Brazilian Journal of Oral Sciences Piracicaba Dental School - UNICAMP EISSN: 1677-3225 Vol. 9, Num. 4, 2010, pp. 470-474

Braz J Oral Sci, Vol. 9, No. 4, October-December, 2010, pp. 470-474

Risk factors for oral candidiasis in Brazilian HIV-infected adult patients

Mariela Dutra Gontijo Moura¹, Soraya de Mattos Camargo Grossman¹, Linaena Méricy da Silva Fonseca², Maria Letícia Ramos-Jorge³, Ricardo Alves Mesquita⁴

¹MSc, Graduate students, Department of Oral Pathology, Dental School, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
²PhD, Assistant Professor, School of Health, Faculdades Pitágoras, Belo Horizonte, MG, Brazil
³PhD, Professor. Department of Dentistry, Federal University of Vales Jequitinhonha and Mucuri, Diamantina, MG, Brazil
⁴PhD, Associate Professor, Department of Oral Pathology, Dental School, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

Received for publication: December 7, 2009 Accepted: August 27, 2010

Code Number: oc10057

Abstract

Aim: The goals of this study were: 1) to estimate the prevalence of oral candidiasis (OC) in a sample of Brazilian HIV-infected adult patients, and 2) to investigate the risk factors for HIVassociated OC in this sample.
Methods: This case-control study included 112 HIV-infected patients treated between 2002 and 2004 at a clinic for sexually transmitted diseases. Data were collected from medical records and clinical examinations. Diagnosis of OC was performed in accordance with the International Classification System and cytological features. Seventeen clinical and laboratorial variables were registered. Univariate analyses were performed on all variables. Multiple logistic regression techniques were used to develop a model and identify the set of variables that may predict risk factors in HIV-infected adult patients with OC.
Results: Prevalence of OC was 31.3%. OC was associated with oral hairy leukoplakia (OHL) [p<0.001; odds ratio (OR) = 10.2 (95%CI: 4.0-26.0)], previous use of fluconazole [p<0.001; OR=27.4 (95%CI: 8.1-92.0)] and viral load [p=0.042; OR=2.3 (95%CI: 1.0-5.3)].
Conclusions: These results are important for the development of strategies to eliminate these risk factors and significantly reduce OC in HIV-infected patients.

Keywords: AIDS, candidiasis, HAART, HIV infection, prevalence ratio, risk factors.

Oral candidiasis (OC) is the most frequent HIV infection-associated oral disease, and can also act as a marker for immunosuppression^1-6. The prevalence and incidence of HIV infection in Brazil are 7.5% and 1.39%, respectively⁵. The literature supports the position that systemically applied antifungal drugs have the greatest efficacy for the treatment of OC. However, these therapies must be prescribed following a thorough assessment of the risk for developing drug-induced toxicities⁶. OC responds to antifungal therapy, but eradication is rarely achieved unless the underlying immune-compromised state is resolved^2,7.

Data about risk factors for HIV infection-associated oral lesions in the South American population are insufficient^1,3,8. Some studies have identified potential risk factors for development of HIV-associated oral diseases^3-4,7,9-11. Moura et al.⁴ demonstrated statistically significant associations between oral hairy leukoplakia (OHL) and HIV-1 viral load, OC, previous use of fluconazole and systemic acyclovir in Brazilian HIV-infected adult patients. Therefore, the goals of this study were: 1) to estimate the prevalence of OC in a sample of Brazilian HIV-infected adult patients, and 2) to investigate the risk factors for HIV-associated OC in this sample.

Between 2002 and 2004, 112 HIV-infected adult volunteers were recruited from the Orestes Diniz Treatment Center of Parasitic and Infectious Diseases (CTR-DIP) (Belo Horizonte, MG, Brazil) to participate in this case-control study, approved by the UFMG’s Bioethics Research Committee (protocol number 339/03). All patients were first diagnosed with HIV-infection by enzyme-linked immunosorbant assay (ELISA) as the primary detection test, and the diagnoses were subsequently confirmed by the Western blot test. The diagnosis for HIV-infection had already been established during the period of the first exam for all patients. A single, validated examiner, trained in oral medicine, conducted the oral clinical exam in accordance with the World Health Organization standards¹². OC diagnosis was based on the published standard presumptive clinical criteria of International Classification Systems¹³. Also, cytological features were considered in the diagnosis of OC: morphologic microscopic observation of fungal mycelial filaments from a non-cultured specimen scraped from the oral mucosa by Periodic Acid Schiff (PAS) staining. Patients with a confirmed diagnosis of OC were included in the case group; those without clinical features of OC were included in the control group.

