Common oral opportunistic infections in Human Immunodeficiency Virus infection/Acquired Immunodeficiency Syndrome: Changing epidemiology; diagnostic criteria and methods; management protocols

There were 36.9 million in the world living with human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) as of 2017, and new infections have seen a reduction by 18% since 2010. But this rate of decline is not sufficient for the goal of eradication of AIDS by 2030. Only 21.7  million people infected with HIV have accesses to antiretroviral therapy, with the rest at risk of the potential complications of HIV infection. It has been shown that oral lesions are diagnostic and prognostic of HIV infection, and many oral opportunistic infections continue to be a major problem, particularly in developing countries. It is therefore important that dental surgeons be aware and updated to recognize and manage the oral effects of HIV infection/AIDS. This chapter describes the classification, diagnosis, and management of oral lesions in these patients, based on our current understanding of the infection. This review also discusses the standardization of diagnosis of oral lesions in HIV infection/AIDS patients, immune reconstitution inflammatory syndrome case definition, and the research priorities formulated at the 7th World Workshop on Oral Health and Disease in AIDS.     

The prevalence of AIDS-associated oral lesions in a cohort of patients with hemophilia

Oral and perioral lesions have been widely reported in homosexual males and intravenous drug abusers who are seropositive for the human immunodeficiency virus (HIV) or have acquired immunodeficiency syndrome (AIDS). Several case reports have also noted some AIDS-associated lesions among persons with hemophilia, but the prevalence of these lesions in hemophilia populations is not known. This study investigated the prevalence of oral and perioral lesions in a cohort of patients receiving care at a hemophilia treatment center. In a sample of 32 patients with a factor VIII deficiency and 5 patients with a factor IX deficiency who underwent oral examinations, more than 80% were HIV seropositive. Cervical lymphadenopathy was present in more than half of the patients who were HIV seropositive but was absent in those who were HIV seronegative. Intraoral AIDS-associated lesions were present only in patients for whom a diagnosis of AIDS had been made, indicating that oral lesions among persons with hemophilia who are HIV seropositive may be less prevalent than among homosexual males or intravenous drug abusers who are HIV seropositive.     

Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden

OBJECTIVES: The purpose of this study was to assess the use of human immunodeficiency virus (HIV)-related oral opportunistic infections as markers of immune suppression and viral burden in adults with HIV/acquired immunodeficiency syndrome (AIDS). METHODS: The population consisted of a single institution observational cohort involving 606 patients with HIV/AIDS with CD4 count data and 277 with plasma viral load measurements examined between 1995 and 1999 for the presence of oral manifestations of HIV. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value is reported for the association of specific oral lesions and lesion sets with CD4 counts <200 cells/mm(3) and with plasma HIV RNA >/=20,000 copies/mL. RESULTS: Lesions with moderate-to-high PPVs for CD4 <200 cells/mm(3) were as follows: Kaposi's sarcoma (100%; P =.035), pseudomembranous candidiasis (82. 2%; P <.001), linear gingival erythema (70.0%; P =.015), hairy leukoplakia (66.3%; P <.001), angular cheilitis (60.0%; P =.128), and erythematous candidiasis (58.3%; P =.061). Necrotizing ulcerative periodontal diseases, HIV salivary gland disease, oral ulcers, and oral warts had PPVs below 50%. Concurrent infection with candidiasis and hairy leukoplakia had the highest PPV of 89.3%; P <. 001. PPVs for HIV RNA >/=20,000 copies/mL ranged from 27.3% to 100%, with significant association only for pseudomembranous candidiasis. CONCLUSIONS: Specific common oral lesions are strongly associated with immune suppression, as measured by CD4 cell counts, and are modestly associated with high viral burden, thus serving as potential clinical markers of HIV viremia and the consequent destruction of the immune system with progressive HIV disease.     

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.     

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.     

