Clinical Infectious Diseases BRIEF REPORT
Primary Prophylaxis for Cryptococcosis With Fluconazole in Human Immunodeficiency Virus– Infected Patients With CD4 T-Cell Counts <100 Cells/µL and Receiving Antiretroviral Therapy Somnuek Sungkanuparph, Chutchaiwat Savetamornkul, and Warisara Pattanapongpaiboon Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
A prospective observational cohort study was conducted in 302 human immunodeficiency virus–infected patients who had a CD4 T-cell count <100 cells/µL and negative serum cryptococcal antigen initiating antiretroviral therapy in a resource-limited setting. During 2-year follow-up, there were no differences of survival rates and occurrences of newly diagnosed cryptococcosis between patients with and without fluconazole for primary prophylaxis of cryptococcosis. Keywords. cryptococcosis; primary prophylaxis; fluconazole; HIV; antiretroviral therapy.
Cryptococcosis is a common opportunistic infection and has become one of the leading causes of death among human immunodeficiency virus (HIV)–infected patients in resource-limited settings, particularly in Africa and Asia. Cryptococcosis causes 15%–20% of AIDS-related mortality in HIV-infected patients [1]. Although scaling up of antiretroviral therapy (ART) has resulted in significant reductions in morbidity and mortality in HIV-infected patients in resource-limited settings, cryptococcosis is still common due to the late presentation to healthcare providers of some HIV-infected patients [2]. Currently, the Infectious Diseases Society of America guidelines for cryptococcal diseases do not routinely recommend primary antifungal prophylaxis for cryptococcosis in HIV-infected patients in the United States due to the lack of survival benefits [3]. However, the role of primary prophylaxis for cryptococcosis has been
Received 17 November 2016; editorial decision 29 December 2016; accepted 14 January 2017; published online January 25, 2017. Presented in part: IDWeek 2016, New Orleans, Louisiana, 26–30 October 2016. Abstract 854. Correspondence: S. Sungkanuparph, Division of Infectious Diseases, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama 6 Road, Bangkok 10400, Thailand (
[email protected]). Clinical Infectious Diseases® 2017;64(7):967–70 © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail:
[email protected]. DOI: 10.1093/cid/cix036
different in resource-limited settings with limited ART availability and a high burden of cryptococcal diseases. In 2003–2004, a multicenter, randomized, double-blind, placebo-controlled trial of primary prophylaxis for cryptococcosis in AIDS patients was conducted in Thailand and showed survival benefit [4]. In 2008, the World Health Organization (WHO) had recommended that antifungal prophylaxis with azoles should be considered for advanced symptomatic HIV-infected patients (WHO clinical stage 4 or CD4 T-cell count <100 cells/µL) in areas where cryptococcal disease is common [5]. Therefore, for almost a decade a primary prophylaxis for cryptococcosis has been recommended for HIV-infected patients with a CD4 count <100 cells/µL in Thailand and other developing countries due to the survival benefit and high prevalence of cryptococcosis [6]. However, the previous study that showed survival benefit of primary prophylaxis for cryptococcosis was conducted prior to the scaling up of ART in Thailand [4]. In addition, the WHO recommendation in 2008 had stated that the level of evidences for primary prophylaxis in HIV-infected patients without ART was strong (C-I, optional - at least one randomized controlled trial with clinical or biological endpoints, or several relevant high-quality scientific studies), but for patients with ART it was weak (C-IV, optional - expert opinion based on evaluation of other evidence) [5]. To date, the relevance of survival benefit of primary prophylaxis for cryptococcosis in patients receiving ART is unclear. Therefore, this study aimed to determine the difference of survival and occurrence of cryptococcosis between HIV-infected patients with and without primary prophylaxis for cryptococcosis with fluconazole. PATIENTS AND METHODS
