单剂量脂质体两性霉素 B 治疗隐球菌性脑膜炎。
Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.
机构信息
From the Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (J.N.J., D.S.L., N.Y.), the Institute for Infection and Immunity, St. George's University London (A.L., S.F.M., T.S.H.), and the Clinical Academic Group in Infection and Immunity, St. George's University Hospitals NHS Foundation Trust (T.S.H.), London, Liverpool School of Tropical Medicine (H.C.M., E.W., D.W., D.G.L., S. Jaffar) and the Department of Public Health, Policy, and Systems, Institute of Population Health (T.C.), and the Department of Pharmacology and Therapeutics, Institute of Systems, Molecular, and Integrative Biology (W.H.), University of Liverpool, Liverpool, and the Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter (T.S.H.) - all in the United Kingdom; the Botswana-Harvard AIDS Institute Partnership (J.N.J., D.S.L., M. Mosepele, T.L., K. Siamisang, N.Y.), the Departments of Internal Medicine (M. Mosepele) and Family Medicine and Public Health (K. Siamisang), University of Botswana, and the Department of Health Services Management, Ministry of Health and Wellness (K. Siamisang) - all in Gaborone, Botswana; the Infectious Diseases Institute, College of Health Sciences (D.B.M., E.K., J.K., E.M., M.K.R., K. Ssebambulidde, L.T., J.R., D.R.B., S. Jjunju, E.N.), and the Department of Medicine, School of Medicine (D.B.M.), Makerere University, Kampala, and Mbarara University of Science and Technology, Mbarara (C. Muzoora, E.N.) - both in Uganda; the University of Minnesota, Minneapolis (D.B.M., J.R., D.R.B.); the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (H.C.M., M. Moyo, H.M., D.G.L.) and the Department of Medicine, Kamuzu University of Health Sciences (H.C.M., M. Moyo), Blantyre, and the Lilongwe Medical Relief Fund Trust (University of North Carolina-Malawi Project), Lilongwe (C.K., M.C.H., C.C.) - all in Malawi; the Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill (M.C.H.); the Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine (G.M., C.S., K.C., A.S.), and the Department of Medicine (G.M., C.S., K.C.), University of Cape Town, and the Department of Radiology, Groote Schuur Hospital (A.S.) - both in Cape Town, South Africa; the Internal Medicine Unit, Faculty of Medicine and Health Sciences, University of Zimbabwe, Harare (C.E.N., A.H., C. Mutata); Institut Pasteur, National Center for Scientific Research, Molecular Mycology Unit and National Reference Center for Invasive Mycoses and Antifungals, Unités Mixtes de Recherche 2000, and Université de Paris, Necker Pasteur Center for Infectious Diseases and Tropical Medicine, Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Institut Hospitalo-Universitaire Imagine - both in Paris (T.B.-C., O.L.).
出版信息
N Engl J Med. 2022 Mar 24;386(12):1109-1120. doi: 10.1056/NEJMoa2111904.
BACKGROUND
Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.
METHODS
In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.
RESULTS
A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).
CONCLUSIONS
Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).
背景
隐球菌性脑膜炎是撒哈拉以南非洲地区导致人类免疫缺陷病毒（HIV）相关死亡的主要原因。尚不清楚是否包含单次高剂量脂质体两性霉素 B 的治疗方案是否有效。
方法
在这项在五个非洲国家开展的 3 期随机对照非劣效性试验中，我们将 HIV 阳性的隐球菌性脑膜炎成人患者以 1:1 的比例随机分配，接受单次高剂量脂质体两性霉素 B（10mg/公斤体重），第 1 天加氟胞嘧啶（100mg/公斤体重/天）和氟康唑（1200mg/天），或接受目前世界卫生组织推荐的治疗方案，包括两性霉素 B 去氧胆酸盐（1mg/公斤体重/天）加氟胞嘧啶（100mg/公斤体重/天），持续 7 天，随后氟康唑（1200mg/天）持续 7 天（对照组）。主要终点为 10 周时的任何原因死亡；试验设计的效能为以 10 个百分点的优势证明非劣效性。
结果
共有 844 名参与者接受了随机分组；814 名参与者被纳入意向治疗人群。在 10 周时，脂质体两性霉素 B 组有 101 名（24.8%；95%置信区间 [CI]，20.7 至 29.3）和对照组有 117 名（28.7%；95% CI，24.4 至 33.4）参与者报告死亡（差异，-3.9 个百分点；单侧 95%CI 的上限为 1.2 个百分点，在非劣效性边界内；P<0.001 表示非劣效性）。脂质体两性霉素 B 组脑脊液中真菌清除率为每天-0.40 对数菌落形成单位（CFU）/毫升，对照组为每天-0.42logCFU/毫升。脂质体两性霉素 B 组的 3 级或 4 级不良事件发生率低于对照组（50.0% vs. 62.3%）。
结论
单次剂量脂质体两性霉素 B 联合氟胞嘧啶和氟康唑与世界卫生组织推荐的 HIV 相关隐球菌性脑膜炎治疗方案不劣效，且不良事件更少。（由欧洲和发展中国家临床试验伙伴关系和其他组织资助；AmbitiON ISRCTN 编号，ISRCTN72509687。）
Zotero 插件