Safety of Triple-Dose Rifampin in Tuberculosis Treatment: A Systematic Review and Meta-Analysis.

Background: There is growing interest in using high-dose rifampin for tuberculosis treatment. Recent studies suggest that triple-dose rifampin (TDR; ≥30 mg/kg/day) may be unsafe. We updated a systematic review to investigate the safety and efficacy of TDR.

Methods: We searched Embase, MEDLINE, Cochrane Central Registry of Controlled Trials, Cochrane Database for Systematic Reviews and clinicaltrials.gov for randomized-controlled trials from January 1, 1965 to February 10, 2024 comparing standard-dose rifampin (SDR) to TDR and/or double-dose rifampin (DDR) in human tuberculosis treatment. The primary outcome was pooled incidence rate ratio (IRR) of severe adverse events (SevAE) between participants receiving TDR and SDR. Pooled relative risk (RR) of death was a key secondary outcome. Meta-analysis was performed by the inverse variance method. Heterogeneity was assessed by I2 and bias assessed by Cochrane Risk of Bias 2. The protocol was prospectively registered (osf.io/kfn5a).

Results: Of the 11315 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 SevAE among participants receiving TDR compared to SDR (IRR 1.48, 95% CI 1.12-1.96, I2 23%), driven by an increase in hepatic events (IRR 1.96, 95% CI 1.21-3.18). Death did not differ between participants receiving TDR and SDR (RR 1.19, 95% CI 0.71-1.99). One limitation is that only two included studies were blinded.

Conclusions: Regimens using TDR were associated with an increase in SevAE, raising concerns regarding safety of TDR in humans.