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

Abstract

Background: 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. Methods: 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 .

Short‐course amphotericin B in addition to sertraline and fluconazole for treatment of HIV‐associated cryptococcal meningitis in rural Tanzania

“…While sertraline added to fluconazole doubled the CSF clearance rate compared with published cohorts, there did not appear to be any survival benefit of sertraline + fluconazole based on the 21% survival at 10‐week. Similarly, in a phase III trial in Uganda, sertraline did not have a survival benefit when given with two weeks of amphotericin and fluconazole . Whether sertraline has any role at all is unclear; however, the benefit of short‐course of amphotericin was clear.…”

“…Similarly, in a phase III trial in Uganda, sertraline did not have a survival benefit when given with two weeks of amphotericin and fluconazole. 20 Whether sertraline has any role at all is unclear; however, the benefit of shortcourse of amphotericin was clear.…”

“…Proportions between the groups were compared using Fisher's exact tests. Overall, 52% (24/46) of the participants were men, and the median age was 37 years (interquartile range (IQR) 32-45) with a median body mass index (BMI) of 21 kg/m 2 (IQR [18][19][20][21][22]. Demographics and clinical parameters at enrolment did not differ between the participant groups ( Table 1).…”

Aspiring Antifungals: Review of Current Antifungal Pipeline Developments

“…A number of other antifungal agents are in various stages of development including nikkomycin (a chitinase inhibitor), and agents repurposed after in vitro antifungal activity was identified (sertraline, auranofin, tamoxifen) [42][43][44][45][46]. These latter agents have been subject to a variety of early clinical trials and in vitro/in vivo studies; however, a clear path forward for their development is yet to be presented.…”

New Approaches for Cryptococcosis Treatment

“…Sertraline use for cryptococcal meningitis treatment alone or in combination with AMB and FLC was investigated in phase III clinical trials (NCT01802385 and NCT03002012), and these studies demonstrated that sertraline did not reduce the mortality rate of patients. This lack of efficacy appears to be multifactorial, and might be associated with insufficient duration of therapeutic sertraline concentrations [71].…”