Sentinels and signposts: The epidemiology and significance of the oral manifestations of HIV disease

A large number of studies attest to the frequency of oral disease in those with HIV infection. Most show that hairy leukoplakia and pseudomembranous candidiasis are the commonest lesions in those with HIV infection and AIDS, with higher prevalence and incidence rates correlating with falling CD4 counts and disease progression. HIV-infected individuals with oral candidiasis or hairy leukoplakia progress to AIDS more rapidly than matched controls without these lesions. Oral candidiasis and hairy leukoplakia increase with time since seroconversion. On the other hand, parotid enlargement in children appears to be associated with slower progression to AIDS. As a consequence of these and other observations, oral lesions are widely included in natural history studies, staging and classification schemes for HIV infection. In addition to their role in the diagnosis of HIV infection and as indicators of the progression of HIV disease, oral lesions are used as clinical correlates of CD4 counts and as criteria for entry into clinical trials.     

Management of the oral mucosal lesions seen in association with HIV infection

Oral lesions cause considerable morbidity in association with HIV infection. Their successful management depends upon accurate diagnosis and the use of appropriate therapy. Various treatment approaches are described for some of the common oral lesions including Kaposi's sarcoma, oral candidiasis, hairy leukoplakia and recurrent oral ulcers associated with HIV disease. This paper will discuss the therapies available in the USA and UK. In other countries some of the drugs discussed will be available in different doses and preparations. In addition other drugs may be available in other parts of the world that are not licensed for use in the USA or UK, and their availability may vary.     

Prevalence and classification of HIV-associated oral lesions

OBJECTIVES: An International Workshop addressed the prevalence and classification of HIV/AIDS associated oral lesions.
DESIGN: Five questions provided the framework for discussion and literature review. What is the prevalence of oral lesions in children and adults? Should the accepted classification of HIV-related oral lesions be modified in the light of recent findings? Why is there a gender difference in the prevalence of oral lesions in developed and developing countries? Are there unusual lesions present in developing countries? Is there any association between modes of transmission and the prevalence of oral lesions?
RESULTS: Workshop discussion emphasized the urgent need for assistance in the development of expertise to obtain accurate global prevalence data for HIV-associated oral lesions. Oral candidiasis has been consistently reported as the most prevalent HIV-associated oral lesion in all ages. Penicilliosis marneffei, a newly described fungal infection, has emerged in South-east Asia. Oral hairy leukoplakia and Kaposi's sarcoma appear to be associated with male gender and male-to-male HIV transmission risk behaviours. These lesions occur only rarely in children.
CONCLUSIONS: Additional prevalence data are needed from developing countries prior to substantially altering the 1993 ECC/WHO Classification of oral lesions associated with adult HIV infection. The workshop confirmed current oral disease diagnostic criteria.     

Oral candidosis and oral hairy leukoplakia as predictors of HAART failure in Brazilian HIV-infected patients

INTRODUCTION: Oral candidosis (OC) and hairy leukoplakia (OHL) are important markers of Human Immunodeficiency Virus (HIV) infection immune status. OBJECTIVES: to evaluate if OC and/or OHL should be considered clinical predictors of immune and virologic failure on HIV-infected Brazilian adults undergoing Highly Active Antiretroviral Therapy (HAART). METHODS: 124 HIV-infected patients who used HAART for a minimum of six months were prospectively evaluated. All of them under-took oral examination and serum CD4+ count and viral load (VL), being divided in two groups, P and A, respectively according to the presence or absence of OC and/or OHL. During a six month period, patients belonging to group A were followed. They were re-examined for new oral lesions. New blood samples were collected and they were subdivided into groups P6 and A6. CD4+ count and VL were compared between groups at baseline and after the six months period. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and relative risk (RR) were obtained in order to assess the accuracy of using OC and OHL as predictors of immune and virologic failure, at baseline and after a six month period. RESULTS: At baseline and after six months, patients with OC and OHL have mean CD4+ count lower and mean VL higher than patients of group A and A6 (p < 0.001). OC had high PPV for immune failure and a moderated PPV for virologic failure. OHL had low PPVs for both measures. DISCUSSION AND CONCLUSIONS: OC and OHL still indicate low serum CD4+ count and high VL, but OC seems to be a better predictor of immune and virologic failure in patients undergoing HAART than OHL.     

