**1. Introduction**

Oral lesions are very common in individuals with HIV (human immunodeficiency virus) infection and AIDS (acquired immune deficiency syndrome). They are reported to occur in 50% of people infected with HIV and in about 80% of people diagnosed with AIDS (Palmer, et al., 1996). Introduction of HAART (highly active anti-retroviral therapy) in 1996 has reduced the mortality and morbidity in people affected with HIV and AIDS as well as improved their quality of life. It has also resulted in a decrease, to a certain extent, in the incidence and prevalence of oral lesions.

Since HIV infection was first diagnosed in 1981, a variety of oral lesions has been associated with infected individuals, and they can be good indicators of the disease in otherwise healthy people. Oral lesions can also help determine the progression of the disease. In developed countries, CD4 lymphocyte counts and HIV viral load are the two main laboratory markers that are used to determine disease progression. However, in certain developing countries, people do not always have access to these tests, and severity of the oral lesions can serve as good indicators of disease progression.

Table 1 highlights the importance of diagnosing and treating oral lesions in individuals with HIV (Coogan, et al., 2005)


Table 1. Importance of oral manifestations of HIV disease

#### **1.1 Classification of oral lesions associated with HIV**

The EC-Clearinghouse on oral problems related to HIV infection and WHO Collaborating Centre on Oral manifestations of the immunodeficiency virus proposed the classification of oral manifestations of HIV infection in September of 1992 based on their strength of

Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 81

high in developing countries (Tukutuku, et al., 1990). Since the discovery of HIV in 1981, candidiasis has been shown to be associated with HIV-infected individuals (Gottlieb, et al., 1981). Previous reports show that oral candidiasis occurs in 54-93% of individuals with AIDS (Schmidt-Westhausen, et al., 1991). In recent reports, due to the introduction of antiretroviral therapy only 20% of individuals infected with HIV showed oral candidiasis

Oral candidiasis is primarily caused by a dimorphic ubiquitous *Candida albicans*. The cell wall of *Candida* is primarily made up of three polysaccharides, mannan, glucan and chitin. *Candida* attaches to oral tissues and dentures with the help of adhesins such as Als1p, Als5p, Int1p and Hwp1p (Chaffin, et al., 1998, Hostetter, 1994). These glycoproteins bind to the extracellular matrix of mammalian cells such as fibrinogen, laminin and collagen (Chaffin, et al., 1998). Candidal adhesion to endothelial surfaces is achieved by the cell surface polysaccharide mannan, which binds to complement receptor 3 (CR3), an integrin found on human cells (Calderone and Braun, 1991). There is increased association of integrin analogs (iC3B and CR3d receptor) and fibronectin receptor with most of the virulent forms of *Candida* (Ollert, et al., 1990). Thus, CR3-like proteins promote adherence of *Candida albicans*

There are three clinical forms of candidiasis: pseudo-membranous (thrush), erythematous (atrophic) and perioral angular chelitis. Proliferation of pseudomembranous fungi forms a gray-white structure composed of inflammatory substrate and matted organisms resting on an erythematous base. These lesions are most commonly evident on the tongue, buccal mucosa, hard and soft palate and pharyngeal tissues. The erythematous form shows mucosal hyperemia and inflammation with a reddened erythematous patches (Calderone and Fonzi, 2001). The mucous membrane appears dry, red and glazed. Affected individuals show burning sensitivity and pain sensation of dry mouth, odynophagia, dysgeusia and smell of yeast infection. Angular chelitis shows commissural involvement as erythematous/hyperkeratotic with fissuring and sensitivity. Individuals receiving HAART show low occurrence of these clinical features. Before the emergence of HAART, the incidence of oral candidiasis was

An early study for treatment of *Candida* infections was carried out by Williams in 1977, where nystatin was compared to no treatment in 56 patients (Williams, et al., 1977). Since then ketoconazole, fluconazole, clotrimazole, itraconazole, neomycin sulphate, colistin, trimethoprin and sulphamethoxazole have been tried in combination and at different concentrations for treatment of oral candidiasis (Hann, et al., 1982, Owens, et al., 1984, Palmblad, et al., 1992, Philpott-Howard, et al., 1993, Rozenberg-Arska, et al., 1991, Vogler, et al., 1987). Most recently ketoconazole and clotrimazole were found most effective in treatment of oral candidiasis (Worthington, et al., 2002). Initial local treatments are first line of therapy (Bensadoun, et al., 2008). Mucosal contact for 2 minutes is recommended either by rinsing, gargling or swallowing.

(Davies, et al., 2006).

**2.2 Pathogenesis** 

to host cells.