HIV/AIDS患者口腔病损的临床特点分析

目的了解艾滋病相关口腔病损的临床特点及其与CD4计数和高效抗逆转病毒治疗（highly active antiretroviral therapy,HAART）之间的关系。方法回顾性研究2012~2013年在我院收治的109例HIV/AIDS患者的临床资料,包括流行病史、艾滋病临床阶段、口腔表现、全身症状、CD4计数、治疗及预后等,通过Excel建立数据库,进行统计学分析。结果 109例HIV/AIDS患者中48例出现艾滋病相关口腔病损,其中口腔念珠菌感染48例（44.03%）,以假膜型为主,口腔深大溃疡5例（4.59%）,卡波西肉瘤和淋巴瘤各2例（1.83%）,牙龈线型红斑、口腔单纯疱疹和口腔疣各1例（0.92%）。CD4〈200个/ul组口腔病损的发生率高于CD4≧200个/ul（P〈0.01）,HAART治疗组口腔病损的发生率低于未治疗组（P〈0.01）,差异有显著性。结论口腔是HIV/AIDS患者最常见的机会性感染部位。口腔病损中以假膜型口腔念珠菌病最常见,其次是口腔深大溃疡、口腔恶性肿瘤。卡波西肉瘤和淋巴瘤死亡率高,早期口腔表现易与淋巴结炎、牙龈炎混淆,应尽早进行病理检查,早期诊断。HIV/AIDS患者口腔病损的发生与CD4计数减少有关,HAART治疗能显著降低口腔病损的发生。     

(A3) HIV Phenotypes, oral lesions, and management of HIV-related disease

Workshop participants discussed: the role of HIV subtypes in disease; the treatment of oral candidiasis; the relationship between and among viral load, CD4+ counts, oral candidiasis and oral hairy leukoplakia, pigmentation; and the development of a reliable oral index to predict disease progression. Regarding HIV, the literature revealed that Type I (HIV-I), in particular group M, is involved in the majority (90%) of documented infections, and groups N and O to a lesser extent. Viral envelope diversity led to the subclassification of the virus into nine subtypes, or clades-A-D, F-H, J, and K-each dominating in different geographical areas. HIV-2, currently occurring mostly in West Africa, appears to be less virulent. No evidence could be produced of any direct impact of type, subtype, or clade on oral lesions, and participants believed that further research is not feasible. Oral candidiasis in patients from resource-poor countries should be prevented. When the condition does occur, it should be treated until all clinical symptoms disappear. Oral rinsing with an antimicrobial agent was suggested to prevent recurrence of the condition, to reduce cost, and to prevent the development of antifungal resistance. Lawsone methyl ether, isolated from a plant (Rhinacanthus nasutus leaves) in Thailand, is a cost-effective mouthrinse with potent antifungal activity. Evidence from a carefully designed prospective longitudinal study on a Mexican cohort of HIV/AIDS patients, not receiving anti-retroviral treatment, revealed that the onset of oral candidiasis and oral hairy leukoplakia was heralded by a sustained reduction of CD4+, with an associated sharp increase in viral load. Analysis of the data obtained from a large cohort of HIV/AIDS patients in India could not establish a systemic or local cause of oral melanin pigmentation. A possible explanation was a dysfunctional immune system that increased melanin production. However, longitudinal studies may contribute to a better understanding of this phenomenon. Finally, a development plan was presented that could provide a reliable prediction of disease progression. To be useful in developing countries, the index should be independent of costly blood counts and viral load.     

Innate immune mechanisms to oral pathogens in oral mucosa of HIV‐infected individuals

A crucial aspect of mucosal HIV transmission is the interaction between HIV, the local environmental milieu and immune cells. The oral mucosa comprises many host cell types including epithelial cells, CD4 + T cells, dendritic cells and monocytes/macrophages, as well as a diverse microbiome predominantly comprising bacterial species. While the oral epithelium is one of the first sites exposed to HIV through oral‐genital contact and nursing infants, it is largely thought to be resistant to HIV transmission via mechanisms that are still unclear. HIV‐1 infection is also associated with predisposition to secondary infections, such as tuberculosis, and other diseases including cancer. This review addresses the following questions that were discussed at the 8th World Workshop on Oral Health and Disease in AIDS held in Bali, Indonesia, 13 September —15 September 2019: (a) How does HIV infection affect epithelial cell signalling? (b) How does HIV infection affect the production of cytokines and other innate antimicrobial factors, (c) How is the mucosal distribution and function of immune cells altered in HIV infection? (d) How do T cells affect HIV (oral) pathogenesis and cancer? (e) How does HIV infection lead to susceptibility to TB infections?     

