Oral and periodontal manifestations of HIV/AIDS

The human immunodeficiency virus (HIV) is a retrovirus belonging to the family of lentiviruses which causes AIDS (acquired immune deficiency syndrome) in humans. Since the identification of this virus, extensive research has been done on HIV to understand its life cycle, routes of transmission, pathogenesis of AIDS and possible cure for the disease. Although attempts to develop anti-HIV drugs and vaccines have been ongoing for a long time, but still many aspects of HIV pathogenesis remain unclear. The main reason because of which the successful treatment of HIV infection is so difficult is “its rapid rate of evolutionary change”. We are still in a process to reconstruct the evolutionary history of HIV in order to develop better vaccines and antiviral agents. In 30% to 80% of HIV-infected individuals, oral manifestations of infection are observed. Oral lesions in AIDS are commonly associated with morbidity in HIV-infected cases. An in-depth understanding of AIDS and its oral manifestations is important for appropriate management of oral lesions in patients infected with HIV.

Historical aspect of HIV

AIDS was first identified in the USA in 1981. The HIV infection was found predominantly in promiscuous male homosexuals and intravenous drug users referred to as “AIDS risk groups” 1. This virus was first isolated in 1983 and soon it was evident that two types of HIV, with slightly different genome structures, were circulating in human populations 2. By the mid-1980’s, it became clear that the virus had spread, largely unnoticed, throughout most of the world. In 1986, WHO developed a provisional clinical AIDS case definition for adults and children 3. The number of cases and deaths among persons with AIDS increased rapidly during the 1980s, followed by substantial declines in new cases and deaths in the late 1990s. According to UNAIDS fact sheet 2014, in 2013 there were 35 million [33.2 million–37.2 million] people living with HIV. The report also highlights that since the start of the epidemic, around 78 million [71 million–87 million] people have become infected with HIV and 39 million [35 million–43 million] people have died of AIDS-related illnesses 4.

The understanding of HIV started with the discovery of simian immunodeficiency viruses (SIVs) which were present in a wide variety of African primates 5. SIVs have been isolated from more than 20 African primate species, but it has been observed that SIVs do not cause disease in their hosts. Genetically and evolutionally there are two distinct types of human AIDS viruses: HIV-1 and HIV-2. Infection caused by HIV-1 is more severe as compared to HIV-2. Evidence suggests a chimpanzee subspecies (Pan troglodytes troglodytes) as the source of HIV-1 infection and the sooty mangabey (Cercocebus Atys, a monkey found in West African rainforests between Senegal and Ghana) as the source of HIV-2 infection in human populations 6. HIV-1 is phylogenetically divided into three groups ‘M’, ‘N’ and ‘O’, with the M group further split into 9 subtypes and 15 circulating recombinant forms. The ‘M’ group of HIV-1 has a global distribution, whereas group ‘N’ and ‘O’ have restricted distribution in West Africa. HIV-2 is phylogenetically divided into seven subtypes and is common in individuals from West Africa.

Structure of HIV

HIV consists of a cylindrical center surrounded by a sphere-shaped lipid bilayer envelope. The virus particle has a diameter of about 1/10,000mm. Structurally, the virus is composed of three components: viral envelope, HIV matrix proteins, and the viral core.

Viral envelope:

As already stated, the viral envelope consists of a lipid bilayer. In the lipid bilayer, there are two major glycoproteins, gp120, and gp41. These glycoproteins are primarily involved in the recognition of CD4+ cells and chemokine receptors, thereby enabling the virus to attach to and invade CD4+ cells. HIV infects cells that carry the following receptor and co-receptor,

CD4: Expressed on the surface of CD4 T-lymphocytes (helper T-lymphocytes) and macrophages (including dendritic cells).

CCR5: Expressed on CD4+ T-lymphocytes and on macrophages.

CXCR4: Expressed on CD4+ T-lymphocytes and T-cell lines.

HIV matrix proteins:

The HIV matrix protein consists of p17 protein, which lies between the envelope and core.

Viral core:

It is formed of viral capsule protein p24 which surrounds two single strands of RNA and the enzymes needed for HIV replication, such as reverse transcriptase, protease, ribonuclease, and integrase. It also contains three out of nine virus genes, namely gag, pol, and env, that contain the information needed to make structural proteins for new virus particles.

‘gag’ gene contains around 1500 nucleotides. It gives rise to a 55-kilodalton (KD) gag precursor protein p55. This protein is later on cleaved into four smaller proteins which form the building blocks for the viral core,

  • CA (Capsid protein p24)
  • MA (Matrix protein p17) (this protein is a part of the “matrix” which anchors the core to the viral envelope)
  • NC (Nucleocapsid protein p9)
  • p6

‘pol’ gene encodes for enzymes required for various cellular processes in HIV which include,

  • Protease
  • RNAse H
  • Integrase

‘env’ gene encodes for a single protein, gp160. After synthesis, this protein travels to the cell surface where it is split into two parts gp120 and gp41 by enzymatic action.

 HIV life cycle

All viruses are obligate, intracellular parasites of cells, which mean that they require a living cell in order to reproduce. The life cycle of HIV starts in a host after its transmission from an infected person (Figure 29.1). The HIV is primarily transmitted by three routes………


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The risk of HIV transmission through these routes is given in Table 29.1.

Figure 29.1 The HIV life cycle

HIV life cycle

Table 29.1 Risk of transmission of HIV through various modes 

Mode of transmission
Risk per exposure
Receptive anal and vaginal intercourse 8, 9~ 0.1–3% and 0.1–0.2%, respectively, per episode
Insertive anal and vaginal intercourse 8, 9~ 0.06% and 0.1%, respectively, per episode
Blood transfusion 10 ~ 95% per exposure
Sharing of needles by drug abusers 11 ~ 0.67% per exposure
Needlestick injuries 12 ~ 0.3–0.4% per exposure
Perinatal transmission 13 ~ 25–30%

The life of HIV starts in a host with the fusion of gp120 glycoprotein on the HIV envelope with the CD4 receptor and one of two co-receptors, CCR5 or CXCR4, on the surface of a CD4+ T- lymphocyte. The virus then fuses to the host cell and releases its genetic material i.e. RNA into the host cell cytoplasm. Next step is the formation of viral DNA. Reverse transcriptase, an HIV enzyme converts the single-stranded HIV RNA to double-stranded HIV DNA. The newly formed HIV DNA then enters the host cell’s nucleus. In the nucleus, the viral DNA gets embedded into the host cell DNA with the help of a viral enzyme, DNA integrase. The integrated HIV DNA is called a provirus. This provirus may remain inactive for many years, producing few or no new copies of HIV. When the host cells get a signal of activation, the viral DNA starts producing copies of HIV genomic material by using the host cell enzyme, RNA polymerase. The m-RNA carrying information of viral proteins is synthesized and long chains of viral proteins are formed. The HIV proteases then…..


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Clinical signs and symptoms associated with HIV infection

After an individual gets infected with HIV, there is an initial burst of viral replication. The population of viral particles in the blood may reach 10,000,000/ml. The infected person may experience flu-like symptoms for up to 2 weeks. The patients usually complain of their condition as ‘worse flu ever’. Other symptoms include fever, swollen glands, sore throat, rash, muscle and joint aches and pains, fatigue, and headache. This phase of HIV infection is referred to as “acute retroviral syndrome” (ARS) or “primary HIV infection”. The seroconversion occurs after 3 to 8 week 14, 15. Because large numbers of viruses are produced during the initial period following infection, they use CD4 cells to replicate and destroy them in the process. Hence, there is a sharp downfall in CD4 cell count.

After the initial TH cell decline, the body starts generating an antibody response against HIV. This reduces the HIV count in the blood. The helper T-cell population recovers and the immune response is generated against the virus which keeps it at low and steady level. This level of virus in the blood is referred to as “viral set point”.

Over a period of time, the immune system fails to cope up with the viral load due to infection of helper T-cells and viral levels rise again. The patient starts experiencing opportunistic infections such as Candida albicans infections of the mouth or vagina, persistent diarrhea, fever, weight loss and reactivation of previous infections such as shingles and tuberculosis. Eventually, the body fails to recover from these infections and the patient dies.