Intergroup comparisons of oral lesions in HIV-positive South Africans

OBJECTIVES: To determine whether there are any differences in the oral manifestations of sub-groups of persons with HIV. These data could provide information for planning of oral health promotion and prevention programmes. DESIGN: A comparative inter-group cross-sectional investigation of the oral manifestations of HIV. Ethnic, gender and sexual orientation differences were taken into consideration. SETTING: Three large general hospitals that offer comprehensive medical investigations and care to persons with HIV. SUBJECTS AND METHODS: A total of 485 HIV-positive adults participated. Clinical examination and, where necessary, swabs or smears of lesions for microbiology, biopsies for histology. MAIN OUTCOME MEASURES: Presence of lesions, associated signs, incidence and type of micro-organisms. RESULTS: A total of 485 HIV-positive persons were examined over a period of 3 years consisting of 225 Blacks, 191 Coloureds (persons of ‘mixed’ descent) and 69 Whites. Data were analysed using, where relevant, the X² test or Fisher's exact test. Heterosexual males revealed a higher prevalence of all oral lesions combined when compared with heterosexual females. A similar finding was evident when HIV-associated periodontal diseases was compared in these two groups. Homosexual males had a higher prevalence of candidal infections than heterosexual males. Coloured heterosexuals had a higher prevalence of oral lesions combined than black heterosexuals. All these results showed statistical significance. CONCLUSIONS: The study tends to show that different patterns of prevalence emerge when inter-group comparisons are made of oral soft tissue diseases evident in HIV-infected South Africans.     

Classification and diagnostic criteria for oral lesions in HIV infection

A consensus has been reached on the classification of the oral manifestations of HIV infection and their diagnostic criteria, based on presumptive and definitive criteria. The former relate to the initial clinical appearance of the lesion and the latter are often the result of special investigations. Candidiasis, hairy leukoplakia, specific forms of periodontal disease [linear gingival erythema, necrotising-(ulcerative) gingivitis and necrotising(ulcerative) periodontitis], Kaposi's sarcoma and non-Hodgkin's lymphoma are strongly associated with HIV infection. Lesions less commonly associated with HIV infection and lesions seen in HIV infection, but not indicative of the disease, are also listed.     

Risk factors for oral hairy leukoplakia in HIV-infected adults of Brazil

BACKGROUND: Oral hairy leukoplakia (OHL) may be an indicator of the progression of Human Immunodeficiency Virus (HIV)-induced immuno-depression, and the evaluation of risk factors leading to OHL is important in the management of these HIV-infected patients. However, there are few studies that analyze risk factors leading to OHL in the Brazilian population. The aim of this case-control study is to present data about prevalence rates and risk factors leading to OHL in a sample of HIV-infected adults in Brazil. METHODS: This case-control study included 111 HIV-infected patients treated at a clinic for sexually transmitted diseases and HIV. In the initial examinations with dentists, variables were collected from all patients. Diagnosis of OHL was performed in accordance with the International Classification System and cytological features. The Fisher and the chi-squared tests were used for statistical analysis. The proportional prevalence and odds ratio were estimated. RESULTS: Outcome presented a positive, statistically significant association among the presence of OHL and viral load of 3000 copies/mul or greater (P = 0.0001; odds ratio (OR) = 5.8), presence of oral candidiasis (P = 0.0000; OR = 11.1), previous use of fluconazole (P = 0.0000; OR = 24.6), and use of systemic acyclovir (P = 0.032; OR = 4.3). Antiretroviral medication presented a negative, statistically significant association with the presence of OHL (P = 0.002; OR = 8.4). CONCLUSIONS: Prevalence of OHL was 28.8%. Viral load, oral candidiasis, previous use of fluconazole, and systemic acyclovir were determined to be risk factors for OHL. Antiretroviral medication proved to be protective against the development of OHL.     

