Meta-Analysis of Clinical Studies Supports the Pharmacokinetic Variability Hypothesis for Acquired Drug Resistance and Failure of Antituberculosis Therapy
Meta-Analysis of Clinical Studies Supports the Pharmacokinetic Variability Hypothesis for Acquired Drug Resistance and Failure of Antituberculosis Therapy
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DOI：
10.1093/cid/cis353
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发表时间：
2012-07-15
影响因子：
11.8
通讯作者：
Gumbo, Tawanda
中科院分区：
文献类型：
--
作者：
Pasipanodya, Jotam G.;Srivastava, Shashikant;Gumbo, Tawanda
背景资料。利用中空纤维结核研究，我们最近证明，不坚持不是ADR的重要因素，只有在错过很大比例的剂量后，才会发生治疗失败。计算机辅助临床试验模拟表明，异烟肼和利福平的药代动力学可变性最好地解释了不良结果。我们感兴趣的是确定临床上异烟肼的药代动力学变异性是否与微生物失效或不良反应有关。遵循了系统审查和荟萃分析指南的首选报告项目。选择报告异烟肼乙酰化状态和微生物学结果的前瞻性、随机、对照临床试验。检查的主要影响是微生物痰转阴、不良反应和复发。效应大小用合并风险比(RR)表示，比较快速和慢速乙酰化药物。13项随机研究，包括1631名快速乙酰化患者和1751名慢速乙酰化患者，符合纳入和排除标准。快速乙酰化者比慢速乙酰化者更有可能发生微生物失败(RR，2.0；95%可信区间[CI]，1.5-2.7)、不良反应(RR，2.0；CI，1.1-3.4)和复发(RR，1.3；CI，0.9-2.0)。即使在含有抗生素的药物方案中，也会遇到更高的失败率。结果未观察到发表偏倚或小研究效应。该方案中单一药物的药代动力学变异性与治疗失败和患者的不良反应显著相关。这表明，结核病的个体化剂量可能比直接观察治疗方案中规定的标准化剂量更有效。
Background. Using hollow-fiber tuberculosis studies, we recently demonstrated that nonadherence is not a significant factor for ADR and that therapy failure only occurs after a large proportion of doses are missed. Computer-aided clinical trial simulations have suggested that isoniazid and rifampin pharmacokinetic variability best explained poor outcomes. We were interested in determining whether isoniazid pharmacokinetic variability was associated with either microbiological failure or ADR in the clinic.Methods. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Prospective, randomized, controlled clinical trials that reported isoniazid acetylation status and microbiological outcomes were selected. The main effects examined were microbiological sputum conversion, ADR, and relapse. Effect size was expressed as pooled risk ratios (RRs) comparing rapid with slow acetylators.Results. Thirteen randomized studies with 1631 rapid acetylators and 1751 slow acetylators met inclusion and exclusion criteria. Rapid acetylators were more likely than slow acetylators to have microbiological failure (RR, 2.0; 95% confidence interval [CI], 1.5-2.7), ADR (RR, 2.0; CI, 1.1-3.4), and relapse (RR, 1.3; CI,.9-2.0). Higher failure rates were encountered even in drug regimens comprising >3 antibiotics. No publication bias or small-study effects were observed for the outcomes evaluated.Conclusions. Pharmacokinetic variability to a single drug in the regimen is significantly associated with failure of therapy and ADR in patients. This suggests that individualized dosing for tuberculosis may be more effective than standardized dosing, which is prescribed in directly observed therapy programs.