is a chemokine with a number of roles: it acts as an activator of T and B-cells; it also acts to downregulate pro-inflammatory cytokines by inhibiting interleukin-1 and

lymphadenopathy will demonstrate free or engulfed trophozoites (which may be seen staining hook-like organisms H&E, either free floating or within macrophages); they are rarely observed in immunocompetent patients, however. The giemsa special stain can be used to highlight the organisms and some labs use immunohistochemistry with *Toxoplasma gondii* antibodies; PCR testing is the gold-standard, however. The histologic differential diagnosis is long—as would be expected in most cases with prominent collections of histiocytes. For this reason, it is advisable to use ancillary testing or special stains when examining lymph nodes with prominent collections of histiocytes. In addition to antibiotics for treatment of acute toxoplasmosis (such as pyrimethamine, sulfadiazine or clindamycin), the centres for disease control and prevention also currently recommend antibiotic prophylaxis for HIV patients with low CD4 counts (less than 200 cells/µL) (Kaplan, et al., 2009). Routine serologic testing of HIV positive patients is also recommended (Kaplan, et al.,

Fig. 6. Toxoplasma Lymphadenitis: Hyperplastic follicle with moth-eaten appearance infiltrated by epithelioid histiocytes (arrow) with adjacent collection of monocytoid B-cells

Castleman's disease, also known as angiofollicular lymphadenopathy, was first described by Castleman and colleagues in the 1950's. The first studies of Castleman's disease predated the recongnition of HIV and it was not until decades later that its connection to HIV and HHV-8 was recognized. We now recognize two distinct histological forms, the hyalinevascular and plasma variants. The plasma cell variant may further be categorized into unicentric and multicentric forms, the latter characteristically HIV-associated and of poorer

The pathogenetic mechanisms leading to the development of Castleman's disease remain debated. Evidence supports HHV-8 as the etiologic agent in at least some cases; in one study, 50% of the unicentric plasma cell variant cases and nearly all cases of the mulcentric form were noted to be positive for HHV-8 (Soulier, et al., 1995). Further evidence in support of HIV and HHV-8 viral pathogens as etiologic agents stems from studies indicating a response of HIV associated multicentric Castleman's disease to antiviral agents (Casper, et al., 2004). Other studies have identified the lymphokine interleukin-6 (IL-6) as a potential contributor to the development of the plasma cell variant (Oksenhendler, et al., 2002). Interleukin-6 is a chemokine with a number of roles: it acts as an activator of T and B-cells; it also acts to downregulate pro-inflammatory cytokines by inhibiting interleukin-1 and

2009).

(arrowhead)

prognosis.

**2.4 Castleman's disease** 

tumour necrosis factor (Jones, et al., 2001). Another study demonstrated that HHV-8 produces an interleukin-6 homologue (Osborne, et al., 1999). These factors together may account for the pathogenesis of the plasma cell variant, especially the multicentric form. The hyaline vascular variant, however, does not demonstrate as strong an association with HHV-8 and is most common in non-HIV patients, some with no evident immune dysregulation; in these cases, the pathogenesis has yet to be elucidated.

The hyaline vascular variant is the most common variant of the unicentric form, representing 80-90% of cases (Ioachim & Medeiros, 2009f). This variant typically presents as enlargement of a lymph node or lymph node group, often in the mediastinal region. This variant is also is more common than the plasma cell variant to affect younger patients. Few systemic symptoms are present in the hyaline vascular variant and most symptoms are related to mass effect. The classical histological features demonstrate preservation of overall lymph node architecture with an abundance of follicles (see Figure 7). In these follicles are one or two (sometime conjoined) germinal centres demonstrating prominent sclerosis and paucicellularity. The mantle/marginal cells of these follicles can be seen to form concentric layers (termed "onion-skinning") around the sclerosed germinal centres. The classic form also demonstrates a hyalinized penetrating vessel passing into the sclerotic germinal centre from the exterior of the follicle (forming so called "lollipop" lesions). Other interfollicular zone changes may be noted including extensive proliferation of small vascular channels (termed "high endothelial venules"). Sclerosis of the lymph node capsule is also a common finding. As noted previously, similar features may also be noted in cases of high-grade HIVassociated lymphadenopathy. The latter usually lack the classical lollipop lesions and the mantle/marginal zone onion-skinning is usually far less prominent. Ancillary tests for HHV-8 may be helpful but typically the diagnosis is made histologically.

Fig. 7. Hyaline Vascular Variant of Castleman's Disease

The plasma cell variant is the less common of the unicentric forms (Ioachim & Medeiros, 2009f). As in the hyaline vascular variant, the unicentric plasma cell variant may present as an enlarging mass. Patients with this histological variant, however, are more prone to systemic clinical symptoms than those patients with the hyaline vascular variant. Typical symptoms include fevers, night sweats, malaise, and weight loss (these symptoms, in conjunction with enlarged lymph nodes often arouse suspicions of a lymphoproliferative disorder; biopsy for diagnosis is generally recommended). The plasma cell variant demonstrates the similar features of onion skinning and lollipop lesions, though the degree of hyalinization of the germinal centres is markedly reduced relative to the hyaline vascular

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 475

The treatment and prognosis of Castleman's disease depends greatly on both the histologic type as well as the presence of absence of multicentric disease. The hyaline vascular variant is often treated only with excision but adjuvant radiation therapy has been used in cases not amenable to complete resection (Roca, 2009). Some cases of both the hyaline vascular and plasma cell variants may be complicated by recurrence (chiefly the latter more than the former) (Roca, 2009). Cases of unicentric disease with persistent symptoms may also require steroids or chemotherapy (Roca, 2009). The multicentric form often requires aggressive treatment, frequently with chemotherapy (using regimens similar to those used in aggressive lymphomas, often combined with the anti-CD20 antibody rituximab) (Mylona, et al., 2008). There is controversy as to the actual benefit of anti-retroviral therapy; in their systematic review of Multicentric Castleman's disease in HIV, Mylona and colleagues determined that the survival outcomes from Multicentric Castleman's disease with and without antiretroviral therapies were comparable (Mylona, et al., 2008). The caveat to this latter observation is the reduction in incidence of Kaposi's sarcoma in patients on

**2.5 Polymorphous post-transplant lymphoproliferative disease-like B-cell** 

transplant lymphoproliferative disorder were encountered.

With the development of immunosuppressive medications permitting greatly improved successes of allogeneic transplant, it was noted that chronically immunosuppressed patients had a uniquely increased risk of a variety of lymphoproliferative disorders. These proliferations, 80% of B-cell lineage (Jacobson & LaCasce, 2010), were termed posttransplant lymphoproliferative disorders to reflect their unique clinicopathologic characteristics. For our purposes, it is interesting to note that, many decades after the concept of iatrogenic immunosuppression was introduced for the purposes of ameliorating transplant outcomes, the HIV/AIDS epidemic revealed an equally dangerous wave of immunosuppression in which many other cases clinically and histologically similar to post-

The first series of HIV-associated post-transplant lymphoproliferative disorders was reported in 1987. Four infant autopsy cases from patients with HIV (at that time, the human T-lymphocyte virus-III) and a clinical picture compatible with AIDS were included in the report. At autopsy, splenic and liver infiltrates were noted. These infiltrates, as well as other microscopic infiltrates in the lungs, were noted to consist of a polymorphous collection of inflammatory cells with a preponderance of lymphocytes. These lymphocytes were noted to be polyclonal by kappa and lamda immunohistochemistry. Currently, this entity is known as HIV-associated polymorphous lymphoproliferative disorder (Raphaёl, et al., 2008). Though few cases have been reported, some small series have explored the clinical and pathologic characteristic of this entity. HIV-associated polymorphous lymphoproliferative disorder typically presents in adults with low CD4 counts (typically less than 200 cells/µL) (Nador, et al., 2003). This entity is identified both within and without lymph nodes and tends most often to present unifocally. In contrast to most HIV-associated lymphomas, HIVassociated polymorphous lymphoproliferative disorder tends to lack a monotonous morphology, often demonstrating a mixture of lymphocytes, plasma cells, immunoblasts and histiocytes (see Figure 9). Of particular interest is the tendency for the majority of cells to bear plasmacytoid morphology. A variable degree of cytologic atypia and even necrosis

antiretrovirals (Mylona, et al., 2008).

**lymproliferative disorder** 

may also be observed.

variant; this may sometimes make the recognition of the lollipop lesions difficult (see Figure 8). Examination of the interfollicular zones is generally very helpful since it demonstrates numerous sheets of mature plasma cells (these generally stand out prominently since prominent plasma cells are rare in lymph nodes). The prominent vascularity noted in the interfollicular zones of the hyaline vascular variant is typically absent. Some cases may have foci demonstrating features of the hyaline vascular variant; when the histologic features of the plasma cell variant dominate, however, the latter diagnosis is appropriate. A number of studies have demonstrated a histological difference between plasma cell variant affected lymph nodes positive and negative for HHV-8 infection. In HHV-8 negative cases, residual hyperplastic follicles are usually notable; in contrast in HHV-8 positive cases, fewer residual follicles are noted and a more prominent interfollicular space vascular proliferation is present. Also, HHV-8 positive immunoblastic cells are also more prominent in the HHV-8 positive cases.

Fig. 8. Plasma Cell Variant of Castleman's Disease: A: Non-hyalinized "lollipop" lesion; B: High-power view demonstrating prominent interfollicular plasma cell infiltrates

Multicentric castleman's disease almost invariably involves multiple lymph nodes most typically demonstrating the histology seen in the unicentric plasma cell variant. The multicentric form has been traditionally under-recognized since its diagnosis requires positive detection of Castleman's disease in multiple locations. This form is also most often present in the context of HIV infection. Patients are nearly always symptomatic, usually presenting with fever, malaise, night sweats and weight loss (the so called B-symptoms) and may also present with hepatosplenomegaly, skin rash, edema and neurologic changes (Ioachim & Medeiros, 2009f). Other laboratory findings include cytopenias, elevated erythrocyte sedimentation rate and elevated C-reactive protein (Ioachim & Medeiros, 2009f). Diagnosis may be confused when a number of the latter clinical signs and symptoms are present, since these are suggestive of the so-called POEMS syndrome (this is a syndrome characterized by the presence of peripheral neuropathy, organomegaly, edema, monoclonal serum paraprotein, and skin changes). POEMS syndrome demonstrates significant diagnostic overlap Castleman's disease, especially the multicentric form. It is felt to be a para-neoplastic syndrome resulting from plasma cell disorders and is felt to have a common pathogenetic link with the plasma cell variant of Castleman's disease via interleukin-6 (Dispenzieri, 2007). The differential diagnosis can be further confused when HIV is considered; the latter, or rather the anti-retroviral drugs used to treat it, can cause peripheral neuropathies, skin changes, edema and other symptoms. In order to avoid diagnostic confusion, specific POEMS criteria have been set forth (Dispenzieri, 2007) and lymphadenopathy should be investigated histopathologically for features of Castleman's disease.

variant; this may sometimes make the recognition of the lollipop lesions difficult (see Figure 8). Examination of the interfollicular zones is generally very helpful since it demonstrates numerous sheets of mature plasma cells (these generally stand out prominently since prominent plasma cells are rare in lymph nodes). The prominent vascularity noted in the interfollicular zones of the hyaline vascular variant is typically absent. Some cases may have foci demonstrating features of the hyaline vascular variant; when the histologic features of the plasma cell variant dominate, however, the latter diagnosis is appropriate. A number of studies have demonstrated a histological difference between plasma cell variant affected lymph nodes positive and negative for HHV-8 infection. In HHV-8 negative cases, residual hyperplastic follicles are usually notable; in contrast in HHV-8 positive cases, fewer residual follicles are noted and a more prominent interfollicular space vascular proliferation is present. Also, HHV-8 positive immunoblastic cells are also more prominent in the HHV-8

Fig. 8. Plasma Cell Variant of Castleman's Disease: A: Non-hyalinized "lollipop" lesion; B:

Multicentric castleman's disease almost invariably involves multiple lymph nodes most typically demonstrating the histology seen in the unicentric plasma cell variant. The multicentric form has been traditionally under-recognized since its diagnosis requires positive detection of Castleman's disease in multiple locations. This form is also most often present in the context of HIV infection. Patients are nearly always symptomatic, usually presenting with fever, malaise, night sweats and weight loss (the so called B-symptoms) and may also present with hepatosplenomegaly, skin rash, edema and neurologic changes (Ioachim & Medeiros, 2009f). Other laboratory findings include cytopenias, elevated erythrocyte sedimentation rate and elevated C-reactive protein (Ioachim & Medeiros, 2009f). Diagnosis may be confused when a number of the latter clinical signs and symptoms are present, since these are suggestive of the so-called POEMS syndrome (this is a syndrome characterized by the presence of peripheral neuropathy, organomegaly, edema, monoclonal serum paraprotein, and skin changes). POEMS syndrome demonstrates significant diagnostic overlap Castleman's disease, especially the multicentric form. It is felt to be a para-neoplastic syndrome resulting from plasma cell disorders and is felt to have a common pathogenetic link with the plasma cell variant of Castleman's disease via interleukin-6 (Dispenzieri, 2007). The differential diagnosis can be further confused when HIV is considered; the latter, or rather the anti-retroviral drugs used to treat it, can cause peripheral neuropathies, skin changes, edema and other symptoms. In order to avoid diagnostic confusion, specific POEMS criteria have been set forth (Dispenzieri, 2007) and lymphadenopathy should be investigated histopathologically for features of Castleman's

High-power view demonstrating prominent interfollicular plasma cell infiltrates

positive cases.

disease.

The treatment and prognosis of Castleman's disease depends greatly on both the histologic type as well as the presence of absence of multicentric disease. The hyaline vascular variant is often treated only with excision but adjuvant radiation therapy has been used in cases not amenable to complete resection (Roca, 2009). Some cases of both the hyaline vascular and plasma cell variants may be complicated by recurrence (chiefly the latter more than the former) (Roca, 2009). Cases of unicentric disease with persistent symptoms may also require steroids or chemotherapy (Roca, 2009). The multicentric form often requires aggressive treatment, frequently with chemotherapy (using regimens similar to those used in aggressive lymphomas, often combined with the anti-CD20 antibody rituximab) (Mylona, et al., 2008). There is controversy as to the actual benefit of anti-retroviral therapy; in their systematic review of Multicentric Castleman's disease in HIV, Mylona and colleagues determined that the survival outcomes from Multicentric Castleman's disease with and without antiretroviral therapies were comparable (Mylona, et al., 2008). The caveat to this latter observation is the reduction in incidence of Kaposi's sarcoma in patients on antiretrovirals (Mylona, et al., 2008).

#### **2.5 Polymorphous post-transplant lymphoproliferative disease-like B-cell lymproliferative disorder**

With the development of immunosuppressive medications permitting greatly improved successes of allogeneic transplant, it was noted that chronically immunosuppressed patients had a uniquely increased risk of a variety of lymphoproliferative disorders. These proliferations, 80% of B-cell lineage (Jacobson & LaCasce, 2010), were termed posttransplant lymphoproliferative disorders to reflect their unique clinicopathologic characteristics. For our purposes, it is interesting to note that, many decades after the concept of iatrogenic immunosuppression was introduced for the purposes of ameliorating transplant outcomes, the HIV/AIDS epidemic revealed an equally dangerous wave of immunosuppression in which many other cases clinically and histologically similar to posttransplant lymphoproliferative disorder were encountered.

The first series of HIV-associated post-transplant lymphoproliferative disorders was reported in 1987. Four infant autopsy cases from patients with HIV (at that time, the human T-lymphocyte virus-III) and a clinical picture compatible with AIDS were included in the report. At autopsy, splenic and liver infiltrates were noted. These infiltrates, as well as other microscopic infiltrates in the lungs, were noted to consist of a polymorphous collection of inflammatory cells with a preponderance of lymphocytes. These lymphocytes were noted to be polyclonal by kappa and lamda immunohistochemistry. Currently, this entity is known as HIV-associated polymorphous lymphoproliferative disorder (Raphaёl, et al., 2008).

Though few cases have been reported, some small series have explored the clinical and pathologic characteristic of this entity. HIV-associated polymorphous lymphoproliferative disorder typically presents in adults with low CD4 counts (typically less than 200 cells/µL) (Nador, et al., 2003). This entity is identified both within and without lymph nodes and tends most often to present unifocally. In contrast to most HIV-associated lymphomas, HIVassociated polymorphous lymphoproliferative disorder tends to lack a monotonous morphology, often demonstrating a mixture of lymphocytes, plasma cells, immunoblasts and histiocytes (see Figure 9). Of particular interest is the tendency for the majority of cells to bear plasmacytoid morphology. A variable degree of cytologic atypia and even necrosis may also be observed.

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 477

et al., 2005; Besson, et al., 2001); this is in contrast to the evident predominance of Kaposi's sarcoma in the pre-anti-retroviral era (Carpenter, et al., 2004). Lymphomas in HIV also demonstrate unique preponderances for extra-nodal sites. Characteristic sites of extra-nodal primary involvement include the gastrointestinal tract and the central nervous system

Epidemiological data suggests that the overall incidence of many lymphomas has fallen since the introduction of anti-retroviral treatment. In particular, Besson et al noted a significant reduction in AIDS-related lymphomas in a retrospective review of lymphoma rates before and after the introduction of anti-retroviral treatment (Besson, et al., 2001). The particularly devastating primary central nervous system lymphoma characteristic of AIDS in the pre-antiretroviral era was found to virtually disappear in Besson et al.'s postantiretroviral cohort (Besson, et al., 2001). Similar observations were made in other studies, noting both improved survival for HIV-associated lymphoma patients and also an overall decrease in incidence (Wolf, et al., 2005; Biggar, et al., 2005; Sacktor, et al., 2001). (One notable exception is Hodgkin's lymphoma in HIV/AIDS patients which, in pre- and postantiretroviral cohorts has shown an increased incidence; this phenomenon will be explored

Burkitt's lymphoma is a highly aggressive lymphoma eponimized for Denis Burkitt, a British surgeon working in Africa in the 1950s. In his seminal paper, Burkitt described a peculiar "sarcoma" demonstrating a predilection for the jaws of African children. This lesion, Burkitt noted, was first described in 1938 by Christiansen; it was Burkitt's attention to the geographic preponderance of this lesion in Africa, in addition to his detailed clinicopathologic description of 38 cases, which led the disease to be named after him however (BURKITT, 1958). In the 1960s, by way of the work of O'Conor and Wright, the pathologic nature of Burkitt's lymphoma was further detailed: in particular, O'Conor identified the lesion as a lymphoma and Wright demonstrated that the lesion could be accurately histologically distinguished from other lymphomas (O'CONOR & DAVIES, 1960; WRIGHT, 1963). Later, in the 1970s, the association of EBV infection and Burkitt's lymphoma was elucidated with the first publication of EBV viral culture from lymphoblasts

The WHO currently acknowledges three major classes of Burkitt's lymphoma: the endemic form (referring to the entity described by Burkitt with a predilection for the jaws of African children); the sporadic form (more common to adults than children and without a specific geographical or anatomical predilection); and Burkitt's lymphoma arising in the context of immunocompromise (Leoncini, et al., 2008). The latter category was only recently added in order to highlight the unique clinical and pathogenetic features of this entity relative to the other two. Of note, all three entities share the common morphologic, immunophenotypic and molecular features which have come to define Burkitt's lymphoma; they are chiefly

The first few cases of HIV/AIDS associated Burkitt's lymphoma were reported in the early 1980s; likely the first case was reported by Doll and List (Doll & List, 1982) with a subsequent small case series reported by Ziegler and colleagues (Ziegler, et al., 1982). These cases all presented in homosexual men with AIDS-like clinical features (though these cases

obtained from Burkitt's lymphoma samples (EPSTEIN, et al., 1964).

distinguished from one another, therefore, on the basis of clinical features.

(Thirlwell, et al., 2003).

**3.1 Burkitt's lymphoma** 

in the later section "Hodgkin's Lymphoma.")

Fig. 9. HIV-associated Polymorphous post-transplant lymphoproliferative disease-like B-cell lymphoproliferative disorder: low-power view demonstrating follicular-lysis; inset: highpower view demonstrating polymorphous infiltrate

The immunophenotypic features of HIV-associated polymorphous lymphoproliferative disorder are also unique. Most cases will demonstrate some form of B-cell phenotype, either in the form of CD20 expression or by prevue of immunoglobulin expression (Nador, et al., 2003). Most, but certainly not all, will demonstrate kappa or lambda light-chain restriction and molecular evidence of clonal immunoglobulin gene rearrangement (Nador, et al., 2003). Some will even demonstrate co-expression of CD20 and CD43, considered an aberrant quality most often observed in B-cell lymphomas (Nador, et al., 2003). The largest series to our knowledge failed to demonstrate any cases demonstrating non-germline T-cell receptor rearrangements (Nador, et al., 2003). Most cases also demonstrate EBV co-infection with few also demonstrating HHV-8 co-infection (Nador, et al., 2003).

HIV-associated polymorphous lymphoproliferative disorders also tend to have a relatively better prognosis than other HIV-associated lymphomas, further reinforcing the debatable malignity of this entity. As noted by Nador and colleagues, many patients will do well, even in the absence of chemotherapy (Nador, et al., 2003). This observation was echoed in one such patient from our institution who responded well by way of optimization of his antiretroviral therapy. Minimal data is available for the development of optimal treatment regimens, however.

#### **3. HIV-associated lymphomas**

HIV patients have a 60-110 fold increased risk of developing a lymphoma relative to the HIV negative population at large (Raphaёl, et al., 2008; Lewden, et al., 2005; Whelan & Scadden, 2006). The incidence of HIV-associated lymphomas also increases with duration of disease (Besson, et al., 2001); this is a notable concern in the modern era of antiretrovirals in which the latency period from HIV infection to the development of AIDS is increasing. In recent studies exploring causes of death among HIV/AIDS patients treated with potent antiviral medications, lymphomas were reported as the most common malignancy (Lewden, et al., 2005; Besson, et al., 2001); this is in contrast to the evident predominance of Kaposi's sarcoma in the pre-anti-retroviral era (Carpenter, et al., 2004). Lymphomas in HIV also demonstrate unique preponderances for extra-nodal sites. Characteristic sites of extra-nodal primary involvement include the gastrointestinal tract and the central nervous system (Thirlwell, et al., 2003).

Epidemiological data suggests that the overall incidence of many lymphomas has fallen since the introduction of anti-retroviral treatment. In particular, Besson et al noted a significant reduction in AIDS-related lymphomas in a retrospective review of lymphoma rates before and after the introduction of anti-retroviral treatment (Besson, et al., 2001). The particularly devastating primary central nervous system lymphoma characteristic of AIDS in the pre-antiretroviral era was found to virtually disappear in Besson et al.'s postantiretroviral cohort (Besson, et al., 2001). Similar observations were made in other studies, noting both improved survival for HIV-associated lymphoma patients and also an overall decrease in incidence (Wolf, et al., 2005; Biggar, et al., 2005; Sacktor, et al., 2001). (One notable exception is Hodgkin's lymphoma in HIV/AIDS patients which, in pre- and postantiretroviral cohorts has shown an increased incidence; this phenomenon will be explored in the later section "Hodgkin's Lymphoma.")

#### **3.1 Burkitt's lymphoma**

476 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Fig. 9. HIV-associated Polymorphous post-transplant lymphoproliferative disease-like B-cell lymphoproliferative disorder: low-power view demonstrating follicular-lysis; inset: high-

The immunophenotypic features of HIV-associated polymorphous lymphoproliferative disorder are also unique. Most cases will demonstrate some form of B-cell phenotype, either in the form of CD20 expression or by prevue of immunoglobulin expression (Nador, et al., 2003). Most, but certainly not all, will demonstrate kappa or lambda light-chain restriction and molecular evidence of clonal immunoglobulin gene rearrangement (Nador, et al., 2003). Some will even demonstrate co-expression of CD20 and CD43, considered an aberrant quality most often observed in B-cell lymphomas (Nador, et al., 2003). The largest series to our knowledge failed to demonstrate any cases demonstrating non-germline T-cell receptor rearrangements (Nador, et al., 2003). Most cases also demonstrate EBV co-infection with few

HIV-associated polymorphous lymphoproliferative disorders also tend to have a relatively better prognosis than other HIV-associated lymphomas, further reinforcing the debatable malignity of this entity. As noted by Nador and colleagues, many patients will do well, even in the absence of chemotherapy (Nador, et al., 2003). This observation was echoed in one such patient from our institution who responded well by way of optimization of his antiretroviral therapy. Minimal data is available for the development of optimal treatment

HIV patients have a 60-110 fold increased risk of developing a lymphoma relative to the HIV negative population at large (Raphaёl, et al., 2008; Lewden, et al., 2005; Whelan & Scadden, 2006). The incidence of HIV-associated lymphomas also increases with duration of disease (Besson, et al., 2001); this is a notable concern in the modern era of antiretrovirals in which the latency period from HIV infection to the development of AIDS is increasing. In recent studies exploring causes of death among HIV/AIDS patients treated with potent antiviral medications, lymphomas were reported as the most common malignancy (Lewden,

power view demonstrating polymorphous infiltrate

also demonstrating HHV-8 co-infection (Nador, et al., 2003).

regimens, however.

**3. HIV-associated lymphomas** 

Burkitt's lymphoma is a highly aggressive lymphoma eponimized for Denis Burkitt, a British surgeon working in Africa in the 1950s. In his seminal paper, Burkitt described a peculiar "sarcoma" demonstrating a predilection for the jaws of African children. This lesion, Burkitt noted, was first described in 1938 by Christiansen; it was Burkitt's attention to the geographic preponderance of this lesion in Africa, in addition to his detailed clinicopathologic description of 38 cases, which led the disease to be named after him however (BURKITT, 1958). In the 1960s, by way of the work of O'Conor and Wright, the pathologic nature of Burkitt's lymphoma was further detailed: in particular, O'Conor identified the lesion as a lymphoma and Wright demonstrated that the lesion could be accurately histologically distinguished from other lymphomas (O'CONOR & DAVIES, 1960; WRIGHT, 1963). Later, in the 1970s, the association of EBV infection and Burkitt's lymphoma was elucidated with the first publication of EBV viral culture from lymphoblasts obtained from Burkitt's lymphoma samples (EPSTEIN, et al., 1964).

The WHO currently acknowledges three major classes of Burkitt's lymphoma: the endemic form (referring to the entity described by Burkitt with a predilection for the jaws of African children); the sporadic form (more common to adults than children and without a specific geographical or anatomical predilection); and Burkitt's lymphoma arising in the context of immunocompromise (Leoncini, et al., 2008). The latter category was only recently added in order to highlight the unique clinical and pathogenetic features of this entity relative to the other two. Of note, all three entities share the common morphologic, immunophenotypic and molecular features which have come to define Burkitt's lymphoma; they are chiefly distinguished from one another, therefore, on the basis of clinical features.

The first few cases of HIV/AIDS associated Burkitt's lymphoma were reported in the early 1980s; likely the first case was reported by Doll and List (Doll & List, 1982) with a subsequent small case series reported by Ziegler and colleagues (Ziegler, et al., 1982). These cases all presented in homosexual men with AIDS-like clinical features (though these cases

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 479

Fig. 10. HIV-associated Burkitt's lymphoma: diffuse "starry-sky" appearance of intermediate-sized cells; inset: high-power of Burkitt cells with scattered macrophages (containing tingible bodies or engulfed debris). The optically clear spaces are fat droplets

Similar immunophenotypic features to the endemic and sporadic Burkitt's forms are observed in HIV-associated Burkitt's lymphoma. The tumour cells are B-cells, demonstrating a variety of possible B-cell antigens including CD19, CD20 and CD22. Burkitt's lymphomas of all types demonstrate characteristic positivity for BCL-6 and CD10 (both immunomarkers of germinal centre phenotype). Unlike diffuse large B-cell lymphomas of germinal centre origin, furthermore, Burkitt's cells are only weakly positive (and often completely negative) for BCL2-. The Ki-67 proliferation immunostain is also characteristically positive nearly in 100%of Burkitt's cells (indicating an extremely high cell proliferation index). To aid in distinguishing Burkitt's lymphomas from precursor B-cell neoplasms (such as pre-B ALL and others, which may have overlapping morphologic features with Burkitt's lymphoma), the TdT stain (a stain indicating a primitive phenotype)

The molecular and cytogenetic features in Burkitt's lymphomas (while not entirely specific) are also characteristic. Translocation of the proto-oncogenic MYC region (which encodes a highly conserved cellular transcription factor) to the transcriptionally active IG heavy chain gene, t(8:14), is the most frequently encountered cytogenetic mutation in Burkitt's lymphoma. As previously noted, this translocation is not specific; MYC:IGH translocations have been observed in many diffuse large B-cell lymphomas (often themselves demonstrating high cellular proliferation indices) as well as other malignancies. Using sensitive molecular techniques, EBV virus sequences are observed in 50-70% of HIVassociated Burkitt's lymphomas. This is in contrast to the endemic form, which are virtually all found to contain EBV sequences, as well as the sporadic form which only rarely are

Chemotherapy for HIV-associated Burkitt's lymphoma is has evolved as the HIV/AIDS epidemic has progressed. Early on, when most HIV-associated Burkitt's patients presented having previously been diagnosed with AIDS, the chemotherapy treatment regimen applied to Burkitt's lymphomas focused on minimizing iatrogenic immunodeficiency. In these cases, the rapid progression characteristic of Burkitt's lymphoma was unfortunately allowed to sway the balance in favor of early mortality from lymphoma (Levine, et al., 2000). Later, with the introduction of anti-retrovirals and the accompanying benefit of improved immunostatus, chemotherapy has evolved toward similar regimens used in the endemic and sporadic Burkitt's lymphomas. Modern HIV-associated Burkitt's lymphomas seem to be

(this biopsy was taken from a mesenteric lymph node).

is characteristically negative in Burkitt's lymphoma.

found to harbor EBV co-infection.

were documented prior to the definition of AIDS and before the discovery of HIV) and involved both nodal and extra-nodal sites. Interestingly, these cases were etiologically associated with immunosuppression, despite a lack of awareness of HIV; the immunocompromised in these cases was originally thought to be associated with CMV infection or drug use.

More than two decades later, Burkitt's lymphoma has become one of the most common malignancies in patients with HIV/AIDS. According to the WHO, Burkitt's lymphoma accounts for 30% of all HIV-associated lymphomas (Raphaёl, et al., 2008); this number has been noted to reach as high as 40% in some series (Spina, et al., 1998). The WHO also notes that in patients with HIV, Burkitt's lymphoma is 1000 times more likely than in patients without concomitant HIV infection (Raphaёl, et al., 2008). An HIV positive patient can furthermore expect a 10-20% lifetime risk of Burkitt's lymphoma (Noy, 2010). In contrast to other HIV/AIDS associated lymphomas, Burkitt's lymphoma often presents relatively early on in the course of infection, often before the severe immunocompromise that precedes most HIV-associated lymphomas (Gaidano, et al., 1998). A recent large study also noted an intriguing decrease in the incidence of Burkitt's lymphoma in cases of profoundly low CD4 counts relative to less immunocompromised AIDS patients (Guech-Ongey, et al., 2010). Despite the distinct classification status afforded to HIV-associated Burkitt's lymphoma relative to other non-immunocompromised Burkitt's cases, controversies persist regarding the need for the distinction. In their cohort of African children with Burkitt's lymphoma, Orem and colleagues noted more similarity than difference between HIV positive and negative patients, with the caveat that HIV-positive Burkitt's patients tended to present with less lymphadenopathy and at higher stage than the others (Orem, et al., 2009). This was in keeping with the previous observations of Spina and colleagues noting similar clinicopathologic features amongst their cohort of HIV-positive and negative Burkitt's patients, including comparable disease free survival rates in HIV patients receiving antiretroviral therapy (Spina, et al., 1998). In contrast, epidemiologic data have suggested that Burkitt's lymphoma age-adjusted incidence may be influenced by HIV status (Mbulaiteye, et al., 2010).

HIV-associated Burkitt's lymphoma demonstrates identical classic histologic features to the other classes of Burkitt's lymphomas (see Figure 10). Whether nodal or extra-nodal, the classic Burkitt's histomorphology is a diffuse effacement of normal tissue architecture by sheets of cohesive intermediately sized (~12 µm) cells with minimal basophilic cytoplasm and central round to oval nuclei usually with multiple distinct nucleoli. These cells are interspersed by larger macrophages (bearing characteristic reniform or kidney-bean shaped nuclei) with enlarged pale cytoplasm often containing engulfed cellular debris; these interspersed "tangible-body" macrophages produced the characteristic "starry-sky" appearance. The macroscopic corollary to this histomorphology is the typical fish-flesh tan white irregular tumour mass. As in most lymphomas, however, there are no macroscopic features characteristic of given specific entity. One unique histopathological feature observed more frequently in HIV-associated Burkitt's lymphomas is Burkitt's lymphoma with a lymphoblastic morphology. In these cases, the tumour cells are notable for their eccentric nuclei, prominent central large nucleoli, and often contain cytoplasmic eosinophilic globules representing immunoglobulin deposits (Leoncini, et al., 2008). These features are observed in up to two-thirds of cases according to the WHO (Leoncini, et al., 2008).

were documented prior to the definition of AIDS and before the discovery of HIV) and involved both nodal and extra-nodal sites. Interestingly, these cases were etiologically associated with immunosuppression, despite a lack of awareness of HIV; the immunocompromised in these cases was originally thought to be associated with CMV

More than two decades later, Burkitt's lymphoma has become one of the most common malignancies in patients with HIV/AIDS. According to the WHO, Burkitt's lymphoma accounts for 30% of all HIV-associated lymphomas (Raphaёl, et al., 2008); this number has been noted to reach as high as 40% in some series (Spina, et al., 1998). The WHO also notes that in patients with HIV, Burkitt's lymphoma is 1000 times more likely than in patients without concomitant HIV infection (Raphaёl, et al., 2008). An HIV positive patient can furthermore expect a 10-20% lifetime risk of Burkitt's lymphoma (Noy, 2010). In contrast to other HIV/AIDS associated lymphomas, Burkitt's lymphoma often presents relatively early on in the course of infection, often before the severe immunocompromise that precedes most HIV-associated lymphomas (Gaidano, et al., 1998). A recent large study also noted an intriguing decrease in the incidence of Burkitt's lymphoma in cases of profoundly low CD4 counts relative to less immunocompromised AIDS patients (Guech-Ongey, et al., 2010). Despite the distinct classification status afforded to HIV-associated Burkitt's lymphoma relative to other non-immunocompromised Burkitt's cases, controversies persist regarding the need for the distinction. In their cohort of African children with Burkitt's lymphoma, Orem and colleagues noted more similarity than difference between HIV positive and negative patients, with the caveat that HIV-positive Burkitt's patients tended to present with less lymphadenopathy and at higher stage than the others (Orem, et al., 2009). This was in keeping with the previous observations of Spina and colleagues noting similar clinicopathologic features amongst their cohort of HIV-positive and negative Burkitt's patients, including comparable disease free survival rates in HIV patients receiving antiretroviral therapy (Spina, et al., 1998). In contrast, epidemiologic data have suggested that Burkitt's lymphoma age-adjusted incidence may be influenced by HIV status

HIV-associated Burkitt's lymphoma demonstrates identical classic histologic features to the other classes of Burkitt's lymphomas (see Figure 10). Whether nodal or extra-nodal, the classic Burkitt's histomorphology is a diffuse effacement of normal tissue architecture by sheets of cohesive intermediately sized (~12 µm) cells with minimal basophilic cytoplasm and central round to oval nuclei usually with multiple distinct nucleoli. These cells are interspersed by larger macrophages (bearing characteristic reniform or kidney-bean shaped nuclei) with enlarged pale cytoplasm often containing engulfed cellular debris; these interspersed "tangible-body" macrophages produced the characteristic "starry-sky" appearance. The macroscopic corollary to this histomorphology is the typical fish-flesh tan white irregular tumour mass. As in most lymphomas, however, there are no macroscopic features characteristic of given specific entity. One unique histopathological feature observed more frequently in HIV-associated Burkitt's lymphomas is Burkitt's lymphoma with a lymphoblastic morphology. In these cases, the tumour cells are notable for their eccentric nuclei, prominent central large nucleoli, and often contain cytoplasmic eosinophilic globules representing immunoglobulin deposits (Leoncini, et al., 2008). These features are

observed in up to two-thirds of cases according to the WHO (Leoncini, et al., 2008).

infection or drug use.