Staging of HIV

The WHO (2005) clinical staging for HIV disease in adults/adolescents and children sorts the patients into one of the four hierarchical clinical stages, ranging from stage 1 (asymptomatic) to stage 4 (AIDS) (Table 29.2). Patients are assigned to a particular stage when they demonstrate at least one clinical condition in that stage’s criteria. Patients remain at a higher stage after they recover from the clinical condition which placed them in that stage

Table 29.2 Clinical staging of HIV disease in adults/adolescents and children 16

Adults/adolescents a
Clinical stage 1
• Asymptomatic
• Persistent generalized lymphadenopathy
• Asymptomatic
• Persistent generalized lymphadenopathy
Clinical stage 2
• Moderate unexplained weight loss (<10% of presumed or measured body weight)
• Recurrent respiratory tract infections (sinusitis, tonsillitis, otitis media, pharyngitis)
• Herpes zoster
• Angular cheilitis
• Recurrent oral ulceration
• Papular pruritic eruption
• Fungal nail infections
• Seborrhoeic dermatitis
• Unexplained persistent hepatosplenomegaly
• Recurrent or chronic upper respiratory tract infections (otitis media, otorrhea, sinusitis, tonsillitis)
• Herpes zoster
• Linear gingival erythema
• Recurrent oral ulceration
• Papular pruritic eruption
• Fungal nail infections
• Extensive wart virus infection
• Extensive molluscum contagiosum
• Unexplained persistent parotid enlargement
Clinical stage 3
• Unexplained severe weight loss (>10% of presumed or measured body weight) Unexplained chronic diarrhea for longer than 1 month
• Unexplained persistent fever (intermittent or constant for longer than 1 month)
• Persistent oral candidiasis
• Oral hairy leukoplakia
• Pulmonary tuberculosis
• Severe bacterial infections (such as pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteremia)
• Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
• Unexplained anaemia (<8g/dl), neutropenia (<0.5 x 109/l) and/or chronic thrombocytopenia (<50 x 109/l)
• Unexplained moderate malnutrition b not adequately responding to standard therapy
• Unexplained persistent diarrhea (14 days or more)
• Unexplained persistent fever (above 37.5°C, intermittent or constant, for longer than one 1 month)
• Persistent oral candidiasis (after first 6 weeks of life)
• Oral hairy leukoplakia
• Lymph node tuberculosis
• Pulmonary tuberculosis
• Severe recurrent bacterial pneumonia
• Acute necrotizing ulcerative gingivitis or periodontitis
• Unexplained anaemia (<8g/dl), neutropenia (<0.5 x 109/l) and/or chronic thrombocytopenia (<50 x 109/l)
• Symptomatic lymphoid interstitial pneumonitis, chronic HIV-associated lung disease, including bronchiectasis
Clinical stage 4c
• HIV wasting syndrome
• Pneumocystis (jiroveci) pneumonia
• Recurrent severe bacterial pneumonia
• Chronic herpes simplex infection (Oro-labial, genital or anorectal of more than 1 month’s duration or visceral at any site)
• Esophageal candidiasis (or candidiasis of trachea, bronchi or lungs)
• Extrapulmonary tuberculosis
• Kaposi sarcoma
• Cytomegalovirus infection (retinitis or infection of other organs)
• Central nervous system toxoplasmosis
• HIV encephalopathy
• Extrapulmonary cryptococcosis, including meningitis
• Disseminated nontuberculous mycobacterial infection
• Progressive, multifocal leukoencephalopathy
• Chronic cryptosporidiosis
• Chronic isosporiasis
• Disseminated mycosis (extrapulmonary histoplasmosis, coccidioidomycosis)
• Lymphoma (cerebral or B-cell non-Hodgkin)
• Symptomatic HIV-associated nephropathy or cardiomyopathy
• Recurrent septicemia (including nontyphoidal Salmonella)
• Invasive cervical carcinoma
• Atypical disseminated leishmaniasis
• Unexplained severe wasting, stunting or severe malnutritiond, not responding to standard therapy
• Pneumocystis (jiroveci) pneumonia
• Recurrent severe bacterial infections (such as empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia)
• Chronic herpes simplex infection (Oro-labial or cutaneous of more than 1 month’s duration or visceral at any site)
• Esophageal candidiasis (or candidiasis of trachea, bronchi or lungs)
• Extrapulmonary tuberculosis
• Kaposi sarcoma
• Cytomegalovirus infection (retinitis or infection of other organs with onset at age more than 1 month)
• Central nervous system toxoplasmosis (after the neonatal period)
• HIV encephalopathy
• Extrapulmonary cryptococcosis, including meningitis
• Disseminated nontuberculous mycobacterial infection
• Progressive, multifocal leukoencephalopathy
• Chronic cryptosporidiosis (with diarrhea)
• Chronic isosporiasis
• Disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidioidomycosis, penicilliosis)
• Cerebral or B-cell non-Hodgkin lymphoma
• HIV-associated nephropathy or cardiomyopathy
a In the development of this table, adolescents were defined as 15 years or older. For those aged less than 15 years, the clinical staging for children should be used.
b For children younger than 5 years, moderate malnutrition is defined as weight-for-height <-2 z-score or mid-upper arm circumference ≥ 115 mm to <125mm.
c Some additional specific conditions can be included in regional classifications, such as penicilliosis in Asia, HIV-associated rectovaginal fistula in southern Africa and reactivation of trypanosomiasis in Latin America.
d For children younger than 5 years of age, severe wasting is defined as weight-for-height <-3 z-score; stunting is defined as length-for-age/height-for-age <-2 z-score; and severe acute malnutrition is either weight for height <-3 z-score or mid-upper arm circumference <115 mm or the presence of edema.

Classification of oral lesions in HIV infection in adults

The first classification of oral lesions associated with HIV infection was given by the European Economic Community in 1986. The list contained 30 diseases which were commonly and less commonly associated with HIV infection. This classification was modified by Pindborg in 1989 17. In 1990, a set of definitions and diagnostic criteria for the common oral lesions seen in association with the HIV infection was proposed by a group of oral AIDS clinicians, epidemiologists, and pathologists 18. In august 1990, a revised classification was proposed based on the discussions during a 2-day EC-sponsored workshop held in Amsterdam 19. This revised classification proposed three groups of lesions, where Group I consisted of lesions strongly associated with HIV infection, Group 2 consisted of lesions less commonly associated with HIV infection and Group 3 was of those lesions only possibly associated with HIV infection. A fourth group was also defined which contained lesions associated with the use of drugs. Also, an attempt was made to clarify the clinical diagnostic criteria of the lesions and conditions listed in Group 1. This classification of the oral manifestations of HIV infections and their diagnostic criteria was again reviewed in 1992 (Table 29.3) 20. Further, a group of authors defined 3 groups of oral manifestations of AIDS based on the intensity and clinical features (Table 29.4) 21.

Table 29.3 Revised classification of oral lesions associated with HIV infection in adults

Lesions strongly associated with HIV infection
A. Candidiasis
• Erythematous
• Pseudomembranous
B. Hairy leukoplakia
C. Kaposi’s sarcoma
D. Non-Hodgkin’s lymphoma
E. Periodontal disease
• Linear gingival erythema
• Necrotizing (ulcerative) gingivitis
• Necrotizing (ulcerative) Periodontitis
GROUP IILesions less commonly associated with HIV infection
A. Bacterial infections
• Mycobacterium avium intracellulare
• Mycobacterium tuberculosis
B. Melanotic hyperpigmentation
C. Necrotizing (ulcerative) stomatitis
D. Salivary gland disease
• Dry mouth due to decreased salivary flow rate
• Unilateral or Bilateral swelling of major salivary glands
E. Thrombocytopenic purpura
F. Ulceration NOS (not otherwise specific)
G. Viral infections
• Herpes simplex virus
• Human papillomavirus (warty-like lesions)
• Condyloma acuminatum
• Focal epithelial hyperplasia
• Verruca vulgaris
• Varicella-Zoster virus
• Herpes zoster
• Varicella
GROUP IIILesions seen in HIV infection
A. Bacterial infection
• Actinomyces israelii
• Escherichia coli
• Klebsiella pneumoniae
B. Cat scratch disease
C. Drug reactions (Ulceration, Erythema multiforme, Lichenoid reaction, Toxic epidermolysis)
D. Fungal infections other than candidiasis
• Cryptococcus neoformans
• Geotrichum candidum
• Histoplasma capsulatum
• Mucoraceae (Mucormycosis/Zygomycosis)
• Aspergillus flavus
E. Neurologic disturbances
• Facial palsy
• Trigeminal neuralgia
F. Recurrent aphthous stomatitis
G. Viral infections
• Cytomegalovirus
• Molluscum contagiosum

Table 29.4 Classification of oral lesions associated with HIV infection based on intensity and features.

