Original Article. Noparat Oniem, M.D., Somnuek Sungkanuparph, M.D.

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1 Original Article Vol. 29 No. 1 Primary prophylaxis for cryptococcosis with fluconazole:- Oniem N & Sungkanuparph S. 5 Primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 cell count < 100 cells/mm 3 in the era of highly active antiretroviral therapy Noparat Oniem, M.D., Somnuek Sungkanuparph, M.D. ABSTRACT Objective: To evaluate the clinical benefit of primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 cell count <100 cells/mm 3 and receiving antiretroviral therapy (ART). Methods: A retrospective cohort study was conducted among HIV-infected patients who had CD4 <100 cells/mm 3 in a university hospital. Patients were categorized into fluconazole group (receiving fluconazole) and control group (not receiving fluconazole). Results: Of 189 patients, 136 were in fluconazole group and 53 in control group. Mean age was 36.3 years and 64.6% were males. Mean CD4 was 35 cells/mm 3. All patients had received ART. Demographics, history of opportunistic infections, time from CD4 <100 cells/mm 3 to ART initiation and ART regimens were similar between two groups (p>0.05). During a median follow-up of 5.9 years, no patient died. One patient (0.7%) in fluconazole group and 2 patients (3.8%) in control group developed cryptococcosis (p=0.190). Kaplan-Meier analysis showed that there was no difference of new cryptococcosis between two groups (log-rank test, p=0.138). Conclusion: In the era that ART is widely available and can be commenced shortly after finding of low CD4, primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 <100 cells/mm 3 may not be necessary and the recommendation should be reconsidered. (J Infect Dis Antimicrob Agents 2012;29:5-10.) Note: Abstract of this study is presented in the 6 th IAS Conference on the HIV Pathogenesis, Treatment, and Prevention, Rome, July Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand. Reprint request: Somnuek Sungkanuparph, M.D., Professor of Medicine, Division of Infectious diseases, Department of Medicine, Ramathibodi Hospital, 270 Rama 6 Road, Bangkok 10400, Thailand. somnuek.sun@mahidol.ac.th Keywords: primary prophylaxis, cryptococcosis, fluconazole, HIV, AIDS 5

2 6 J INFECT DIS ANTIMICROB AGENTS Jan-April 2012 INTRODUCTION Cryptococcosis is a serious opportunistic infection in HIV-infected patients. Prior to the era of highly active antiretroviral therapy (HAART), a million new cases of cryptococcosis per year world wide and at least 500,000 deaths are estimated. 1 Cryptococcosis is also a frequent cause of death in resource-limited countries. 2,3 In Thailand, cryptococcal meningitis is the third most common opportunistic infection in HIVinfected patients. 4 Several randomized clinical trials have demonstrated that primary prophylaxis with fluconazole reduces the incidence of cryptococcosis in advanced HIV-infected patients, particularly those with CD4 cell counts <100 cells/mm However, only a randomized controlled trial in Thailand could demonstrate a survival benefit. 6 This could be explained with the higher incidence of disease and limited capacity of diagnosis and antifungal treatment in countries with limited resources. Although primary prophylaxis with fluconazole is not generally recommended in developed countries, it is recommended in the Thai National HIV Treatment Guidelines 8,9 and is widely used in Thailand. World Health Organization (WHO) has advised that antifungal prophylaxis with fluconazole should be considered for HIV-infected patients with WHO clinical stage 4 or CD4 <100 cells/mm 3 in areas where cryptococcal disease is common (C-I) with the note of the limited evidence of survival benefit from prophylaxis and the uncertain benefit of prophylaxis in persons receiving HAART. 10 Of note, all the studies of primary prophylaxis for cryptococcosis, including the randomized controlled study in Thailand that showed the survival benefit, were conducted in the period that HAART was not available. A recent study by Parkes-Ratanshi R et al had enrolled patients who were waiting to receive ART and those who had recently started ART but not yet had a significant improvement in their immune status. 7 Currently, HAART are widely accessible in Thailand. The clinical benefit of primary prophylaxis for cryptococcosis in the real-life setting and in the HAART period has never been evaluated. This study was aimed to evaluate the survival benefit of primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 cell count < 100 cells/ mm 3 in the current real-life setting and to compare rate of new cryptococcosis between patients who received and did not receive primary prophylaxis. METHODS A retrospective cohort study was conducted in HIV-infected patients in an outpatient clinic of a tertiarycare (800-bed) hospital in Bangkok, Thailand. The study included HIV-infected patients who visited HIV clinic between 1998 and Inclusion criteria were 1) aged greater than 15 years old, 2) had CD4 cell count < 100 cells/mm 3, 3) had no previous diagnosis of cryptococcosis, 4) had negative serum cryptococcal antigen, and 5) had followed up for at least 6 months. Patients whose medical records or result of the baseline CD4 was not available were excluded. The medical records were retrieved and reviewed. Baseline data included age, gender, underlying diseases, date of first diagnosis of HIV infection, previous opportunistic infections, hepatitis B virus and hepatitis C virus coinfections, antiretroviral regimen and CD4 cell count. Study patients were categorized into two groups: patients who received fluconazole for primary prophylaxis were classified as fluconazole group ; those who did not receive fluconazole were as control group. In fluconazole group, the cohort started at the date of the start of fluconazole for prophylaxis when CD4 cell count < 100 cells/mm 3. In control group, the cohort started at the date of first CD4 cell count < 100 cells/mm 3. The new diagnosis of cryptococcosis and