(Mbulaiteye, et al., 2010).

Fig. 10. HIV-associated Burkitt's lymphoma: diffuse "starry-sky" appearance of intermediate-sized cells; inset: high-power of Burkitt cells with scattered macrophages (containing tingible bodies or engulfed debris). The optically clear spaces are fat droplets (this biopsy was taken from a mesenteric lymph node).

Similar immunophenotypic features to the endemic and sporadic Burkitt's forms are observed in HIV-associated Burkitt's lymphoma. The tumour cells are B-cells, demonstrating a variety of possible B-cell antigens including CD19, CD20 and CD22. Burkitt's lymphomas of all types demonstrate characteristic positivity for BCL-6 and CD10 (both immunomarkers of germinal centre phenotype). Unlike diffuse large B-cell lymphomas of germinal centre origin, furthermore, Burkitt's cells are only weakly positive (and often completely negative) for BCL2-. The Ki-67 proliferation immunostain is also characteristically positive nearly in 100%of Burkitt's cells (indicating an extremely high cell proliferation index). To aid in distinguishing Burkitt's lymphomas from precursor B-cell neoplasms (such as pre-B ALL and others, which may have overlapping morphologic features with Burkitt's lymphoma), the TdT stain (a stain indicating a primitive phenotype) is characteristically negative in Burkitt's lymphoma.

The molecular and cytogenetic features in Burkitt's lymphomas (while not entirely specific) are also characteristic. Translocation of the proto-oncogenic MYC region (which encodes a highly conserved cellular transcription factor) to the transcriptionally active IG heavy chain gene, t(8:14), is the most frequently encountered cytogenetic mutation in Burkitt's lymphoma. As previously noted, this translocation is not specific; MYC:IGH translocations have been observed in many diffuse large B-cell lymphomas (often themselves demonstrating high cellular proliferation indices) as well as other malignancies. Using sensitive molecular techniques, EBV virus sequences are observed in 50-70% of HIVassociated Burkitt's lymphomas. This is in contrast to the endemic form, which are virtually all found to contain EBV sequences, as well as the sporadic form which only rarely are found to harbor EBV co-infection.

Chemotherapy for HIV-associated Burkitt's lymphoma is has evolved as the HIV/AIDS epidemic has progressed. Early on, when most HIV-associated Burkitt's patients presented having previously been diagnosed with AIDS, the chemotherapy treatment regimen applied to Burkitt's lymphomas focused on minimizing iatrogenic immunodeficiency. In these cases, the rapid progression characteristic of Burkitt's lymphoma was unfortunately allowed to sway the balance in favor of early mortality from lymphoma (Levine, et al., 2000). Later, with the introduction of anti-retrovirals and the accompanying benefit of improved immunostatus, chemotherapy has evolved toward similar regimens used in the endemic and sporadic Burkitt's lymphomas. Modern HIV-associated Burkitt's lymphomas seem to be

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 481

The macroscopic and microscopic features of diffuse large B-cell lymphoma in HIV/AIDS are comparable to those seen in the non-HIV population. Diffuse large B-cell lymphoma generally causes uniform enlargement of a node or group of nodes, often with a characteristic "fish flesh" macroscopic cut surface. On microscopic exam, sheets of large cells typically efface the normal lymph node architecture (these cells are often greater than 12 µm in maximal dimension) (see Figure 11). These neoplastic cells will demonstrate variable cytoplasm, variably sized nuclei, often with clumping or vesciculated chromatin and variable nucleoli. Areas of necrosis may be present, either as individual cells or clusters of cells. Mitotic figures are common and markedly atypical mitoses may be frequent. Often, however, it is difficult to ascribe any specific morphologic features other than diffuse architecture and large cell size to diffuse large B-cell lymphomas. When involving extranodal sites, the same diffuse pattern of effaced normal tissue architecture can also be seen, sometimes producing an obvious mass suspicious for a metastatic lesion. The predominant cell type will be the large neoplastic B-cell with variable numbers of intervening fibroblasts and inflammatory cells, sometimes producing a desmoplastic response. In these circumstances, it may be necessary to exclude a malignancy of origin other than the hematolymphoid system such as a carcinoma; these differential diagnoses are usually

Fig. 11. Diffuse Large B-cell Lymphoma: A: Diffuse pattern of infiltration by pleomorphic large cells; B: CD20 immunostain confirming B-cell lineage; C: CD10 immunostain suggesting germinal centre phenotype; D: BCL2 immunostain strongly and diffusely positive, as is consistent with a B-cell neoplasm; E: BCL6 immunostain suggesting germinal

Immunophenotyping, either by immunohistochemistry or flow cytometry (or ideally both) is required. Diffuse large B-cell lymphomas must, by definition, express one or more of the B-cell markers (e.g. CD19, CD20, CD79a, PAX5, etc.). Diffuse large B-cell lymphomas will frequently be positive for BCL2, though poorly differentiated forms may show only focal or patchy staining. Subsequent stratification of the lesion into "germinal centre" or "nongerminal centre" types is then recommended; the former will generally demonstrate expression of either BCL6 or CD10 (both germinal centre markers) whereas the latter are typically both BCL6 and CD10 negative and may also be MUM-1 positive. This form of stratification can be helpful in directing treatment. More specifically, it has been

quickly excluded using a panel of immunohistochemical stains.

centre phenotype

treated most commonly with combinations of cyclophosphamide, vincristine, doxorubicin, cytarabine, methotrexate with or without rituximab. Use of the latter anti-CD20 antibody (used frequently to augment the chemotherapeutic response in numerous B-cell lymphomas) remains controversial, in particular relative to the potential immunocompromise that the latter may induce (Levine, et al., 2000); studies exploring optimal treatment regimens in HIV-associated Burkitt's lymphoma are limited given the relative rarity of cases (Noy, 2010).

#### **3.2 Diffuse large B-cell lymphoma**

Diffuse large B-cell lymphoma is a heterogeneous category of lymphomas typified by an aggressive clinical aspect, a large cell histomorphology (i.e. neoplastic cells greater than twotimes the normal lymphocyte) and B-cell immunophenotype. This category has been the subject of a multitude of classifications over the course of the previous half-century. Currently, the most commonly used WHO classification acknowledges a number of possible "large B-cell" entities, of which diffuse large B-cell lymphoma not otherwise specified is probably the most common. Other diffuse large B-cell lymphoma subtypes (other than the NOS subtype) include rare entities such as primary diffuse large B-cell lymphoma of the central nervous system (an entity characteristically found in HIV/AIDS patients). The current WHO classification schema also allows for molecular and immunohistochemical subgroups in addition to morphologic classes; some of these subgroups have gained notoriety for their distinct therapeutic responses. While a complete description of diffuse large B-cell lymphoma is beyond the scope of this chapter, we will focus heretofore on the specific distinguishing features of HIV/AIDS related diffuse large B-cell lymphomas.

While the most recent edition of the WHO Classification of Hematolymphoid tumours suggests that diffuse large B-cell lymphoma in HIV is second to Burkitt's lymphoma as the most common lymphoma encountered in HIV/AIDS, newer studies have suggested that diffuse large B-cell lymphoma may in fact be more common (Raphaёl, et al., 2008; Mantina, et al., 2010; Gucalp & Noy, 2010). There also appear to have been changes in the incidence of diffuse large B-cell lymphoma over the course of the HIV/AIDS epidemic: at the outset in the early to mid 1980s, diffuse large cell lymphoma was very infrequently diagnosed; a marked increase in this diagnosis was seen toward the mid to late 1990s, however (Levine, et al., 2000). These latter results may relate to the observation that diffuse large B-cell lymphoma in HIV/AIDS appears to afflict patients in the setting of long-standing infection with concomitantly low CD4 counts, in contrast to other HIV-associated lymphomas (Raphaёl, et al., 2008). As with most HIV-associated lymphomas, diffuse large B-cell lymphoma can often be found in extra-nodal sites; this entity, furthermore, is commonly associated with central nervous system involvement (Agarwal, et al., 2009); furthermore, while overall numbers of central nervous system lymphomas in HIV/AIDS have dropped since the onset of the antiretroviral era, diffuse large-B-cell lymphoma currently seems to be the most frequent offender in the central nervous system (Agarwal, et al., 2009). Important clinical prognostic factors have been noted as pertaining to HIV-associated diffuse large Bcell lymphoma: Vaccher and colleagues noted the importance of CD4 counts, in addition to the other factors incorporated into the international prognostic index (namely age, advanced stage disease, elevated levels of serum lactate dehydrogenase as an indicator of rapid neoplastic cell turnover, extranodal spread and functional performance status) (Vaccher, et al., 1996).

treated most commonly with combinations of cyclophosphamide, vincristine, doxorubicin, cytarabine, methotrexate with or without rituximab. Use of the latter anti-CD20 antibody (used frequently to augment the chemotherapeutic response in numerous B-cell lymphomas) remains controversial, in particular relative to the potential immunocompromise that the latter may induce (Levine, et al., 2000); studies exploring optimal treatment regimens in HIV-associated Burkitt's lymphoma are limited given the

Diffuse large B-cell lymphoma is a heterogeneous category of lymphomas typified by an aggressive clinical aspect, a large cell histomorphology (i.e. neoplastic cells greater than twotimes the normal lymphocyte) and B-cell immunophenotype. This category has been the subject of a multitude of classifications over the course of the previous half-century. Currently, the most commonly used WHO classification acknowledges a number of possible "large B-cell" entities, of which diffuse large B-cell lymphoma not otherwise specified is probably the most common. Other diffuse large B-cell lymphoma subtypes (other than the NOS subtype) include rare entities such as primary diffuse large B-cell lymphoma of the central nervous system (an entity characteristically found in HIV/AIDS patients). The current WHO classification schema also allows for molecular and immunohistochemical subgroups in addition to morphologic classes; some of these subgroups have gained notoriety for their distinct therapeutic responses. While a complete description of diffuse large B-cell lymphoma is beyond the scope of this chapter, we will focus heretofore on the

specific distinguishing features of HIV/AIDS related diffuse large B-cell lymphomas.

While the most recent edition of the WHO Classification of Hematolymphoid tumours suggests that diffuse large B-cell lymphoma in HIV is second to Burkitt's lymphoma as the most common lymphoma encountered in HIV/AIDS, newer studies have suggested that diffuse large B-cell lymphoma may in fact be more common (Raphaёl, et al., 2008; Mantina, et al., 2010; Gucalp & Noy, 2010). There also appear to have been changes in the incidence of diffuse large B-cell lymphoma over the course of the HIV/AIDS epidemic: at the outset in the early to mid 1980s, diffuse large cell lymphoma was very infrequently diagnosed; a marked increase in this diagnosis was seen toward the mid to late 1990s, however (Levine, et al., 2000). These latter results may relate to the observation that diffuse large B-cell lymphoma in HIV/AIDS appears to afflict patients in the setting of long-standing infection with concomitantly low CD4 counts, in contrast to other HIV-associated lymphomas (Raphaёl, et al., 2008). As with most HIV-associated lymphomas, diffuse large B-cell lymphoma can often be found in extra-nodal sites; this entity, furthermore, is commonly associated with central nervous system involvement (Agarwal, et al., 2009); furthermore, while overall numbers of central nervous system lymphomas in HIV/AIDS have dropped since the onset of the antiretroviral era, diffuse large-B-cell lymphoma currently seems to be the most frequent offender in the central nervous system (Agarwal, et al., 2009). Important clinical prognostic factors have been noted as pertaining to HIV-associated diffuse large Bcell lymphoma: Vaccher and colleagues noted the importance of CD4 counts, in addition to the other factors incorporated into the international prognostic index (namely age, advanced stage disease, elevated levels of serum lactate dehydrogenase as an indicator of rapid neoplastic cell turnover, extranodal spread and functional performance status) (Vaccher, et

relative rarity of cases (Noy, 2010).

**3.2 Diffuse large B-cell lymphoma** 

al., 1996).

The macroscopic and microscopic features of diffuse large B-cell lymphoma in HIV/AIDS are comparable to those seen in the non-HIV population. Diffuse large B-cell lymphoma generally causes uniform enlargement of a node or group of nodes, often with a characteristic "fish flesh" macroscopic cut surface. On microscopic exam, sheets of large cells typically efface the normal lymph node architecture (these cells are often greater than 12 µm in maximal dimension) (see Figure 11). These neoplastic cells will demonstrate variable cytoplasm, variably sized nuclei, often with clumping or vesciculated chromatin and variable nucleoli. Areas of necrosis may be present, either as individual cells or clusters of cells. Mitotic figures are common and markedly atypical mitoses may be frequent. Often, however, it is difficult to ascribe any specific morphologic features other than diffuse architecture and large cell size to diffuse large B-cell lymphomas. When involving extranodal sites, the same diffuse pattern of effaced normal tissue architecture can also be seen, sometimes producing an obvious mass suspicious for a metastatic lesion. The predominant cell type will be the large neoplastic B-cell with variable numbers of intervening fibroblasts and inflammatory cells, sometimes producing a desmoplastic response. In these circumstances, it may be necessary to exclude a malignancy of origin other than the hematolymphoid system such as a carcinoma; these differential diagnoses are usually quickly excluded using a panel of immunohistochemical stains.

Fig. 11. Diffuse Large B-cell Lymphoma: A: Diffuse pattern of infiltration by pleomorphic large cells; B: CD20 immunostain confirming B-cell lineage; C: CD10 immunostain suggesting germinal centre phenotype; D: BCL2 immunostain strongly and diffusely positive, as is consistent with a B-cell neoplasm; E: BCL6 immunostain suggesting germinal centre phenotype

Immunophenotyping, either by immunohistochemistry or flow cytometry (or ideally both) is required. Diffuse large B-cell lymphomas must, by definition, express one or more of the B-cell markers (e.g. CD19, CD20, CD79a, PAX5, etc.). Diffuse large B-cell lymphomas will frequently be positive for BCL2, though poorly differentiated forms may show only focal or patchy staining. Subsequent stratification of the lesion into "germinal centre" or "nongerminal centre" types is then recommended; the former will generally demonstrate expression of either BCL6 or CD10 (both germinal centre markers) whereas the latter are typically both BCL6 and CD10 negative and may also be MUM-1 positive. This form of stratification can be helpful in directing treatment. More specifically, it has been

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 483

his newly reported disease, he abandoned any further academic exploration of this peculiar lymphadenopathy (and, furthermore, abandoned his life's work soon after) (Mukherhee, 2010). The disease was later further characterized by Samuel Wilks, who coined the eponym "Hodgkin disease" (Stone, 2010). It was not until decades after the first descriptions of Hodgkin's lymphoma that the microscopic feature of the disease—the Reed-Sternberg cell was discovered by Carl Sternberg of Germany (followed by Dorothy Reed Mendenhall) (Mukherhee, 2010). The current state of the art suggests that the Reed-Sternberg cell is a germinal centre B-cells, as evidenced by the detection of immunoglobulin gene rearrangements; these cells, it is thought, demonstrate abortive differentiation and therefore do not proceed to produce immunoglobulin (Ioachim & Medeiros, 2009g). Reed-Sternberg cells have also been found to produce a number of pro-inflammatory cytokines; these, it is believed, contribute to the spectrum of "by-stander" non-neoplastic inflammatory cells which make up the majority of the cellular constituents in Hodgkin's lymphomas (Ioachim

One of the earliest series of Hodgkin's lymphomas in a cohort of probable AIDS patients was reported by Ioachim and colleagues (Ioachim, et al., 1985). In this series, only 3 of 21 patients in this study were diagnosed with Hodgkin's lymphoma (Ioachim, et al., 1985). Since these first cases were diagnosed, many more cases of Hodgkin's lymphoma in HIV/AIDS patients have been identified and modern epidemiologic data suggests that HIVpositive patients have at least a 2-10-fold increased risk of developing Hodgkin's lymphoma relative to the HIV-negative population (Carbone, et al., 2009; Sissolak, et al., 2010). Despite this increase, Hodgkin's lymphoma is infrequent relative to diffuse large B-cell lymphoma and Burkitt's lymphoma (the latter two accounting for at least 60% of HIV-associated

The pathobiology of HIV-associated Hodgkin's lymphoma serves to demonstrate the unique environment of immunocompromise that HIV infection causes, even in patients with relatively high CD4 counts or on antiretroviral regimens. More specifically, epidemiologists have observed not only an increased incidence of Hodgkin's lymphoma with severe AIDS related immunocompromise but also a paradoxical increased incidence of Hodgkin's lymphoma in HIV-positive patients without AIDS after the introduction of antiretrovirals. In their large cohort study for instance, Biggar and colleagues noted that there was an increased risk of development of Hodgkin's lymphoma in HIV-positive patients with only moderate immunosuppression (Biggar, et al., 2006). Experts have offered hypotheses to explain these unique observations. It is thought that the Reed-Sternberg cell of Hodgkin's lymphoma relies upon intact immunomodulatory signals from T-cells. With T-cell numbers sufficiently stabilized in HIV-infection treated with antiretrovirals—but in an immunologically active environment caused by chronic HIV infection with upregulated inflammatory cytokine production—Reed-Sternberg cells may be inadvertently stimulated and Hodgkin's lymphoma may develop (Sissolak, et al., 2010). Despite the relatively low risk of Hodgkin's lymphoma in HIV-infection, therefore, it is incumbent that HIV patients on anti-retroviral therapy be carefully surveilled for the development of potential Hodgkin's

As noted previously, HIV/AIDS patients are at extremely high risk for lymphadenopathy; when these patients present with symptoms of fever, chills, night sweats and weight loss, furthermore, a long differential must be considered—with lymphomas high on the list. Most HIV-associated Hodgkin's cases will present with lymphadenopathy, typically in a cervical

& Medeiros, 2009g).

lymphoma.

lymphomas) (Raphaёl, et al., 2008).

demonstrated by means of both gene expression profiling (and the surrogate use of immunophenotyping) that diffuse large B-cell lymphomas with a germinal centre phenotype/gene expression profile have a better prognosis (Chang, et al., 2004). Additional staining with Ki67 to demonstrate neoplastic cell proliferation index is also recommended. Diffuse large B-cell lymphomas typically demonstrate a Ki67 proliferation index less than 60-70%; higher indices may suggest a more aggressive entity. High Ki67 index in combination with BCL6 positivity and weak BCL2 staining raises the possibility of a lymphoma intermediate between a diffuse large B-cell and Burkitt's lymphoma. Staining with CD38 or CD138 is also helpful in ruling out a potentially highly aggressive plasmablastic phenotype. Studies have also demonstrated a negative association between HIV-associated diffuse large B-cell lymphoma progression free-survival as well as overall survival and co-infection with EBV (Park, et al., 2007). In our experience however studies exploring the contribution of EBV to the specific pathogenesis of HIV-associated diffuse large B-cell lymphoma are lacking.

The treatment of HIV-associated diffuse large B-cell lymphoma has traditionally been the same as those cases in the HIV-negative population, namely with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone. This approach has been met with controversy however as a variety of studies using more traditionally "aggressive" chemotherapy regimens, regimens with concomitant rituximab therapy and even regimens incorporating a reduction in antiretroviral therapy have shown promising results in their own rights. Navaro and colleagues demonstrated that patients with HIV-associated diffuse large B-cell lymphoma treated with routine chemotherapy but with additional antiretrovirals demonstrated no significant differences in clinical and laboratory parameters relative to HIV-negative cases of diffuse large B-cell lymphoma (with the caveat that HIV cases were more likely to present with B-symptoms) (Navarro, et al., 2005) Ezzat and colleagues recently indicated that a combination of rituximab with standard chemotherapy and antiretrovirals improved the survival of HIV patients with diffuse large B-cell lymphoma; this study also incorporated epidemiologic data from before and after the antiretroviral era to elucidate a difference in survivability (Ezzat, et al., 2007). In a recent study, Dunleavy and colleagues performed a trial of chemotherapy using short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab after having halted antiretroviral therapy for the duration of the chemotherapy (with subsequent restart after completion) (Dunleavy, et al., 2010). In their cohort of 33 authors reported a progression free survival and overall survival of 84% and 68% respectively after a median follow-up of 5 years; 10 deaths were reported with 5 attributed to HIV (3 due to purported previous persistent mycobacterial infection) (Dunleavy, et al., 2010). Head-to-head outcome comparisons, with and without antiretroviral therapy (with particular attention to the longterm effects of short-term iatrogenic HIV-related immunosuppression) have yet to be reported.

#### **3.3 Hodgkin's lymphoma**

Thomas Hodgkin, a British physician, first described this strange disease in 1832. Over the course of his work as a pathologist working in Guy's Hospital's anatomical library in London, he noted a number of patients at autopsy with bizarre lymphadenopathy (Mukherhee, 2010). These patients were frequently young and male and died rapidly after a brief fever-stricken illness (Mukherhee, 2010). Having received a less than stellar response to

demonstrated by means of both gene expression profiling (and the surrogate use of immunophenotyping) that diffuse large B-cell lymphomas with a germinal centre phenotype/gene expression profile have a better prognosis (Chang, et al., 2004). Additional staining with Ki67 to demonstrate neoplastic cell proliferation index is also recommended. Diffuse large B-cell lymphomas typically demonstrate a Ki67 proliferation index less than 60-70%; higher indices may suggest a more aggressive entity. High Ki67 index in combination with BCL6 positivity and weak BCL2 staining raises the possibility of a lymphoma intermediate between a diffuse large B-cell and Burkitt's lymphoma. Staining with CD38 or CD138 is also helpful in ruling out a potentially highly aggressive plasmablastic phenotype. Studies have also demonstrated a negative association between HIV-associated diffuse large B-cell lymphoma progression free-survival as well as overall survival and co-infection with EBV (Park, et al., 2007). In our experience however studies exploring the contribution of EBV to the specific pathogenesis of HIV-associated diffuse

The treatment of HIV-associated diffuse large B-cell lymphoma has traditionally been the same as those cases in the HIV-negative population, namely with a combination of cyclophosphamide, doxorubicin, vincristine, and prednisone. This approach has been met with controversy however as a variety of studies using more traditionally "aggressive" chemotherapy regimens, regimens with concomitant rituximab therapy and even regimens incorporating a reduction in antiretroviral therapy have shown promising results in their own rights. Navaro and colleagues demonstrated that patients with HIV-associated diffuse large B-cell lymphoma treated with routine chemotherapy but with additional antiretrovirals demonstrated no significant differences in clinical and laboratory parameters relative to HIV-negative cases of diffuse large B-cell lymphoma (with the caveat that HIV cases were more likely to present with B-symptoms) (Navarro, et al., 2005) Ezzat and colleagues recently indicated that a combination of rituximab with standard chemotherapy and antiretrovirals improved the survival of HIV patients with diffuse large B-cell lymphoma; this study also incorporated epidemiologic data from before and after the antiretroviral era to elucidate a difference in survivability (Ezzat, et al., 2007). In a recent study, Dunleavy and colleagues performed a trial of chemotherapy using short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab after having halted antiretroviral therapy for the duration of the chemotherapy (with subsequent restart after completion) (Dunleavy, et al., 2010). In their cohort of 33 authors reported a progression free survival and overall survival of 84% and 68% respectively after a median follow-up of 5 years; 10 deaths were reported with 5 attributed to HIV (3 due to purported previous persistent mycobacterial infection) (Dunleavy, et al., 2010). Head-to-head outcome comparisons, with and without antiretroviral therapy (with particular attention to the longterm effects of short-term iatrogenic HIV-related immunosuppression) have yet to be

Thomas Hodgkin, a British physician, first described this strange disease in 1832. Over the course of his work as a pathologist working in Guy's Hospital's anatomical library in London, he noted a number of patients at autopsy with bizarre lymphadenopathy (Mukherhee, 2010). These patients were frequently young and male and died rapidly after a brief fever-stricken illness (Mukherhee, 2010). Having received a less than stellar response to

large B-cell lymphoma are lacking.

reported.

**3.3 Hodgkin's lymphoma** 

his newly reported disease, he abandoned any further academic exploration of this peculiar lymphadenopathy (and, furthermore, abandoned his life's work soon after) (Mukherhee, 2010). The disease was later further characterized by Samuel Wilks, who coined the eponym "Hodgkin disease" (Stone, 2010). It was not until decades after the first descriptions of Hodgkin's lymphoma that the microscopic feature of the disease—the Reed-Sternberg cell was discovered by Carl Sternberg of Germany (followed by Dorothy Reed Mendenhall) (Mukherhee, 2010). The current state of the art suggests that the Reed-Sternberg cell is a germinal centre B-cells, as evidenced by the detection of immunoglobulin gene rearrangements; these cells, it is thought, demonstrate abortive differentiation and therefore do not proceed to produce immunoglobulin (Ioachim & Medeiros, 2009g). Reed-Sternberg cells have also been found to produce a number of pro-inflammatory cytokines; these, it is believed, contribute to the spectrum of "by-stander" non-neoplastic inflammatory cells which make up the majority of the cellular constituents in Hodgkin's lymphomas (Ioachim & Medeiros, 2009g).

One of the earliest series of Hodgkin's lymphomas in a cohort of probable AIDS patients was reported by Ioachim and colleagues (Ioachim, et al., 1985). In this series, only 3 of 21 patients in this study were diagnosed with Hodgkin's lymphoma (Ioachim, et al., 1985). Since these first cases were diagnosed, many more cases of Hodgkin's lymphoma in HIV/AIDS patients have been identified and modern epidemiologic data suggests that HIVpositive patients have at least a 2-10-fold increased risk of developing Hodgkin's lymphoma relative to the HIV-negative population (Carbone, et al., 2009; Sissolak, et al., 2010). Despite this increase, Hodgkin's lymphoma is infrequent relative to diffuse large B-cell lymphoma and Burkitt's lymphoma (the latter two accounting for at least 60% of HIV-associated lymphomas) (Raphaёl, et al., 2008).

The pathobiology of HIV-associated Hodgkin's lymphoma serves to demonstrate the unique environment of immunocompromise that HIV infection causes, even in patients with relatively high CD4 counts or on antiretroviral regimens. More specifically, epidemiologists have observed not only an increased incidence of Hodgkin's lymphoma with severe AIDS related immunocompromise but also a paradoxical increased incidence of Hodgkin's lymphoma in HIV-positive patients without AIDS after the introduction of antiretrovirals. In their large cohort study for instance, Biggar and colleagues noted that there was an increased risk of development of Hodgkin's lymphoma in HIV-positive patients with only moderate immunosuppression (Biggar, et al., 2006). Experts have offered hypotheses to explain these unique observations. It is thought that the Reed-Sternberg cell of Hodgkin's lymphoma relies upon intact immunomodulatory signals from T-cells. With T-cell numbers sufficiently stabilized in HIV-infection treated with antiretrovirals—but in an immunologically active environment caused by chronic HIV infection with upregulated inflammatory cytokine production—Reed-Sternberg cells may be inadvertently stimulated and Hodgkin's lymphoma may develop (Sissolak, et al., 2010). Despite the relatively low risk of Hodgkin's lymphoma in HIV-infection, therefore, it is incumbent that HIV patients on anti-retroviral therapy be carefully surveilled for the development of potential Hodgkin's lymphoma.

As noted previously, HIV/AIDS patients are at extremely high risk for lymphadenopathy; when these patients present with symptoms of fever, chills, night sweats and weight loss, furthermore, a long differential must be considered—with lymphomas high on the list. Most HIV-associated Hodgkin's cases will present with lymphadenopathy, typically in a cervical

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 485

Treatment approaches for HIV-associated Hodgkin's lymphomas are often similar to those used in non-HIV patients. Limited disease may be treated by a combination of adriamycin, bleomycin, vinblastine and dacarbazine chemotherapy, often with adjuvant radiation therapy to the involved area (if restricted to an amenable nodal region). Advanced cases are not typically amenable to radiation therapy (Sissolak, et al., 2010). Advanced cases may also be considered for bone marrow transplant. The use of rituximab as an adjuvant biological agent may also be considered; those cases demonstrating a large complement of CD20 cells (whether Reed-Sternberg or not) may respond (Sissolak, et al., 2010). Notably, studies looking at the appropriateness of traditional treatments for Hodgkin's disease in the context of HIV-positivity remain ongoing and optimal regimens may yet be discovered. Despite the potential etiologic impact of antiretroviral therapy in cases of HIV-associated Hodgkin's lymphoma, its use is still warranted given the reduction in risk of opportunistic infection (and other HIV-associated malignancies) in order that optimal chemotherapeutic regimens

Plasmablastic lymphoma is a highly aggressive B-cell lymphoma characterized histologically by a diffuse proliferation of large cells with plasmacytoid features. This entity was only recently recognized and has been shown to occur not only in HIV/AIDS patients but in other immunodeficient individuals, in particular in patients chronically immunosuppressed from solid organ transplants (Rafaniello Raviele, et al., 2009). In its most recent editions, probably owing to its unique clinicopathologic features, plasmablastic lymphoma was classified as an entity unto itself (Raphaёl, et al., 2008). Many authors (and other previous classifications) consider plasmablastic lymphoma to be a variant of diffuse large B-cell lymphoma; Chang and colleagues, for example, demonstrated that plasmablastic lymphoma shows a number of overlapping genomic lesions with diffuse large B-cell lymphoma by comparative genomic hybridization techniques (Chang, et al., 2009). Nonetheless, from a treatment and prognostic perspective, plasmablastic lymphoma appears to differ from diffuse large B-cell lymphoma and its classification as a distinct entity

A number of reports have noted plasmablastic lymphoma arising from transformation from various low-grade lymphomas. Ouansafi and colleagues demonstrated evolution of a follicular lymphoma to plasmablastic lymphoma by means of sequence comparison of the immunoglobulin heavy chain gene rearrangements in both tumours (Ouansafi, et al., 2010). Another report of a plasmablastic lymphoma was described arising in concert with a monoclonal population of plasma cells suggesting potential transformation of the former from the latter (Qing, et al., 2011). Even more intriguing is the case report of concurrent plasmablastic lymphoma and classical Hodgkin's lymphoma arising in a patient with relative immunosuppression from history of chronic lymphocytic leukemia/lymphoma; this case was notably EBV positive (Foo, et al., 2010). The grand majority of cases, however,

Estimates of the incidence of plasmablastic lymphoma are based on the few reported cases and small series; a recent review of the literature reported approximately 180 cases of plasmablastic lymphoma (Rafaniello Raviele, et al., 2009). While this number is undoubtedly an underestimate (since at least one other unreported case from our own institution in the previous 5 years was encountered), it speaks to the rarity of this entity. The majority of cases

be instituted (Carbone, et al., 2009).

is reasonable (Montes-Moreno, et al., 2010).

appear not to represent transformation from a lower grade lesion.

**3.4 Plasmablastic lymphoma** 

distribution (Sissolak, et al., 2010). Perhaps due to the unique pathobiology of HIVassociated Hodgkin's lymphomas, many HIV-associated Hodgkin patients present at a relatively young age (in addition to possibly presenting earlier on in the course of infection). Many of these patients will also present with advanced stage disease relative to the HIVnegative population (Sissolak, et al., 2010). High clinical suspicion warrants lymph node biopsy, which is required for accurate diagnosis. Most authorities also recommend an initial staging bone marrow biopsy given that 40-60% of cases present with bone marrow involvement (Sissolak, et al., 2010).

While a complete discussion of the possible histological subtypes of Hodgkin's lymphoma is beyond the scope of this chapter, it is warranted to discuss the histopathologic features of the most common form, namely the mixed cellularity subtype of classical Hodgkin's lymphoma. As in all the classical Hodgkin lymphoma subtypes, mixed cellularity subtype is characterized by the presence of scattered Reed-Sternberg cells (see Figure 12). These have a characteristic morphology: the cells are large (~15-40 µm) with abundant lightly basophilic cytoplasm and they have a central bilobed nucleus, each lobe having a central large inclusion-like eosinophilic nucleolus. More importantly relative to the other forms of Hodgkin's lymphoma, the mixed cellularity subtype demonstrates a diffuse effacement of normal lymph node architecture by a mixed population of inflammatory cells consisting of variable number of eosinophils, small lymphocytes, histiocytes, plasma cells and neutrophils. Also, this subtype lacks the characteristic fibrous bands of sclerosis that typify the nodular sclerosing subtype.

Fig. 12. Hodgkin's lymphoma: A: High-power view demonstrating Reed-Sternberg cell (arrow); B & C: CD15 and CD30 immunostains, respectively; D: EBV stain positive in Reed-Sternberg cell (arrow)

The immunophenotype is also characteristic of mixed cellularity Hodgkin's lymphoma. In particular, the Reed-Sternberg cell is characteristically positive for CD15 (a membrane protein involved in cell adhesion present on a number of hematolymphoid lineage cells) and CD30 (a marker of cell activation). Reed-Sternberg cells seen in Classical Hodgkin's lymphoma are also characteristically negative for the standard B-cell markers CD19 and CD20. Proof of the B-cell nature of Reed-Sternberg cells, however, may be derived from their frequent positive staining for PAX5, a B-cell transcription factor. Most cases of HIVassociated Hodgkin's lymphoma are also positive for EBV co-infection, often identifiable using the immunostain for the EBV-latent membrane protein antigen. This is in contrast to notably fewer cases of EBV positivity outside of HIV-infection (Carbone, et al., 2009).

Treatment approaches for HIV-associated Hodgkin's lymphomas are often similar to those used in non-HIV patients. Limited disease may be treated by a combination of adriamycin, bleomycin, vinblastine and dacarbazine chemotherapy, often with adjuvant radiation therapy to the involved area (if restricted to an amenable nodal region). Advanced cases are not typically amenable to radiation therapy (Sissolak, et al., 2010). Advanced cases may also be considered for bone marrow transplant. The use of rituximab as an adjuvant biological agent may also be considered; those cases demonstrating a large complement of CD20 cells (whether Reed-Sternberg or not) may respond (Sissolak, et al., 2010). Notably, studies looking at the appropriateness of traditional treatments for Hodgkin's disease in the context of HIV-positivity remain ongoing and optimal regimens may yet be discovered. Despite the potential etiologic impact of antiretroviral therapy in cases of HIV-associated Hodgkin's lymphoma, its use is still warranted given the reduction in risk of opportunistic infection (and other HIV-associated malignancies) in order that optimal chemotherapeutic regimens be instituted (Carbone, et al., 2009).

#### **3.4 Plasmablastic lymphoma**

484 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

distribution (Sissolak, et al., 2010). Perhaps due to the unique pathobiology of HIVassociated Hodgkin's lymphomas, many HIV-associated Hodgkin patients present at a relatively young age (in addition to possibly presenting earlier on in the course of infection). Many of these patients will also present with advanced stage disease relative to the HIVnegative population (Sissolak, et al., 2010). High clinical suspicion warrants lymph node biopsy, which is required for accurate diagnosis. Most authorities also recommend an initial staging bone marrow biopsy given that 40-60% of cases present with bone marrow

While a complete discussion of the possible histological subtypes of Hodgkin's lymphoma is beyond the scope of this chapter, it is warranted to discuss the histopathologic features of the most common form, namely the mixed cellularity subtype of classical Hodgkin's lymphoma. As in all the classical Hodgkin lymphoma subtypes, mixed cellularity subtype is characterized by the presence of scattered Reed-Sternberg cells (see Figure 12). These have a characteristic morphology: the cells are large (~15-40 µm) with abundant lightly basophilic cytoplasm and they have a central bilobed nucleus, each lobe having a central large inclusion-like eosinophilic nucleolus. More importantly relative to the other forms of Hodgkin's lymphoma, the mixed cellularity subtype demonstrates a diffuse effacement of normal lymph node architecture by a mixed population of inflammatory cells consisting of variable number of eosinophils, small lymphocytes, histiocytes, plasma cells and neutrophils. Also, this subtype lacks the characteristic fibrous bands of sclerosis that typify

Fig. 12. Hodgkin's lymphoma: A: High-power view demonstrating Reed-Sternberg cell (arrow); B & C: CD15 and CD30 immunostains, respectively; D: EBV stain positive in Reed-

notably fewer cases of EBV positivity outside of HIV-infection (Carbone, et al., 2009).

