Background

Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.

Methods

We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.

Findings

58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3–5·0]), moxifloxacin (2·9% [1·6–5·0]), bedaquiline (1·7% [0·7–4·2]), and clofazimine (1·6% [0·5–5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3–16·0]; kanamycin: 7·5% [4·6–11·9]; capreomycin: 8·2% [6·3–10·7]), aminosalicylic acid (11·6% [7·1–18·3]), and linezolid (14·1% [9·9–19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.

Interpretation

Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.

Funding

Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

中文翻译：

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多药耐药结核病治疗中与药物相关的不良事件：单个患者数据的荟萃分析。

背景

多药耐药结核病的治疗需要长期治疗，同时需要多种二线药物。这些药物与许多不良事件有关，这些不良事件可能导致严重的发病率，例如耳聋，在某些情况下可能导致死亡。我们的目的是估计与不同结核病药物相关的不良事件的绝对和相对频率，以为临床医生和结核病项目选择最佳治疗方案提供有用的信息。

方法

我们使用个人水平的患者数据进行了荟萃分析，这些数据来自报告不良事件的研究，这些不良事件导致抗结核药物的永久停用。我们使用为先前的耐多药结核病治疗和结果进行荟萃分析而创建的数据库，对该数据库进行了系统的文献综述，该文献综述了2009年1月1日至2015年8月31日之间发布的文献（2016年4月15日更新），要求作者提供个人的患者信息。我们还考虑了这项分析研究，以响应世卫组织在2018年的公开呼吁提供患者水平的数据。进行了比例的荟萃分析和基于手臂的网络荟萃分析，以评估每种结核病药物不良事件的发生率。

发现

确定了58项研究，其中50项来自针对耐多药结核病治疗的最新个人患者荟萃分析。这些分析中的35项，共9178例患者，被纳入我们的分析。通过比例荟萃分析，不良事件发生率低导致永久停药的药物包括左氧氟沙星（1·3％[95％CI 0·3-5·0]），莫西沙星（2·9％[1·6] –5·0]），苯达喹啉（1·7％[0·7-4·2]）和氯法齐明（1·6％[0·5-5·3]）。三种永久性停药的不良事件发生率相对较高，导致永久停药（阿米卡星：10·2％[6·3-16·0]；卡那霉素：7·5％[4·6-11·9] ]；开普霉素：8·2％[6·3-10·7]），氨基水杨酸（11·6％[7·1-18·3]）和利奈唑胺（14·1％[9·9-19] ·6]）。由于纳入研究与排除研究之间没有重大差异，因此选择研究的偏倚风险被认为较低。研究之间的差异对于分析的大多数结果均很重要。

解释

氟喹诺酮类，氯法齐明和苯达喹啉的不良事件发生率最低，导致永久性停药，而二线可注射药物，氨基水杨酸和利奈唑胺的发生率最高。这些结果表明，密切监测不良事件对正在接受多药耐药结核病治疗的患者很重要。我们的结果还强调了迫切需要更安全和耐受性更强的药物，以减少多药耐药结核患者自身治疗的发病率。

资金

加拿大卫生研究院，疾病控制与预防中心（美国），美国胸科学会，欧洲呼吸学会和美国传染病学会。