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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., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Objective: Compare the safety and efficacy of topical gentian violet with that of nystatin oral suspension (NYS) for the treatment of oropharyngeal candidiasis in HIV-1-infected adults in resource-limited settings., Design: Multicenter, open-label, evaluator-blinded, randomized clinical trial at eight international sites, within the AIDS Clinical Trials Group., Study Participants and Intervention: Adult HIV-infected participants with oropharyngeal candidiasis, stratified by CD4 cell counts and antiretroviral therapy status at study entry, were randomized to receive either gentian violet (0.00165%, BID) or NYS (500 000 units, QID) for 14 days., Main Outcome Measure(s): Cure or improvement after 14 days of treatment. Signs and symptoms of oropharyngeal candidiasis were evaluated in an evaluator-blinded manner., Results: The study was closed early per Data Safety Monitoring Board after enrolling 221 participants (target = 494). Among the 182 participants eligible for efficacy analysis, 63 (68.5%) in the gentian violet arm had cure or improvement of oropharyngeal candidiasis versus 61 (67.8%) in the NYS arm, resulting in a nonsizable difference of 0.007 (95% confidence interval: -0.129, 0.143). There was no sizable difference in cure rates between the two arms (-0.0007; 95% confidence interval: -0.146, 0.131). No gentian violet-related adverse events were noted. No sizable differences were identified in tolerance, adherence, quality of life, or acceptability of study drugs. In gentian violet arm, 61 and 39% of participants reported 'no' and 'mild-to-moderate' staining, respectively. Cost for medication procurement was significantly lower for gentian violet versus NYS (median $2.51 and 19.42, respectively, P = 0.01)., Conclusion: Efficacy of gentian violet was not statistically different than NYS, was well tolerated, and its procurement cost was substantially less than NYS.

Human immunodeficiency virus (HIV)-associated oral disease among people living with HIV infection includes oral candidiasis, oral hairy leukoplakia, Kaposi sarcoma, oral warts, herpes simplex virus ulcers, major aphthous ulcers or ulcers not otherwise specified, HIV salivary gland disease, and atypical gingival and periodontal diseases. Diagnosis of some oral lesions is based on clinical appearance and behavior, whereas others require biopsy, culture, or imaging for definitive diagnosis. Management strategies including pharmacologic and nonpharmacologic approaches are discussed in this article. Dentists also need to be cognizant of the potential oral side effects of HIV antiretroviral medications., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Oral candidiasis is a clinical fungal infection that is the most common opportunistic infection affecting the human oral cavity. This article reviews the pathogenesis, clinical presentations, diagnosis and treatmentstrategies for oral candidiasis.

Objective: We aimed to examine if smoking is an independent predictor of oral candidiasis (OC) among HIV-1 infected persons., Methods: The cross-sectional part of this study evaluated 631 adult dentate HIV-1 seropositive persons examined for OC from 1995-2000 at the University of North Carolina Hospitals in Chapel Hill, NC. In the second part, from the above sample, a total of 283 individuals who were free of HIV-associated oral diseases at baseline were followed up for 2 years to assess incident OC events. Data collected from medical record review, interview questionnaires, and clinical examinations were analyzed using chi-squared tests and t-tests. Logistic regression models were developed for prevalent OC employing the likelihood ratio test, whereas Poisson regression models were developed for assessing cumulative incidence of OC. These models included a variety of independent variables to adjust for confounding., Results: Thirteen percent of participants had OC only; 4.6% had OC with Oral Hairy Leukoplakia; and 69.7% had neither. Smoking was associated with OC in all models [prevalent OC - current smokers: logistic regression - Odd ratio (95% CI) = 2.5 (1.3, 4.8); Incident OC - current smokers: Poisson regression (main effects model) - Incidence rate ratio (95% CI) = 1.9 (1.1, 3.8)]. Other Poisson regression models suggested evidence for effect modification between CD4 cell count and incident OC by smoking., Conclusion: Smoking is an independent risk factor for the development of OC in HIV-1 infected persons, and the risk of OC is modified by CD4 cell count which measures strength of the immune system., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Background: Oropharyngeal candidiasis (OPC) is a major cause of morbidity in patients with malignancies. It is a common complication of head and neck radiation therapy and can result in pain, dysgeusia (taste changes), anorexia, malnutrition, and esophageal or systemic dissemination. Clinicians should be aware of current epidemiology, elements of diagnosis, and therapeutic trials guiding the recent recommendations for prophylaxis and management of OPC, a disease often incorrectly perceived as benign., Methods: This review discusses OPC with focus in head and neck cancer patients receiving radiotherapy., Results: Local treatments are recommended as first-line therapy in milder forms of OPC. In the setting of local therapy, products that provide prolonged contact time and are not sucrose sweetened may result in successful prevention and management with low risk of oral/dental complications., Conclusion: Diagnosis and management of OPC is required in head and neck cancer patients treated with radiation. Local therapy is suggested as first-line treatment for OPC, unless severe clinical infection or high risk immune suppression necessitate systemic therapy. The availability of effective locally delivered (topical) medications may provide potential for prophylaxis for carriers of Candida species in head and cancer patients during radiation therapy.

