Identifying new antifungals effective for cryptococcal meningitis (CM) remains a priority given the high costs, toxicity, and limited availability of current first line 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, randomized, placebo-controlled clinical trial.
We assessed 18-week survival among HIV-infected adults with cryptococcal meningitis from March 2015 to May 2017. Participants were recruited in Kampala and Mbarara, Uganda and randomly assigned to receive standard therapy (7-14 days of amphotericin + fluconazole starting at 800 mg daily) 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 an additional 10 weeks prior to tapering. Secondary outcomes included the rate of fungal clearance from cerebral spinal fluid (CSF), adverse events, incidence of relapse, quantitative neurocognitive performance and depression scores.
The trial was stopped for futility after enrolling 460 of a planned 550 patients. The 18-week mortality was 52% in the sertraline group and 46% in the placebo group (hazard ratio for sertraline, 1.21; 95% CI, 0.93-1.57; p=0.16) (Figure). The rate of fungal clearance from CSF was similar between groups (-0.33 (95% CI, -0.36 to -0.30) vs -0.32 (95% CI, -0.35 to -0.30) log10 CFU/mL CSF/day; p=0.37), as was incidence of grade ≥ 4 adverse events (24% vs 26%; p=0.63). While there was no difference in overall neurocognitive performance between groups among survivors at day 14, there was a trend towards improved depression scores among those receiving sertraline (CES-D score of 14 (95% CI, 11-16) vs 17 (95% CI, 14-20) for those receiving placebo; p=0.06). Incidence of relapse (1% in each group) and re-hospitalizations (13% in each group) were similar. Despite the use of high dose sertraline, no cases of serotonin syndrome were observed in the trial. Mortality was similar among antiretroviral naïve and antiretroviral experienced patients.
Sertraline did not reduce mortality among patients with HIV-associated cryptococcal meningitis at tested doses. Investigations are currently underway to better understand the reasons for sertraline inactivity, which may be multifactorial and possibly related to inadequate drug concentrations, drug-drug interactions, or unknown immune effects.