3 Vol. 29 No. 1 Primary prophylaxis for cryptococcosis with fluconazole:- Oniem N & Sungkanuparph S. 7 death from any cause were determined and compared between the two groups. The diagnosis of cryptococcosis was based on one or more of the following: positive culture for Cryptococcus neoformans, positive cryptococcal antigen, positive India ink preparation and histopathology compatible with cryptococcosis. The primary end point was the mortality and the secondary end point was new event of cryptococcosis. Categorical data is presented as frequency and percentage. Continuous data is presented as mean and standard deviation or median and interquartile rage (IQR) for data with and without normal distribution, respectively. Categorical variables between the two groups were compared using Chi square or Fisher s exact test as appropriate. Continuous variables between the two groups were compared using Student s t test and Mann-Whitney U test as appropriate. Kaplan-Meier analysis with the log-rank test was used to determine and compare the probability to develop cryptococcosis between the two groups. All analysis was performed using SPSS program version 16.0 (Chicago, IL, U.S.A.). A p value of < 0.05 was considered statistical significance. The study was approved by the institutional review board. RESULTS There were 189 patients included in the study: 136 in fluconazole group and 53 in control group. The characteristics of the patients are shown in Table 1. Of all, mean (SD) age was 36.3 (10.9) years and 64.6% of patients were males. Mean (SD) CD4 cell count was 35 (25) cells/mm 3 and 56.6% of patients had previous diagnosis of opportunistic infections other than cryptococcosis, such as tuberculosis (36 patients, 19.0%), Pneumocystis pneumonia (PCP, 46 patients, 24.3%), CMV disease (14 patients, 7.4%) and others. All patients had subsequently received HAART at a 7 median (IQR) time of 2 (0-7) weeks after the finding of CD4 < 100 cells/mm 3. Non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens were commonly used (92.6% of patients). There were no differences of baseline characteristics between fluconazole group and control group (Table 1). No patient in either group died from any causes. During a median (IQR) follow-up time of 5.9 ( ) years, 1 patient (0.7%) in fluconazole group and 2 patients (3.8%) in control group developed cryptococcosis (p = 0.190). Median (range) time to develop cryptococcosis was 5.4 ( ) months after the finding of CD4 < 100 cells/mm 3. Kaplan-Meier analysis showed that there was no difference of the probability to develop cryptococcosis between the two groups (log-rank test, p = 0.138). There was no event of cryptococcosis development in either group after one-year follow up. DISCUSSION The results from the present study have shown that fluconazole for primary prophylaxis of cryptococcosis in HIV-infected patient with CD4 cell count < 100 cells/mm 3 in the era of HAART did not provide any survival benefit. As previously noted in WHO recommendation for primary prophylaxis for cryptococcosis with fluconazole, there was limited evidence of survival benefit from prophylaxis and uncertain benefit of prophylaxis in persons receiving HAART. 10 The results from the present study provide information for consideration regarding this concern. The new events of cryptococcosis in both fluconazole group and control group were similar. Although the rate of new diagnosis of cryptococcosis was slightly higher in control group (3.8% vs. 0.7%), there was no statistical significance. The median followup time of 5.9 years in the present study ensured the

