Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.
Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.
复制标题
DOI：
10.1056/nejmoa2111904
复制
发表时间：
2022-03-24
期刊：
影响因子：
--
通讯作者：
Ambition Study Group
中科院分区：
文献类型：
--
作者：
Jarvis JN;Lawrence DS;Meya DB;Kagimu E;Kasibante J;Mpoza E;Rutakingirwa MK;Ssebambulidde K;Tugume L;Rhein J;Boulware DR;Mwandumba HC;Moyo M;Mzinganjira H;Kanyama C;Hosseinipour MC;Chawinga C;Meintjes G;Schutz C;Comins K;Singh A;Muzoora C;Jjunju S;Nuwagira E;Mosepele M;Leeme T;Siamisang K;Ndhlovu CE;Hlupeni A;Mutata C;van Widenfelt E;Chen T;Wang D;Hope W;Boyer-Chammard T;Loyse A;Molloy SF;Youssouf N;Lortholary O;Lalloo DG;Jaffar S;Harrison TS;Ambition Study Group
隐球菌脑膜炎是撒哈拉以南非洲与艾滋病毒有关的死亡的主要原因。基于II期数据，我们进行了III期随机对照非劣效性试验，以确定基于单次高剂量脂质体阿霉素B的治疗方案的疗效。博茨瓦纳、马拉维、南非、乌干达和津巴布韦的HIV阳性隐球菌性脑膜炎成人患者按1：1的比例随机接受诱导治疗：（i）单次、高剂量脂质体阿替西汀B 10 mg/kg联合14天氟胞嘧啶100 mg/kg/天和氟康唑1200 mg/天（AmBisome组），或（ii）目前WHO推荐的治疗：阿替西汀B脱氧胆酸盐（1 mg/kg/天）+氟胞嘧啶（100 mg/kg/天），随后7天氟康唑1200 mg/天（对照组）。主要终点是10周时的全因死亡率，试验在10%的界值下显示非劣效性。我们随机分配了844名参与者。无失访。在意向性治疗分析中，AmBisome组的10周死亡率为24.8%（101/407; 95%置信区间[CI] 20.7-29.3%），对照组为28.7%（117/407; 95% CI 24.4-33.4%）。死亡率的绝对差异为-3.9%，单侧95%置信区间上限为1.2%。AmBisome组脑脊液中的真菌清除率为-0.40 log 10 CFU/ml/天，对照组为-0.42 log 10 CFU/ml/天。AmBisome组中发生3级或4级不良事件的受试者少于对照组（50.0% vs. 62.3%）。单剂量脂质体阿替霉素B（10 mg/kg）联合氟胞嘧啶和氟康唑治疗HIV相关隐球菌脑膜炎不劣于当前WHO推荐的标准治疗，且不良事件较少。（试验注册号：ISRCTN 72509687。）
Cryptococcal meningitis is a leading cause of HIV-related mortality in sub-Saharan Africa. Based on phase-II data, we performed a phase-III randomized controlled non-inferiority trial to determine the efficacy of a single high-dose liposomal amphotericin B based treatment regimen. HIV-positive adults with cryptococcal meningitis in Botswana, Malawi, South Africa, Uganda and Zimbabwe were randomized 1:1 to induction therapy of either (i) single, high-dose liposomal amphotericin B 10mg/kg given with 14 days of flucytosine 100mg/kg/day and fluconazole 1200mg/day (AmBisome group), or (ii) the current WHO recommended treatment of 7 daily doses of amphotericin B deoxycholate (1mg/kg/day) plus flucytosine (100mg/kg/day), followed by 7 days of fluconazole 1200mg/day (control group). The primary endpoint was all-cause mortality at 10 weeks with the trial powered to show non-inferiority at a 10% margin. We randomized 844 participants. None were lost-to-follow-up. In intention-to-treat analysis, 10-week mortality was 24.8% (101 of 407; 95% confidence interval [CI] 20.7-29.3%) in the AmBisome group and 28.7% (117 of 407; 95% CI 24.4-33.4%) in controls. The absolute difference in mortality was -3.9%, with an upper 1-sided 95% confidence interval of 1.2%. Fungal clearance from cerebrospinal fluid was -0.40 log10 CFU/ml/day in the AmBisome group and -0.42 log10 CFU/ml/day in the control group. Fewer participants experienced grade 3 or 4 adverse events in the AmBisome group than the control group (50.0% vs. 62.3%). Single dose liposomal amphotericin B (10mg/kg) on a backbone of flucytosine and fluconazole was non-inferior to the current WHO recommended standard of care for HIV-associated cryptococcal meningitis and associated with fewer adverse events. (Trial registration number: ISRCTN72509687.)