Oral fungal and bacterial infections in HIV-infected individuals: an overview in Africa

Oral opportunistic infections developing secondary to human immunodeficiency virus (HIV) infection have been reported from the early days of the epidemic and have been classified by both the EC-Clearinghouse and the World Health Organisation (WHO). Among the fungal infections, oral candidiasis, presenting in African HIV-infected patients has been sporadically documented. We review the literature with respect to candidal carriage, oral candidiasis prevalence and the predictive value of oral candidiasis for a diagnosis of underlying HIV disease in African HIV-infected patients. The use of oral candidiasis as a marker of disease progression, the species of yeasts isolated from the oral cavity in Africa and the resistance of the yeasts to antifungal agents and treatment regimens are discussed. Orofacial lesions as manifestations of the systemic mycoses are rarely seen in isolation and few cases are reported in the literature from Africa. In spite of the high incidence of noma, tuberculosis, chronic osteomyelitis and syphilis in Africa, surprisingly there have been very few reported cases of the oral manifestations of these diseases in HIV-positive individuals. Orofacial disease in HIV-infected patients is associated with marked morbidity, which is compounded by malnutrition. The authors indicate specific research areas, initially directed at the most effective management strategies, which would complete data in this important area.     

Oral candidiasis and human immunodeficiency virus infection

The association of oral candidiasis with the human immunodeficiency virus (HIV) infection has been known since the advent of the acquired immunodeficiency syndrome (AIDS) pandemic. Oral candidiasis is one of the earliest premonitory signs of HIV infection and its diagnosis may have grave prognostic implications for the eventual development of full blown AIDS. There is now an expanding body of data on novel clinical variants of this 'old' disease, its epidemiology in HIV seropositive individuals and, advances in its management, particularly with respect to the recently introduced bis-triazole antifungals. Current concepts pertaining to the epidemiology, clinical features, pathogenesis, laboratory diagnosis and management of oral candidiasis in HIV infection are reviewed.     

Dental considerations for the paediatric AIDS/HIV patient

HIV infection and AIDS are spreading rapidly among the world's children, especially among African-American and Hispanic children in the USA, and those in developing countries. Although recent research has identified several ways of preventing perinatal transmission of HIV, most of these methods are too expensive for widespread use in developing countries, where the epidemic is most severe. Oral manifestations are early and common clinical indicators of HIV infection and progression in children, as in adults, although the specific manifestations differ between adults and children. Oropharyngeal candidiasis is the most common sign of HIV infection in children and is significantly associated with markers of HIV disease progression. Other common oral manifestations in children include herpes simplex, linear gingival erythema, parotid enlargement and recurrent aphthous ulceration. Further research is needed on the ways in which oral manifestations can be used as predictors of disease progression; on the impact of the limited availability of health care for impoverished families who are disproportionately affected by HIV infection; and on supportive care and its impact on infected children's quality of life.     

Prognostic significance of HIV-associated oral lesions and their relation to therapy

The oral manifestations of HIV infection have been considered to be of value in assessing disease progression in the developed world. However, the potential use of oral lesions as prognostic markers in resource-poor countries has yet to be fully investigated. There is reasonably compelling evidence in the developed world for an association between oral lesions and viral load. However, the true nature of this association is less clear and there are few data available from the developing world. With the introduction of HAART, a change in prevalence of the oral manifestations of HIV infection has been observed, including regression of oral candidiasis, Kaposi's sarcoma and oral hairy leukoplakia. However, oral condylomata and herpes simplex virus infection appear to persist with HMRT therapy. Further research in partnership with resource-poor countries is required to document disease progression and the associated oral lesions in both adults and children.     

