EFFECT OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY ON VAGINAL Candida spp. ISOLATION IN HIV-INFECTED COMPARED TO HIV-UNINFECTED WOMEN

Efeito da terapia anti-retroviral altamente ativa no isolamento vaginal de Candida spp. em mulheres infectadas por HIV comparado às não infectadas

Silvia de Souza Dantas ALCZUK Patrícia de Souza BONFIM-MENDONÇA Sheila Cristina ROCHA-BRISCHILIARI Cristiane Suemi SHINOBU-MESQUITA Helen Priscilla Rodrigues MARTINS Fabrícia GIMENES André Luelsdorf Pimenta de ABREU Maria Dalva de Barros CARVALHO Sandra Marisa PELLOSO Terezinha Inez Estivalet SVIDZINSKI Marcia Edilaine Lopes CONSOLARO About the authors

Abstracts

 Vulvovaginal candidiasis (VVC) in HIV-infected women contributed to the impairment of their quality of life. The aim of this study was to evaluate the effect of highly active antiretroviral therapy (HAART) use on the vaginal Candida spp. isolation in HIV-infected compared to HIV-uninfected women. This cross-sectional study included 178 HIV-infected (HIV group) and 200 HIV-uninfected women (control) that were studied at the Specialized Assistance Service (SAE) for sexually transmitted diseases (STD)/AIDS of the city of Maringá, Brazil, from April 1 to October 30, 2011. The yeasts were isolated and identified by phenotypic and molecular methods. The in vitro antifungal susceptibility to fluconazole, itraconazole, nystatin and amphotericin B was tested by the reference microdilution method. Higher frequencies of total vaginal Candida spp. isolation were found in the HIV-infected group than in the control group. However, both groups showed a similar frequency of colonization and VVC. Although C. albicans was the most frequent and sensitive to azolics and polyenes in both HIV-infected and uninfected women, the emerging resistance of C. glabrata to amphotericin B in the HIV-infected women was observed. Although higher frequency of vaginal Candida spp. isolation had been observed in the HIV-infected than in HIV-uninfected women, colonization and VVC showed similar frequency in both groups, indicating that HAART appears to protect against vaginal colonization and VVC.


Candidíase vulvovaginal (CVV) em mulheres infectadas pelo HIV contribuiu substancialmente para a diminuição da sua qualidade de vida. O objetivo deste estudo foi avaliar o efeito do uso de terapia anti-retroviral altamente ativa (HAART) no isolamento de Candida spp. vaginais em mulheres HIV positivas comparado às não infectadas por HIV. Este estudo transversal incluiu 178 mulheres infectadas pelo HIV (grupo HIV) e 200 mulheres não infectadas (grupo controle) acompanhadas no Serviço de Assistência Especializada (SAE) para as doenças sexualmente transmissíveis (DST)/AIDS da cidade de Maringá/Brasil, de 1 abril a 30 de outubro de 2011. As leveduras foram isoladas e identificadas por métodos fenotípicos e moleculares. A susceptibilidade in vitro aos antifúngicos fluconazol, itraconazol, nistatina e anfotericina B foi avaliada pelo método de referência de microdiluição. Nós encontramos maior frequência de isolamento vaginal total de Candida spp. no grupo HIV do que no grupo controle. Entretanto, foi observada frequência similar de colonização e CVV entre os dois grupos. Apesar de C. albicans ser a mais frequente e sensível a azólicos e polienos em mulheres infectadas pelo HIV e não infectadas, foi detectada emergente resistência de C. glabrata a AMB nas mulheres infectadas pelo HIV. Embora tenha sido observada maior frequência de isolamento vaginal de Candida spp. nas mulheres infectadas pelo HIV do que nas não infectadas, colonização e CVV apresentaram frequência similar em ambos os grupos, o que indica que HAART parece proteger contra colonização vaginal e CVV.

