Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial.
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 wit...
| Publicado en: | Lancet Infectious Diseases Vol. 19; no. 8; pp. 843 - 852 |
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| Autores principales: | , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Elsevier B.V.
Aug2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=138082977&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 138082977 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14733099 KIL jtl: Lancet Infectious Diseases issn: 14733099 maglogo: N pubinfo: dt: Aug2019 vid: 19 iid: 8 pid: 467 pub: Elsevier B.V. place: New York, New York artinfo: ui: 138082977 138082977 NLM31345462 138082977 10.1016/S1473-3099(19)30127-6 NLM31345462 138082977 ppf: 843 ppct: 9 formats: tig: atl: Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial. aug: au: Rhein, Joshua Huppler Hullsiek, Kathy Tugume, Lillian Nuwagira, Edwin Mpoza, Edward Evans, Emily E Kiggundu, Reuben Pastick, Katelyn A Ssebambulidde, Kenneth Akampurira, Andrew Williams, Darlisha A Bangdiwala, Ananta S Abassi, Mahsa Musubire, Abdu K Nicol, Melanie R Muzoora, Conrad Meya, David B Boulware, David R affil: Department of Medicine, Medical School, University of Minnesota, Minneapolis, MN, USA; Infectious Diseases Institute, Makerere University, Kampala, Uganda sug: subj: Meningitis, Cryptococcal Drug Therapy Cryptococcus Drug Effects AIDS-Related Opportunistic Infections Drug Therapy HIV Infections Complications Sertraline Hydrochloride Administration and Dosage Drugs Therapeutic Use Uganda Human Treatment Outcomes Double-Blind Studies Fluconazole Therapeutic Use Female Male Meningitis, Cryptococcal Mortality Adult Antifungal Agents Therapeutic Use Cost Benefit Analysis Amphotericin B Therapeutic Use Meningitis, Cryptococcal Cerebrospinal Fluid Validation Studies Comparative Studies Evaluation Research Multicenter Studies Funding Source Adult: 19-44 years Female Male 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. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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