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

Bedaquiline (BDQ), a potentially transformative new tuberculosis (TB) drug, is undergoing rapid scale-up globally, largely in the absence of drug susceptibility testing (DST). Crucially, there are little data from programmatic settings where, compared to clinical trials, patients are more likely to develop drug resistance.We collected baseline (pre-BDQ initiation) and follow-up isolates from a convenience sample of 40 drug resistant (DR)-TB patients who remained culture positive after at least four months of BDQ-based treatment. We performed DST in MGIT 960 (1µg/ml), targeted deep sequencing (Rv0678, atpE, pepQ) and whole genome sequencing on paired isolates. In this cohort, 8% (3/40) of patients harbored M.tb isolates that were BDQ-resistant at baseline, 47% (19/40) had acquired BDQ-resistance, and 45% (18/40) were BDQ-susceptible at both time points. Eighty-six percent (19/22) of BDQ-resistant patients at or after month four had prior clofazimine exposure vs. 56% (10/18) of BDQ-suceptible patients. Diverse combinations of single nucleotide polymorphisms and insertions or deletions were seen in the Rv0678 and pepQ genes, many previously undescribed, and were associated with phenotypic resistance. Acquisition of BDQ resistance in programmatic settings may be common, and may be a particular risk for patients with baseline fluoroquinolone-resistant TB, prior clofazimine use, and fewer than four effective drugs during the intensive treatment phase. Rapid BDQ DST should be made urgently available in resource-constrained settings together with scale-up of DR-TB all-oral regimens.