Ability of HIV/AIDS patients to self-diagnose oral opportunistic infections

OBJECTIVES: To assess the accuracy of HIV/AIDS patients' self-diagnosis of common HIV-related oral opportunistic infections. METHODS: 245 HIV/AIDS patients were interviewed regarding the current presence of oral candidiasis (OC), oral hairy leukoplakia (OHL), and oral ulcers prior to an oral examination by an oral medicine trained dentist examiner. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) are reported for the patient's oral lesion diagnosis compared to the dentist's diagnosis based on established presumptive clinical criteria as the gold standard. RESULTS: Self-diagnosis accuracy was greatest for pseudomembraneous OC (PPV 42.9%; NPV 93.5%), followed by oral ulcers (PPV 35.7%; NPV 98.3%) and OHL (PPV 23.5%; NPV 86.4%). Past experience with the lesion improved diagnostic accuracy, and bothersome symptoms accompanying the lesion had significant impact only for pseudomembraneous OC and oral ulcers. CONCLUSIONS: Moderate accuracy of patient self-assessment of oral lesions, with tendency to under rather than over report lesion presence, supports the use of patient self-assessment of these lesions to augment clinician diagnosis in clinical trials. Additionally, HIV/AIDS patients are unlikely to believe they have active OC that would lead to on-demand antifungal use, unless they have had prior experience with the lesion or it is at least moderately bothersome.     

Oral manifestations associated with human immunodeficiency virus infection in a Spanish population

A study was made of the oral manifestations in 396 patients with human immunodeficiency virus (HIV) infection. The following risk groups were established: intravenous drug users (79.5%), homosexuals (7.8%), homosexual intravenous drug users (3.3%). heterosexuals (8.1%) and hemophiliacs/transfusion patients (1.3%). The oral lesions, in decreasing order of frequency, were: periodontal disease (78.28%). candidiasis (65.65%). hairy leukoplakia (16.16%). herpes simplex virus lesions (5.30%), Kaposi's sarcoma (2.27%), recurrent aphthous ulceration (RAS) (1.01%), lichen planus (0.5%), non-Hodgkin's lymphoma (0.25%). tuberculous lesion of the tongue (0.25%) and ulcerations of uncertain etiology (0.25%). Attention is drawn to the greater predominance of these lesions in patients with CD4 values of less than 200/mm³, compared with those who have higher lymphocyte counts.     

Prognostic value of oral candidosis and hairy leukoplakia in 111 Mexican HIV-infected patients

A follow-up study was carried out to evaluate the prognostic value of hairy leukoplakia (HL) and oral candidosis (OC) in a cohort of 111 asymptomatic Mexican HIV infected patients. Oral exams were performed at baseline and every 6 months, from September 1989 to March 1994. Chi-square contingency table test, the Kruskall-Wallis one-way analysis of variance, the Kaplan-Meier product-limit method and the log rank test were used for the analysis. Univariate and multivariate Cox's proportional hazards analysis were also performed. Fifty-four patients (51%) progressed to AIDS (initially 36 CDC-II and 18 CDC-III). Individuals with HL and/or OC, showed faster development to AIDS than subjects without lesions or other HIV-related manifestations (P=0.008). The presence of OC, HL or both always remained significant despite adjustment for total lymphocytes, CDC stage, zidovudine therapy or its combinations. Oral lesions in HIV infection may be regarded with other clinical and laboratory studies as markers of HIV disease progression and as indicators to begin antiretroviral treatment.     

Oral manifestations in 101 Cambodians with HIV and AIDS.