The immunophenotype is also characteristic of mixed cellularity Hodgkin's lymphoma. In particular, the Reed-Sternberg cell is characteristically positive for CD15 (a membrane protein involved in cell adhesion present on a number of hematolymphoid lineage cells) and CD30 (a marker of cell activation). Reed-Sternberg cells seen in Classical Hodgkin's lymphoma are also characteristically negative for the standard B-cell markers CD19 and CD20. Proof of the B-cell nature of Reed-Sternberg cells, however, may be derived from their frequent positive staining for PAX5, a B-cell transcription factor. Most cases of HIVassociated Hodgkin's lymphoma are also positive for EBV co-infection, often identifiable using the immunostain for the EBV-latent membrane protein antigen. This is in contrast to

involvement (Sissolak, et al., 2010).

the nodular sclerosing subtype.

Sternberg cell (arrow)

Plasmablastic lymphoma is a highly aggressive B-cell lymphoma characterized histologically by a diffuse proliferation of large cells with plasmacytoid features. This entity was only recently recognized and has been shown to occur not only in HIV/AIDS patients but in other immunodeficient individuals, in particular in patients chronically immunosuppressed from solid organ transplants (Rafaniello Raviele, et al., 2009). In its most recent editions, probably owing to its unique clinicopathologic features, plasmablastic lymphoma was classified as an entity unto itself (Raphaёl, et al., 2008). Many authors (and other previous classifications) consider plasmablastic lymphoma to be a variant of diffuse large B-cell lymphoma; Chang and colleagues, for example, demonstrated that plasmablastic lymphoma shows a number of overlapping genomic lesions with diffuse large B-cell lymphoma by comparative genomic hybridization techniques (Chang, et al., 2009). Nonetheless, from a treatment and prognostic perspective, plasmablastic lymphoma appears to differ from diffuse large B-cell lymphoma and its classification as a distinct entity is reasonable (Montes-Moreno, et al., 2010).

A number of reports have noted plasmablastic lymphoma arising from transformation from various low-grade lymphomas. Ouansafi and colleagues demonstrated evolution of a follicular lymphoma to plasmablastic lymphoma by means of sequence comparison of the immunoglobulin heavy chain gene rearrangements in both tumours (Ouansafi, et al., 2010). Another report of a plasmablastic lymphoma was described arising in concert with a monoclonal population of plasma cells suggesting potential transformation of the former from the latter (Qing, et al., 2011). Even more intriguing is the case report of concurrent plasmablastic lymphoma and classical Hodgkin's lymphoma arising in a patient with relative immunosuppression from history of chronic lymphocytic leukemia/lymphoma; this case was notably EBV positive (Foo, et al., 2010). The grand majority of cases, however, appear not to represent transformation from a lower grade lesion.

Estimates of the incidence of plasmablastic lymphoma are based on the few reported cases and small series; a recent review of the literature reported approximately 180 cases of plasmablastic lymphoma (Rafaniello Raviele, et al., 2009). While this number is undoubtedly an underestimate (since at least one other unreported case from our own institution in the previous 5 years was encountered), it speaks to the rarity of this entity. The majority of cases

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 487

In order to distinguish plasmablastic lymphoma for other diffuse lymphomas (and to rule out a simple but more common diffuse large B-cell lymphoma), immunophenotyping is crucial. In plasmablastic lymphoma, in addition to demonstrating minimal positivity for leukocyte common antigen (CD45), CD20 and CD79a, the tumoural cells are invariably positive for CD138; these features are of striking resemblance to the normal immunophenotype of plasma cells. Other post germinal centre markers such as MUM-1 and CD38 are also often positive. Some additional pathologic features that may potentially confuse the diagnosis include positivity for CD3, CD4 and CD56, all of which have been reported to be positive in some cases of plasmablastic lymphoma (Rafaniello Raviele, et al., 2009). Given the primary immunophenotypic differential diagnosis of a plasma cell malignancy (i.e. based on the combination of CD38, CD138, MUM-1 positivity with CD45, CD20 and CD79a negativity), the plasmablastic moniker is assigned given the histomorphology in combination with the absence of clinical features in support of a plasma cell dyscrasia. Plasma cell neoplasms also do not demonstrate positivity for EBV. Other possible differential diagnoses include carcinomas and melanomas, which can be ruled out by the way of an immunohistochemical panel of cytokeratins and melanoma markers. Goedhals et al. explored the electron microscopic features of ten plasmablastic lymphomas and found that 90% of cases demonstrated the consistent plasma cell features of eccentric

nuclei with concentric perinuclear endoplasmic reticulum (Goedhals, et al., 2006)

al., 2009); trials looking at optimal treatment regimens are lacking, however.

**3.5 Primary effusion/body cavity lymphoma** 

EBV.

The outcomes in cases of plasmablastic lymphoma are usually poor. In their in depth review, Raviele and colleagues noted disease related deaths in 59.6% of cases of oral-type plasmablastic lymphoma at an average of 10.4 months post-diagnosis as compared to 58.6%at an average of 6.2 months for the extra-oral type (Rafaniello Raviele, et al., 2009). Raviele and colleagues also noted a survival advantage to the use of highly active antiretrovirals (Rafaniello Raviele, et al., 2009). Given the rarity of plasmablastic lymphoma, there are few studies addressing optimal chemotherapeutics; one large series of published cases noted that the most common chemotherapeutic regimen in plasmablastic lymphoma cases is CHOP (Castillo, et al., 2010). Other more intensive regimens have also been used (e.g. the CODOX-M, often used for HIV-associated Burkitt's lymphoma cases). Two case reports have noted responses to chemotherapy with bortezomib (Bibas, et al., 2010; Bose, et

Primary effusion/body cavity lymphoma is a rare aggressive lymphoma with a peculiar propensity for the serous cavities of the body, namely the peritoneum, pleura and pericardium. These lymphomas are also not primarily associated with a solid component though they may later develop nearby solid tumours and may extend to involve of lymph nodes. Primary effusion lymphoma is characteristically a disease of HIV/AIDS patients, though rare cases have been reported in HIV negative patients. Primary effusion lymphomas are also almost invariably positive for HHV-8 and may show co-infection with

Knowles and colleagues diagnosed the first cases of primary effusion lymphoma in 1989. Three cases were originally reported, all occurring in homosexual HIV-positive males with clinical features of AIDS. Each case presented with a body cavity effusion containing cytologically malignant cells and quickly died. The effusions were all noted to contain populations of large cells with generous eosinophilic to amphophilic cytoplasm,

are encountered in the HIV/AIDS setting and many, though not all, of the remaining cases are associated with transplant related immunosuppression (Rafaniello Raviele, et al., 2009). The majority of cases, furthermore, were found to be EBV positive (Rafaniello Raviele, et al., 2009).

While most cases of plasmablastic lymphoma have demonstrated an odd predilection for the oral cavity, many reports have noted a number of broad ranging almost invariably extranodal sites. A number of reported cases have demonstrated involvement of the central nervous system (Ustun, et al., 2009); involvement of the gastrointestinal tract has also been reported (Rafaniello Raviele, et al., 2009); there are even unique reports of plasmablastic lymphoma involving the penis and vulva (Sun, et al., 2011; Chabay, et al., 2009). Studies have furthermore demonstrated some intriguing clinicopathological factors pertaining to the primary site of plasmablastic lymphomas. Hanra and colleagues for instance, in comparing oral and extraoral cases of plasmablastic lymphoma, demonstrated a distinct survival difference favouring the oral forms (Hansra, et al., 2010).

Plasmablastic lymphoma has also demonstrated different clinicopathologic features in the HIV/AIDS population relative to other immunosuppressed populations. Castillo et al. demonstrated that HIV positive cases of plasmablastic lymphoma tend to occur in younger, typically male patients with a notable preponderance for the oral cavity (Castillo, et al., 2010). Castillo et al. also demonstrated a distinct survival difference between the HIV positive and negative cases of plasmablastic lymphoma, favouring those from HIV positive patients (Castillo, et al., 2010).

Regardless of the primary site or of HIV status, plasmablastic lymphoma demonstrates consistent histological characteristics (see Figure 13). Plasmablastic lymphoma shows a monomorphic morphology comprised of large cells with abundant often-eosinophilic cytoplasm and eccentrically located hyperchromatic nucleus often containing one or more nucleoli. The tumoural cells demonstrate a uniformly diffuse architecture, often with a number of interspersed apoptotic bodies and mitotic figures. Intermingled macrophages or smaller plasma cells may be noted; in some cases in which the latter are particularly abundant, the plasmablastic lymphoma with "plasmacytic differentiation" may be applied.

Fig. 13. A: Plasmablastic Lymphoma. B: LCA positive in reactive small T lymphocytes and negative in large neoplastic cells. C: CD138 positive in large neoplastic cells. D: EMA positive in large neoplastic cells. E: MUM-1 positive in large neoplastic cells. F: Lambda light chain positive in large neoplastic cells

are encountered in the HIV/AIDS setting and many, though not all, of the remaining cases are associated with transplant related immunosuppression (Rafaniello Raviele, et al., 2009). The majority of cases, furthermore, were found to be EBV positive (Rafaniello Raviele, et al., 2009). While most cases of plasmablastic lymphoma have demonstrated an odd predilection for the oral cavity, many reports have noted a number of broad ranging almost invariably extranodal sites. A number of reported cases have demonstrated involvement of the central nervous system (Ustun, et al., 2009); involvement of the gastrointestinal tract has also been reported (Rafaniello Raviele, et al., 2009); there are even unique reports of plasmablastic lymphoma involving the penis and vulva (Sun, et al., 2011; Chabay, et al., 2009). Studies have furthermore demonstrated some intriguing clinicopathological factors pertaining to the primary site of plasmablastic lymphomas. Hanra and colleagues for instance, in comparing oral and extraoral cases of plasmablastic lymphoma, demonstrated a distinct

Plasmablastic lymphoma has also demonstrated different clinicopathologic features in the HIV/AIDS population relative to other immunosuppressed populations. Castillo et al. demonstrated that HIV positive cases of plasmablastic lymphoma tend to occur in younger, typically male patients with a notable preponderance for the oral cavity (Castillo, et al., 2010). Castillo et al. also demonstrated a distinct survival difference between the HIV positive and negative cases of plasmablastic lymphoma, favouring those from HIV positive

Regardless of the primary site or of HIV status, plasmablastic lymphoma demonstrates consistent histological characteristics (see Figure 13). Plasmablastic lymphoma shows a monomorphic morphology comprised of large cells with abundant often-eosinophilic cytoplasm and eccentrically located hyperchromatic nucleus often containing one or more nucleoli. The tumoural cells demonstrate a uniformly diffuse architecture, often with a number of interspersed apoptotic bodies and mitotic figures. Intermingled macrophages or smaller plasma cells may be noted; in some cases in which the latter are particularly abundant, the plasmablastic lymphoma with "plasmacytic differentiation" may be applied.

Fig. 13. A: Plasmablastic Lymphoma. B: LCA positive in reactive small T lymphocytes and negative in large neoplastic cells. C: CD138 positive in large neoplastic cells. D: EMA

positive in large neoplastic cells. E: MUM-1 positive in large neoplastic cells. F: Lambda light

survival difference favouring the oral forms (Hansra, et al., 2010).

patients (Castillo, et al., 2010).

chain positive in large neoplastic cells

In order to distinguish plasmablastic lymphoma for other diffuse lymphomas (and to rule out a simple but more common diffuse large B-cell lymphoma), immunophenotyping is crucial. In plasmablastic lymphoma, in addition to demonstrating minimal positivity for leukocyte common antigen (CD45), CD20 and CD79a, the tumoural cells are invariably positive for CD138; these features are of striking resemblance to the normal immunophenotype of plasma cells. Other post germinal centre markers such as MUM-1 and CD38 are also often positive. Some additional pathologic features that may potentially confuse the diagnosis include positivity for CD3, CD4 and CD56, all of which have been reported to be positive in some cases of plasmablastic lymphoma (Rafaniello Raviele, et al., 2009). Given the primary immunophenotypic differential diagnosis of a plasma cell malignancy (i.e. based on the combination of CD38, CD138, MUM-1 positivity with CD45, CD20 and CD79a negativity), the plasmablastic moniker is assigned given the histomorphology in combination with the absence of clinical features in support of a plasma cell dyscrasia. Plasma cell neoplasms also do not demonstrate positivity for EBV. Other possible differential diagnoses include carcinomas and melanomas, which can be ruled out by the way of an immunohistochemical panel of cytokeratins and melanoma markers. Goedhals et al. explored the electron microscopic features of ten plasmablastic lymphomas and found that 90% of cases demonstrated the consistent plasma cell features of eccentric nuclei with concentric perinuclear endoplasmic reticulum (Goedhals, et al., 2006)

The outcomes in cases of plasmablastic lymphoma are usually poor. In their in depth review, Raviele and colleagues noted disease related deaths in 59.6% of cases of oral-type plasmablastic lymphoma at an average of 10.4 months post-diagnosis as compared to 58.6%at an average of 6.2 months for the extra-oral type (Rafaniello Raviele, et al., 2009). Raviele and colleagues also noted a survival advantage to the use of highly active antiretrovirals (Rafaniello Raviele, et al., 2009). Given the rarity of plasmablastic lymphoma, there are few studies addressing optimal chemotherapeutics; one large series of published cases noted that the most common chemotherapeutic regimen in plasmablastic lymphoma cases is CHOP (Castillo, et al., 2010). Other more intensive regimens have also been used (e.g. the CODOX-M, often used for HIV-associated Burkitt's lymphoma cases). Two case reports have noted responses to chemotherapy with bortezomib (Bibas, et al., 2010; Bose, et al., 2009); trials looking at optimal treatment regimens are lacking, however.

#### **3.5 Primary effusion/body cavity lymphoma**

Primary effusion/body cavity lymphoma is a rare aggressive lymphoma with a peculiar propensity for the serous cavities of the body, namely the peritoneum, pleura and pericardium. These lymphomas are also not primarily associated with a solid component though they may later develop nearby solid tumours and may extend to involve of lymph nodes. Primary effusion lymphoma is characteristically a disease of HIV/AIDS patients, though rare cases have been reported in HIV negative patients. Primary effusion lymphomas are also almost invariably positive for HHV-8 and may show co-infection with EBV.

Knowles and colleagues diagnosed the first cases of primary effusion lymphoma in 1989. Three cases were originally reported, all occurring in homosexual HIV-positive males with clinical features of AIDS. Each case presented with a body cavity effusion containing cytologically malignant cells and quickly died. The effusions were all noted to contain populations of large cells with generous eosinophilic to amphophilic cytoplasm,

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 489

tumour cells; this can usually be accomplished reliably with immunohistochemical staining

Fig. 14. Primary Effusion Lymphoma: Large cells with clear-coloured cytoplasmic bodies (vescicles containing immunoglobulin); note the eccentrically placed nuclei in a number of the cells, others with large atypical lobated nuclei and prominent nucleoli. Compare the size.

Despite its rarity, a number of studies have explored the molecular pathogenesis of primary effusion/body cavity lymphoma. Gene expression profile studies in primary effusion/body cavity lymphoma have demonstrated a unique profile relative to other aggressive lymphomas; these results tend to substantiate the distinct clinicopathologic distinction of primary effusion/body cavity lymphomas from other lymphomas (Ueda, et al., 2010). Other studies have demonstrated a number of complex cytogenetic abnormalities as well as a reduction in tumour-suppressor gene expression in primary effusion/body cavity lymphoma (Luan, et al., 2010; O'Hara, et al., 2009); these features may further contribute to

Most published cases appear to be treated with CHOP or derivations thereof. Fewer cases have been treated with a more "aggressive" approach in line with regimens such as doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone. Some reported cases were also tried on an antiviral regimen (e.g. interferon alpha and cidofovir); the efficacy of these drugs in this context is uncertain, however. Unfortunately, regardless of the chemotherapy regimen, outcomes are poor. In Boulanger and colleagues' cohort, for example, only 14 of 28 patients received clinical remission and only 32% were alive after a median follow-up of 3.2 years (Boulanger, et al., 2005). Most patients who relapse, furthermore, will die of disease (Boulanger, et al., 2005). As in other HIV-associated lymphomas, prognosis appears to be improved with the early incorporation of anti-

T-cell lymphomas occurring in HIV/AIDS are substantially rarer that B-cell lymphomas. In their large cohort study of 302,834 AIDS patients, Biggar and colleagues noted that only 1.4%of non-hodgkin's lymphomas were of T-cell phenotype (Biggar, et al., 2001). Nonetheless, considering the extreme rarity of T-cell lymphomas in general, Biggar and colleagues estimated a relative risk of 15 of a T-cell lymphoma in the HIV positive

retroviral medications (Boulanger, et al., 2005; Carbone, et al., 2010).

population relative to the HIV negative population (Biggar, et al., 2001).

difference of the neoplastic cells with the small normally sized (dark stained) round

for the HHV-8 latency-associated nuclear antigen.

lymphocyte nucleus at the bottom left.

the aggressiveness of this lesion.

**3.6 T-cell lymphomas** 

anisonucleosis and clumped chromatin. Several multinucleated giant cells and abnormal mitotic figures were also noted. The malignant effusion cells were positive for CD45, indicating a hematolymphoid origin, but were negative for B- and T-cell markers as well as a variety of myelomonocytic markers. Subsequent restriction fragment analysis of the DNA obtained from the neoplastic cells revealed immunoglobulin gene rearrangements, suggesting a B-cell origin. The three original cases were also found to be EBV positive; these cases were not tested for HHV-8 positivity in the original publication

Since the first reported cases, several more have been reported; this entity is nonetheless very rare relative to the other HIV/AIDS-associated lymphomas and accounts for approximately 3% (Boulanger, et al., 2005). The WHO notes that this lymphoma is most commonly encountered in HIV patients, but that some cases have been encountered in HIVseronegative patients and even within the context of immunocompetence (Raphaёl, et al., 2008). Primary effusion/body cavity lymphoma cells are almost invariably HHV-8 positive. This is of particular interest in those cases encountered in immunocompetent patients since, as a result of the high prevalence of HHV-8 infection, there is a notably increased risk in peoples (especially males) of the Mediteranean (Said & Cesarman, 2008).

In one of the largest and more recent series of primary effusion/body cavity lymphomas, Boulanger and colleagues reported a wide age range (33-78 years) with only one female of 28 cases (Boulanger, et al., 2005). While the majority of cases were noted to originate in patients from populations with low HHV-8 seroprevalence, Boulanger et al. did note that a substantial number (38%) of patients originated from geographic areas with seroprevalence higher than 5% (Boulanger, et al., 2005). Most cases were noted to present with effusions, predominantly pleural (Boulanger, et al., 2005). Primary effusion/body cavity lymphoma typically remains restricted to the original presenting body cavity (Carbone, et al., 2010). Involved serosal surfaces are often diffusely thickened (Carbone, et al., 2010). Interestingly, 42% of Boulanger et al.'s cases presented with additional extra-cavitary lesions. It has also been documented that many primary effusion/body cavity lymphoma patients have preceding or complicating Kaposi's sarcoma (Boulanger, et al., 2005). Most patients are also profoundly immunosuppressed; in the HIV-positive cohort of Boulanger et al. for example, the average CD4 count was below 200 cells/µL (Boulanger, et al., 2005).

Diagnosis of primary effusion/body cavity lymphoma is typically made on cytologic examination of effusion contents (see Figure 14). As Carbone and colleagues note, the malignant cells of primary effusion/body cavity lymphoma have an appearance resembling a combination of immunoblastic and anaplastic features (Carbone, et al., 2010). A variable degree of plasma cell differentiation may also be noted; a background of pronounced cellular debris and numerous mitoses often accompanies these features. A mixture of reactive inflammatory cells as well as admixed mesothelial cells will also be noted. These morphological features result in a differential diagnosis that may include Burkitt's lymphoma (which may also involve body cavities); as with most lymphomas, however, the immunophenotype will typically indicate the diagnosis. The effusive nature of this lymphoma is highly conducive to flow cytometry. Primary effusion/body cavity lymphoma, as noted previously, demonstrates CD45, CD138 and MUM-1 positivity in the context of dim or negative immunostaining for B-cell markers. This immunohistochemical pattern reflects the plasmablastic phenotype of primary effusion/body cavity lymphoma. Interestingly, a few cases have noted aberrant T-cell antigen expression (Carbone, et al., 2010). The diagnostic clincher, however, is the demonstration of HHV-8 positivity in the

anisonucleosis and clumped chromatin. Several multinucleated giant cells and abnormal mitotic figures were also noted. The malignant effusion cells were positive for CD45, indicating a hematolymphoid origin, but were negative for B- and T-cell markers as well as a variety of myelomonocytic markers. Subsequent restriction fragment analysis of the DNA obtained from the neoplastic cells revealed immunoglobulin gene rearrangements, suggesting a B-cell origin. The three original cases were also found to be EBV positive; these

Since the first reported cases, several more have been reported; this entity is nonetheless very rare relative to the other HIV/AIDS-associated lymphomas and accounts for approximately 3% (Boulanger, et al., 2005). The WHO notes that this lymphoma is most commonly encountered in HIV patients, but that some cases have been encountered in HIVseronegative patients and even within the context of immunocompetence (Raphaёl, et al., 2008). Primary effusion/body cavity lymphoma cells are almost invariably HHV-8 positive. This is of particular interest in those cases encountered in immunocompetent patients since, as a result of the high prevalence of HHV-8 infection, there is a notably increased risk in

In one of the largest and more recent series of primary effusion/body cavity lymphomas, Boulanger and colleagues reported a wide age range (33-78 years) with only one female of 28 cases (Boulanger, et al., 2005). While the majority of cases were noted to originate in patients from populations with low HHV-8 seroprevalence, Boulanger et al. did note that a substantial number (38%) of patients originated from geographic areas with seroprevalence higher than 5% (Boulanger, et al., 2005). Most cases were noted to present with effusions, predominantly pleural (Boulanger, et al., 2005). Primary effusion/body cavity lymphoma typically remains restricted to the original presenting body cavity (Carbone, et al., 2010). Involved serosal surfaces are often diffusely thickened (Carbone, et al., 2010). Interestingly, 42% of Boulanger et al.'s cases presented with additional extra-cavitary lesions. It has also been documented that many primary effusion/body cavity lymphoma patients have preceding or complicating Kaposi's sarcoma (Boulanger, et al., 2005). Most patients are also profoundly immunosuppressed; in the HIV-positive cohort of Boulanger et al. for example,

Diagnosis of primary effusion/body cavity lymphoma is typically made on cytologic examination of effusion contents (see Figure 14). As Carbone and colleagues note, the malignant cells of primary effusion/body cavity lymphoma have an appearance resembling a combination of immunoblastic and anaplastic features (Carbone, et al., 2010). A variable degree of plasma cell differentiation may also be noted; a background of pronounced cellular debris and numerous mitoses often accompanies these features. A mixture of reactive inflammatory cells as well as admixed mesothelial cells will also be noted. These morphological features result in a differential diagnosis that may include Burkitt's lymphoma (which may also involve body cavities); as with most lymphomas, however, the immunophenotype will typically indicate the diagnosis. The effusive nature of this lymphoma is highly conducive to flow cytometry. Primary effusion/body cavity lymphoma, as noted previously, demonstrates CD45, CD138 and MUM-1 positivity in the context of dim or negative immunostaining for B-cell markers. This immunohistochemical pattern reflects the plasmablastic phenotype of primary effusion/body cavity lymphoma. Interestingly, a few cases have noted aberrant T-cell antigen expression (Carbone, et al., 2010). The diagnostic clincher, however, is the demonstration of HHV-8 positivity in the

cases were not tested for HHV-8 positivity in the original publication

peoples (especially males) of the Mediteranean (Said & Cesarman, 2008).

the average CD4 count was below 200 cells/µL (Boulanger, et al., 2005).

tumour cells; this can usually be accomplished reliably with immunohistochemical staining for the HHV-8 latency-associated nuclear antigen.

Fig. 14. Primary Effusion Lymphoma: Large cells with clear-coloured cytoplasmic bodies (vescicles containing immunoglobulin); note the eccentrically placed nuclei in a number of the cells, others with large atypical lobated nuclei and prominent nucleoli. Compare the size. difference of the neoplastic cells with the small normally sized (dark stained) round lymphocyte nucleus at the bottom left.

Despite its rarity, a number of studies have explored the molecular pathogenesis of primary effusion/body cavity lymphoma. Gene expression profile studies in primary effusion/body cavity lymphoma have demonstrated a unique profile relative to other aggressive lymphomas; these results tend to substantiate the distinct clinicopathologic distinction of primary effusion/body cavity lymphomas from other lymphomas (Ueda, et al., 2010). Other studies have demonstrated a number of complex cytogenetic abnormalities as well as a reduction in tumour-suppressor gene expression in primary effusion/body cavity lymphoma (Luan, et al., 2010; O'Hara, et al., 2009); these features may further contribute to the aggressiveness of this lesion.

Most published cases appear to be treated with CHOP or derivations thereof. Fewer cases have been treated with a more "aggressive" approach in line with regimens such as doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone. Some reported cases were also tried on an antiviral regimen (e.g. interferon alpha and cidofovir); the efficacy of these drugs in this context is uncertain, however. Unfortunately, regardless of the chemotherapy regimen, outcomes are poor. In Boulanger and colleagues' cohort, for example, only 14 of 28 patients received clinical remission and only 32% were alive after a median follow-up of 3.2 years (Boulanger, et al., 2005). Most patients who relapse, furthermore, will die of disease (Boulanger, et al., 2005). As in other HIV-associated lymphomas, prognosis appears to be improved with the early incorporation of antiretroviral medications (Boulanger, et al., 2005; Carbone, et al., 2010).

#### **3.6 T-cell lymphomas**

T-cell lymphomas occurring in HIV/AIDS are substantially rarer that B-cell lymphomas. In their large cohort study of 302,834 AIDS patients, Biggar and colleagues noted that only 1.4%of non-hodgkin's lymphomas were of T-cell phenotype (Biggar, et al., 2001). Nonetheless, considering the extreme rarity of T-cell lymphomas in general, Biggar and colleagues estimated a relative risk of 15 of a T-cell lymphoma in the HIV positive population relative to the HIV negative population (Biggar, et al., 2001).

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 491

Fig. 15. Peripheral T-cell Lymphoma: A: Atypical cells expanding paracortical interfollicular regions; B: High-power demonstrating atypical cells (larger than normal interfollicular cells)

Fig. 16. Anaplastic Large Cell Lymphoma: A: Low-power view of lymph node involved by anaplastic large cell lymphoma showing subcapsular sinus involvement by tumour cells; B: High-power view of tumour cells demonstrating the characteristic hallmark cells (large nuclei with convoluted semi-lunar shapes); C: CD30 immunostain (diffuse positivity in

Fig. 17. Mycosis Fungoides: Lymph node demonstrating paracortical expansion by atypical

The typical T-cell lineage markers CD2, CD3, CD5, CD7, CD4, CD8 and CD43 are variably positive in T-cell lymphomas; these markers are useful at demonstrating aberrant phenotype (such as an aberrant CD4:CD8 ratio) or to hint at T-cell lineage neoplasm when the other T-cell markers are negative. The normal progression of T-cell marker ontogenesis

lymphoid infiltrate; inset: large (cerebriform) sezary cells of mycosis fungoides

tumour cells); D: ALK-1 immunostain (diffuse positivity in tumour cells)

with mitotic figures present; C: Diffuse CD3 positivity confirming T-cell lineage

The first documented HIV positive T-cell lymphoma was noted in 1988 by Nasr and colleagues (Nasr, et al., 1988). This case consisted of a large cell lymphoma demonstrating loss of CD3 but with preservation of CD2 and CD4 immunoreactivity. Although CD30 and ALK-1 immunoreactivity were not reported in this case, the reported morphologic features seem most in keeping with anaplastic large cell lymphoma. The earliest reported T-cell lymphoma in a patient with suspected AIDS, however, predated Nasr and colleagues' case by four years; this case was reported in Japan in a patient with AIDS-defining clinical characteristics but co-infected by human t-cell lymphoma/leukemia virus-1 (Kobayashi, et al., 1984).

The most common T-cell lymphoma encountered in HIV-positive patients appears to be peripheral T-cell lymphoma, unspecified (Biggar, et al., 2001; Arzoo, et al., 2004). Several cases of anaplastic large cell lymphoma, NK/T-cell lymphoma and angioimmunoblastic Tcell lymphoma have also been reported, however (Biggar, et al., 2001; Arzoo, et al., 2004; Perez, et al., 2010; Castillo, et al., 2011). A few cases of enteropathy-associated T-cell lymphoma as well as adult T-cell leukemia/lymphoma have also been reported, though little specific information pertaining to the role of HIV in these cases could be gleaned (Arzoo, et al., 2004; Castillo, et al., 2011).

In the largest case series to date, Castilo and colleagues noted that the bulk of HIVassociated T-cell lymphomas occurred in males, typically presenting at high stage (stage III-IV), and often accompanied by B-symptoms (fever, night sweats and weight loss) (Castillo, et al., 2011). Similar clinical characteristics were noted in other smaller cohorts (Arzoo, et al., 2004; Perez, et al., 2010). Many T-cell lymphomas in HIV patients will also present with skin findings, apparently in greater proportions than HIV-associated B-cell lymphomas (Arzoo, et al., 2004).

Peripheral T-cell lymphoma, unspecified, typically occurs in lymph nodes and consists of medium to large-sized lymphocytes with irregular nuclei. The neoplastic T-cells usually show a diffuse pattern of involvement, preferentially involving the paracortical zones, often sparing the lymphoid follicles (see Figure 16). HIV-associated anaplastic large cell lymphoma also demonstrates a range of histological features. A range of cell size may be noted from the typical large anaplastic cell to the so-called small cell variant (see Figure 17). These cells may form loosely cohesive clusters, diffuse sheets and, as is often seen in lymph nodes, may present as subtle subcapsular aggregates. Angioimmunoblastic lymphoma, in contrast, is most common described as a diffuse process often completely obliterating the lymph node architecture; most commonly the lymph node will be replaced by an arborizing network of proliferating endothelial cells interspersed by an infiltrate of atypical lymphocytes, often accompanied by various non-neoplastic inflammatory cells. Mycosis fungoides is characterized by band like superficial dermal infiltrates of atypical lymphocytes (often described as "cerebriform") (see Figure 18). When these atypical cerebriform lymphocytes are noted in the peripheral blood or in lymph nodes, the Sezary syndrome is suspected (sezary syndrome does not always demonstrate the same epidermotropism as mycosis fungoides, however, and the skin changes in this context may be non-specific). NK/T-cell lymphomas occur most often in the aerodigestive tract where they often manifest as mucosal ulceration by atypical lymphocytes. These atypical lymphocytes may have ample cytoplasm and irregular convoluted nuclear membranes. An angioinvasive pattern is also common to NK/T-cell lymphoma, typically with associated areas of necrosis.

The first documented HIV positive T-cell lymphoma was noted in 1988 by Nasr and colleagues (Nasr, et al., 1988). This case consisted of a large cell lymphoma demonstrating loss of CD3 but with preservation of CD2 and CD4 immunoreactivity. Although CD30 and ALK-1 immunoreactivity were not reported in this case, the reported morphologic features seem most in keeping with anaplastic large cell lymphoma. The earliest reported T-cell lymphoma in a patient with suspected AIDS, however, predated Nasr and colleagues' case by four years; this case was reported in Japan in a patient with AIDS-defining clinical characteristics but co-infected by human t-cell lymphoma/leukemia virus-1 (Kobayashi, et

The most common T-cell lymphoma encountered in HIV-positive patients appears to be peripheral T-cell lymphoma, unspecified (Biggar, et al., 2001; Arzoo, et al., 2004). Several cases of anaplastic large cell lymphoma, NK/T-cell lymphoma and angioimmunoblastic Tcell lymphoma have also been reported, however (Biggar, et al., 2001; Arzoo, et al., 2004; Perez, et al., 2010; Castillo, et al., 2011). A few cases of enteropathy-associated T-cell lymphoma as well as adult T-cell leukemia/lymphoma have also been reported, though little specific information pertaining to the role of HIV in these cases could be gleaned

In the largest case series to date, Castilo and colleagues noted that the bulk of HIVassociated T-cell lymphomas occurred in males, typically presenting at high stage (stage III-IV), and often accompanied by B-symptoms (fever, night sweats and weight loss) (Castillo, et al., 2011). Similar clinical characteristics were noted in other smaller cohorts (Arzoo, et al., 2004; Perez, et al., 2010). Many T-cell lymphomas in HIV patients will also present with skin findings, apparently in greater proportions than HIV-associated B-cell lymphomas (Arzoo,

Peripheral T-cell lymphoma, unspecified, typically occurs in lymph nodes and consists of medium to large-sized lymphocytes with irregular nuclei. The neoplastic T-cells usually show a diffuse pattern of involvement, preferentially involving the paracortical zones, often sparing the lymphoid follicles (see Figure 16). HIV-associated anaplastic large cell lymphoma also demonstrates a range of histological features. A range of cell size may be noted from the typical large anaplastic cell to the so-called small cell variant (see Figure 17). These cells may form loosely cohesive clusters, diffuse sheets and, as is often seen in lymph nodes, may present as subtle subcapsular aggregates. Angioimmunoblastic lymphoma, in contrast, is most common described as a diffuse process often completely obliterating the lymph node architecture; most commonly the lymph node will be replaced by an arborizing network of proliferating endothelial cells interspersed by an infiltrate of atypical lymphocytes, often accompanied by various non-neoplastic inflammatory cells. Mycosis fungoides is characterized by band like superficial dermal infiltrates of atypical lymphocytes (often described as "cerebriform") (see Figure 18). When these atypical cerebriform lymphocytes are noted in the peripheral blood or in lymph nodes, the Sezary syndrome is suspected (sezary syndrome does not always demonstrate the same epidermotropism as mycosis fungoides, however, and the skin changes in this context may be non-specific). NK/T-cell lymphomas occur most often in the aerodigestive tract where they often manifest as mucosal ulceration by atypical lymphocytes. These atypical lymphocytes may have ample cytoplasm and irregular convoluted nuclear membranes. An angioinvasive pattern is also common to NK/T-cell

al., 1984).

et al., 2004).

(Arzoo, et al., 2004; Castillo, et al., 2011).

lymphoma, typically with associated areas of necrosis.