A prospective observational cohort study was conducted among HIV-infected patients in an HIV clinic of a university hospital in Bangkok, Thailand. The study included HIV-infected patients who visited the HIV clinic between 2000 and 2015. Inclusion criteria were (1) age >15 years; (2) a CD4 count <100 cells/µL; (3) no previous diagnosis of cryptococcosis; and (4) negative serum cryptococcal antigen. Patients were excluded if they had a history of allergic reaction to a fluconazole, pregnancy, elevation of liver enzymes (aspartate aminotransferase or alanine aminotransferase >3 times the upper normal limit), or active liver disease, or had received fluconazole or other antifungal agents to treat any fungal infection, such as oral candidiasis, for >2 weeks. Primary prophylaxis with fluconazole was prescribed at the discretion of the attending physicians. Written informed consent was obtained from all study patients. The study was approved by the Committee on Human Rights Related to Research Involving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University. BRIEF REPORT • CID 2017:64 (1 April) • 967
Study patients were categorized into 2 groups: patients who received fluconazole 400 mg weekly for primary prophylaxis (fluconazole group) and those who did not receive fluconazole (control group). In the fluconazole group, the cohort started at the date of the initiation of fluconazole for the primary prophylaxis when the CD4 count was <100 cells/µL. In the control group, the cohort started at the date of first CD4 count <100 cells/µL. Baseline data included age, sex, underlying diseases, risk of HIV acquisition, duration of HIV infection, previous opportunistic infections, CD4 cell count, hepatitis B virus, and hepatitis C virus coinfections, and antiretroviral regimen. A 2-year follow up after the start of ART was observed in both groups. The new diagnosis of cryptococcosis and death from any cause were determined and compared between the 2 groups. The diagnosis of cryptococcosis was based on 1 or more of the following: positive serum cryptococcal antigen, positive India ink preparation, and positive culture for Cryptococcus neoformans. The primary endpoint was the mortality rate and the secondary endpoint was the new diagnosis of cryptococcosis. Based on at least 90% power to detect a difference in survival rates between the 2 groups with a ratio of 2:1 (fluconazole group:control group) and a 5% significance level, a total of 255 patients are required. This is the observed difference in a previous study of primary prophylaxis [4]. Adjusting for an anticipated dropout proportion of 18%, 302 patients are required overall. For statistical analysis, categorical variables between the 2 groups were compared using χ2 or Fisher exact test as appropriate. Continuous variables between the 2 groups were compared using Student t test and Mann-Whitney U test as appropriate. Kaplan-Meier analysis with the log-rank test was used to determine and compare the survival and probability to develop cryptococcosis between the 2 groups. All analysis was performed using SPSS software version 18.0 (IBM SPSS, Chicago, Illinois). A P value of <.05 was considered statistically significant. RESULTS
A total of 302 patients (201 in the fluconazole group and 101 in the control group) were studied. Of all, 195 (64.6%) patients were men and the mean age was 37.9 (standard deviation [SD], 9.2) years. One hundred eighty-three (60.6%) patients had a history of opportunistic infections other than cryptococcosis. Median CD4 cell count was 31 (interquartile range [IQR], 15–54) cells/µL. Of all, 91.1% of the patients received nonnucleoside reverse transcriptase inhibitor–based regimens. The demographics, risk of HIV acquisition, history of opportunistic infections, hepatitis B or C virus coinfection, Venereal Disease Research Laboratory (VDRL) serostatus, baseline CD4 cell counts, and ART regimens were similar between the 2 groups (P > .05), as summarized in Table 1. 968 • CID 2017:64 (1 April) • BRIEF REPORT
Table 1. Baseline Characteristics and Outcomes of 302 Human Immunodeficiency Virus–Infected Patients Primary Prophylaxis for Cryptococcosis Characteristics and Outcomes
Yes (n = 201)
Age, y, mean (SD)
37.7 (9.2)
No (n = 101) P Value 38.3 (9.0)
.582
Sex Male
.899 129 (64.2)
66 (65.3)
72 (35.8)
35 (34.7)
Heterosexual
186 (92.5)
91 (90.1)
Homosexual
Female Risks of HIV infection
.616 10 (5.0)
8 (7.9)
Intravenous drug use
4 (2.0)