BACKGROUND: The HIV/AIDS epidemic in Cambodia has become a major problem in the last 7-8 years, mainly because in this formerly war-stricken country the socioeconomic situation is only slowly improving. Since only very few studies have been published to date on the oral health status of Cambodian HIV/AIDS patients, it was the purpose of the present investigation to study oral manifestations in Cambodian patients with HIV disease. METHODS: One hundred one Cambodian patients with HIV infection or AIDS were examined for the presence of oral manifestations in one medical center in Phomh Penh, Cambodia. RESULTS: Sixty-three men and 38 women with a median age of 32 years were examined (age range 7.5-63.5 years). Of these patients, 42.6% were smokers, 46.5% of men were heavy drinkers and 90.5% of men were promiscuous compared with 5.3% of women. The most frequent AIDS-defining diseases were wasting syndrome (54.5%), Pneumocystis carinii pneumonia (PcP) (19.8%) and tuberculosis (18.8%). Puritic papular eruption, a common cutaneous manifestation in HIV-infected patients, was seen in 17.8% of patients. Candida-associated infections of the oral cavity were most common. Among the patients, 52.5% revealed pseudomembranous candidiasis and 35.6% had bilateral hairy leukoplakia. Only 10% of patients had no oral lesions. Also common were necrotising ulcerative gingivo-periodontal diseases (27.7%). CONCLUSION: The general health status of 101 Cambodian patients with HIV infection and AIDS was poor, and they demonstrated a large number of oral manifestations. Antiretroviral therapy is presently not available and only a fraction of patients receives antimycotic treatment (25.7%). HIV infection and the AIDS epidemic in Cambodia have become a serious problem and patients urgently need adequate diagnosis and antiretroviral therapies.     

Cytokine profiles in parotid saliva from HIV-1-infected individuals: changes associated with opportunistic infections in the oral cavity

The purpose of this study was to quantitate levels of cytokines in parotid saliva of subjects infected with human immunodeficiency virus-1 (HIV-1) and to determine if the cytokine profiles differ in subjects with an oral opportunistic infection, i.e., candidiasis or oral hairy leukoplakia. Parotid saliva samples were obtained from HIV-infected individuals with or without candidiasis or oral hairy leukoplakia and from healthy controls and were assessed by ELISA for levels of interleukin (IL)-1, IL-2, IL-4, IL-5, IL-10, transforming growth factor-beta, tumor necrosis factor-alpha and interferon (IFN)-gamma. Saliva from HIV-infected subjects with oral candidiasis had significantly higher levels of IFN-gamma than that seen in HIV-infected individuals with no oral disease and significantly higher levels of IL-2, IL-5 and IFN-gamma than saliva of healthy controls. No significant difference was seen in cytokine levels in saliva from HIV-infected subjects with no oral infections and healthy controls. The HIV-infected subjects with oral hairy leukoplakia displayed significantly higher levels of both IL-1 alpha and IFN-gamma compared with the HIV and no oral disease group and a higher level of IFN-gamma than seen in saliva from the healthy control group. In comparing cytokine levels from both HIV and oral disease groups, significant differences were detected in levels of IL-5 and IL-10. These results indicate that the profile of salivary cytokines is altered as a result of the oral opportunistic infection candidiasis or oral hairy leukoplakia and also by concurrent HIV infection.     

Detection of Epstein-Barr virus in oral scrapes in HIV infection, in hairy leukoplakia, and in Healthy non-HIV-infected people

Epstein-barr Virus (EBV) has been implicated in the pathogenesis of oral hairy leukoplakia (OHL). EBV is normally detected by lesional biopsy. The objectives of this study were to examine oral scrapes containing squamous epithelial cells from healthy non-HIV-infected people with and without clincial lesions of OHL, and from healthy non-HIV-infected controls, for EBV-DNA by the polymerase chain reaction (PCR). EBV-DNA was detected in 65% of HIV-infected individuals it was found as frequently in those without OHL as in those with. Moreover, EBV-DNA was not detected in all HIV-infected individuals, nor in all OHL as in those with. Moreover, EBV-DNA was not detected in all Hiv-infected individuals, nor in all OHL> The results suggest that the presence or absenc e of detectable EBV-DNA in oral scrapes, though a guide, cannot be regarded as absolutely reliable in the diagnosis or exclusion of OHL.     

