Oral candidiasis and seborrheic dermatitis in HIV-infected patients on highly active antiretroviral therapy

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1 HIV Medicine (2004), 5, ORIGINAL RESEARCH r 2004 British HIV Association Oral candidiasis and seborrheic dermatitis in HIV-infected patients on highly active antiretroviral therapy I Dunic, 1 S Vesic 1 and DJ Jevtovic 2 1 Institute of Dermatovenereology, and 2 Institute for Infectious and Tropical Diseases, Clinical Centre of Serbia, Belgrade, Serbia & Montenegro Background Mucocutaneous manifestations such as oral candidiasis (OC) and seborrheic dermatitis (SD) are very common HIV-related opportunistic events and are usually initial markers of immunodeficiency. Aim The purpose of this study was to evaluate the efficacy of highly active antiretroviral therapy (HAART) in the regression of HIV-associated OC and SD. Methods In a prospective study, 120 HIV-infected patients with OC and SD were divided into two groups: HAART-treated patients (group 1, n 5 76) and non-haart-treated patients (group 2, n 5 44). Non- HAART-treated patients were given antimicrobial therapy. Study subjects were matched for sex, age, risk, and stage of HIV infection. The results were analysed by w 2 test and the Kaplan-Meier method. Results At baseline, OC was evident in 59 (77.7%) of the HAART-treated patients and in 34 (77.3%) of the non-haart-treated patients, while SD was present in 19 (25.0%) of the HAART-treated patients and in 17 (38.6%) of the non-haart-treated patients. After a median follow-up period of 22 months, regression of OC and SD occurred in 49 (83.1%) and 16 (84.2%) of the HAART-treated patients, respectively. In the control group, regression of OC and SD occurred in only five (14.7%) and seven (41.2%) patients, respectively, during the same period. Conclusions HAART showed greater efficacy than standard antimicrobial therapy for the treatment of OC and SD in HIV-infected patients. Keywords: HAART, HIV, oral candidiasis, seborrheic dermatitis Received: 19 April 2003, accepted 9 September 2003 Introduction Mucocutaneous manifestations of HIV infection are reflections of reduced immune function, producing opportunistic conditions that include oral candidiasis (OC) and seborrheic dermatitis (SD) [1,2]. Clinical manifestations of these opportunistic infections are extensive and severe, and may occur at any stage of HIV infection, but are often the earliest clinical features of HIV infection [3 5]. Furthermore, in the presence of known HIV infection, they are highly predictive of the terminal development of the full syndrome [6]. Correspondence: Ivana Dunic, Institute of Dermatovenereology, Pasterova 2, Belgrade, Serbia & Montenegro. Tel: ; fax: ; iva001@eunet.yu Oral candidiasis is the most common oral feature of opportunistic fungal infection, occurring in 90% patients during the course of HIV disease, and is an important criterion in most clinical staging systems for HIV infection [4,7]. SD is a common skin condition among HIV-infected persons, with a prevalence of 7 50%, and is also closely related to the stage of HIV infection [6,8]. The introduction of highly active antiretroviral therapy (HAART) has resulted in a dramatic decline in the incidence of opportunistic infections. HAART has led to reductions in disease progression and mortality [5,9 13]. The aim of the study was to evaluate the efficacy of HAART regarding the regression of HIV-associated OC and SD. 50

2 Oral candidiasis and seborrheic dermatitis in HIV-infected patients on HAART 51 Methods This prospective control study was conducted between 1998 and 2002, during which time 120 participants were enrolled. Informed consent was obtained from all patients. The study was approved by the Ethics Committee of the Clinical Centre of Serbia. A total of 120 HIV-infected patients (53 women and 67 men; ages ranging from 9 to 67 years) with mucocutaneous manifestations were divided into two groups: 76 patients treated with HAART (59 OC and 19 SD) and 44 non- HAART-treated patients (34 OC and 17 SD; control group) treated with antimicrobial therapy. Diagnoses of OC and SD were based on clinical manifestations (Figs 1 and 2) and confirmed using smears taken from lesions and examined by potassium hydroxide preparation for Candida albicans, plus fungal cultures to identify