2 (2.0)
Blood transfusion
1 (0.5)
…
Opportunistic infectionsa
.210
Tuberculosis
73 (36.3)
27 (26.7)
Pneumocystis jirovecii pneumonia
53 (26.4)
21 (20.8)
Cytomegalovirus disease
11 (5.5)
9 (8.9)
Toxoplasmosis
9 (4.5)
2 (2.0)
Mycobacterium avium complex disease
3 (1.5)
1 (1.0)
Others
7 (3.5)
3 (3.0)
HBV
22 (10.9)
11 (10.9)
.882
HCV
13 (6.5)
7 (6.9)
.876
Hepatitis virus coinfection
Duration of HIV diagnosis, mo, median (IQR)
2.1 (0.5–4.3)
2.0 (0.7–4.2)
.621
Baseline CD4, cells/µL, median (IQR)
26 (14–49)
35 (17–65)
.084
Baseline HIV RNA, log copies/mL, median (IQR)
5.4 (4.9–5.7)
5.2 (4.8–5.7)
.658
187 (93.0)
88 (87.1)
14 (7.0)
13 (12.9)
Initial ART regimen NNRTI-based PI-based
.090
Post-ART CD4 count, cells/µL, median (IQR) 1y
172 (124–249) 202 (145–330)
.150
2y
262 (198–377) 294 (223–401)
.890
Patients with undetectable HIV RNA 1y
181 (90.0)
91 (90.1)
.989
2y
178 (88.6)
88 (87.1)
.718
Newly developed cryptococcosis
5 (2.5)
5 (5.0)
.311
Deathb
1 (0.5)
1 (1.0)
Outcomes
Type of cryptococcosis
.619 >.99
Meningitis
3 (1.5)
3 (3.0)
Lymphadenitis
1 (0.5)
1 (1.0)
Disseminated infection
1 (0.5)
1 (1.0)
Data are presented as No. (%) unless otherwise indicated. Abbreviations: ART, antiretroviral therapy; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IQR, interquartile range; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor; SD, standard deviation. a
Some patients had >1 opportunistic infection.
b
Causes of death were sepsis and respiratory failure, not related to cryptococcosis.
At 1 and 2 years of ART, the median CD4 count of all patients was 184 (IQR, 129–275) cells/µL and 271 (IQR, 202– 380) cells/µL, respectively, and were not different between the 2 groups (Table 1). Of all, 90.1% and 88.1% of patients had
undetectable HIV RNA (<40 copies/mL) at 1 and 2 years of ART, respectively (Table 1). During a 2-year follow-up period, 1 patient in each group died (P = .619). Causes of death were sepsis and respiratory failure, not related to cryptococcosis. Five patients (2.5%) in the fluconazole group and 5 patients (5.0%) in the control group developed newly diagnosed cryptococcosis (P = .311; Table 1). Kaplan-Meier analysis showed that there was no difference of occurrence of cryptococcosis between the 2 groups (log-rank test, P = .221). Among 10 patients with cryptococcosis, the median time to develop cryptococcosis was 4.1 (IQR, 2.4–8.9) months after ART initiation: 3.5 (IQR, 2.2–11.7) months in the fluconazole group and 4.7 (IQR, 1.7–8.0) months in the control group (P = .690). DISCUSSION
Primary prophylaxis for cryptococcosis in HIV-infected patients with CD4 counts <100 cells/µL has been widely used in resource-limited settings for almost a decade due to the survival benefit from the previous study [4] and the WHO recommendation [5] in the pre-ART era. After scaling up of ART in resource-limited settings, the benefits of this prophylaxis in patients receiving ART is unclear. In the situation that primary prophylaxis for cryptococcosis has no survival benefit, it could be outweighed by the risks. These include drug–drug interactions, induction of antifungal drug resistance, affected ART compliance, and costs. A previous study of drug–drug interaction showed that coadministration of nevirapine and fluconazole resulted in an increased trough plasma nevirapine level compared with the use of nevirapine alone [7]. A recent study also reported the emergence of fluconazole resistance in clinical isolates of Cryptococcus neoformans in Uganda, where primary prophylaxis with fluconazole has been used [8]. The results from the present study have shown that there was no survival benefit from using fluconazole for primary prophylaxis of cryptococcosis in HIV-infected patients receiving ART, even though their CD4 counts were <100 cells/µL. In addition, the mortality rate of all patients was also much lower than that in the previous study [4]. This could be explained by the reasons that all patients in the present study had received ART. ART markedly reduced the mortality rate in HIV-infected patients who presented with cryptococcosis [9]. Furthermore, ART in patients who developed cryptococcosis was initiated at 4–6 weeks after starting antifungal therapy according to the Thai national guidelines established in 2008. A previous study has established that deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at an earlier time [10]. The results from the present study have also shown that there was no difference of the occurrence of newly diagnosed
