Publication date: Mar 22, 2025
Background: In STAND and SimpliciTB, clinical trials for drug-susceptible tuberculosis (TB), regimens containing pretomanid, pyrazinamide, and other agents (PaZX) had more hepatotoxicity than the standard-of-care regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE). In Nix-TB and ZeNix, clinical trials for drug-resistant TB, the regimen of bedaquiline, pretomanid, and linezolid (BPaL) demonstrated a favorable benefit-risk profile. We compare the hepatic safety of HRZE, PaZX, and BPaL in their respective populations. Methods: In this post-hoc analysis of data from six clinical trials, rates of treatment-emergent elevations of alanine transaminase (ALT) during the first eight weeks of treatment were estimated by Kaplan-Meier (KM) analysis and compared via log-rank testing and Cox modeling. Results: The KM-estimated probabilities of treatment-emergent ALT elevations greater than 3 times the upper limit of normal (>3xULN) were 5.36%, 12.7%, and 11.4% for HRZE, PaZX, and BPaL, respectively, with the only significant (p < 0.05) difference being HRZE versus PaZX. The probabilities of ALT elevations >8xULN were 2.68%, 4.58%, and 1.05%, with the only significant difference being PaZX versus BPaL. Conclusions: BPaL and HRZE have similar hepatic safety profiles in their respective populations. Pretomanid and pyrazinamide should be co-administered only when the benefit outweighs the risk.
| Concepts | Keywords |
|---|---|
| Bedaquilinepretomanidlinezolid | Alt |
| Burger | Bpal |
| Efficiency | Drug |
| Germany | Group |
| Hrze | |
| Https | |
| International | |
| Medrxiv | |
| Pazx | |
| Preprint | |
| Pretomanid | |
| Pyrazinamide | |
| Safety | |
| Treatment | |
| Weeks |