Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort

Catherine Hewison, Uzma Khan, Mathieu Bastard, Nathalie Lachenal, Sylvine Coutisson, Elna Osso, Saman Ahmed, Palwasha Khan, Molly F Franke, Michael L Rich, Francis Varaine, Nara Melikyan, Kwonjune J Seung, Malik Adenov, Sana Adnan, Narine Danielyan, Shirajul Islam, Aleeza Janmohamed, Hayk Karakozian, Maureen Kamene Kimenye, Ohanna Kirakosyan, Begimkul Kholikulov, Aga Krisnanda, Andargachew Kumsa, Garmaly Leblanc, Leonid Lecca, Mpiti Nkuebe, Shahid Mamsa, Shrivani Padayachee, Phone Thit, Carole D Mitnick, Helena Huerga, Catherine Hewison, Uzma Khan, Mathieu Bastard, Nathalie Lachenal, Sylvine Coutisson, Elna Osso, Saman Ahmed, Palwasha Khan, Molly F Franke, Michael L Rich, Francis Varaine, Nara Melikyan, Kwonjune J Seung, Malik Adenov, Sana Adnan, Narine Danielyan, Shirajul Islam, Aleeza Janmohamed, Hayk Karakozian, Maureen Kamene Kimenye, Ohanna Kirakosyan, Begimkul Kholikulov, Aga Krisnanda, Andargachew Kumsa, Garmaly Leblanc, Leonid Lecca, Mpiti Nkuebe, Shahid Mamsa, Shrivani Padayachee, Phone Thit, Carole D Mitnick, Helena Huerga

Abstract

Background: Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion. Evaluate safety of longer MDR/RR-TB regimens containing bedaquiline and/or delamanid.

Methods: Multicentre (16 countries), prospective, observational study reporting incidence and frequency of clinically relevant adverse events of special interest (AESIs) among patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. The AESIs were defined a priori as important events caused by bedaquiline, delamanid, linezolid, injectables, and other commonly used drugs. Occurrence of these events was also reported by exposure to the likely causative agent.

Results: Among 2296 patients, the most common clinically relevant AESIs were peripheral neuropathy (26.4%), electrolyte depletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 21.5 (95% confidence interval [CI]: 19.8-23.2), 20.7 (95% CI: 19.1-22.4), and 9.7 (95% CI: 8.6-10.8), respectively. QT interval was prolonged in 2.7% or 1.8 (95% CI: 1.4-2.3)/1000 person-months of treatment. Patients receiving injectables (N = 925) and linezolid (N = 1826) were most likely to experience events during exposure. Hearing loss, acute renal failure, or electrolyte depletion occurred in 36.8% or 72.8 (95% CI: 66.0-80.0) times/1000 person-months of injectable drug exposure. Peripheral neuropathy, optic neuritis, and/or myelosuppression occurred in 27.8% or 22.8 (95% CI: 20.9-24.8) times/1000 patient-months of linezolid exposure.

Conclusions: AEs often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring and drug durations should reflect expected safety profiles of drug combinations.

Clinical trials registration: NCT02754765.

Keywords: MDR-TB; QT prolongation; adverse events; linezolid; new drugs.

Conflict of interest statement

Potential conflicts of interest. C. D. M. is a member of the Akagera Scientific Advisory Board for development of lipid-based, nanoparticle delivery of anti-tuberculosis (TB) drugs (one payment was made to Partners In Health as honorarium for this work). M. R. declared 5% of time spent on a National Institute of Allergy and Infectious Disease–sponsored grant, an observational study of multidrug-resistant TB treatment regimens, and 5% of time spent as an expert consultant on operational research for a World Health Organization EURO project S. P. reports being a subinvestigator on the Pragmatic Clinical Trial for a More Effective Concise and Less Toxic MDR-TB Treatment Regimen(s) (TB-PRACTECAL) trial, sponsored by Médecins Sans Frontières, as an employee of the Tuberculosis & HIV Investigative Network. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
EndTB study sites chart. Abbreviations: MDR, multidrug-resistant; RR, rifampicin-resistant, TB resistant to rifampicin and isoniazid; TB, tuberculosis.

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