Journal Article

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

Nuwagira, Edwin, Bahr, Nathan C, Flynn, Andrew G, Boulware, David R, Mwesigye, James, Kaboggoza, Julian, Sadiq, Alisat, Okirwoth, Michael, Walukaga, Stewart, Jawed, Bilal, Mpoza, Edward, Merry, Matthew, Luggya, Tonny, Laker, Eva, Kiggundu, Reuben, Muganzi, Davis, Nicol, Melanie R, Namuju, Carolyne, Kwizera, Richard, Pastick, Katelyn A, Kugonza, Florence, Rhein, Joshua, Muzoora, Conrad, Bangdiwala, Ananta S, Kirumira, Paul, Cresswell, Fiona V, Stadelman, Anna, Atwine, Leo, Nielsen, Kirsten, Tadeo, Kiiza K, Huppler Hullsiek, Kathy, Ssebambulidde, Kenneth, Ahimbisibwe, Cynthia, Stephens, Nicole, Tugume, Lillian, Meya, David B, Musubire, Abdu K, Ndyetukira, Jane Francis, Morawski, Bozena M, Akampurira, Andrew, Mukaremera, Liliane, Abassi, Mahsa, Evans, Emily E, Namudde, Alice, Fujita, Ayako W, Williams, Darlisha A, Lofgren, Sarah M

2019

Overview

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. 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. 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. 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. National Institutes of Health and Medical Research Council, Wellcome Trust.

• Publisher: Elsevier Ltd,Elsevier Limited
• Subject: Adjuvants, Pharmaceutic - therapeutic use / Adult / Adults / AIDS-Related Opportunistic Infections - drug therapy / Amphotericin B / Amphotericin B - therapeutic use / Antidepressants / Antifungal Agents - therapeutic use / Biocompatibility / Brain research / Cerebrospinal fluid / Charitable foundations / Clinical trials / Cost-Benefit Analysis / Cryptococcus - drug effects / Double-Blind Method / Double-blind studies / Drug dosages / Drug therapy / Female / Fluconazole / Fluconazole - therapeutic use / Fungal infections / HIV / HIV Infections - complications / Human immunodeficiency virus / Humans / Infections / Infectious diseases / Intravenous administration / Male / Medical research / Meningitis / Meningitis, Cryptococcal - cerebrospinal fluid / Meningitis, Cryptococcal - drug therapy / Meningitis, Cryptococcal - mortality / Mortality / Oral administration / Patients / Randomization / Sertraline / Sertraline - administration & dosage / Studies / Therapy / Toxicity / Treatment Outcome / Uganda