Oral HIV‐associated Kaposi sarcoma

J Oral Pathol Med (2012) Kaposi sarcoma (KS), an AIDS defining condition, remains one of the most commonly HIV‐associated neoplasms. While the use of highly active antiretroviral therapy (HAART) has brought about a dramatic decrease in the prevalence and incidence of AIDS‐KS worldwide, this has not been the case in resource‐poor sub‐Saharan African countries, where HIV has reached epidemic proportions and human herpesvirus‐8 infection is endemic. Oral involvement is a common manifestation of AIDS‐associated KS and may be an early presenting finding of HIV infection. The clinical manifestation of oral KS can vary and may have an unpredictable course ranging from mild to fulminant. Rapidly progressive facial lymphoedema associated with extensive advanced oral KS portends a poor prognosis. Oral KS may regress with antiretroviral therapy or may flare up as part of the immune reconstitution inflammatory syndrome. The oral lesions of AIDS‐KS are best managed with HAART together with systemic chemotherapy. This article provides a review of contemporary knowledge of the biology, pathology, clinical features and management of oral AIDS‐KS.     

Urban legends series: oral manifestations of HIV infection

Human immunodeficiency virus‐related oral lesions (HIV‐OLs), such as oral candidiasis (OC) and oral hairy leukoplakia (OHL), have been recognized as indicators of immune suppression since the beginning of the global HIV epidemic. The diagnosis and management of HIV disease and spectrum of opportunistic infection has changed over the past 30 years as our understanding of the infection has evolved. We investigated the following controversial topics: (i) Are oral manifestations of HIV still relevant after the introduction of highly active antiretroviral therapy (HAART)? (ii) Can we nowadays still diagnose HIV infection through oral lesions? (iii) Is the actual classification of oral manifestations of HIV adequate or does it need to be reviewed and updated? (iv) Is there any novelty in the treatment of oral manifestations of HIV infection? Results from extensive literature review suggested the following: (i) While HAART has resulted in significant reductions in HIV‐OLs, many are still seen in patients with HIV infection, with OC remaining the most common lesion. While the relationship between oral warts and the immune reconstitution inflammatory syndrome is less clear, the malignant potential of oral human papillomavirus infection is gaining increasing attention. (ii) Effective antiretroviral therapy has transformed HIV from a fatal illness to a chronic manageable condition and as a result expanded screening policies for HIV are being advocated both in developed and in developing countries. Affordable, reliable, and easy‐to‐use diagnostic techniques have been recently introduced likely restricting the importance of HIV‐OLs in diagnosis. (iii) The 1993 EC‐Clearinghouse classification of HIV‐OLs is still globally used despite controversy on the relevance of periodontal diseases today. HIV‐OL case definitions were updated in 2009 to facilitate the accuracy of HIV‐OL diagnoses by non‐dental healthcare workers in large‐scale epidemiologic studies and clinical trials. (iv) Research over the last 6 years on novel modalities for the treatment of HIV‐OLs has been reported for OC and OHL.     

Oral manifestations of HIV infection in relation to clinical and CD4 immunological status in northern and southern Thai patients

OBJECTIVES: To assess prevalence and variations in the oral manifestations of HIV in HIV-infected subjects in southern Thailand (a new HIV epidemic) and northern Thailand (a mature epidemic), and the association with age, sex, risk behaviours, CD4 count and medication used. SUBJECTS AND METHODS: A total of 102 and 135 HIV-infected individuals were enrolled in northern and southern hospitals, respectively. Oral and haematological examination was performed after sociodemographic interview of the patients. Clinical history was retrieved from patients' medical records. RESULTS: Oral candidiasis (OC, 55%), oral hairy leucoplakia (OHL, 21%) and HIV-associated-periodontal disease (14%) were among the most common oral lesions in southern Thailand. OHL (38%), OC (25%), HIV-associated-periodontal disease (15%) were the three most common lesions in the north. A significant association was found between any oral lesion, OC, particularly the pseudomembranous type (PC), and CD4 < 200 cells mm(-3) at both sites. A negative relationship was found between systemic antifungal treatment and OC including PC and erythematous candidiasis (EC) in the southern data. OHL showed a positive relationship with male sex and a negative relationship with antiretroviral treatment in the northern site. Younger age and being a current smoker were positively associated with oral lesions in the southern group. CONCLUSION: OC, particularly PC, could be useful as a marker for immunosuppression, particularly where CD4 count cannot be determined routinely. Antifungal treatment is of benefit in the subjects who cannot afford highly active antiretroviral therapy (HAART).     

