This rigorously conducted placebo-controlled, double-blind, randomized trial has demonstrated the antimycobacterial activity, safety, and tolerability of bedaquiline in patients with MDR pulmonary TB. Patients receiving bedaquiline in addition to a BR during the initial 8 weeks of MDR treatment reached sputum culture negativity in the MGIT system significantly more quickly than patients receiving placebo and were at lower risk of acquisition of additional drug resistance over the whole duration of follow-up.
The statistical approach assessing the main outcome of culture conversion used in the present study differs slightly from that in the previous publication (5
) and accords with the method that will be followed with 24-week bedaquiline dosing in the second stage of this study. Only subjects who experience sputum culture conversion and submit a confirmed negative sample at 24 weeks are scored as converted (A), which is more stringent than scoring outcomes according to culture status irrespective of whether participants left the study before 24 weeks or not (B). Bedaquiline retained a statistically significant advantage with both approaches despite the fact that 50% of the discontinued subjects receiving bedaquiline had attained culture negativity before discontinuation compared to only 12.5% receiving placebo. A point can certainly be made in this context that long-term studies involving MDR TB patients should follow simple, flexible protocols and ensure strong support for adherence to treatment and participation in follow-up study assessments.
An important part of this trial was the thorough assessment of drug susceptibility of isolates obtained from the sputum of all of the enrolled patients before and during treatment. Even after acknowledging the difficulties with resistance testing of PZA (7
), EMB (10
), and Eth (16
), the results summarized in paint a very disturbing picture that emphasizes the potential weakness of commonly used standardized regimens for the treatment of MDR TB. The overall resistance at baseline to the remaining “first-line” agents EMB, PZA, and SM exceeded 66%; furthermore, 13% of the isolates were resistant to KAN and OFL. That this is a realistic picture is supported by other studies from the United States (4
) and by molecular genetic studies of resistance among isolates from the Western Cape Province of South Africa (8
The acquisition of additional resistance during the trial, mainly in the placebo group, especially in the form of OFL or KAN resistance leading to a pre-XDR resistance profile, despite documentation of directly observed therapy, is reason for grave concern. Additional resistance was acquired by 5 of 21 patients with available baseline sensitivity results (23.8%) in the placebo group, and in four cases this occurred, or commenced, during the first 8 weeks of treatment. In four patients (19%) this included developing resistance to OFL. In two subjects this was detected during the first 8 weeks of treatment and in one subject each during the periods 9 to 24 weeks and 25 to 104 weeks after commencing treatment. In the bedaquiline group, only one patient acquired resistance to KAN and CAP who had had baseline resistance to INH, RMP, PZA, SM, EMB, and Eth. Not surprisingly, although culture negative at 24 weeks, this patient became culture positive again upon completion of 104 weeks of therapy. It seems that even with good treatment adherence, the available second-line agents are often inadequate to protect each other from the development of resistance (2
). No significant decrease in susceptibility to bedaquiline was observed in the bedaquiline treatment group.
Fewer resistance results were available in bedaquiline-treated subjects who not only achieved culture negativity more rapidly but also submitted a larger proportion of sputum samples that did not grow a culture for resistance testing (bedaquiline, 4/7 [57%]; placebo, 5/15 [33%]; Fisher exact test, P
= 0.097). A likely explanation is a lower bacterial sputum load, which would further reduce the chance for the development of resistance. Despite the low number of observations, preventing these findings from reaching statistical significance, and despite lacking clinically detectable very early bactericidal activity (15
), it is noteworthy that bedaquiline may protect against the acquisition of additional resistance and XDR TB in patients with MDR TB.
Although a large proportion of patients experienced adverse events during the period of BR treatment, the incidence was similar in the patients who received bedaquiline (82.6%) compared to those who had received placebo (79.2%). Other recent studies of MDR TB treatment in southern Africa have recorded a similarly high incidence of adverse events (17
). The majority of the adverse events recorded here were of mild or moderate intensity. Nonetheless, the frequency of these events probably contributes significantly to the difficulties encountered in managing MDR TB. These were compounded in this trial by the reluctance of some patients to continue with the necessary arduous schedule of investigations and assessments required for the evaluation of a new agent.
The observed terminal elimination half-life of bedaquiline and M2 of ~5.5 months can likely be explained by slow release of bedaquiline and M2 from peripheral tissue compartments. Both bedaquiline and M2 accumulate in various tissues in preclinical species (12
), which is likely a result of the cationic amphiphilic characteristics of these compounds. Cationic amphiphilic drugs (CAD) may cause intracellular accumulation of phospholipids in association with drug accumulation (a finding indicative of phospholipidosis), as has been observed for bedaquiline and M2 preclinically, as well as for many marketed drugs (6
). Upon termination of drug intake, the phospholipidosis is reversible as the drug is eliminated from the tissues. The time course of reversal is dependent on the dissociation rate constant of the CAD from the phospholipid and the elimination rate of the CAD from the tissue, which may result in a prolonged elimination half-life (14
The final results of the first stage of this randomized controlled study confirm the significant bactericidal activity of bedaquiline in patients treated for MDR TB. The addition of bedaquiline for 8 weeks was safe and associated with earlier culture negativity. The overall incidence of adverse events was high and reflects the poor tolerability of the second-line companion agents. The emergence of drug resistance was substantial and may have been reduced by the concurrent administration of bedaquiline. Further study of the emergence of resistance among patients being treated for MDR TB is needed.