RationaleBedaquiline 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.ObjectivesWe analysed pre-existing and emerging bedaquiline resistance in bedaquiline-based MDR-TB therapies, and risk factors associated with treatment failure and death.MethodsIn 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 ResultsAt 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).ConclusionsMDR-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.

Evaluation of novel anti-tuberculosis (TB) medicines for the treatment of multidrug-resistant (MDR)-TB continues to be of high interest on the TB research agenda. We assessed treatment outcomes in patients with pulmonary MDR-TB who received bedaquiline containing treatment regimens in the Republic of Moldova, a high-burden country of MDR-TB.MethodWe systematically analysed the “SIMETB” national electronic TB database in the Republic of Moldova and performed a retrospective propensity score matched comparison of treatment outcomes in a cohort of patients with MDR-TB who started treatment during 2016–2018 with a bedaquiline-containing regimen (bedaquiline cohort) and a cohort of patients treated without bedaquiline (non-bedaquiline cohort).ResultsFollowing propensity score matching, 114 patients were assigned to each cohort of MDR-TB patients. Patients in the bedaquiline cohort had a higher 6 month sputum culture conversion rate than those in the non-bedaquiline cohort, (66.7% versus 40.3%, p<0.001). Patients under bedaquiline containing regimens had a higher cure rate assessed by both WHO and TBNET definitions (55.3% versus 24.6%, p=0.001 and 43.5% versus 19.6% p=0.004, correspondingly), as well, a lower mortality rate (8.8% versus 20.2%, p<0.001, by WHO and 10.9% versus 25.2%, p=0.01, by TBNET). In patients who previously failed on MDR-TB treatment, more than 40% of patients achieved cure with a bedaquiline-containing regimen.ConclusionsBedaquiline-based MDR-TB treatment regimens result in better disease resolution when compared to bedaquiline-sparing MDR-TB treatment regimens under programmatic conditions in a country with a high-burden of MDR-TB.