HIV; Vulvovaginal candidiasis; Candida spp.; Antiretroviral therapy


INTRODUCTION

Vulvovaginal candidiasis (VVC) is a disease caused by the abnormal growth of yeast-like fungi in the mucosa of the female genital tract by members of the genus Candida 2121 Reese RE, Betts RF. Antibiotic use. In: Reese RE, Betts RF. A practical approach to infectious diseases. 3rd ed. Boston: Little, Brown and Company; 1991.. These yeasts, in particular C. albicans, are well adapted to the human body, and are capable of colonizing it without producing signs of disease in conditions of physiological equilibrium2828 Wei YP, Feng J, Luo ZC. Isolation and genotyping of vaginal non-albicans Candida spp. in women from two different ethnic groups in Lanzhou, China. Int J Gynaecol Obstet. 2010;110:227-30. doi:10.1016/j.ijgo.2010.04.026.
https://doi.org/10.1016/j.ijgo.2010.04.0...
. However, under conditions that disrupt the delicate balance between the host and this commensal fungus, a parasitic relationship may occur, resulting in the development of infections termed candidiasis, including VVC2Brasil. Ministério da Saúde. AIDS Boletim Epidemiológico julho - dezembro 2010/janeiro - julho 2012. Bol Epidemiol Aids. 2012;8:9-79.. For development of VVC, predisposing factors related to the host are very important, mainly being immunosuppressive diseases, such as HIV infection1313 Martins HP, da Silva MC, Paiva LC, Svidzinski TI, Consolaro ME. Efficacy of fluconazole and nystatin in the treatment of vaginal Candida species. Acta Derm Venereol. 2012;92:78-82. doi:10.2340/00015555-1194.
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, 1515 Moragues MD, Omaetxebarria MJ, Elguezabal N, Sevilla MJ, Conti S, Polonelli L, et. al. A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities. Infect Immun. 2003;71:5273-9..

Because it strikes millions of women annually, causing great discomfort, interfering with sexual and affective relations and impairing work performance, VVC has been considered an important worldwide public-health problem5Dalben-Dota KF, Faria MG, Bruschi ML, Pelloso SM, Lopes-Consolaro ME, Svidzinski TI. Antifungal activity of propolis extract against yeasts isolated from vaginal exudates. J Altern Complement Med. 2010;16:285-90. doi:10.1089/acm.2009.0281.
https://doi.org/10.1089/acm.2009.0281...
, 2424 Sobel JD. Vulvovaginal candidosis. Lancet. 2007;369(9577):1961-71.. In HIV-infected women, the impact of VVC on top of other medical complications that stem from the viral infection and its treatment certainly contributes to the impairment of their quality of life. It must still be considered that out of HIV-infected individuals worldwide (around 40 million), nearly half are women1616 Mumtaz G, Hilmi N, Akala FA, Semini I, Riedner G, Wilson D, et al. HIV-1 molecular epidemiology evidence and transmission patterns in the Middle East and North Africa. Sex Transm Infect. 2011;87:101-6. doi:10.1136/sti.2010.043711.
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, raising concerns about VVC. In Brazil, HIV infection occurs in 0.5% of the population, with a trend toward expansion of the epidemic among women, from a ratio of 18.5 men:1 woman in the 1980s to 1.5:1 in 20042Brasil. Ministério da Saúde. AIDS Boletim Epidemiológico julho - dezembro 2010/janeiro - julho 2012. Bol Epidemiol Aids. 2012;8:9-79..

