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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., Competing Interests: 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., (Copyright ©The authors 2022.)

Background: Evaluation of novel anti-tuberculosis (TB) drugs 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 MDR-TB country., Method: We systematically analysed the SIMETB national electronic TB database 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)., Results: Following 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 World Health Organization (WHO) and TBnet definitions (55.3% versus 24.6%; p=0.001 and 43.5% versus 19.6%; p=0.004, respectively), as well as a lower mortality rate (8.8% versus 20.2%; p<0.001 and 10.9% versus 25.2%; p=0.01, respectively). In patients who previously failed on MDR-TB treatment, >40% of patients achieved a cure with a bedaquiline-containing regimen., Conclusions: Bedaquiline-based MDR-TB treatment regimens result in better disease resolution when compared with bedaquiline-sparing MDR-TB treatment regimens under programmatic conditions in a country with a high burden of MDR-TB., Competing Interests: Conflict of interest: D. Chesov has nothing to disclose. Conflict of interest: J. Heyckendorf reports personal fees for lectures from Chiesi, Gilead, Janssen and Lucane, outside the submitted work. Conflict of interest: S. Alexandru has nothing to disclose. Conflict of interest: A. Donica has nothing to disclose. Conflict of interest: E. Chesov has nothing to disclose. Conflict of interest: M. Reimann has nothing to disclose. Conflict of interest: V. Crudu has nothing to disclose. Conflict of interest: V. Botnaru has nothing to disclose. Conflict of interest: C. Lange reports personal fees for lectures from Chiesi, Gilead, Janssen, Lucane, Novartis, Oxoid, Berlin-Chemie and Thermo Fisher, personal fees for meeting attendance from Oxford Immunotec, outside the submitted work., (Copyright ©ERS 2021.)

Multidrug-resistant tuberculosis (MDR-TB) is a serious problem in the former Soviet Union and may appear during TB treatment. We aimed to estimate the prevalence of, timing of and factors associated with MDR-TB diagnosis during TB treatment in Moldova, which was part of the former Soviet Union. We analysed data on 3 754 confirmed non-MDR-TB cases (between January 1, 2007 and December 31, 2010) in the Moldovan TB surveillance database, where patients provided sputum specimens for drug-susceptibility testing, multiple times, during treatment. We estimated the percentage of individuals with confirmed baseline non-MDR-TB that were diagnosed with MDR-TB during treatment, documented the time at which MDR-TB was diagnosed, and used a failure-time model to identify factors associated with MDR-TB diagnosis. Between 7.2% and 9.2% of initially non-MDR-TB cases were diagnosed with MDR-TB during treatment. Half of these MDR-TB diagnoses occurred with 3 months of the initial diagnosis. An increased MDR-TB risk during treatment was associated with baseline resistance to first-line TB drugs (linear increase in risk per additional drug), previous incarceration and HIV co-infection. MDR can appear rapidly during TB treatment. Policy considerations should emphasise management during early treatment by increasing ambulatory TB treatment to prevent nosocomial transmission, and ensuring universal rapid diagnostics access to prevent acquisition and transmission of drug resistance.

Multidrug-resistant tuberculosis (MDR-TB) is a major concern in countries of the former Soviet Union. The reported risk of resistance among tuberculosis (TB) cases in the Republic of Moldova is among the highest in the world. We aimed to produce high-resolution spatial maps of MDR-TB risk and burden in this setting. We analysed national TB surveillance data collected between 2007 and 2010 in Moldova. High drug susceptibility testing coverage and detailed location data permitted identification of subregional areas of higher MDR-TB risk. We investigated whether the distribution of cases with MDR-TB risk factors could explain this observed spatial variation in MDR-TB. 3447 MDR-TB cases were notified during this period; 24% of new and 62% of previously treated patients had MDR-TB. Nationally, the estimated annual MDR-TB incidence was 54 cases per 100 000 persons and >1000 cases per 100 000 persons within penitentiaries. We identified substantial geographical variation in MDR-TB burden and hotspots of MDR-TB. Locations with a higher percentage of previously incarcerated TB cases were at greater risk of being MDR-TB hotspots. Spatial analyses revealed striking geographical heterogeneity of MDR-TB. Methods to identify locations of high MDR-TB risk and burden should allow for better resource allocation and more appropriate targeting of studies to understand local mechanisms driving resistance.