Fig. 15. Peripheral T-cell Lymphoma: A: Atypical cells expanding paracortical interfollicular regions; B: High-power demonstrating atypical cells (larger than normal interfollicular cells) with mitotic figures present; C: Diffuse CD3 positivity confirming T-cell lineage

Fig. 16. Anaplastic Large Cell Lymphoma: A: Low-power view of lymph node involved by anaplastic large cell lymphoma showing subcapsular sinus involvement by tumour cells; B: High-power view of tumour cells demonstrating the characteristic hallmark cells (large nuclei with convoluted semi-lunar shapes); C: CD30 immunostain (diffuse positivity in tumour cells); D: ALK-1 immunostain (diffuse positivity in tumour cells)

Fig. 17. Mycosis Fungoides: Lymph node demonstrating paracortical expansion by atypical lymphoid infiltrate; inset: large (cerebriform) sezary cells of mycosis fungoides

The typical T-cell lineage markers CD2, CD3, CD5, CD7, CD4, CD8 and CD43 are variably positive in T-cell lymphomas; these markers are useful at demonstrating aberrant phenotype (such as an aberrant CD4:CD8 ratio) or to hint at T-cell lineage neoplasm when the other T-cell markers are negative. The normal progression of T-cell marker ontogenesis

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 493

cutaneous sites of involvement by Kaposi's sarcoma in AIDS cases, next to the gastrointestinal tract and the lungs (Ioachim, et al., 1995). Cases demonstrating primarily nodal involvement may be entirely asymptomatic, with the exception of lymphadenopathy. In these cases the clinical differential diagnosis can be lengthy and histological diagnosis is

Lymph nodes involved by Kaposi's sarcoma are typically enlarged and demonstrate preserved architecture in areas not invaded by the tumour, often with follicular hyperplasia (see Figure 18). Involvement of lymph nodes by Kaposi's sarcoma typically begins in the form of triangular nodules with later encroachment into the cortex and medulla; these initial nodules may form wedges with bases parallel to the node capsule. Circular whorledpatterned nodules are also common and can be found throughout the nodal parenchyma. The cells within Kaposi's nodules are spindled with intervening slit-like vascular spaces. The neoplastic cells are usually fairly uniform with plump nuclei; mitoses may be present but are usually not numerous. Characteristic hyaline globules may be seen within Kaposi cells and in nearby histiocytes. Infiltration of tumour foci by lymphocytes, plasma cells and

Fig. 18. Kaposi's Sarcoma: A: Low-power view of a lymph node involved by subcapsular nodules of Kaposi's sarcoma; B: Focus of neoplastic endothelial cells encroaching upon a follicle; C: High-power view of neoplastic endothelial cells with notable tumour cell cytoplasmic hyaline globules; D: HHV-8 immunostain demonstrating diffuse positivity

The morphologic differential diagnosis includes many vascular lesions, though the morphologic features are usually characteristic in Kaposi's sarcoma. Bacillary angiomatosis may show nodule formation but typically does not contain the uniformly plump monotonous spindle cells with intervening slit-like spaces seen in Kaposi's sarcoma. The vascular proliferation and hyalinization that may be seen in HIV-associated lymphadenopathy or Castleman's disease may be confused with Kaposi's sarcoma. Angiosarcomas should also be included in the differential diagnosis, though this typically demonstrates are much more sarcomatoid appearance with more marked atypia, necrosis and numerous mitoses. Confusion is avoided by using an immunohistochemical panel including markers for endothelial cells (such as CD31, CD34 or Factor VIII) in combination

Antiretroviral therapy is used both to prevent Kaposi's sarcoma but also to treat it. Nonetheless, HIV patients with Kaposi's sarcoma may not respond curatively to antiretroviral optimization and some cases treated with antiretrovirals de novo have been known to develop more severe disease due to the so-called immune reconstitution inflammatory syndrome (in which the presumed increased in inflammatory mediators

required.

hemosiderin-laden macrophages is also frequent.

with a stain for HHV-8.

proceeds from CD7 to CD2, CD3 and CD5 (in immature T-cells) and then onto CD4 and CD8 (in mature T-cells); the loss of one of the so-called pan-T-Cell markers CD2, CD3, CD5 or CD7 is helpful in the identification of an aberrant (plausibly neoplastic) phenotype. In one of the largest series of HIV-associated anaplastic large cell lymphomas, Perez and colleagues noted that the majority of cases were positive for one or more of CD45, CD2, CD3, CD5, CD4 and CD43 (Perez, et al., 2010); the uniting feature in all cases of ALCL, however, is diffuse strong CD30 positivity. Although the CD30 stain is not entirely specific to anaplastic large cell lymphoma (since this stain is a marker of activated cells), its presence in a diffuse pattern in cells with typically anaplastic morphology is characteristic. Also commonly positive in anaplastic large cell lymphoma is CD45 (also known as leukocyte common antigen, a marker indicating hematolymphoid origin). Interestingly, ALK-1 was noted to be positive in only two of their cases; this is in stark contrast to the non HIVassociated anaplastic large cell lymphomas, which are typically ALK-1 positive (Perez, et al., 2010; Nava, et al., 2008). Although this lack of ALK-1 positivity may represent a distinct molecular feature of HIV-associated anaplastic large cell lymphoma, to our knowledge, no studies have explored this as yet. The neoplastic T-cells in angioimmunoblastic T-cell lymphoma, in addition to staining positive for a number of pan-T-cell markers, are typically positive for CD4 but negative for CD3. These cells also stain positive for a number of markers of follicular centre origin including CD10 and BCL-6. The lymphocytic infiltrates in mycosis fungoides syndrome will often demonstrate a lack of CD3 and CD8 staining often with pronounced CD4 positivity. NK/T-cell lymphoma also demonstrates positivity for one or more pan-T-cell markers, in addition to positivity for CD56 and (unlike most T-cell lymphomas) EBV. These features can easily be demonstrated efficiently, and with only minimal tissue, using flow cytometry.

Most patients with HIV-associated peripheral T-cell lymphomas are treated with a CHOPbased chemotherapy regimen, though a variety of other regimens have also been employed (Castillo, et al., 2011). While most patients seem to demonstrate a complete or partial response to initial therapy, the majority die of progressive disease (Castillo, et al., 2011). A statistically significant improvement in the survival curve of HIV-associated peripheral Tcell lymphomas was also noted in patients treated with anti-retrovirals (Castillo, et al., 2011).

#### **3.7 Lymph node findings in HIV/AIDS related Kaposi's sarcoma**

We will limit the discussion of Kaposi's sarcoma in HIV/AIDS to those aspects pertaining to lymph node disease. Whether due to its underlying viral etiology or to the endothelial differentiation of the malignant cell of interest, Kaposi sarcoma often manifests itself in lymph nodes. The disease was first described in 1872 by Moritz Kaposi as a pigmented sarcoma of skin (Mesri, et al., 2010), this form probably represented the modern sporadic subtype seen predominantly in the Mediterranean. In the 1950s, Kaposi's sarcoma was encountered in Africa (Mesri, et al., 2010); this may have represented the first discovery of Kaposi's sarcoma in association with the as yet unknown HIV. When the HIV outbreak was identified, Kaposi's sarcoma was observed to be the most frequent (and AIDS defining) malignancy in this immunocompromised population. It was not until 1996 that a viral pathogen was discovered in association with Kaposi's sarcoma, later named the Kaposi sarcoma herpes virus, or HHV-8 (Mesri, et al., 2010).

Ioachim and colleagues undertook an intriguing study of extra-cutaneous Kaposi's sarcoma in AIDS patients; they noted that lymph nodes were the third most common extra-

proceeds from CD7 to CD2, CD3 and CD5 (in immature T-cells) and then onto CD4 and CD8 (in mature T-cells); the loss of one of the so-called pan-T-Cell markers CD2, CD3, CD5 or CD7 is helpful in the identification of an aberrant (plausibly neoplastic) phenotype. In one of the largest series of HIV-associated anaplastic large cell lymphomas, Perez and colleagues noted that the majority of cases were positive for one or more of CD45, CD2, CD3, CD5, CD4 and CD43 (Perez, et al., 2010); the uniting feature in all cases of ALCL, however, is diffuse strong CD30 positivity. Although the CD30 stain is not entirely specific to anaplastic large cell lymphoma (since this stain is a marker of activated cells), its presence in a diffuse pattern in cells with typically anaplastic morphology is characteristic. Also commonly positive in anaplastic large cell lymphoma is CD45 (also known as leukocyte common antigen, a marker indicating hematolymphoid origin). Interestingly, ALK-1 was noted to be positive in only two of their cases; this is in stark contrast to the non HIVassociated anaplastic large cell lymphomas, which are typically ALK-1 positive (Perez, et al., 2010; Nava, et al., 2008). Although this lack of ALK-1 positivity may represent a distinct molecular feature of HIV-associated anaplastic large cell lymphoma, to our knowledge, no studies have explored this as yet. The neoplastic T-cells in angioimmunoblastic T-cell lymphoma, in addition to staining positive for a number of pan-T-cell markers, are typically positive for CD4 but negative for CD3. These cells also stain positive for a number of markers of follicular centre origin including CD10 and BCL-6. The lymphocytic infiltrates in mycosis fungoides syndrome will often demonstrate a lack of CD3 and CD8 staining often with pronounced CD4 positivity. NK/T-cell lymphoma also demonstrates positivity for one or more pan-T-cell markers, in addition to positivity for CD56 and (unlike most T-cell lymphomas) EBV. These features can easily be demonstrated efficiently, and with only

Most patients with HIV-associated peripheral T-cell lymphomas are treated with a CHOPbased chemotherapy regimen, though a variety of other regimens have also been employed (Castillo, et al., 2011). While most patients seem to demonstrate a complete or partial response to initial therapy, the majority die of progressive disease (Castillo, et al., 2011). A statistically significant improvement in the survival curve of HIV-associated peripheral Tcell lymphomas was also noted in patients treated with anti-retrovirals (Castillo, et al., 2011).

We will limit the discussion of Kaposi's sarcoma in HIV/AIDS to those aspects pertaining to lymph node disease. Whether due to its underlying viral etiology or to the endothelial differentiation of the malignant cell of interest, Kaposi sarcoma often manifests itself in lymph nodes. The disease was first described in 1872 by Moritz Kaposi as a pigmented sarcoma of skin (Mesri, et al., 2010), this form probably represented the modern sporadic subtype seen predominantly in the Mediterranean. In the 1950s, Kaposi's sarcoma was encountered in Africa (Mesri, et al., 2010); this may have represented the first discovery of Kaposi's sarcoma in association with the as yet unknown HIV. When the HIV outbreak was identified, Kaposi's sarcoma was observed to be the most frequent (and AIDS defining) malignancy in this immunocompromised population. It was not until 1996 that a viral pathogen was discovered in association with Kaposi's sarcoma, later named the Kaposi

Ioachim and colleagues undertook an intriguing study of extra-cutaneous Kaposi's sarcoma in AIDS patients; they noted that lymph nodes were the third most common extra-

**3.7 Lymph node findings in HIV/AIDS related Kaposi's sarcoma** 

sarcoma herpes virus, or HHV-8 (Mesri, et al., 2010).

minimal tissue, using flow cytometry.

cutaneous sites of involvement by Kaposi's sarcoma in AIDS cases, next to the gastrointestinal tract and the lungs (Ioachim, et al., 1995). Cases demonstrating primarily nodal involvement may be entirely asymptomatic, with the exception of lymphadenopathy. In these cases the clinical differential diagnosis can be lengthy and histological diagnosis is required.

Lymph nodes involved by Kaposi's sarcoma are typically enlarged and demonstrate preserved architecture in areas not invaded by the tumour, often with follicular hyperplasia (see Figure 18). Involvement of lymph nodes by Kaposi's sarcoma typically begins in the form of triangular nodules with later encroachment into the cortex and medulla; these initial nodules may form wedges with bases parallel to the node capsule. Circular whorledpatterned nodules are also common and can be found throughout the nodal parenchyma. The cells within Kaposi's nodules are spindled with intervening slit-like vascular spaces. The neoplastic cells are usually fairly uniform with plump nuclei; mitoses may be present but are usually not numerous. Characteristic hyaline globules may be seen within Kaposi cells and in nearby histiocytes. Infiltration of tumour foci by lymphocytes, plasma cells and hemosiderin-laden macrophages is also frequent.

Fig. 18. Kaposi's Sarcoma: A: Low-power view of a lymph node involved by subcapsular nodules of Kaposi's sarcoma; B: Focus of neoplastic endothelial cells encroaching upon a follicle; C: High-power view of neoplastic endothelial cells with notable tumour cell cytoplasmic hyaline globules; D: HHV-8 immunostain demonstrating diffuse positivity

The morphologic differential diagnosis includes many vascular lesions, though the morphologic features are usually characteristic in Kaposi's sarcoma. Bacillary angiomatosis may show nodule formation but typically does not contain the uniformly plump monotonous spindle cells with intervening slit-like spaces seen in Kaposi's sarcoma. The vascular proliferation and hyalinization that may be seen in HIV-associated lymphadenopathy or Castleman's disease may be confused with Kaposi's sarcoma. Angiosarcomas should also be included in the differential diagnosis, though this typically demonstrates are much more sarcomatoid appearance with more marked atypia, necrosis and numerous mitoses. Confusion is avoided by using an immunohistochemical panel including markers for endothelial cells (such as CD31, CD34 or Factor VIII) in combination with a stain for HHV-8.

Antiretroviral therapy is used both to prevent Kaposi's sarcoma but also to treat it. Nonetheless, HIV patients with Kaposi's sarcoma may not respond curatively to antiretroviral optimization and some cases treated with antiretrovirals de novo have been known to develop more severe disease due to the so-called immune reconstitution inflammatory syndrome (in which the presumed increased in inflammatory mediators

Benign and Malignant Lymphoproliferative Disorders in HIV/AIDS 495

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results in unintentional cytokinetic stimulation of the sarcoma) (Mesri, et al., 2010; Di Lorenzo, et al., 2007). Localized disease may respond to surgery or radiation therapy (though lymph node disease is frequently not localized) and more widespread disease is treated with chemotherapeutic regimens, typically including liposomal anthracyclines and taxanes (Di Lorenzo, et al., 2007). Newer biological therapies including the vascular endothelial growth factor receptor and tyrosine kinase inhibitors are currently being investigated (Di Lorenzo, et al., 2007). Some early studies exploring the use of antivirals (such as gancyclovir and foscarnet) have noted encouraging results though more definitive studies are ongoing (Di Lorenzo, et al., 2007).

## **4. Conclusion**

In the three decades since the beginning of the modern HIV/AIDS epidemic, a great deal of advancement has been made in the understanding of retrovirology, immunology and hematolymphoid pathology. In these 30 years, the recognition of a unique and fastidious retrovirus causing AIDS has occurred, its biologic interaction with human cells has been detailed, and the variety of possible resulting illnesses following infection have been documented. In particular, the range of malignant disease that may occur in HIV/AIDS has been widely enumerated and, thankfully, has shown a distinct reduction in incidence and prevalence since the introduction of antiretroviral therapy, truly a modern medical elixir able to prolong life in a medical context once tantamount to a death sentence.

The above discussion should not only serve to highlight the unique clinical features of HIVassociated hematolymphoid disorders but also demonstrate the unique pathologic work-up necessary to ensure accurate classification and clinical follow-up. In particular, we emphasized the need to obtain tissue biopsies in any scenario in which a potential malignancy is considered. Furthermore, for the pathologist readership, it is imperative to properly handle and work-up a lymph node biopsy from any case in which there is a suspicion of lymphoma; we especially encourage the use of flow cytometry which is an invaluable tool in the diagnosis of lymphoid neoplasms and is extremely helpful in proper classification. Also, in addition to the standard H&E evaluation, a panel of immunohistochemical stains is usually needed to properly identify the lineage, malignant potential and classification of a lymphoid lesion. Many hematolymphoid malignancies require further molecular or cytogenetic work-up as well, the latter requiring fresh tissue.

#### **5. References**


results in unintentional cytokinetic stimulation of the sarcoma) (Mesri, et al., 2010; Di Lorenzo, et al., 2007). Localized disease may respond to surgery or radiation therapy (though lymph node disease is frequently not localized) and more widespread disease is treated with chemotherapeutic regimens, typically including liposomal anthracyclines and taxanes (Di Lorenzo, et al., 2007). Newer biological therapies including the vascular endothelial growth factor receptor and tyrosine kinase inhibitors are currently being investigated (Di Lorenzo, et al., 2007). Some early studies exploring the use of antivirals (such as gancyclovir and foscarnet) have noted encouraging results though more definitive

In the three decades since the beginning of the modern HIV/AIDS epidemic, a great deal of advancement has been made in the understanding of retrovirology, immunology and hematolymphoid pathology. In these 30 years, the recognition of a unique and fastidious retrovirus causing AIDS has occurred, its biologic interaction with human cells has been detailed, and the variety of possible resulting illnesses following infection have been documented. In particular, the range of malignant disease that may occur in HIV/AIDS has been widely enumerated and, thankfully, has shown a distinct reduction in incidence and prevalence since the introduction of antiretroviral therapy, truly a modern medical elixir

The above discussion should not only serve to highlight the unique clinical features of HIVassociated hematolymphoid disorders but also demonstrate the unique pathologic work-up necessary to ensure accurate classification and clinical follow-up. In particular, we emphasized the need to obtain tissue biopsies in any scenario in which a potential malignancy is considered. Furthermore, for the pathologist readership, it is imperative to properly handle and work-up a lymph node biopsy from any case in which there is a suspicion of lymphoma; we especially encourage the use of flow cytometry which is an invaluable tool in the diagnosis of lymphoid neoplasms and is extremely helpful in proper classification. Also, in addition to the standard H&E evaluation, a panel of immunohistochemical stains is usually needed to properly identify the lineage, malignant potential and classification of a lymphoid lesion. Many hematolymphoid malignancies require further molecular or cytogenetic work-up as well, the latter requiring fresh tissue.

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**21** 

*Brazil* 

**Sexual Dysfunctions** 

*Institute of Psychiatry, University of São Paulo* 

Although HIV-positive individuals kept a central role in the maintenance of the epidemic, only from the 12th World AIDS Conference, held in Geneva in 1998, the sexuality of people living with HIV/AIDS received more systematic attention (Schiltz and Sandfort 2000). After receiving the diagnosis of HIV infection is common for people to become involved in a state of negative mood and decrease the frequency of sexual activity and those who remain with sexual practices most likely do so without adequate protection (Rosser, Gobby and Carr 1999). The adhesion to safe sex practices after diagnosis of HIV infection may have a negative impact on sexual functioning of most subjects (Newshan, Taylor and Gold 1998). The individuals that have partnership are significantly more likely to maintain sexual activity than those without (Stein et al. 2005). On the professionals, the sexual functioning is often overlooked among the care of HIV positive patients. Generally, information about the relationship between hormonal factors, psychological factors, drug effects, disease stage, and sexual functioning are not spoken by health professionals (Newshan et al. 1998). In addition, one must consider that individuals who acquire HIV through sexual or parenteral (excluding blood transfusions) are already part of a population at higher risk for sexual dysfunction, as many risk factors for HIV are also to the occurrence of sexual dysfunction, such as conflicts with the orientation or sexual identity, depression, and psychological

Several factors may modify the sexual response. Beginning in youth, sexual dysfunctions are highly prevalent in all age groups. Symptoms of sexual dysfunction include erectile dysfunction, loss of libido, premature or delayed ejaculation, orgasmic disturbances, arousal

For the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) ((APA) 2000), the fundamental concepts of the principals sexual dysfunctions are: *Dyspareunia* is recurrent or persistent genital pain associated with sexual intercourse in men or women. *Female orgasmic disorder* is the delay of orgasm following normal excitement and sexual activity. Due to the widely varied sexual response in women, it must be judged by a clinician to be significant taking into account the person's age and situation. *Female sexual arousal disorder* is inability to attain or maintain until completion of sexual activity adequate lubrication in response to sexual excitement. *Hypoactive sexual desire disorder* is deficient or absent sexual fantasies and desire for sexual activity. This judgment must be made by a clinician taking into account the individual's age and life circumstances. *Male erectile disorder (impotence)* is recurring inability to achieve or maintain an erection until

problems related to self-image (Hijazi, Nandwani and Kell 2002).

difficulties, and dyspareunia, among others (Lewis et al. 2004).

**1. Introduction** 

Marco de Tubino Scanavino


Marco de Tubino Scanavino *Institute of Psychiatry, University of São Paulo Brazil* 

## **1. Introduction**

502 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

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CNS involvement, coexistence of other malignancies, possible viral etiology, and dismal outcome.*Ann.Hematol.,*Vol.88,No.4,(Apr),pp.351-358,1432-0584; 0939-5555 Vaccher, E., Tirelli, U., Spina, M., et al.(1996).Age and serum lactate dehydrogenase level are

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*Atlas & Synopsis of Clinical Dermatology,*Wolff, K., Johnson, R. and Suurmond, D.,

henselae antibodies among human immunodeficiency virus-infected patients from

Although HIV-positive individuals kept a central role in the maintenance of the epidemic, only from the 12th World AIDS Conference, held in Geneva in 1998, the sexuality of people living with HIV/AIDS received more systematic attention (Schiltz and Sandfort 2000). After receiving the diagnosis of HIV infection is common for people to become involved in a state of negative mood and decrease the frequency of sexual activity and those who remain with sexual practices most likely do so without adequate protection (Rosser, Gobby and Carr 1999). The adhesion to safe sex practices after diagnosis of HIV infection may have a negative impact on sexual functioning of most subjects (Newshan, Taylor and Gold 1998). The individuals that have partnership are significantly more likely to maintain sexual activity than those without (Stein et al. 2005). On the professionals, the sexual functioning is often overlooked among the care of HIV positive patients. Generally, information about the relationship between hormonal factors, psychological factors, drug effects, disease stage, and sexual functioning are not spoken by health professionals (Newshan et al. 1998). In addition, one must consider that individuals who acquire HIV through sexual or parenteral (excluding blood transfusions) are already part of a population at higher risk for sexual dysfunction, as many risk factors for HIV are also to the occurrence of sexual dysfunction, such as conflicts with the orientation or sexual identity, depression, and psychological problems related to self-image (Hijazi, Nandwani and Kell 2002).

Several factors may modify the sexual response. Beginning in youth, sexual dysfunctions are highly prevalent in all age groups. Symptoms of sexual dysfunction include erectile dysfunction, loss of libido, premature or delayed ejaculation, orgasmic disturbances, arousal difficulties, and dyspareunia, among others (Lewis et al. 2004).

For the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) ((APA) 2000), the fundamental concepts of the principals sexual dysfunctions are: *Dyspareunia* is recurrent or persistent genital pain associated with sexual intercourse in men or women. *Female orgasmic disorder* is the delay of orgasm following normal excitement and sexual activity. Due to the widely varied sexual response in women, it must be judged by a clinician to be significant taking into account the person's age and situation. *Female sexual arousal disorder* is inability to attain or maintain until completion of sexual activity adequate lubrication in response to sexual excitement. *Hypoactive sexual desire disorder* is deficient or absent sexual fantasies and desire for sexual activity. This judgment must be made by a clinician taking into account the individual's age and life circumstances. *Male erectile disorder (impotence)* is recurring inability to achieve or maintain an erection until

reported dyspareunia, while no men without AIDS reported it (de Tubino Scanavino and Abdo 2010). Male dyspareunia is not commonly reported in the literature, possibly because

There are four important factors associated with sexual dysfunctions in HIV/AIDS patients:

At the first moment, the condition of being HIV seropositive may cause feelings of loss of sexual attractiveness, reduction of sexual desire and sexual satisfaction. Moreover, they may be confronted with the absence of sexual partners, particularly when revealing their serological status. In addition, the sexual response may be undermined by fear or guilt in coming to contaminate partnerships (Newshan et al. 1998, Schiltz and Sandfort 2000). A representative French study with HIV outpatients showed association among sexual difficulties and the discrimination by friends and partners, suffering by lipodystrophy, very disturbing HIV related symptoms. The authors recommend psychological support for HIV experience for improves the sexual life (Bouhnik et al. 2008). Feelings of guilt by have acquiring the HIV on sexual transmission may become a psychogenic factor and influence negatively the sexual response. Maybe because of this point, sexual dysfunctions are more prevalent on homosexual men than intravenous drug users (Sollima et al. 2001). In fact, gay and bisexual men have higher rates of sexual dysfunctions (Catalan and Meadows 2000) or just complaint more to the physicians on the disorder due to valorize more the sexual

Depression is one of the most important mental factors associated with sexual dysfunctions (Ciesla and Roberts 2001). A study on 300 HIV infected men found the older age and depression were associated with erectile dysfunction, and current higher CD4 account was

The most common factors associated with female sexual dysfunction are the psychosocial aspects of HIV infection and the negative body image associated with use of medications

Hypogonadism was one of the most frequent causes of sexual dysfunction before HAART. Currently, HIV infected individuals may have testosterone levels higher than non infected individuals. Moreover, estradiol is often higher in men (50% of them) on HAART possibly because the augmentation of the peripheral conversion of the androgens to estrogens in lipid tissues (Bell et al. 2006, Goldmeier et al. 2002). But the role of estradiol in HIV sexual dysfunctions is not clear. The expected decrease in blood of the gonadotropin hormones was not confirmed (Collazos et al. 2002a), and one study observed improving on sexual function despite higher blood levels of estradiol (Collazos et al. 2002b). On the other side, an study on rabbits found estrogen receptors in cavernous body, and found pathophysiological changes in erectile function when rabbits are under continuous estrogen intake (Srilatha and Adaikan 2004). Another study with older men found that the balance between testosterone

that cause lipodystrophy (Bell et al. 2006, Hijazi et al. 2002, Luzi et al. 2009).

it is not regularly investigated in studies of male sexual function.

mental, hormonal, pharmachological, and other morbid conditions.

**3. Etiology** 

**3.1 Mental factors** 

function than others.

**3.2 Hormonal factors** 

protective (Crum-Cianflone et al. 2007).

completion of the sexual activity. *Male orgasmic disorder* is delay or absence of orgasm following normal excitement and sexual activity. Due to the widely varied sexual response in men, it must be judged by a clinician to be significant, taking into account the person's age and situation. *Premature ejaculation* is the ejaculation with minimal sexual stimulation before or shortly after penetration and before the person wishes it. The condition is persistent or occurs frequently and causes significant distress (APA, 2000).

Factors such as lack of ability, poor sex education, and psychological conflicts play an important role in the development of sexual dysfunction at the start of sexual activity (Lewis et al. 2004). Life habits and morbid conditions become important risk factors for sexual dysfunction during aging; these factors include hypertension, diabetes, depression, heart disease, sex hormone deficiency, smoking, sedentary life style, and drug addiction (Moreira et al. 2001). Socioeconomic factors, such as education, employment and marital status, have also been related to sexual difficulties (Nicolosi et al. 2003).

Highly active antiretroviral therapy (HAART) has previously been shown to provide the best clinical management for HIV-infected patients, as it decreases the prevalence of hypogonadism and advanced HIV disease, which are principal causes of sexual dysfunction in people infected with HIV (Danoff 1996, Collazos 2007). However the prevalence on sexual dysfunctions in the HAART years show high rates (Collazos 2007). In this chapter we analyze the etiologic factors involved on sexual dysfunctions of HIV/AIDS people. We also describe the most prevalent sexual dysfunctions in males, and females. We propose steps for assessment, and diagnosis of the sexual dysfunction in HIV/AIDS people. We talk about the principal therapeutic strategies for recover healthy sexual function of this people. Finally, we comment on the prognostic factors.

#### **2. Epidemiology**

The prevalence rates of sexual dysfunctions in HIV/AIDS patients were reviewed: 46% presented with erectile dysfunction (range 9-74%), 39% with ejaculatory disturbances (range 36-42%), 44% with decreased libido (range 24-73%), and 27% with orgasmic disorders (range 7-49%). The high interval of range is because so much different designs and methods used in the HIV sexual dysfunctions studies (Collazos 2007). There are differences on the most prevalent sexual dysfunctions among men, and women.

The most prevalent female sexual dysfunctions are low sexual desire, orgasmic dysfunction, and dyspareunia (Hijazi et al. 2002, Luzi et al. 2009). A higher frequency (36%) of sexual inactivity during the last 12 months in female with AIDS has been reported by a Brazilian study (de Tubino Scanavino and Abdo 2010), which is in according with another study of females with HIV/AIDS, of which 28% reported having no sexual partners for an average of 69 months (Lambert, Keegan and Petrak 2005). We already know that HIV/AIDS females that has partners keep more the sexual activity than who does not have. But in the Brazilian study the female also does not maintain sexual arousal until the end of the sex, and probably this may partly explain the sexual inactivity because these women seem to find sex unsatisfactory (de Tubino Scanavino and Abdo 2010).

On men infected by HIV the most prevalent sexual dysfunctions are erectile dysfunction and premature ejaculation. In Brazil, a case-control study nested in a cross-sectional population study with people who reported AIDS found that almost 50% of the male reported ejaculatory symptoms, and 33% of the men living with AIDS reported erectile dysfunction (de Tubino Scanavino and Abdo 2010). In this study 12% of men with AIDS also

completion of the sexual activity. *Male orgasmic disorder* is delay or absence of orgasm following normal excitement and sexual activity. Due to the widely varied sexual response in men, it must be judged by a clinician to be significant, taking into account the person's age and situation. *Premature ejaculation* is the ejaculation with minimal sexual stimulation before or shortly after penetration and before the person wishes it. The condition is

Factors such as lack of ability, poor sex education, and psychological conflicts play an important role in the development of sexual dysfunction at the start of sexual activity (Lewis et al. 2004). Life habits and morbid conditions become important risk factors for sexual dysfunction during aging; these factors include hypertension, diabetes, depression, heart disease, sex hormone deficiency, smoking, sedentary life style, and drug addiction (Moreira et al. 2001). Socioeconomic factors, such as education, employment and marital status, have

Highly active antiretroviral therapy (HAART) has previously been shown to provide the best clinical management for HIV-infected patients, as it decreases the prevalence of hypogonadism and advanced HIV disease, which are principal causes of sexual dysfunction in people infected with HIV (Danoff 1996, Collazos 2007). However the prevalence on sexual dysfunctions in the HAART years show high rates (Collazos 2007). In this chapter we analyze the etiologic factors involved on sexual dysfunctions of HIV/AIDS people. We also describe the most prevalent sexual dysfunctions in males, and females. We propose steps for assessment, and diagnosis of the sexual dysfunction in HIV/AIDS people. We talk about the principal therapeutic strategies for recover healthy sexual function of this people. Finally,

The prevalence rates of sexual dysfunctions in HIV/AIDS patients were reviewed: 46% presented with erectile dysfunction (range 9-74%), 39% with ejaculatory disturbances (range 36-42%), 44% with decreased libido (range 24-73%), and 27% with orgasmic disorders (range 7-49%). The high interval of range is because so much different designs and methods used in the HIV sexual dysfunctions studies (Collazos 2007). There are differences

The most prevalent female sexual dysfunctions are low sexual desire, orgasmic dysfunction, and dyspareunia (Hijazi et al. 2002, Luzi et al. 2009). A higher frequency (36%) of sexual inactivity during the last 12 months in female with AIDS has been reported by a Brazilian study (de Tubino Scanavino and Abdo 2010), which is in according with another study of females with HIV/AIDS, of which 28% reported having no sexual partners for an average of 69 months (Lambert, Keegan and Petrak 2005). We already know that HIV/AIDS females that has partners keep more the sexual activity than who does not have. But in the Brazilian study the female also does not maintain sexual arousal until the end of the sex, and probably this may partly explain the sexual inactivity because these women seem to find sex

On men infected by HIV the most prevalent sexual dysfunctions are erectile dysfunction and premature ejaculation. In Brazil, a case-control study nested in a cross-sectional population study with people who reported AIDS found that almost 50% of the male reported ejaculatory symptoms, and 33% of the men living with AIDS reported erectile dysfunction (de Tubino Scanavino and Abdo 2010). In this study 12% of men with AIDS also

on the most prevalent sexual dysfunctions among men, and women.

unsatisfactory (de Tubino Scanavino and Abdo 2010).

persistent or occurs frequently and causes significant distress (APA, 2000).

also been related to sexual difficulties (Nicolosi et al. 2003).

we comment on the prognostic factors.

**2. Epidemiology** 

reported dyspareunia, while no men without AIDS reported it (de Tubino Scanavino and Abdo 2010). Male dyspareunia is not commonly reported in the literature, possibly because it is not regularly investigated in studies of male sexual function.

## **3. Etiology**

There are four important factors associated with sexual dysfunctions in HIV/AIDS patients: mental, hormonal, pharmachological, and other morbid conditions.

#### **3.1 Mental factors**

At the first moment, the condition of being HIV seropositive may cause feelings of loss of sexual attractiveness, reduction of sexual desire and sexual satisfaction. Moreover, they may be confronted with the absence of sexual partners, particularly when revealing their serological status. In addition, the sexual response may be undermined by fear or guilt in coming to contaminate partnerships (Newshan et al. 1998, Schiltz and Sandfort 2000).

A representative French study with HIV outpatients showed association among sexual difficulties and the discrimination by friends and partners, suffering by lipodystrophy, very disturbing HIV related symptoms. The authors recommend psychological support for HIV experience for improves the sexual life (Bouhnik et al. 2008). Feelings of guilt by have acquiring the HIV on sexual transmission may become a psychogenic factor and influence negatively the sexual response. Maybe because of this point, sexual dysfunctions are more prevalent on homosexual men than intravenous drug users (Sollima et al. 2001). In fact, gay and bisexual men have higher rates of sexual dysfunctions (Catalan and Meadows 2000) or just complaint more to the physicians on the disorder due to valorize more the sexual function than others.

Depression is one of the most important mental factors associated with sexual dysfunctions (Ciesla and Roberts 2001). A study on 300 HIV infected men found the older age and depression were associated with erectile dysfunction, and current higher CD4 account was protective (Crum-Cianflone et al. 2007).

The most common factors associated with female sexual dysfunction are the psychosocial aspects of HIV infection and the negative body image associated with use of medications that cause lipodystrophy (Bell et al. 2006, Hijazi et al. 2002, Luzi et al. 2009).

## **3.2 Hormonal factors**

Hypogonadism was one of the most frequent causes of sexual dysfunction before HAART. Currently, HIV infected individuals may have testosterone levels higher than non infected individuals. Moreover, estradiol is often higher in men (50% of them) on HAART possibly because the augmentation of the peripheral conversion of the androgens to estrogens in lipid tissues (Bell et al. 2006, Goldmeier et al. 2002). But the role of estradiol in HIV sexual dysfunctions is not clear. The expected decrease in blood of the gonadotropin hormones was not confirmed (Collazos et al. 2002a), and one study observed improving on sexual function despite higher blood levels of estradiol (Collazos et al. 2002b). On the other side, an study on rabbits found estrogen receptors in cavernous body, and found pathophysiological changes in erectile function when rabbits are under continuous estrogen intake (Srilatha and Adaikan 2004). Another study with older men found that the balance between testosterone

The diagnosis of sexual dysfunctions follows some steps for diagnosis: consistent doctorpatient relationship, investigation of clinical history and physical examination, investigation of the sexual life history, assessment on sexual response, and check the hormonal serum

The clinical history compreends the assessment on the immunological conditions, comorbidities, and medications. Severe immunological damage may indicates AIDS diagnosis. The poor health condition undermine physical and sexual response. Nevertheless the hypogonadism should be investigated. On the physical examination the gynecomaestia and testicular atrophy may indicates hypogonadism (Rosen et al. 2006). Hypogonadism is defined as low levels of testosterone (< 300 nh/dL) in early morning, with associated clinical manifestations, including sexual dysfunction, weight and muscle mass loss, fatigue,

We already spoke on the most frequent comorbidity and the use of some medications which

The sexual history should starts investigating the concepts on sexuality of the family (father and mother), following to the patient's sexual history, finishing with focus about some

When sexuality is very repressed, it could undermine to live a broad experience of sex and love in adolescence and young adult life (Basson 2008), which are fundamental to sexual maturing process. The non psychological and sexual maturing and possible internal conflicts influence the sexual response. When somebody lives in a dysfunctional family in childhood and has early contact with the erotic experience (sexual abuse or permissive family ambience), it could be traumatic and harm the personality development, as the children experience feelings of being unprotected, unsafety, shame or guilt. Then, this person could presents sexual problems (aversion, excessive drive, sexual difficulties) later in

On sexual violence suffered during childhood and adolescence many studies have reported serious psychological effects and sexual consequences (Gwandure 2007, Greenberg 2001, Whetten et al. 2006). Victims of violence often have a high frequency of the stress posttraumatic disorder, depression, suicidal ideation and low self-esteem (Gwandure 2007) (Greenberg 2001, Whetten et al. 2006). This psychopathological issues are risk factors for HIV / AIDS in adult life, as negative moods promote sexual practices without the use of condoms and, therefore, exposure to virus (Gwandure 2007). Thus, research has documented the association between childhood sexual abuse and higher frequency of sexual risk behavior in adult life (Gwandure 2007, Greenberg 2001, Whetten et al. 2006, Sikkema et al. 2008). At the same time, in several studies of HIV-positive individuals is described childhood sexual abuse, which frequency varies between 24% and 76% (Whetten et al. 2006, Bedimo, Kissinger and Bessinger 1997, Kalichman et al. 2002, Liebschutz et al. 2000,

levels.

**4.1 Clinical history and physical examination** 

depressed mood, and anemia (Crum et al. 2005).

also influence the sexual response.

**4.2.1 Sexuality on origin family** 

your life (Noll, Trickett and Putnam 2003).

**4.2 Sexual history** 

specific gender issues.

Segurado et al. 2008).

(decreased) and oestradiol (higher) are associated with erectile dysfunction (Srilatha, Adaikan and Chong 2007).

Hyperprolactinemia may be associated with sexual dysfunction as it decreases the gonadotropin releases and have been found in part of the HIV individuals, but one study does not found difference in prolactin levels between patients with and without sexual difficulties (Collazos et al. 2002b).

#### **3.3 Pharmacological factors**

HAART era shows high rates of sexual dysfunction despite the improvement of health conditions. Anedotical report from studies suggest association among protease inhibitors and sexual dysfunctions, but just a few studies found a kind of evidence on it. These studies have found a possible effect on testosterone receptor by protease inhibitors (Yang et al. 2005, Baker, Vaughn and Fanestil 1978). Other evidences to explain sexual dysfunction by an effect of HAART are scarce. Future studies on pharmacological issues may specify the etiologic role of antiretrovirals to sexual dysfunction.

