{"doi":"10.1183/13993003.00621-2021","title":"Emergence of bedaquiline resistance in a high tuberculosis burden country","abstract":"<jats:sec><jats:title>Rationale</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of<jats:italic>Mycobacterium tuberculosis</jats:italic>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.</jats:p></jats:sec><jats:sec><jats:title>Measurements and main results</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>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.</jats:p></jats:sec>","journal":"European Respiratory Journal","year":2022,"id":607886,"datarank":0.7064295301968502,"base_score":4.709530201312334,"endowment":4.709530201312334,"self_citation_contribution":0.7064295301968502,"citation_network_contribution":0.0,"self_endowment_contribution":0.7064295301968502,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":110,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":399669,"name":"Dumitru Chesov","orcid":"0000-0001-6203-5020","position":1,"is_corresponding":false},{"id":859078,"name":"Florian P. Maurer","orcid":"0000-0001-8353-5964","position":2,"is_corresponding":false},{"id":96122,"name":"Sönke Andres","orcid":null,"position":3,"is_corresponding":false},{"id":813652,"name":"Christian Utpatel","orcid":"0000-0001-5416-8253","position":4,"is_corresponding":false},{"id":649694,"name":"Ivan Barilar","orcid":"0000-0002-4789-2777","position":5,"is_corresponding":false},{"id":1560990,"name":"Ana Donica","orcid":null,"position":6,"is_corresponding":false},{"id":560346,"name":"Maja Reimann","orcid":"0000-0002-2385-2287","position":7,"is_corresponding":false},{"id":96123,"name":"Stefan Niemann","orcid":"0000-0002-6604-0684","position":8,"is_corresponding":false},{"id":663363,"name":"Christoph Lange","orcid":"0000-0003-0119-409X","position":9,"is_corresponding":false},{"id":399672,"name":"Valeriu Crudu","orcid":"0000-0001-5059-8002","position":10,"is_corresponding":false},{"id":28448,"name":"Jan Heyckendorf","orcid":"0000-0003-4203-8421","position":11,"is_corresponding":false},{"id":813651,"name":"Matthias Merker","orcid":"0000-0003-1386-2331","position":12,"is_corresponding":false},{"id":1560985,"name":"Elena Chesov","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Emergence of bedaquiline resistance in a high tuberculosis burden country","abstract":"<jats:sec><jats:title>Rationale</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Objectives</jats:title><jats:p>We analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>In a cross-sectional cohort study, we employed patient data, whole-genome sequencing (WGS) and phenotyping of<jats:italic>Mycobacterium tuberculosis</jats:italic>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.</jats:p></jats:sec><jats:sec><jats:title>Measurements and main results</jats:title><jats:p>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).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>MDR-TB treatments based on bedaquiline require a functional background regimen to achieve high cure rates and to prevent the evolution of bedaquiline resistance. 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