The global changing pattern of the oral manifestations of HIV

The significance of the oral manifestations of HIV has been widely recognised since the start of the epidemic. It is estimated that more than 38 million people are living with HIV currently, with more than a third presenting with oral manifestations. Access to optimum clinical management and effective treatment in resource‐rich countries has led to a remarkable decrease in some of the oral manifestations in the HIV population but this is not mirrored in developing countries, where most HIV‐positive patients reside. In this paper, a review of the literature since the start of the HIV infection in different parts of the world is presented to highlight the current significance of the oral conditions in this population. Oral candidiasis was repeatedly reported as the most encountered oral manifestation of HIV in different countries, including in studies on groups on anti‐retroviral therapy. Over time salivary gland disease was reported less in developed countries but was encountered more in developing countries. There is evidence to show that the prevalence of oral warts increased with the establishment of anti‐retroviral therapy. A review of the worldwide prevalence of HIV‐related oral conditions indicates that except for oral hairy leucoplakia, the prevalence of all other nine commonly reported oral conditions remained the same or increased over time. Oral opportunistic infections in HIV‐infected patients are an ongoing clinical burden mainly in developing countries. Maintaining research in the subject and improving access to HIV treatment will help address the oral health inequalities around the world.     

Host factors associated with HIV-related oral candidiasis. A review.

Human immunodeficiency virus (HIV)-related oral candidiasis affects approximately one third of HIV-seropositive patients and more than 90% of patients with AIDS. It is necessary to identify patients who have a greater risk of candidiasis developing, so that interventions can be designed to reduce the frequency. This is particularly important because there is evidence that Candida species are immunosuppressive and therefore candidiasis may adversely affect the prognosis of patients with HIV. Susceptibility to HIV-related oral candidiasis is associated with xerostomia, severity of disease, depression of cell-mediated immunity, and older age (greater than 35 years). The frequency of HIV-related oral candidiasis is notably increased when the CD4 lymphocyte count falls to less than 300 cells/mm3. Xerostomia appears to be a better predictor of HIV-related oral candidiasis than CD4 count and should be prevented (e.g., by avoiding xerogenic drugs) and treated, when necessary, to minimize the risk of oral candidiasis.     

Innovations for prevention and care of oral candidiasis in HIV‐infected individuals: Are they available?—A workshop report

Oral candidiasis (OC) is the most prevalent HIV‐related oral lesion in patients on combined anti‐retroviral therapy (cART) or without cART. Management is challenged in some patients by development of resistance to azole drugs, such as fluconazole. Recent scientific knowledge about OC pathogenesis, the role of OC in the immune reconstitution inflammatory syndrome (IRIS), the relationship of OC with the microbiome, and novelties in OC treatment was discussed in an international workshop format. Literature searches were conducted to address five questions: (a) Considering the pathogenesis of Candida spp. infection, are there any potential therapeutic targets that could be considered, mainly in HIV‐infected individuals resistant to fluconazole? (b) Is oral candidiasis part of IRIS in HIV patients who receive cART? (c) Can management of the oral microbiome reduce occurrence of OC in patients with HIV infection? (d) What are the recent advances (since 2015) regarding plant‐based and alternative medicines in management of OC? and (e) Is there a role for photodynamic therapy in management of OC in HIV‐infected patients? A number of the key areas where further research is necessary were identified to allow a deeper insight into this oral condition that could help to understand its nature and recommend alternatives for care.     

Oral lesions and conditions associated with human immunodeficiency virus infection in 300 south Indian patients

BACKGROUND: Human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) is a major health problem in India. The National AIDS Control Organisation (NACO) of India reports a seropositivity of 25.03 per thousand for the whole country, as of October 1999. In spite of this high prevalence there are very few reports of oral lesions and conditions in Indian HIV/AIDS patients, which are important in early diagnosis and management of these patients. OBJECTIVE AND SETTING: The present report describes the oral lesions in 300 HIV positive symptomatic patients presenting to us at RAGAS-YRG CARE, a non-governmental organisation in Chennai, South India, over a period of 9 months in 1998. METHOD: Lesions were diagnosed on clinical appearance using international criteria. RESULTS: Of the 300 patients 89% had acquired the infection through heterosexual contact. There were 205 males and 95 females, aged from 7 months to 72 years. Forty-seven percent of the patients were in the age group 21-30 years. CD4 counts were ascertained for 105 patients, 64 (62%) had CD4 counts < or = 200. A total of 217 (72%) of the 300 patients had some oral lesion when examined. Gingivitis (47%) and pseudomembranous candidiasis (33%) were the most common oral lesions. The other oral lesions seen were oral mucosal pigmentation (23%), erythematous candidiasis (14%), periodontitis (9%), angular cheilitis (8%), oral ulcers (3%), oral hairy leukoplakia (3%), hyperplastic candidiasis (1%), oral submucous fibrosis (2%) and one case of leukoplakia. CONCLUSIONS: Oral lesions occur commonly in HIV infection. A comprehensive oral examination may not only suggest HIV disease but may also be useful in monitoring the disease progression. This is a cost-effective procedure, which may be useful in screening large populations in developing countries like India.     