It has been reported ejaculatory dysfunction associated by use of didanosine (Hijazi et al. 2002). The neuropathy is a possible complication by use of some antiretrovirals and may be a sexual dysfunction factor for some patients (Rogstad et al. 1999).

However, HIV infected individuals use a lot of other medications that are associated with decrease on sexual response. Medications such as ketoconazole, fluconazole, ganciclovir, megestrol, methadone and cimetidine may decrease the level of testosterone and cause sexual dysfunction (Newshan et al. 1998, Daniell 2002). Antihypertensives, diuretics, hypolipemics, benzodiazepines, antidepressants, and antipsychotics are also associated with sexual dysfuncitons (Asboe et al. 2007, Lue 2000, Daniell 2002, Bruckert et al. 1996).

#### **3.4 Comorbid conditions**

Some morbid conditions are common in HIV people and some of them are often associated with sexual dysfunction as hepathopathy, diabetes, hyperlipidemia, hypertension, vascular disease, alcohol dependence (Moreira et al. 2001).

## **4. Diagnosis**

When a patient comes for receiving care on sexual function, he needs time and more than one meeting with the health professional, to bind and reveal your intimate life problems.

But if a patient seeks medical care for other reasons but also has sexual problems, difficultly he will talk about spontaneously. Moreover, sexual life is poored investigated by practitioners, indeed in mental health settings. It also occurs on HIV/AIDS clinical context. In a research in the United Kingdom on HIV clinics, 60% of the physicians do not ask on sexual functioning of female HIV infected (Bell et al. 2006) despite the sexual difficulties are very prevalent on HIV women.

For this reason, in order to investigate sexual function of HIV people, the first point to consider is an appropriate doctor patient relationship (Lawlor and Braunack-Mayer 2004), which is basic to investigate clinical and sexual symptoms of the patients. It is important an attitude of open minded and free of judgments by the professional.

(decreased) and oestradiol (higher) are associated with erectile dysfunction (Srilatha,

Hyperprolactinemia may be associated with sexual dysfunction as it decreases the gonadotropin releases and have been found in part of the HIV individuals, but one study does not found difference in prolactin levels between patients with and without sexual

HAART era shows high rates of sexual dysfunction despite the improvement of health conditions. Anedotical report from studies suggest association among protease inhibitors and sexual dysfunctions, but just a few studies found a kind of evidence on it. These studies have found a possible effect on testosterone receptor by protease inhibitors (Yang et al. 2005, Baker, Vaughn and Fanestil 1978). Other evidences to explain sexual dysfunction by an effect of HAART are scarce. Future studies on pharmacological issues may specify the

It has been reported ejaculatory dysfunction associated by use of didanosine (Hijazi et al. 2002). The neuropathy is a possible complication by use of some antiretrovirals and may be

However, HIV infected individuals use a lot of other medications that are associated with decrease on sexual response. Medications such as ketoconazole, fluconazole, ganciclovir, megestrol, methadone and cimetidine may decrease the level of testosterone and cause sexual dysfunction (Newshan et al. 1998, Daniell 2002). Antihypertensives, diuretics, hypolipemics, benzodiazepines, antidepressants, and antipsychotics are also associated with

Some morbid conditions are common in HIV people and some of them are often associated with sexual dysfunction as hepathopathy, diabetes, hyperlipidemia, hypertension, vascular

When a patient comes for receiving care on sexual function, he needs time and more than one meeting with the health professional, to bind and reveal your intimate life

But if a patient seeks medical care for other reasons but also has sexual problems, difficultly he will talk about spontaneously. Moreover, sexual life is poored investigated by practitioners, indeed in mental health settings. It also occurs on HIV/AIDS clinical context. In a research in the United Kingdom on HIV clinics, 60% of the physicians do not ask on sexual functioning of female HIV infected (Bell et al. 2006) despite the sexual difficulties are

For this reason, in order to investigate sexual function of HIV people, the first point to consider is an appropriate doctor patient relationship (Lawlor and Braunack-Mayer 2004), which is basic to investigate clinical and sexual symptoms of the patients. It is important an

attitude of open minded and free of judgments by the professional.

sexual dysfuncitons (Asboe et al. 2007, Lue 2000, Daniell 2002, Bruckert et al. 1996).

Adaikan and Chong 2007).

difficulties (Collazos et al. 2002b).

etiologic role of antiretrovirals to sexual dysfunction.

disease, alcohol dependence (Moreira et al. 2001).

a sexual dysfunction factor for some patients (Rogstad et al. 1999).

**3.3 Pharmacological factors** 

**3.4 Comorbid conditions** 

very prevalent on HIV women.

**4. Diagnosis** 

problems.

The diagnosis of sexual dysfunctions follows some steps for diagnosis: consistent doctorpatient relationship, investigation of clinical history and physical examination, investigation of the sexual life history, assessment on sexual response, and check the hormonal serum levels.

#### **4.1 Clinical history and physical examination**

The clinical history compreends the assessment on the immunological conditions, comorbidities, and medications. Severe immunological damage may indicates AIDS diagnosis. The poor health condition undermine physical and sexual response. Nevertheless the hypogonadism should be investigated. On the physical examination the gynecomaestia and testicular atrophy may indicates hypogonadism (Rosen et al. 2006). Hypogonadism is defined as low levels of testosterone (< 300 nh/dL) in early morning, with associated clinical manifestations, including sexual dysfunction, weight and muscle mass loss, fatigue, depressed mood, and anemia (Crum et al. 2005).

We already spoke on the most frequent comorbidity and the use of some medications which also influence the sexual response.

## **4.2 Sexual history**

The sexual history should starts investigating the concepts on sexuality of the family (father and mother), following to the patient's sexual history, finishing with focus about some specific gender issues.

#### **4.2.1 Sexuality on origin family**

When sexuality is very repressed, it could undermine to live a broad experience of sex and love in adolescence and young adult life (Basson 2008), which are fundamental to sexual maturing process. The non psychological and sexual maturing and possible internal conflicts influence the sexual response. When somebody lives in a dysfunctional family in childhood and has early contact with the erotic experience (sexual abuse or permissive family ambience), it could be traumatic and harm the personality development, as the children experience feelings of being unprotected, unsafety, shame or guilt. Then, this person could presents sexual problems (aversion, excessive drive, sexual difficulties) later in your life (Noll, Trickett and Putnam 2003).

On sexual violence suffered during childhood and adolescence many studies have reported serious psychological effects and sexual consequences (Gwandure 2007, Greenberg 2001, Whetten et al. 2006). Victims of violence often have a high frequency of the stress posttraumatic disorder, depression, suicidal ideation and low self-esteem (Gwandure 2007) (Greenberg 2001, Whetten et al. 2006). This psychopathological issues are risk factors for HIV / AIDS in adult life, as negative moods promote sexual practices without the use of condoms and, therefore, exposure to virus (Gwandure 2007). Thus, research has documented the association between childhood sexual abuse and higher frequency of sexual risk behavior in adult life (Gwandure 2007, Greenberg 2001, Whetten et al. 2006, Sikkema et al. 2008). At the same time, in several studies of HIV-positive individuals is described childhood sexual abuse, which frequency varies between 24% and 76% (Whetten et al. 2006, Bedimo, Kissinger and Bessinger 1997, Kalichman et al. 2002, Liebschutz et al. 2000, Segurado et al. 2008).

No Yes

**Characteristics Organic Psychogenic** 

Age of onset Older Younger Onset Insidious Quick Pattern Constant Variable

Masturbation Yes No

Erection No Yes

self-administered in research or clinical settings (Rosen et al. 1997).

Table 1. Clinical difference between organic and psychogenic sexual dysfunction

Some standardized instruments for quick assessment of sexual response can be used, as the health practitioners often find it difficult to investigate the sex lives of patients. For female we can use The Female Sexual Function Index (FSFI) to assess female sexual function. The FSFI is a self-responsive questionnaire with 19 multiple choice questions divided into six main domains. The questionnaire evaluates phases of the sexual cycle (desire, excitement and orgasm), sexual satisfaction and dyspareunia in the last four weeks (Rosen et al. 2000). For male there is The International Index of Erectile Function (IIEF) which addresses the relevant domains of male sexual function (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), is psychometrically tested, readily

The Figure 1 shows generally items for investigating sexual function (de Tubino Scanavino

In general items evaluating sexual function involves the follows (de Tubino Scanavino and Abdo 2010): "Did you have sexual intercourse during the last 12 months?", "Do you need to be stimulated by your partner to begin sexual intercourse?", "Is stimulation (foreplay) necessary for you for a long time before sexual intercourse?", "If there is no previous reciprocal stimulation (foreplay), do you and your partner proceed to genital sexual intercourse?", "Do you masturbate regularly?", "Do you usually have sexual desire?", "Do you feel pain during sexual intercourse?". Items evaluating female sexual function involves the follows: "When you kiss and hug during sexual intercourse, do you feel sexual arousal and does the vagina become wet?", "Do you maintain sexual arousal and a wet vagina until the end of sexual intercourse?", "Do you reach orgasm during sexual activity (inside the vagina or outside on the clitoris)?". Items evaluating male sexual function involves the follows: "Do you feel the pleasure of getting an erection and keeping it until the end of sexual intercourse?", "Do you always manage to maintain an erection (hard penis) until the end of sexual intercourse?", "Do you ejaculate (expel white liquid through the penis) quicker than you want?", "Do you ejaculate (expel white liquid through the penis) later than you want?", "Do you ejaculate (expel white liquid through the penis) at the desired time for

Adverse life events and/or problems on the onset of sex life

Men: penile nocturnal

and Abdo 2010).

you?".

**4.3 Assessment on sexual response** 

#### **4.2.2 Own sexual history**

The own sexual history is very important. The first sexual experiences with boys or girls, the first complete sexual relationship, the exercise of masturbation are all significant steps in sexual maturing process, which compreend gaining knowledge on your body (erogenous zones) and of the others. When somebody has sexual difficulties in early sexual experiences and are not prepared to deal with, it could promote negative attitude regarding sex, and new experiences will be avoided, undermining the sexual maturing (Lewis et al. 2004). A person with sexual inexperiece is under higher risk for sexual dysfunction (Lewis et al. 2004), and, in turn, a person with sexual dysfunction is under higher risk for unsafe sex behavior (Rosen et al. 2006), even if become infected by HIV.

#### **4.2.3 Gender issues**

Some specific gender issues are also important to be investigated. For men, homosexual orientation presents a special vulnerability for sexual dysfunction, maybe because the process to accept the sexual orientation, the difficulties to deal with low acceptance by family and society, and the problems with gender identity (Coleman, Rosser and Strapko 1992). Some studies have reported higher rates of sexual dysfunction in HIV infected men who have sex with men (Cove and Petrak 2004).

For women, the mental health is a strong point to be investigated. Depression is a strong risk factor for sexual dysfunction (Cyranowski et al. 2004) and when treated can improve substancially the sexual dysfunction symptoms (Clayton et al. 2007).

Less investigated but so important is self-image and body image. Self-image compreends the perception from herself of the female issue, and the erotic issue. They are steps of sexual developing and are determinant to woman fells secure to engage in sexual experiences in adult life. The prejudice on body image by lipodystrophy has been considered the most important factor for sexual dysfunction in HIV infected women (Luzi et al. 2009) and could also influence to women do not engage in sex with partners.

Another important point on female sexual function is the presence of positive feelings for the partner (Basson 2008) and the sexual partner hability, as we know a lot of women just have positive sexual experiences when they are estimulated by a partner in an appropriate context, which involve affect and foreplay (Basson 2008).

#### **4.2.4 Difference between organic and psychogenic sexual dysfunction**

It is also relevant in sexual history to distinguish between characteristcs of organic or psychogenic sexual dysfunction (Table 1) (Speckens et al. 1993, Hatch, de la Peña and Fisher 1987). The psychogenic occurs more often in younger individuals, the onset is rapid, it could be related with adverse life events (when it appears soon after HIV diagnosis, e.g.) or problematic onset sex lives, the presentation is not constant and it changes depending on the partners, or the situations, and could not be presented in masturbation. Moreover, the organic occurs more often in older men, the onset is insidious, it does not have relation with life adverse events, the presentation is constant, and it also occurs in masturbation. For men, when the nocturnal penile erection is present it is suggestive of psychogenic etiology. Considering HIV infection we could think that individuals just seropositive with good health conditions probably presents sexual dysfunction by psychogenic etiology, and individuals with poor imunological conditions or AIDS diagnosis probably presents sexual dysfunction by organic factors.

508 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

The own sexual history is very important. The first sexual experiences with boys or girls, the first complete sexual relationship, the exercise of masturbation are all significant steps in sexual maturing process, which compreend gaining knowledge on your body (erogenous zones) and of the others. When somebody has sexual difficulties in early sexual experiences and are not prepared to deal with, it could promote negative attitude regarding sex, and new experiences will be avoided, undermining the sexual maturing (Lewis et al. 2004). A person with sexual inexperiece is under higher risk for sexual dysfunction (Lewis et al. 2004), and, in turn, a person with sexual dysfunction is under higher risk for unsafe sex

Some specific gender issues are also important to be investigated. For men, homosexual orientation presents a special vulnerability for sexual dysfunction, maybe because the process to accept the sexual orientation, the difficulties to deal with low acceptance by family and society, and the problems with gender identity (Coleman, Rosser and Strapko 1992). Some studies have reported higher rates of sexual dysfunction in HIV infected men

For women, the mental health is a strong point to be investigated. Depression is a strong risk factor for sexual dysfunction (Cyranowski et al. 2004) and when treated can improve

Less investigated but so important is self-image and body image. Self-image compreends the perception from herself of the female issue, and the erotic issue. They are steps of sexual developing and are determinant to woman fells secure to engage in sexual experiences in adult life. The prejudice on body image by lipodystrophy has been considered the most important factor for sexual dysfunction in HIV infected women (Luzi et al. 2009) and could

Another important point on female sexual function is the presence of positive feelings for the partner (Basson 2008) and the sexual partner hability, as we know a lot of women just have positive sexual experiences when they are estimulated by a partner in an appropriate

It is also relevant in sexual history to distinguish between characteristcs of organic or psychogenic sexual dysfunction (Table 1) (Speckens et al. 1993, Hatch, de la Peña and Fisher 1987). The psychogenic occurs more often in younger individuals, the onset is rapid, it could be related with adverse life events (when it appears soon after HIV diagnosis, e.g.) or problematic onset sex lives, the presentation is not constant and it changes depending on the partners, or the situations, and could not be presented in masturbation. Moreover, the organic occurs more often in older men, the onset is insidious, it does not have relation with life adverse events, the presentation is constant, and it also occurs in masturbation. For men, when the nocturnal penile erection is present it is suggestive of psychogenic etiology. Considering HIV infection we could think that individuals just seropositive with good health conditions probably presents sexual dysfunction by psychogenic etiology, and individuals with poor imunological conditions or AIDS diagnosis probably presents sexual

behavior (Rosen et al. 2006), even if become infected by HIV.

substancially the sexual dysfunction symptoms (Clayton et al. 2007).

**4.2.4 Difference between organic and psychogenic sexual dysfunction** 

also influence to women do not engage in sex with partners.

context, which involve affect and foreplay (Basson 2008).

dysfunction by organic factors.

who have sex with men (Cove and Petrak 2004).

**4.2.2 Own sexual history** 

**4.2.3 Gender issues** 


Table 1. Clinical difference between organic and psychogenic sexual dysfunction

## **4.3 Assessment on sexual response**

Some standardized instruments for quick assessment of sexual response can be used, as the health practitioners often find it difficult to investigate the sex lives of patients. For female we can use The Female Sexual Function Index (FSFI) to assess female sexual function. The FSFI is a self-responsive questionnaire with 19 multiple choice questions divided into six main domains. The questionnaire evaluates phases of the sexual cycle (desire, excitement and orgasm), sexual satisfaction and dyspareunia in the last four weeks (Rosen et al. 2000). For male there is The International Index of Erectile Function (IIEF) which addresses the relevant domains of male sexual function (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction), is psychometrically tested, readily self-administered in research or clinical settings (Rosen et al. 1997).

The Figure 1 shows generally items for investigating sexual function (de Tubino Scanavino and Abdo 2010).

In general items evaluating sexual function involves the follows (de Tubino Scanavino and Abdo 2010): "Did you have sexual intercourse during the last 12 months?", "Do you need to be stimulated by your partner to begin sexual intercourse?", "Is stimulation (foreplay) necessary for you for a long time before sexual intercourse?", "If there is no previous reciprocal stimulation (foreplay), do you and your partner proceed to genital sexual intercourse?", "Do you masturbate regularly?", "Do you usually have sexual desire?", "Do you feel pain during sexual intercourse?". Items evaluating female sexual function involves the follows: "When you kiss and hug during sexual intercourse, do you feel sexual arousal and does the vagina become wet?", "Do you maintain sexual arousal and a wet vagina until the end of sexual intercourse?", "Do you reach orgasm during sexual activity (inside the vagina or outside on the clitoris)?". Items evaluating male sexual function involves the follows: "Do you feel the pleasure of getting an erection and keeping it until the end of sexual intercourse?", "Do you always manage to maintain an erection (hard penis) until the end of sexual intercourse?", "Do you ejaculate (expel white liquid through the penis) quicker than you want?", "Do you ejaculate (expel white liquid through the penis) later than you want?", "Do you ejaculate (expel white liquid through the penis) at the desired time for you?".

Gender issues Men who have sex

Sexual abuse

The onset Masturbation exercise First complete intercourse

with men

Women

Organic Psychogenic

Testosterone Estradiol Gonadotropin Prolactin Estrogen Sex hormonebinding globulin

Lipid profile

Metabolic Carbohydrate

If medication is the principal factor you can try another drug that has poor influence on sexual response, such as nevirapine (Collazos 2007, Collazos et al. 2002c) or atazanavir

Sexual orientation Gender issues

Mental health Self-image Body image Feelings for the

partner Hability of the partner

1. Consistent doctor-patient relationship

2. Clinical history and physical examination

4. Assessment on sexual response

5. Laboratory

assessment Hormonal

Fig. 2. Steps for the diagnosis

**5.1.1 Antiretrovirals** 

(Bernal et al. 2005).

Immunological Co-morbidities Hypogonadism

3. Sexual history Family Repression

Own sexual history

Characteristics of the

dysfunction

Desire Arousal Orgasm Resolution Satisfaction


Fig. 1. Items for assessment the sexual function (de Tubino Scanavino and Abdo 2010).

#### **4.4 Laboratory assessment**

Laboratory assessment may involve a sexual hormones screening including testosterone, estrogen, estradiol, prolactin, gonadotropin. It is important check the serum free testosterone or the levels of sex hormone-binding globulin because it usually is increased in HIV infected individuals (Hofbauer and Heufelder 1996). When organic etiology is suspected, more profound evaluations can take place, such as Doppler ultrasonography (arterial obstruction) or nerve conduction study (neuropathy).

The Figure 2 summarizes the steps for the diagnosis.

## **5. Treatment**

The treatment of sexual dysfunctions on HIV/AIDS patients involves pharmacotherapy, psychotherapy interventions, and psychoeducational approaches on safer sex.

#### **5.1 Pharmacotherapy**

For pharmacologycal management may be considered the changing of the antiretroviral used, the association of phosphodiesterase-5 inhibitors, testosterone replacement when hypogonadism was diagnosed, and letrozole if estradiol is increased.

clitoris)?".

Fig. 1. Items for assessment the sexual function (de Tubino Scanavino and Abdo 2010).

(arterial obstruction) or nerve conduction study (neuropathy).

The Figure 2 summarizes the steps for the diagnosis.

Laboratory assessment may involve a sexual hormones screening including testosterone, estrogen, estradiol, prolactin, gonadotropin. It is important check the serum free testosterone or the levels of sex hormone-binding globulin because it usually is increased in HIV infected individuals (Hofbauer and Heufelder 1996). When organic etiology is suspected, more profound evaluations can take place, such as Doppler ultrasonography

The treatment of sexual dysfunctions on HIV/AIDS patients involves pharmacotherapy,

For pharmacologycal management may be considered the changing of the antiretroviral used, the association of phosphodiesterase-5 inhibitors, testosterone replacement when

psychotherapy interventions, and psychoeducational approaches on safer sex.

hypogonadism was diagnosed, and letrozole if estradiol is increased.

"Did you have sexual intercourse during the last 12 months?", "Do you need to be stimulated by your partner to begin sexual intercourse?", "Is stimulation (foreplay)

stimulation (foreplay), do you and your partner proceed to genital sexual intercourse?", "Do you masturbate regularly?", "Do you usually have sexual desire?", "Do

"When you kiss and hug during sexual intercourse, do you feel sexual arousal and does the vagina become wet?", "Do you maintain sexual arousal and a wet vagina until the end of sexual intercourse?", "Do you reach orgasm during sexual activity (inside the vagina or outside on the

"Do you feel the pleasure of getting an erection and keeping it until the end of sexual intercourse?", "Do you always manage to maintain an erection (hard penis) until the end of sexual intercourse?", "Do you ejaculate (expel white liquid through the penis) quicker than you want?", "Do you ejaculate (expel white liquid through the penis) later than you want?", "Do you ejaculate (expel white liquid through the penis) at the desired time for you?".

necessary for you for a long time before sexual intercourse?", "If there is no previous reciprocal

you feel pain during sexual intercourse?".

Items for men and women

Items specifically for

Items specifically for men

**4.4 Laboratory assessment** 

**5. Treatment** 

**5.1 Pharmacotherapy** 

women


Fig. 2. Steps for the diagnosis

#### **5.1.1 Antiretrovirals**

If medication is the principal factor you can try another drug that has poor influence on sexual response, such as nevirapine (Collazos 2007, Collazos et al. 2002c) or atazanavir (Bernal et al. 2005).

If the most important factor is the psychogenic can use supportive therapy in early period after HIV diagnosis. It should foccuses in demystify the stigmas from HIV/AIDS as mortal disease and as associated to non conventional sex behavior. The supportive approach would

A structured supportive approach could be necessary for the women who suffered sexual

People who have severe sexual conflicts because grown in a family with high sexual repression or suffered childhood sexual abuse, a processual approach could be recomended

Psychosexual therapy such as sensitive focus or masturbation training are indicated when

As most of the population did not receive sexual education, the psychoeducational approach is always useful involving anatomy concepts, the differences between male and

Psychoeducational approach on safer sex is offered concomitant with the treatment of the sexual dysfunction. Always the approach involves the patient and his or her partner. Safer sex counseling is fundamental for explaining the risk for contact with different strains of

Finally, psychoeducational approach should stimulate lifestyle modification including safer sex, exercise, recreational drugs information, modifications of cardiovascular risk factors

The sexual function before HIV diagnosis, the current physical and mental health, and the psychosocial support are important factors to improve sexual response. A medical team updated with knowledge on human sexuality is essential for diagnosis, and treatment of the sexual dysfunctions. When these conditions are preserved the results on therapeutics are

The problem is that in many times the sexual issues are not investigated by health professionals, and just a few of patients will talk about sexual problems spontaneously. As sexual dysfunction is so prevalent in general population and in people living with HIV, a lot of them, keep without caring on sexual difficulties. On addiction, sexual dysfunction has impact on quality of life, very often influencing negative attitudes by the individual, including bad adherence to antiretroviral regimens, and to safer sex strategies (Trotta et al. 2007, Trotta et al. 2008). Moreover, HIV infected people with sexual dysfuntion have

HIV, and favouring the development of the resistence to antiretrovirals.

good (Wasserman et al. 2008, Richardson et al. 2007, Schrader et al. 2005).

the acceptance of HIV seropositivity is solved and the sexual dysfunctions remains.

**5.2.1 Supportive** 

**5.2.2 Processual** 

as psychoanalysis.

**5.2.3 Psychosexual** 

**5.2.4 Psychoeducational** 

female sexual response, e.g.

(Rosen et al. 2006).

**6. Prognosis** 

diminish the fear and guilt.

violence could overcoming and retake sexual life.

**5.3 Psychoeducational approach on safer sex** 

The Figure 3 summarizes the treatment.

## **5.1.2 Phosphodiesterase-5 inhibitors**

The use of phosphodiesterase-5 inhibitors is highly recommended in male sexual dysfunction, but one should be careful about drug interactions with antiretrovirals, particularly with protease inhibitors (especially ritonovir) because both are metabolized by the cytochrome P-450 system. Because the increases of serum concentration of phosphodiesterase-5 inhibitors when associated with protease inhibitors and cetoconazol, the dosage should be reduced (Merry et al. 1999, Rosen et al. 2006). The phosphodiesterase-5 inhibitors most often used are sildenafil, tadalafil and vardenafil.

Poppers (amyl nitrate) are contraindicated by men user of phosphodiesterase-5 inhibitors because lowers blood pressure especially in combination with phosphodiesterase-5 inhibitors.

## **5.1.3 Testosterone replacement**

If the patient reaches the diagnostic criteria for hypogonadism there is some options for testosterone replacement.

On the other side, testosterone replacement is not prescribed for HIV patients without decreases on free testosterone blood levels because does not improve sexual dysfunctions have been reported in this condition, and they will be exposed to the adverse effects (Collazos 2007). Sometimes testosterone replacement could be problematic even to hypogonadal male, as in the report of three HIV infected patients with erectile dysfunction whose present low testosterone and SHBG despite are receiving long-term oxandrolone in addition to testosterone replacement therapy, beyond HAART. Discontinuation of oxandrolone led to the normalization or improvement of testosterone levels in all three patients with symptomatic improvement in one patient. The authors hypothesized the first pass metabolism of orally administered oxandrolone may decrease hepatic synthesis of SHBG, allowing exogenously supplied testosterone to be excreted (Wasserman, Segal-Maurer and Rubin 2008).

By the way, the testosterone replacement shows good results in sexual dysfunction of most of hypogonadal HIV infected individuals (Cofrancesco, Whalen and Dobs 1997, Rabkin, Rabkin and Wagner 1997, Rabkin, Wagner and Rabkin 1999, Rabkin, Wagner and Rabkin 2000, Seftel et al. 2004) and the replacement by testosterone gel topic shows good benefits (Schrader et al. 2005).

## **5.1.4 Letrozole**

Finally, some improvement in sexual desire has been reported in a few patients on HAART who were treated with letrozole, an aromatase inhibitor that inhibits the conversion of testosterone to estradiol. Thirteen men who have sex with men on HAART with low sexual desire as well as raised estradiol levels were randomly allocated to receive either parenteral testosterone or letrozole for six weeks. Standardized instruments pointed out improvement in desire, and frequency of sexual acts in both treatment arms (Richardson et al. 2007).

#### **5.2 Psychotherapy**

The psychotherapic approaches on sexual dysfunction of HIV infected people involve supportive, processual, psychosexual, and psychoeducational therapies.

The use of phosphodiesterase-5 inhibitors is highly recommended in male sexual dysfunction, but one should be careful about drug interactions with antiretrovirals, particularly with protease inhibitors (especially ritonovir) because both are metabolized by the cytochrome P-450 system. Because the increases of serum concentration of phosphodiesterase-5 inhibitors when associated with protease inhibitors and cetoconazol, the dosage should be reduced (Merry et al. 1999, Rosen et al. 2006). The phosphodiesterase-5

Poppers (amyl nitrate) are contraindicated by men user of phosphodiesterase-5 inhibitors because lowers blood pressure especially in combination with phosphodiesterase-5

If the patient reaches the diagnostic criteria for hypogonadism there is some options for

On the other side, testosterone replacement is not prescribed for HIV patients without decreases on free testosterone blood levels because does not improve sexual dysfunctions have been reported in this condition, and they will be exposed to the adverse effects (Collazos 2007). Sometimes testosterone replacement could be problematic even to hypogonadal male, as in the report of three HIV infected patients with erectile dysfunction whose present low testosterone and SHBG despite are receiving long-term oxandrolone in addition to testosterone replacement therapy, beyond HAART. Discontinuation of oxandrolone led to the normalization or improvement of testosterone levels in all three patients with symptomatic improvement in one patient. The authors hypothesized the first pass metabolism of orally administered oxandrolone may decrease hepatic synthesis of SHBG, allowing exogenously supplied testosterone to be excreted (Wasserman, Segal-

By the way, the testosterone replacement shows good results in sexual dysfunction of most of hypogonadal HIV infected individuals (Cofrancesco, Whalen and Dobs 1997, Rabkin, Rabkin and Wagner 1997, Rabkin, Wagner and Rabkin 1999, Rabkin, Wagner and Rabkin 2000, Seftel et al. 2004) and the replacement by testosterone gel topic shows good benefits

Finally, some improvement in sexual desire has been reported in a few patients on HAART who were treated with letrozole, an aromatase inhibitor that inhibits the conversion of testosterone to estradiol. Thirteen men who have sex with men on HAART with low sexual desire as well as raised estradiol levels were randomly allocated to receive either parenteral testosterone or letrozole for six weeks. Standardized instruments pointed out improvement in desire, and frequency of sexual acts in both treatment arms

The psychotherapic approaches on sexual dysfunction of HIV infected people involve

supportive, processual, psychosexual, and psychoeducational therapies.

**5.1.2 Phosphodiesterase-5 inhibitors** 

**5.1.3 Testosterone replacement** 

testosterone replacement.

Maurer and Rubin 2008).

(Schrader et al. 2005).

(Richardson et al. 2007).

**5.2 Psychotherapy** 

**5.1.4 Letrozole** 

inhibitors.

inhibitors most often used are sildenafil, tadalafil and vardenafil.

## **5.2.1 Supportive**

If the most important factor is the psychogenic can use supportive therapy in early period after HIV diagnosis. It should foccuses in demystify the stigmas from HIV/AIDS as mortal disease and as associated to non conventional sex behavior. The supportive approach would diminish the fear and guilt.

A structured supportive approach could be necessary for the women who suffered sexual violence could overcoming and retake sexual life.

## **5.2.2 Processual**

People who have severe sexual conflicts because grown in a family with high sexual repression or suffered childhood sexual abuse, a processual approach could be recomended as psychoanalysis.

### **5.2.3 Psychosexual**

Psychosexual therapy such as sensitive focus or masturbation training are indicated when the acceptance of HIV seropositivity is solved and the sexual dysfunctions remains.

## **5.2.4 Psychoeducational**

As most of the population did not receive sexual education, the psychoeducational approach is always useful involving anatomy concepts, the differences between male and female sexual response, e.g.

#### **5.3 Psychoeducational approach on safer sex**

Psychoeducational approach on safer sex is offered concomitant with the treatment of the sexual dysfunction. Always the approach involves the patient and his or her partner. Safer sex counseling is fundamental for explaining the risk for contact with different strains of HIV, and favouring the development of the resistence to antiretrovirals.

Finally, psychoeducational approach should stimulate lifestyle modification including safer sex, exercise, recreational drugs information, modifications of cardiovascular risk factors (Rosen et al. 2006).

The Figure 3 summarizes the treatment.

## **6. Prognosis**

The sexual function before HIV diagnosis, the current physical and mental health, and the psychosocial support are important factors to improve sexual response. A medical team updated with knowledge on human sexuality is essential for diagnosis, and treatment of the sexual dysfunctions. When these conditions are preserved the results on therapeutics are good (Wasserman et al. 2008, Richardson et al. 2007, Schrader et al. 2005).

The problem is that in many times the sexual issues are not investigated by health professionals, and just a few of patients will talk about sexual problems spontaneously. As sexual dysfunction is so prevalent in general population and in people living with HIV, a lot of them, keep without caring on sexual difficulties. On addiction, sexual dysfunction has impact on quality of life, very often influencing negative attitudes by the individual, including bad adherence to antiretroviral regimens, and to safer sex strategies (Trotta et al. 2007, Trotta et al. 2008). Moreover, HIV infected people with sexual dysfuntion have

(hormonal, metabolic). The management strategies by health professionals with expertise in human sexuality involves pharmacology and psychotherapy interventions. Always the psychoeducational approach on safer sex will be developed in parallel with others interventions. The recovery of the sexual function, associated with a good adherence to safe sex practices, will improve the quality of life of the people living with HIV/AIDS and help

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Asboe, D., J. Catalan, S. Mandalia, N. Dedes, E. Florence, W. Schrooten, C. Noestlinger & R.

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Clayton, A., S. Kornstein, A. Prakash, C. Mallinckrodt & M. Wohlreich (2007) Changes in

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94.

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infected women. *Int J STD AIDS,* 8, 332-5.

**8. References** 


Fig. 3. Interventions

increased risk of transmission of drug-resistant strains because the higher sexual risk behavior, and inadvertent use of phosphodiesterase-5 inhibitors without medical recommendations with higher likelihood of negative interaction with antiretrovirals (Trotta et al. 2007, Trotta et al. 2008).

Another important point is on the scarcity of health professional team with expertise in human sexuality. A so private issue needs professionals with hability to approach on these intimate issues of the patients. Otherwise the patients do not open your sexual problems to them.

When the patient receives attention on your sexual life, he feels valuable, and will be more open to engage in positive ways as on adherence to medications as on safer sex strategies.

## **7. Conclusion**

Sexuality is a very important point to quality of life. A person who becomes infected by HIV particularly by sexual contact could be extremely confused about continuing engaging in sexual intercourses. The consequences mostly are negative attitudes toward life, harm on quality of life, sexual risk behaviors, and bad adherence to antiretrovirals. People who are living with HIV/AIDS are extremely important to epidemia control. Take care of your sexual life may improve your self steam and your protective behaviors.

By the way, the approach on sexual dysfunction in HIV infected people involves multiple variables and includes the assessment on clinical history (morbid conditions, medications), sexual history (family and own), sexual function (male and female), and laboratory studies

Estradiol increased (low

Women who suffered

Severe sexual repression Childhood sexual abuse Dysfunctional family

Poor sexual education Poor knowledge on human sexuality

Poor knowledge on sexual health

increased risk of transmission of drug-resistant strains because the higher sexual risk behavior, and inadvertent use of phosphodiesterase-5 inhibitors without medical recommendations with higher likelihood of negative interaction with antiretrovirals (Trotta

Another important point is on the scarcity of health professional team with expertise in human sexuality. A so private issue needs professionals with hability to approach on these intimate issues of the patients. Otherwise the patients do not open your sexual problems to

When the patient receives attention on your sexual life, he feels valuable, and will be more open to engage in positive ways as on adherence to medications as on safer sex strategies.

Sexuality is a very important point to quality of life. A person who becomes infected by HIV particularly by sexual contact could be extremely confused about continuing engaging in sexual intercourses. The consequences mostly are negative attitudes toward life, harm on quality of life, sexual risk behaviors, and bad adherence to antiretrovirals. People who are living with HIV/AIDS are extremely important to epidemia control. Take care of your

By the way, the approach on sexual dysfunction in HIV infected people involves multiple variables and includes the assessment on clinical history (morbid conditions, medications), sexual history (family and own), sexual function (male and female), and laboratory studies

sexual life may improve your self steam and your protective behaviors.

sex desire) Letrozole

diagnosis Supportive therapy

sexual violence Supportive therapy

Reduce the dosage Does not use with

poppers

replacement

Psychoanalysis

therapy

partner

Psychoeducational

Strategies for safer sex to the patient and to the

**Intervention Problem Management strategy**  1. Pharmacotherapy Antiretrovirals Change medication Association with Phosphodiesterase-5

inhibitors

Hypogonadism Testosterone

2. Psychotherapy Early period after HIV

3. Psychoeducational on safer

et al. 2007, Trotta et al. 2008).

sex

them.

**7. Conclusion** 

Fig. 3. Interventions

(hormonal, metabolic). The management strategies by health professionals with expertise in human sexuality involves pharmacology and psychotherapy interventions. Always the psychoeducational approach on safer sex will be developed in parallel with others interventions. The recovery of the sexual function, associated with a good adherence to safe sex practices, will improve the quality of life of the people living with HIV/AIDS and help controlling the epidemia.

