Background: Mortality from HIV-associated cryptococcal meningitis (CM) remains unacceptably high. Identifying new effective antifungals is of paramount importance. We evaluated the efficacy of adjunctive sertraline, previously demonstrated to be active against Cryptococcus neoformans both in vitro and in murine models.
Methods: 144 HIV-infected persons with first episode of CM were prospectively enrolled in a phase IIb, open-label clinical trial in Kampala, Uganda between Aug 2013-2014. Sertraline at doses of 100-400 mg/day was added to standard therapy (amphotericin + fluconazole 800mg/day). Early fungicidal activity (EFA) was measured as the rate of cryptococcal clearance in serial quantitative CSF cultures and calculated by mixed effect model for all participants with at least 2 CSF cultures (N=122). Sertraline concentrations in plasma were measured using high performance chromatography–mass spectrometry in 77 subjects to evaluate how rapidly sertraline achieves steady state. In vitro susceptibility was assessed on a subset of C. neoformans isolates (N=95) to determine target 90% minimum inhibitory concentration (MIC90).
Results: Those receiving any dose of sertraline had 28% faster rate of clearance compared with recent historical controls (Table): EFA -0.39 vs. -0.30 for those with vs. without sertraline (p=0.03). Sertraline reached steady state in plasma by day 7, with a median level of 215 (IQR, 126-305) ng/mL at 200mg/day and 400 (IQR, 281-556) ng/mL at 400mg/day. Plasma levels were 68% of steady state levels by day 3. The projected steady state brain tissue concentration at 200mg/day was a median of 3.5 (IQR, 2.1-5.0) mcg/mL and at 400mg/day was 6.6 (4.6-9.2) mcg/mL. Among Cryptococcus isolates, the MIC90 was ≤1 mcg/mL for 9.5%, ≤2 mcg/mL for 30.5%, ≤4 mcg/mL for 84%, and ≤8 mcg/mL for 99% of isolates. In vitro synergy studies (n=9) found a median 2-fold reduction in the MIC90 with a combination of sertraline and fluconazole. For sertraline at doses 200-400mg/day, the incidence of paradoxical IRIS or relapse through 12 weeks was 1%.
Conclusions: Sertraline provides fungicidal activity against C. neoformans with improvements in CSF clearance rates and appears to reach therapeutic levels in vivo. This widely available off-patent oral medication ($0.05 per 100mg tablet) provides a promising adjunct for CM treatment when added to standard antifungal therapy. This pilot justifies a larger randomized trial to elucidate whether sertraline has a survival benefit for the treatment of CM.