Seven cardinal lesions that are strongly associated with HIV infection
Oral candidosis
Hairy leukoplakia
Kaposi sarcoma
Linear gingival erythema,
Necrotizing ulcerative gingivitis
Necrotizing ulcerative periodontitis
Non-Hodgkin lymphoma
GROUP IIAtypical Ulcers
Salivary glands diseases
Viral infection such as cytomegalovírus (CMV), herpes simplex virus (HSV), papillomavirus (HPV), and herpes zoster virus (HZV).
GROUP IIILesion rarer than those in groups 1 and 2
Diffuse osteomyelitis
Squamous cell carcinoma

Classification of oral lesions in HIV-infected pediatric patients

According to World Health Organization (WHO), 2 million children had been infected with HIV worldwide by June, 1998. It represented 7% of the total estimated infected population of almost 30 million. In pediatric patients, the orofacial manifestations are among the earliest and commonest manifestations of HIV disease. The guidelines for the diagnosis and management of HIV-related oral diseases in children were developed by the collaborative work group on the oral manifestations of pediatric HIV infection in March 1994 and May 1995. The framework was adapted from the classification system of the European Collaborative Clearing house on oral problems related to HIV infection and the WHO collaborating center on oral manifestations of the HIV (Table 29.5) 22.

Table 5 Orofacial lesions associated with pediatric HIV infection

Group I
Lesions commonly associated with pediatric HIV infection
A. Candidiasis
• Pseudomembranous
• Erythematous
• Angular cheilitis
B. Herpes simplex virus infection
C. Linear gingival erythema
D. Parotid enlargement
E. Recurrent aphthous ulcers
• Minor
• Major
• Herpetiform
GROUP IILesions less commonly associated with pediatric HIV infection
A. Bacterial infections of oral tissues
B. Periodontal diseases
• Necrotizing (ulcerative) gingivitis
• Necrotizing (ulcerative) stomatitis
• Necrotizing stomatitis
C. Seborrheic dermatitis
D. Viral infections
• Cytomegalovirus
• Human papillomavirus
• Molluscum contagiosum
• Varicella-Zoster virus
i. Herpes zoster
ii. Varicella
E. Xerostomia
Group IIILesions strongly associated with HIV infection but rare in children
A. Neoplasms
• Kaposi’s sarcoma
• Non-Hodgkin’s lymphoma
B. Oral hairy leukoplakia
C. Tuberculosis-related ulcers

Anti-retroviral therapy

The anti-retroviral therapy (ART) has evolved tremendously since the introduction of zidovudine (AZT) which was approved by the US FDA in 1987 23. Zidovudine (AZT) is a nucleoside reverse transcriptase inhibitor (NRTI). Subsequently, more NRTI drugs were introduced but even in combination, they were not able to suppress the virus for long periods of time and patients still inevitably died 24. With extensive research on anti-retroviral drugs, highly active anti-retroviral therapy (HAART) was introduced. HAART involves a combination of multiple antiretroviral drugs. The treatment with HAART for HIV-infected patients was published by Hammer et al. (1997) 25 and Gulick et al. (1997) 26. The new therapy combining 2 NRTIs with a new class of anti-retrovirals, protease inhibitors, namely indinavir. This treatment resulted in impressive benefit with a 60-80% reduction in AIDS rate, death, and hospitalization. Presently, six classes of antiretroviral agents are used for the treatment of HIV-infected patients,

  • Nucleoside analog reverse transcriptase inhibitors (NRTIs):e.g. Lamivudine, Didanosine, Abacavir, Emtricitabine, Zidovudine, Stavudine, and Tenofovir.
  • Non-nucleoside analog reverse transcriptase inhibitors (NNRTIs): e.g. Efavirenz, Delavirdine, Etravirine, and Nevirapine.
  • Protease inhibitors (PIs): e.g. Atazanavir, Darunavir, Saquinavir, Indinavir, Nelfinavir, and Ritonavir.
  • Integrase inhibitors (IIs): e.g. Dolutegravir and Raltegravir.
  • Fusion inhibitors (FIs): e.g. Enfuvirtide and Maraviroc.
  • Chemokine receptor antagonists (CCR5 antagonists): e.g. Aplaviroc, Vicriviroc, and Maraviroc

Table 29.6 Oral and facial adverse effects of anti-retroviral drugs

Class of drug
Oral side effect
Nucleoside analog reverse transcriptase inhibitorsXerostomia

Protease inhibitors

Nucleoside analog reverse transcriptase inhibitors

Erythema multiforme

Non-nucleoside analog reverse transcriptase inhibitors
IndinavirProtease inhibitorCheilitis
Protease inhibitorTaste disturbances
ZidovudineNucleoside analog reverse transcriptase inhibitorHyperpigmentation
StavudineNucleoside analog reverse transcriptase inhibitorsLipodystrophy
Protease inhibitor

Protease inhibitor

Parotid lipomatosis

Nucleoside analog reverse transcriptase inhibitor

Oral Ulcers
EnfuvirtideFusion inhibitorLip enlargement
RitonavirProtease inhibitorFacial edema
Protease inhibitorsPerioral paresthesia

Inspite of the introduction of HAART, which results in a marked rise in helper T-cells and a reduction in viral load to a point below the level of detection, the individual is still considered to be infected with HIV, because the virus remains sequestered somewhere in the body and becomes detectable in blood if medications are discontinued or if the virus becomes drug-resistant 27-30.

When to start ART?

Early detection and treatment of HIV has a great impact on improving survival and reducing the incidence of HIV infection at the community level. The HIV virus cannot be completely eradicated from the body with current medications, so the goals of ART include prolongation of life and improvement in the quality of life, greatest possible reduction in viral load for as long as possible, immune reconstitution that is both quantitative and qualitative, rational sequencing of drugs and reduction of HIV transmission by suppression of viral load. The WHO working group recommendations on when to start ART in adults, adolescents, pregnant and breastfeeding women and children are given in Table 29.7.

Table 29.7 Summary of recommendations on when to start ART in adults, adolescents, pregnant and breastfeeding women and children 31

Children 1–5 years Old aInitiate ART in all, regardless of WHO clinical stage and CD4 cell count
Children ≥5 years oldInitiate ART if CD4 cell count ≤500 cells/mm3
• Initiate ART in all children with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 counts ≤350 cells/mm3
Initiate ART regardless of CD4 cell count
• WHO clinical stage 3 or 4
• Active TB disease
Adults and adolescents (≥10 years)Initiate ART if CD4 cell count ≤500 cells/mm3
• As a priority, initiate ART in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 counts ≤350 cells/mm3
Initiate ART regardless of WHO clinical stage and CD4 cell count in
• Active TB disease
• HBV coinfection with severe chronic liver disease
• Pregnant and breastfeeding women with HIV
• HIV-positive individual in a serodiscordant partnership (to reduce HIV transmission risk)
a: Initiate ART in all HIV-infected children below 18 months of age with a presumptive clinical diagnosis of HIV infection.

Oral and periodontal manifestations of HIV infection

The oral manifestations of HIV infection are important components of AIDS…..


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Fungal infections:

The fungal infections are commonly seen in immunocompromised patients, especially suffering from AIDS. The most common fungal infection of the oral cavity in AIDS patients is Candidiasis. Other less common fungal infections include Histoplasmosis, Cryptococcosis, Coccidioidomycosis and Liner gingival erythema.


The oropharyngeal candidiasis is the most common fungal infection seen in AIDS patients 37, 38. Candida albicans is the predominant causative agent of all forms of mucocutaneous candidiasis. Other Candidal species which may be associated with candidiasis are C. glabrata, C. parapsilosis, C. tropicalis and C. krusei. The presence of oral candidiasis is significantly associated with lower CD4 : CD8 ratio and a reduced CD4 cell count below 200 cells/mm3 (39, 40). The oral candidiasis is frequently seen in three different forms: erythematous candidiasis, pseudomembranous candidiasis, and angular cheilitis. In patients with full-blown AIDS, the pseudomembranous form of candidiasis is most common, while erythematous candidiasis is more predominant in patients with HIV infection 39, 42. The erythematous candidiasis is one of the most commonly misdiagnosed oral manifestations of AIDS. Clinically, it appears as a red, flat, subtle lesion either on the dorsal surface of the tongue and/or the hard/soft palates.  The pseudomembranous candidiasis is characterized by creamy white curd-like plaques on the buccal mucosa, tongue, and other oral mucosal surfaces that can be wiped away, leaving a red or bleeding underlying surface. Another form of candidiasis, hyperplastic candidiasis is differentiated from the pseudomembranous candidiasis by the clinical feature that the white plaques cannot be removed by scraping and is common on the buccal mucosa. Pseudomembranous candidiasis should be differentiated from oral hairy leukoplakia, which is usually located at the sides of the tongue and cannot be scraped off. The angular cheilitis is characterized by cracking, peeling, or ulceration involving the corners of the mouth. This form of candidiasis is commonly present with other forms of candidiasis. The patient is more likely to be symptomatic with complaints of burning pain while eating spicy foods or drinking acidic beverages.


