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

Jerry Nedelman; M. Li; M. Olugbosi; R. Bruning-Barry; J. Ambroso; M. Cevik; S. Gillespie; D. J. Sloan; M. Beumont; E. Sun

doi:10.5588/ijtldopen.25.0199

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

Jerry Nedelman^*, M. Li, M. Olugbosi, R. Bruning-Barry, J. Ambroso, M. Cevik, S. Gillespie, D. J. Sloan, M. Beumont, E. Sun

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: In STAND and SimpliciTB, clinical trials for drug-susceptible 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 drugresistant TB, the regimen of bedaquiline, pretomanid, and linezolid (BPaL) demonstrated a favorable benefitrisk 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 8 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 3x the upper limit of normal (.3xULN) were 5.36%, 12.7%, and 11.4% for HRZE, PaZX, and BPaL, respectively. The only significant (p, 0.05) difference was 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.

Original language	English
Pages (from-to)	464-470
Number of pages	7
Journal	IJTLD open
Volume	2
Issue number	8
DOIs	https://doi.org/10.5588/ijtldopen.25.0199
Publication status	Published - 13 Aug 2025

Keywords

Bedaquiline
Hepatotoxicity
Linezolid
Moxifloxacin
Tuberculosis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Copyright © 2025 The Authors. This is an open access article published by The Union under the terms of the Creative Commons Attribution License CC-BY.
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Cite this

@article{dcca5c74ab7147beb6b6d93c163b8166,

title = "Hepatic safety of pretomanid-and pyrazinamide-containing regimens in TB Alliance clinical trials",

abstract = "BACKGROUND: In STAND and SimpliciTB, clinical trials for drug-susceptible 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 drugresistant TB, the regimen of bedaquiline, pretomanid, and linezolid (BPaL) demonstrated a favorable benefitrisk 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 8 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 3x the upper limit of normal (.3xULN) were 5.36\%, 12.7\%, and 11.4\% for HRZE, PaZX, and BPaL, respectively. The only significant (p, 0.05) difference was 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.",

keywords = "Bedaquiline, Hepatotoxicity, Linezolid, Moxifloxacin, Tuberculosis",

author = "Jerry Nedelman and M. Li and M. Olugbosi and R. Bruning-Barry and J. Ambroso and M. Cevik and S. Gillespie and Sloan, \{D. J.\} and M. Beumont and E. Sun",

note = "Funding: This work was supported by TB Alliance (Global Alliance for TB Drug Development) with funding from Australia{\textquoteright}s Department of Foreign Affairs and Trade, the Gates Foundation [OPP1129600], the Foreign, Commonwealth and Development Office (United Kingdom), Germany{\textquoteright}s Federal Ministry of Education and Research through KfW, Irish Aid, and the United States Agency for International Development.",

year = "2025",

month = aug,

day = "13",

doi = "10.5588/ijtldopen.25.0199",

language = "English",

volume = "2",

pages = "464--470",

journal = "IJTLD open",

issn = "3005-7590",

publisher = "International Union against Tubercul. and Lung Dis.",

number = "8",

}

TY - JOUR

T1 - Hepatic safety of pretomanid-and pyrazinamide-containing regimens in TB Alliance clinical trials

AU - Nedelman, Jerry

AU - Li, M.

AU - Olugbosi, M.

AU - Bruning-Barry, R.

AU - Ambroso, J.

AU - Cevik, M.

AU - Gillespie, S.

AU - Sloan, D. J.

AU - Beumont, M.

AU - Sun, E.

N1 - Funding: This work was supported by TB Alliance (Global Alliance for TB Drug Development) with funding from Australia’s Department of Foreign Affairs and Trade, the Gates Foundation [OPP1129600], the Foreign, Commonwealth and Development Office (United Kingdom), Germany’s Federal Ministry of Education and Research through KfW, Irish Aid, and the United States Agency for International Development.

PY - 2025/8/13

Y1 - 2025/8/13

N2 - BACKGROUND: In STAND and SimpliciTB, clinical trials for drug-susceptible 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 drugresistant TB, the regimen of bedaquiline, pretomanid, and linezolid (BPaL) demonstrated a favorable benefitrisk 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 8 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 3x the upper limit of normal (.3xULN) were 5.36%, 12.7%, and 11.4% for HRZE, PaZX, and BPaL, respectively. The only significant (p, 0.05) difference was 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.

AB - BACKGROUND: In STAND and SimpliciTB, clinical trials for drug-susceptible 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 drugresistant TB, the regimen of bedaquiline, pretomanid, and linezolid (BPaL) demonstrated a favorable benefitrisk 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 8 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 3x the upper limit of normal (.3xULN) were 5.36%, 12.7%, and 11.4% for HRZE, PaZX, and BPaL, respectively. The only significant (p, 0.05) difference was 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.

KW - Bedaquiline

KW - Hepatotoxicity

KW - Linezolid

KW - Moxifloxacin

KW - Tuberculosis

U2 - 10.5588/ijtldopen.25.0199

DO - 10.5588/ijtldopen.25.0199

M3 - Article

AN - SCOPUS:105014636356

SN - 3005-7590

VL - 2

SP - 464

EP - 470

JO - IJTLD open

JF - IJTLD open

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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