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.     

Prevalence of oral mucosal lesions in adults undergoing highly active antiretroviral therapy in Hong Kong

Aim:  Highly active antiretroviral therapy (HAART) has altered the prevalence and incidence of oral mucosal lesions of HIV infection. Recent reports show a variation in the prevalence of oral mucosal lesions in different population groups. Understanding the prevalence of these lesions is of paramount importance in the efficient delivery of dental care to such cohorts. The aim of the present study was to investigate the prevalence of oral mucosal lesions and salivary parameters during HAART in an ethnic Chinese cohort in Hong Kong. Methods: A cross‐sectional estimation of the prevalence of oral mucosal lesions was carried out in 101 HIV‐infected ethnic Chinese in Hong Kong using the European Community–Clearinghouse classification. Results: The prevalence of oral mucosal lesions was more common in patients who were classified at baseline as Centers for Disease Control (CDC) C3 category than CDC A2, A3, B2, and B3 (P < 0.05). An overall prevalence of 1.98% was observed for oral Kaposi’s sarcoma. Additionally, the HIV group on HAART (0.37 ± 0.23 mL/min) had significantly lower salivary flow rates (P < 0.01) compared with the healthy group (0.49 ± 0.15 mL/min). Conclusions: Although HAART appears to markedly reduce the prevalence of oral mucosal lesions during the course of HIV disease, regular systematic oral screening is still warranted for such populations for the early diagnosis and management of pathologies, such as Kaposi’s sarcoma.     

Effects of long‐term use of HAART on oral health status of HIV‐infected subjects

J Oral Pathol Med (2010) 39 : 397–406 Background: The aim of this study was to determine the effects of long‐term use of highly active antiretroviral therapy (HAART) on oral health status of HIV‐infected subjects. Methods: Oral examination and measurement of saliva flow rate of both unstimulated and wax‐stimulated whole saliva were performed in HIV‐infected subjects with and without HAART, and in non‐HIV individuals. The following data were recorded; duration and risk of HIV infection, type and duration of HAART, CD4 cell count, viral load, presence of orofacial pain, oral dryness, oral burning sensation, oral lesions, cervical caries, and periodontal pocket. Multiple logistic regression analysis was performed to determine the effects of long‐term use of HAART on oral health status of HIV‐infected subjects. Results: One hundred and fifty‐seven HIV‐infected subjects – 99 on HAART (age range 23–57 years, mean 39 years) and 58 not on HAART (age range 20–59 years, mean 34 years) – and 50 non‐HIV controls (age range 19–59 years, mean 36 years) were enrolled. The most common HAART regimen was 2 NRTI + 2 NNRTI. HIV‐infected subjects without HAART showed greater risks of having orofacial pain, oral dryness, oral lesions, and periodontal pockets than those with short‐term HAART (P < 0.01). The subjects with long‐term HAART were found to have a greater risk of having oral lesions than those with short‐term HAART (P < 0.05). The unstimulated and stimulated salivary flow rates of the subjects with HAART were significantly lower than in those without HAART (P < 0.05). Conclusion: We conclude that long‐term HAART has adverse effects on oral health status of HIV‐infected subjects.     