Use of the highly active antiretroviral therapy (HAART) has extended the life span of HIV-infected persons. However, some studies have reported that even for users of this continuous therapy opportunistic infections remain a serious problem3Centers for Disease Control and Prevention. Guidelines for prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children. MMWR. 2009;58(RR-04):1-198. [cited 2009 Sep 15]. Available from: http://www.cdc.gov.
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, 1818 Oliveira PM, Mascarenhas RE, Lacroix C, Ferrer SR, Oliveira RP, Cravo EA, et al. Candida species isolated from the vaginal mucosa of HIV-infected women in Salvador, Bahia, Brazil. Braz J Infect Dis. 2011;15:239-44.. Nevertheless, to the authors' knowledge, few studies have related vaginal Candida colonization and VVC in HIV-infected women to HAART use in different populations, have enrolled relatively few HIV-infected women1515 Moragues MD, Omaetxebarria MJ, Elguezabal N, Sevilla MJ, Conti S, Polonelli L, et. al. A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities. Infect Immun. 2003;71:5273-9., only treated specific clinical conditions as Candida colonization1414 Merenstein D, Hu H, Wang C, Hamilton P, Blackmon M, Chen H, et al. Colonization by Candida species of the oral and vaginal mucosa in HIV-infected and noninfected women. AIDS Res Hum Retroviruses. 2013;29:30-4. doi:10.1089/aid.2012.0269.
https://doi.org/10.1089/aid.2012.0269...
, lacked appropriate matched controls9Grinsztejn B, Bastos FI, Veloso VG, Friedman RK, Pilotto JH, Schechter M, et al. Assessing sexually transmitted infections in a cohort of women living with HIV/AIDS, in Rio de Janeiro, Brazil. Int J STD AIDS. 2006;17:473-8. doi:10.1258/095646206777689071.
https://doi.org/10.1258/0956462067776890...
, 1515 Moragues MD, Omaetxebarria MJ, Elguezabal N, Sevilla MJ, Conti S, Polonelli L, et. al. A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities. Infect Immun. 2003;71:5273-9., or have been restricted to specialized subpopulations such as women with symptoms of vulvovaginitis2323 Ribeiro MA, Paula CR, John R, Perfect JR, Cox GM. Phenotypic and genotypic evaluation of fluconazole resistance in vaginal Candida strains isolated from HIV-infected women from Brazil. Med Mycol. 2005;43:647-50.. There are some available studies that were performed before the broad use of HAART or in populations that do not regularly use this therapy1Beltrame A, Matteelli A, Carvalho AC, Saleri N, Casalini C, Capone S, et al. Vaginal colonization with Candida spp. in human immunodeficiency virus-infected women: a cohort study. Int J STD AIDS. 2006;17:260-6. doi:10.1258/095646206776253435.
https://doi.org/10.1258/0956462067762534...
, 7Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing for yeasts. 3rd ed. Wayne: CLSI; 2008. (CLSI M27-A3). , 9Grinsztejn B, Bastos FI, Veloso VG, Friedman RK, Pilotto JH, Schechter M, et al. Assessing sexually transmitted infections in a cohort of women living with HIV/AIDS, in Rio de Janeiro, Brazil. Int J STD AIDS. 2006;17:473-8. doi:10.1258/095646206777689071.
https://doi.org/10.1258/0956462067776890...
, 2323 Ribeiro MA, Paula CR, John R, Perfect JR, Cox GM. Phenotypic and genotypic evaluation of fluconazole resistance in vaginal Candida strains isolated from HIV-infected women from Brazil. Med Mycol. 2005;43:647-50. , 2727 van de Wijgert JH, Morrison CS, Cornelisse PG, Munjoma M, Moncada J, Awio P, et al. Bacterial vaginosis and vaginal yeast, but not vaginal cleansing, increase HIV-1 acquisition in African women. J Acquir Immune Defic Syndr. 2008;48:203-10. doi:10.1097/QAI.0b013e3181743936.
https://doi.org/10.1097/QAI.0b013e318174...
.

The aim of this study was to evaluate the effect of HAART use on the vaginal Candida spp. isolation in two clinical conditions: colonization and VVC, in HIV-infected compared to HIV-uninfected women. In addition, the antifungal susceptibility of Candida species to the most commonly used antifungal drugs was evaluated.