The following variables were obtained from the case and control groups: age, gender, race, route of transmission, CD4 T lymphocytes count, viral load, platelets count, salivary flow, xerostomia, OHL, previous use of fluconazole, previous use of systemic acyclovir, use of highly active anti-retroviral therapy (HAART), use of zidovudine (AZT), intravenous drug use, smoking, and alcohol consumption. The CD4 T lymphocyte count was divided into <200 cells/mm³ and >200 cells/mm³. The viral load was divided into <3,000 copies/µL and >3,000 copies/µL. Platelet count was divided into <150,000/mm³ and >150,000/mm^3,4,14-16. The measurement of the salivary flow was performed through the collection of stimulated saliva, over the course of five minutes, in accordance to Tárzia¹⁷. The salivary flow was identified as normal (> 0.70mL/min), moderately low (0.50 to 0.70 mL/min), low (0.30 to 0.49 mL/min), or severely low (0 to 0.29 mL/min)¹⁷. Xerostomia was identified when the patient complained of dry mouth. The diagnosis of OHL was established according to clinical features and exfoliative cytology^18-19. OHL was treated with topical applications of either podophyllin resin (25%) (prepared at UFMG’s pharmacy), or podophyllin resin (25%) together with acyclovir cream (5%) (EMS-Genéricos^®, São Bernardo do Campo, SP, Brazil)²⁰. Smoking individuals were identified as those who had smoked >100 cigarettes over their lifetime and smoked at the time of the study. Non-smoking individuals were identified as those who had not smoked >100 cigarettes in their lifetime¹⁶. Alcohol consumption was considered when the patient consumed alcohol on a daily basis.

Statistical analysis of data was performed using the Statistical Package for Social Service (SPSS) software program (version 16.0, SPSS Inc., Chicago, IL, USA). Univariate analyses were performed on all variables of this study using the Fisher’s and Chi-squared tests (2-sided tests). Statistical significance was at a level of 0.05. The results of this analysis were expressed as an odds ratio (OR) with a 95% confidence interval (CI). Variables with p<0.25 were identified and included in the multivariate analyses. Multiple logistic regression techniques were then used to develop a model and identify the set of variables that may predict risk indicators in HIV-infected adult patients with OC.

The sample included 35 (31.3%) HIV-infected adult patients with OC and 77 (68.7%) patients who did not have OC. The majority of patients, 82 (73.2%), were men. Sixtyfive patients (58.0%) were Caucasian and 47 (42.0%) were Black. Age varied from 20 to 59 years (mean age of 39.5 years). Regarding the route of transmissions, the sample included 4 (3.6%) intravenous drug users, 13 (11.6%) not informed, 51 (45.5%) heterosexuals, 40 (35.7%) men who have sex with men (MSM) and 4 (3.6%) bisexuals. Of the 35 patients with OC, 20 (57.1%) were heterosexual, 8 (22.8%) were MSM, 2 (5.7%) were bisexual, 1 (2.8%) was intravenous drug user, and 4 (11.4%) did not inform.

OC was erythematous in 19 cases (54.3%), pseudomembranous in 10 cases (28.6%), and both in 06 cases (17.1%). Angular cheilitis (9 cases) was also identified in our study, but all cases were in association with erythematous OC. Table 1 summarizes the proportional prevalence and univariate analyses. Statistically significant association was identified between the viral load of 3,000 copies/µL or greater (p=0.042; OR=2.3), the OHL (p<0.001; OR=10.2) and the previous use of fluconazole (p<0.001; OR=27.4) with OC. Platelets count (<150,000/mm³), HAART (patients that did not take), gender (men), reduction of salivary flow, previous use of systemic acyclovir, use of AZT (patients that did not take) and intravenous drug use (patients that did not use) were more frequently present in association with OC, though without a significant relationship (table 1).

Table 2 demonstrates the logistic regression models. Multiple logistic regression tests confirmed the statistically significant association between the previous use of fluconazole and OHL with OC, regardless of the use of HAART. Adjusted results showed that HIV-infected patients with OHL, and those who had previously used fluconazole, were 3.6 times (95% CI=1.1-12.3) and 14.3 times (95% CI=3.8-53.6) more likely to present OC, respectively, regardless of the use of HAART.

