Hepatic safety of pretomanid- and pyrazinamide-containing regimens in TB Alliance clinical trials

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.

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.

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 8xULN were 2.68%, 4.58%, and 1.05%, with the only significant difference being PaZX versus BPaL.

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. Competing Interest Statement JA and RB-B: Consultants for TB Alliance paid through RTI International. MB, JN, MO, ES: Employees of TB Alliance. ML: Former employee of TB Alliance. MB: Stock in J&J. SG: Grants or contracts from TB Alliance, EDCTP. ML: Stock in J&J, Merck. JN: Stock in Novartis, Sandoz. DS: Grant from EDCTP; member of Medical Monitoring Team for SimpliciTB. Funding Statement This work was supported by TB Alliance (Global Alliance for TB Drug Development) with funding from the Department of Foreign Affairs and Trade (Australia), the Gates Foundation (OPP1129600), the Foreign, Commonwealth and Development Office (United Kingdom), the Federal Ministry of Education and Research through KfW (Germany), Irish Aid, and the United States Agency for International Development. This work was supported in part by the Gates Foundation (OPP1129600). The conclusions and opinions expressed in this work are those of the author(s) alone and shall not be attributed to the Foundation. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. Please note works submitted as a preprint have not undergone a peer review process. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This work is a meta-analysis of data obtained from six clinical trials conducted by TB Alliance. Each trial had multiple sites and multiple ethics committees. In the Methods\Data section of the manuscript, I have added the statement: "Details about ethics committees are provided in the Supplementary Material" All committees are now listed in the Supplementary Material, along with a statement quoted from the Clinical Study Report about their approvals of the studies. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability Data are or will soon be available at TB-PACTS (TB-PACTS | Critical Path Institute (c-path.org)). As described in the Narrative for Case 3 and in Table S11, ALT elevations for one participant were hard-coded from local labs and are not included in the data at TB-PACTS.