MATERIAL AND METHODS

This was a cross-sectional study that included a group of 178 HIV-infected and 200 HIV-uninfected women, who were studied at the Specialized Assistance Service (SAE) for sexually transmitted diseases (STD)/AIDS in the city of Maringá, Brazil, from April 1 to October 30, 2011. Inclusion criteria were women having diagnoses of HIV/AIDS confirmed by two different methods (HIV group), or confirmed diagnosis as HIV-uninfected (control group). Exclusion criteria were: hysterectomized women, pregnant or postpartum women, women of less than 18 years of age, women with no history of sexual activity, women that had some degree of difficulty in understanding the study, women suffering vaginal bleeding, or women that had undergone sexual intercourse/vaginal douching within the 48 hours preceding collection of the vaginal sample.

The women signed the consent form to participate in the study, and completed a standardized questionnaire with information regarding symptoms of VVC. The HIV group also responded to a questionnaire regarding socio-demographic characteristics, obstetrical and gynecological history, and sexual behavior. Data regarding HIV infection, including the period of infection (years), CD4+ T lymphocyte count, HIV viral load values, and HAART use were obtained from the medical records of each woman. A single health professional was responsible for contacting the women, administering the questionnaire, and collecting the vaginal sample. This research was approved by the Committee for Ethics in Research Involving Humans at the State University of Maringá, Paraná, Brazil (reports No. 185/2007 and No. 085/2011).

Vaginal samples were collected with sterile swabs and a disposable vaginal speculum, inoculated in sterile saline, and immediately seeded onto plates containing Sabouraud dextrose agar (SDA) (Difco, USA), with the addition of 100 mg/mL chloramphenicol, and incubated at 25 °C for up to five days. A pool of the colonies grown on each plate was subcultured on CHROMágar Candida ® (Probac, France) to assure the purity of the isolates and to identify mixed cultures. Beginning with the pure culture, the yeasts were identified by classical phenotypic methods1111 Kurtzman C, Fell JW, Boekhout T. The yeasts: a taxonomic study. 4th ed. Amsterdam: Elsevier: 1998.. Additionally, the identification of yeasts was confirmed using matrix-assisted laser-desorption/ionization time-of-flight mass spectroscopy assay (MALDI TOF-MS). For MALDI TOF-MS identification, yeasts were prepared2626 Spanu T, Posteraro B, Fiori B, D'Inzeo T, Campoli S, Ruggeri A, et al. Direct maldi-tof mass spectrometry assay of blood culture broths for rapid identification of Candida species causing bloodstream infections: an observational study in two large microbiology laboratories. J Clin Microbiol. 2012;50:176-9. doi:10.1128/jcm.05742-11.
https://doi.org/10.1128/jcm.05742-11...
and the measurements were performed1919 Pascon RC, Bergamo RF, Spinelli RX, de Souza ED, Assis DM, Juliano L, et al. Amylolytic microorganism from São Paulo zoo composting: isolation, identification, and amylase production. Enzyme Res. 2011:679624. doi:10.4061/2011/679624.
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with Microflex LT mass spectrometer (Bruker Daltonics, Germany) using FlexControl software (version 3.0, Bruker Daltonics, Germany). The yeasts were stored in Sabouraud dextrose broth (SDB) (Difco, USA) with 10% glycerol at -20 °C.

Women were evaluated for the presence of clinical signs and symptoms of VVC by SAE doctors. Candida vaginal colonization was defined as culture positive for yeasts from women without signs and symptoms of VVC. Women with a positive culture were considered to have VVC if they reported at least two symptoms of this pathology (discharge, burning, vaginal itching, dysuria or dyspareunia), and signs of VVC reported by doctors1212 Lopes Consolaro ME, Aline Albertoni T, Shizue Yoshida C, Mazucheli J, Peralta RM, Estivalet Svidzinski TI. Correlation of Candida species and symptoms among patients with vulvovaginal candidiasis in Maringa, Parana, Brazil. Rev Iberoam Micol. 2004;21:202-5..