Cytokine profiles in parotid saliva from HIV‐1‐infected individuals: changes associated with opportunistic infections in the oral cavity

The purpose of this study was to quantitate levels of cytokines in parotid saliva of subjects infected with human immunodeficiency virus‐1 (HIV‐1) and to determine if the cytokine profiles differ in subjects with an oral opportunistic infection, i.e., candidiasis or oral hairy leukoplakia. Parotid saliva samples were obtained from HIV‐infected individuals with or without candidiasis or oral hairy leukoplakia and from healthy controls and were assessed by ELISA for levels of interleukin (IL)‐1, IL‐2, IL‐4, IL‐5, IL‐10, transforming growth factor‐β, tumor necrosis factor‐α and interferon (IFN)‐γ. Saliva from HIV‐infected subjects with oral candidiasis had significantly higher levels of IFN‐γ than that seen in HIV‐infected individuals with no oral disease and significantly higher levels of IL‐2, IL‐5 and IFN‐γ than saliva of healthy controls. No significant difference was seen in cytokine levels in saliva from HIV‐infected subjects with no oral infections and healthy controls. The HIV‐infected subjects with oral hairy leukoplakia displayed significantly higher levels of both IL‐1α and IFN‐γ compared with the HIV and no oral disease group and a higher level of IFN‐γ than seen in saliva from the healthy control group. In comparing cytokine levels from both HIV and oral disease groups, significant differences were detected in levels of IL‐5 and IL‐10. These results indicate that the profile of salivary cytokines is altered as a result of the oral opportunistic infection candidiasis or oral hairy leukoplakia and also by concurrent HIV infection.     

Prevalence of oral disease among adults with primary HIV infection

Objective: To explore the type and prevalence of oral mucosal lesions among adults with primary HIV infection (PHI) compared with HIV‐negative adults at high risk for HIV disease, and in relation to HIV viral load. Methods: We conducted standardized oral examinations to identify specific oral mucosal lesions among adults with PHI, both pre‐seroconversion and post‐ seroconversion‐recently infected, compared with HIV‐negative adults. We compared the group with oral lesions to those without oral lesions with respect to HIV‐RNA load and CD4 + T‐cell count. Results: Among 115 adults (predominantly men), pseudomembranous candidiasis was the most common oral lesion among those with PHI, and was found in 4% of the 23 participants in pre‐seroconversion and in 9% of 69 participants with post‐seroconversion recent infection, compared with none found among 23 HIV negatives. Among those with PHI, the median viral load was higher and the median CD4 + T‐cell count lower among the 15 participants with an oral lesion of any type than among the 77 participants without oral lesions (P = 0.02 and 0.04, respectively). Conclusion: This finding suggests that individuals with PHI who have oral lesions may be more likely to transmit HIV because of their higher viral load.     

Risk indicators for oral candidiasis and oral hairy leukoplakia in HIV-infected adults

OBJECTIVES: Oral candidiasis (OC) and oral hairy leukoplakia (OHL) are the most common oral mucosal diseases associated with HIV infection. Independent risk indicators associated with these sentinel opportunistic diseases have not been established in mixed race and gender adult populations in the southeast USA. The purposes of this study were 1) to estimate prevalence of OC and OHL among an HIV-1 positive adult population, and 2) to develop explanatory multivariable models for each disease outcome. METHODS: This cross-sectional study evaluated 631 adult dentate HIV-1 seropositive persons examined for HIV-associated oral mucosal diseases between 1995 and 2000 at University of North Carolina Hospitals in Chapel Hill, North Carolina using data collected from medical record review, interview questionnaire and clinical examination. We analyzed the data using t-tests, anova, and unconditional logistic regression. RESULTS: Prevalent OC was associated with low CD4+ cell count [<200 cells/microl, adj. OR = 12.7 (95%CI: 4.9-32.9)], antiretroviral combination therapy [OR = 0.6 (0.3-0.9)], and current smoking [OR = 2.5 (1.3-4.8)]. Prevalent OHL was associated with low CD4+ cell count [<200 cells/microl, OR = 7.2 (2.7-18.9)], antifungal medication use [OR = 1.8 (1.1-2.9)], current recreational drug use [OR = 2.5 (1.3-4.9)], and male gender [OR = 2.5 (1.3-4.8)]. CONCLUSIONS: While CD4+ cell count, and antiretroviral medication were important risk indicators for OC, and OHL, cigarette smoking appears to be an important risk indicator for OC in HIV-1-infected populations.     

