Clinical Infectious Diseases Safety of Bedaquiline and Delamanid • CID 2022:XX (XX XX) • 1 MAJOR ARTICLE Received 25 August 2021; editorial decision 5 January 2022; published online 13 January 2022. a C. H. and U. K. contributed equally to this work. b C. D. M. and H. H. contributed equally to this work. Correspondence: Catherine Hewison, Medical Department, Médecins Sans Frontières, 14-34 avenue Jean Jaurès, 75019, Paris, France (cathy.hewison@paris.msf.org) and (cathammer@ rocketmail.com) Clinical Infectious Diseases ® 2022;XX(XX):1–8 © The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com https://doi.org/10.1093/cid/ciac019 Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort Catherine Hewison, 1,a, Uzma Khan, 2,a Mathieu Bastard, 3 Nathalie Lachenal, 4 Sylvine Coutisson, 4 Elna Osso, 5 Saman Ahmed, 6 Palwasha Khan, 2 Molly F. Franke, 5 Michael L. Rich, 5,7 Francis Varaine, 1 Nara Melikyan, 3 Kwonjune J. Seung, 5,7 Malik Adenov, 8 Sana Adnan, 9 Narine Danielyan, 10 Shirajul Islam, 11 Aleeza Janmohamed, 6 Hayk Karakozian, 12 Maureen Kamene Kimenye, 13 Ohanna Kirakosyan, 14 Begimkul Kholikulov, 15 Aga Krisnanda, 16 Andargachew Kumsa, 17 Garmaly Leblanc, 18 Leonid Lecca, 19 Mpiti Nkuebe, 20 Shahid Mamsa, 9 Shrivani Padayachee, 21 Phone Thit, 22 Carole D. Mitnick, 5,7,b and Helena Huerga 3,b ; on behalf of the endTB Study Observational Study Team 1 Medical Department, Médecins Sans Frontières, Paris, France; 2 Interactive Research and Development Global, Singapore, Singapore; 3 Field Epidemiology Department, Epicentre, Paris, France; 4 Pharmacovigilance Unit, Médecins Sans Frontières, Geneva, Switzerland; 5 Partners In Health, Boston, Massachusetts, USA, and Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, USA; 6 Interactive Research and Development, Karachi, Pakistan; 7 Brigham and Women’s Hospital, Boston, Massachusetts, USA; 8 National Scientifc Center of Phthisiopulmonology, MOH RK (NSCP MOH RK), Almaty, Kazakhstan; 9 Indus Health Network, Karachi, Pakistan; 10 Medical Department, Médecins Sans Frontières, Tbilisi, Georgia; 11 Interactive Research and Development, Dhaka, Bangladesh; 12 Medical Department, Médecins Sans Frontières, Bishkek, Krygystan; 13 National Tuberculosis Program, Nairobi, Kenya; 14 Medical Department, Médecins Sans Frontières, Yerevan, Armenia; 15 Medical Department, Médecins Sans Frontières, Minsk, Belarus; 16 Aga Krisnanda, Interactive Research and Development, Jakarta, Indonesia; 17 Partners In Health, Addis Ababa, Ethiopia; 18 Zanmi Lasante, Cange, Haiti; 19 Socios En Salud Sucursal Peru, Lima, Peru; 20 Partners In Health, Maseru, Lesotho; 21 Interactive Research and Development, Durban, South Africa; and 22 Medical Department, Médecins Sans Frontières, Yangon, Myanmar Background. Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment comple- tion. 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 rele- vant adverse events of special interest (AESIs) among patients who received MDR/RR-TB treatment containing bedaquiline and/or delamanid. Te AESIs were defned 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 de- pletion (26.0%), and hearing loss (13.2%) with an incidence per 1000 person months of treatment, 1000 person-months of treatment 21.5 (95% confdence 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 ofen 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 refect expected safety profles of drug combinations. Clinical Trials Registration. NCT02754765. Keywords. MDR-TB; adverse events; new drugs; QT prolongation; linezolid. The treatment for multidrug-resistant/rifampin-resistant tu- berculosis (MDR/RR-TB) has been notorious for its toxicity, long duration, and poor effectiveness. While the adverse events (AEs) experienced by patients receiving these mul- tiple combinations of drugs are common and well known to clinicians, they have often been poorly documented and frequently considered as unavoidable. Many drugs, such as injectables (kanamycin, amikacin, and capreomycin), ethionamide/prothionamide, cycloserine/terizidone, and para-aminosalicylic acid (PAS), have been used for decades; patients have rarely been offered choices despite the know- ledge that patients would suffer AEs. However, with the in- creased use of bedaquiline and delamanid and the so-called repurposed drugs, such as linezolid and clofazimine, the ex- perience of treating MDR/RR-TB has changed for patients and clinicians alike. The Unitaid-funded endTB project, comprising an observational study and 2 randomized con- trolled clinical trials, was established to increase access to and Downloaded from https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac019/6506720 by guest on 18 February 2022