Safety of treatment regimens containing bedaquiline and delamanid in the endTB cohort.

Hewison C Khan U Bastard M Lachenal N Coutisson S Osso E Ahmed S Khan P Franke MF Rich ML Varaine F Melikyan N Seung KJ Adenov M Adnan S Danielyan N Islam S Janmohamed A Karakozian H Kimenye MK Kirakosyan O Kholikulov B Krisnanda A Kumsa A Leblanc G Lecca L Nkuebe M Mamsa S Padayachee S Thit P Mitnick CD Huerga H
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2022 Jan 13; doi: 10.1093/cid/ciac019. Epub 2022 01 13
MDR-TB QT prolongation adverse events linezolid new drugs


RATIONALE: Safety of treatment for multidrug-resistant tuberculosis (MDR/RR-TB) can be an obstacle to treatment completion.

OBJECTIVES: 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 (AESI) amongst 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 in 26.4%, electrolyte depletion in 26.0%, and hearing loss in 13.2% of patients. Per 1000 person-months of treatment, the incidence of these events was 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 who received 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: Adverse events often related to linezolid and injectable drugs were more common than those frequently attributed to bedaquiline and delamanid. MDR-TB treatment monitoring schedules and individual drug durations should reflect expected safety profiles of drug combinations.

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