the causitive organism, and for Pityrosporum ovale, at the beginning of the study and during the follow-up period. The HAART regimen consisted of one protease inhibitor (saquinavir, nelfinavir, ritonavir or indinavir) and two reverse transcriptase inhibitors (zidovudine, didanosine, stavudine, lamivudine or abacavir). The HAART-treated patients did not receive standard dermatological therapy. In the control group, patients took systemic antifungal therapy (e.g. fluconazole and itraconazole) for the treatment of OC and a combination of topical antimicotics and topical corticosteroids (e.g. clotrimazole and hydrocortisone) for the treatment of SD. All patients were seen every 4 weeks. Skin and oral examinations were performed and mucocutaneous disease was evaluated as absent or still present. The CD4 cell count and viral load were also measured. The CD4 cell counts were obtained from peripheral blood samples and analysed on a fluorescence-activated cell sorter (FACS), while plasma HIV RNA was measured by a quantitative reverse transcriptation polymerase chain reaction assay (Amplicor HIV Monitor Test; Roche Molecular Systems, Somerville, NJ, USA), with a lower limit of detection of 200 HIV-1 RNA copies/ml (2.31 log 10 ). Statistics The differences in the frequency of an opportunistic infection across groups was assessed using the w 2 test. The efficacy of HAART was analysed using Kaplan-Meier life tables and Cox s regression. Results Mucocutaneous manifestations were studied in 120 HIVinfected patients divided into two groups: a HAART-treated group of 76 patients, and a control group of 44 non- Fig. 1 Pseudomembranous type of oral candidiasis in a patient with AIDS. Fig. 2 Seborrheic dermatitis of the face in a patient with AIDS. HAART-treated patients. The median age in both groups was 37 years. Sex distribution and clinical stage were similar in all patients. Of the transmission groups, intravenous drug users were the most frequent, representing 28.9% of the HAART-treated patients and 63.6% of the non-haart-treated patients, while patients with heterosexual, homosexual and transfusion transmission were less frequent in both groups. At the beginning of the study, OC was diagnosed in 59 (77.7%) of 76 patients in the HAART group, and in 34

3 52 I Dunic et al. (77.3%) of 44 patients in the control group. After a median follow-up period of 22 months, regression of OC was observed in 49 (83.1%) HAART recipients, and in only five (14.7%) nontreated patients. The regression of OC was significantly higher in HAART-treated patients compared with the control group (Po 0.01, w 2 test). Initially, SD was present in 19 (25%) of 76 HAARTtreated patients and in 17 (38.6%) of 44 nontreated patients. During the median follow-up period of 22 months, regression of SD occurred in 16 (84.2%) patients on HAART and in seven (41.2%) patients in the control group. Thus, regression of SD was significantly more common in HAART-treated patients than in the control group (Po0.05, w 2 test). These clinical findings were correlated with CD4 cell count and viral load. At the beginning of treatment, the CD4 cell count was cells/ml in HAARTtreated patients, and the HIV RNA level was log 10 copies/ml. At the end of the follow-up period, the CD4 cell count was , and the viral load was (most patients achieved an undetectable viral load of 1.9 log 10 ). This difference was tested using the Wilcoxon test (z , Po0.01). Thus, in the control group the CD4 cell count was below 180 cells/ml and the viral load was around 5.8 log 10 copies/ml, and did not change much during the period of observation. The efficacy of HAART compared with standard antimicrobial therapy was analysed using the Kaplan-Meier method. The median duration of therapy needed to maintain the resolution of OC was 26 months in HAART recipients. The probability of resolution of OC over 30 months was 20% among patients not on HAART. The difference between groups was analysed by Cox s regression model, which showed a larger effect of HAART treatment (P ; OR ; 95% CI ), in comparison with standard antimicrobial therapy (P ; OR ; 95% CI ) (Fig. 3). The median duration of therapy to maintain the resolution of SD in HAART-treated patients was 38 months. However, the probability of resolution of SD did not differ significantly between groups after