TY - JOUR
T1 - Adjunctive sertraline for HIV-associated cryptococcal meningitis
T2 - a randomised, placebo-controlled, double-blind phase 3 trial
AU - ASTRO-CM Team
AU - Rhein, Joshua
AU - Huppler Hullsiek, Kathy
AU - Tugume, Lillian
AU - Nuwagira, Edwin
AU - Mpoza, Edward
AU - Evans, Emily E.
AU - Kiggundu, Reuben
AU - Pastick, Katelyn A.
AU - Ssebambulidde, Kenneth
AU - Akampurira, Andrew
AU - Williams, Darlisha A.
AU - Bangdiwala, Ananta S.
AU - Abassi, Mahsa
AU - Musubire, Abdu K.
AU - Nicol, Melanie R.
AU - Muzoora, Conrad
AU - Meya, David B.
AU - Boulware, David R.
AU - Ndyetukira, Jane Francis
AU - Ahimbisibwe, Cynthia
AU - Kugonza, Florence
AU - Namuju, Carolyne
AU - Sadiq, Alisat
AU - Namudde, Alice
AU - Mwesigye, James
AU - Tadeo, Kiiza K.
AU - Kirumira, Paul
AU - Okirwoth, Michael
AU - Luggya, Tonny
AU - Kaboggoza, Julian
AU - Laker, Eva
AU - Atwine, Leo
AU - Muganzi, Davis
AU - Walukaga, Stewart
AU - Jawed, Bilal
AU - Merry, Matthew
AU - Stadelman, Anna
AU - Stephens, Nicole
AU - Flynn, Andrew G.
AU - Fujita, Ayako W.
AU - Kwizera, Richard
AU - Mukaremera, Liliane
AU - Lofgren, Sarah M.
AU - Cresswell, Fiona V.
AU - Morawski, Bozena M.
AU - Bahr, Nathan C.
AU - Nielsen, Kirsten
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/8
Y1 - 2019/8
N2 - 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.
AB - 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.
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U2 - 10.1016/S1473-3099(19)30127-6
DO - 10.1016/S1473-3099(19)30127-6
M3 - Article
C2 - 31345462
AN - SCOPUS:85069697857
SN - 1473-3099
VL - 19
SP - 843
EP - 851
JO - The Lancet Infectious Diseases
JF - The Lancet Infectious Diseases
IS - 8
ER -