**2.4 Treatment** 

**2.3 Clinical features** 

relatively high in persons with AIDS.

association with the presence of HIV infection: ("Classification and Diagnostic Criteria for Oral Lesions in HIV Infection. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus," 1993). More recently in 2002, an international workshop was convened to discuss the classification of oral lesions associated with HIV/AIDS almost 2 decades after the virus was first identified (Patton, et al., 2002) and it was agreed that the original EC-Clearinghouse classification could still be used in current times. Table 2 summarizes the classification of oral lesions associated with HIV.


Table 2. Classification of oral lesions associated with HIV

In this chapter, we will discuss only those lesions that are commonly seen in persons infected with HIV.

#### **2. Candidiasis**

#### **2.1 Background**

Candidiasis is a common opportunistic infection caused by an overgrowth of the *Candida*  microorganisms already present in the oral cavity**.** Incidence of oral candidiasis has been high in developing countries (Tukutuku, et al., 1990). Since the discovery of HIV in 1981, candidiasis has been shown to be associated with HIV-infected individuals (Gottlieb, et al., 1981). Previous reports show that oral candidiasis occurs in 54-93% of individuals with AIDS (Schmidt-Westhausen, et al., 1991). In recent reports, due to the introduction of antiretroviral therapy only 20% of individuals infected with HIV showed oral candidiasis (Davies, et al., 2006).

### **2.2 Pathogenesis**

80 Global View of HIV Infection

association with the presence of HIV infection: ("Classification and Diagnostic Criteria for Oral Lesions in HIV Infection. EC-Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of the Immunodeficiency Virus," 1993). More recently in 2002, an international workshop was convened to discuss the classification of oral lesions associated with HIV/AIDS almost 2 decades after the virus was first identified (Patton, et al., 2002) and it was agreed that the original EC-Clearinghouse classification could still be used in current times. Table 2 summarizes the classification of

> Group 2: Lesions less commonly associated with

**Bacterial infections:**  *Mycobacterium avium-*

hyperpigmentation Necrotizing (ulcerative)

Salivary gland disease Dry mouth due to decreased salivary flow Unilateral/bilateral swelling of salivary glands Thrombocytopenia purpura Non-specific ulcerations

**Viral infections:**  Herpes simplex virus Human papillomavirus Condyloma acuminatum Focal epithelial hyperplasia

Verruca vulgaris Varicella-zoster virus

In this chapter, we will discuss only those lesions that are commonly seen in persons

Candidiasis is a common opportunistic infection caused by an overgrowth of the *Candida*  microorganisms already present in the oral cavity**.** Incidence of oral candidiasis has been

Table 2. Classification of oral lesions associated with HIV

*Mycobacterium tuberculosis* 

Group 3: Lesions seen in

**Bacterial infections:**  *Actinomyces israelii Escherichia coli Klebsiella pneumonia*  Cat-scratch disease

Drug reactions (ulcerative, erythema multiforme, lichenoid, toxic epidermolysis) Epitheliod (bacillary)

**Fungal infection other than** 

**Neurological disturbances:** 

Trigeminal neuralgia

*Cryptococcus neoformans Geotrichum candidum Histoplasma capsulatum Mucoraceae (mucomycosis* 

HIV infection

angiomatosis

**candidiasis** 

*zygomycosis) Aspergilus flavus* 

Facial palsy

HIV infection

*intracellularae* 

Melanogic

stomatitis

oral lesions associated with HIV.

Group 1: Lesions strongly associated with HIV

Non-Hodgkin's lymphoma Periodontal disease (linear

gingival erythema, necrotizing ulcerative gingivitis, necrotizing ulcerative periodontitis)

infected with HIV.

**2. Candidiasis 2.1 Background** 

infection

Candidiasis Hairy leukoplakia Kaposi's sarcoma

Oral candidiasis is primarily caused by a dimorphic ubiquitous *Candida albicans*. The cell wall of *Candida* is primarily made up of three polysaccharides, mannan, glucan and chitin. *Candida* attaches to oral tissues and dentures with the help of adhesins such as Als1p, Als5p, Int1p and Hwp1p (Chaffin, et al., 1998, Hostetter, 1994). These glycoproteins bind to the extracellular matrix of mammalian cells such as fibrinogen, laminin and collagen (Chaffin, et al., 1998). Candidal adhesion to endothelial surfaces is achieved by the cell surface polysaccharide mannan, which binds to complement receptor 3 (CR3), an integrin found on human cells (Calderone and Braun, 1991). There is increased association of integrin analogs (iC3B and CR3d receptor) and fibronectin receptor with most of the virulent forms of *Candida* (Ollert, et al., 1990). Thus, CR3-like proteins promote adherence of *Candida albicans* to host cells.

