Bedaquiline resistance delays recovery and raises failure in RR-TB

Rising resistance to bedaquiline is eroding the power of one of the few life-saving drugs for rifampicin-resistant tuberculosis (RR-TB). Researchers, led by corresponding author Sean Wasserman, set out to describe what happens to people whose TB is resistant to bedaquiline and to compare them with matched patients whose TB remains bedaquiline-susceptible. They used a retrospective and matched cohort design, examining isolates identified between January 2018 and June 2023 and selecting 1:1 matched controls with bedaquiline-susceptible RR-TB from a prospective observational study at the same facility. The study focused on patient-level outcomes that matter to clinicians and patients: how long it takes for bacteriological tests to turn negative, whether patients have unfavourable outcomes by modified WHO definitions, and whether they achieve TB-free survival through 18 months. By tying laboratory results to clinical follow-up, the team aimed to paint a clearer picture of how bedaquiline resistance changes the course of RR-TB and to highlight gaps in case management.

The investigators measured three primary outcomes: time to sputum culture conversion (SCC), a modified WHO-defined unfavourable outcome, and TB-free survival (alive, with SCC, and in care or treatment completed) through 18 months. Adjusted analyses used Cox proportional hazards models. The findings were stark. At 18 months, only 43 patients (52%) achieved TB-free survival; 17 (20%) failed to achieve sustained SCC, and there were 19 deaths (23%). Among survivors (n=63), 50 (80%) were still on treatment. WHO treatment outcomes after treatment initiation were unfavourable in 54 patients (67%), driven by treatment failure in 35 patients (43%). Median time to SCC was 175 days (IQR 100-254) in the bedaquiline-resistant cohort compared with 32 days (IQR 30-42 days) in the matched bedaquiline-susceptible cohort. Baseline smear microscopy grade (HR 0.41, 95% CI 0.23-0.73, p=0.003) and bedaquiline resistance (HR 0.06, 95% CI 0.02-0.23, p<0.001) were both associated with reduced likelihood of SCC.

These results show that current treatment options for bedaquiline-resistant TB lead to much longer therapy, delayed microbiological response, and poor clinical outcomes. Patients with bedaquiline-resistant RR-TB took many months longer to clear cultures and were much more likely to experience treatment failure or to remain on treatment at 18 months. The findings underline that rising bedaquiline resistance threatens the gains made against RR-TB and that standard care as delivered in this study was often insufficient. For clinicians and policy makers, the study suggests an urgent need to improve detection of bedaquiline resistance, to develop and deploy alternative regimens and drugs, and to define clearer case management strategies for affected patients. For patients and communities, the message is that resistance to bedaquiline substantially complicates treatment and recovery, reinforcing the importance of resistance surveillance and investment in new treatment options.