Analysis of HPV 16 and 18 by in situ hybridization in oral papilloma of HIV+ patients

Human immunodeficiency virus (HIV) infection facilitates the development of other infections and lesions including oral papilloma, which has been associated with human papillomavirus (HPV). In analyzing the presence of HPV 16 and 18 by in situ hybridization in oral papillomas from five HIV+ male dental patients, HPV 16 and 18 were observed in 9 of 16 (52.2%) histopathologic specimens. All positive lesions occurred in heterosexual males admitting to oral sexual contact with a female partner (Pearson's correlation; p = 0.0088). These results suggest that oral sexual behavior may be a contributing factor in the presence of HPV 16 and 18 in oral papilloma.     

Association among vitamin D, oral candidiasis, and calprotectinemia in HIV

Vitamin D deficiency is associated with negative health outcomes, including infections. Vitamin D modulates inflammation and down-regulates the expression of calprotectin, a molecule which influences neutrophil functions and which has been linked to oral candidiasis (OC), the most prevalent oral lesion in human immunodeficiency virus (HIV). We hypothesized a positive association between vitamin D deficiency and OC, and that this effect was partially modulated by calprotectinemia. Plasma calprotectin and serum 25 (OH) vitamin D levels were measured in stored samples from 84 HIV-seropositive Chicago women enrolled in the Oral Substudy of the Women's Interagency HIV Study (WIHS). OC and vitamin D deficiency were diagnosed in, respectively, 14 (16.7%) and 46 (54.8%) of those studied. Vitamin D deficiency was positively associated with OC (p = 0.011) and with higher calprotectinemia (p = 0.019) in univariate analysis. After adjustment for CD4, HIV viral load, HIV treatment, and tobacco and heroin/methadone use, vitamin D deficiency remained a significant predictor of OC (OR 5.66; 95% confidence interval 1.01-31.71). This association weakened after adjustment for calprotectinemia, supporting a role for calprotectinemia as a moderator of this effect. These findings support studies to examine the effect of vitamin D status on calprotectinemia, neutrophil functions, and opportunistic mucosal infections in HIV.     

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?     

Human papillomavirus infection and its association with HIV

Human papillomavirus (HPV) can infect oral mucosa, causing asymptomatic infection or warty lesions. Several case-control studies have confirmed HPV as an independent risk factor for squamous cell carcinoma. HPV-related cancers seem to have better prognoses and different risk factors than do HPV-negative ones. HIV-infected patients are known to be at increased risk for persistent genital and anal high-risk HPV infections and intraepithelial neoplasm. Since the era of highly active antiretroviral therapy, the prevalence and persistence of warty lesions in oral mucosa have increased. Oral squamous cell carcinoma was recently added in the case definitions for common HIV-related oral mucosa lesions. The increased risk of HPV infection in HIV patients has been associated with impaired immune response to HPV, highly active antiretroviral therapy, aging of the HIV-infected patients, and direct interaction between the 2 viruses. HPV32 seems to be much more prevalent in asymptomatic HPV infections and warts among those infected with HIV than among those in the general population. Regarding HIV genes, there is evidence of an interaction between HPV and tat, rev, and vpr. HIV might play a role in HPV-associated pathogenesis by exhorting oncogenic stimuli via tat and rev or visa versa.     

Pediatric oral HIV research in the developing world

This article is a review of the literature between 2003 (since the last workshop) and April 2009 (Beijing workshop). It focuses on the prevalence of oral lesions associated with HIV infection, oral lesions as predictors of HIV infection, oral lesions as markers of the efficacy of highly active antiretroviral treatment and quality of life, caries risk, the management of oral lesions, and epidemiologic tests for clinical significance of oral lesions.     

