Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial

ASTRO-CM Team, Joshua Rhein, Kathy Huppler Hullsiek, Katelyn A. Pastick, Darlisha A. Williams, Ananta S. Bangdiwala, Mahsa Abassi, Melanie R. Nicol, David B. Meya, David R. Boulware

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Background: Identifying new antifungals for cryptococcal meningitis is a priority given the inadequacy of current therapy. Sertraline has previously shown in vitro and in vivo activity against cryptococcus. We aimed to assess the efficacy and cost-effectiveness of adjunctive sertraline in adults with HIV-associated cryptococcal meningitis compared with placebo. Methods: In this double-blind, randomised, placebo-controlled trial, we recruited HIV-positive adults with cryptococcal meningitis from two hospitals in Uganda. Participants were randomly assigned (1:1) to receive standard therapy with 7–14 days of intravenous amphotericin B (0·7–1·0 mg/kg per day) and oral fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered orally or via nasogastric tube at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. The primary endpoint was 18-week survival, analysed by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT01802385. Findings: Between March 9, 2015, and May 29, 2017, we screened 842 patients with suspected meningitis and enrolled 460 of a planned 550 participants, at which point the trial was stopped for futility. Three patients in the sertraline group and three patients in the placebo group were lost to follow-up and therefore discontinued before study end. At 18 weeks, 120 (52%) of 229 patients in the sertraline group and 106 (46%) of 231 patients in the placebo group had died (hazard ratio 1·21, 95% CI 0·93–1·57; p=0·15). The fungal clearance rate from cerebrospinal fluid was similar between groups (0·43 –log10 CFU/mL per day [95% CI 0·37–0·50] in the sertraline group vs 0·47 –log10 CFU/mL per day [0·40–0·54] in the placebo group; p=0·59), as was occurrence of grade 4 or 5 adverse events (72 [31%] of 229 vs 75 [32%] of 231; p=0·98), most of which were associated with amphotericin B toxicity. Interpretation: Sertraline did not reduce mortality and should not be used to treat patients with HIV-associated cryptococcal meningitis. The reasons for sertraline inactivity appear to be multifactorial and might be associated with insufficient duration of therapeutic sertraline concentrations. Funding: National Institutes of Health and Medical Research Council, Wellcome Trust.

Original languageEnglish (US)
Pages (from-to)843-851
Number of pages9
JournalThe Lancet Infectious Diseases
Volume19
Issue number8
DOIs
StatePublished - Aug 2019

Bibliographical note

Funding Information:
We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke ( R01NS086312 ), the Fogarty International Center ( K01TW010268 , R25TW009345 ), the National Institute of Allergy and Infectious Diseases ( T32AI055433 ), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials ( M007413/1 ), and Grand Challenges Canada ( S4–0296–01 ). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15–011 ) to THRiVE-2. The DELTAS Africa I nitiative i s an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science i n Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z ) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota.

Funding Information:
JR and DRB report grants from the National Institutes of Health, and DBM reports grants from the National Institutes of Health and Medical Research Council/Wellcome Trust, outside of the submitted work. All other authors declare no competing interests.

Funding Information:
We thank the study participants, the trial scientific review board, members of independent review boards at each study site, members of the trial data safety and monitoring board including Joseph N Jarvis, Jason V Baker, Mohammed Lamorde, and Marcel Wolbers, as well as members of our trial steering committee, including John R Perfect, Graeme Meintjes, and Edward N Janoff. This research was supported by the National Institute of Neurologic Diseases and Stroke (R01NS086312), the Fogarty International Center (K01TW010268, R25TW009345), the National Institute of Allergy and Infectious Diseases (T32AI055433), UK Medical Research Council/Department for International Development/Wellcome Trust Global Clinical Trials (M007413/1), and Grand Challenges Canada (S4?0296?01). DBM was also supported by DELTAS Africa Initiative (grant number DEL-15?011) to THRiVE-2. The DELTAS Africa Initiative is an independent funding scheme of the African Academy of Sciences (AAS) Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency) with funding from the Wellcome Trust (grant number 107742/Z/15/Z) and the UK Government. The views expressed in this publication are our own and not necessarily those of AAS, NEPAD Agency, Wellcome Trust, or the UK Government. This work was supported in part by the Doris Duke Charitable Foundation through a grant supporting the Doris Duke International Clinical Research Fellows Program at the University of Minnesota.

Publisher Copyright:
© 2019 Elsevier Ltd

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