High frequency of bedaquiline resistance in programmatically treated drug-resistant TB patients with sustained culture-positivity in Cape Town, South Africa

Abstract Introduction Bedaquiline (BDQ) is a lifesaving new tuberculosis (TB) drug undergoing global scale-up. Data on resistance emergence in programmatic settings, especially in patients resistant to other drugs with potentially weak background regimens, is scarce. Such individuals are a priority for novel drug access yet a potential source of population-level resistance. Methods We collected culture isolates from 40 drug resistant (DR)-TB patients, culture-positive after ≥4 months of BDQ-based treatment at baseline (pre-BDQ treatment initiation) and follow-up (closest post-four-month isolate). We did MGIT960 (1μg/ml) BDQ drug susceptibility testing (DST), targeted deep sequencing (TDS; Rv0678, atpE, pepQ ), and whole genome sequencing (WGS). Contemporaneous programmatic BDQ DST was unavailable. Results Eight percent (3/40) of patients’ strains were BDQ resistant at baseline, and 47% (19/40) gained BDQ phenotypic resistance [88% (15/17) due to acquisition, 12% (2/17) reinfection]. Several single nucleotide polymorphisms and indels in rv0678 and pepQ were associated with phenotypic resistance but none in rv0676c and rv1979c (potential lineage markers). TDS detected low-level variants undetected by WGS, however, none were in genes without WGS-detected variants. Patients with baseline fluoroquinolone-resistance, clofazimine exposure, and ≤4 effective drugs were more likely to be BDQ-resistant at follow-up. Conclusion BDQ resistance acquisition, for which we identified risk factors, was common in these programmatically treated patients. Our study highlights risks associated with implementing new drugs in such populations. Likely BDQ resistance transmission occurred. Routine BDQ DST should urgently accompany scale-up of new all oral regimens, however, rapid BDQ genotypic DST remains challenging given the diversity of variants observed.