4 8 J INFECT DIS ANTIMICROB AGENTS Jan-April 2012 Table 1. Baseline characteristics between HIV-infected patients in fluconazole group and control group. Characteristics Fluconazole group (n=136) Control group (n=53) P value Gender, number (%) Male 85 (62.5) 37 (69.8) Female 51 (37.5) 16 (30.2) Age, years, mean + SD Previous OIs, number (%) 81 (59.6) 26 (49.1) Tuberculosis 25 (18.4) 11 (20.8) PCP 36 (26.5) 10 (18.9) CMV disease 11 (8.1) 3 (5.7) Toxoplasmosis 5 (3.7) 0 (0) Penicillosis 2 (1.5) 0 (0) MAC infection 2 (1.5) 0 (0) Others 3 (2.2) 1 (1.9) HBV co-infection, number (%) 12/112 (10.7) 2/41 (4.9) HCV co-infection, number (%) 4/104 (3.8) 2/35 (5.7) Baseline CD4, mean, + SD Received HAART, number (%) 136 (100) 53 (100) - ART regimen, number (%) NNRTI-based 132 (97.1) 45 (84.6) PI-based 4 (2.9) 8 (15.4) Time from CD4 <100 cell/mm 3 to receive 1.2 (0-7.2) 2.2 ( ) HAART, weeks, median (IQR) Duration of follow-up, years, median (IQR) 5.6 ( ) 6.8 ( ) OIs = opportunistic infections, HBV = hepatitis B virus, HCV = hepatitis C virus long-term effect of fluconazole prophylaxis and it did not show any benefit of fluconazole prophylaxis in terms of prevention of new events of cryptococcosis. This finding is different from the results from previous studies that fluconazole prophylaxis can decrease the occurrence of cryptococcosis. 5,6 Of note, these previous studies were conducted in the period that HAART was not available. HAART may play an important role in immune reconstitution and decrease the risk of acquiring opportunistic infections. A previous study in Thailand had demonstrated that HAART significantly decreased the relapse rate of

5 Vol. 29 No. 1 Primary prophylaxis for cryptococcosis with fluconazole:- Oniem N & Sungkanuparph S. 9 cryptococcosis. 11 Thus, the results from the present study may suggest that fluconazole for primary prophylaxis of cryptococcosis in HIV-infected patients receiving HAART is not necessary. This warrants the need of further study in a prospective randomized control trial to confirm our findings. Of note, all patients in the present study had negative serum cryptococcal antigen. The role of screening for serum cryptococcal antigen among HIVinfected patients with CD4 < 100 cells/mm 3 has been established. 12 This warrants the importance of the screening for serum cryptococcal antigen prior to omitting primary prophylaxis for cryptococcosis with fluconazole. There are limitations in the present study, such as the retrospective design, relatively small sample size and small number of patients in control group. However, this retrospective cohort study allowed us to study the long-term effect of primary prophylaxis. Regarding the sample size, we had included the cases in the 12-year period that HAART had been available to enlarge the size of study sample as much as possible. In conclusion, in the era that HAART is widely available and can be commenced shortly after the finding of low CD4 cell count, primary prophylaxis for cryptococcosis with fluconazole among HIV-infected patients with CD4 < 100 cells/mm 3 may not be necessary and the recommendation should be reconsidered. However, a large randomized control trial designed to confirm our findings should be conducted. References 1. Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009;23: McCarthy KM, Morgan J, Wannemuehler KA, et al. Population-based surveillance for cryptococcosis in 9 an antiretroviral-naive South African province with a high HIV seroprevalence. AIDS 2006;20: French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002;16: Chariyalertsak S, Sirisanthana T, Saengwonloey O, Nelson KE. Clinical presentation and risk behaviors of patients with acquired immunodeficiency syndrome in Thailand, : regional variation and temporal trends. Clin Infect Dis 2001;32: Chang LW, Phipps WT, Kennedy GE, Rutherford GW. Antifungal interventions for the primary prevention of cryptococcal disease in adults with HIV. Cochrane Database Syst Rev 2005;(3):CD Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, Mootsikapun P, Boonyaprawit P. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIVinfected patients with severe immune deficiency. HIV Med 2004;5: Parkes-Ratanshi R, Kamali A, Wakeham K, et al. Successful primary prevention of cryptococcal disease using fluconazole prophylaxis in HIVinfected Ugandan adults [Abstract 32]. Program and abstracts of the 16 th Conference on Retrovirus and Opportunistic Infections. Montreal, Canada; February 8-11, Chitwarakorn A, Woratanarat T, Lo Y. Thailand National Guidelines for the Clinical Management of HIV Infection in Children and Adults. 6 th ed. Nonthaburi, Thailand: Ministry of Public Health, Ministry of Public Health. Thailand National Antiretroviral Treatment Guideline 2006/2007. Bangkok: The Agricultural Co-operative Federation of Thailand, World Health Organization. Essential Prevention and Care Interventions for Adults and Adolescents Living with HIV in Resource-Limited Setting.

6 10 J INFECT DIS ANTIMICROB AGENTS Jan-April 2012 Geneva: WHO, Jongwutiwes U, Kiertiburanakul S, Sungkanuparph S. Impact of antiretroviral therapy on the relapse of cryptococcosis and survival of HIV-infected patients with cryptococcal infection. Curr HIV Res 2007;5: Pongsai P, Atamasirikul K, Sungkanuparph S. The role of serum cryptococcal antigen screening for the early diagnosis of cryptococcosis in HIVinfected patients with different ranges of CD4 cell counts. J Infect 2010;60:474-7.