Should Antiretroviral Therapy Be Delayed for 10 Weeks for Patients Treated with Fluconazole for Cryptococcal Meningitis?

Clinical Infectious Diseases, Oct 2010

Bicanic, Tihana, Jarvis, Joseph N., Muzoora, Conrad, Harrison, Thomas S.

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Should Antiretroviral Therapy Be Delayed for 10 Weeks for Patients Treated with Fluconazole for Cryptococcal Meningitis?

Clinical Infectious Diseases 0 Financial support. National Institutes of Health National Institute of Allergy and Infectious Diseases (K23AI073192-01A2). Potential conflicts of interest. All authors: no conflicts 1 Should Antiretroviral Therapy Be Delayed for 10 Weeks for Patients Treated with Fluconazole for Cryptococcal Meningitis? 2 David R. Boulware Division of Infectious Disease and International Medicine, University of Minnesota , Minneapolis, Minnesota , USA 3 Centre for Infection, Department of Cellular and Molecular Medicine, St George's University of London , London , United Kingdom 4 Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town 5 Infectious Diseases Unit, GF Jooste Hospital , Cape Town , South Africa 6 Department of Medicine, Mbarara University Hospital , Mbarara , Uganda 7 Tihana Bicanic 986 ? CID 2010:51 (15 October) ? CORRESPONDENCE One fundamental question for any clin ical trial is appropriate outcome measures. We take the position that survival is a better outcome measure than known mortality. Cryptococcal meningitis has a near 100% mortality rate within 6 months in the absence of ART [ 5, 6 ]. In a time-toevent analysis, right-hand censoring is generally considered acceptable to evaluate participants who are lost to follow-up, yet we question the appropriateness of doing so in all scenarios. This is particularly germane to 3 (or possibly 4) participants in the delayed arm who were lost to followup before 2 weeks and who did not initiate ART. Considering them a success by using time-to-event analysis before censoring at 2 weeks creates a subtle systematic bias. The overall concern is a type I error due to relatively small sample size, underpowered nature of the trial, inadequacy of randomization (eg, unequal CD4+ cell counts between the 2 groups [median, 27 vs 52 cells/mL), and post hoc registration, which is further complicated by early stoppage. Unexplained shifts in 1 or 2 participants could become important. Nevertheless, the overall conclusion is likely correct that after cryptococcal meningitis, when treatment includes a regimen of nevirapine with 800 mg of fluconazole, immediate ART results in higher mortality rates. The authors? conclusion that ?early initiation of ART most likely resulted in increased rates of cryptococcal IRIS [immune reconstitution inflammatory syndrome]? [1, p 1536] is unsubstantiated speculation, because no attempt was made to assess patients for cryptococcal IRIS. The final question is whether this trial?s result is generalizable, particularly if efavirenz were used instead of nevirapine, the nevirapine dosage were adjusted to 200 mg daily while 800 mg of fluconazole was given, amphotericin were used, or the degree of immunosuppression between the 2 groups were fully equal. Additional trials are needed. To the Editor?Makadzange et al [ 1 ], in their trial comparing immediate with deferred antiretroviral therapy (ART) in Zimbabwean patients with cryptococcal meningitis (CM), state that, for patients who are receiving a regimen of fluconazole monotherapy, ?outcomes are improved if treatment [ART] is initiated at least 10 weeks after initiation of treatment for CM? (p 1538). We believe that this conclusion, which has already been relayed by a newsletter popular with practicing clinicians [ 2 ] and is likely to inform clinical practice in sub-Saharan Africa, is not supported by the data. The trial clearly reveals the risks of immediate use of ART (within 72 h) in patients with CM treated with fluconazole monotherapy (800 mg daily). The patients in the immediate ART arm had a 3-year mortality rate of 88% and a median survival of 4 weeks, compared with the patients in the delayed (by 10 weeks) ART arm, who had a 3-year mortality rate of 54%. Because of the fact that the median follow-up period was only 27 days and one-half of the deaths occurred within 2 weeks, we would be interested to see the mortality data at 10 weeks. From the survival curve and considering the small sample sizes of the respective studies, this survival rate in the delayed ART arm would seem not to be substantially different from that in a number of other cohorts from Africa in whom ART was started 4?6 weeks after the start of antifungal therapy [ 3?7 ]?assuming that the study populations are comparable (in fact, in the Makadzange cohort, only slightly more than one-half of the eligible patients were enrolled, and the proportion of patients with altered mental function was relatively low [18.5%]). The important point is that the study by Makadzange and colleagues does not tell us anything about starting ART at 2, 3, 4, 5, or 6 weeks after the start of antifungal therapy, the time points currently chosen by most clinicians. For patients who are initially receiving amphotericin B as antifungal therapy, the Southern African HIV Clinicians Society recommends starting ART at 2?4 weeks and the Infectious Diseases Society of America recommends starting ART at 2?10 weeks