Emergence of bedaquiline and clofazimine resistance after interruption of drug-resistant TB therapy in a high HIV prevalence setting

PROJECT NARRATIVE Bedaquiline is the first new TB drug to receive FDA approval in 40 years and has already transformed the treatment of multidrug- and extensively drug-resistant (M/XDR TB). Many patients, however, interrupt M/XDR TB therapy prematurely and because bedaquiline has an extremely long half-life, treatment interruptions pose a particular risk of causing bedaquiline resistance and eventual treatment failure. This study will investigate the risk of developing bedaquiline resistance after interruption of therapy in a cohort of patients with M/XDR TB in South Africa. Integrating traditional microbiology with novel genetic sequencing techniques, pharmacokinetic sampling, and pharmacometric modeling, the study addresses an urgent global public health problem that stands to undermine the utility of this new and critical medication.