The diagnosis of candidiasis is made by exfoliative cytology by utilizing 10% potassium hydroxide (KOH) slide preparation of a scraping from an active lesion and/or periodic acid-Schiff / Papanicolaou-stained preparations which demonstrate fungal pseudohyphae. A positive exfoliative cytology is most commonly seen with a smear of pseudomembranous candidiasis 43. Culture is not routinely indicated, but if performed, it identifies the Candida species and helps to predict resistance. It also helps in determining the drug resistance in case of recurrent and refractory infections.


In mild to moderate cases of both erythematous and pseudomembranous candidiasis, topical agents including clotrimazole troches, nystatin oral suspension, and nystatin pastilles are used. It should be remembered that regular nystatin oral suspension contains 50% sucrose, which is cariogenic. On the other hand, clotrimazole oral treatment is formulated with fructose, which is less cariogenic.

In severe cases, systemic anti-fungal therapy is given. Most widely used systemic anti-fungal drug is fluconazole. Other drugs are itraconazole and voriconazole. Voriconazole is given in cases of resistance to fluconazole (Table 29.8). The golden rule to be remembered while giving local or systemic anti-fungal therapy is that therapy must be continued for at least 2 weeks in order to reduce organism colony-forming units to the levels low enough to prevent recurrence 44.

Table 29.8 Anti-fungal therapy for HIV/AIDS patients with candidiasis

Topical agents (mild to moderate candidiasis)
Clotrimazole troches10 mg
One troche to be dissolved in mouth 5 times a day for two weeks
Nystatin oral suspension500,000 units
5 ml to be swished in the mouth for as long as possible and then swallowed 4 times a day for two weeks
Nystatin pastilles100,000 units
1 pastille to be dissolved in mouth 4 times a day for two weeks
Systemic agent (moderate to severe candidiasis)
Fluconazole100 mg
Two tablets to be taken on day one followed by a single tablet per day for a period of two weeks
Itraconazole oral suspension 10 mg/10 ml
To be swished in the mouth and swallowed, 10 ml/day for two weeks. To be taken without food.
Voriconazole200 mg
One tablet to be taken twice daily for two weeks or at least 7 days following resolution of the symptoms

The introduction of ‘azoles’, most importantly fluconazole has led to increased incidences of periodic acid Schiff Candida albicans as well as the emergence of non-albicans species such as Candida glabrata, which are inherently resistant to this class of drug 45. Other factors which are associated with the development of azole-resistant strains of Candida include previous exposure to azoles, low CD4 count and the presence of non-albicans species 46, 47. To avoid resistance, systemic therapy of anti-fungal agents should be reserved for the severe cases only and mild to moderate cases should be treated with topical application of these agents.

Refractory Candidiasis:

Refractory candidiasis refers to candidiasis which fails to respond to antifungal treatment with appropriate doses for a standard duration of time 48. The most clinically significant refractory candidiasis is fluconazole-refractory disease which is associated with significant morbidity. The factors associated with refractory candidiasis are advanced HIV disease (CD4 lymphocyte counts <50 cells/µL) and previous exposure to chronic antifungal therapy 48. The treatment of refractory candidiasis is often difficult, especially when the patient becomes unresponsive to the treatment over a period of time. In the management of an unresponsive case, the most important step is to identify the drugs that have already been tried on the patient with their dosage, whether with that dosage the condition was resolved or increasing the dosage was required to resolve the condition. Generally, patients who are not responsive to clotrimazole, nystatin, ketoconazole, or itraconazole tablets, respond to fluconazole. Patients who are not responsive to fluconazole may or may not respond to its higher dosage. Flucytosine may be added with fluconazole in these patients.


Histoplasmosis is caused by inhalation of H. capsulatum microconidia into the lungs. After inhalation, the microconidia rapidly convert to the yeast phase within the lung parenchyma. In patients with an appropriate cell-mediated response, the infection remains focused with either caseating or noncaseating granuloma formation. In patients with a defective cell-mediated response and in HIV-infected individuals, particularly those with lower CD4 counts, the infection spreads widely in the body. Within next two to three weeks the infection spreads throughout the reticuloendothelial system. It has been proposed that in an attempt to clear the infection, macrophages phagocytose the yeast and carry them to regional lymph nodes 49.

Oral manifestations:

Oral lesions are rarely seen in histoplasmosis and are more frequent with disseminated histoplasmosis. Goodwin et al. (1980) 50 have shown that up to two third of patients with chronic disseminated histoplasmosis have oropharyngeal involvement. The most commonly affected areas are buccal mucosa, tongue, palate, gingiva, and lips 51-54. It has also been reported that patients with initial oropharyngeal involvement, subsequently developed disseminated disease. Hence, periodic re-evaluation is required to rule out any systemic involvement 52. Oral lesions may manifest in different forms such as papular, ulcerative, nodular, vegetative, furunculoid, granulomatous, or plaque-like lesions. The most commonly seen lesions are in the form of shallow or deeply infiltrated ulcerations with a pseudomembrane 51, 55, 56.


The diagnosis of histoplasmosis is based on clinical findings, histopathology, cultures, serologic test, including complement fixation test, immunodiffusion, and histoplasmin skin test. A positive culture provides the strongest evidence for the disease, but the culture is mostly positive in chronic disease rather than after the initial infection. In HIV-infected patients, the serological tests are of limited significance due to less production of antibodies. In these patients, direct immunofluorescence is the test of choice for diagnosis 57.


In immunocompetent patients, the disease is self-limiting 53. In HIV-infected patients with disseminated histoplasmosis, the mortality rate is high. Many of these patients are those who have never received ART before the diagnosis with histoplasmosis 58-60. The prophylactic treatment should be given to those patients who have advanced HIV infection and who live in areas where histoplasmosis is highly endemic 61. A prophylactic dose of itraconazole, 200 mg daily can be considered for patients with CD4 counts <150 cells/mm3. The prophylactic treatment can be stopped if the CD4 counts remain >150 cells/mm3 for 6 months. The treatment of the disease involves administration of IV liposomal amphotericin B (3 mg/kg daily) for at least 2 weeks or until the patient clinically improves. In the case of less severe disease, oral itraconazole, 200 mg 3 times daily for 3 days followed by 200 mg twice daily. The discontinuation of the therapy should be based on the monitoring of serum or urine for histoplasma antigen and CD4 counts of the patient. A rise in the antigen level suggests relapse. In such a case, the patient should be re-considered for treatment and the drugs of choice are liposomal amphotericin B, oral posaconazole, voriconazole and fluconazole 62-66.


In HIV-infected patients, this disease is most commonly caused by Cryptococcus neoformans, but occasionally by Cryptococcus gattii. The presence of C. neoformans is worldwide whereas C. gattii is commonly found in Australia and similar subtropical regions and in the Pacific Northwest. C. neoformans is encapsulated round-to-oval yeast. It is surrounded by a polysaccharide capsule ranging in size from 1 to >30 microns, when cultivated in the laboratory 67. It has been proposed that this fungal infection occurs via inhalation of the basidiospores or unencapsulated forms, leading to colonization in the airways and subsequent respiratory infection 68, 69. The absence of an intact cell-mediated response in patients with severe HIV infection results in systemic dissemination and increased cryptococcal burden. Following systemic dissemination, the disease may involve any organ of the body. Cryptococcosis in patients with severe HIV infection commonly manifests as subacute meningitis or meningoencephalitis with fever, malaise, and headache 70. The pulmonary cryptococcosis may clinically manifest as acute respiratory distress syndrome, mimicking pneumocystis pneumonia.

Oral manifestations:

The oral cavity is rarely involved in cryptococcosis and only a few case reports are available in the literature so far 71, 72. The lesion clinically appears as ulceration in the oral mucosa, but a definitive diagnosis cannot be made depending on the clinical appearance of the lesion, since microbial infections and trauma may have a similar clinical appearance. Definitive diagnosis is made by taking a biopsy of the lesion and its examination.


