Arbiv Omri A, Holmes Thomas, Kim Marie JeongMin, Yan Marie, Romanowski Kamila, Brode Sarah K, Burman William J, Menzies Dick, Johnston James C
Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Institute of Health Policy, Management, and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
Clin Infect Dis. 2025 Aug 1;81(1):119-128. doi: 10.1093/cid/ciaf004.
Recent studies suggest that triple-dose rifampin (TDR; ≥30 mg/kg/d) may be unsafe. We updated a systematic review to investigate the safety and efficacy of TDR.
We searched Embase, MEDLINE, Cochrane CENTRAL, Cochrane Database for Systematic Reviews, and clinicaltrials.gov for randomized, controlled trials from 1 January 1965 to 10 February 2024 that compared standard-dose rifampin (SDR) with TDR and/or double-dose rifampin (DDR) in human tuberculosis treatment. The primary outcome was pooled incidence rate ratio (IRR) of severe adverse events (SevAEs) between participants who received TDR and those who received SDR. Pooled relative risk (RR) of death was a key secondary outcome. Meta-analysis was performed using the inverse variance method. Heterogeneity was assessed using I2, and bias was assessed using Cochrane Risk of Bias 2. The protocol was prospectively registered (osf.io/kfn5a).
Of the 11 315 articles identified, 17 met inclusion criteria, enrolling 2313 SDR participants (17 studies), 2238 receiving DDR (12 studies), and 1199 receiving TDR (11 studies). Six studies had a high risk of bias. There was an increase in pooled SevAEs among participants who received TDR compared with those who received SDR (IRR, 1.48; 95% confidence interval [CI], 1.12-1.96; I2, 23%), driven by hepatic events (IRR, 1.96; 95% CI, 1.21-3.18). Death did not differ between participants who received TDR and SDR (RR, 1.19; 95% CI, .71-1.99). One limitation is that only 2 included studies were blinded.
Regimens that used TDR were associated with an increase in SevAEs, raising concerns regarding safety of TDR regimens.
近期研究表明，三联剂量利福平（TDR；≥30mg/kg/天）可能不安全。我们更新了一项系统评价，以研究TDR的安全性和有效性。
我们检索了Embase、MEDLINE、Cochrane CENTRAL、Cochrane系统评价数据库和clinicaltrials.gov，查找1965年1月1日至2024年2月10日期间在人类结核病治疗中比较标准剂量利福平（SDR）与TDR和/或双倍剂量利福平（DDR）的随机对照试验。主要结局是接受TDR的参与者与接受SDR的参与者之间严重不良事件（SevAE）的合并发病率比（IRR）。死亡的合并相对风险（RR）是一个关键次要结局。采用逆方差法进行荟萃分析。使用I²评估异质性，使用Cochrane偏倚风险2评估偏倚。该方案已进行前瞻性注册（osf.io/kfn5a）。
在识别出的11315篇文章中，17篇符合纳入标准，纳入了2313名接受SDR的参与者（17项研究）、2238名接受DDR的参与者（12项研究）和1199名接受TDR的参与者（11项研究）。6项研究存在高偏倚风险。与接受SDR的参与者相比，接受TDR的参与者中合并SevAE有所增加（IRR，1.48；95%置信区间[CI]，1.12 - 1.96；I²，23%），主要由肝脏事件导致（IRR，1.96；95%CI，1.21 - 3.18）。接受TDR和SDR的参与者之间的死亡情况没有差异（RR，1.19；95%CI，0.71 - 1.99）。一个局限性是仅2项纳入研究采用了盲法。
使用TDR的治疗方案与SevAE增加相关，这引发了对TDR治疗方案安全性的担忧。