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.

Purpose: The aims of this systematic review were to determine, in patients receiving cancer therapy, the prevalence of clinical oral fungal infection and fungal colonization, to determine the impact on quality of life and cost of care, and to review current management strategies for oral fungal infections., Methods: Thirty-nine articles that met the inclusion/exclusion criteria were independently reviewed by two calibrated reviewers, each using a standard form. Information was extracted on a number of variables, including study design, study population, sample size, interventions, blinding, outcome measures, methods, results, and conclusions for each article. Areas of discrepancy between the two reviews were resolved by consensus. Studies were weighted as to the quality of the study design, and recommendations were based on the relative strength of each paper. Statistical analyses were performed to determine the weighted prevalence of clinical oral fungal infection and fungal colonization., Results: For all cancer treatments, the weighted prevalence of clinical oral fungal infection was found to be 7.5% pre-treatment, 39.1% during treatment, and 32.6% after the end of cancer therapy. Head and neck radiotherapy and chemotherapy were each independently associated with a significantly increased risk for oral fungal infection. For all cancer treatments, the prevalence of oral colonization with fungal organisms was 48.2% before treatment, 72.2% during treatment, and 70.1% after treatment. The prophylactic use of fluconazole during cancer therapy resulted in a prevalence of clinical fungal infection of 1.9%. No information specific to oral fungal infections was found on quality of life or cost of care., Conclusions: There is an increased risk of clinically significant oral fungal infection during cancer therapy. Systemic antifungals are effective in the prevention of clinical oral fungal infection in patients receiving cancer therapy. Currently available topical antifungal agents are less efficacious, suggesting a need for better topical agents.

Background: Oropharyngeal candidiasis (OPC) is the most common opportunistic infection among persons infected with human immunodeficiency virus (HIV). Once-daily miconazole 50 mg buccal tablet (MBT) is a novel delivery system using an extended-spectrum azole with potent in vitro activity against many Candida species, including some that may be resistant to other azoles., Methods: This phase 3, double-blind, double-dummy, multicenter trial evaluated 578 randomized patients with HIV infection and OPC. The study compared the efficacy and safety of MBT once daily with clotrimazole 10 mg troches (CT) 5 times daily for 14 days. The co-primary efficacy endpoints were clinical cure at test of cure (TOC) visit (days 17-22) in the intent-to-treat (ITT) and per protocol (PP) populations., Results: Clinical cure rate at TOC visit for MBT-treated patients was statistically noninferior to CT-treated patients in both the ITT (61% vs 65%) and PP (68% vs 74%) populations. Secondary endpoints, safety, and tolerability were similar between treatment groups., Conclusions: In this large trial, once-daily MBT was shown to be noninferior to CT 5 times daily in the treatment of OPC in HIV-positive patients. MBT offers an effective, safe, and well-tolerated topical treatment option for OPC administered as a convenient once-daily dose.

Joint occurrence of two or more diseases may impact their transmission, clinical presentation, management approaches, and treatment efficacy. Although oral candidiasis (OC) and oral hairy leukoplakia (OHL) are the most commonly occurring opportunistic oral diseases of HIV-infected patients, literature describing their joint occurrence is sparse. The purpose of this project was to develop an explanatory multivariable model for joint occurrence of OC and OHL (OC-OHL). This cross-sectional study examined 631 adult dentate HIV-1 seropositive persons for OC and OHL from 1995-2000 at the University of North Carolina Hospitals in Chapel Hill, NC. Data collected from medical record review, interviews and clinical examinations were analyzed using chi(2) tests, t itests, and nonparametric tests. Multivariable proportional odds models were developed, using the likelihood ratio test and adjusting for several demographic, behavioral, and biological factors. Thirteen percent of participants had OC only; 12.8% had OHL only; 4.6% had OC-OHL; whereas 69.7% had neither. Occurrence of OC-OHL was independently associated with CD4+ counts less than 200 cells per microliter (adjusted odds ratio [OR] (95% confidence interval {CI}) = 13.4 (6.6, 27.2) and CD4+ counts 200-499 cells per microliter (OR = 3.9 [1.9, 8.1]); current smokers (OR = 2.3 [1.4, 3.8]); and whites (OR = 1.7 [1.1, 2.5]). Combination antiretroviral therapy was protective (OR = 0.5 [0.3, 0.9]). In an HIV-1-infected population, lower CD4+ cell counts and smoking were important independent risk indicators for joint occurrence of OC and OHL.