Epstein-Barr virus infection and expression in oral lesions

OBJECTIVE: The prevalence of Epstein-Barr virus (EBV) and the recently discovered Kaposi's sarcoma associated herpes virus, human herpesvirus 8 (KSHV or HHV8), was determined within oral lesions common to HIV infection including OHL, pseudoOHL (PHL), oral lymphoma, oral aphthous ulcers, and an oral Kaposi's sarcoma. METHODS: DNA and RNA were extracted from oral lesions. EBV and HHV8 genomes were detected by Southern blot and polymerase chain reaction (PCR), and viral expression was analyzed using PCR amplification of cDNA. RESULTS: Multiple EBV strains were detected within OHL with recombination across repeat sequences generating new viral variants. EBV expression in OHL included expression of some viral genes, usually expressed in latent infections, that induce the EBV receptor. EBV replication was detected only within OHL lesions but not within adjacent Kaposi's tissue or oral aphthous ulcers while HHV8 was only detected within the Kaposi's lesions. CONCLUSIONS: These findings indicate that the OHL lesion is unique with viral replication and superinfection with additional EBV strains. Expression of the EBV receptor within the OHL lesion may promote superinfection which then activates EBV replication. The consistent detection of EBV replication only within OHL lesions and the detection of HHV8 only within Kaposi's sarcoma, strengthens the etiologic link between EBV and HHV8 infection to these specific pathologies.     

Oral lesions among persons with HIV disease with and without highly active antiretroviral therapy in southern India

BACKGROUND: The advent of highly active antiretroviral therapy (HAART) has changed the scenario of human immunodeficiency virus (HIV) infection. HIV patients in India have now access to generic HAART and this is the first report describing oral lesions in patients on HAART from our country. METHODS: Oral lesions were studied in HIV seropositive patients (n = 50 on HAART and n = 50 not on HAART) attending a tertiary HIV referral care centre in India and patients on HAART were followed up. RESULTS: There was a difference in the occurrence of oral candidiasis (OC) between HAART and non-HAART participants (8%, 24%; P < 0.05). Pseudomembranous candidiasis was 4% and 18% in HAART and non-HAART groups respectively (P < 0.05). In patients with CD4 count 200, pigmentation was 43.8% in the HAART group and 14.8% in the non-HAART group (P < 0.05). CONCLUSION: The prevalence of OC in patients who had access to HAART was less when compared with those who did not have access to HAART.     

口腔艾滋病的临床及研究进展

目的 被誉为世纪恶魔的艾滋病正在全球肆虐。根据国家最新资料,我国于1985年首次发现艾滋病病人。截止今年6月底,全国累计报告艾滋病病毒感染者26085例,其中艾滋病病人1111例,死亡584例。据专家估计,至2000年底,全国实际艾滋病病毒感染者已超过60万人,这不能不引起广大医务工作者,包括口腔医务工作者的高度警惕和重视。本文介绍了与艾滋病毒感染有关的主要口腔粘膜损害、交叉感染途径及治疗原则,旨在帮助口腔医务工作者对艾滋病的临床及研究进展有一个正确的认识。     

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 Candida colonization and its relation with predisposing factors in HIV‐infected children and their uninfected siblings in Brazil: the era of highly active antiretroviral therapy

J Oral Pathol Med (2010) 39 188–194 Objectives: To evaluate predisposing factors such as orofacial manifestations, immunosuppression status and antiretroviral therapy in relation to oral colonization by Candida spp. in Brazilian HIV‐infected children and their uninfected siblings in the era of highly active antiretroviral therapy (HAART). Methods: Whole stimulated saliva was collected from 65 HIV‐infected children (HIV+) and 40 uninfected siblings (HIV–), followed by assessment of orofacial manifestation, caries indexes and the number of cavitated dentinal carious teeth (CDT). The salivary samples were cultured and the colonies were counted. After which they were identified by sugar assimilation and fermentation (API 20C). Data was analyzed using chi‐square, Mann–Whitney, Spearman tests and logistic regression. Results: Regarding positive growth, HIV+ presented 80% (52/65) and HIV? 57.5% (23/40) (P = 0.013). Absence of antiretroviral therapy and HAART increased the probability of Candida isolation (P < 0.05). Mean CD4%, immune‐status and history of recurrent oral candidiasis (OC) had no influence on Candida isolation. Mixed Candida spp. cultures were observed in HIV+ (40%) and HIV? (52%): C. albicans was more frequently found in both groups, with a higher prevalence in HIV+ (P = 0.05); other non‐albicans species were isolated in HIV+ and HIV?. Low prevalence of orofacial manifestations was observed in HIV+ (10.7% of OC). There was an association between means of CDT and Candida growth (P < 0.05) and a positive correlation between number of CDT and Candida cfu‐counts in HIV+ and HIV?. Mean CD4% and immune‐status had no influence on Candida isolation. Absence of antiretroviral therapy and HAART increased the probability of Candida isolation (P < 0.05). Conclusions: The HIV infected children had a significantly higher prevalence of oral Candida spp. compared to their uninfected siblings. Absence of HAART and presence of dentinal carious teeth increased significantly Candida spp. colonization in these children.     

