Haigh Kathryn A, Twabi Hussein H, Boloko Linda, Namale Phiona E, Lutje Vittoria, Nevitt Sarah, Davies Geraint
Department for Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, UK.
Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.
EClinicalMedicine. 2024 Oct 3;77:102857. doi: 10.1016/j.eclinm.2024.102857. eCollection 2024 Nov.
Tuberculosis (TB) remains a significant cause of mortality globally, yet first-line treatment has hardly changed for fifty years. The dose of rifampicin, the most important drug in this regimen, has been historically based on pragmatic cost- and risk-benefit considerations. Evidence suggests the current recommended dose (8-12 mg/kg) may not maximise the potential benefits of this drug. We sought to evaluate the efficacy and safety of higher doses of rifampicin in adults with presumed drug-susceptible TB.
In this systematic review we searched MEDLINE, EMBASE, CENTRAL and Global Health databases for randomised controlled trials up to 31 July 2024 of adults with presumed drug-susceptible TB receiving first-line treatment with an intervention of rifampicin doses higher than currently recommended. Meta-analyses were performed using random effects models where background regimens were the same. Risk ratio was used as the measure for treatment effect. Outcomes of interest related to efficacy and safety.
Of the 5441 total records identified by our searches, nineteen studies (6332 patients, 31.0% female) were eligible for the systematic review and twelve (3763 patients, 31.0% female) for meta-analysis. Rifampicin doses varied from 8 to 35 mg/kg and implementation of the intervention varied between trials. There was no evidence for increased efficacy with higher doses of rifampicin, however the majority of trials investigated minimally increased doses (up to 20 mg/kg). At higher doses (>20 mg/kg), there may be evidence of increased risk of drug-induced liver injury, albeit with no consistent dose-response relationship.
Evidence on the efficacy of higher doses of rifampicin in the first-line regimen for TB remains incomplete. While higher doses appear generally safe, the risk of drug-induced liver injury may be increased above doses of 20 mg/kg. Larger clinical trials reporting definitive outcomes are needed to determine whether dosing up to 40 mg/kg could safely improve treatment outcomes or reduce duration of first-line therapy.
WHO, Wellcome Trust.
结核病仍是全球范围内一个重要的致死原因，然而一线治疗方案在过去五十年几乎没有改变。利福平是该治疗方案中最重要的药物，其剂量一直基于实际的成本和风险效益考量来确定。有证据表明，目前推荐的剂量（8 - 12毫克/千克）可能无法使该药物的潜在益处最大化。我们旨在评估更高剂量利福平在疑似药物敏感型结核病成人患者中的疗效和安全性。
在这项系统评价中，我们检索了MEDLINE、EMBASE、CENTRAL和全球卫生数据库，以查找截至2024年7月31日的随机对照试验，这些试验涉及接受一线治疗且利福平剂量高于当前推荐剂量的疑似药物敏感型结核病成人患者。在背景治疗方案相同的情况下，使用随机效应模型进行荟萃分析。治疗效果的衡量指标采用风险比。关注的结果涉及疗效和安全性。
在我们检索到的5441条记录中，19项研究（6332例患者，31.0%为女性）符合系统评价的纳入标准，12项研究（3763例患者，31.0%为女性）符合荟萃分析的纳入标准。利福平剂量从8毫克/千克到35毫克/千克不等，不同试验中干预措施的实施情况也有所不同。没有证据表明更高剂量的利福平能提高疗效，不过大多数试验研究的是剂量仅略微增加（最高达20毫克/千克）的情况。在更高剂量（>20毫克/千克）时，可能有证据表明药物性肝损伤的风险增加，尽管没有一致的剂量 - 反应关系。
关于更高剂量利福平在结核病一线治疗方案中的疗效证据仍然不完整。虽然更高剂量总体上似乎是安全的，但药物性肝损伤的风险在剂量超过20毫克/千克时可能会增加。需要开展更大规模、报告明确结果的临床试验，以确定剂量高达40毫克/千克是否能安全地改善治疗效果或缩短一线治疗疗程。
世界卫生组织、惠康信托基金会。