after the start of amphotericin B?based therapy [ 8, 9 ]. A randomized trial comparing initiation of ART at 2 weeks and 5 weeks after the start of amphotericin B? based therapy is commencing soon in Uganda and South Africa (NCT01075152, Because of the poorer rates of clearance with fluconazole-based regimens compared with amphotericin B?based regimens [ 3, 4, 7 ] and evidence that organism load is associated with immune reconstitution inflammatory syndrome (IRIS) [ 10, 11 ], it may be that time to ART initiation needs to be longer for patients initially treated with fluconazole regimens. However, assertions that ART initiation ?should be delayed?until culture results are negative or titers have decreased significantly? [1, p 1538] are not backed up by the evidence. In studies in Uganda and Malawi of fluconazole-based treatment, ART has been started at 4 weeks [ 4, 6 ]. Although causes of death are hard to ascertain, deaths presumed to be due to subsequent IRIS reactions have not been common in these cohorts. Any risks of earlier ART initiation need to be balanced against the well-documented high ongoing risk of death from opportunistic infections if ART is delayed: in a large South African cohort with advanced human immunodeficiency virus infection, despite a median time from enrollment to ART initiation of only 34 days, almost one-half of all deaths in the program occurred during this pretreatment period [ 12 ]. We believe that the valid conclusion to be drawn from the study by Makadzange et al [ 1 ] is that it is inadvisable to start ART simultaneously or within 3 days after starting antifungal treatment for CM in patients receiving a regimen of fluconazole monotherapy. However, a firm conclusion to wait until 10 weeks to start ART is not justified by the data presented and risks excess mortality from other opportunistic infections. More rapidly active initial regimens (higher fluconazole dose, combination with flucytosine, and 1 week of treatment with amphotericin B) may be a better strategy than continuing to treat with 800 mg of fluconazole per day and delaying ART. Phase 3 studies in Africa of such regimens are planned. Acknowledgments Financial support. T.B. and J.J. are funded by the Wellcome Trust, UK (WT081794 and WT 089966). Potential conflicts of interest. All authors: no conflicts. References Reply to Boulware, Grant et al, and Bicanic et al To the Editor?We appreciate the comments provided by several readers regarding our article [ 1 ], because concurrent cryptococcal meningitis (CM) and human immunodeficiency virus (HIV) infection continues to be one of the leading causes of death among patients with AIDS in subSaharan Africa. In our study, the overall mortality rate of 73% is exceedingly high but comparable to findings in other subSaharan cohorts [ 2 ]. Our study tested the hypothesis that early initiation of ART could lead to improved clinical outcomes in patients with HIV infection and CM. CORRESPONDENCE ? CID 2010:51 (15 October) ? 987 1. Makadzange AT , Ndhlovu CE , Takarinda K , et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-Saharan Africa . Clin Infect Dis 2010 ; 50 ( 11 ): 1532 - 1538 . 2. Carter M. Risk of IRIS means that HIV treatment should be delayed for patients taking fluconazole for cryptococcal meningitis. NAM Web site . 3A5FFA0E-CD35 - 41AE - 903C -AFC382975233 .asp . Published 10 May 2010 . Accessed 10 May 2010 . 3. Bicanic T , Meintjes G , Wood R , et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviralnaive or antiretroviral-experienced patients treated with amphotericin B or fluconazole . Clin Infect Dis 2007 ; 45 ( 1 ): 76 - 80 . 4. Longley N , Muzoora C , Taseera K , et al. Dose response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda . Clin Infect Dis 2008 ; 47 ( 12 ): 1556 - 1561 . 5. Kambugu A , Meya DB , Rhein J , et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy . Clin Infect Dis 2008 ; 46 ( 11 ): 1694 - 1701 . 6. Nussbaum JC , Jackson A , Namarika D , et al. Combination flucytosine and high-dose fluconazole compared with fluconazole monotherapy for the treatment of cryptococcal meningitis: a randomized trial in Malawi . Clin Infect Dis 2010 ; 50 ( 3 ): 338 - 344 . 7. Bicanic T , Wood R , Meintjes G , et al. High dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV: a randomized study . Clin Infect Dis 2008 ; 47 : 123 - 130 . 8. Guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients . South Afr J HIV Med 2007 ; 28 : 25 - 35 . 9. 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 ( 3 ): 291 - 322 . 10. Lortholary O , Fontanet A , Memain N , Martin A , Sitbon K , Dromer F. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France . AIDS 2005 ; 19 ( 10 ): 1043 - 1049 . 11. Shelburne SA III, Darcourt J , White AC Jr, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy . Clin Infect Dis 2005 ; 40 ( 7 ): 1049 - 1052 . 12. Lawn SD , Harries AD , Anglaret X , Myer L , Wood R . Early mortality among adults accessing antiretroviral treatment programmes in sub-Saharan Africa . AIDS 2008 ; 22 ( 15 ): 1897 - 1908 .

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Bicanic, Tihana, Jarvis, Joseph N., Muzoora, Conrad, Harrison, Thomas S.. Should Antiretroviral Therapy Be Delayed for 10 Weeks for Patients Treated with Fluconazole for Cryptococcal Meningitis?, Clinical Infectious Diseases, 2010, 986-987, DOI: 10.1086/656437