The in vitro antifungal activity assay was performed for fluconazole (FLU, Pfizer Inc. , NY, USA), itraconazole (ITRA, Janssen Pharmaceutical, NJ, USA), nystatin (NYST, Sigma Pharma, MO, USA) and Amphotericin B (AMB, Squibb Pharmaceutical, NJ, USA). All yeasts isolated were tested by means of the Clinical Laboratory Standards Institute reference broth microdilution method for fluconazol and itraconazol, with modifications for other drugs4Clinical and Laboratory Standards Institute. Reference method for broth dilution antifungal susceptibility testing for yeasts. 3rd ed. Wayne: CLSI; 2008. (CLSI M27-A3). , 5Dalben-Dota KF, Faria MG, Bruschi ML, Pelloso SM, Lopes-Consolaro ME, Svidzinski TI. Antifungal activity of propolis extract against yeasts isolated from vaginal exudates. J Altern Complement Med. 2010;16:285-90. doi:10.1089/acm.2009.0281.
https://doi.org/10.1089/acm.2009.0281...
. The minimum inhibitory concentration (MIC) for azoles was defined as the first well with a significant growth reduction (approximately 50%) compared to that of the positive control. In the case of NYST and AMB, the MIC was defined as the lowest concentration capable of inhibiting 90% of the growth1717 Nardin ME, Morano S, Ahumada C, Volta G, Fernandez S, Méndez E. Prevalence of the vulvovaginal candidosis and its relationship with some risk factors. Rev Argent Micol. 2000;22:13-9.. The endpoints for antifungal agents: isolates with MIC between 16 and 32 µg/mL for FLU, 0.25 to 0.5 µg/mL for ITRA, and 8 to 32 µg/mL for NYST were considered as dose-dependent susceptibility (DDS). Isolates with an MIC ≤ 8 µg/mL for FLU, ≤ 0.125 µg/mL for ITRA, ≤ 4 µg/mL for NYST, and ≤ 1 µg/mL for AMB were susceptible (S). Those with an MIC ≥ 64 µg/mL for FLU, ≥ 1 µg/mL for ITRA, ≥ 64 µg/mL for NYST and ≥ 2 µg/mL for AMB were resistant (R).

The statistical analysis was performed using the STATA for Statistics and Data Analysis 9.1 software. All variables were expressed as absolute and relative frequencies. The frequencies of Candida spp. isolation from the vaginal mucosa, and also colonization and VVC, were calculated by the crude odds ratio (OR) with a 95% confidence interval (CI), and were evaluated between groups by the Chi-square test (χ2) with Yates correction. A value of p < 0.05 was considered significant.

RESULTS

Figure 1 is an overview of the study and results.


Table 1 describes the socio-demographic and clinical characteristics of the two groups. The median age of the HIV group was 41.24 ± 10.31 years, and for the control group it was 42.22 ± 14.14 years (p > 0.05). Considering all women studied, Candida spp. isolation from the vaginal mucosa and VVC was significantly associated with the 31 to 40 years of age group (p = 0.0286 and p = 0.0131, respectively). For the groups studied, only the control group showed association with age, since vaginal yeast colonization was significantly associated with the 31 to 40 years of age group (p = 0.0185). Data regarding HIV infection, including the period of HIV infection, CD4+ T lymphocyte count, HIV viral load values and correct use of HAART were not significantly associated with Candida spp. total isolation, colonization or VVC.

Table 1
Relationship between total Candida vaginal isolation, colonization and VCC, as well as the socio-demographic characteristics, obstetrical and gynecological history, sexual behavior and data regarding HIV of 178 HIV-infected women

The HIV infected group showed a higher frequency of colonization than VVC (52.8% and 47.2%, respectively, p = 0.05), and the control group showed more frequent VVC than colonization (55.5% and 44.4%, respectively; p = 0.01). However, comparing the two groups, Candida spp. total vaginal isolation was more frequent in the HIV group (n = 36/178, 20.2%) than in the control group (18/200, 9.0%; p = 0.003). For clinical conditions, the HIV group showed a similar frequency of vaginal colonization (19/178, 10.7%) (OR = 2.9; 95% CI 0.91-9.6; p = 0.1072) and VVC (17/178, 9.5%) (OR = 1.879; 95% CI 0.8657-1.994; p = 0.4057) to the control group (n = 8/200, 4.0%; n = 10/200, 5.0%, respectively) (Table 2).

