A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis
A Trial of a Shorter Regimen for Rifampin-Resistant Tuberculosis
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DOI：
10.1056/nejmoa1811867
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发表时间：
2019-03-28
影响因子：
158.5
通讯作者：
Rusen, I. D.
中科院分区：
文献类型：
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作者：
Nunn, Andrew J.;Phillips, Patrick P. J.;Rusen, I. D.
背景孟加拉国的队列研究显示，在2011年接受比世界卫生组织(WHO)推荐的方案更短的现有药物的耐多药结核病患者中，有希望获得良好的治愈率。方法：我们在对氟喹诺酮类和氨基糖苷类药物敏感的利福平耐药结核病参与者中进行了一项3期非劣势试验。参与者按2：1的比例随机分配，接受包括大剂量莫西沙星在内的短期方案(9至11个月)或遵循2011年世卫组织指南的长期方案(20个月)。主要疗效结果是132周时状态良好，由132周时结核分枝杆菌培养阴性和以前的情况定义，没有干预阳性培养或以前的不利结果。有利地位组间差异的95%置信限上限为10个百分点或更低，用于确定非劣势。结果424名接受随机分组的参与者中，383人包括在修改的意向治疗人群中。长期方案组79.8%的参与者报告状态良好，短期方案组78.8%的参与者报告良好状态-在调整人类免疫缺陷病毒状态后，差异为1.0个百分点(95%可信区间[CI]，-7.5至9.5)(非劣势组P=0.02)。关于非自卑感的结果在按方案人群中的321名参与者中是一致的(调整后的差异，-0.7个百分点；95%可信区间，-10.5到9.1)。在长期方案组和短期方案组中，45.4%的参与者发生了3级或更高级别的不良事件，48.2%的参与者发生了不良事件。短疗程组有11.0%的受试者QT间期或校正的QT间期(用Fridericia公式计算)延长至500毫秒，而长疗程组的这一比例为6.4%(P=0.14)；由于短疗程组的发生率更高，参与者受到密切监测，一些人接受了药物调整。短程方案组死亡率为8.5%，长程方案组死亡率为6.4%，对氟喹诺酮类药物和氨基糖苷类药物的获得性耐药率分别为3.3%和2.3%。结论在对氟喹诺酮类药物和氨基糖苷类药物敏感的耐利福平肺结核患者中，短程方案的疗效不亚于长程方案，安全性与长程方案相似。
BACKGROUNDCohort studies in Bangladesh showed promising cure rates among patients with multidrug-resistant tuberculosis who received existing drugs in regimens shorter than that recommended by the World Health Organization (WHO) in 2011.METHODSWe conducted a phase 3 noninferiority trial in participants with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides. Participants were randomly assigned, in a 2:1 ratio, to receive a short regimen (9 to 11 months) that included high-dose moxifloxacin or a long regimen (20 months) that followed the 2011 WHO guidelines. The primary efficacy outcome was a favorable status at 132 weeks, defined by cultures negative for Mycobacterium tuberculosis at 132 weeks and at a previous occasion, with no intervening positive culture or previous unfavorable outcome. An upper 95% confidence limit for the between-group difference in favorable status that was 10 percentage points or less was used to determine noninferiority.RESULTSOf 424 participants who underwent randomization, 383 were included in the modified intention-to-treat population. Favorable status was reported in 79.8% of participants in the long-regimen group and in 78.8% of those in the short-regimen group - a difference, with adjustment for human immunodeficiency virus status, of 1.0 percentage point (95% confidence interval [CI], -7.5 to 9.5) (P=0.02 for noninferiority). The results with respect to noninferiority were consistent among the 321 participants in the per-protocol population (adjusted difference, -0.7 percentage points; 95% CI, -10.5 to 9.1). An adverse event of grade 3 or higher occurred in 45.4% of participants in the long-regimen group and in 48.2% in the short-regimen group. Prolongation of either the QT interval or the corrected QT interval (calculated with Fridericia's formula) to 500 msec occurred in 11.0% of participants in the short-regimen group, as compared with 6.4% in the long-regimen group (P=0.14); because of the greater incidence in the short-regimen group, participants were closely monitored and some received medication adjustments. Death occurred in 8.5% of participants in the short-regimen group and in 6.4%in the long-regimen group, and acquired resistance to fluoroquinolones or aminoglycosides occurred in 3.3% and 2.3%, respectively.CONCLUSIONSIn persons with rifampin-resistant tuberculosis that was susceptible to fluoroquinolones and aminoglycosides, a short regimen was noninferior to a long regimen with respect to the primary efficacy outcome and was similar to the long regimen in terms of safety.