New approaches to Candida and oral mycotic infections: Workshop 2A

This workshop reviewed aspects of the following: oral fungal disease in HIV-infected patients and the predictive value of oral mucosal disease in HIV progression; the role of the oral biofilms in mucosal disease; microbial virulence factors and the pseudomembranous oral mucosal disease process; the role that oral mucosal disease may have in HIV transmission; and the available topical antifungal treatment. This article summarizes the ensuing discussions and raises pertinent problems and potential research directions associated with oral fungal disease in HIV-infected patients, including the frequency of oral candidosis, the role of the intraoral biofilm in the development of oral mucosal disease, and host-pathogen interactions, as well as the development of the fetal oral mucosa, neonatal nutrition, and the role of oral candidosis in this setting. Finally, discussions are summarized on the use of inexpensive effective antifungal mouthwashes in resource-poor countries, the potential stigmata that may be associated with their use, as well as novel topical medications that may have clinical applicability in managing oral candidal infections in HIV-infected patients.     

Patterns of oral manifestation of HIV/AIDS among 225 Nigerian patients

Objective:  The purpose of this study was to determine the prevalence of the oral manifestations of HIV/AIDS and to correlate the prevalence of these lesions with the stages of the disease in the Ife-Ijesa zone, Nigeria. No comprehensive data were available for correlating it with the staging of HIV/AIDS in this region.
Subjects:  The pattern of oral HIV lesions as classified by the EC-Clearinghouse was studied in 225 confirmed consecutive HIV-infected patients in this zone.
Methods:  Clinical dental examinations were conducted under natural daylight on all consenting HIV patients, sitting in an upright chair, using dental mirrors and probes.
Results:  The prevalence of oral HIV lesions was 84.0%, with lesions ranging in number from one to six. The commonest HIV lesion was pseudo-membranous candidiasis (43.1%) followed by erythematous candidiasis (28.9%), angular cheilitis (28.9%), linear gingival erythema (24.0%) and ulcerations (8.9%). Lesions less commonly found were oral hairy leukoplakia (1.3%) and salivary gland swellings (1.3%). Heterosexual intercourse was the most common mode of transmission (94.7%) and HIV-1 (96.9%) the most prevalent pathogen among the study population. The majority of the patients were in the WHO clinical stage III (59.1%) and presented late.
Conclusions:  The prevalence of oral HIV lesions in the present study was high.     

HIV infection and periodontal diseases: an overview of the post-HAART era

HIV infection remains a global health problem of unprecedented dimensions, although the development of highly active antiretroviral therapy (HAART) has significantly modified the course of HIV disease into a manageable chronic disease with longer survival and improved quality of life in HIV-infected subjects. Among the HIV-associated infections, oral lesions have been recognized as prominent features since the beginning of the epidemic and continue to be important. Periodontal diseases strongly associated with HIV infection are classified as linear gingival erythema, necrotizing ulcerative gingivitis and necrotizing ulcerative periodontitis and are included among the cardinal oral lesions. Although oral candidiasis appears to be the infection more significantly decreased after the introduction of HAART, the current literature suggests that the prevalence and course of periodontal lesions have also been modified. Higher prevalence of opportunistic microorganisms has been frequently detected in the subgingival flora of HIV-infected individuals, probably due to the immune status of those patients, as colonization and overgrowth of atypical pathogenic species is facilitated by immunosuppression. Additional research is required regarding biological issues such as the role of oral immune factors and periodontal disease in the persistency of HIV infection, the possibility of oral transmission and the re-emerging of HIV infection.     

HIV/TB co-infection: literature review and report of multiple tuberculosis oral ulcers.