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., (Copyright Blackwell Munksgaard, 2005.)

Objectives: To establish incidence rates and risk factors for HIV-associated oral candidiasis (OC), oral hairy leukoplakia (OHL), and any HIV-associated oral diseases (HIV-OD)., Design: This prospective, cumulative case-control study followed 283 initially oral disease-free HIV-1-infected men and women for 2 years. Incidence rate ratios (IRR) and incidence proportions for OC, OHL, and HIV-OD were estimated. Multivariable analyses using Poisson regression determined the most parsimonious best-fitting model explaining the outcomes., Results: Incidence rate (per 1000 person-months) was 9.3 for OC, 6.8 for OHL, and 13.5 for HIV-OD. Incidence of OC was associated with low CD4 count (adjusted IRR = 3.0 (95% CI = 1.7, 5.1)), smoking (IRR = 1.9 (1.0, 3.8)) and combination antiretroviral therapy (IRR = 0.3 (0.1, 0.8)). Incidence of OHL was associated with low CD4 count, conditional upon smoking status. Conclusions Low CD4 count and smoking are important risk factors for HIV-associated OC and OHL. Antiretroviral medications are protective for OC but not for OHL.

Oropharyngeal candidiasis, typically caused by Candida albicans, is the most common oral disease associated with human immunodeficiency virus type 1 (HIV-1) infection. Secretory leukocyte protease inhibitor (SLPI), a 12-kDa antiprotease, suppresses the growth of C. albicans in vitro. To determine whether the mucosal protein plays a role in protecting oral tissues against fungal infection, we conducted a cross-sectional study investigating the oral and systemic health and salivary SLPI levels in 91 dentate HIV-1-infected adults receiving medical care in the southeastern United States. Participants with a self-reported history of clinical oropharyngeal candidiasis during the previous 2 years constituted the test group (n = 52), while the comparison group (n = 39) had no oropharyngeal candidiasis during that period. Data collected from medical records, oral examination, and SLPI enzyme-linked immunosorbent assay quantitation of whole saliva were analyzed by t test, analysis of variance, linear regression, and unconditional logistic regression. The test group had a significantly higher mean salivary SLPI level than the comparison group (1.9 microg/ml versus 1.1 microg/ml, P < 0.05). Linear regression modeling identified CD4 cell count and history of oropharyngeal candidiasis as key predictors of salivary SLPI and revealed a significant interaction (P < 0.05) between immunosuppression (CD4 cell count below 200 cells/ microl) and positive history of oropharyngeal candidiasis in predicting salivary SLPI level. By logistic regression modeling, a salivary SLPI level exceeding 2.1 microg/ml, low CD4 count, antiretroviral monotherapy, and smoking were key predictors of oropharyngeal candidiasis. These data support a key role for SLPI in the oral mucosal defense against C. albicans. The antimicrobial mucosal protein may serve as an indicator of previous oropharyngeal candidiasis infection among immunosuppressed persons.

Objective: A systematic review of randomized clinical trials published between 1966 and April 2000 was undertaken to determine the strength of evidence for the effectiveness of antifungal drugs (nystatin, clotrimazole, amphotericin B, fluconazole, ketoconazole, and itraconazole) to prevent and treat oral candidiasis in human immunodeficiency virus-positive patients., Study Design: An automated database search identified 366 articles. Six met inclusion and exclusion criteria with respect to prophylaxis; 12 met criteria for treatment of oral candidiasis., Results: The evidence for the prophylactic efficacy of fluconazole is good, although insufficient to draw conclusions about the other antifungals. Evidence for treatment effectiveness is insufficient for amphotericin B but good for nystatin, clotrimazole, fluconazole, ketoconazole, and itraconazole., Conclusion: Suggestions for strengthening the evidence base include the following: use of larger, more well-defined groups; control for immunologic status, viral load, history of oral candidiasis, past exposure to antifungals, baseline oral Candida carriage, drug interactions, and antiretroviral therapy; and consistent use of compliance monitors, fungal speciation, and susceptibility testing.