Hepatic Safety of Bedaquiline, Delamanid, and Pretomanid: A Systematic Review and Meta-analysis

Novel anti-tuberculosis (TB) drugs have been shown to effectively treat drug-resistant TB (DR-TB). However, there is a risk of hepatotoxicity. We aimed to evaluate the incidence of hepatotoxicity in TB patients receiving bedaquiline (BDQ), delamanid (DLM), and/or pretomanid (Pa). This meta-analysis (PROSPERO: CRD42024564922) systematically explored electronic databases (i.e., Clinicaltrials.gov, Cochrane CENTRAL, Embase, PROQUEST, PubMed, ScienceDirect, and SinoMed) for clinical trials reporting the incidence of hepatotoxicity upon administering BDQ, DLM, and/or Pa. Primary endpoints were the overall incidence of elevated liver enzymes, particularly alanine transferase (ALT), aspartate transferase (AST), and gamma-glutamyl transferase (GGT). Proportion meta-analysis was performed for each outcome of interest. Sixteen trials with pooled 4086 participants. The combination of BDQ + Pa was associated with increased ALT (10.6%) and AST (10.4%). Among the individual drugs, Pa-containing regimens had the highest incidence of elevated liver enzymes (ALT [18.9%], AST [20.3%], and GGT [12.8%]). DLM-containing regimens had the lowest incidence (ALT [0.2%], AST [0.7%], and GGT [1%]). For BDQ-containing regimens, the incidence of elevated liver enzymes was similar to the standard of care (SOC): ALT (5.5%) vs. (6.9%) and AST (7.5%) vs. (10.8%), respectively. GGT elevation was more common among the groups receiving BDQ compared to SOC (10% vs. 3.1%). Overall, all the included trials were of high or fair quality. Among all the studied drugs, DLM alone demonstrated the highest hepatic safety, while regimens containing BDQ, Pa, or their combination showed higher hepatotoxic risks compared to SOC. We recommend regular liver function monitoring for DR-TB patients receiving these novel anti-TB drugs.