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

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.

Figure 1:. Modified CONSORT diagram of study participants.

Persons with suspected were screened for the study. Those with cryptococcal meningitis meeting enrolment criteria and providing consent were randomised in a 1:1 distribution to receive adjunctive sertraline or matched placebo. Even proportions of participants were ART-experienced in each treatment group, and constituted nearly half of the patients enrolled. All 460 randomized participants were included in the primary analysis using all available data.

Figure 2:. Kaplan-Meier survival plot for sertraline and placebo.

Kaplan-Meier survival plot for sertraline (grey line) and placebo (black line). Overall 18-week mortality was 52% in the sertraline group compared to 46% in the placebo group, resulting in a hazard ratio of 1·21 (95% CI, 0·93–1·57; p=0·15).

Figure 3:. Plasma concentrations of sertraline among trial participants.

Steady state plasma concentrations while receiving 400mg/day were measured between 7 and 14 days of sertraline therapy and averaged. Participants receiving ART had ~45% lower median plasma sertraline concentrations (P<·001). Sertraline concentrations were similar at 4 weeks when receiving 200mg/day of sertraline, regardless of ART-status.