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.     

(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.     

Oral lesions in HIV infection in developing countries: an overview

HIV infection is a major global health problem affecting developing and developed countries alike. Oral lesions that are associated with this disease are important, since they affect the quality of life of the patient and are useful markers of disease progression and immunosuppression. Oral lesions in HIV infection have been well-documented in developed countries, but there are fewer reports on oral lesions from developing countries. Oral candidiasis is the most common opportunistic infection seen in all continents. Kaposi's sarcoma has been reported only from Africa and Latin America, while histoplasmosis and penicilliosis were reported in patients with advanced disease from Thailand. HIV-associated salivary gland disease has a high prevalence in Africa and Latin America, especially in the pediatric group. It is clear that there are considerable regional variations in the oral manifestations of HIV infection, depending both on the populations studied and on the clinical expertise available, among other factors. Well-designed and -documented studies are necessary for the correct assessment of the nature and magnitude of the problem in developing countries, if oral health measures are to be effectively formulated for the HIV-infected.     

Aetiological factors for oral manifestations of HIV

OBJECTIVES: Describe the oral diseases in HIV-infected individuals in London, UK and identify social and medical factors related to the presence of specific oral diseases.
DESIGN: Cross-sectional analytic study.
SETTING: Dental clinics.
SUBJECTS: Consecutive sample of 456 patients with HIV infection.
METHODS: Social and medical history and clinical examinations. Univariate and logistic regression analysis.
OUTCOMES: Presence of HIV-associated oral disease.
RESULTS: 80% of patients with AIDS and 50% of patients with HIV had a specific oral disease. The most common diseases were hairy leukoplakia (30%), erythematous candidiasis (24%), pseudomembranous candidiasis (14%), angular chielitis (6%), necrotising periodontal disease (8%) and non-recurrent ulceration (6%).
CONCLUSIONS: The presence of erythematous candidiasis was not related to advanced HIV disease. Pseudomembranous candidiasis, hairy leukoplakia and mucosal ulceration were significantly associated with advanced HIV disease. Smoking was also identified as a strong aetiological factor in oral diseases. Longitudinal studies are required to further explore the prognostic significance of oral diseases in HIV infection.     

(B1) Candida and mycotic infections

Oral candidiasis (OC) is the most common mucosal manifestation of HIV infection. This workshop examined OC and other mycoses associated with HIV infection. Historically, blood CD4 cell numbers were the primary prognosticator for the development of OC. However, a study that statistically evaluated the predictive role of HIV viral load vs. CD4 cell counts revealed viral load to be a stronger predictor for OC. The role of biofilms and antifungal resistance in recalcitrant OC is unclear at present. In general, micro-organisms including yeasts in biofilms are more resistant to antifungals than their planktonic counterparts. When the remaining organisms are eliminated, the few resistant organisms may not be problematic, because they are present in low numbers. Unusual exotic mycoses in HIV-infected patients are more common in patients from the developing than the developed world. These infections may be recurrent and recalcitrant to therapy, be present in multiple and uncommon sites, increase with the progression of HIV disease, and may play a role similar to that of the more common mycoses. Typing and subtyping of yeasts are probably not critical to the clinical management of candidiasis caused by Candida albicans and non-albicans strains, including C. dubliniensis, because it is responsive to antifungal therapy. C. glabrata is probably the only exception. The presence of oral thrush in infants younger than 6 months of age is associated with an increased post-natal transmission risk of HIV infection. Thus, perinatal retroviral therapy should be combined with the treatment of oral thrush to prevent the post-natal acquisition of HIV.     

Paediatric AIDS - related linear gingival erythema: a form of erythematous candidiasis?

