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利福平耐药结核的短疗程方案试验
A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis


Andrew J. Nunn ... 呼吸系统疾病 • 2019.03.28
NEJM 动画解读

结核的短疗程方案
相关阅读
• 利福平耐药结核的新治疗方案 • 碳青霉烯类药物治疗耐多药结核病 • 理解广泛耐药结核的流行病学

摘要


背景

世界卫生组织(WHO)2011年对耐多药结核的治疗方案提出了建议,而孟加拉国队列研究表明,耐多药结核患者以比上述方案时间短的治疗方案接受现有药物治疗后,达到了很有前景的治愈率。

 

方法

我们在对氟喹诺酮类药物和氨基糖苷类药物敏感的利福平耐药结核患者中开展了一项3期非劣效性试验。以2∶1的比例将参与者随机分组,分别接受包含大剂量莫西沙星的短疗程方案(9~11个月)或遵循2011年WHO指南的长疗程方案(20个月)治疗。主要疗效结局是132周时的良好状态,良好状态的定义为132周及之前一次检测中结核分枝杆菌培养结果呈阴性,并且两次检测之间无阳性培养结果,之前也无不良结局。利用良好状态组间差异的95%置信区间上限≤10个百分点确定非劣效性。

 

结果

在被随机分组的424例参与者中,383例被纳入改良意向治疗人群。长疗程方案组79.8%的参与者和短疗程方案组78.8%的参与者报告了良好状态,根据人类免疫缺陷病毒状态校正后的差异为1.0个百分点(95%置信区间[CI],-7.5~9.5)(对于非劣效性,P=0.02)。在符合方案人群的321例参与者中,非劣效性结果一致(校正的差异,-0.7个百分点;95% CI,-10.5~9.1)。长疗程方案组45.4%的参与者和短疗程方案组48.2%的参与者发生了3级或更高级别的不良事件。短疗程方案组11.0%参与者和长疗程方案组6.4%参与者的QT间期或校正QT间期(利用Fridericia公式计算)延长至500 ms(P=0.14);由于短疗程方案组的发生率较高,因此我们对参与者进行了密切监测,并对一些参与者的用药进行了调整。短疗程方案组8.5%的参与者和长疗程方案组6.4%的参与者死亡,两组分别有3.3%和2.3%的参与者对氟喹诺酮类药物或氨基糖苷类药物产生了获得性耐药。

 

结论

在对氟喹诺酮类药物和氨基糖苷类药物敏感的利福平耐药性结核患者中,短疗程方案的主要疗效结局不劣于长疗程方案,安全性与长疗程方案相似(由美国国际开发署[U.S. Agency for International Development]等资助;在Current Controlled Trials注册号为ISRCTN78372190;在ClinicalTrials.gov注册号为NCT02409290)。





作者信息

Andrew J. Nunn, M.Sc., Patrick P.J. Phillips, Ph.D., Sarah K. Meredith, M.Sc., Chen-Yuan Chiang, Dr.Philos., Francesca Conradie, M.B., Ch.B., Doljinsuren Dalai, M.D., Armand van Deun, Ph.D., Phan-Thuong Dat, Ph.D., Ngoc Lan, Ph.D., Iqbal Master, M.B., Ch.B., Tesfamarium Mebrahtu, M.D., Daniel Meressa, M.D., Ronelle Moodliar, M.Med., Nosipho Ngubane, M.B., Ch.B., Karen Sanders, M.Sc., Stephen Bertel Squire, Ph.D., Gabriela Torrea, Ph.D., Bazarragchaa Tsogt, Ph.D., and I.D. Rusen, M.D. for the STREAM Study Collaborators*
From the Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL), London (A.J.N, P.P.J.P., S.K.M., K.S.), and the Liverpool School of Tropical Medicine, Liverpool (S.B.S.) — both in the United Kingdom; International Union against Tuberculosis and Lung Disease (the Union), Paris (C.-Y.C., A.D., I.D.R.); the Department of Internal Medicine, Wanfang Hospital, and School of Medicine, Taipei Medical University (C.-Y.C.) — both in Taipei, Taiwan; the University of Witwatersrand, Faculty of Health Sciences, Johannesburg (F.C.), King Dinizulu Hospital Complex, Kwazulu Natal (I.M., N.N.), and Think TB and HIV Investigative Network, Durban (R.M.) — all in South Africa; National Center for Communicable Diseases (D.D.) and the Mongolian Tuberculosis Coalition (B.T.) — both in Ulaanbaatar, Mongolia; the Institute of Tropical Medicine, Antwerp, Belgium (A.D., G.T.); Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam (P.-T.D., N.L.); Armauer Hansen Research Institute (T.M.), and St. Peter’s Tuberculosis Specialized Hospital and Global Health Committee (D.M.) — all in Addis Ababa, Ethiopia; the Division of Research and Development, Vital Strategies, New York (I.D.R.); and the Dalla Lana School of Public Health, University of Toronto, Toronto (I.D.R.). Address reprint requests to Mr. Nunn at the MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, 90 High Holborn, 2nd Fl., London WC1V 6LJ, United Kingdom, or at a.nunn@ucl.ac.uk. *A complete list of the STREAM study collaborators is provided in the Supplementary Appendix, available at NEJM.org.

 

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