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. 2022 Mar 24;59(3):2100621.
doi: 10.1183/13993003.00621-2021. Print 2022 Mar.

Emergence of bedaquiline resistance in a high tuberculosis burden country

Elena Chesov  1   2   3   4   5 , Dumitru Chesov  1   3   4   5 , Florian P Maurer  6   7 , Sönke Andres  6 , Christian Utpatel  8 , Ivan Barilar  8 , Ana Donica  2 , Maja Reimann  3   4   9 , Stefan Niemann  3   6   8 , Christoph Lange  2   3   9   10   11 , Valeriu Crudu  2 , Jan Heyckendorf  3   4   9   5 , Matthias Merker  12   8   13   5
Affiliations

Emergence of bedaquiline resistance in a high tuberculosis burden country

Elena Chesov et al. Eur Respir J. .

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 out of 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, four (15.3%) patients harboured strains which acquired bedaquiline resistance under therapy, while one (3.8%) patient 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 (OR 1.92 per unit increase, 95% CI 1.15-3.21; p=0.012).

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.

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Conflict of interest statement

Conflict of interest: E. Chesov has nothing to disclose. Conflict of interest: D. Chesov has nothing to disclose. Conflict of interest: F.P. Maurer has nothing to disclose. Conflict of interest: S. Andres has nothing to disclose. Conflict of interest: C. Utpatel has nothing to disclose. Conflict of interest: I. Barilar has nothing to disclose. Conflict of interest: A. Donica has nothing to disclose. Conflict of interest: M. Reimann has nothing to disclose. Conflict of interest: S. Niemann reports grants from EXC 2167 Precision Medicine in Inflammation, grants from Leibniz Science Campus Evolutionary Medicine of the LUNG, grants from German Center for Infection Research, during the conduct of the study. Conflict of interest: C. Lange reports personal fees from Chiesi, Gilead, Janssen, Novartis, Oxfordimmunotec and Insmed, outside the submitted work. Conflict of interest: V. Crudu has nothing to disclose. Conflict of interest: J. Heyckendorf has nothing to disclose. Conflict of interest: M. Merker has nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Study flow chart. MDR-TB: multidrug-resistant tuberculosis; MTBC: Mycobacterium tuberculosis complex.
FIGURE 2
FIGURE 2
Proportions of negative treatment outcomes, relative to the number of drugs used despite predicted resistance at baseline, for patients in the Republic of Moldova who received bedaquiline and at least four additional drugs as part of their multidrug-resistant tuberculosis regimen (2016–2018). Numbers indicate patients per category.
See this image and copyright information in PMC

Comment in

References

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