It has been suggested that OC represents a relevant marker of immune system status in HIV-infected patients, and is also a clinical predictor of AIDS progression^3-4,7,11,14. the current study. In our study, this may be attributed to the In the present study, the prevalence of OC was 31.3%. Most fact that HAART is easily accessible in Brazil, especially in studies have reported prevalence rates of OC between 17.2% CTR-DIP, which contributes to the improvement of patient and 58.6%^3,7,11,21. immunity, favoring an increase in the CD4 T lymphocyte

It is intuitive to expect an increase of OC in patients count (>200 cells/mm³)⁴ . with low CD4 T lymphocyte count (<200 cells/mm³)^3,7,9-Previous studies have reported a heterogeneous division ^10,14,22-23. Campisi et al.²⁴, Ghate et al.⁹ and Shiboski et al.²⁵ of viral load, ranging from 3,000 to 30,000 copies/µL^3,14,22did not find any relation between OC and low CD4 T ^23,25. The high viral load presented a significant association lymphocyte count in HIV-infected adults, as is reflected in with OC, as reported in the findings of other studies^3,14,23,25.

Mercante et al.¹⁰ and Coogan et al.²⁶ suggested that viral load may be a more important predictor for oropharyngeal candidiasis than CD4 T lymphocyte count.

OC was more frequent in patients with platelet count <150,000, though without a significant association. Patton et al.²⁷ observed that platelet count <150,000 may predispose HIV-infected patients to the development of oral manifestations, as verified in 15.5% of 516 patients. One possible explanation for our results is the fact that the number of individuals with platelet count <150,000 was small (1.7%).

OC can be considered a measure of assessment of the need to begin antiretroviral medication1^{1,7-8,11,14,25,28}. In contrast, we did not find statistically significant association between HAART and OC. Tappuni and Fleming²⁸ found no association between antiretroviral medication and the presence of OC. Thompson et al.¹ confirmed that OC remains a significant infection in advanced AIDS, even with HAART.

Gender, salivary flow, xerostomia, previous use of systemic acyclovir, use of AZT, intravenous drug use, smoking, and alcohol consumption do not represent risk indicators for OC^{7,14,24-26,29}. Although it was not statistically significant, in the present study, OC was proportionally more frequent in men, in patients with a reduced salivary flow, with previous use of systemic acyclovir, who were not taking AZT and who did not use intravenously drug.

Although our study was directed towards OC, the presence of OHL and OC was also verified, simultaneously, as being the two most common oral lesions in HIV-infected adults. The association between the presence of OC and OHL verified in this study has also been observed in many other studies in the US and Europe^3,7,11,27,29.

The previous use of fluconazole was a strong indicator of risk for OC. Schmidt-Westhausen et al.³⁰ found different results, and they concluded that the presence of oral lesions associated with HIV-infection did not have a correlation with the use of fluconazole. It is possible that Candida resistance to fluconazole is responsible for our finding. The high incidence of mucosal and deep seated forms of candidiasis in HIV-infected patients has resulted in the use of fluconazole. Their widespread use has been followed by an increase in antifungal resistance and Candida resistance. Various factors may contribute to fluconazole resistance, such as the degree of immunosuppression of the patients, the chemotherapeutic use of drugs and the intrinsic resistance of Candida species² . Fluconazole used for prolonged periods can select for less susceptible species Candida². The resistance of Candida, isolated to currently available antifungal drugs, is a highly relevant factor because it presents important implications for morbidity and mortality^1,6. Systemically applied antifungal drugs have the greatest efficacy for the treatment of oral candidiasis. However, these therapies must be prescribed following a thorough assessment of the risk for developing drug-induced toxicities, the likelihood of Candida species resistance, and the cost-effectiveness of medications. Fluconazole prophylaxis should be reserved for patients at high risk for recurrence of fungal infections, and not for routine prophylaxis⁶. Additionally, another explanation for the association of OC with previous use of fluconazole could be the fact that patients with HIV infection can have recurrent OC and that are treated with fluconazole¹ .

These results are important for the development of strategies to eliminate these indicators of risk and significantly reduce OC in Brazilian HIV-infected adult patients.

This study was supported by grants from the the National Council for Scientific and Technological Development (CNPq #301490/2007-4). Mesquita RA is research fellows of the CNPq.

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