Table 2
Frequencies of Candida spp. vaginal total isolation, colonization and vulvovaginal candidiasis (VVC) in HIV-infected and uninfected women in southern Brazil

With respect to yeast species in the present study, C. albicans was the most frequently isolated in both the HIV (n = 26, 72.2%; p = 0.02) and control groups (n = 10, 55.6%; p = 0.05). With respect to yeast species in different clinical conditions, the HIV group showed more C. albicans than the control in VVC (p = 0.007; OR 3.1; 95% CI 1.24-9.05) and in colonization (p = 0.005; OR 2.9; 95% CI 0.91-10.87). In the HIV group, the following non-albicans species were identified: C. glabrata (n = 7), C. parapsilosis (n = 2) and C. rugosa (n = 1). In the control group, the following were identified: C. glabrata (n = 5), C. parapsilosis (n = 2) and C. tropicalis (n = 1). Thus, in both groups, C. glabrata was the second most common yeast isolated (19.4% and 27.8%, for the HIV and control groups, respectively) (Table 2).

Table 3 shows the interpretation of the antifungal activity results for drugs as well as for susceptibility, dose-dependent susceptibility or resistance. In general, the C. albicans isolates showed no resistance to the antifungal agents tested for both the HIV and the control group. The results for amphotericin B were 100% sensitivity. For nystatin, the results showed elevated rates of vaginal isolates of C. albicans and non-albicans species with dose-dependent susceptibility. Of the non-albicans species identified in the HIV group, only C. glabrata showed resistance, one (4.8%) to FLU, two (9.5%) to ITRA, and another two (9.5%) to AMB. In the control group, two non-albicans yeasts (23.3%) showed resistance to FLU and one (6.7%) to ITRA; the two resistant species found in this group were C. glabrata and C. tropicalis.

Table 3
Interpretation of the results for minimal inhibitory concentration (MIC) for antifungal drugs in vaginal yeasts from HIV-infected (n = 36, C. albicans = 26) and HIV-uninfected groups (n = 18, C. albicans = 10)

DISCUSSION

In the present study, Candida spp. total vaginal isolation was significantly more frequent in the HIV group than in the control group. However, a similar frequency of colonization and VVC in the HIV and control groups was shown, which is consistent with the results of the most HIV-infected women enrolled in this study that showed excellent control of the infection. Further, the data regarding HIV infection were not associated with Candida spp. isolation from the vaginal mucosa, colonization or VVC.

The results found in this study differ from those described in other populations that also had good control of HIV infection. In these studies, the frequency of VVC in the HIV group was similar to the control group, but the frequency of colonization was higher7Duerr A, Heilig CM, Meikle SF, Cu-Uvin S, Klein RS, Rompalo A, et al. Incident and persistent vulvovaginal candidiasis among human immunodeficiency virus-infected women: risk factors and severity. Obstet Gynecol. 2003;101:548-56. , 1515 Moragues MD, Omaetxebarria MJ, Elguezabal N, Sevilla MJ, Conti S, Polonelli L, et. al. A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities. Infect Immun. 2003;71:5273-9.. Also, for vaginal Candida colonization, the results differ from those in which the risk of colonization in HIV-infected women with CD4+ T-cell counts below 100-200 cells/mm3 was three or four times higher, compared to immunocompetent HIV-infected or HIV-uninfected women1Beltrame A, Matteelli A, Carvalho AC, Saleri N, Casalini C, Capone S, et al. Vaginal colonization with Candida spp. in human immunodeficiency virus-infected women: a cohort study. Int J STD AIDS. 2006;17:260-6. doi:10.1258/095646206776253435.
https://doi.org/10.1258/0956462067762534...
, 7Duerr A, Heilig CM, Meikle SF, Cu-Uvin S, Klein RS, Rompalo A, et al. Incident and persistent vulvovaginal candidiasis among human immunodeficiency virus-infected women: risk factors and severity. Obstet Gynecol. 2003;101:548-56..

