A safety evaluation of bedaquiline for the treatment of multi-drug resistant tuberculosis.

Introduction: Outcomes of treatment for resistant tuberculosis are poor, with long treatment duration and poor tolerability. Bedaquiline is a novel anti-mycobacterial drug, which has a very long terminal elimination half-life. Bedaquiline was approved in 2012 for drug-resistant tuberculosis following improved time to culture conversion and cure rates in a phase 2b study; but mortality was higher in the bedaquiline arm, resulting in a black box warning despite the fact that almost all deaths occurred after bedaquiline was stopped. Areas covered: The authors review safety data of bedaquiline used for rifampicin-resistant tuberculosis from the phase 2 studies, and from case series and observational cohorts. The authors focus on QT interval prolongation, hepatotoxicity, and mortality. Expert opinion: Bedaquiline markedly reduced mortality and improved treatment success in observational studies, resulting in bedaquiline being strongly recommended for rifampicin-resistant tuberculosis by the World Health Organization. In the phase 2 studies participants randomised to bedaquiline had higher rates of liver enzyme elevation and modest QT interval prolongation. Severe QT prolongation was an infrequent cause of bedaquiline interruption despite the frequent use of concomitant drugs that also prolong the QT interval. While awaiting results of phase 3 randomised controlled trials, tuberculosis treatment programmes should strengthen pharmacovigilance.