Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline
Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline
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DOI：
10.1056/nejmoa1313865
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发表时间：
2014-08-21
影响因子：
158.5
通讯作者：
Dannemann, Brian
中科院分区：
文献类型：
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作者：
Diacon, Andreas H.;Pym, Alexander;Dannemann, Brian
贝达喹啉（Sirturo, TMC207）是一种抑制分枝杆菌ATP合成酶的二苯基喹啉，在多药耐药结核病患者的首选背景方案中添加8周后，可加速痰培养转化。在这项2b期试验中，我们随机分配了160名新诊断的、涂片阳性的、耐多药结核病患者，接受400 mg贝达喹啉每日1次，持续2周，随后接受200 mg每周3次，持续22周，或安慰剂，这两种治疗方案均与首选背景方案联合使用。主要疗效终点为液体肉汤中痰培养转化时间。患者从基线开始随访120周。结果与安慰剂相比，贝达喹啉将培养转化的中位时间从125天缩短至83天（贝达喹啉组的风险比为2.44；95%可信区间为1.57 ~ 3.80；Cox回归分析P< 0.001），并提高了24周（79% vs. 58%, P = 0.008）和120周（62% vs. 44%, P = 0.04）的培养转化率。根据世界卫生组织对耐多药结核病的结局定义，贝达喹啉组120周治愈率为58%，安慰剂组为32% （P = 0.003）。两组总的不良事件发生率相似。贝达喹啉组有10例死亡，安慰剂组有2例死亡，没有明显的因果关系。结论：与安慰剂相比，在首选背景方案中加入贝达喹啉24周可使培养转化更快，并且在120周时显著增加培养转化。贝达喹啉组的死亡人数多于安慰剂组。（由杨森制药公司资助；TMC207-C208 ClinicalTrials.gov号码，NCT00449644。）
BACKGROUNDBedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks.METHODSIn this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline.RESULTSBedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P< 0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P = 0.008) and at 120 weeks (62% vs. 44%, P = 0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P = 0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident.CONCLUSIONSThe addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.)