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

Hewison, CatherineORCID logo; Khan, Uzma; Bastard, Mathieu; Lachenal, Nathalie; Coutisson, Sylvine; Osso, Elna; Ahmed, Saman; Khan, PalwashaORCID logo; Franke, Molly F; Rich, Michael L; +22 more...Varaine, Francis; Melikyan, Nara; Seung, Kwonjune J; Adenov, Malik; Adnan, Sana; Danielyan, Narine; Islam, Shirajul; Janmohamed, Aleeza; Karakozian, Hayk; Kamene Kimenye, Maureen; Kirakosyan, Ohanna; Kholikulov, Begimkul; Krisnanda, Aga; Kumsa, Andargachew; Leblanc, Garmaly; Lecca, Leonid; Nkuebe, Mpiti; Mamsa, Shahid; Padayachee, Shrivani; Thit, Phone; Mitnick, Carole D; and Huerga, Helena (2022) Safety of Treatment Regimens Containing Bedaquiline and Delamanid in the endTB Cohort. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 75 (6). pp. 1006-1013. ISSN 1058-4838 DOI: 10.1093/cid/ciac019
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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.

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