Kannabiran Bhavani Perumal, Arthanari Jayanthi, Bhaskar Adhin, Narayanan Mukesh Kumar Sathya, Inbaraj Leeberk Raja
Department of Clinical Research, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India.
Department of Statistics, ICMR-National Institute for Research in Tuberculosis, Chennai, Tamil Nadu, India.
Indian J Med Res. 2025 May;161(5):449-460. doi: 10.25259/IJMR_1673_2024.
Background & objectives Evidence suggests that higher doses of rifampicin aid in faster culture conversion, but its effects on unfavourable outcomes are unclear. We aimed to synthesise evidence on the efficacy and safety of high-dose rifampicin (>15 mg/kg) containing anti-tuberculosis regimen compared to a regimen with standard dose of rifampicin in adults with pulmonary tuberculosis. Methods We searched for studies from MEDLINE, Embase, Web of Science, Google Scholar, and the Cochrane Library without geographical restriction. We included randomised controlled trials that evaluated high-dose rifampicin (>15 mg/kg for 8 wk) with a six-month duration. Our outcomes of interest were sputum conversion at eight wk, mortality, treatment failure at six months, Grade 3 and Grade 4 hepatotoxicity, and adverse events leading to treatment discontinuation. Two authors independently screened titles, abstracts, and full texts and extracted data. We performed a meta-analysis using the RevMan web software as per the Cochrane Handbook for Systematic Reviews of Interventions. Results Out of 3950 articles screened, we included nine for meta-analysis. High-dose rifampicin (≥15 mg/kg) showed little benefit compared to the standard dose for sputum conversion at eight wk [(83% vs. 78%, Relative risk (RR) 1.05 (95% confidence interval (CI): 1.0-1.09), Number needed to treat (NNT)-24)] and this benefit was higher as the rifampicin dose increased [20-30 mg RR: 1.07 (95% CI 1.02-1.14), NNT-17]; >30 mg RR: 1.12 (95% CI 1.04 -1.20) NNT-9]. However, treatment failure and mortality showed no benefit with high-dose rifampicin. Grade 3 and 4 hepatotoxicity and treatment discontinuation due to toxicity had a dose-response relationship and were significantly higher in the more than 30 mg/kg group [RR: 4.01 (95%CI 1.75-9.19), Number needed to harm -20]. Interpretation & conclusions High doses of rifampicin (≥15 mg/kg) increased the rate of sputum culture conversion after two months of the intensive phase. There was no difference in mortality and treatment failure between high-dose rifampicin and standard arms. In the subgroup analysis, the 20-30 mg/kg dose exhibited a beneficial effect in sputum conversion with no significant risk of hepatotoxicity and adverse drug reactions (ADR) leading to treatment discontinuation. This dose could be administered with close monitoring of adverse events and hepatotoxicity. There is an urgent need for adequately powered trials that assess long-term treatment outcomes, including recurrence.
背景与目的 有证据表明，较高剂量的利福平有助于更快实现痰菌转阴，但其对不良结局的影响尚不清楚。我们旨在综合分析含高剂量利福平（>15mg/kg）的抗结核方案与含标准剂量利福平方案相比，在成人肺结核患者中的疗效和安全性证据。方法 我们在MEDLINE、Embase、Web of Science、谷歌学术和Cochrane图书馆中检索研究，无地域限制。我们纳入了评估高剂量利福平（>15mg/kg，疗程8周）且疗程为6个月的随机对照试验。我们感兴趣的结局包括8周时的痰菌转阴、死亡率、6个月时的治疗失败、3级和4级肝毒性以及导致治疗中断的不良事件。两位作者独立筛选标题、摘要和全文并提取数据。我们按照Cochrane干预措施系统评价手册，使用RevMan网络软件进行荟萃分析。结果 在筛选的3950篇文章中，我们纳入了9篇进行荟萃分析。与标准剂量相比，高剂量利福平（≥15mg/kg）在8周时痰菌转阴方面益处不大[（83%对78%，相对危险度（RR）1.05（95%置信区间（CI）：1.0 - 1.09），需治疗人数（NNT）-24）]，且随着利福平剂量增加这种益处更高[20 - 30mg RR：1.07（95%CI 1.02 - 1.14），NNT - 17]；>30mg RR：1.12（95%CI 1.04 - 1.20），NNT - 9]。然而，高剂量利福平在治疗失败和死亡率方面无益处。3级和4级肝毒性以及因毒性导致的治疗中断存在剂量反应关系，在超过30mg/kg组中显著更高[RR：4.01（95%CI 1.75 - 9.19），需伤害人数 - 20]。解读与结论 高剂量利福平（≥15mg/kg）在强化期两个月后提高了痰培养转阴率。高剂量利福平和标准治疗组在死亡率和治疗失败方面无差异。在亚组分析中，20 - 30mg/kg剂量在痰菌转阴方面显示出有益效果，且无显著的肝毒性和导致治疗中断的药物不良反应（ADR）风险。该剂量可在密切监测不良事件和肝毒性的情况下给药。迫切需要有足够样本量的试验来评估长期治疗结局，包括复发情况。