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patients treated with highly active antiretroviral therapy. *J Acquir Immune Defic* 

disturbances and sexual hormones with specific antiretroviral drugs. *AIDS,* 16,

hypogonadism and erectile dysfunction among HIV-infected men during the preand post-HAART eras: diagnosis, pathogenesis, and management. *AIDS Patient* 

Furtek, S. Medina & M. R. Wallace (2007) Erectile dysfunction and hypogonadism

(2004) Lifetime depression history and sexual function in women at midlife. *Arch* 

aromatase activity in adipose fibroblasts cause low sexual desire in patients with


**22** 

Arne N. Gjorgov

*Republic of Macedonia* 

*Retired Lecturer Epidemiologist, Skopje,* 

**AIDS Changed America with the Twin** 

**Consequences of Condomization** 

**Breast Cancer Epidemic: Exploring the** 

Breast cancer as an epidemic disease which suddenly emerged along with the AIDS in the United States at the beginning of the 1980s, continued its unabated rise ever since and steadily continued its unprecedented epidemic advance worldwide. Initially affecting mainly the advanced, developed and 'rich' countries of the West, the breast cancer epidemic is now increasingly affecting the developing, less-advanced and 'poor' countries of all parts of the world. The 'latent period' of transition from the 'West" to the East and South, took less than a decade to extend. The epidemic of breast cancer along with the other accompanying, widespread diseases in women of all ages became better apparent now and

More than 34 years ago, a case-control study was initiated and completed in the U.S. in order to test an *a priori* hypothesis that a reduced or eliminated exposure to human seminal factors during the reproductive life-spans of women is an etiologic risk factor of developing breast cancer in American married women (Gjorgov, 1978a,b; Gjorgov, 1979; 1980, 1990, 1991, 1994a,b,c, 1996, 1998b). The hypothesis-testing study was jointly carried out at the University of North Carolina, School of Public Health (Epidemiology), at Chapel Hill, NC, and at the University of Pennsylvania School of Medicine and Hospital, in Philadelphia, PA, between 1974 and 1978, more than eight years before mutual epidemics of AIDS and breast cancer ever emerged. The results of the study corroborated the evidence of a significant association between exposure to barrier contraception (condom use and withdrawal practice) and the development of breast cancer in American and other women. In addition, the results provided evidence of a potential for primary (non-chemical) prevention/protection against breast cancer at individual, familial and community levels. Quantifying the risk, the results of the study indicated that women who used condoms and/or practiced withdrawal had a risk of developing breast cancer of 5.2 times greater (95%CI 3.1 – 8.7) than women who used non-barrier methods for fertility-control and family-planning purposes (diaphragm, IUDs, rhythm, oral-contraceptive pills, cream-jellies, and tubal ligation). By using Bayes' conditional theorem, it was estimated that 17% of women in the mainstream population using condoms / withdrawal were likely to develop breast cancer, versus 3.9% of women using non-barrier contraceptive methods. The evidence challenged head on the widespread misperception that all women are at an 'equal risk of

**1. Introduction** 

is increasingly attracting more attention and concern


## **AIDS Changed America with the Twin Breast Cancer Epidemic: Exploring the Consequences of Condomization**

Arne N. Gjorgov *Retired Lecturer Epidemiologist, Skopje, Republic of Macedonia* 

## **1. Introduction**

518 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Rosser, B. R. S., J. M. Gobby & W. P. Carr. 1999. The unsafe sexual behavior of persons. 18-

Schiltz, M. A. & T. G. Sandfort (2000) HIV-positive people, risk and sexual behaviour. *Soc Sci* 

Schrader, S., A. Mills, M. Scheperle & J. E. Block (2005) Improvement in sexual functioning

Segurado, A. C., E. Batistella, V. Nascimento, P. E. Braga, E. Filipe, N. Santos & V. Paiva

Sikkema, K. J., P. A. Wilson, N. B. Hansen, A. Kochman, S. Neufeld, M. S. Ghebremichael &

Sollima, S., M. Osio, F. Muscia, P. Gambaro, A. Alciati, M. Zucconi, T. Maga, F. Adorni, T.

Speckens, A. E., M. W. Hengeveld, G. A. Lycklama à Nijeholt, A. M. van Hemert & K. E.

Srilatha, B. & P. G. Adaikan (2004) Estrogen and phytoestrogen predispose to erectile

Srilatha, B., P. G. Adaikan & Y. S. Chong (2007) Relevance of oestradiol-testosterone balance in erectile dysfunction patients' prognosis. *Singapore Med J,* 48, 114-8. Stein, M., D. S. Herman, E. Trisvan, P. Pirraglia, P. Engler & B. J. Anderson (2005) Alcohol

Trotta, M. P., A. Ammassari, R. Murri, P. Marconi, M. Zaccarelli, A. Cozzi-Lepri, R.

suboptimal adherence to antiretrovirals. *AIDS Patient Care STDS,* 22, 291-9. Trotta, M. P., A. Ammassari, R. Murri, A. Monforte & A. Antinori (2007) Sexual dysfunction

Wasserman, P., S. Segal-Maurer & D. Rubin (2008) Low sex hormone-binding globulin and

Whetten, K., J. Leserman, K. Lowe, D. Stangl, N. Thielman, M. Swartz, L. Hanisch & L. Van

HIV-positive sample from the deep south. *Am J Public Health,* 96, 1028-30. Yang, Y., T. Ikezoe, T. Takeuchi, Y. Adachi, Y. Ohtsuki, S. Takeuchi, H. P. Koeffler & H.

hypogonadal, HIV-positive males. *Clin Cornerstone,* 7 Suppl 4, S26-31. Seftel, A. D., R. J. Mack, A. R. Secrest & T. M. Smith (2004) Restorative increases in serum

and satisfaction in nonresponders to testosterone gel: clinical effectiveness in

testosterone levels are significantly correlated to improvements in sexual

(2008) Sexual abuse victimisation and perpetration in a cohort of men living with HIV/AIDS who have sex with women from São Paulo, Brazil. *AIDS Care,* 20, 15-20.

T. Kershaw (2008) Effects of a coping intervention on transmission risk behavior among people living with HIV/AIDS and a history of childhood sexual abuse. *J* 

Bini & A. d'Arminio Monforte (2001) Protease inhibitors and erectile dysfunction.

Hawton (1993) Discrimination between psychogenic and organic erectile

dysfunction: do ER-alpha and ER-beta in the cavernosum play a role? *Urology,* 63,

use and sexual risk behavior among human immunodeficiency virus-positive

Acinapura, N. Abrescia, P. De Longis, V. Tozzi, A. Scalzini, V. Vullo, E. Boumis, P. Nasta, A. Monforte, A. Antinori & A. a. A. S. Group (2008) Self-reported sexual dysfunction is frequent among HIV-infected persons and is associated with

testosterone levels in association with erectile dysfunction among human immunodeficiency virus-infected men receiving testosterone and oxandrolone. *J* 

Scoyoc (2006) Prevalence of childhood sexual abuse and physical trauma in an

Taguchi (2005) HIV-1 protease inhibitor induces growth arrest and apoptosis of human prostate cancer LNCaP cells in vitro and in vivo in conjunction with blockade of androgen receptor STAT3 and AKT signaling. *Cancer Sci,* 96, 425-33.

28.

*Med,* 50, 1571-88.

*AIDS,* 15, 2331-3.

382-6.

functioning. *J Androl,* 25, 963-72.

*Acquir Immune Defic Syndr,* 47, 506-13.

dysfunction. *J Psychosom Res,* 37, 135-45.

persons. *Alcohol Clin Exp Res,* 29, 837-43.

in HIV infection. *Lancet,* 369, 905-6.

*Sex Med,* 5, 241-7.

Breast cancer as an epidemic disease which suddenly emerged along with the AIDS in the United States at the beginning of the 1980s, continued its unabated rise ever since and steadily continued its unprecedented epidemic advance worldwide. Initially affecting mainly the advanced, developed and 'rich' countries of the West, the breast cancer epidemic is now increasingly affecting the developing, less-advanced and 'poor' countries of all parts of the world. The 'latent period' of transition from the 'West" to the East and South, took less than a decade to extend. The epidemic of breast cancer along with the other accompanying, widespread diseases in women of all ages became better apparent now and is increasingly attracting more attention and concern

More than 34 years ago, a case-control study was initiated and completed in the U.S. in order to test an *a priori* hypothesis that a reduced or eliminated exposure to human seminal factors during the reproductive life-spans of women is an etiologic risk factor of developing breast cancer in American married women (Gjorgov, 1978a,b; Gjorgov, 1979; 1980, 1990, 1991, 1994a,b,c, 1996, 1998b). The hypothesis-testing study was jointly carried out at the University of North Carolina, School of Public Health (Epidemiology), at Chapel Hill, NC, and at the University of Pennsylvania School of Medicine and Hospital, in Philadelphia, PA, between 1974 and 1978, more than eight years before mutual epidemics of AIDS and breast cancer ever emerged. The results of the study corroborated the evidence of a significant association between exposure to barrier contraception (condom use and withdrawal practice) and the development of breast cancer in American and other women. In addition, the results provided evidence of a potential for primary (non-chemical) prevention/protection against breast cancer at individual, familial and community levels. Quantifying the risk, the results of the study indicated that women who used condoms and/or practiced withdrawal had a risk of developing breast cancer of 5.2 times greater (95%CI 3.1 – 8.7) than women who used non-barrier methods for fertility-control and family-planning purposes (diaphragm, IUDs, rhythm, oral-contraceptive pills, cream-jellies, and tubal ligation). By using Bayes' conditional theorem, it was estimated that 17% of women in the mainstream population using condoms / withdrawal were likely to develop breast cancer, versus 3.9% of women using non-barrier contraceptive methods. The evidence challenged head on the widespread misperception that all women are at an 'equal risk of

AIDS Changed America with the Twin

Breast Cancer Epidemic: Exploring the Consequences of Condomization 521

of primary prevention of the most frequent diseases of women of all ages, the cancer of the breast as an epidemic diseases, especially in the industrialized and affluent world of the

Cancer of the breast is the truly a major marker of the condomization impact upon the health and lives of women in urgent need for solution. Other manifestations of the ill-effect of condomization of women's sexuality are also taken into considerations. All-inclusive data of female specific diseases and phenomena were collected from epidemiologic and clinical studies as well as from psychological and social investigations of female predominance, higher incidence, prevalence and mortality rates, and female to male ration (F:M) of various conditions and diseases (**Table 1).** Because of data limitations, only some of the most

Ovarian cancer, (incidence and death rates), cysts, polycystic syndrome (PCOS), and

Anorexia-bulimia ('eating') disorders, prevalence, in 90 : 10 girls / young women to boys

West, in the last three decades, since the early 1980s, and ever since.

frequent afflictions of women and girls were subject to review in the study.

Endometrial cancer (incidence and death rates), other pelvic tumors-fibroids

Dysmerrhea, menstrual irregularities, cessation, breast pain, hot flashes, craps Abortion: Spontaneous, habitual, artificial, and 'missed abortion'; Pseudocyesis

Thyroid cancer, incidence cases and rates is 3.5 - 7 : 1 in females to males; Osteoporosis, fractures, prevalence, more than 80 : 20 in female to males;

**Other female predominant diseases: Ratio female : male (referred)** 

Multiple sclerosis, prevalence 3 : 1 (National Academy of Sciences,.2011)

their specific, reproductive and natural functions. (Gjorgov, 1996b)

Table 1. Comprehensive woman's health: specific sex- (gender-) diseases in women, and

It should be mentioned here that some of the gender specific morbidly is also observed in domestic female animals, such as the **BSE**, *bovine spongiform encephalopathy,* and created in laboratory animals' mammary carcinomas and other tumors as well. It has been assumed, perhaps with some justification, that the persistent disproportion of higher female prevalence rates and aggregates of the specific gender diseases in females is also related to

**Exclusively female diseases and dysfunctions:** 

Cervical cancer (incidence and death rates), and lesions

Chronic pelvic pain, Pelvic congestion syndrome, Bloating **Specific, predominantly female diseases: Ratio female : male**  Breast cancer, incidence cases and rates is 100 : 1 in males;

Thyroid disease (Hashimoto), prevalence 10 : 1

Graves disease, prevalence 7 : 1 Sjogren's syndrome, prevalence 9 : 1 Lupus erythematosus, prevalence 8 : 1 Rheumatoid arthritis, prevalence 2.5 : 1

Scleroderma, prevalence 3 : 1

female-to-male ratios

dysfunctions,

Endometriosis,

/ young men.

Vulvodynia, Pain during sex

Female sexual dysfunctions (FSD),

breast cancer' and that the disease is a 'random' event in the lives of women (Gjorgov, 1980; 2009b). The newly revealed carcinogenic and other devastating effects and consequences of condomization of female sexuality showed to be operative even at a frequency of use of 50% of condom use. The quantification in the study of the latent period of development of breast cancer was shown to be between 2½ and 5 years, rather than the prevailing arbitrary assumptions of 15-20 years. Almost 80 percent of the etiologic fraction of the putative risk factor, which could indicate a potential preventive gain, was attributed in the study to the condomized and coitus interruptus birth control. One of the most favored inferences of the study was that the marriage is a profoundly biological woman-man union, with physiologic impact on spouses/couples, particularly on woman, along with the customary definition of marriage is a social, economic, psychological, traditional, and legal man-woman unit. Anticipation turned postulate has been that condomization could adversely affect this oldest human institution, the marriage.

The major unforeseen development in the epidemiology of breast cancer, lingering during the past three decades, beginning from the early 1980s, and continuing through the 1990s and 2000s, is the introduced policy of condomization of women's sexuality, as a supposed 'safe' prophylaxis against the HIV/AIDS transmission in the populations. As postulated, the newly introduced mechanical device, the condom, in the intimate (sexual) reproductive ecosystem, has substantially changed (corrupted) the primordial inter-human microenvironment, by eliminating the postulated putative protective factors (the prostaglandins?), that is, by introducing on an unprecedented scale technical effects of absolute male sterility in intimate (sexual) woman-man communication and other marital relations. The new development seem almost for certain to have had substantially supported / confirmed both an indirect causality of the tested evidence of the condom to breast cancer link, and the potential of primary (non-chemical, natural) prevention of the current, excess and unabated breast cancer epidemic.

There is a variety of gender- (sex-) specific diseases or dysfunction in women of all ages, related or not to the perpetual changes of the physiology of the reproductive system and changes of functions and events during the women's the child-bearing life-span. The definition of female-specific diseases is a pragmatic one and consists of specific female organs and systems (the internal and external reproductive organs), and mutual organs in both genders (breast, thyroid, bones) which are preponderantly and 'specifically' present in female. The central postulate is that the condomization is deleterious to all of the normal life functions of women and their reproductive events.

By entering the New Millennium, the beginning of the 21st Century in particular, the twin epidemics and burden of the HIV/AIDS transmission and breast cancer epidemic are likely to remain a major medical problem and great public health burden. The objective of this study was to try to explore the magnitude of the unknown impact and "unintended consequences" of a social action (Fox, 2004), such as the mass condomization, upon the health and lives of women. Accordingly, the study will attempt to provide answer(s) to what is the problem and what has to be done about the worsening morbidity and mortality of women in the changing world, what has been done--or not done--in the past, and especially what seems to be needed to investigate and to be done in the future, in terms of prevention and protection of reproductive health, life processes, truthful birth control, and (un)happiness of women in today's contemporary societies. The methods of the study are assessments of the trends, postulated etiology (root causes), epidemiology and the potential

breast cancer' and that the disease is a 'random' event in the lives of women (Gjorgov, 1980; 2009b). The newly revealed carcinogenic and other devastating effects and consequences of condomization of female sexuality showed to be operative even at a frequency of use of 50% of condom use. The quantification in the study of the latent period of development of breast cancer was shown to be between 2½ and 5 years, rather than the prevailing arbitrary assumptions of 15-20 years. Almost 80 percent of the etiologic fraction of the putative risk factor, which could indicate a potential preventive gain, was attributed in the study to the condomized and coitus interruptus birth control. One of the most favored inferences of the study was that the marriage is a profoundly biological woman-man union, with physiologic impact on spouses/couples, particularly on woman, along with the customary definition of marriage is a social, economic, psychological, traditional, and legal man-woman unit. Anticipation turned postulate has been that condomization could adversely affect this oldest

The major unforeseen development in the epidemiology of breast cancer, lingering during the past three decades, beginning from the early 1980s, and continuing through the 1990s and 2000s, is the introduced policy of condomization of women's sexuality, as a supposed 'safe' prophylaxis against the HIV/AIDS transmission in the populations. As postulated, the newly introduced mechanical device, the condom, in the intimate (sexual) reproductive ecosystem, has substantially changed (corrupted) the primordial inter-human microenvironment, by eliminating the postulated putative protective factors (the prostaglandins?), that is, by introducing on an unprecedented scale technical effects of absolute male sterility in intimate (sexual) woman-man communication and other marital relations. The new development seem almost for certain to have had substantially supported / confirmed both an indirect causality of the tested evidence of the condom to breast cancer link, and the potential of primary (non-chemical, natural) prevention of the

There is a variety of gender- (sex-) specific diseases or dysfunction in women of all ages, related or not to the perpetual changes of the physiology of the reproductive system and changes of functions and events during the women's the child-bearing life-span. The definition of female-specific diseases is a pragmatic one and consists of specific female organs and systems (the internal and external reproductive organs), and mutual organs in both genders (breast, thyroid, bones) which are preponderantly and 'specifically' present in female. The central postulate is that the condomization is deleterious to all of the normal life

By entering the New Millennium, the beginning of the 21st Century in particular, the twin epidemics and burden of the HIV/AIDS transmission and breast cancer epidemic are likely to remain a major medical problem and great public health burden. The objective of this study was to try to explore the magnitude of the unknown impact and "unintended consequences" of a social action (Fox, 2004), such as the mass condomization, upon the health and lives of women. Accordingly, the study will attempt to provide answer(s) to what is the problem and what has to be done about the worsening morbidity and mortality of women in the changing world, what has been done--or not done--in the past, and especially what seems to be needed to investigate and to be done in the future, in terms of prevention and protection of reproductive health, life processes, truthful birth control, and (un)happiness of women in today's contemporary societies. The methods of the study are assessments of the trends, postulated etiology (root causes), epidemiology and the potential

human institution, the marriage.

current, excess and unabated breast cancer epidemic.

functions of women and their reproductive events.

of primary prevention of the most frequent diseases of women of all ages, the cancer of the breast as an epidemic diseases, especially in the industrialized and affluent world of the West, in the last three decades, since the early 1980s, and ever since.

Cancer of the breast is the truly a major marker of the condomization impact upon the health and lives of women in urgent need for solution. Other manifestations of the ill-effect of condomization of women's sexuality are also taken into considerations. All-inclusive data of female specific diseases and phenomena were collected from epidemiologic and clinical studies as well as from psychological and social investigations of female predominance, higher incidence, prevalence and mortality rates, and female to male ration (F:M) of various conditions and diseases (**Table 1).** Because of data limitations, only some of the most frequent afflictions of women and girls were subject to review in the study.


Table 1. Comprehensive woman's health: specific sex- (gender-) diseases in women, and female-to-male ratios

It should be mentioned here that some of the gender specific morbidly is also observed in domestic female animals, such as the **BSE**, *bovine spongiform encephalopathy,* and created in laboratory animals' mammary carcinomas and other tumors as well. It has been assumed, perhaps with some justification, that the persistent disproportion of higher female prevalence rates and aggregates of the specific gender diseases in females is also related to their specific, reproductive and natural functions. (Gjorgov, 1996b)

AIDS Changed America with the Twin

sexuality as a trivial, only 'recreational' gender activity.

**3. Sources, population and methods** 

regular editions of the WHO-IARC CI5 volumes.

(Statistical Package for Social Sciences), Version 16, 2008.

**4.1 Perplexing breast cancer incidence rise worldwide** 

**4. Epidemiological and clinical results and consequences** 

**3.1 Sources** 

**3.2 Population** 

**3.3 Methods** 

Secretariat, 1994):

Breast Cancer Epidemic: Exploring the Consequences of Condomization 523

corrupted and destroyed the micro-environment of intimate (sexual) human ecosystem, by creating technical effects of sterile mating and un-physiological primordial woman-man communication and other relations. The unspoken ideas and intuitive popular knowledge of sex as a necessary part of life, health and survival of woman in marriage, and perhaps her beauty, was replaced by a conceptual vacuum in research, attitude and mindsets of sex and

Global breast cancer data are updated in five-year reports published by the World Health Organization International Agency on Cancer Research (IARC), in Lyon, France, titled: "Cancer Incidence in Five Continents" (CI5s), volumes III-IX. (Waterhouse et al, 1977, 1982; Muir et al., 1987; Parkin et al, 1992; Parkin et al., 1997, 2002; Cirado et al., 2007). For achieving the objectives volumes III to IX, 1968 to 2002, inclusive, in duration of 35 years for most centers.

Population under study consists of contingencies of women affected by breast cancer and other malignant diseases, collected by the national or regional Cancer Registries in 180 to 300 countries and population situations globally, with data quantified in average incidence rates (crude and age-standardized), collected in five-year periods, and reported by the

For appraisal of existing, reliable and controlled data, collected internationally by the World Health Organization throughout several decades. Common statistical procedures [means, standard deviations, 95% CI (confidence intervals) of the risks, correlation coefficients, twoway statistical significances at P<.01 and P<.05 levels] were used for testing the differences, the temporal and spacial changes of the epidemic disease. Correlation and regression analyses, in order to test the statistical significance of the trends and rates of the diseases, and possible extrapolations. The necessary graphical figures and tables of the results and trends are also presented. The analysis of the multitude of data was done by using the SPSS

The rapid rise of breast cancer in the U.S. was first noted by the media, perplexed over the "highest breast cancer incidence rate (of 92.1) ever seen" in the U.S., in 1984. The type of tidal wave ('tsunami') onslaught of breast cancer heralded an emerging, unprecedented epidemic of a malignant (not contagious) disease in the medical history. Thus reaching for a first time in human medical history an unprecedented epidemic of malignant disease. Starting by 1987, the crude incidence rate (based on the number of new cases) was almost entirely replaced by ageadjusted incidence rates (computed on out of sight number of new cases). Correlation between the breast cancer incidence rates and prevalence rates of condom use were invariably positive at statistically significant levels, as presented in **Table 2** (Gjorgov, 1998; Gjorgov, 2000; UN

## **2. Evidence-based and theoretical etiology of the breast cancer epidemic**

The provided evidence and inferences of the initial, hypothesis-testing study of etiology and prevention of breast cancer showed to be new and different from the widely and routinely accepted conceptions about the women's ill-health. The etiological link between the use of condom and breast cancer development in American and other married women, corroborated in a field study, was subsequently confirmed in a dramatic way by the explicitly predicted, natural experiment of the breast cancer outbreak/epidemic and the perplexing, rapid rise (Dinse et al. 1999), related to condomization campaigns and rumors for prophylaxis against the emergent mysterious infections.

The biological plausibility off the purported causal link of the carcinogenic effects between the of use of barrier methods of contraception, that is, use of condoms and/or withdrawal (*coitus interruptus*) and breast cancer in American and other women has been also corroborated elsewhere (Lê et al., 1989 in France, and Pikhut et al, 1991 in the former USSR). The indirect causality of breast cancer exposure to condom use was defined as an inverse ecological risk factor due to the absence, elimination or reduction of certain protective biological factors in the seminal fluid (the prostaglandins?), thus inducing technical effects of absolute male sterility in the prime biological woman-man communications. It has also been observed that the dichotomy of sexuality and procreative functions of female is much more complex, moving through incrementally deteriorating phases, than it has been presumed. Although intertwined, the distinct sexuality and reproduction capacities in women might offer a 'window of opportunity' to act coherently in achieving the imperatives of both control of the individual fertility and control of the global population growth.

Population-growth control could hardly proceed successfully by applying incorrect, deadly, and deceptive values of the technological method. The carcinogenic effects and lifethreatening consequences of the barrier contraceptive methods, such as the new/old, hightech condom device, along with the ancient technique of withdrawal, are cases in point: they cannot be assumed to be appropriate methods upon which a mass application of a proper population-growth control policy could be maintained. The contemporary social life and norms are practically incompatible with the bygone tradition of large families and multiparity households. It has been calculated and observed that a woman has to have at least eight or more full term normal pregnancies (FTNPs), i.e., children, in order to be virtually protected against breast cancer. The Nature has not changed and made no adjustments to facilitate the modern human tendency for reduced reproduction. The modern medical history, not yet written, has already shown that any misconception and even inadvertent error in the sphere of human reproduction is bound to inflict tremendous harm on women and society, such as the mass condomization of female sexuality in the mainstream population. It is the purpose of this study to try to clarify the damage of the condom-related "reproductive freedom" fallacy and the scientific and individual ignorance and errors in condomized control of fertility, without passing judgment.

Although the main attention and concern has been focused on the 'hormonal,' oral contraceptive pills, the condom use and the uncritical campaigns for its use in any situation resulted in grave consequences on health and lives of women and girls, in terms of the ongoing breast cancer epidemic and rampant 'eating' disorders. Even though the use of condoms dates for more than one century (in England at least), the condoms have been overlooked as the possible cause of the widespread ill-effects and grave consequences in women. The introduction of mass condomization of female sexuality has completely corrupted and destroyed the micro-environment of intimate (sexual) human ecosystem, by creating technical effects of sterile mating and un-physiological primordial woman-man communication and other relations. The unspoken ideas and intuitive popular knowledge of sex as a necessary part of life, health and survival of woman in marriage, and perhaps her beauty, was replaced by a conceptual vacuum in research, attitude and mindsets of sex and sexuality as a trivial, only 'recreational' gender activity.

## **3. Sources, population and methods**

## **3.1 Sources**

522 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

The provided evidence and inferences of the initial, hypothesis-testing study of etiology and prevention of breast cancer showed to be new and different from the widely and routinely accepted conceptions about the women's ill-health. The etiological link between the use of condom and breast cancer development in American and other married women, corroborated in a field study, was subsequently confirmed in a dramatic way by the explicitly predicted, natural experiment of the breast cancer outbreak/epidemic and the perplexing, rapid rise (Dinse et al. 1999), related to condomization campaigns and rumors

The biological plausibility off the purported causal link of the carcinogenic effects between the of use of barrier methods of contraception, that is, use of condoms and/or withdrawal (*coitus interruptus*) and breast cancer in American and other women has been also corroborated elsewhere (Lê et al., 1989 in France, and Pikhut et al, 1991 in the former USSR). The indirect causality of breast cancer exposure to condom use was defined as an inverse ecological risk factor due to the absence, elimination or reduction of certain protective biological factors in the seminal fluid (the prostaglandins?), thus inducing technical effects of absolute male sterility in the prime biological woman-man communications. It has also been observed that the dichotomy of sexuality and procreative functions of female is much more complex, moving through incrementally deteriorating phases, than it has been presumed. Although intertwined, the distinct sexuality and reproduction capacities in women might offer a 'window of opportunity' to act coherently in achieving the imperatives of both control of the individual fertility and control of the global population growth. Population-growth control could hardly proceed successfully by applying incorrect, deadly, and deceptive values of the technological method. The carcinogenic effects and lifethreatening consequences of the barrier contraceptive methods, such as the new/old, hightech condom device, along with the ancient technique of withdrawal, are cases in point: they cannot be assumed to be appropriate methods upon which a mass application of a proper population-growth control policy could be maintained. The contemporary social life and norms are practically incompatible with the bygone tradition of large families and multiparity households. It has been calculated and observed that a woman has to have at least eight or more full term normal pregnancies (FTNPs), i.e., children, in order to be virtually protected against breast cancer. The Nature has not changed and made no adjustments to facilitate the modern human tendency for reduced reproduction. The modern medical history, not yet written, has already shown that any misconception and even inadvertent error in the sphere of human reproduction is bound to inflict tremendous harm on women and society, such as the mass condomization of female sexuality in the mainstream population. It is the purpose of this study to try to clarify the damage of the condom-related "reproductive freedom" fallacy and the scientific and individual ignorance and errors in

Although the main attention and concern has been focused on the 'hormonal,' oral contraceptive pills, the condom use and the uncritical campaigns for its use in any situation resulted in grave consequences on health and lives of women and girls, in terms of the ongoing breast cancer epidemic and rampant 'eating' disorders. Even though the use of condoms dates for more than one century (in England at least), the condoms have been overlooked as the possible cause of the widespread ill-effects and grave consequences in women. The introduction of mass condomization of female sexuality has completely

**2. Evidence-based and theoretical etiology of the breast cancer epidemic** 

for prophylaxis against the emergent mysterious infections.

condomized control of fertility, without passing judgment.

Global breast cancer data are updated in five-year reports published by the World Health Organization International Agency on Cancer Research (IARC), in Lyon, France, titled: "Cancer Incidence in Five Continents" (CI5s), volumes III-IX. (Waterhouse et al, 1977, 1982; Muir et al., 1987; Parkin et al, 1992; Parkin et al., 1997, 2002; Cirado et al., 2007). For achieving the objectives volumes III to IX, 1968 to 2002, inclusive, in duration of 35 years for most centers.

## **3.2 Population**

Population under study consists of contingencies of women affected by breast cancer and other malignant diseases, collected by the national or regional Cancer Registries in 180 to 300 countries and population situations globally, with data quantified in average incidence rates (crude and age-standardized), collected in five-year periods, and reported by the regular editions of the WHO-IARC CI5 volumes.

#### **3.3 Methods**

For appraisal of existing, reliable and controlled data, collected internationally by the World Health Organization throughout several decades. Common statistical procedures [means, standard deviations, 95% CI (confidence intervals) of the risks, correlation coefficients, twoway statistical significances at P<.01 and P<.05 levels] were used for testing the differences, the temporal and spacial changes of the epidemic disease. Correlation and regression analyses, in order to test the statistical significance of the trends and rates of the diseases, and possible extrapolations. The necessary graphical figures and tables of the results and trends are also presented. The analysis of the multitude of data was done by using the SPSS (Statistical Package for Social Sciences), Version 16, 2008.

## **4. Epidemiological and clinical results and consequences**

## **4.1 Perplexing breast cancer incidence rise worldwide**

The rapid rise of breast cancer in the U.S. was first noted by the media, perplexed over the "highest breast cancer incidence rate (of 92.1) ever seen" in the U.S., in 1984. The type of tidal wave ('tsunami') onslaught of breast cancer heralded an emerging, unprecedented epidemic of a malignant (not contagious) disease in the medical history. Thus reaching for a first time in human medical history an unprecedented epidemic of malignant disease. Starting by 1987, the crude incidence rate (based on the number of new cases) was almost entirely replaced by ageadjusted incidence rates (computed on out of sight number of new cases). Correlation between the breast cancer incidence rates and prevalence rates of condom use were invariably positive at statistically significant levels, as presented in **Table 2** (Gjorgov, 1998; Gjorgov, 2000; UN Secretariat, 1994):

AIDS Changed America with the Twin

(female) population

rate, respectively (**Figure 1**).

Breast Cancer Epidemic: Exploring the Consequences of Condomization 525

Quantifying the impact of condomization on breast cancer epidemic, it was estimated that an increase of condom use by 1 (one) percentage point, the gradient of increase of the breast cancer incidence will correspond to rate of 3.85 per 100,000 female population, globally. For North America, the increase of breast cancer incidence would correspond to a rate of 4.4/100,000 per one percent condom-use prevalence increase, and increase between 2.1 and

Fig. 1. Breast cancer rise in the United States, 1973-1987. Crude incidence rates, per 100,000

Whether the condomization was intended for the feminist's allure only and latter adjusted for prophylaxis of the newly discovered HIV virus, is hard to come by. In one of available sources, the assertion about 'political decision' for condom-use promotion remained ambivalent: Ehrchardt "For the male condom, no controlled trials were demanded before it

Globally, the average number of breast cancer cases rose by 22% in the last two periods, between 1993-1997 and 1998-2002 (between CI2 VIII and IX Editions), showing difference in the medians of cases 1893.0 and 2735.5, and mode between 595 and 1840, respectively. The upsurge of breast cancer as an epidemic disease emerged rapidly in the United States after 1981, the first and 'the highest ever recorded' reported by the mass media incidence rates, foreboding the trends during the time period 1981 and 1986 and later. The escalation of breast cancer of 57.7 percent increase was recorded in a short period of six years between 1981 and 1986, with 80.1 incidence rate (per 100.000 female population) and 126.2 incidence

gained approval as an HIV prophylactic" (Ehrchardt, 1992).

3.6 breast cancer incidence rates for various European countries. (Gjorgov, 1998a).


SOURCES: Parkin DM et al. 1992; United Nations Secretariat,.1994; Gjorgov AN., 1998, 2000 \*p < .05 (significance level); \*\*p < .01 and/or \*\*p < .0001 (significance levels)

Table 2. Breast Cancer: Age-adjusted Rates (per 100,000) and Condom-Use Prevalence (percentages), 1983-1987, and Correlation coefficients, by Global Regions, Developmental Stage, Race, and Rural-Urban Places,

**WORLDWIDE (166)** 6.4 - 104.2 1 - 15 .860\*\*

(USA and Canada) 52.2 - 104.2 10 - 15 .748\*\*

**NEW ZEALAND (22)** 56.1 - 64.3 10 – 14 .564\*\*

Developed regions (140) 35.7 - 104.2 5 - 15 .834\*\* Developing countries/regions (25) 6.4 - 43.7 1 - 3 .594\*\*

White women (131) 31.1 - 104.2 2 - 15 .855\*\* Africans & Afro-Americans (12) 10.2 - 71.6 1 – 12 .541\* Orientals (23) 16.9 - 64.0 2 - 3 .821\*\*

Urban populations (21) 31.1 - 104.2 3 - 15 .907\*\* Rural populations (26) 6.4 - 58.8 1 - 10 .932\*\*

Table 2. Breast Cancer: Age-adjusted Rates (per 100,000) and Condom-Use Prevalence (percentages), 1983-1987, and Correlation coefficients, by Global Regions, Developmental

(significance level); \*\*p < .01 and/or \*\*p < .0001 (significance levels)

SOURCES: Parkin DM et al. 1992; United Nations Secretariat,.1994; Gjorgov AN., 1998, 2000 \*p < .05

Breast cancer age-adjusted incidence rates,+ 1983-1987 (Lowest and highest rates)

Condom-use prevalence, estimates, in %++ 1987

26.2 - 40.5 2 - 3 .548\*

35.7 - 73.5 5 – 13 .777\*\*

31.1 - 43.7 3 - 5 .438

6.4 - 24.6 1 - 3 .558\*\*

Correlation coefficient (Spearman r)

Region and number of countries/centres

(Columbia, Costa Rica, Cuba, Equador, Paraguay, Puerto Rico, Martinique,

(Portugal, Spain, Italy, France, Norway, Finland, Denmark, Sweden, Holland, Iceland, West Germany, Switzerland

(Czechoslovakia, GDR, Poland, Estonia, Latvia, Slovenia, Romania, Russia, and

**NORTH AMERICA (46)** 

**SOUTH AMERICA (12)** 

**WEST EUROPE (42)** 

**EAST EUROPE (17)** 

**UK, AUSTRALIA,** 

**URBANIZATION** 

Japan & other)

**RACE** 

**AFRICA** and **ASIA (27)** 

(Algeria, Gambia, Mali; China, India,

**DEVELOPMENTAL STAGE** 

Stage, Race, and Rural-Urban Places,

Brazil and other)

and other)

other)

Quantifying the impact of condomization on breast cancer epidemic, it was estimated that an increase of condom use by 1 (one) percentage point, the gradient of increase of the breast cancer incidence will correspond to rate of 3.85 per 100,000 female population, globally. For North America, the increase of breast cancer incidence would correspond to a rate of 4.4/100,000 per one percent condom-use prevalence increase, and increase between 2.1 and 3.6 breast cancer incidence rates for various European countries. (Gjorgov, 1998a).

Fig. 1. Breast cancer rise in the United States, 1973-1987. Crude incidence rates, per 100,000 (female) population

Whether the condomization was intended for the feminist's allure only and latter adjusted for prophylaxis of the newly discovered HIV virus, is hard to come by. In one of available sources, the assertion about 'political decision' for condom-use promotion remained ambivalent: Ehrchardt "For the male condom, no controlled trials were demanded before it gained approval as an HIV prophylactic" (Ehrchardt, 1992).

