Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis
Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis
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DOI：
10.1016/s2213-2600(20)30047-3
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发表时间：
2020-04-01
影响因子：
76.2
通讯作者：
Menzies, Dick
中科院分区：
文献类型：
--
作者：
Lan, Zhiyi;Ahmad, Nafees;Menzies, Dick
背景耐多药结核病的治疗需要联合多种二线药物的长期治疗。这些药物与许多不良事件有关，这些不良事件可导致严重的发病率，如耳聋，在某些情况下可导致死亡。我们的目的是估计与不同的结核病药物相关的不良事件的绝对和相对频率，以提供有用的信息，为临床医生和结核病规划在选择最佳的治疗protocols.Methods我们做了荟萃分析，使用个人水平的患者数据，从研究报告的不良事件，导致永久性停用抗结核药物。我们使用了一个数据库，该数据库是为我们之前对耐多药结核病治疗和结局的荟萃分析而创建的，我们对2009年1月1日至2015年8月31日（更新于2016年4月15日）期间发表的文献进行了系统综述，并要求作者提供个体患者水平的信息。我们还考虑了为响应世卫组织2018年的公开呼吁而提供患者水平数据的研究。Meta分析的比例和臂为基础的网络Meta分析，以估计每种结核病drug.Findings的不良事件的发生率，确定了58项研究，其中包括50项研究的更新的个体患者数据的荟萃分析耐多药结核病治疗。其中35项研究（9178例患者）纳入我们的分析。使用比例荟萃分析，导致永久停药的不良事件发生风险较低的药物包括左氧氟沙星（1个中心点3% [95% CI 0个中心点3-5个中心点0]），阿托沙星（2个中心点9% [1个中心点6-5个中心点0]），贝达喹啉（1个中心点7% [0个中心点7-4个中心点2]）和氯法齐明（1个中心点6% [0个中心点5-5个中心点3]）。三种二线注射药物导致永久停药的不良事件发生率相对较高（阿米卡星：10个中心点2% [6个中心点3-16个中心点0];卡那霉素：7个中心点5% [4个中心点6-11个中心点9];卷曲霉素：8中心点2% [6中心点3-10中心点7]）、氨基水杨酸（11中心点6% [7中心点1-18中心点3]）和利奈唑胺（14中心点1% [9中心点9-19中心点6]）。研究选择的偏倚风险被判定为较低，因为纳入和排除的研究之间没有重要差异。研究之间的变异性是显着的大多数outcomeanalysed.Interpretation氟喹诺酮类药物，氯法齐明，贝达喹啉的不良事件发生率最低，导致永久停药，而二线注射药物，氨基水杨酸，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耐多药结核病治疗的患者非常重要。我们的研究结果还强调迫切需要更安全和更好的耐受性药物，以减少耐多药结核病患者治疗本身的发病率。版权所有（c）2020世界卫生组织。由爱思唯尔有限公司出版。保留所有权利。
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 center dot 3% [95% CI 0 center dot 3-5 center dot 0]), moxifloxacin (2 center dot 9% [1 center dot 6-5 center dot 0]), bedaquiline (1 center dot 7% [0 center dot 7-4 center dot 2]), and clofazimine (1 center dot 6% [0 center dot 5-5 center dot 3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10 center dot 2% [6 center dot 3-16 center dot 0]; kanamycin: 7 center dot 5% [4 center dot 6-11 center dot 9]; capreomycin: 8 center dot 2% [6 center dot 3-10 center dot 7]), aminosalicylic acid (11 center dot 6% [7 center dot 1-18 center dot 3]), and linezolid (14 center dot 1% [9 center dot 9-19 center dot 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. Copyright (c) 2020 World Health Organization. Published by Elsevier Ltd. All rights reserved.