The results are encouraging, since HAART seems to protect against vaginal colonization and VVC, and some investigators have reported a relationship between vaginal Candida colonization and VVC with heterosexual transmission of HIV. Recent research has shown that women with vaginal yeasts were more likely to acquire HIV, and the condition may contribute more to the HIV epidemic than previously thought2727 van de Wijgert JH, Morrison CS, Cornelisse PG, Munjoma M, Moncada J, Awio P, et al. Bacterial vaginosis and vaginal yeast, but not vaginal cleansing, increase HIV-1 acquisition in African women. J Acquir Immune Defic Syndr. 2008;48:203-10. doi:10.1097/QAI.0b013e3181743936.
https://doi.org/10.1097/QAI.0b013e318174...
. It was shown that treatment of VVC in HIV-infected women can reduce genital shedding of HIV RNA and DNA by 3.2 and 3 times, respectively1717 Nardin ME, Morano S, Ahumada C, Volta G, Fernandez S, Méndez E. Prevalence of the vulvovaginal candidosis and its relationship with some risk factors. Rev Argent Micol. 2000;22:13-9..

For the HIV and control groups, C. glabrata was the second most common yeast isolated, in agreement with other studies1Beltrame A, Matteelli A, Carvalho AC, Saleri N, Casalini C, Capone S, et al. Vaginal colonization with Candida spp. in human immunodeficiency virus-infected women: a cohort study. Int J STD AIDS. 2006;17:260-6. doi:10.1258/095646206776253435.
https://doi.org/10.1258/0956462067762534...
, 1515 Moragues MD, Omaetxebarria MJ, Elguezabal N, Sevilla MJ, Conti S, Polonelli L, et. al. A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities. Infect Immun. 2003;71:5273-9.. Older studies described higher rates of vaginal colonization with non-albicans species in HIV-infected than in uninfected women7Duerr A, Heilig CM, Meikle SF, Cu-Uvin S, Klein RS, Rompalo A, et al. Incident and persistent vulvovaginal candidiasis among human immunodeficiency virus-infected women: risk factors and severity. Obstet Gynecol. 2003;101:548-56. , 1717 Nardin ME, Morano S, Ahumada C, Volta G, Fernandez S, Méndez E. Prevalence of the vulvovaginal candidosis and its relationship with some risk factors. Rev Argent Micol. 2000;22:13-9.. With respect to yeast species in different clinical conditions, the HIV group showed more C. albicans than the control group in VVC and in colonization, similar to other studies1Beltrame A, Matteelli A, Carvalho AC, Saleri N, Casalini C, Capone S, et al. Vaginal colonization with Candida spp. in human immunodeficiency virus-infected women: a cohort study. Int J STD AIDS. 2006;17:260-6. doi:10.1258/095646206776253435.
https://doi.org/10.1258/0956462067762534...
. In some studies, C. albicans was related to symptoms in HIV-infected women2222 Ribeiro MA, Miranda AE, Gambale W, Paula CR. Prevalence and exoenzyme secretion by Candida albicans isolates from oral and vaginal mucosas of HIV-infected women. Mycopathologia. 2004;157:255-61., but in others no relationship between symptoms and the yeast species isolated1515 Moragues MD, Omaetxebarria MJ, Elguezabal N, Sevilla MJ, Conti S, Polonelli L, et. al. A monoclonal antibody directed against a Candida albicans cell wall mannoprotein exerts three anti-C. albicans activities. Infect Immun. 2003;71:5273-9. was found.