The diagnosis of cryptococcosis is made by blood/CSF (cerebrospinal fluid) culture, CSF microscopy with India ink staining, or cryptococcal antigen (CrAg) detection. In HIV-positive patients having a cryptococcal infection, the blood cultures are positive in approximately 55% of all blood cultures and the CSF cultures are positive in approximately 95% of all CSF cultures. Within 7 days, visible colonies can be seen in the culture.


The drugs of choice for the treatment of cryptococcosis are amphotericin B, flucytosine, and fluconazole.


Two fungal species implicated in causing coccidioidomycosis are Coccidioides immitis and Coccidioides posadasii. These fungi grow as a mold in the soil and develop hyphae in their saprobic form, producing arthroconidia. The inhalation of these arthroconidia leads to the infection in both humans and animals. In immunocompetent patients, this pulmonary infection is self-limiting but in immunocompromised patients such as in HIV infection, the disease may present as a fulminant, disseminated infection.

Oral manifestations:

The oral lesions are rarely present in this disease. The lesion may be ulcerative or nodular, commonly involving tongue and buccal mucosa. The ulcers are often deep with indurated borders and may mimic carcinoma.


The diagnosis of this condition is made on the basis of microscopic examination of the involved tissue, culture, serologic test and a coccidioidal skin test conversion from negative to positive after the onset of clinical signs and symptoms 73. The microscopic examination of the involved tissue by using hematoxylin-eosin staining or silver staining reveals fungal spherules. Detection of IgM and IgG antibodies in serum or CSF are diagnostic of the disease.


Amphotericin B has been used traditionally for the treatment of coccidioidomycosis. Once the acute symptoms of the disease subside, lifelong suppressive therapy with ketoconazole (400 mg/day orally) or fluconazole (400-600 mg/day orally) must be instituted in immunosuppressed patients to prevent relapses.

Linear gingival erythema (LGE):

LGE is also referred to as “red band gingivitis”. The LGE is limited to the soft tissue of the periodontium and clinically appears as an erythematous linear band that extends approximately 2 mm to 3 mm from the free gingival margin. The area with the red band may or may not be associated with bleeding or discomfort. The anterior teeth are most commonly associated with this condition, but it may extend to posterior teeth also. The disease may also appear as a diffused erythematous zone from the gingival margin into the vestibule. The LGE is not significantly associated with dental plaque. Bleeding is usually present after gentle probing. It has been demonstrated that there may be a relationship between LGE and presence of subgingival colonization of Candida species in patients with HIV infection 74. The latest classification of periodontal diseases by the American Academy of Periodontology has also grouped this condition under “gingival disease of fungal origin” 75.


The treatment includes professional oral prophylaxis and improved maintenance of at home oral hygiene. Twice-daily rinse with 0.12% chlorhexidine gluconate suspension for 2 weeks is recommended in these patients.

Gingival and Periodontal Diseases:


The development of periodontitis is a result of host-microbial interaction resulting in the destruction of periodontal supporting structures. In HIV infection the host immune system is……..123


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The second aspect of periodontitis in HIV-positive patients is the immune response and the question addressed is regarding any significant difference in the immune response against periodontopathogens in HIV-infected patients as compared to uninfected individuals. It has been well established that most of the connective tissue destruction in periodontitis is caused by host response 92, 93. In HIV-positive patients, higher levels of pro-inflammatory mediators have been detected in GCF and their levels in GCF have been suggested as prognostic factors for the progression of tissue destruction in these patients. Studies have reported significantly increased levels of interferon-γ 94, prostaglandin E2 (PGE2) 95 and matrix metalloproteinase -1 (MMP-1) in HIV-positive patients.

Necrotizing ulcerative gingivitis and periodontitis:

The necrotizing ulcerative gingivitis (NUG) is a non-contagious infection of the gingiva characterized by gingival necrosis, bleeding, and pain (Figure 29.2). Acute necrotizing ulcerative gingivitis (ANUG) is the acute presentation of NUG, which is the usual course the disease takes. Necrotizing ulcerative periodontitis (NUP) may be an extension of NUG into the periodontal structures resulting in attachment loss. However, many authors suggest that NUG and NUP may be different diseases. The primary pathogens for this disease are anaerobic bacteria such as P. intermedia and Fusobacterium as well as spirochetes, such as Treponema. Along with this fungal species have also been isolated from ANUG/ANUP lesions.

The characteristic feature of the disease is ulceration of the interdental papillae which rapidly progresses to the destruction of underlying alveolar bone. There is spontaneous bleeding from the lesion and it is associated with severe pain. In highly immunocompromised patients, extensive destruction of tissue is seen which involves exfoliation of teeth within 3-6 months of disease onset, with the sequestration of necrotic alveolar bone and necrotic involvement of the adjacent mandible and maxilla. A detailed description of the management of ANUG/ANUP patients has been given in chapter 27 “Acute gingival and periodontal conditions”.

Viral infections

Herpes Simplex:

The etiological agent of herpes simplex is herpes simplex virus (HSV) which belongs to herpesviridae family. The herpesviridae family consists of viruses responsible for various diseases in humans. There are eight known human herpesviruses (HHV). The viruses in the herpesviridae family have been divided into α, β, and γ herpesvirinae subfamilies on the basis of their biological properties including host range, replication cycle and cell tropism 96. The herpes simplex viruses (HSV)-1 and -2 (HHV-1 and HHV- 2), and varicella-zoster virus (VZV; HHV-3) belong to α subfamily. Cytomegalovirus (CMV; HHV-5), HHV-6 variants A and B, and HHV-7 belong to β subfamily. Epstein-Barr virus (EBV; HHV-4) and Kaposi sarcoma-associated herpesvirus (KSHV; HHV-8) belong to γ subfamily. Strikingly the members of c-herpesvirinae are strongly associated with neoplastic disease. EBV has been found to be associated with Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, T and natural killer cell lymphoma, and post-transplant lymphoma 97-100.

The HSV-1 infection is acquired in the childhood and is responsible for orolabial ulcers.  HSV-2 causes anogenital ulcers and is transmitted sexually. However, HSV-2 associated oral lesions and HSV-1 associated genital lesions are also seen which are caused due to orogenital sexual practice. Once infected, the individual harbors the infection throughout the life because the virus becomes permanently latent in the nerve root ganglia corresponding to the site of inoculation of the virus (the trigeminal ganglia for orolabial infection and the sacral ganglia for genital infection). A detailed description of HSV-induced oral ulcers is available in “Acute gingival and periodontal conditions”.

Many recent studies have suggested that genital HSV-2 is facilitating the acquisition of HIV-1 infection.  In a meta-analysis, it was concluded that HSV-2 infection increases the risk of HIV-1 acquisition approximately 3-fold in both men and women and individuals with primary HSV infection are even more susceptible to HIV-1 infection 101.

Clinical manifestations of HSV in HIV-infected patients:

The HSV reactivation among the HIV-1-infected individuals clinically presents with vesicular and ulcerative lesions of the oral and anogenital areas which are similar to as seen in HIV-1-uninfected individuals. The anogenital lesions in HSV reactivation may often remain unrecognized because early lesions are small and may manifest as hypersensitive erythematous papules in the case of perianal internal lesions in women, which are difficult to visualize. The declined CD4 count is significantly associated with increased frequency of genital ulcers 102. Severe and frequent recurrent oral or genital herpes ulcers cause significant morbidity to the patient. It must be noted that the frequent atypical presentations of genital HSV may often lead to an inaccurate diagnosis. The gold standard for diagnosis of HSV infection is polymerase chain reaction (PCR) testing of samples taken from mucocutaneous lesions 103.


The anti-viral agents recommended in HSV infection include nucleoside analogs such as acyclovir, valacyclovir, and famciclovir. These agents inhibit HSV-1 and HSV-2 replication through specific inhibition of a virally encoded thymidine kinase.

Varicella Zoster:

Varicella-zoster virus (VZV) belongs to the herpesvirus family. Like other herpesviruses, VZV has the capacity to persist in the body after the primary (first) infection as a latent infection. VZV persists in sensory nerve ganglia. Its primary infection causes chickenpox in children and reactivation results in herpes zoster (shingles). The clinical presentation of varicella in children infected with HIV is usually similar to that seen in immunocompetent children. However, the duration of the lesions formation is longer and resolution is delayed in HIV-positive patients 104-106. Also, the reactivation of the infection is more common in HIV infected immunocompromised individuals as compared to healthy immunocompetent individuals. The most common complication in immunocompromised individuals with varicella is cutaneous bacterial super-infections 107.