cryptococcosis between patients with and without primary prophylaxis. Again, this could be from the effect of immune restoration with ART. A recent study in West Africa has demonstrated that the incidence of cryptococcosis is decreasing when the use of ART is increasing in the region [11]. A prior randomized controlled trial study of primary prophylaxis for cryptococcosis by Parkes-Ratanshi and colleagues had shown that the risk of developing cryptococcosis was significantly higher in placebo group than in the fluconazole group [12]. This different finding could be explained by the fact that this prior study enrolled patients before starting ART while we enrolled patients who were initiated ART in the present study. In this prior study, only 85% of patients were started ART at a median of 11 weeks after enrollment, and most of the cases with cryptococcosis had occurred within the first few months. Importantly, this prior study had also demonstrated the same finding as the present study— that there was no survival benefit from primary prophylaxis for cryptococcosis. There are some limitations to the present study. All study patients had received ART and negative serum cryptococcal antigen. The results may not be applicable for settings in which ART is not widely accessed and well sustained or where serum cryptococcal antigen could not be performed. In conclusion, in settings where ART is widely available and HIV-infected patients who have CD4 counts <100 cells/µL are initiated on ART, primary prophylaxis for cryptococcosis with fluconazole has no survival benefit and may not be necessary. The recommendations in developing countries regarding this prophylaxis should be reconsidered. Note Potential conflicts of interest. All authors: No potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. 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; 23:525–30. 2. IeDEA and ART Cohort Collaborations. Immunodeficiency at the start of combination antiretroviral therapy in low-, middle-, and high-income countries. J Acquir Immune Defic Syndr 2014; 65: e8–16. 3. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:291–322. 4. Chetchotisakd P, Sungkanuparph S, Thinkhamrop B, Mootsikapun P, Boonyaprawit P. A multicentre, randomized, double-blind, placebo-controlled trial of primary cryptococcal meningitis prophylaxis in HIV-infected patients with severe immune deficiency. HIV Med 2004; 5:140–3. 5. World Health Organization. Essential prevention and care interventions for adults and adolescents living with HIV in resource-limited settings. Geneva, Switzerland: WHO, 2008. Available at: http://www.who.int/hiv/pub/plhiv/plhiv_ treatment_care.pdf. Accessed 17 November 2016. 6. Jackson A, Hosseinipour MC. Management of cryptococcal meningitis in sub-saharan Africa. Curr HIV/AIDS Rep 2010; 7:134–42.
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7. Manosuthi W, Athichathanabadi C, Uttayamakul S, Phoorisri T, Sungkanuparph S. Plasma nevirapine levels, adverse events and efficacy of antiretroviral therapy among HIV-infected patients concurrently receiving nevirapine-based antiretroviral therapy and fluconazole. BMC Infect Dis 2007; 7:14. 8. Smith KD, Achan B, Hullsiek KH, et al; ASTRO-CM/COAT Team. Increased antifungal drug resistance in clinical isolates of cryptococcus neoformans in Uganda. Antimicrob Agents Chemother 2015; 59:7197–204. 9. 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; 5:355–60.
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10. Boulware DR, Meya DB, Muzoora C, et al; COAT Trial Team. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med 2014; 370:2487–98. 11. Bamba S, Lortholary O, Sawadogo A, Millogo A, Guiguemdé RT, Bretagne S. Decreasing incidence of cryptococcal meningitis in West Africa in the era of highly active antiretroviral therapy. AIDS 2012; 26:1039–41. 12. Parkes-Ratanshi R, Wakeham K, Levin J, et al; Cryptococcal Trial Team. Primary prophylaxis of cryptococcal disease with fluconazole in HIV-positive Ugandan adults: a double-blind, randomised, placebo-controlled trial. Lancet Infect Dis 2011; 11:933–41.
