新发现 耐多药结核病治疗成功的相关因素：个体患者数据荟萃分析

　　摘要

　　背景：目前耐多药结核病的治疗效果仍然很差。本研究旨在评估耐多药结核病患者治疗成功和死亡与不同药物的使用以及这些药物的最佳数量、疗程的关联。

　　方法：本研究为个体患者数据荟萃分析，检索了MEDLINE、Embase和Cochrane图书馆，确定了2009年1月1日到2016年4月30日间发表的可能符合条件的观察性和实验性研究。还检索了2009年以来发表的关于耐多药结核病治疗的所有系统综述的参考文献。合格研究须满足以下条件：研究必须报告了至少有25名成人（年龄>18岁）的队列的治疗转归（治疗完成[成功]、失败或复发）。本研究使用了由研究人员提供的关于患者临床特征、治疗和转归的合格研究中的匿名个体患者数据。采用倾向性评分匹配的广义混合效应logistic或线性回归，计算目前用于耐多药结核病治疗的特定药物以及药物数量、疗程的治疗成功或死亡的调整比值比和风险差。

　　结果：50项研究中来自25个国家的12030例患者，其中7346例（61%）治疗成功，1017例（8%）失败或复发，1729例（14%）死亡。相较于失败或复发患者，使用利奈唑胺（调整风险差：0.15，95%置信区间：0.11～0.18）、左氧氟沙星（0.15，0.13～0.18）、碳青霉烯类（0.14，0.06～0.21）、莫西沙星（0.11，0.08～0.14）、贝达喹啉（0.10, 0.05至0.14）和氯法齐明（0.06，0.01～0.10）可显著提高治疗成功率。使用利奈唑胺（-0.20，-0.23～-0.16）、左氧氟沙星（-0.06，-0.09～-0.04）、莫西沙星（-0.07，-0.10～-0.04）或贝达喹啉（-0.14，-0.19～-0.10）显著降低死亡率。与没有任何注射药物的方案相比，阿米卡星存在些微益处，但卡那霉素和卷曲霉素的疗效较差。其余药物的疗效轻微改善或无改善。体外药敏试验耐药但仍在使用的大部分药物，其疗效明显较差。有效药物的最佳数量在强化期为5种，继续期为4种。经调整的分析中，基于模拟I2计算的特定药物的异质性高达其估计值的近一半，但药物数量和疗程的异质性相对较低。

　　结论：虽然研究数据的观察性质限制了推断，但是使用利奈唑胺、新一代氟喹诺酮类、贝达喹啉、氯法齐明和碳青霉烯类治疗耐多药结核病的疗效明显更好。研究发现强调了进行试验的必要性，以确定这些药物治疗耐多药结核病的最佳组合和疗程。

编译：苏茜      审校：阮云洲  李仁忠

　　（供稿单位：中国疾控中心结核病预防控制中心）

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis

Summary

Background Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis.

Methods In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration.

Findings Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0.15, 95% CI 0.11 to 0.18), levofloxacin (0.15, 0.13 to 0.18), carbapenems (0.14, 0.06 to 0.21), moxifloxacin (0.11, 0.08 to 0.14), bedaquiline (0.10, 0.05 to 0.14), and clofazimine (0.06, 0.01 to 0.10). There was a significant association between reduced mortality and use of linezolid (–0.20, –0.23 to –0.16), levofloxacin (–0.06, –0.09 to –0.04), moxifloxacin (–0.07, –0·10 to –0.04), or bedaquiline (–0.14, –0.19 to –0.10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses.

Interpretation Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition.

参考文献：Ahmad N, Ahuja SD, Akkerman OW, et al. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis [J]. Lancet, 2018, 392(10150): 821-834.