In HIV-infected adults, the chances of herpes zoster are much more as compared to non-infected individuals. It has been reported that the incidence rate of herpes zoster among HIV-infected patients is 30-50 cases per 1000 persons/years 108-110. The usual presentation of herpes zoster among HIV-infected patients is similar to that of uninfected individuals with one sticking difference which is a higher frequency of shingles recurrences. It has been reported that around 20%-30% of HIV-infected patients develop one or more subsequent episodes of herpes zoster which may involve same or different dermatomes 108, 110. Further, these patients frequently manifest atypical cutaneous lesions which are usually in the form of multiple hyperkeratotic papules (3–20 mm in diameter) which follow no dermatomal pattern 111, 112. In severely immunocompromised patients the systemic dissemination of VZV may result in VZV pneumonia, encephalitis, and hepatitis. However, with the use of HAART, the mortality associated with disseminated zoster has been substantially reduced 113, 114.

Oral lesions:

Intra-oral vesicles of varicella, when present, are seen on the tongue, buccal mucosa, gingiva, palate, and oropharynx. They generally are not very painful. After resolution of the condition, the virus becomes latent in the sensory ganglia. Reactivation of the virus is characterized by pain and tenderness in the dermatome, corresponding to the affected sensory ganglion. The facial and oral presentation of the disease is characterized by the formation of vesicles on the side of the face or in the oral mucosa in one of the divisions of the trigeminal nerve. These painful vesicles end abruptly in the midline. The vesicles ulcerate within three to four days and form pustules. Healing takes place within 7-10 days with scar formation with hypo/hyperpigmentation areas.

Know more…………Ramsay-Hunt syndrome:

When there is involvement of facial and auditory nerve via geniculate ganglion, facial paralysis, vesicles on the external ear, tinnitus and deafness may occur. This condition is known as Ramsay-Hunt syndrome. More than half the patients have pain as their first symptom while as few as 2% have a rash as the initial symptom 115. Treatment of the condition involves administration of anti-viral drugs and corticosteroids.




The primary drugs used for the treatment of VZV infection is acyclovir (800 mg, administered 4 times per day). Preferably, treatment should begin as soon as possible (within 72 hours of onset of skin rash) and continued for at least 7 days or until all lesions have dried and crusted. In the case of disseminated VZV infection, intravenous administration of acyclovir is recommended.

Human Papillomavirus (HPV):

Human papillomavirus (HPV) is one of the most common agents of sexually transmitted diseases worldwide 116. More than 50 strains of HPV exist. The most common genotypes found in the mouth of patients with HIV infection are 2, 6, 11, 13, 16 and 32. Studies have found an increased prevalence of HPV in individuals who are also HIV-infected 117. It has been demonstrated the in immunocompetent individuals, abnormalities such as papillomas associated with HPV are uncommon. However, in HIV-infected immunocompromised patients, oral mucosal abnormalities such as papillomas are more common 118. The HPV infection is primarily associated with males, HSV-2 seropositivity, older age in HIV-seronegative individuals and oral-genital contact 119. A positive association has been found between HPV infection and a subset of oral squamous cell carcinoma (OSCC), especially those arising from the base of the tongue and tonsils 120.

Cytomegalovirus (CMV):

CMV is usually an uncommon cause of intraoral ulceration in patients with HIV disease. It must be noted that intraoral ulcerations with CMV are indicative of systemic dissemination of CMV infection 121. The early diagnosis of CMV infection is important because of the serious consequences of systemic involvement such as retinitis and meningitis. In around 90% of the patients who die because of AIDS, CMV has been detected in one or more organ systems 122. In the oral cavity, CMV may be present as a single large necrotic painful ulcer and less often as multiple ulcers, present for weeks or months and any site may be involved 123. The most common sites involved are buccal and labial mucosa. Often the ulcerations are indistinguishable from the non-specific ulceration caused due to chronic HSV and major aphthous ulceration. It has been suggested by some authors that CMV oral lesions in HIV-infected patients may be the initial manifestation of AIDS 124-127. The drug of choice for the treatment of CMV infection is gancyclovir.

Oral hairy Leukoplakia (OHL):

OHL is an Epstein-Barr virus (EBV)-associated disease which is almost exclusively seen in people with immunosuppression, particularly in HIV-infected individuals. The disease was first observed in 1981 and reported in 1984 as a common, benign, asymptomatic, white, non-removable lesion of the lateral borders of the tongue in patients with HIV infection 128. The lesions cannot be rubbed off and are mostly symptomless. It occurs in up to 50% of the patients with untreated HIV, particularly those with CD4 count less than 0.3 × 109/L 129.

Clinical features:

OHL lesions are often bilateral or sometimes unilateral, white or gray patches which cannot be rubbed off, present mainly on the lateral lingual margins and sometimes on the dorsum or ventrum of the tongue. The term ‘hairy’ used to describe this leukoplakia signifies corrugated appearance or projections (hairy projections) on the surface of white patches. Lesions on the inferior surface of the tongue are flat. Most commonly the lesions are asymptomatic but in some cases, patient complains of burning sensation 130.


Although exact etiopathogenesis of OHL still needs to be elucidated, EBV infection facilitated by immunodeficiency in HIV-infected patients has been suggested to be the primary etiology of this disease. EBV is acquired by over 90% of the world population during childhood/adolescence. Following infection, the infected individual remains a carrier for a lifetime. The virus is shed in saliva. It has been proposed that infection of superficial epithelial cells by EBV in saliva and productive EBV replication, converge to produce OHL 131. In immunocompetent patients, the virus is unable to replicate in tongue epithelial cells 132.

Evidence for the involvement of EBV in the etiopathogenesis of OHL comes from immunohistochemical 133, 134 analysis and EBV-DNA identification using molecular techniques such as Southern blotting and in situ hybridization (ISH) 134-137, which have demonstrated EBV antigens in the tissue sections. Studies have demonstrated herpes virus particles in the intercellular spaces using negative staining electron microscopy on thin tissue sections 128, 135, 138, 139. The transcripts expressed from the EBV BHLF1 and BCRF1 genes, which in cultured lymphoid cells are associated with the lytic replication cycle, have also been demonstrated indicating active viral replication 140. Further, it has been demonstrated that……


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Another possible etiological agent is Candida. Around 43% to 80% of the OHL lesions have demonstrated candidal hyphae 136, 138, 143. However, aggressive antifungal therapy to completely eliminate the fungal infection has failed to resolve the condition 128. The human papilloma virus was also implicated as an etiological factor in the pathogenesis of OHL. However, this association was not supported by various studies which used electron microscopy 135, 138, immunostaining, and DNA hybridization 135.


Microscopic examination demonstrates ballooning degeneration of the keratocytes of the upper stratum spinosum, hyperkeratosis, and mild or absent subepithelial inflammation. Keratinized ‘‘hair-like’’ projections can be seen. Koilocytosis with pyknotic nuclei and perinuclear halos in the prickle cell layer are visible. Intranuclear inclusions can be seen. Frequently, Candidal hyphae and leukocytes surrounding the hyphae can be seen in the histological section 133, 143.


Whenever a patient with clinical finding of OHL comes to the clinician, it is mandatory to go for the evaluation of the immune status of the patient. If the immunosuppression is diagnosed, further investigations should be done to find out the underlying cause of immunosuppression. Provisional diagnosis can be made, based on clinical findings. If the clinical features of the lesion are vague, then the histopathological examination is recommended. However, the histological examination is not definitive because koilocytotic changes are not specific to OHL 144 and corrugated histological pattern with mild parakeratosis and keratin projections can be seen in normal lateral borders of the tongue 145.

Definitive diagnosis of the OHL is made by the detection of replicating EBV in tissue. In most instances in situ hybridization of biopsy specimens with the use of EBV-specific DNA probes to detect EBV antigens is adequate. The findings from exfoliative cytology demonstrate nuclear beading in the vacuolated or ballooned squames which indicate viral replication. The exact diagnosis requires ultrastructural examination of the EBV 139, 146. However, clinically the requirement of a definitive diagnosis of OHL in the management of HIV-infected patients is rare.


Treatment of the OHL is seldom required because the lesion is usually asymptomatic, has not been shown to undergo any malignant transformation 147 and may resolve spontaneously 128. In HIV-infected patients on HAART, the lesion usually resolves spontaneously. Application of topical retinoids (e.g., 0.1% vitamin A) has been shown to improve the appearance of OHL-affected oral surfaces 148.  Other treatments include topical podophyllin application 149, surgical excision 150 and cryotherapy 151, but none prevents the recurrence of the lesion after therapy. Antifungal therapy may reduce the extent of the lesion but does not eradicate the infection.