## **2.3 Clinical features**

There are three clinical forms of candidiasis: pseudo-membranous (thrush), erythematous (atrophic) and perioral angular chelitis. Proliferation of pseudomembranous fungi forms a gray-white structure composed of inflammatory substrate and matted organisms resting on an erythematous base. These lesions are most commonly evident on the tongue, buccal mucosa, hard and soft palate and pharyngeal tissues. The erythematous form shows mucosal hyperemia and inflammation with a reddened erythematous patches (Calderone and Fonzi, 2001). The mucous membrane appears dry, red and glazed. Affected individuals show burning sensitivity and pain sensation of dry mouth, odynophagia, dysgeusia and smell of yeast infection. Angular chelitis shows commissural involvement as erythematous/hyperkeratotic with fissuring and sensitivity. Individuals receiving HAART show low occurrence of these clinical features. Before the emergence of HAART, the incidence of oral candidiasis was relatively high in persons with AIDS.

#### **2.4 Treatment**

An early study for treatment of *Candida* infections was carried out by Williams in 1977, where nystatin was compared to no treatment in 56 patients (Williams, et al., 1977). Since then ketoconazole, fluconazole, clotrimazole, itraconazole, neomycin sulphate, colistin, trimethoprin and sulphamethoxazole have been tried in combination and at different concentrations for treatment of oral candidiasis (Hann, et al., 1982, Owens, et al., 1984, Palmblad, et al., 1992, Philpott-Howard, et al., 1993, Rozenberg-Arska, et al., 1991, Vogler, et al., 1987). Most recently ketoconazole and clotrimazole were found most effective in treatment of oral candidiasis (Worthington, et al., 2002). Initial local treatments are first line of therapy (Bensadoun, et al., 2008). Mucosal contact for 2 minutes is recommended either by rinsing, gargling or swallowing.

Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 83

Fig. 3. Pseudo-membranous Candidiasis

Fig. 4. Atrophic/Erythematous Candidiasis

Systemic treatments are considered in high-risk patients only when local therapy fails (Charlier, et al., 2006). When topical and systemic therapy fails, intravenously administered amphotericin B and echinocandins are considered in high-risk patients. Intermittent use of antifungal agents has been advocated to prevent development of resistant fungal infections (Samaranayake, et al., 2002). Recently, gel formulation of fluconazole has proven to be a better alternative treatment form than tablet formulation (Nairy, et al.).

Fig. 1. Cell wall of *Candida albicans* 

Fig. 2. Hypertrophic Candidiasis

Fig. 3. Pseudo-membranous Candidiasis

Systemic treatments are considered in high-risk patients only when local therapy fails (Charlier, et al., 2006). When topical and systemic therapy fails, intravenously administered amphotericin B and echinocandins are considered in high-risk patients. Intermittent use of antifungal agents has been advocated to prevent development of resistant fungal infections (Samaranayake, et al., 2002). Recently, gel formulation of fluconazole has proven to be a better alternative treatment

form than tablet formulation (Nairy, et al.).

Fig. 1. Cell wall of *Candida albicans* 

Fig. 2. Hypertrophic Candidiasis

Fig. 4. Atrophic/Erythematous Candidiasis

Individuals with HIV/AIDS: Clinical Manifestations in the Oral Cavity in the Post-HAART Era 85

anti-retroviral drugs. However, if OHL is seen in an HIV-infected person, it may indicate failure of current therapy. Differential diagnosis of this condition includes oral candidiasis, lichen planus, other forms of leukoplakia, HPV (human papilloma virus) associated

OHL is a relatively benign condition with low morbidity and does not require any specific treatment. Most of the time, these lesions resolve spontaneously. However, several treatment options are available for those who feel uncomfortable or have cosmetic concerns due to the lesion. Since the lesion is caused by multiplication of the Epstein-Barr virus topical and systemic anti-viral agents work effectively in resolving the lesion. High doses of Acyclovir (800 mg 5 times a day) (Resnick, et al., 1988), Valacyclovir (1000 mg 3 times a day), and Famciclovir (500 mg 3 times a day) have all been shown to resolve the lesions in 1-2 weeks (Schofer, et al., 1987). However, once the effect of the anti-viral agent wears off, the

Topical application of Podophyllin resin in 25% solution has produced resolution of the lesion in 1-2 weeks (Gowdey, et al., 1995). Topical therapy with retinoic acid has also been shown to cause resolve the lesions due to inhibition of Epstein-Barr virus replication. Ablative and cryotherapy have also had success in treatment of the lesions. Although the above treatment options are effective in resolving the lesion, OHL can recur several weeks after treatment since none of these agents eliminate the latent state

intraepithelial neoplasia, and oral squamous cell carcinoma.

Fig. 6. Oral Hairy Leukoplakia

lesions can recur several weeks later.

**3.4 Treatment** 

of infection.

Fig. 5. Angular Chelitis
