Emergence of bedaquiline-resistance in a high-burden country of tuberculosis

Eur Respir J. 2021 Sep 9:2100621. doi: 10.1183/13993003.00621-2021. Online ahead of print.

ABSTRACT

RATIONALE: Bedaquiline has been classified as a Group A drug for the treatment of multidrug-resistant tuberculosis (MDR-TB) by the World Health Organization, however globally emerging resistance threatens the effectivity of novel MDR-TB treatment regimens.

OBJECTIVES: We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.

METHODS: In a cross-sectional cohort study, we employed patient data, whole genome sequencing (WGS) and phenotyping of Mycobacterium tuberculosis complex (MTBC) isolates. We could retrieve baseline isolates from 30.5% (62/203) of all MDR-TB patients who received bedaquiline between 2016 and 2018 in the Republic of Moldova. This includes 26 patients for whom we could also retrieve a follow-up isolate.

MEASUREMENTS AND MAIN RESULTS: At baseline, all MTBC isolates were susceptible to bedaquiline. Among 26 patients with available baseline and follow-up isolates, 4/26 (15.3%) patients harbored strains which acquired bedaquiline resistance under therapy, while 1/26 (3.8%) patients was re-infected with a second bedaquiline resistant strain. Treatment failure and death were associated with cavitary disease (p=0.011), and any additional drug prescribed in the bedaquiline containing regimen with WGS-predicted resistance at baseline (p=0.012, OR 1.92 per unit increase, 95%CI 1.15-3.21).

CONCLUSIONS: MDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. Novel MDR-TB therapies with bedaquiline require timely and comprehensive drug resistance monitoring.

PMID:34503982 | DOI:10.1183/13993003.00621-2021