In relation to antifungal susceptibility, C. albicans showed no resistance to the antifungal agents tested for both the HIV and the control group and 100% of sensibility for amphotericin B. These results reinforce previous findings showing that amphotericin B is an excellent and highly efficacious therapeutic option for vaginal C. albicans including in HIV-infected women8Ghannoum MA, Rice LB. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin Microbiol Rev. 1999;12:501-17.. For nystatin, the results of this study are in accordance with others that have shown elevated rates of vaginal isolates with dose-dependent susceptibility, and also some resistance5Dalben-Dota KF, Faria MG, Bruschi ML, Pelloso SM, Lopes-Consolaro ME, Svidzinski TI. Antifungal activity of propolis extract against yeasts isolated from vaginal exudates. J Altern Complement Med. 2010;16:285-90. doi:10.1089/acm.2009.0281.
https://doi.org/10.1089/acm.2009.0281...
. Nystatin has been used for several decades as one of the principal treatments for vaginal Candida spp. in Brazil2323 Ribeiro MA, Paula CR, John R, Perfect JR, Cox GM. Phenotypic and genotypic evaluation of fluconazole resistance in vaginal Candida strains isolated from HIV-infected women from Brazil. Med Mycol. 2005;43:647-50.. This history may partly explain the elevated dose-dependent susceptibility rate observed in both groups studied. Large-scale use of fluconazole began more recently, which may also partly explain the better therapeutic activity of this drug against C. albicans found in the present study.

Non-albicans species showed resistance to fluconazole and itraconazole. In general, these results are not surprising since the management of women with non-albicans species, mainly C. glabrata, is difficult because of the lower sensitivity of non-albicans species to both azoles6Dota KFD, Shinobu CS, Patussi EV, Consolaro MEL, Svidzinski TIE. Susceptibility to vaginal yeast in most used antifungal in Maringá, Paraná, Brazil. Acta Bioquim Clin Latinoam. 2008;110:66-72. , 2525 Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy PR, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol. 1998;178:203-11. and polyenes1010 Holland J, Young ML, Lee O, C-A Chen S. Vulvovaginal carriage of yeasts other than Candida albicans. Sex Transm Infect. 2003;79:249-50.. To the authors' knowledge, this is one of the first studies to show amphotericin B resistance in C. glabrata isolated from HIV-infected women. The importance of the results in relation to antifungal susceptibility is confirmed by the report which found no trials that addressed treatment of VVC in HIV-infected women2020 Ray A, Ray S, George AT, Swaminathan N. Interventions for prevention and treatment of vulvovaginal candidiasis in women with HIV infection. Cochrane Database Syst Rev. 2011(8):Cd008739. doi:10.1002/14651858.CD008739.pub2
https://doi.org/10.1002/14651858.CD00873...
. However, there is a need to evaluate drugs and drug regimens for VVC treatment and prophylaxis in HIV-infected women.

In conclusion, this study found higher frequencies of total vaginal Candida spp. isolation in the HIV-infected women with prolonged HAART use, in relation to HIV-uninfected. However, a similar frequency of colonization and VVC in the HIV and control groups was shown. Thus, the results are encouraging, since HAART seems to protect against vaginal colonization and VVC. Although C. albicans was the most frequent and sensitive to azolics and polyenes in both HIV-infected and uninfected women, the emerging resistance of C. glabrata to amphotericin B in the HIV-infected women studied was observed. If this proves to be correct, implementing routine culture identifications of vaginal Candida spp. in HIV-infected women could help in guiding treatment, assisting in care, and improving the quality of life of these patients. Once the resistance of C. glabrata to amphotericin B is detected, and this yeast is intrinsically resistant to azoles, it is important to have knowledge of their involvement in VVC of HIV-positive women.

ACKNOWLEDGMENTS

This study was supported by grants from the Fundação Araucária Apoio ao Desenvolvimento Científico e Tecnológico do Paraná, the Ministério da Saúde do Brasil, (Grant number EFP 00002873-SISCT) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, AUX-PE-PRODOC 2571/2010), Brazilian Government.

  • AUTHOR DISCLOSURE STATEMENT
    No competing financial interests exist.

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Publication Dates

  • Publication in this collection
    Mar-Apr 2015

History

  • Received
    24 Mar 2014
  • Accepted
    07 July 2014
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