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

Abstract

Identifying new antifungals for cryptococcal meningitis remains a priority given the inadequacy of current therapy. Sertraline has previously demonstrated in vitro and in vivo activity against Cryptococcus . We evaluated the efficacy of adjunctive sertraline for cryptococcal meningitis in a double-blind, randomised, placebo-controlled clinical trial. We assessed 18-week survival among HIV-infected Ugandan adults with cryptococcal meningitis enrolled from 09 March 2015 to 29 May 2017. Participants were randomly assigned to receive standard therapy with 7–14 days of amphotericin (0·7–1·0 mg/kg/day) + fluconazole (starting at 800 mg/day) with either adjunctive sertraline or placebo. Sertraline was administered at a dose of 400 mg/day for 2 weeks, followed by 200 mg/day for 12 weeks, then tapered off over 3 weeks. Randomisation in a 1:1 ratio was performed with variable block sizes of 2 and 4, with stratification by site (Kampala or Mbarara) and antiretroviral status (experienced or naïve). Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov , number . The trial was stopped for futility after enrolling 460 of a planned 550 participants. The 18-week mortality was 52% (120/229) in the sertraline group and 46% (106/231) in the placebo group (hazard ratio for sertraline, 1.21; 95%CI, 0·93–1·57; P =0·15). The rate of fungal clearance from cerebrospinal fluid was similar between groups, as was incidence of grade 4 or 5 adverse events (31% in the sertraline group vs. 33% in those receiving placebo; p=0·98). The incidence of relapse and paradoxical immune reconstitution inflammatory syndrome were low in both groups, and re-hospitalization rates were similar. 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 may be related to insufficient duration of therapeutic sertraline concentrations. National Institutes of Health, Medical Research Council/Wellcome Trust.