Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance

Abstract

The 2-year follow-up results for a randomized placebo-controlled study of 47 patients with multidrug-resistant pulmonary tuberculosis treated with either the new diarylquinoline TMC207, recently renamed bedaquiline, or placebo, added to the first 8 weeks of a background regimen, are presented. Bedaquiline significantly reduced the time to culture conversion over 24 weeks (hazard ratio, 2.253; 95% confidence interval, 1.08 to 4.71; P = 0.031). With the exception of nausea reported in 26% of patients receiving bedaquiline and none receiving placebo, adverse events occurred at similar frequencies in both groups of patients: bilateral hearing impairment, extremity pain, acne, and noncardiac chest pain occurred in 13 and 21%, 17 and 13%, 9 and 17%, and 4 and 17% of patients, respectively, receiving bedaquiline or placebo. Excluding resistance to ethambutol and ethionamide, only one patient receiving bedaquiline acquired resistance to companion drugs, but five patients receiving placebo (4.8% versus 21.7%; P = 0.18) acquired resistance to companion drugs, and resistance to ofloxacin was acquired in four patients receiving placebo and none receiving bedaquiline (0% versus 22%; 0 = 0.066). In all, 23 patients (49%), including 13 receiving placebo (54%) and 10 receiving bedaquiline (44%), discontinued the study prior to its completion, 12 during the first 24 weeks of treatment. Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring. Bedaquiline may contribute to the management of multidrug-resistant tuberculosis by effecting more rapid sputum culture negativity and by preventing acquired resistance to companion drugs.

Figures

Fig 1

Patient disposition and culture status. All 47 randomized patients were analyzed for safety. For the efficacy analysis, 44 patients were available: 2 subjects (one in each group) were diagnosed with XDR TB on a sputum sample submitted before enrollment and were withdrawn within 2 weeks of randomization, and 1 subject in the bedaquiline group remained culture negative at baseline.

Fig 2

Proportion of patients with positive sputum cultures and time to conversion. (A) Culture conversion over 24 weeks among subjects who discontinued during the first 24 weeks carried forward as not converting (hazard ratio, 2.253; 95% CI, 1.08 to 4.71; P = 0.031). In the bedaquiline (orange line, above) and placebo (blue line, below) groups, the times to 50% culture conversion were 78 and 129 days, respectively, and 17/21 (81.0%) and 15/23 (65.2%) of the subjects, respectively, submitted negative sputum samples at week 24. (B) Culture conversion over 24 weeks among subjects who discontinued scored according to their culture status at the time of discontinuation and kept in the analysis (hazard ratio, 3.135; 95% CI, 1.51 to 6.53; P = 0.002). In the bedaquiline (orange line, above) and placebo (blue line, below) groups, the times to 50% culture conversion were 68 and 126 days, respectively, and 19/21 (90.5%) and 16/23 (69.6%) of the subjects, respectively, were culture negative at week 24 or at the time of discontinuation.