LAUSR

BACKGROUND Novel regimens have revolutionized multidrug-resistant tuberculosis (MDR-TB) treatment; however, medication adherence remains challenging and poorly characterized. We hypothesized that bedaquiline adherence, measured using electronic dose monitoring, would predict MDR-TB treatment outcomes. SETTING Prospective cohort study in KwaZulu-Natal, South Africa. METHODS Adults with MDR-TB and HIV initiating bedaquiline and on antiretroviral therapy (ART) were eligible. Separate electronic dose monitoring devices measured bedaquiline and ART adherence through six months, calculated as observed versus expected doses. Whole genome sequencing was performed to identify bedaquiline resistance-associated variants. RESULTS From November 2016 through February 2018, 199 participants with MDR-TB and HIV were enrolled and followed through treatment completion (median 17.2 months IQR 12.2-19.6). Median bedaquiline adherence was higher than ART adherence (97 vs. 89%, p<0.001), but correlated (r2=0.68, p<0.001). High bedaquiline adherence (≥90%) compared to lower adherence was associated with improved rates of end of treatment successful outcome (83.4% vs. 46.3%, p<0.001), decreased mortality (11.0% vs. 29.6% p=0.004), and improved retention in care through end of treatment (94.5% vs. 79.6% p=0.002). Modelling identified a highly significant, but linear association between bedaquiline adherence and outcome. On multivariable analysis, bedaquiline adherence was independently associated with mortality and outcome. Bedaquiline resistance-associated variants were seen in 12% (7/57) of sequenced isolates (7% baseline, 5% emergent) with only 28.6% experiencing successful treatment outcome. CONCLUSIONS Bedaquiline adherence through 6-months independently predicted end of MDR-TB treatment outcome, but a specific bedaquiline adherence threshold was not identified. Interventions to optimize bedaquiline adherence are urgently needed to improve MDR-TB HIV treatment outcomes.