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

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: Regimens that used TDR were associated with an increase in SevAEs, raising concerns regarding safety of TDR regimens.

Keywords: epidemiology; meta-analysis; rifampin; systematic review; tuberculosis.