Oral innate immunity in HIV infection in HAART era

Oral innate immunity, an important component in host defense and immune surveillance in the oral cavity, plays a crucial role in the regulation of oral health. As part of the innate immune system, epithelial cells lining oral mucosal surfaces not only provide a physical barrier but also produce different antimicrobial peptides, including human β‐defensins (hBDs), secretory leukocyte protease inhibitor (SLPI), and various cytokines. These innate immune mediators help in maintaining oral homeostasis. When they are impaired either by local or systemic causes, various oral infections and malignancies may be developed. Human immunodeficiency virus (HIV) infection and other co‐infections appear to have both direct and indirect effects on systemic and local innate immunity leading to the development of oral opportunistic infections and malignancies. Highly active antiretroviral therapy (HAART), the standard treatment of HIV infection, contributed to a global reduction of HIV‐associated oral lesions. However, prolonged use of HAART may lead to adverse effects on the oral innate immunity resulting in the relapse of oral lesions. This review article focused on the roles of oral innate immunity in HIV infection in HAART era. The following five key questions were addressed: (i) What are the roles of oral innate immunity in health and disease?, (ii) What are the effects of HIV infection on oral innate immunity?, (iii) What are the roles of oral innate immunity against other co‐infections?, (iv) What are the effects of HAART on oral innate immunity?, and (v) Is oral innate immunity enhanced by HAART?     

Mode of HIV transmission associated with risk of oral lesions in HIV‐infected subjects in Thailand

J Oral Pathol Med (2010) 39 195–200 Background: The aim of this study was to determine if route of human immunodeficiency virus (HIV) transmission is associated with the risk of oral lesions in HIV‐infected subjects in Thailand. Methods: A cross‐sectional study was performed in 186 HIV‐infected heterosexuals (aged 21–65 years, mean 32 years), and 82 HIV‐infected intravenous drug users (IVDUs) (aged 16–50 years, mean 30 years). The following information was recorded: route of HIV transmission, total lymphocyte cell counts, weight, smoking habit, alcohol consumption, medications, presence of denture, plaque index, and presence of oral lesions. The association between mode of HIV transmission and the risk of oral lesions among the subjects was determined by multiple logistic regression analysis. Results: Oral lesions were found in 138 HIV‐infected heterosexuals (75%) and in 37 HIV‐infected IVDUs (46%). Oral candidiasis (OC) was the most common lesion among both groups (44% vs. 28%), followed by hairy leukoplakia (HL) (33% vs. 10%). Multiple logistic regression analysis showed a significant association between mode of HIV transmission and the risk of oral lesions after controlling for the total lymphocyte cell counts and other confounding factors [OR 3.1; 95% CI 1.5–6.4; P = 0.002]. OC was significantly associated with heterosexual route of HIV transmission [OR 2.4; 95% CI 1.2–4.7; P = 0.014]. Similar association was also observed with HL [OR 3.7; 95% CI 1.5–9.1; P = 0.004]. Conclusions: Mode of HIV transmission is associated with the risk of oral lesions in HIV‐infected subjects in Thailand. Further studies should be performed to determine if the risk of oral lesions is associated with differences in HIV‐subtypes.     

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.     