Globally, the average number of breast cancer cases rose by 22% in the last two periods, between 1993-1997 and 1998-2002 (between CI2 VIII and IX Editions), showing difference in the medians of cases 1893.0 and 2735.5, and mode between 595 and 1840, respectively. The upsurge of breast cancer as an epidemic disease emerged rapidly in the United States after 1981, the first and 'the highest ever recorded' reported by the mass media incidence rates, foreboding the trends during the time period 1981 and 1986 and later. The escalation of breast cancer of 57.7 percent increase was recorded in a short period of six years between 1981 and 1986, with 80.1 incidence rate (per 100.000 female population) and 126.2 incidence rate, respectively (**Figure 1**).

AIDS Changed America with the Twin

percentages tested.

Breast Cancer Epidemic: Exploring the Consequences of Condomization 527

Fig. 3. Breast cancer trends in the U.S., 1980-2002. Observed crude and age-adjusted incidence rates: Projected 21% decline 1986-2000, and Postulated preventive impact, in

postulated downward trends of 50 to 80 percent of breast cancer in the U.S.

The overall epidemiology of the breast cancer epidemic in the **United States** is presented in the **Figure 3**. There is a dual presentation of the trends of the breast cancer progression in the past two-and-a-half decades, from 1980 to 2002. The breast cancer rising trends are presented in crude and age-adjusted incidence rates. The two incidence rates differ considerably, mainly because the age-adjusted rates, showing lower rates, were derived according to moving U.S. census populations, instead to the conventional World Standard Population 1960 (WSP). In the same **Figure 3** is presented the official, wrong prediction (in 1986) of 'declining' breast cancer trend until 2000, and also are presented two personal predictions of the future,

#### **4.2 Breast cancer epidemic changes in time, places and populations**

The force of the rising incidence of breast cancer has been seen all over the world, the attempts of denigrating its surprise emergence and astonishing effect and magnitude notwithstanding. The new development of breast cancer as an epidemic disease could be best seen in **Figure 2**, as recorded for **Connecticut**, in the last 35 years.

Fig. 2. Breast cancer trends in Connecticut, 1968-2002. Crude and age-adjusted incidence rates, per 100,000

The **Figure 2** reliably confirms the fact of a steep and steady increase of the breast cancer epidemic, for both races, since the Cancer Registry of Connecticut in New Haven, was first cancer registry in the world, established in 1936. (It may be of interest to note that there was a fluctuation of the breast cancer incidence rates for the Afro-Americans, an event rarely observed before.)

The force of the rising incidence of breast cancer has been seen all over the world, the attempts of denigrating its surprise emergence and astonishing effect and magnitude notwithstanding. The new development of breast cancer as an epidemic disease could be

Fig. 2. Breast cancer trends in Connecticut, 1968-2002. Crude and age-adjusted incidence

The **Figure 2** reliably confirms the fact of a steep and steady increase of the breast cancer epidemic, for both races, since the Cancer Registry of Connecticut in New Haven, was first cancer registry in the world, established in 1936. (It may be of interest to note that there was a fluctuation of the breast cancer incidence rates for the Afro-Americans, an event rarely

rates, per 100,000

observed before.)

**4.2 Breast cancer epidemic changes in time, places and populations** 

best seen in **Figure 2**, as recorded for **Connecticut**, in the last 35 years.

Fig. 3. Breast cancer trends in the U.S., 1980-2002. Observed crude and age-adjusted incidence rates: Projected 21% decline 1986-2000, and Postulated preventive impact, in percentages tested.

The overall epidemiology of the breast cancer epidemic in the **United States** is presented in the **Figure 3**. There is a dual presentation of the trends of the breast cancer progression in the past two-and-a-half decades, from 1980 to 2002. The breast cancer rising trends are presented in crude and age-adjusted incidence rates. The two incidence rates differ considerably, mainly because the age-adjusted rates, showing lower rates, were derived according to moving U.S. census populations, instead to the conventional World Standard Population 1960 (WSP). In the same **Figure 3** is presented the official, wrong prediction (in 1986) of 'declining' breast cancer trend until 2000, and also are presented two personal predictions of the future, postulated downward trends of 50 to 80 percent of breast cancer in the U.S.

AIDS Changed America with the Twin

527 to 1833) since 1998-1992.

100,000

Oxford, probably thought of during the decade 1960s.

Breast Cancer Epidemic: Exploring the Consequences of Condomization 529

seems that the infamous title of "Breast cancer capital of the world" has shifted from the San Francisco Bay Area to the Ferrara Region, Italy, with a crude incidence rate of 201.8 in the 1998-2002 period, and an increase of 263 percent in the number of breast cancer cases (from

In other parts of the Western world, the **Oxford** Region, the UK experienced immediate high increase of breast cancer and without apparent delay after the U.S. (**Figure 5**). The steady rise of the breast cancer incidence has been happening continuously and all 5-year time periods after 1980. In the mid-1990s, the Cancer Research UK organized, in cooperation with other European countries and North-American regions, so-called population-based, chemopreventive community trials against epidemic breast cancer, by giving the drug *tamoxifen* to great number healthy women, in duration of five years, The enthusiastic chemo-preventive trials ended prematurely, with impractical results for breast prevention. No other idea or projects were envisioned or proposed for testing a potential primary (non-chemical) prevention of breast cancer. Circumstantial and fragmentary evidence seems to suggest that the idea of global condomization has originated at the 'R. Doll' Institute of Epidemiology in

Fig. 5. Breast cancer in Oxford, UK, 1968-2002. Crude and age-adjusted incidence rates, per

Additional data support the analogous development of breast cancer rise in other parts of the country, such as the **San Francisco Bay Area** (**Figure 4**), which was subsequently and perhaps justifiably called "the Breast Cancer Capital of the World," for the highest incidence in America in the 1983-1987 period, reaching the excess incidence rate.

The first, the NCI confident forecast of decline of breast cancer incidence rates between 1986 until 2000, by 21 percent, was patently wrong from the outset. The predicted decline of breast cancer, published in 1986 proved to be quite off center: the incidence rates of the disease almost doubled by the end of the 20th Century. The wrongly computed forecast of decline probably reflected the same percentage of decline of the disease during the 1970s, and was computed maybe before the statistical data were in following the 1981unexpected breast cancer jump; The second prediction of decline of the breast cancer incidence rates between 50 to 80 percent, as related to the 1980 situation, remained theoretical estimates, based on etiological fraction percent, contingent on implementation of primary prevention and elimination of the corroborated etiological risk factor of semi-official policy of condomization of the mainstream population(s) against the HIV/AIDS transmissions, along with the application of Bayes' probability theorem computation, and yet to be

Fig. 4. Breast cancer in San Francisco Bay Area, CA, 1986-2002, by race. Crude and ageadjusted incidence rates, per 100,000

The same pattern of rapid rise of breast cancer was recorded in **Seattle, WA**, with an extraordinary jump of 27.8 percent of crude incidence rate (from 95.8 to 121.8) within one period of 1978-82 (before AIDS epidemic) to 1983-87 (the initial tide of the AIDS outbreak in the U.S.). (Figure not presented.) According to the data in the latest (IX) volume of the CI5, it

Additional data support the analogous development of breast cancer rise in other parts of the country, such as the **San Francisco Bay Area** (**Figure 4**), which was subsequently and perhaps justifiably called "the Breast Cancer Capital of the World," for the highest incidence

The first, the NCI confident forecast of decline of breast cancer incidence rates between 1986 until 2000, by 21 percent, was patently wrong from the outset. The predicted decline of breast cancer, published in 1986 proved to be quite off center: the incidence rates of the disease almost doubled by the end of the 20th Century. The wrongly computed forecast of decline probably reflected the same percentage of decline of the disease during the 1970s, and was computed maybe before the statistical data were in following the 1981unexpected breast cancer jump; The second prediction of decline of the breast cancer incidence rates between 50 to 80 percent, as related to the 1980 situation, remained theoretical estimates, based on etiological fraction percent, contingent on implementation of primary prevention and elimination of the corroborated etiological risk factor of semi-official policy of condomization of the mainstream population(s) against the HIV/AIDS transmissions, along

in America in the 1983-1987 period, reaching the excess incidence rate.

with the application of Bayes' probability theorem computation, and yet to be

Fig. 4. Breast cancer in San Francisco Bay Area, CA, 1986-2002, by race. Crude and age-

The same pattern of rapid rise of breast cancer was recorded in **Seattle, WA**, with an extraordinary jump of 27.8 percent of crude incidence rate (from 95.8 to 121.8) within one period of 1978-82 (before AIDS epidemic) to 1983-87 (the initial tide of the AIDS outbreak in the U.S.). (Figure not presented.) According to the data in the latest (IX) volume of the CI5, it

adjusted incidence rates, per 100,000

seems that the infamous title of "Breast cancer capital of the world" has shifted from the San Francisco Bay Area to the Ferrara Region, Italy, with a crude incidence rate of 201.8 in the 1998-2002 period, and an increase of 263 percent in the number of breast cancer cases (from 527 to 1833) since 1998-1992.

In other parts of the Western world, the **Oxford** Region, the UK experienced immediate high increase of breast cancer and without apparent delay after the U.S. (**Figure 5**). The steady rise of the breast cancer incidence has been happening continuously and all 5-year time periods after 1980. In the mid-1990s, the Cancer Research UK organized, in cooperation with other European countries and North-American regions, so-called population-based, chemopreventive community trials against epidemic breast cancer, by giving the drug *tamoxifen* to great number healthy women, in duration of five years, The enthusiastic chemo-preventive trials ended prematurely, with impractical results for breast prevention. No other idea or projects were envisioned or proposed for testing a potential primary (non-chemical) prevention of breast cancer. Circumstantial and fragmentary evidence seems to suggest that the idea of global condomization has originated at the 'R. Doll' Institute of Epidemiology in Oxford, probably thought of during the decade 1960s.

Fig. 5. Breast cancer in Oxford, UK, 1968-2002. Crude and age-adjusted incidence rates, per 100,000

AIDS Changed America with the Twin

100,000

WHO-IARC CI5 reports.

Breast Cancer Epidemic: Exploring the Consequences of Condomization 531

**Sweden** has always been a lead-country of high breast cancer incidence (**Figure 7**). The country has an interesting epidemiology of the disease, since the current, global breast cancer epidemic seems to have started much earlier there, during the decade of the 1970s, ten years before the epidemic was first recorded in the U.S. in the 1980s. Part of the puzzle lies in the information that condomization ("for non-contraceptive use") was first introduced in Sweden (Hinman, 1978; Valdiserri, 1988), in the 1970s decade, before

Fig. 7. Breast cancer in Sweden, 1971-2002. Crude and age-adjusted incidence rates, per

On the other side of the globe, in Australia, the rise of the breast cancer epidemic in the **New South Wales** showed the familiar European model of advent (**Figure 8**). According to the separate Annual Reports of the Cancer Registry of the Province NSW, the rise of breast cancer was apparently steeper than presented by the presentation in 5-year periods of the

campaigns of condomization were carried out in the rest of the world.

At least two more high-risk regions of breast cancer epidemic in Europe deserve mention, in France and Sweden. The breast cancer epidemic in **France** (**Figure 6**) may prove of interest because of the fact that the North-Rhine Region is both one of the best developed regions, and one with the highest incidence rates in EU. The City of Strasbourg, where the multinational European Parliament is located, is also an important place where much of the debates and policies about breast cancer control, mainly for rectifying the early-detection screening policy, has been and is expected to continue to eventually consider primary prevention of the breast cancer epidemic soon.

Fig. 6. Breast cancer in Bas-Rhin, France, 1975-2002. Crude and age-adjusted incidence rates, per 100,000

At least two more high-risk regions of breast cancer epidemic in Europe deserve mention, in France and Sweden. The breast cancer epidemic in **France** (**Figure 6**) may prove of interest because of the fact that the North-Rhine Region is both one of the best developed regions, and one with the highest incidence rates in EU. The City of Strasbourg, where the multinational European Parliament is located, is also an important place where much of the debates and policies about breast cancer control, mainly for rectifying the early-detection screening policy, has been and is expected to continue to eventually consider primary

Fig. 6. Breast cancer in Bas-Rhin, France, 1975-2002. Crude and age-adjusted incidence rates,

prevention of the breast cancer epidemic soon.

per 100,000

**Sweden** has always been a lead-country of high breast cancer incidence (**Figure 7**). The country has an interesting epidemiology of the disease, since the current, global breast cancer epidemic seems to have started much earlier there, during the decade of the 1970s, ten years before the epidemic was first recorded in the U.S. in the 1980s. Part of the puzzle lies in the information that condomization ("for non-contraceptive use") was first introduced in Sweden (Hinman, 1978; Valdiserri, 1988), in the 1970s decade, before campaigns of condomization were carried out in the rest of the world.

Fig. 7. Breast cancer in Sweden, 1971-2002. Crude and age-adjusted incidence rates, per 100,000

On the other side of the globe, in Australia, the rise of the breast cancer epidemic in the **New South Wales** showed the familiar European model of advent (**Figure 8**). According to the separate Annual Reports of the Cancer Registry of the Province NSW, the rise of breast cancer was apparently steeper than presented by the presentation in 5-year periods of the WHO-IARC CI5 reports.

AIDS Changed America with the Twin

Breast Cancer Epidemic: Exploring the Consequences of Condomization 533

women. During the past three decades, the increase of breast cancer in Kuwaiti women did not reach the higher incidence of the immigrant, Non-Kuwaiti women in the country.

Fig. 9. Breast cancer in Kuwait, 1974-2002, by Kuwaiti and Non-Kuwaiti women. Crude

The other regions and countries of the world followed suit. In **Miyagi**, **Japan**, the **Figure 10** shows a steadily but moderately increasing breast cancer incidence rates. Nevertheless, the slow-moving breast cancer epidemic revealed an extraordinary evidence / proof of the peculiar characteristics of the breast cancer epidemic, the increase of the incidence in the younger women, most notably in the reproductive age-

and age-adjusted incidence rates, per 100,000

span of women (**Figure 11**).

Fig. 8. Breast cancer in New South Wales, Australia, 1973-2002. Crude and age-adjusted incidence rates, per 100,000

In Asia, the experience of **Kuwait** (**Figure 9**) of the breast cancer epidemic rise was somewhat peculiar. First, Kuwait long enjoyed the distinction to be listed as a country with the lowest rate of breast cancer in the world. I worked and as Director of the National Cancer Registry at the Kuwait Cancer Control Centre for a long while, was able to observe the situation and the ensuing profound changes with regard breast cancer. (Gjorgov, 1986). Second, the breast cancer onslaught happened fast and affected very young, married multipara-women (not less than 4 pregnancies), between 23 to 35 years of age. The surgeons from Europe, worked in the local hospitals, were the first to voice alarm of the unusual in their practice pattern of performing mastectomies to such a young-age group of patients. Third, contrary to the American and European experience, the Non-Kuwaiti, immigrant women, had persistently had a higher incidence rate of breast cancer than the Kuwaiti

Fig. 8. Breast cancer in New South Wales, Australia, 1973-2002. Crude and age-adjusted

In Asia, the experience of **Kuwait** (**Figure 9**) of the breast cancer epidemic rise was somewhat peculiar. First, Kuwait long enjoyed the distinction to be listed as a country with the lowest rate of breast cancer in the world. I worked and as Director of the National Cancer Registry at the Kuwait Cancer Control Centre for a long while, was able to observe the situation and the ensuing profound changes with regard breast cancer. (Gjorgov, 1986). Second, the breast cancer onslaught happened fast and affected very young, married multipara-women (not less than 4 pregnancies), between 23 to 35 years of age. The surgeons from Europe, worked in the local hospitals, were the first to voice alarm of the unusual in their practice pattern of performing mastectomies to such a young-age group of patients. Third, contrary to the American and European experience, the Non-Kuwaiti, immigrant women, had persistently had a higher incidence rate of breast cancer than the Kuwaiti

incidence rates, per 100,000

women. During the past three decades, the increase of breast cancer in Kuwaiti women did not reach the higher incidence of the immigrant, Non-Kuwaiti women in the country.

Fig. 9. Breast cancer in Kuwait, 1974-2002, by Kuwaiti and Non-Kuwaiti women. Crude and age-adjusted incidence rates, per 100,000

The other regions and countries of the world followed suit. In **Miyagi**, **Japan**, the **Figure 10** shows a steadily but moderately increasing breast cancer incidence rates. Nevertheless, the slow-moving breast cancer epidemic revealed an extraordinary evidence / proof of the peculiar characteristics of the breast cancer epidemic, the increase of the incidence in the younger women, most notably in the reproductive agespan of women (**Figure 11**).

AIDS Changed America with the Twin

periods, per 100,000

Breast Cancer Epidemic: Exploring the Consequences of Condomization 535

Fig. 11. Breast cancer Age-specific incidence rates in Miyagi, Japan, 1968-2002, by five-year

Fig. 10. Breast cancer in Miyagi, Japan, 1968-2002. Crude and age-adjusted incidence rates, per 100,000

Fig. 10. Breast cancer in Miyagi, Japan, 1968-2002. Crude and age-adjusted incidence rates,

per 100,000

Fig. 11. Breast cancer Age-specific incidence rates in Miyagi, Japan, 1968-2002, by five-year periods, per 100,000

AIDS Changed America with the Twin

Breast Cancer Epidemic: Exploring the Consequences of Condomization 537

Fig. 13. Shift of breast cancer trends in Europe, 1983-1987, by time periods and countries.

Changes of age-adjusted incidence rates, in percentages.

The conventional view that breast cancer is a "disease of affluence" had to be changed in the meantime by the epidemiology and empirical research of the disease in Afro-American women in the U.S., as well as in less industrialized (Krieger, 2002) and other "poor" countries. Three more situations could demonstrate the sudden changes in the trends of breast cancer developments (in %) in a number of centers in the **United States** (**Figure 12**) and in **Europe** (**Figure 13**), from negative-decreasing to positive-increasing breast cancer trends.

Fig. 12. Shift of breast cancer trends in the United States, 1983-1987, by time periods and regions. Changes of age-adjusted incidence rates, in percentages.

The conventional view that breast cancer is a "disease of affluence" had to be changed in the meantime by the epidemiology and empirical research of the disease in Afro-American women in the U.S., as well as in less industrialized (Krieger, 2002) and other "poor" countries. Three more situations could demonstrate the sudden changes in the trends of breast cancer developments (in %) in a number of centers in the **United States** (**Figure 12**) and in **Europe** (**Figure 13**), from negative-decreasing to positive-increasing breast cancer

Fig. 12. Shift of breast cancer trends in the United States, 1983-1987, by time periods and

regions. Changes of age-adjusted incidence rates, in percentages.

trends.

Fig. 13. Shift of breast cancer trends in Europe, 1983-1987, by time periods and countries. Changes of age-adjusted incidence rates, in percentages.

AIDS Changed America with the Twin

faster pace afterwards, such as, for instance, Italy.

than at the end of the reproduction life time of menopause.

by age and year of cancer registration (February 2010)

Age groups

**Crude** 

**Ageadj. rates** 

Breast Cancer Epidemic: Exploring the Consequences of Condomization 539

The unexpected shift towards young women was manifested in a remarkable peak of the disease in the of 35-39 year age-group, as a "debut" phenomenon, assuming that condomization was the first and perhaps the main mode of fertility control and family planning. Almost exactly the same situation was observed in Warsaw City (Poland), with the "debut" peak in 1987, compared with the age-specific distribution before the condomuse campaigns, in the period 1968-1972. (Figure not shown.) In the Volume VII of the CI5 (Parkin et al., 1997), and to a lesser degree in the Volumes VIII (Parkin, 2002) and IX (Cirado, 2007), there were more than 60 cases of age-specific distribution in which the first highest incidence of breast cancer was located in younger age groups, bellow 50, and even below 40 years of age. The "debut" phenomenon was mainly seen in countries with low baseline breast cancer incidence and where the breast cancer epidemic has been developing at a

The debut peaks showed that they are not static phenomena and not a rare situation. Data from the Malta National Cancer Registry (2010) showed that "debut" peaks popped up in the past decades in almost every year in a ten-year decade, and continued to be still present in subsequent cohorts of women **(Table 3).** Not less than 50-60 breast cancer age-specific distributions in the 1988-1992 period (CI5-VII) showed the highest peaks in younger women. The pattern of "debut" peaks is reminiscent to the epidemiological pattern of breast cancer age-specific incidence in Europe before and immediately after the WWII, with the so-called 'Clemmesen's hook' (Storm, 2011), similar but not equal with the "debut" phenomenon, because it happens to young women, in the prime of their reproductive sexuality, rather

**1998 1999 2000 2001 2002 2003 2004 2005 2006 2007** 

15-19 0 0 0.07 0 0 0 0 0 0 0 20-24 0 0 0.07 0 0 0 0 0 0 0 25-29 0 0.08 0 0 0 0 0 0 0 0 30-34 0.17 0.18 0.09 0.60 0.33 0.24 0.08 0.07 0.15 0.35 35-39 0.36 0.29 0.37 030 0.79 0.40 0.41 0.58 0.33 0.41 40-44 1.13 1.68 0.75 0.60 0.87 1.09 1.39 1.44 1.27 1.48 45-49 1.76 1.43 1.57 1.68 0.97 1.02 0.80 **2.05** 1.32 1.40 50-54 2.47 1.60 1.91 2.22 **2.19** 1.77 2.14 1.53 1.80 1.92 55-59 2.29 2.26 2.29 2.18 2.07 2.68 2.33 2.00 **2.52** 2.04 60-64 1.50 2.56 2.62 1.59 2.89 **3.59** 2.61 3.76 3.20 3.00 65-69 3.23 3.27 3.09 2.34 1.64 2.28 2.13 3.50 3.30 **3.65**  70-74 **4.12** 2.28 3.21 2.56 **3.15** 1.27 **3.58** 2.19 3.62 3.44 75-79 2.09 **4.71** 3.83 3.07 2.50 **4.26** 2.95 **4.53** 4.41 3.82 80-84 4.12 3.75 **6.34** 3.43 2.36 3.48 2.86 4.39 2.87 3.85 85+ 3.60 3.95 1.55 4.10 3.02 3.72 4.63 3.65 2.90 4.22

**rates 106.75 110.34 110.44 100.75 99.57 108.40 109.67 128.81 127.50 131.74** 

Table 3. Cancer of the breast: Maltese Islands-Trends in Incidence 1998-2007. Incidence rates,

**72.61 72.30 70.55 64.35 64.99 67.70 66.84 79.56 75.82 77.78** 

#### **4.3 Inner developments of the breast cancer epidemic**

The distribution of the age-specific incidence rates among young women, bellow 45 years of age, during the seven period of five-year intervals (35 years duration), between 1968 and 2002, clearly demonstrates the shift of the breast cancer epidemic towards younger, reproductive-age groups, ostensibly most frequently exposed to the purported risk factor of condomization. In addition to the situation in **Miyagi** (**Figure 11**), an extraordinary evidence of breast cancer descending in young women is evident in **Shanghai,** China (**Figure 14**). Perhaps a foreboding development of the disease in the country, the extraordinary shift of breast cancer incidence towards younger women was recorded in Shanghai in just a single five-year period, 1973-1978. In 2008, an alarming among many other studies appeared that rightly claimed that "China is on the point end of a breast cancer epidemic" (Linos et al. 2008). However, the solution in averting the predicted, impending breast cancer epidemic was seen and recommended in reductions of "modifiable risk factors," such as, alcohol intake, parity, hormone use, and adult weight gain... Condomization as a means for the restrictive reproductive policy was neither investigated nor mentioned in the study.

Fig. 14. Breast Cancer in Shanghai, China, 1975 and 1987-1988: "Debut" peak. Age-specific incidence rates, per 100,000

The distribution of the age-specific incidence rates among young women, bellow 45 years of age, during the seven period of five-year intervals (35 years duration), between 1968 and 2002, clearly demonstrates the shift of the breast cancer epidemic towards younger, reproductive-age groups, ostensibly most frequently exposed to the purported risk factor of condomization. In addition to the situation in **Miyagi** (**Figure 11**), an extraordinary evidence of breast cancer descending in young women is evident in **Shanghai,** China (**Figure 14**). Perhaps a foreboding development of the disease in the country, the extraordinary shift of breast cancer incidence towards younger women was recorded in Shanghai in just a single five-year period, 1973-1978. In 2008, an alarming among many other studies appeared that rightly claimed that "China is on the point end of a breast cancer epidemic" (Linos et al. 2008). However, the solution in averting the predicted, impending breast cancer epidemic was seen and recommended in reductions of "modifiable risk factors," such as, alcohol intake, parity, hormone use, and adult weight gain... Condomization as a means for the

restrictive reproductive policy was neither investigated nor mentioned in the study.

Fig. 14. Breast Cancer in Shanghai, China, 1975 and 1987-1988: "Debut" peak. Age-specific

incidence rates, per 100,000

**4.3 Inner developments of the breast cancer epidemic** 

The unexpected shift towards young women was manifested in a remarkable peak of the disease in the of 35-39 year age-group, as a "debut" phenomenon, assuming that condomization was the first and perhaps the main mode of fertility control and family planning. Almost exactly the same situation was observed in Warsaw City (Poland), with the "debut" peak in 1987, compared with the age-specific distribution before the condomuse campaigns, in the period 1968-1972. (Figure not shown.) In the Volume VII of the CI5 (Parkin et al., 1997), and to a lesser degree in the Volumes VIII (Parkin, 2002) and IX (Cirado, 2007), there were more than 60 cases of age-specific distribution in which the first highest incidence of breast cancer was located in younger age groups, bellow 50, and even below 40 years of age. The "debut" phenomenon was mainly seen in countries with low baseline breast cancer incidence and where the breast cancer epidemic has been developing at a faster pace afterwards, such as, for instance, Italy.

The debut peaks showed that they are not static phenomena and not a rare situation. Data from the Malta National Cancer Registry (2010) showed that "debut" peaks popped up in the past decades in almost every year in a ten-year decade, and continued to be still present in subsequent cohorts of women **(Table 3).** Not less than 50-60 breast cancer age-specific distributions in the 1988-1992 period (CI5-VII) showed the highest peaks in younger women. The pattern of "debut" peaks is reminiscent to the epidemiological pattern of breast cancer age-specific incidence in Europe before and immediately after the WWII, with the so-called 'Clemmesen's hook' (Storm, 2011), similar but not equal with the "debut" phenomenon, because it happens to young women, in the prime of their reproductive sexuality, rather than at the end of the reproduction life time of menopause.


Table 3. Cancer of the breast: Maltese Islands-Trends in Incidence 1998-2007. Incidence rates, by age and year of cancer registration (February 2010)

AIDS Changed America with the Twin

Breast Cancer Epidemic: Exploring the Consequences of Condomization 541

Fig. 15. Breast Cancer in Korea, 1988-2002. Age-specific incidence rates, per 100,000

Most likely, the "debut" phenomenon is closely related with another puzzling issue of the breast cancer epidemic, the growing cases of ductal carcinoma in-situ (DCIS), or simply insitu breast cancer, whose incidence, has gone up exponentially, up to 30 percent of the annual number of registered breast cancer cases, since the 1980s (National Cancer Institute, 2001). The in-situ (DCIS) cases in fact, testify of the evolving nature and lack of understanding of the global breast cancer epidemic. The in-situ breast cancer epitomizes also the conceptual vacuum in professional dealing with the breast cancer epidemic, because of misconception of DCIS as a random event in lives of women; not reporting of DCIS in the annual reports of incidence rate of breast cancer; exaggerated and not true claims of excellent ("nearly 100%") survival rate; unduly and unreasonably defined in-situ cases as non-breast cancer (0-zero stage); the systemic background of the in-situ cases is ignored and treatment is as a local disease. The early-detection screening, for finding most and more of the DCIS cases, has always been mired with uncertainty of further course of the in-situ finding into aggressive and metastatic breast cancer, the extent of treatment, and the dilemma about the usefulness of the early detection as the basic tenet of the breast cancer strategy.

#### **4.4 Reproductive age and breast cancer**

Age of women as such has almost invariably been defined among the strongest risk factor of breast cancer. The assertion of randomness has frequently accompanied the age factor. The international experience, however, points out to the long held observation that this assessment is not universally correct and that is in principle wrong. **Figure 15**  shows that breast cancer in **Korea** is confined to middle-aged women, to the reproductive-age span women, with declining incidence after the peri-menopausal age of 50. In most of Asian populations (Japan, Malaysia, India), the breast cancer profiles exhibit the same pattern.

The pattern of breast cancer age distribution in Korea was similar to those in many European countries, which could still be seen in Porto, Portugal, evocative to the old rather than new European models. (Figure not presented)

Hidden behind the common reference of "cancer incidence increase" lies the fact that the increase is created to a high extent by the rise of breast cancer, while the category of "the rest of cancers" is actually decreasing. [The categories of breast cancer and "all cancers without skin cancer (C44)" are given as such and, for the purposes of this study, is computed a new category of "rest of cancers," meaning 'all cancers' minus breast cancer)]. The data of the **SEER** (Surveillance, Epidemiology, and End Results) program, containing nine registration centers in the U.S. and, since it stands for about 10 percent of the U.S. population, considered representative sample of the country, showed that the number of breast cancer rose by 11.6 percent, while the "rest" of cancers increased by 8.7 percent, between the two consecutive periods of 1993-97 and 1998-2002. The **Figure 16** presents data of increasing breast cancer age-adjusted incidence rates (16.8%) compared to the decreasing "rest" of cancer (-7.5%) in Afro-American women during the aforementioned two 5-year periods. There was exactly the same reciprocal increase of breast cancer (7.7%) and decrease (-4.3%) of the 'rest of cancers' in Afro-American women in Connecticut, and unexpected decrease (of -4.9%) of the 'rest' of cancers (age-adjusted incidence rates), and increase (1.2%) in white women in the San Francisco Bay Area, CA.

Most likely, the "debut" phenomenon is closely related with another puzzling issue of the breast cancer epidemic, the growing cases of ductal carcinoma in-situ (DCIS), or simply insitu breast cancer, whose incidence, has gone up exponentially, up to 30 percent of the annual number of registered breast cancer cases, since the 1980s (National Cancer Institute, 2001). The in-situ (DCIS) cases in fact, testify of the evolving nature and lack of understanding of the global breast cancer epidemic. The in-situ breast cancer epitomizes also the conceptual vacuum in professional dealing with the breast cancer epidemic, because of misconception of DCIS as a random event in lives of women; not reporting of DCIS in the annual reports of incidence rate of breast cancer; exaggerated and not true claims of excellent ("nearly 100%") survival rate; unduly and unreasonably defined in-situ cases as non-breast cancer (0-zero stage); the systemic background of the in-situ cases is ignored and treatment is as a local disease. The early-detection screening, for finding most and more of the DCIS cases, has always been mired with uncertainty of further course of the in-situ finding into aggressive and metastatic breast cancer, the extent of treatment, and the dilemma about the usefulness of the early detection as the basic tenet of the breast cancer

Age of women as such has almost invariably been defined among the strongest risk factor of breast cancer. The assertion of randomness has frequently accompanied the age factor. The international experience, however, points out to the long held observation that this assessment is not universally correct and that is in principle wrong. **Figure 15**  shows that breast cancer in **Korea** is confined to middle-aged women, to the reproductive-age span women, with declining incidence after the peri-menopausal age of 50. In most of Asian populations (Japan, Malaysia, India), the breast cancer profiles

The pattern of breast cancer age distribution in Korea was similar to those in many European countries, which could still be seen in Porto, Portugal, evocative to the old rather

Hidden behind the common reference of "cancer incidence increase" lies the fact that the increase is created to a high extent by the rise of breast cancer, while the category of "the rest of cancers" is actually decreasing. [The categories of breast cancer and "all cancers without skin cancer (C44)" are given as such and, for the purposes of this study, is computed a new category of "rest of cancers," meaning 'all cancers' minus breast cancer)]. The data of the **SEER** (Surveillance, Epidemiology, and End Results) program, containing nine registration centers in the U.S. and, since it stands for about 10 percent of the U.S. population, considered representative sample of the country, showed that the number of breast cancer rose by 11.6 percent, while the "rest" of cancers increased by 8.7 percent, between the two consecutive periods of 1993-97 and 1998-2002. The **Figure 16** presents data of increasing breast cancer age-adjusted incidence rates (16.8%) compared to the decreasing "rest" of cancer (-7.5%) in Afro-American women during the aforementioned two 5-year periods. There was exactly the same reciprocal increase of breast cancer (7.7%) and decrease (-4.3%) of the 'rest of cancers' in Afro-American women in Connecticut, and unexpected decrease (of -4.9%) of the 'rest' of cancers (age-adjusted incidence rates), and increase (1.2%) in white

strategy.

**4.4 Reproductive age and breast cancer** 

than new European models. (Figure not presented)

women in the San Francisco Bay Area, CA.

exhibit the same pattern.

Fig. 15. Breast Cancer in Korea, 1988-2002. Age-specific incidence rates, per 100,000

AIDS Changed America with the Twin

compared with the increase of the "rest" of cancers.

anymore.)

Breast Cancer Epidemic: Exploring the Consequences of Condomization 543

declined for minus 6.7% between decades 1993-97 and 1998-2002. The Shanghai City, a fast developing urban conglomerate, and similar to Hong Kong in population and number of breast cancer cases, showed the same trends of increase, of 29.8%, of breast cancer (ageadjusted incidence rates), and increase of 9.7% of the "rest" of cancers. Once again, the differing end-results of breast cancer between the two Chinese metropolises may corroborate the evidence that increase of the disease in Hong Kong, along with the decrease of the "rest" of cancers, is more related to other than poisonous risk factors in the environment, than the (fast) increase of breast cancer in Shanghai (together with the "rest" of cancers), which might be related to ecological pollution of presumed exposures to noxious workplace environments. The notion of better controlled environment-related cancers, defined as "rest" of cancers and excluding breast cancer, might be seen in the following examples for the two periods between 1993-97 and 1998-2002: Higher breast cancer rise and trailing rise of the "rest" of cancers is observed in Sweden, at country level again, with 3.3% breast cancer rise and -1.6% decline of the "rest" of cancers), Geneva (Switzerland, with a 6.2% breast cancer rise and -3.0% decline of the "rest" of cancers), Tyrol (Austria, with 4.9% breast cancer rise, and a practically stalled rise of "rest" of cancers, of 0.3%). Virtually, almost all centers of cancer registration in the world, for the two aforementioned periods, showed much higher percentages of breast cancer rises as

The intermediate figures and other tabulated data which are to be presented, will try to corroborate once again the underlying tested theory (hypothesis) of the exposure forces of the misconceived barrier contraception as the main risk factor, attributed as the root cause of the epidemic of the gender-specific diseases. Almost no other known alteration in the interhuman environment or corruption of the intimate (sexual) woman-man ecosystem has taken place in the population(s), but the misconceived ubiquitous mass condomization, making this overlooked fallacy an exceedingly hazardous "minefield" to the health, lives and happiness of women and girls in the modern world. In contemporary dictionary of profitdriven healthcare system, the biological risk factors and exposure to ever-rising breast cancer and other epidemic diseases in women are considered as "keeping the healthy people in the risk pool" and "death spiral." From the deliberately maintaining the "risk pool" leading to scare, anxiety and "death spiral" of cost and uncertainties, new health-care dynamics are created, by which the insurance companies recruit eternal number of cases of breast-cancer affected women for "downstream" clinical activities, deceptively defined and disguised as "preventive health care for women," and which include "preventive screening," "preventive mammography programs" for "early detection," and clinical treatments (surgery and chemotherapy). (The failed, previously carried out community "chemo-prevention" trials on healthy women with *tamoxifen* against breast cancer, in a number of European and North American regions, in the 1990s, is not an active option

Most of the results and data evaluated in the study would stay open-ended, to monitor the further developments of the increasing trends of the breast cancer epidemic, until after the decision and public option for intervention is implemented for practical elimination of the breast cancer epidemic and the accompanied diseases-tumors of female reproductive system. (Practical elimination of the excess breast cancer epidemic worldwide might be defined as is a virtual 'eradication' of the disease(s) to low incidence rates of sporadic cases

the disease(s) at individual, familial and community levels.)

