A Review of the Evidence for Using Bedaquiline (TMC207) to Treat Multi-Drug Resistant Tuberculosis

Abstract

Existing therapies for multi-drug resistant tuberculosis (MDR-TB) have substantial limitations, in terms of their effectiveness, side-effect profile, and complexity of administration. Bedaquiline is a novel diarylquinoline antibiotic that has recently been investigated as an adjunct to existing therapies for MDR-TB. Currently, limited clinical data are available to evaluate the drug's safety and effectiveness. In two small randomized-controlled clinical studies, bedaquiline given for 8 or 24 weeks has been shown to improve surrogate microbiological markers of treatment response, but trials have not yet evaluated its impact on clinical failure and relapse. Safety concerns include an increased mortality in the bedaquiline arm of one study, an increased incidence of QT segment prolongation on electrocardiogram, and hepatotoxicity. Until further research data are available, the use of bedaquiline should be confined to settings where carefully selected patients can be closely monitored.

Fig. 1

Summary of first Phase 2 study. *Subjects were excluded from the mITT analysis, as subjects did not meet inclusion criteria despite being randomized. **Calculations based upon mITT analysis. ***P values calculated using uncorrected χ ² statistic with data from the modified intention to treat analysis. ****Culture results in discontinuing patients reported for time of last available culture [19]. Italicized P values were calculated from data in papers. ^aContinuing patients: refers only to patients continuing follow-up, excluding subjects withdrawing prior to stated time points (8 weeks, 24 weeks, and 104 weeks). Source: data from [18, 19]. BDQ bedaquiline, mITT modified intent to treat, na not available, XDR-TB extensively drug-resistant tuberculosis

Fig. 2

Summary of second Phase 2 study. *Excluded from mITT analysis. Subject was excluded after being randomized, before receiving bedaquiline, based on an adverse event. **Calculations based upon mITT analysis. ***A subject was considered responder (missing = failure) if at least 2 cultures from sputa collected at least 25 days apart were MGIT culture negative (as well as all intermediate cultures), this culture negativity was not followed by a confirmed positive MGIT culture (or a single positive sputum result after which the subject completed the trial), and the subject did not discontinue up to the time point being analyzed. ****A subject was considered responder (no overruling) if at least 2 cultures from sputa collected at least 25 days apart were MGIT culture negative (as well as all intermediate cultures) and this culture negativity was not followed by a confirmed positive MGIT culture (or a single positive sputum result after which the subject completed or discontinued the trial) up to the time point being analyzed. ^aContinuing patients: refers only to patients continuing follow-up, excluding subjects withdrawing prior to stated time points (24 weeks, 72 weeks, and 104 weeks). Source: data from [17]. BDQ bedaquiline, DST Drug susceptibility testing, MGIT Mycobacteria Growth Indicator Tube, mITT modified intention to treat, Na not available

Fig. 3

Summary of third Phase 2 study data from [17]. BDQ bedaquiline, DS drug susceptible, mITT modified intention to treat, TB tuberculosis. ^aContinuing patients: refers only to patients continuing follow-up, excluding subjects withdrawing prior to stated time points (24 weeks)