Human immunodeficiency virus/tuberculosis (HIV/TB) co-infected subjects demonstrate enhanced HIV replication and plasma viremia; CD4+ T-cell depletion; morbidity and mortality; and susceptibility to secondary bacterial and fungal infections compared to subjects solely infected with HIV. As the incidence of HIV/TB infection has been increasing, one would have expected to encounter oral lesions of tuberculosis more frequently. However, such oral lesions are uncommon. The lesions usually occur as ulcerations of the tongue. We report an additional case in an HIV/TB co-infected 39 year-old black male, who presented with chronic, painless, multiple oral ulcers, occurring simultaneously on the tongue, bilaterally on the palate and mucosa of the alveolar ridge. Microscopic examination confirmed the presence of chronic necrotizing granulomatous inflammation, with the identification of acid fast bacilli in the affected oral mucosal tissue. Anti-retroviral and anti-tuberculous treatment resulted in the resolution of the oral lesions. Confirmatory histopathological diagnosis following a biopsy is essential to determine the exact nature of chronic oral ulceration in an HIV individual and especially to distinguish between oral squamous cell carcimoma, lymphoma, infection (bacterial or fungal) and non-specific or aphthous type ulceration.     

Occurrence of oral lesions in relation to clinical and immunological status among HIV-infected adult Tanzanians

OBJECTIVE: To determine the association, if any, between the presence of oral lesions and clinical and immunological status of untreated HIV-infected adults in Tanzania. DESIGN: A cross-sectional study. SETTING: AIDS Clinical Trial Clinic (ATCC) at Muhimbili Medical Centre in Dar-es-Salaam, Tanzania. SUBJECTS: 192 HIV-infected individuals not receiving treatment; 156 individuals confirmed to be HIV-seronegative acted as a control group. METHODS: Examination of oral structures, determination of HIV serostatus, clinical status, and peripheral CD4+ T cell and total lymphocyte counts. MAIN OUTCOME MEASURE: Presence of oral lesions. RESULTS: Intra-oral lesions were seen among 7.7% of the HIV-seronegative, 10.4% of the HIV-seropositive and 36.8% of the AIDS groups, respectively. Enlarged parotid glands were seen in 20% of the AIDS patients, 11.9% of the HIV-seropositives, and 5.1% of the HIV seronegatives. Enlargement of submandibular salivary glands was seen in 29.6% of the AIDS patients, 31.3% of the HIV-seropositives compared with 14.7% among the HIV-seronegatives. Multiple regression analysis was used to calculate adjusted odds ratio (OR) for presence of oral lesions. OR for an intra-oral lesion was 1.6 (95% CI = 0.5; 5.0) among the HIV-seropositives and 8.2 (95% CI = 3.5; 19.7) among the AIDS patients using the HIV-seronegatives as reference. OR for an intra-oral lesion was 0.9 (95% CI = 0.3; 2.9) in HIV-infected patients with peripheral CD4+ T cell count of between 200-500 cells mm-3 and 2.7 (95% CI = 0.9; 7.7) in patients with less than 200 cells mm-3. OR for an intra-oral lesion was 0.4 (95% CI = 0.2; 0.9) for patients with peripheral total lymphocyte counts of between 1000-2000 cells mm-3 and 0.9 (95 CI = 0.4; 2.0) for patients with less than 1000 cells mm-3. CONCLUSION: The association of oral lesions with the clinical stage of HIV infection and to a lesser extent peripheral CD4+ T cell count does suggest that these lesions could be used as additional markers of immunosuppression and AIDS.     

Clinical manifestations and risk factors for oral immune reconstitution inflammatory syndrome in Mexico

The immune reconstitution inflammatory syndrome (IRIS) is a rare acute complication presenting in people living with HIV (PLWH) within the first 6 months of starting combined antiretroviral therapy (cART). While there is relevant information about its pathogenesis and clinical spectrum, IRIS‐oral lesions (IRIS‐OLs) have been scarcely described. Thus, to establish the incidence and clinical characteristics of IRIS‐OLs, data from a cohort of 158 HIV individuals starting cART, followed for 6 months, were obtained retrospectively. IRIS‐OLs developed in 11.4% of the individuals, in a median time of 87.5 days, with oral candidiasis being the most frequent manifestation detected in eight individuals (5.1%). The study emphasizes the importance of the correct diagnosis and management of these lesions.