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 Eight subjects were withdrawn for noncompliance or default, and seven withdrew consent, citing the rigorous program of investigations for safety and pharmacokinetic monitoring.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. M ultidrug-resistant (MDR) tuberculosis (TB) is a serious form of TB and the term MDR implies resistance to at least the essential first-line agents isoniazid (INH) and rifampin (RMP); because INH and RMP are no longer effective, patients with MDR pulmonary TB must be treated for at least 20 months with potentially toxic, less efficacious drugs (20). MDR Mycobacterium tuberculosis isolates will frequently also be resistant to the other first-line drugs pyrazinamide (PZA), ethambutol (EMB), or streptomycin (or SM) and, at times, other drugs such as ethionamide (Eth), a fluoroquinolone, or injectable drugs such as kanamycin (KAN), amikacin, or capreomycin (CAP). MDR TB with additional resistance to the last two mentioned classes is termed extensively drug-resistant (XDR). The spread of MDR TB, particularly among communities with a high prevalence of human immunodeficiency virus (HIV) infection, is threatening the foundations of TB control programs worldwide (19). TMC207, recently renamed bedaquiline, is a diarylquinoline with a novel mode of action specifically inhibiting mycobacterial ATP synthase (1).The present randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and efficacy of bedaquiline when it is added to a background regimen (BR) in newly d...

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…292 In phase 2 trials, 2-month sputum culture conversion increased after 8-week therapy from 9% with multidrug background therapy and placebo to 48% with background therapy and bedaquiline, and the increase was sustained at 6 months. 365,366 Mortality was higher in the bedaquiline group than the placebo group, but most of the deaths in the bedaquiline group occurred after completion of the 6-month course of bedaquiline treatment, and causes of death were widely variable. This suggests that the increased mortality associated with bedaquiline in the small phase 2 study is a chance finding.…”

“…Although encouraging initial observations have been made of faster culture conversion in early bactericidal activity and phase 2 studies of bedaquiline, 365,366 and high rates of culture conversion in French 367 and South African patients with XDR tuberculosis (100% in the French cohort and 85% in the South African cohort), 324 another analysis 368 indicated that the 120-week culture conversion rate was 70% in patients with pre-XDR tuberculosis and 62% in XDR tuberculosis when bedaquiline was used with companion drugs and an optimised background regimen. Thus, even with newer drugs such as bedaquiline, treatment failure will be common in patients with XDR tuberculosis or those with resistance beyond XDR tuberculosis, for which no effective therapy is available and so it remains programmatically incurable.…”

Novel Treatments for Drug-Resistant Tuberculosis

“…The study investigators later reported twoyear follow-up results of the same patient cohort, though it is important to note that the study drug (bedaquiline or placebo) had been administered only during the first eight weeks of their treatment. 19 In longitudinal follow-up, patients in the bedaquiline group experienced increased rates of culture conversion at 24 weeks, with 81% of patients in the bedaquiline group having negative sputum compared with 65% of patients in the placebo group (P = 0.03). In addition, there was a trend toward reduced acquisition of additional resistance to accompanying drugs among patients who had received bedaquiline.…”

“…[18][19][20] A summary of the study is presented in Table 2. In the first stage of the study, 47 patients with newly diagnosed smear-positive MDR-TB were randomized to receive bedaquiline (which at that time was referred to as TMC207) or placebo, in combination with a standard five-drug MDR-TB treatment regimen, for a period of eight weeks.…”

Bedaquiline: a new weapon against MDR and XDR-TB

“…In second stage of the previous phase 2 trial, Diacon et al 28 presented the 2-year follow-up results for a RCT of 47 MDR-TB patients treated with either the bedaquiline, or placebo. These treatments were added for the first 8 weeks of a background regimen.…”