Kaposi’s Sarcoma (KS):

It is the most common malignancy associated with HIV infection. It is a malignant, multifocal systemic disease that originates from the vascular endothelium and has a variable clinical course. This malignancy was first described by Moritz Kaposi, a Hungarian dermatologist in 1872. Human herpesvirus 8 (HHV-8) is a crucial factor in disease pathogenesis, however, the exact mechanism of disease pathogenesis has not been elucidated 152. Skin is most commonly involved in KS. Other than skin, mucous membranes, lymphatic system, and viscera, in particular, the lung and gastrointestinal tract may also be involved in this disease. Studies have demonstrated that the incidence of KS is much higher in homosexual and bisexual men who are infected with HIV as compared to patients who acquired HIV infection parenterally or through transfusion products or intravenous drug use 153.

Pathogenesis of KS:

A lot of research has been done to understand the pathogenesis of KS and its association with HIV infection. From the present evidence, it is clear that proliferating KS spindle tumor cells are of endothelial origin. The circulating blood mononuclear and endothelial ‘‘progenitor cells’’ are believed to be the source of early KS lesions 154. Two well-accepted concepts of the pathogenesis of KS are altered cytokine expression and associated herpesvirus with KS.

Altered cytokine expression:

In HIV infection, there is a loss or impairment of CD4 cell function 155. As a result, there is an altered expression of cytokine including interleukin-1, tumor necrosis factor-α, and interleukin-6 156. In HIV-infected patient, these cytokines in blood have been shown to induce vascular endothelial cells to assume the characteristic spindle shape 157. Also, it has been demonstrated in various in vitro studies that these cytokines are associated with increased expression of a number of angiogenic growth factors (eg, basic fibroblast growth factor). Finally, the transactivating protein, HIV Tat, which is derived from HIV virus in HIV-infected patient, synergistically in combination with basic fibroblast growth factor, results in the induction and proliferation of cells derived from KS 158. Other mitogens which have been proposed to be associated with the pathogenesis of KS include oncostatin M, interleukin-6, and scatter factor. Further, the integrin expression and process of apoptosis during cellular proliferation and neovascularization have also been considered as important factors in the pathogenesis of KS 158.

Association of Herpesvirus 8 with KS:

Kaposi’s sarcoma-associated herpesvirus (KSHV; HHV-8) which belongs to γ subfamily of herpesviridae family has been found to be associated with various human cancers, including Kaposi sarcoma (KS) 159, 160, primary effusion lymphoma (PEL) 161, and the plasmablastic variant of multicentric Castleman disease (MCD) 162, 163.

There is strong evidence that KS is linked with the sexually transmitted virus, human herpesvirus 8 (KSHV). This association was first reported by Chang et al. (1994)159 who found that more than 90% of HIV-KS tissue samples were positive for herpesvirus-like DNA sequences. The polymerase chain reaction analysis have demonstrated the presence of KSHV genomic DNA in the lesions, semen, and peripheral blood of patients with KS 164.

Clinical presentation:

The skin lesion of KS clinically appears as red, blue, or purplish lesions that are flat or nodular, and solitary or multiple (Figure 29.3). There are multiple clinicopathologic forms of skin associated KS (Figure 29.4) which include patch, plaque, nodular, lymphadenopathic,  infiltrative, florid, telangiectatic,  ecchymotic, keloidal, angiomatous etc. The most common oral site of the lesion is hard palate, but it can also occur on the gingival surfaces and elsewhere in the mouth. The lesion may get easily injured by chewing, resulting in bleeding, which may interfere with eating or speaking. Clinically, KS should be differentiated from other entities, including pyogenic granuloma, hemangioma, bacillary angiomatosis, and gingival enlargement caused by cyclosporine and other drugs.

Figure 29.3 Fully developed Kaposi’s Sarcoma on palate of a HIV positive patient

Kaposi's Sarcoma in HIV positive patient


The definitive diagnosis requires histological examination. The histopathological picture is characterized by the proliferation of both spindle cells and blood vessels. The blood vessels are dilated and eosinophilic hyaline globules are present. Hemosiderin deposition is prominent. Extravasated red blood cells can be seen surrounding the blood vessels.

Figure 29.4 A 32 years old HIV-positive patient showing oral and disseminated AIDS-associated  cutaneous Kaposi’s sarcoma papules

Kaposi's Sarcoma on palate of a HIV positive patient

Cutaneous Kapos's sarcoma papules

Cutaneous Kaposi's sarcoma papules

Kaposi's sarcoma cutaneous papules


The first line of treatment of KS is antiretroviral therapy.  It reduces the HIV viral load and raises the CD4+ T cell count, both of which indirectly contribute to the pathogenesis of KS. Along with the reduction in viral load, some of the protease inhibitors have been shown to have specific antineoplastic effects 165, 166. Other therapies for the treatment of KS include immunotherapy, radiation, intralesional chemotherapy, interferon therapy, cryotherapy and occasionally lasers.

Other diseases associated with HIV infection

Bacillary (Epitheloid) Angiomatosis:

Bacillary epithelioid angiomatosis (BEA) is a rare cutaneous/mucosal disorder usually affecting patients infected with HIV. This lesion is often misdiagnosed as a vascular tumor. This angioproliferative disease was first described by Stoler et al. in 1983 167. The disease is caused by two species of Gram-negative bacilli: Bartonella (Rochalimaea) henselae and Bartonella (Rochalimaea) Quintana 168. Skin and regional lymph nodes are most commonly involved in this disease. Other less commonly involved organs are liver, spleen, bone, oral mucosa, gastrointestinal tract, lung and brain 169-173.  In the most common presentation of the disease, the skin lesions are multiple and reddish in color. Because of the dermatological manifestations, bacillary angiomatosis may be mistaken for Kaposi’s sarcoma. The differentiation of bacillary angiomatosis from Kaposi’s sarcoma is made by histological examination. Histopathological picture of BEA reveals an “epithelioid” proliferation of angiogenic cells accompanied by an acute inflammatory cell infiltrate. The condition can also be diagnosed by genetic amplification by means of polymerase chain reaction confirming the presence of genetic material of causative bacteria. BEA is a potentially fatal illness; however, it can be treated with relatively inexpensive and non-toxic antibiotics if an early diagnosis is made 174. Therapy with erythromycin or doxycycline is usually effective.

Non-Hodgkin’s Lymphoma (NHL):

Non-Hodgkin’s lymphoma is the second most common malignancy associated with HIV infection. It has been observed that > 90% of HIV-associated NHL cases are derived from B-cells and the majority are high-grade. In most of the cases (70% to 80%) NHL has an extra-oral presentation. Oral NHL is seen only in 3% of cases 175. Clinically, the lesion may appear as soft-tissue masses with or without ulceration and tissue necrosis. Oral NHL commonly involves the gingival, palatal and alveolar mucosa.

Diagnosis of NHL is made with incisional tissue biopsy which demonstrates diffused and aggressive lymphoid infiltration with the replacement of the normal tissue by the proliferation of large cells with hyperchromatic central round nuclei, several nucleoli near the basal membrane and abundant eosinophilic cytoplasm. The radiographs demonstrate widening of the periodontal ligament space, loss of lamina dura and bone destruction.

Management of NHL in HIV-infected patients consists of systemic chemotherapy given in conjunction with HAART. Along with this, supportive care consists of administration of hematopoietic growth factors and prophylaxis for HIV-associated infections 176.

Squamous Cell Carcinoma (SCC):

The factors which have been linked with the development of SCC in patients with HIV infection include the use of tobacco/alcohol, HPV infection, immunodeficiency and possibly genetic factors 177. It has been demonstrated that HIV-positive patients are more likely to have a more advanced stage of oral SCC and poorer survival (57% survival at 1 year and 32% at 2 years) as compared to patients who are HIV negative (74% and 59%, respectively) 178 (Figure 29.5). The proposed etiological factors associated with the development of SCC in HIV-infected patients are increased cellular growth and proliferation caused by viral interference with tumor suppressor proteins (p53, Rb), the activity of the HIV transactivator of transcription protein and role of human papillomavirus.

Figure 29.5 Squamous cell carcinoma in HIV positive patient

Squamous cell carcinoma in HIV positive patient

The oncogenic HPV-16 and HPV-18 have been frequently found associated with oral warts 179. One investigation demonstrated the presence of EBV in 17.59 % of all oral tumors and in 63.1 % of SCC of the tongue in 12 patients, suggesting its potential association with etiopathogenesis of oral SCC 180.

