New analysis compares liver safety of TB regimens

Tuberculosis treatment can involve powerful drugs that carry risks for the liver. In clinical trials for drug-susceptible TB (STAND and SimpliciTB), regimens containing pretomanid, pyrazinamide, and other agents (PaZX) showed more signs of liver injury than the standard-of-care regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). In separate trials for drug-resistant TB (Nix-TB and ZeNix), the regimen of bedaquiline, pretomanid, and linezolid (BPaL) had a favorable benefit-risk profile. To sort out how these regimens compare on liver safety, researchers led by corresponding author Jerry Nedelman performed a post-hoc analysis pooling data from six clinical trials. The team focused on early liver changes that emerge during treatment and aimed to directly compare HRZE, PaZX, and BPaL within their respective trial populations. By examining shared safety measurements across those trials, the investigators sought to clarify whether newer regimens that include pretomanid carry greater hepatic risk than established options.

The analysis looked specifically at treatment-emergent elevations of alanine transaminase (ALT) during the first eight weeks of treatment. Rates were estimated using Kaplan-Meier (KM) analysis and compared with log-rank testing and Cox modeling. For ALT elevations greater than 3 times the upper limit of normal (>3xULN), the KM-estimated probabilities were 5.36% for HRZE, 12.7% for PaZX, and 11.4% for BPaL; the only statistically significant difference reported was HRZE versus PaZX (p < 0.05). For more severe ALT elevations greater than 8xULN, the KM estimates were 2.68% for HRZE, 4.58% for PaZX, and 1.05% for BPaL, with the only significant difference being PaZX versus BPaL. These results come from the pooled trial data and the specified statistical methods, and they quantify how often clinically meaningful liver enzyme rises occurred with each regimen in the early treatment period.

Taken together, the pooled analysis led by Jerry Nedelman concludes that BPaL and HRZE have similar hepatic safety profiles within their respective trial populations, while regimens that combine pretomanid and pyrazinamide (PaZX) showed higher rates of ALT elevations in these datasets. The authors emphasize a cautious approach to co-administering pretomanid and pyrazinamide: that combination should be used only when the expected benefit outweighs the increased risk of liver enzyme elevations. For clinicians and patients, these findings underline the importance of considering liver risk when choosing TB regimens and of weighing benefits and harms specific to the drug-resistant or drug-susceptible populations studied. The analysis is focused on early treatment liver changes and uses standard statistical tools to make comparisons across multiple trials, offering clearer numbers to inform those benefit-risk decisions.