Three vertically HIV-infected children showed, in addition to oral candidiasis, HIV-gingivitis, which healed on antimycotic treatment. The intense linear gingival erythema of a fourth child was also clinically evaluated as a possible form of erythematous oral candidiasis. Direct microscopic examination of material from the gingival lesions of the latter disclosed yeast cells and hyphae. Subsequent culture, biochemical and serological tests identified the yeast as Candida dubliniensis. As the patient was on long-term prophylaxis with fluconazole, ketoconazole was administered and led to a good clinical response. This is the first report implicating this new Candida species as a pathogen in linear gingival erythema in a HIV-positive individual. The case reports presented provide evidence that linear gingival erythema may be of candidal origin. Further clinical and laboratory observations are required to establish whether this condition constitutes a variant of erythematous candidiasis associated with paediatric HIV infection.     

A systematic review of the management of oral candidiasis associated with HIV/AIDS.

The purpose of this review was to investigate the management of oral candidiasis in HIV/AIDS patients and to evaluate the different guidelines available for its management. A number of topical and systemic antifungal medications are used to treat oral candidiasis in HIV-positive patients. Milder episodes of oral candidiasis respond to topical therapy with nystatin, clotrimazole troches or oral ketoconazole. Fluconazole has been extensively evaluated as a treatment for candidiasis. With HIV-infection, a cure rate of 82% has been achieved with a daily oral dose of 50 mg. Fluconazole was found to be a better choice of treatment for relapsing oropharyngeal candidiasis, resulting in either better cure rates or better prevention of relapse. Intravenous amphotericin B has been found to be effective in azole-refractory candidiasis and is well tolerated. Topical therapies are effective for uncomplicated oropharyngeal candidiasis; however, patients relapsed more quickly than those treated with oral systemic antifungal therapy. Nystatin appeared less effective than clotrimazole and the azoles in the treatment of oropharyngeal candidiasis. Clotrimazole was found to be just as effective for resolution of clinical symptoms as the azoles, except when patient compliance was poor. Fluconazole-treated patients were more likely to remain disease-free during the fluconazole follow-up period than those treated with other antifungal agents.     

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.     

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.     

Greater severity and extent of periodontal breakdown in 136 south Indian human immunodeficiency virus seropositive patients than in normal controls: a comparative study using community periodontal index of treatment needs.

Apart from the more or less distinctive forms of periodontal disease associated with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome there remains considerable uncertainty as to whether or not conventional destructive periodontitis is exacerbated in HIV positive individuals. This is especially so in developing countries, from which few studies have been reported. The present study compared the severity and extent of periodontal break down in 136 HIV positive individuals from Chennai, South India, with 136 age-matched controls from the same low socio-economic and ethnic group. All surfaces of all teeth were scored for the community periodontal index of treatment needs (CPITN). Statistical analysis was performed using SPSS package. The results of the present study show that CPITN is a simple, useful technique to assess periodontal status in immunosuppressed patients and that periodontitis is associated with immunosuppression and oral candidiasis. The assessment of periodontal statuscould thus be a useful tool in minimally invasive screening of populations for HIV disease, especially in those parts of the world, like India and Africa, with high prevalence and rising incidence.     

Periodontal diseases and HIV infection

The workshop considered six related questions about periodontal changes seen in HIV infection. 1) To what extent are specific periodontal changes associated with HIV? 2) Are conventional periodontal diseases modified by HIV infection? The changes associated with HIV appear to be modified presentations of conventional diseases. Research should identify initiation and progression factors for necrotizing diseases. 3) What is the role of geography and transmission groups? These questions cannot be answered without greater standardisation of research methods. 4) Has the epidemiology of these changes changed with the advent of new therapies? The data required to answer this question should be available soon but this question is irrelevant to the vast majority of people with HIV. 5) What pathogens are involved in periodontal changes seen in HIV infection? The role of Candida spp. and other potential pathogens requires further investigation. 6) What management protocols are suitable for the periodontal diseases? The significance of periodontal diseases among people with HIV in developing countries is not known. Further research is needed of the effectiveness of interventions especially necrotizing disease in developing countries. The quality of research of these diseases would be enhanced by standardized approaches. A list of relevant variables might prevent their omission from studies.     

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.