Abstract & Commentary
Treatment of MDR Bedaqualine Appears to be a Major Advance in Treatment of MDR-TB
By Dean L. Winslow, MD, FACP, FIDSA
Clinical Professor of Medicine and Pediatrics Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Associate Editor of Infectious Disease Alert
Dr. Winslow is a consultant for Siemens Diagnostic.
SYNOPSIS: Bedaquiline (a unique diarylquinoline) was studied vs. placebo in a prospective randomized trial when added to a standard 5-drug regimen in the treatment of multidrug-resistant (MDR) tuberculosis. Treatment with bedaquiline when added to a preferred background for 24 weeks resulted in significantly more and faster culture conversion than placebo. There were more deaths in the bedaquline group but almost allone most occurred after treatment ended.
SOURCE: Diacon AH, et al. Multidrug-resistant tuberculosis and culture conversion with bedaquiline. New Eng J Med 2014;371: 723-732.
In this Janssen-sponsored Phase 2b trial, 160 patients with newly diagnosed multidrug-resistant TB were randomized to either bedaquiline or placebo combined with a standard 5-drug background regimen. The bedaquiline or placebo was used for the initial 24 weeks of treatment followed by an additional 12-18 months of the background regimen to complete a total 18-24 month course of treatment.
Compared to placebo, bedaquiline reduced the median time to sputum culture conversion from 125 to 83 days. At 24 weeks the rate of culture conversion was 79% vs. 58% for bedaquiline vs. placebo. At 120 weeks the cure rates for bedaquiline vs. placebo were 58% and 32% respectively. The overall incidence of adverse effects was similar between the two groups but there were 10 deaths in the bedaquiline group vs. 2 deaths in the placebo group.
COMMENTARY
Bedaquiline is the first new antimicrobial specifically developed to treat TB that we have had for many years. The drug is interesting in that it has a novel mechanism of action: inhibition of mycobacterial ATP synthetase. Bedaquiline was initially approved by the FDA under the accelerated approval process based on 72-week data from this Phase 2 clinical trial. The 120-week results are reported above. Interestingly these longer-term follow up data showed that while only 2 patients in the placebo group died, 10 patients in the bedaquiline arm died.
The FDA, in this same issue of NEJM published an editorial explaining their rationale for continuing to support the use of bedaquiline for drug-resistant TB while awaiting additional safety and efficacy data from ongoing confirmatory clinical trials.1 Reassuringly only one of the deaths in the bedaquiline arm occurred during the bedaquiline treatment phase and appeared to be due to progression of TB, not side effect of medication. In fact, none of the 9 deaths observed in the bedaquiline arm during the follow-up treatment period while receiving background drug appeared to be treatment-related.
Tuberculosis remains a huge scourge worldwide with 10-year case fatality rates in HIV-negative patients exceeding 70% in the absence of effective treatment. Bedaqualine appears to be a major advance in the treatment of multi-drug resistance TB.
Reference
- Cox E and Laessig K. FDA approval of bedaquiline—the benefit-risk balance for drug-resistant TB. N Engl J Med 2014; 371: 689-691.