Oral hyperpigmentation:

The color of the oral mucosa and skin is determined by the melanogenic activity of melanocytes, rather than the number of melanocytes in the epithelium. The melanin pigment is present in epithelial basal cells and particularly in subepithelial connective tissue. Melanin is synthesized in melanocytes with the help of enzyme tyrosinase which plays a critical role in the biosynthesis of both brown/black eumelanin and yellow/red pheomelanin. The production of melanin is controlled by various locally produced factors such as proopiomelanocortin and its derivative peptides, particularly α-melanocyte-stimulating hormone (α-MSH), melanocortin 1 receptor (MC1R), adrenergic and cholinergic agents, growth factors, cytokines, and nitric oxide 181. Melanocytes can produce both eumelanin and pheomelanin. The proportion of their synthesis depends on the degree of functional activity of the α-MSH/MC1R intracellular pathway. The etiopathogenesis of hyperpigmented lesions is not fully understood in HIV-positive patients, however, HIV-induced cytokine dysregulation which may result from medications used in ART and adrenocortical dysfunction has been proposed to be responsible for the etiopathogenesis of HIV-induced hyperpigmentation 181.

Hyperpigmentation of oral mucosa in HIV-infected patients can be seen as brown-black macules and diffuse areas of melanosis, seen primarily on the buccal mucosa, gingiva, hard palate, and lateral borders of the tongue. The systemic administration of zidovudine, ketoconazole, and clofazimine has been found to be associated with oral hyperpigmentation. However, in most of the patients, the cause is unknown 182.

Atypical ulcers:

The deterioration of immunoregulation in HIV-infected patients is also associated with abnormally activated immune system. The abnormal activity of the immune system may induce injury to the self-antigens. Major aphthous ulcers are primarily caused because of this inappropriate activity of the immune system. They occur in approximately 2-3% of HIV-infected individuals. The clinical presentation of these ulcers is same as seen in uninfected individuals. The ulcers are large solitary or multiple, chronic, deep and painful. However, the ulcers in HIV-positive patients last longer and are less responsive to therapy.

Another reason for oral atypical ulcers is viral infections. As already discussed in the section of viral infections in HIV, various viral infections such as HSV, VZV, EBV, CMV etc. may present with atypical ulcers in the oral cavity. It has been shown that the persistence and severity of oral lesions is more in patients with low CD4 count and oral CMV-induced ulcers are indicative of systemic CMV infection 183.

The recurrent aphthous stomatitis is more common in HIV-infected patients as compared to uninfected persons. It presents with painful, recurring ulcers of the oral cavity. The systemic conditions associated with recurrent aphthous stomatitis are Crohn’s disease, ulcerative colitis, gluten-sensitive enteropathy, Behcet’s syndrome, Reiter’s syndrome, Sweet’s syndrome, cyclic neutropenia and nutritional deficiencies 184.

The treatment for oral atypical ulcers includes…….


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HIV-related salivary gland diseases:

Salivary gland diseases in patients with HIV infection result in adverse effects on oral health. The conditions associated with salivary gland involvement primarily include xerostomia and salivary gland enlargement due to various pathologies like lymphoepithelial lesions, cysts involving the salivary gland tissue and/or intraglandular lymph nodes, Sjögren’s syndrome-like conditions, diffuse infiltrative lymphocytosis syndrome (DILS). In European and North America studies, the prevalence of salivary gland enlargement in HIV-infected patients has been reported to be around 1%-10% 186, with benign lymphoepithelial lesions (BLEC) present in 3%-6% of these cases 187, 188. Whereas, the average prevalence of HIV-associated salivary gland diseases in Africa was estimated to be 19% 189.

Salivary gland enlargement:

The salivary gland involvement is most commonly associated with enlargement of the salivary gland with or without xerostomia 190. Inflammation and infection of salivary glands are the second most common reasons for salivary gland involvement followed by neoplasms 191. The exact etiopathogenesis of salivary gland enlargement in HIV-positive patients is still not clear. However, the development of BLEC within the parotid gland seems to be the commonest etiology. BLEC are single or multiple cysts within lymph nodes situated mainly along the tail of the parotid gland that get entrapped in the tissue during parotid gland embryogenesis. The enlargement of the parotid gland may also result from the proliferation of glandular epithelium which gets trapped within the intra-parotid lymph nodes. It has been demonstrated that HIV has a predilection for lymphoid tissue and increased concentration of virus is present in these lymph nodes 187, 192, 193. Another reason for salivary gland enlargement in HIV-positive patients is “Diffuse infiltrative CD8 lymphocytosis syndrome”. This disease is characterized by bilateral parotid gland enlargement, CD8 lymphocytosis, cervical lymphadenopathy and diffused visceral (commonly involving lung) CD8 lymphocytic infiltration 194. Further, it has been found that HLA- DR5 positive patients are predisposed to this pathology 195.


There is no specific treatment for salivary gland enlargement in HIV-infected patients. Occasionally, the disease may resolve with HAART. The indicated surgical treatment is superficial parotidectomy. However, it is associated with significant morbidity, so its application is limited.  Aspiration of cystic lesions has been suggested, however, it may also be of limited use because of multiple cysts 195. Radiotherapy, with 24 Gy in 1.5 Gy daily fractions has been reported to be useful for long-term cosmetic control of the enlargement 196.


One of the major factors for dental decay in HIV-infected patients is xerostomia. In these patients, xerostomia is primarily drug induced (mainly due to  nucleoside  transcriptase  inhibitors,  protease inhibitors),  as  well  as  anticholinergics, antihistamines, decongestants, antihypertensive agents,  tricyclic  antidepressants and narcotic  analgesics. Other reasons for xerostomia include HIV-induced salivary gland diseases, Sjogren’s syndrome etc.  Approximately 30% to 40% of HIV-infected individuals experience moderate to severe xerostomia. The management of xerostomia involves rehydration minimizing the consumption of alcohol and caffeine, and using artificial saliva. Use of pilocarpine or cevimeline can be advised to stimulate salivary flow.

Dental management of HIV-infected children and adolescents

With the spread of HIV/AIDS pandemic, more and more pediatric population is getting infected with HIV. With the help of an early diagnosis and prompt treatment with recent therapies, quality of life and life span of HIV infected children can be significantly increased. The oral opportunistic infections significantly deteriorate the systemic health of small children because of their inability to take adequate nutrition. Thus, a combined effort of physician and dentist is required to manage children with HIV infection.

The common oral manifestations of HIV infection in children are oral candidiasis, angular cheilitis, parotid gland swelling, xerostomia, dental caries, aphthous ulcers, herpetic stomatitis, hairy leukoplakia, linear gingival erythema, necrotizing ulcerative periodontitis (NUP) and other destructive diseases.

Management of these children and adolescents infected with HIV include complete documentation of oral and extraoral findings and subsequent three-month evaluation. The continuity of oral/dental care, especially when problems are detected on routine examination must be ensured. It has been observed that the HIV-infected children fail to comply with the dental appointment, even though they may be receiving an appropriate medical attention. Young children and older phobic children may require behavioral management techniques. Their treatment may require outpatient sedation or general anesthesia. A pediatric dentist is required to evaluate the ability of these children to cooperate in the outpatient setting. The caretakers of small kids should be educated to discontinue inappropriate use of bottle feeding to induce sleep. An immediate referral to a dentist is required if any signs or symptoms of caries are noted. Certain medications used in the treatment of HIV-associated diseases may contain cariogenic substances (simple sugars) such as nystatin rinses and troches. Some other medications may cause xerostomia which is again an important contributory factor in caries development. In these patients, “over-the-counter” fluoride rinses are advised. An early detection and treatment of oral diseases by the oral health care providers in HIV-positive children is a key factor in improving the quality of life and the lifespan of these children.


HIV can be considered as the worst pandemic which has ever affected the mankind. However, the introduction of HAART has significantly improved the lifespan and quality of life of HIV-infected patients. The oral manifestations of HIV and AIDS are usually the first indicators of HIV infection. Early recognition, diagnosis, and treatment of HIV-associated oral lesions may reduce the morbidity of the patient. We are still looking for a definite cure for this disease but till we achieve that goal, the prime objectives of every dental health professional are prevention, diagnosis, treatment, and control of oral manifestations associated with HIV infection.

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Periobasics: A textbook of periodontics and implantology

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