Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial
Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial
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DOI：
10.1016/s1473-3099(19)30127-6
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发表时间：
2019-08-01
影响因子：
56.3
通讯作者：
Nielsen, Kirsten
中科院分区：
文献类型：
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作者：
Rhein, Joshua;Hullsiek, Kathy Huppler;Nielsen, Kirsten
鉴于目前治疗隐球菌性脑膜炎的不足，确定新的抗真菌药物是当务之急。舍曲林先前已显示出体外和体内抗隐球菌的活性。我们的目的是评估的疗效和成本效益的预防舍曲林在成人与艾滋病毒相关的隐球菌性脑膜炎与安慰剂相比，在这个双盲，随机，安慰剂对照试验，我们招募了艾滋病毒阳性的成人隐球菌性脑膜炎从两家医院在乌干达。受试者被随机分配（1：1）接受标准治疗，7-14天静脉注射阿替西汀B（0.7-1.0 mg/kg/天）和口服氟康唑（800 mg/天开始），同时服用舍曲林或安慰剂。舍曲林口服或经鼻胃管给药，剂量为400 mg/d，持续2周，随后为200 mg/d，持续12周，然后逐渐减少超过3周。主要终点是18周生存期，按意向治疗分析。本研究注册于ClinicalTrials.gov，编号NCT 01802385。结果2015年3月9日至2017年5月29日，我们筛选了842例疑似脑膜炎患者，并招募了计划的550名参与者中的460名，此时试验因无效而停止。舍曲林组3例患者和安慰剂组3例患者失访，因此在研究结束前停药。18周时，舍曲林组229例患者中有120例（52%）死亡，安慰剂组231例患者中有106例（46%）死亡（风险比1.21，95%CI 0.93-1.57; p=0.15）。两组脑脊液真菌清除率相似（舍曲林组为0.43 -log 10 CFU/mL/天[95% CI 0.37-0.50]，安慰剂组为0.47 -log 10 CFU/mL/天[0.40-0.54]; p=0.59），4级或5级不良事件的发生率也是如此（229人中的72人[31%]对231人中的75人[32%]; p=0.98），其中大多数与舍曲林B毒性有关。解释舍曲林不能降低死亡率，不应用于治疗患者与艾滋病病毒相关的隐球菌脑膜炎舍曲林不活动的原因似乎是多因素的，可能与舍曲林治疗浓度的持续时间不足有关。版权所有（C）2019 Elsevier Ltd.保留所有权利。
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 -log 10 CFU/mL per day [95% CI 0.37-0.50] in the sertraline group vs 0.47 -log 10 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.