Oral mucosal Langerhans' cells as target, effector and vector in HIV infection

The mechanism underlying a transition of the oral cavity mucosal epithelium towards susceptibility to opportunistic infections in HIV-seropositive patients was investigated. Phenotypic markers CD1a, HLA-DR, and CD86 of oral mucosal Langerhans' cells (LCs), p17 core protein of human immunodeficiency virus (HIV), and CD45RO of memory T cells were labeled on oral hairy leukoplakia lesional biopsies and clinically normal autologous tissue of HIV-infected patients. HIV p17 protein was detected in association with mucosal LCs, mainly within the lesional epithelium. There were significant correlations between the detection of HIV p17 and the depletion of LCs, and between the depletion of LCs and the presence of hairy leukoplakia lesions. Conjugates of activated LCs and memory T cells were also evident in the submucosal area of lesional biopsies. The findings from this study support the hypothesis that oral mucosal LCs are also the target of HIV infection. Cytopathic changes of LCs caused by productive HIV infection may contribute to selective depletion of LCs, which may impair the mucosal immunologic protection against colonization by microorganisms causing HIV-associated oral mucosal lesions.     

Lack of evidence for local immune activity in oral hairy leukoplakia and oral wart lesions

BACKGROUND: Oral warts, caused by human papillomavirus (HPV), and oral hairy leukoplakia (OHL) caused by Epstein-Barr virus (EBV), are common oral manifestations in HIV-infected persons. Although both conditions occur most often with reduced blood CD4+ T-cell numbers, oral warts and OHL rarely occur simultaneously, suggesting that dysfunctions in other secondary local immune parameters are also involved. The present study evaluated tissue-associated proinflammatory and T-helper cytokine and chemokine mRNA expression and the presence of T cells in each lesion. METHODS: Biopsies were taken from lesion-positive and adjacent lesion-negative sites of HIV+ persons with oral warts or OHL and lesion-negative sites from HIV+ persons who were oral HPV or EBV DNA-positive (matched controls). Cytokine/chemokine mRNA expression was quantified by real-time polymerase chain reaction. CD3, CD4, and CD8 cells were identified by immunohistochemistry. RESULTS: No differences were detected in tissue-associated cytokine/chemokine mRNA expression in warts or OHL when compared to lesion-negative sites. Immunohistochemical analysis of T cells showed CD8+ cells exclusively, but few cells were present in either lesion. No differences were detected between lesion-positive and -negative control sites of each pathologic condition. CONCLUSION: Little evidence was found for local immune reactivity to either oral warts and OHL, suggesting that CD4+ T cells are a primary host defense against both oral warts and OHL, but with nonimmune factors potentially responsible for the divergent prevalence of each.     

Low prevalence of oral mucosal lesions in HIV-1 seropositive African women

In Nairobi (Kenya) 334 women prostitutes of whom 80.5% were HIV-1 positive, were examined for oral mucosal lesions; 15.6% of seropositive, and 4.6% of seronegative, women had oral mucosal lesions, predominantly oral candidiasis. In the seropositives, 8.6% had erythematous, 1.1% had hyperplastic candidiasis, and 0.4% had hairly leukoplakia as the only oral lesions; 0.4% had a combination of erythematous and hyperplastic candidiasis, and 1.5% had combinations of pseudomembranous and erythematous candidiasis in the presence of hairly leukoplakia. Of the 211 seropositive women for whom we knew the first date on which a positive serologic test was obtained, the likelihood of developing an oral mucosal lesion was found to be dependent on the duration of seropositivity. The low incidence of oral mucosal lesions in this population may be due to the relatively recent acquisition of HIV-1 infection.     

Oral manifestations of HIV infection in 75 Dutch patients

Seventy-five consecutive HIV-infected patients, including 33 AIDS cases were examined. One or more oral mucosal lesions were observed in 57 (76%); candidiasis was the most common finding (52%). Others included hairy leukoplakia (16%), periodontal disease (16%) and Kaposi's sarcoma (4%). Diversity of study design and methods allowed no reliable comparison with other reports.