the second year of follow-up. Cox s regression model was calculated to examine the influence of treatments. There were no significant differences between HAART (P ; OR ; 95% CI ) and antimicrobial therapy (P ; OR ; 95% CI ) (Fig. 4). Discussion The results of this study show that HAART decreases the prevalence of oral candidiasis and seborrheic dermatitis in Probability Time (months) Fig. 3 The effect of HAART on the regression of oral candidiasis in 49 (83.1%) patients in comparison with five (14.7%) patients in the control group. Probability Time (months) Fig. 4 The effect of HAART on the regression of seborrheic dermatitis in 16 (84.2%) patients in comparison with seven (41.2%) patients in the control group. patients with AIDS [10 16]. During the follow-up period, the prevalence of these opportunistic disorders markedly decreased in patients treated with HAART. In the control group, regression was distinctly less common than in the HAART-treated patients. Standard antimicrobial therapy is of limited value in the treatment of HIV-related opportunistic disorders, as it has no activity on the recovery of immune system functions. During the follow-up period most of the HAART-treated patients were free of dermatological events. However, in the control group, long-term antimicrobial therapy was needed. Oral candidiasis is usually asymptomatic but may easily be revealed upon inspection of the oral cavity. The most common clinical type of candidiasis in our series was pseudomembranous, while erythematous and angular

4 Oral candidiasis and seborrheic dermatitis in HIV-infected patients on HAART 53 cheilitis were much less common. The appearance of these oral manifestations correlated with a low CD4 cell count (below 100 cells/ml) and a very high level of viral replication. Similar immunological and virological markers were observed among patients with SD. The yeast-line fungus P. ovale, as a member of the resident (normal) skin flora, may cause SD, especially in immunodeficiency conditions, when Pityrosporum becomes part of the contaminant (transient) skin flora causing the disease. In the control group, after topical antifungal treatment in combination with topical corticosteroid creams for skin inflammation, with a reduction of P. ovale, SD resolved for a limited period of time. Only with HAART is it possible to achieve a strong and persistent increase in the CD4 T-cell count, as well as recovery of immune control of infections. These clinical observations are supported by our data, as well as the findings of others [16 18]. The use of HAART has resulted in restoration of the immune system and a decline in opportunistic infections [19,20]. These data are also a reflection of varying HAART initiation strategies over the past decade. A limitation of this study was the small number of patients in the control group, which could bias the results. Antiretroviral therapy was initiated at the optimal time, before the risk period was approached, i.e. when the CD4 cell count dropped below 300 but above 250 cells/ml. Thus, an optimal immunological response may be achieved, avoiding drug toxicity for as long as possible [20,21]. Highly active antiretroviral therapy has resulted in a change in the natural history and clinical manifestations of opportunistic infections. Our findings have shown that HAART had greater efficacy in the treatment of both OC and SD, and a stronger impact on the regression of opportunistic disorders compared with standard treatment. Acknowledgements We wish to express our gratitude to Dr Olgica Djurkovic Djakovic for critically reading the manuscript and for useful suggestions. The work was supported by a grant from the Serbian Ministry of Science and Technology (project no. M1474). References 1 Johnson RA Cutaneous manifestations of human immunodeficiency virus disease, In: Freedberg IM, Eisen AZ, Wolf K, eds. Fitzpatrick s Dermatology in General Medicine, 5th edn. New York, McGraw-Hill 1999: Munoz-Perez MA, Rodriguez-Pichardo A, Camacho F, Colmenero MA. Dermatological finding correlated with CD4 lymphocyte count in a prospective 3 year study of 1161 patients with human immunodeficiency virus disease predominantly acquired through intravenous drug abuse. Br J Dermatol 1998; 139: Schaub N, Gilli L, Rufli T. 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