Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline

TLDR

The study evaluates whether adding bedaquiline to a preferred background regimen accelerates sputum‑culture conversion in patients with newly diagnosed, smear‑positive multidrug‑resistant tuberculosis. In a phase‑2b randomized trial of 160 patients, bedaquiline was administered for 8 weeks (400 mg daily for 2 weeks, then 200 mg three times weekly) with a preferred background regimen, and the primary endpoint was time to sputum‑culture conversion in liquid broth. Bedaquiline shortened median time to culture conversion from 125 to 83 days, increased conversion rates at 24 and 120 weeks, and raised cure rates to 58% versus 32% with placebo, though it was associated with a higher, non‑causal death rate. The trial was funded by Janssen Pharmaceuticals and registered as NCT00449644.

Abstract

Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks.In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline.Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P<0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P=0.008) and at 120 weeks (62% vs. 44%, P=0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P=0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident.The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.).