Fig. 16. Diverging trends of increase of breast cancer, and decrease of the 'rest' of all cancers in Afro-American women, 1993-2002, SEER - 9 regions. Age-standardized incidence rates, per 100,000

The differences in incidence rates and the diverging, comparative trends of increase and decrease of breast cancer and the 'rest' of cancers in women of both races (white and Afro-American), living in a reasonably same environment, gives credence to the evidence that the environmental chemicals/toxins, and of the women's nature culprit estrogen theory, are not the likely risk factors of the disease. The root cause of the modern-time women's suffering (breast cancer), is in certain other areas, such as, the "inverse" etiological risk factor at play at personal, intimate (sexual) and familial levels, as postulated.

Exactly the same pattern of diverging trends of rising breast cancer incidence rates as contrasted to decreasing incidence all other forms of cancer ('rest" of cancers) has been determined in Sweden in the past, Poland (Warsaw City) at the recent past and other centers in the world, according to the latest CI5 data ( 1998-2002). The same source shows that breast cancer incidence rates increased for 14.1% in Hong Kong, while the "rest" of cancer

Fig. 16. Diverging trends of increase of breast cancer, and decrease of the 'rest' of all cancers in Afro-American women, 1993-2002, SEER - 9 regions. Age-standardized incidence rates,

The differences in incidence rates and the diverging, comparative trends of increase and decrease of breast cancer and the 'rest' of cancers in women of both races (white and Afro-American), living in a reasonably same environment, gives credence to the evidence that the environmental chemicals/toxins, and of the women's nature culprit estrogen theory, are not the likely risk factors of the disease. The root cause of the modern-time women's suffering (breast cancer), is in certain other areas, such as, the "inverse" etiological risk factor at play

Exactly the same pattern of diverging trends of rising breast cancer incidence rates as contrasted to decreasing incidence all other forms of cancer ('rest" of cancers) has been determined in Sweden in the past, Poland (Warsaw City) at the recent past and other centers in the world, according to the latest CI5 data ( 1998-2002). The same source shows that breast cancer incidence rates increased for 14.1% in Hong Kong, while the "rest" of cancer

at personal, intimate (sexual) and familial levels, as postulated.

per 100,000

declined for minus 6.7% between decades 1993-97 and 1998-2002. The Shanghai City, a fast developing urban conglomerate, and similar to Hong Kong in population and number of breast cancer cases, showed the same trends of increase, of 29.8%, of breast cancer (ageadjusted incidence rates), and increase of 9.7% of the "rest" of cancers. Once again, the differing end-results of breast cancer between the two Chinese metropolises may corroborate the evidence that increase of the disease in Hong Kong, along with the decrease of the "rest" of cancers, is more related to other than poisonous risk factors in the environment, than the (fast) increase of breast cancer in Shanghai (together with the "rest" of cancers), which might be related to ecological pollution of presumed exposures to noxious workplace environments. The notion of better controlled environment-related cancers, defined as "rest" of cancers and excluding breast cancer, might be seen in the following examples for the two periods between 1993-97 and 1998-2002: Higher breast cancer rise and trailing rise of the "rest" of cancers is observed in Sweden, at country level again, with 3.3% breast cancer rise and -1.6% decline of the "rest" of cancers), Geneva (Switzerland, with a 6.2% breast cancer rise and -3.0% decline of the "rest" of cancers), Tyrol (Austria, with 4.9% breast cancer rise, and a practically stalled rise of "rest" of cancers, of 0.3%). Virtually, almost all centers of cancer registration in the world, for the two aforementioned periods, showed much higher percentages of breast cancer rises as compared with the increase of the "rest" of cancers.

The intermediate figures and other tabulated data which are to be presented, will try to corroborate once again the underlying tested theory (hypothesis) of the exposure forces of the misconceived barrier contraception as the main risk factor, attributed as the root cause of the epidemic of the gender-specific diseases. Almost no other known alteration in the interhuman environment or corruption of the intimate (sexual) woman-man ecosystem has taken place in the population(s), but the misconceived ubiquitous mass condomization, making this overlooked fallacy an exceedingly hazardous "minefield" to the health, lives and happiness of women and girls in the modern world. In contemporary dictionary of profitdriven healthcare system, the biological risk factors and exposure to ever-rising breast cancer and other epidemic diseases in women are considered as "keeping the healthy people in the risk pool" and "death spiral." From the deliberately maintaining the "risk pool" leading to scare, anxiety and "death spiral" of cost and uncertainties, new health-care dynamics are created, by which the insurance companies recruit eternal number of cases of breast-cancer affected women for "downstream" clinical activities, deceptively defined and disguised as "preventive health care for women," and which include "preventive screening," "preventive mammography programs" for "early detection," and clinical treatments (surgery and chemotherapy). (The failed, previously carried out community "chemo-prevention" trials on healthy women with *tamoxifen* against breast cancer, in a number of European and North American regions, in the 1990s, is not an active option anymore.)

Most of the results and data evaluated in the study would stay open-ended, to monitor the further developments of the increasing trends of the breast cancer epidemic, until after the decision and public option for intervention is implemented for practical elimination of the breast cancer epidemic and the accompanied diseases-tumors of female reproductive system. (Practical elimination of the excess breast cancer epidemic worldwide might be defined as is a virtual 'eradication' of the disease(s) to low incidence rates of sporadic cases the disease(s) at individual, familial and community levels.)

AIDS Changed America with the Twin

2001; 358: 1467-70 (pp. 843-44).

**4.6 Thyroid cancer** 

"Right to Know" legislation about life and death matters."

by **Carolyn Sayre** (NY Times, Oct. 15, 2010), as follows:

are incomplete and out of reality.

Breast Cancer Epidemic: Exploring the Consequences of Condomization 545

OC pills as a presumed preventive measure against cancer in women should be questioned and rejected as an interpretation of its effects, as highlighted previously in a discussion about 'Tubal ligation and risk of ovarian cancer" in the same journal, Lancet

Women may change the contraceptive methods during their reproductive lifetimes, and may frequently, even sporadically still use condoms, because of planned ignorance of its carcinogenic effects. It is anticipated that the termination of the main and perhaps the sole risk factor of breast / ovarian cancers, the universal condomization of women's sexuality, will bring about immediate health gain in the community. A practical 'eradication' of the diseases to levels of sporadic cases, is expected to reached in a speedy decline of the current, excess epidemics of breast and ovarian cancers, in a mirror image of the rapid rise of the sex- (gender-) specific malignant epidemics as they entered the human race more than two-and-a-half decades ago. What might help in defining and providing primary prevention of ovarian and breast cancer epidemics in the advanced courtiers of the West, including the UK, is the empowerment of the British and other women with the

An initial hypothesis-testing study, in the mid-1970s, showed evidence of a significant association between the exposure to condom use and the breast cancer development in American and other married women. During the mid-1980s, another field study corroborated the evidence of a postulated association between condom use and thyroid cancer in women as well. The study also confirmed the close relationship between these two female "sex- (gender-) specific" diseases of the breast and thyroid glands along with other accompanying diseases, tumors and cancers of female reproductive tract (Gjorgov, 1999). A feedback was communicated to the New York Times, entitled: "Pseudo Answers to the Thyroid Cancer Contingency: Times Essentials" - "The Rising Incidence of Thyroid cancer,"

"The thyroid disorders and tumors, along with the other epidemic diseases that afflict women, such as breast cancer, showed to have the same etiologic root cause: the CONDOMIZATION of women's sexuality. I have investigated in the field of thyroid cancer and I strongly believe that the aforementioned Times essentials of thyroid cancer

Firstly, the information in the article should have provided separate data of women (i.e., for the so-named in the article "certain groups"?) and should not referred to "people" rather than women throughout the article. The existing evidence suggests that the female thyroid cancer may etiologically differ from that in males. Besides the assumed environmental causes, the reproductive causes apparently play a major, additional causative role in the development of thyroid cancer in women. The female-male difference of the root causes of thyroid cancer in the past three decades (since the beginning of 1980s) may confirm or provide further evidence of the potential of primary (non-chemical) prevention of the disease in women to a great extent. The existing epidemiological evidence points out to a situation that thyroid cancer falls into the same category of the female sex- (gender-) specific diseases, along with breast cancer. While the ratio of breast cancer is about 100 in women to 1 in men, the ratio of thyroid cancer in

#### **4.5 Ovarian cancer**

Besides breast cancer, an integral part of the comprehensive research of the reproductive health of women is the ovarian and endometrial cancers. In this regard, observations and results in joint breast-ovarian cancer research experience are presented. The following commentary to highly publicized results in prevention of ovarian cancer by oral contraceptive pills is presented: Adjacent to cancer of the ovary are considered the polycystic syndrome, menstrual irregularities, endometriosis, female sexual dysfunction, low pelvic pain, craps, bloating.

The following critical comment was communicated to Prof. Valerie Beral, the Director of the **Cancer Research UK** and the lead author of the "Study: the Pill Protects against Ovarian Cancer," as reported by Washington Post Online, January 25, 2008 (Fragments):

"The Oxford study reported only a partial truth about the prevention / protection against ovarian cancer in the United Kingdom and elsewhere. Yet, the research of the root cause of the epidemic extent of ovarian cancer has NOT been done.

Despite the brief, but interrupted, heated exchange with the author and other presiding colleagues 14 years ago, at the 'Lancet International Breast Cancer Challenge Conference' (Brugge, Belgium, April 1994), about the tested evidence… that the CONDOMIZATION of women's sexuality, as the main root cause of the rising epidemics of epidemic breast cancer and other malignancies (ovarian and endometrial cancers), has been ignored and circumvented time and again, and not investigated to date…

It is a real wonder that there were such women who used oral contraceptive pills during the long era of indiscriminate promotion of 'condom culture;' a minority of 'nonpolitically correct' women and couples who rejected, even periodically the use of condoms, perhaps by listening to their inner sense of impaired sexuality and health consequences. For, many millions of women suffered and died mainly in the Western world, including the UK, during the twin breast and ovarian epidemics. The deadly, false belief of the exposure to (use of) condoms as a "safe" device for fertility-control and family-planning purposes has apparently taken a heavy human toll, and puts many more lives in jeopardy.

Despite the controversial assertion (that OC pills 'increase' breast cancer while decreasing ovarian cancer), the fact remains that the OC pills (with prevalent use during the 1970s), did not create the breast cancer epidemic, but the condomization of female sexuality (since the beginning of the 1980s), has predictably precipitated the unprecedented natural experiment of rapid breast cancer rise as an epidemic disease, or has 'coincided' with the emergence of the current, unabated breast / ovarian / gynecological cancer epidemics. According to previous evidence, the preventive effect is recognized not because of the OC-pill chemical content, i.e., "the first medication…(which) cuts ovarian cancer," as claimed by the authors of the aforementioned statistical study, but rather because of the non-use or abandoned barriers contraceptive methods (mainly condoms), associated with the observed protection of ovarian / breast cancer.

The OC-pill claim as protective factor also contradicted the added statement by the authors of 'other protective measures' against ovarian cancer which included 'advice' for "having children or getting tubes tied." Those two human conditions (pregnancies or tubal ligation) oppose the presumed OC-pill preventive effects, for they contain neither exogenous, OC pill's estrogens nor any other medication. Consequently, the role of the OC pills as a presumed preventive measure against cancer in women should be questioned and rejected as an interpretation of its effects, as highlighted previously in a discussion about 'Tubal ligation and risk of ovarian cancer" in the same journal, Lancet 2001; 358: 1467-70 (pp. 843-44).

Women may change the contraceptive methods during their reproductive lifetimes, and may frequently, even sporadically still use condoms, because of planned ignorance of its carcinogenic effects. It is anticipated that the termination of the main and perhaps the sole risk factor of breast / ovarian cancers, the universal condomization of women's sexuality, will bring about immediate health gain in the community. A practical 'eradication' of the diseases to levels of sporadic cases, is expected to reached in a speedy decline of the current, excess epidemics of breast and ovarian cancers, in a mirror image of the rapid rise of the sex- (gender-) specific malignant epidemics as they entered the human race more than two-and-a-half decades ago. What might help in defining and providing primary prevention of ovarian and breast cancer epidemics in the advanced courtiers of the West, including the UK, is the empowerment of the British and other women with the "Right to Know" legislation about life and death matters."

## **4.6 Thyroid cancer**

544 HIV and AIDS – Updates on Biology, Immunology, Epidemiology and Treatment Strategies

Besides breast cancer, an integral part of the comprehensive research of the reproductive health of women is the ovarian and endometrial cancers. In this regard, observations and results in joint breast-ovarian cancer research experience are presented. The following commentary to highly publicized results in prevention of ovarian cancer by oral contraceptive pills is presented: Adjacent to cancer of the ovary are considered the polycystic syndrome, menstrual irregularities, endometriosis, female sexual dysfunction,

The following critical comment was communicated to Prof. Valerie Beral, the Director of the **Cancer Research UK** and the lead author of the "Study: the Pill Protects against Ovarian

"The Oxford study reported only a partial truth about the prevention / protection against ovarian cancer in the United Kingdom and elsewhere. Yet, the research of the root cause

Despite the brief, but interrupted, heated exchange with the author and other presiding colleagues 14 years ago, at the 'Lancet International Breast Cancer Challenge Conference' (Brugge, Belgium, April 1994), about the tested evidence… that the CONDOMIZATION of women's sexuality, as the main root cause of the rising epidemics of epidemic breast cancer and other malignancies (ovarian and endometrial cancers), has been ignored and

It is a real wonder that there were such women who used oral contraceptive pills during the long era of indiscriminate promotion of 'condom culture;' a minority of 'nonpolitically correct' women and couples who rejected, even periodically the use of condoms, perhaps by listening to their inner sense of impaired sexuality and health consequences. For, many millions of women suffered and died mainly in the Western world, including the UK, during the twin breast and ovarian epidemics. The deadly, false belief of the exposure to (use of) condoms as a "safe" device for fertility-control and family-planning purposes has apparently taken a heavy human toll, and puts many more

Despite the controversial assertion (that OC pills 'increase' breast cancer while decreasing ovarian cancer), the fact remains that the OC pills (with prevalent use during the 1970s), did not create the breast cancer epidemic, but the condomization of female sexuality (since the beginning of the 1980s), has predictably precipitated the unprecedented natural experiment of rapid breast cancer rise as an epidemic disease, or has 'coincided' with the emergence of the current, unabated breast / ovarian / gynecological cancer epidemics. According to previous evidence, the preventive effect is recognized not because of the OC-pill chemical content, i.e., "the first medication…(which) cuts ovarian cancer," as claimed by the authors of the aforementioned statistical study, but rather because of the non-use or abandoned barriers contraceptive methods (mainly condoms), associated with

The OC-pill claim as protective factor also contradicted the added statement by the authors of 'other protective measures' against ovarian cancer which included 'advice' for "having children or getting tubes tied." Those two human conditions (pregnancies or tubal ligation) oppose the presumed OC-pill preventive effects, for they contain neither exogenous, OC pill's estrogens nor any other medication. Consequently, the role of the

Cancer," as reported by Washington Post Online, January 25, 2008 (Fragments):

of the epidemic extent of ovarian cancer has NOT been done.

circumvented time and again, and not investigated to date…

the observed protection of ovarian / breast cancer.

**4.5 Ovarian cancer** 

lives in jeopardy.

low pelvic pain, craps, bloating.

An initial hypothesis-testing study, in the mid-1970s, showed evidence of a significant association between the exposure to condom use and the breast cancer development in American and other married women. During the mid-1980s, another field study corroborated the evidence of a postulated association between condom use and thyroid cancer in women as well. The study also confirmed the close relationship between these two female "sex- (gender-) specific" diseases of the breast and thyroid glands along with other accompanying diseases, tumors and cancers of female reproductive tract (Gjorgov, 1999).

A feedback was communicated to the New York Times, entitled: "Pseudo Answers to the Thyroid Cancer Contingency: Times Essentials" - "The Rising Incidence of Thyroid cancer," by **Carolyn Sayre** (NY Times, Oct. 15, 2010), as follows:

"The thyroid disorders and tumors, along with the other epidemic diseases that afflict women, such as breast cancer, showed to have the same etiologic root cause: the CONDOMIZATION of women's sexuality. I have investigated in the field of thyroid cancer and I strongly believe that the aforementioned Times essentials of thyroid cancer are incomplete and out of reality.

Firstly, the information in the article should have provided separate data of women (i.e., for the so-named in the article "certain groups"?) and should not referred to "people" rather than women throughout the article. The existing evidence suggests that the female thyroid cancer may etiologically differ from that in males. Besides the assumed environmental causes, the reproductive causes apparently play a major, additional causative role in the development of thyroid cancer in women. The female-male difference of the root causes of thyroid cancer in the past three decades (since the beginning of 1980s) may confirm or provide further evidence of the potential of primary (non-chemical) prevention of the disease in women to a great extent. The existing epidemiological evidence points out to a situation that thyroid cancer falls into the same category of the female sex- (gender-) specific diseases, along with breast cancer. While the ratio of breast cancer is about 100 in women to 1 in men, the ratio of thyroid cancer in

AIDS Changed America with the Twin

methods, Oral contraceptive, Diet

**(Gjorgov, 2003)** 

**4.7 Other reproductive-health adverse effects** 

below:

significant results. The study was published in the journal

Breast Cancer Epidemic: Exploring the Consequences of Condomization 547

controlling for regional, especially on American and European variables and other developmental and racial variables reiterated the conclusion of a common root cause of breast and thyroid cancers. A series of dietary factors investigated in the study showed no

"*Libri Oncologici*" in Zagreb, Croatia. A brief summary of the "(Gjorgov, 1998a), is presented

**Risk Factors Of Female Thyroid Cancer In Kuwait: A Retrospective Study (Summary) Background.** A case-control study was conducted in Kuwait during 1984-1985, in order to ascertain the reproductive characteristics, contraceptive practice, and dietary habits of 101 women with primary thyroid cancer (TC), aged 19-65 years, and a comparative group of 98 control women, free of the disease, and matched by age and nationality status. Information was obtained by personal interview with a questionnaire. **Objectives.** The study investigated the relationship between the risk factors in the domain of fertility control, known or postulated to be related to breast cancer, and the risk of TC in women. **Results**. The study showed that both groups of cases and controls were homogeneous and comparable in almost all studied factors. Differences at statistically significant levels were observed, however, in two contraceptive exposures: the TC patients reported more frequent and more extended use of condoms than the controls (P<.05), whereas the controls reported more extended exposure to oral contraceptives than the TC cases (P<.01). The highest relative risk (odds ratio) to the disease, OR = 4.3 (95%CI: 0.5--39.2), and adjusted OR = 7.1 (95%CI: 0.6--78.9), was observed for women with condom use of more than two years. In regard to the dietary factors, no appreciative differences were found for most of the investigated food items, except a difference of borderline significance of higher consumption of sugared products among the TC cases, and a significant difference of a higher consumption of sugared drinks among the controls. **Conclusions.** The findings of barrier contraceptive risk factors (condoms) in this study may help explain the similarity and analogy of the epidemiology of these predominantly

female sex-specific neoplasms, cancer of the thyroid and cancer of the breast.

**4.7.1 Adverse effects of condomization on female sexual dysfunction** 

Online, 2003, is presented in the following rapid response (Gjorgov, 2003):

**Key words:** Reproduction, Contraception, Barrier methods, Condom, Non-barrier

Besides the new investigations into some new phenomena falling under a diagnosis of "FSDs" (female sexual dysfunctions), as further collateral, potential side effects of changed inter-human (woman-man) micro-environment could also come under consideration for investigation both the increased frequencies of divorce, and the more frequent reports of women's unhappiness. The assumption of condomization being associated with allegedly newly defined condition 'FSD' – Female sexual dysfunction – and the ensuing discussion in the **British Medical Journal**-

**Condomization of female sexuality - the cause of the FSD (Female Sexual Dysfunction)** 

"In the recent article about the female sexual dysfunction (FSD) (Moynihan, 2003) and in the ensuing rapid reactions and debate about the subject matter, the keystone factor of the

women is unanimously around or greater than three times of that of men.

Perhaps no one should be so mystified about the emerging, epidemic thyroid diseases nowadays, including the erratic thyroid cancer. Along with the other epidemic diseases which afflict women, such as breast cancer and the thyroid disorders have, almost certainly, the same etiologic root cause: the condomization of women's sexuality.

Inferring from the NYT article, it could be assumed that out the 45,000 thyroid cancer cases in the U.S. there were at least 1,125,000 thyroid-nodule biopsies, out of which about 843,750 thyroid-nodule biopsies were performed to about 33,750 women a year. It may confirm the assessment that the magnitude of the number of biopsies and other diagnostic procedures equal the scale of clinical diagnostic activities conducted to the epidemic of breast cancer.

It is anticipated that both widespread, epidemic diseases in women, breast cancer and thyroid disorders / nodules, could practically be eliminated ('eradicated' to sporadic cases), by a still pending, primary (non-chemical) prevention of the current breast cancer epidemic.."

(The comment was first communicated to the 'mystifying emergence' of Oprah's Thyroid Club almost three years earlier, on October 25, 2007),

The idea of similarity of risk factors of breast and thyroid cancers along with other female specific cancers, diseases and other phenomena was not widely known. The availability of the exceptionally rich cancer data in the WHO-IARC editions of the 'Cancer Incidence in Five Continents' (in last six editions) offered an opportunity to test the association, on global as well as regional scale (North America, South America, Europe, Asia, Australia, Africa), in addition to race (white, Afro-American), and developmental stage (developed and developing countries). The following **Table 4** presents the correlation coefficients and significance levels, of world data.


Legend:

**<sup>+</sup>**Age-adjusted according to World Standard Population (WSP), **\***Statistical significance p<.05 **\*\***Statistical significance p<.01 or p<.001

Table 4. Thyroid Cancer: Correlation coefficients with Breast cancer and other Cancers of reproductive system in women, World data: 1968-2002. Age-adjusted incidence rates, per 100,000.female population.

The results showed positive associations for breast, ovarian and endometrial cancer on global scale, and negative association with the cancer of the cervix uteri. The results are in accord with the postulated condomization exposure of women. The correlations coefficients

Perhaps no one should be so mystified about the emerging, epidemic thyroid diseases nowadays, including the erratic thyroid cancer. Along with the other epidemic diseases which afflict women, such as breast cancer and the thyroid disorders have, almost

Inferring from the NYT article, it could be assumed that out the 45,000 thyroid cancer cases in the U.S. there were at least 1,125,000 thyroid-nodule biopsies, out of which about 843,750 thyroid-nodule biopsies were performed to about 33,750 women a year. It may confirm the assessment that the magnitude of the number of biopsies and other diagnostic procedures equal the scale of clinical diagnostic activities conducted to the

It is anticipated that both widespread, epidemic diseases in women, breast cancer and thyroid disorders / nodules, could practically be eliminated ('eradicated' to sporadic cases), by a still pending, primary (non-chemical) prevention of the current breast cancer

(The comment was first communicated to the 'mystifying emergence' of Oprah's Thyroid

Vol. V: 1878- 1982

**<sup>+</sup>**Age-adjusted according to World Standard Population (WSP), **\***Statistical significance p<.05

Table 4. Thyroid Cancer: Correlation coefficients with Breast cancer and other Cancers of reproductive system in women, World data: 1968-2002. Age-adjusted incidence rates, per

The results showed positive associations for breast, ovarian and endometrial cancer on global scale, and negative association with the cancer of the cervix uteri. The results are in accord with the postulated condomization exposure of women. The correlations coefficients

**# of places 80 104 159 166 183 211 300**  Breast Ca. .212\* .265\* .205\* .323\* .166\* .284\*\* .225\*\* Cervix Ca. -.027 -.142 .041 -.060 -.118 -.208\*\* -.084 Uterus Ca. .400\*\* .232\*\* .274\*\* .205\*\* ,230\*\* ..322\*\* .271\*\* Ovary Ca. .078\* .080 .294\*\* .158\* .029 .224\*\* .538\*\*

Vol. VI: 1983- 1987

Vol. VII: 1988- 1992

Vol. VIII: 1993- 1997

Vol. IX: 1998- 2002

The idea of similarity of risk factors of breast and thyroid cancers along with other female specific cancers, diseases and other phenomena was not widely known. The availability of the exceptionally rich cancer data in the WHO-IARC editions of the 'Cancer Incidence in Five Continents' (in last six editions) offered an opportunity to test the association, on global as well as regional scale (North America, South America, Europe, Asia, Australia, Africa), in addition to race (white, Afro-American), and developmental stage (developed and developing countries). The following **Table 4** presents the correlation coefficients and

women is unanimously around or greater than three times of that of men.

epidemic of breast cancer.

significance levels, of world data.

Vol. III: 1968- 1972

**\*\***Statistical significance p<.01 or p<.001

100,000.female population.

Club almost three years earlier, on October 25, 2007),

Vol. IV: 1973- 1977

epidemic.."

Country / Population

Legend:

certainly, the same etiologic root cause: the condomization of women's sexuality.

controlling for regional, especially on American and European variables and other developmental and racial variables reiterated the conclusion of a common root cause of breast and thyroid cancers. A series of dietary factors investigated in the study showed no significant results. The study was published in the journal

"*Libri Oncologici*" in Zagreb, Croatia. A brief summary of the "(Gjorgov, 1998a), is presented below:

**Risk Factors Of Female Thyroid Cancer In Kuwait: A Retrospective Study (Summary) Background.** A case-control study was conducted in Kuwait during 1984-1985, in order to ascertain the reproductive characteristics, contraceptive practice, and dietary habits of 101 women with primary thyroid cancer (TC), aged 19-65 years, and a comparative group of 98 control women, free of the disease, and matched by age and nationality status. Information was obtained by personal interview with a questionnaire. **Objectives.** The study investigated the relationship between the risk factors in the domain of fertility control, known or postulated to be related to breast cancer, and the risk of TC in women. **Results**. The study showed that both groups of cases and controls were homogeneous and comparable in almost all studied factors. Differences at statistically significant levels were observed, however, in two contraceptive exposures: the TC patients reported more frequent and more extended use of condoms than the controls (P<.05), whereas the controls reported more extended exposure to oral contraceptives than the TC cases (P<.01). The highest relative risk (odds ratio) to the disease, OR = 4.3 (95%CI: 0.5--39.2), and adjusted OR = 7.1 (95%CI: 0.6--78.9), was observed for women with condom use of more than two years. In regard to the dietary factors, no appreciative differences were found for most of the investigated food items, except a difference of borderline significance of higher consumption of sugared products among the TC cases, and a significant difference of a higher consumption of sugared drinks among the controls. **Conclusions.** The findings of barrier contraceptive risk factors (condoms) in this study may help explain the similarity and analogy of the epidemiology of these predominantly female sex-specific neoplasms, cancer of the thyroid and cancer of the breast.

**Key words:** Reproduction, Contraception, Barrier methods, Condom, Non-barrier methods, Oral contraceptive, Diet

## **4.7 Other reproductive-health adverse effects**

## **4.7.1 Adverse effects of condomization on female sexual dysfunction**

Besides the new investigations into some new phenomena falling under a diagnosis of "FSDs" (female sexual dysfunctions), as further collateral, potential side effects of changed inter-human (woman-man) micro-environment could also come under consideration for investigation both the increased frequencies of divorce, and the more frequent reports of women's unhappiness. The assumption of condomization being associated with allegedly newly defined condition 'FSD' – Female sexual dysfunction – and the ensuing discussion in the **British Medical Journal**-Online, 2003, is presented in the following rapid response (Gjorgov, 2003):

#### **Condomization of female sexuality - the cause of the FSD (Female Sexual Dysfunction) (Gjorgov, 2003)**

"In the recent article about the female sexual dysfunction (FSD) (Moynihan, 2003) and in the ensuing rapid reactions and debate about the subject matter, the keystone factor of the

AIDS Changed America with the Twin

evidence-based suggestion is simple and brief:

is long overdue to make the British and other women happy."

**Condoms, Condoms, Condoms…and Abortions. A critical reply** 

issue of condoms, "missed abortion," and breast cancer:

(predominant) use of condoms?

controversial.

women's ill health.

**4.7.2 Condomization, abortions, 'missed abortions,' and pseudopregnancy** 

ecosystem.

Breast Cancer Epidemic: Exploring the Consequences of Condomization 549

understanding of the FSD; - Contrary to what was mentioned, sex is NOT "Like Dancing": Sex is a physiological impact; - There is evidence that the continuing promotion of condoms use as a "normal sexual behavior" and/or (PC) contraceptive practice is lethal (breast cancer); - "Sexual functioning is an integral part of our lives" and perhaps of (gender) physical survival; - The feminist nonsense as a recipe for producing FSD: "masturbation" in females; - The "Conspiracy of Silence" for FSD is even more so for the unabated breast cancer epidemic; - The FSD, "as potentially epidemic condition" could and should be better handled in the services and domain of the Gynecologists-Obstetricians rather than the Urologists. - The "environmental intervention" in FSD, like in the breast cancer epidemic: Eradication of the "INVERSE" environmental factor, the barrier of the condom use that is eliminating, reducing or making absence the protective biological mechanisms in the intimate and subtle, inter-human (sexual) environment and

No wonder that the FSD is so prevalent in British and American women (reportedly, about 43%), for both are "high-risk" populations of breast cancer and are among the leading breast-cancer epidemic countries, with the highest breast cancer incidence and death rates in the world. Since the CONDOMIZATION of human sexuality seems to be the singular most important factor in the women's sexual dysfunction, my humble and

ABOLISH THE USE OF CONDOMS FOR CONTRACEPTIVE, FERTILITY-CONTROL AND FAMILY-PLANNING PURPOSES in the British marriages and couples, and make an urgent shift to the "non-barrier" methods of contraception (Gjorgov & Narod, 2001a). It

The following letter to the **Editor of the New York Times**, referring to the editorial "Abortion, Condoms and Bush," by **Nicholas D. Kristof,** NYT November 5, 2006, tackles the

"Mr. Kristof seems biased and medically ill-informed by discussing a biological issue like abortions and condoms. What kind of abortion "rise" and "fall" throughout the past (three) decades and during (six) presidential periods? Discussion of temporal changes of all (i) the artificial, (ii) spontaneous, and (iii) so-called "missed" abortions? And, on top of this professional mix-up and mystery of abortions, a cause-and-effect link is added to the

The (i) artificial abortions are carried out by demands, and reflect a fertility capacity of at least the woman. The artificial abortions burden the soul of the women in tremendous psychological pain, are reluctantly performed, and socially have always been quite

The (ii) spontaneous abortions reflect an infertility / sub-fertility status of both partners, usually married, and may indicate a hidden plight in building the family. The infertility condition is an acknowledged risk factor of development of breast cancer and other

The (iii) "missed abortion" is an utterance of professional, clinical perplexity. As a

female sexuality is amazingly missing across the board: the factor MAN. This background of culturally conditioned deficit convinced me that the research on FSD is being taken out of context. In addition, it seems that the FSD is not a static condition, developing by random choice and aimless. As emphasized in the article and the comments, the FSD has certainly a poorly understood etiology, but it might be evolving into some realms of unknown end-result(s).

More than 25 years ago, a hypothesis-testing study2 on primary breast cancer prevention and etiology was completed jointly at the University of North Carolina School of Public Health, at Chapel Hill, NC, and at the University of Pennsylvania School of Medicine and Hospital, in Philadelphia, PA, USA, during the mid-1970s. The study has tested and corroborated an a priori hypothesis on "semen factors" (deficiency) that an extended exposure to (use of) barrier contraception, specifically, the long-term condom use, and/or withdrawal practice, is significantly associated with the development of breast cancer in married American and other women, including the British women. Besides defining a new approach to the etiology of and the potential for a primary (non-chemical) prevention of breast cancer, another main contribution, I believe, of my cancer research has been the evidence-based inference that SEX along with marriage and love is a fundamental PHYSIOLOGICAL unit, above and beyond the psychological, social, economic, reproductive and legal linkage. The final report of the study, entitled, "BARRIER CONTRACEPTION AND BREAST CANCER" (Gjorgov, 1980) was published as a monograph by S. Karger Med. Publ., Basel-New York, in the distant 1980. (Since the book has been effectively banned from the public view and professional information, the breast cancer research was first published in the dissertation format, in 1979, by the University of Michigan Dissertation International, Ann Arbor, MI 48106; UMI publication # 79-14352.)

It was further indicated in the study that breast cancer is a systemic disease and not a random event, and that the breast carcinogenesis is most likely passing through nonspecific and unrecognized phases, manifesting itself in a number of trivial or undistinguishable symptoms in women's lives (Gjorgov, 1995), presumably such as the FSD, and eventually reaching a definite stage of overt breast cancer and other accompanying disease end-results, as predicted (Gjorgov, 1993, 1994a; Gjorgov, 1994b). An experimental trial (Gjorgov, 1999) of sterile mating on a colony of small laboratory animals corroborated the preventive efficacy of the semen factors (the prostaglandins) on mammary neoplastic tumors, and on the general impact on animal-female lives and health. The condom use introduces technical effects of absolute male sterility in marriages, placing an impregnable wall between the protective biology of man and woman, and converting their marriages into infertile male partners. It is quite conceivable that many a woman may feel the ill- effects ("female sex problems") because of the persistent and un-physiological condom use, and that the woman is reflexively trying to protect herself by escape, distancing, separation or reluctance against the unwittingly afflicting insults (!) upon her done by her technically sterile husband. It seems quite evident and certain that during the long evolution, Nature has not adjusted the species to sterile mating, including the humans.

Within the framework of the tested "semen-factor" (condom) hypothesis in breast cancer, partial comments, opinion and paraphrases on the FSD debate: - Perhaps "Body-mind" rather than "Mind-body" relationships is a better model than the psychiatric and social

female sexuality is amazingly missing across the board: the factor MAN. This background of culturally conditioned deficit convinced me that the research on FSD is being taken out of context. In addition, it seems that the FSD is not a static condition, developing by random choice and aimless. As emphasized in the article and the comments, the FSD has certainly a poorly understood etiology, but it might be evolving into some realms of

More than 25 years ago, a hypothesis-testing study2 on primary breast cancer prevention and etiology was completed jointly at the University of North Carolina School of Public Health, at Chapel Hill, NC, and at the University of Pennsylvania School of Medicine and Hospital, in Philadelphia, PA, USA, during the mid-1970s. The study has tested and corroborated an a priori hypothesis on "semen factors" (deficiency) that an extended exposure to (use of) barrier contraception, specifically, the long-term condom use, and/or withdrawal practice, is significantly associated with the development of breast cancer in married American and other women, including the British women. Besides defining a new approach to the etiology of and the potential for a primary (non-chemical) prevention of breast cancer, another main contribution, I believe, of my cancer research has been the evidence-based inference that SEX along with marriage and love is a fundamental PHYSIOLOGICAL unit, above and beyond the psychological, social, economic, reproductive and legal linkage. The final report of the study, entitled, "BARRIER CONTRACEPTION AND BREAST CANCER" (Gjorgov, 1980) was published as a monograph by S. Karger Med. Publ., Basel-New York, in the distant 1980. (Since the book has been effectively banned from the public view and professional information, the breast cancer research was first published in the dissertation format, in 1979, by the University of Michigan Dissertation International, Ann Arbor, MI 48106; UMI publication

It was further indicated in the study that breast cancer is a systemic disease and not a random event, and that the breast carcinogenesis is most likely passing through nonspecific and unrecognized phases, manifesting itself in a number of trivial or undistinguishable symptoms in women's lives (Gjorgov, 1995), presumably such as the FSD, and eventually reaching a definite stage of overt breast cancer and other accompanying disease end-results, as predicted (Gjorgov, 1993, 1994a; Gjorgov, 1994b). An experimental trial (Gjorgov, 1999) of sterile mating on a colony of small laboratory animals corroborated the preventive efficacy of the semen factors (the prostaglandins) on mammary neoplastic tumors, and on the general impact on animal-female lives and health. The condom use introduces technical effects of absolute male sterility in marriages, placing an impregnable wall between the protective biology of man and woman, and converting their marriages into infertile male partners. It is quite conceivable that many a woman may feel the ill- effects ("female sex problems") because of the persistent and un-physiological condom use, and that the woman is reflexively trying to protect herself by escape, distancing, separation or reluctance against the unwittingly afflicting insults (!) upon her done by her technically sterile husband. It seems quite evident and certain that during the long evolution, Nature has not adjusted the species to

Within the framework of the tested "semen-factor" (condom) hypothesis in breast cancer, partial comments, opinion and paraphrases on the FSD debate: - Perhaps "Body-mind" rather than "Mind-body" relationships is a better model than the psychiatric and social

unknown end-result(s).