Human immunodeficiency virus-associated Kaposi sarcoma as an immune reconstitution inflammatory syndrome: a literature review and case report

BACKGROUND: Kaposi sarcoma (KS) is the most common human immunodeficiency virus (HIV)-associated neoplasm (HIV-KS). Highly active antiretroviral therapy (HAART) results in a decrease in the incidence and prevalence of HIV-KS as well as in clinical improvement. However, in a subset of subjects who are HIV seropositive, KS may recrudesce early following the introduction of HAART as an immune reconstitution inflammatory syndrome (IRIS). METHODS: The management of a patient who is HIV seropositive with rapid clinical worsening of oral KS lesions shortly after the initiation of HAART was documented. Repeated serologic testing for CD4(+) T-cell count and microscopic examination of two biopsy specimens of the oral lesion, one taken before and the other taken after cytotoxic chemotherapy, followed by surgical excision was the treatment modality used. RESULTS: Microscopic examination of the incisional biopsy specimen taken from the oral lesion at the time of the initial consultation confirmed the clinical diagnosis of KS. The sequential serological tests showed a progressive increase in CD4(+) T-cell counts that paralleled the rapid clinical worsening of the KS disease. This was consistent with the diagnosis of IRIS-associated HIV-KS. Subsequent cytotoxic chemotherapy brought about resolution of the IRIS and regression of the HIV-KS lesions. Microscopic examination of a biopsy specimen obtained after cytotoxic chemotherapy did not show any of the original KS. The residual palatal exophytic mass was excised. CONCLUSIONS: IRIS-associated HIV-KS is not a disease, but rather a temporary paradoxical immunoinflammatory reaction brought about by improvement in immune status following HAART. IRIS-associated HIV-KS can be controlled effectively by limited systemic cytotoxic chemotherapy in the setting of HAART.     

Changes in oral cytokeratin expression in HIV-infected subjects with long-term use of HAART

Oral Diseases (2012) 18 , 793–801 Objectives: The objectives of this study were to determine (i) the expression of oral cytokeratins (CKs) among human immunodeficiency virus (HIV)‐infected subjects compared with non‐HIV controls, (ii) the oral CK expression in the subjects with highly active antiretroviral therapy (HAART) compared with those without HAART, and (iii) factors associated with the expression of oral CKs. Materials and methods: Oral tissues from buccal mucosa were obtained by punched biopsy in HIV‐infected subjects with and without HAART, and non‐HIV individuals. The samples were processed for immunohistochemical studies of CK1, CK13, CK14, CK16, and involucrin. The staining intensity was scored and recorded. Logistic regression analysis and multi‐way ANOVA test were performed. Results: The expression of CK13, CK14, and CK16 was found to be significantly different between HIV‐infected subjects and non‐HIV individuals (P < 0.05). The expression of those CKs was also significantly different between those who were and were not on HAART (P < 0.05). No significant difference between the groups was observed regarding CK1 and involucrin. Conclusions: Oral epithelial cell differentiation as marked by the CK expression is affected by HIV infection and use of HAART. CKs may be the useful biomarkers to identify HIV‐infected subjects who are at risk of malignant transformation of the oral mucosa because of HIV infection and HAART.     

Decline in the rate of oral opportunistic infections following introduction of highly active antiretroviral therapy

In recent years the management of human immunodeficiency virus (HIV)-positive individuals has been based on highly active antiretroviral therapy (HAART) comprising a combination of nucleoside analogues or the combination of these agents with protease inhibitors. The aim of the present study was to describe the prevalence of oral lesions in a cohort of 103 HIV-seropositive patients on HAART, to compare these data with the prevalence of lesions prior to HAART and to correlate these finding with the immunologic data. A total of 103 HIV-seropositive patients on HAART were selected. Oral lesions associated with HIV infection and immunological parameters were registered. On re-examination 6 months after the first evaluation, 61/103 patients were available. Comparing the prevalence of oral lesions before and after the onset of HAART, the number of oral lesions was significantly lower (P=0.001). The number of CD4+ cells increased and the viral load decreased significantly after initiation of HAART (P=0.001 and P= 0.0001). On re-examination 6 months later, the prevalence of lesions again decreased significantly (P=0.001). The immunological benefits of HAART may prevent HIV-associated oral lesions in patients with advanced HIV disease. Our results showed that oral manifestations decrease on HAART, but in four patients the immunological effects of therapy did not provide sufficient protection against human papillomavirus (HPV)induced lesions.