Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid

Juliano Timm; Anna Bateson; Priya Solanki; Ana Paleckyte; Adam A Witney; Sylvia A D Rofael; Stella Fabiane; Morounfolu Olugbosi; Timothy D McHugh; Eugene Sun

doi:10.1371/journal.pgph.0002283

Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid

PLOS Glob Public Health. 2023 Oct 18;3(10):e0002283. doi: 10.1371/journal.pgph.0002283. eCollection 2023.

Authors

Affiliations

¹ TB Alliance, New York City, New York, United States of America.
² Centre for Clinical Microbiology, University College London, Royal Free Campus, London, United Kingdom.
³ Institute of Infection and Immunity, St George's, University of London, London, United Kingdom.
⁴ Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
⁵ MRC Clinical Trials Unit at University College London, London, United Kingdom.
⁶ TB Alliance, Pretoria, South Africa.

Abstract

Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials-STAND, Nix-TB, ZeNix and SimpliciTB-were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes. Data from >1,000 TB patients enrolled from 2015 to 2020 in 12 countries was assessed. We identified 2 (0.3%) participants with linezolid BR. Pretomanid BR was also rare, with similar rates across TB drug resistance types (0-2.1%). In contrast, bedaquiline BR was more prevalent among participants with highly resistant TB or longer prior treatment histories than those with newly diagnosed disease (5.2-6.3% vs. 0-0.3%). Bedaquiline BR was a risk factor for bacteriological failure or relapse in Nix-TB/ZeNix; 3/12 (25%, 95% CI 5-57%) participants with vs. 6/185 (3.2%, 1.2-6.9%) without bedaquiline BR. Across trials, we observed no linezolid AR, and only 3 cases of bedaquiline AR, including 2 participants with poor adherence. Overall, pretomanid AR was also rare, except in ZeNix patients with bedaquiline BR. WGS analyses revealed novel mutations in canonical resistant genes and, in 7 MTB isolates, the genetic determinants could not be identified. The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs.

Copyright: © 2023 Timm et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Grants and funding

This work was supported by TB Alliance with funding from Australia’s Department of Foreign Affairs and Trade, the Bill & Melinda Gates Foundation, Germany’s Federal Ministry of Education and Research through KfW, Irish Aid, Netherlands Ministry of Foreign Affairs, United Kingdom Department of Health, United Kingdom Foreign, Commonwealth and Development Office, and the United States Agency for International Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.