Delamanid for extensively drug-resistant tuberculosis
New therapies are needed to address the imminent rise of drug-resistant infections. Delamanid is one of two new drugs approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in the past 40 years. The clinical evaluation of delamanid included a subgroup of patients with extensively drug-resistant tuberculosis (XDR-TB), which is more difficult to treat than MDR-TB. This evaluation provides an opportunity for a post hoc analysis of outcomes.
Our evaluation of delamanid in a single cohort proceeded with a 3-month randomized, controlled trial (a 2-month treatment period with a 1-month follow-up) (Trial 204), a 6-month open-label trial (Trial 208), and a 24-month follow-up study (Trial 116) (1,2). In all three trials, patients also received an optimized background treatment regimen recommended by the World Health Organization (WHO) (3). In the analysis population, infection with XDR-TB was confirmed at baseline (4). In Trial 204, the primary end point was 2-month sputum-culture conversion, which was defined as a negative culture for 5 consecutive weeks. Sustained sputum-culture conversion was defined as sputum-culture conversion without positive culture results through the remainder of treatment (the follow-up period was 24 months from the date of randomization). Investigators assessed treatment outcomes with the use of WHO cohort definitions aggregated into two groups: successful treatment, defined as cure plus treatment completion, and unsuccessful treatment, defined as treatment failure, default (the interruption of treatment for any reason for 2 consecutive months without medical approval), or death (3). Microbiologic assessments were performed with the use of solid media. For treatment outcomes, patients were stratified according to receipt of treatment with delamanid for 6 months or more (i.e., those participating in Trials 204 and 208) and receipt of treatment for 2 months or less (i.e., only those participating in Trial 204).
Patients receiving delamanid for 2 months had a higher rate of 2-month sputum-culture conversion than patients receiving placebo (7 of 16 [44%] vs. 1 of 10 [10%], P=0.10). Mortality was lower among patients treated with delamanid for 6 months or more than among patients treated with delamanid for 2 months or less (0 of 17 vs. 2 of 9 [22%], P=0.11) (Table 1), with one death occurring at 181 days and the other at 309 days after randomization into Trial 204 (the cause of death was not recorded for either patient since the deaths occurred outside the timeframe of the trial). Rates of sustained sputum-culture conversion were higher, but not significantly so, among patients treated for 6 months or more than among those treated for 2 months or less (13 of 17 [77%] vs. 4 of 9 [44%], P=0.19), and rates of successful treatment outcomes were higher, but not significantly so, among patients treated with delamanid for 6 months or more than among patients treated for 2 months or less (11 of 17 [65%] vs. 4 of 9 [44%], P=0.42). Patients with 2-month sputum-culture conversion were 2 times as likely to have sustained sputum-culture conversion as those without conversion (P=0.02) and 2.6 times as likely to have a successful treatment outcome (P=0.007).
These data are hypothesis generating and offer insight into discussions of the predictive value of early sputum-culture conversion, which the Food and Drug Administration has described as “reasonably likely to predict clinical benefit,” (5) although the specific time points for early sputum-culture conversion in XDR-TB are unknown. The study was limited by sample size and the potential for bias; however, it provides initial indications of 2-month sputum-culture conversion as a surrogate end point and provides data on treatment outcomes among patients with XDR-TB who were treated with delamanid.
The studies in this analysis were approved by institutional review boards at each site and written informed consent was obtained for patients in all studies.
References
1. Gler MT, Skripconoka V, Sanchez-Garavito E, et al. Delamanid
for multidrug-resistant pulmonary tuberculosis.
N Engl J Med
2012;366:2151-2160
Free Full Text
|
Web of Science
|
Medline
2. Wells C, Gupta R, Hittel N, et al. Long-term mortality
assessment of multidrug resistant tuberculosis patients treated
with delamanid.
Eur Respir J 2015;45:1-3
CrossRef
|
Web of Science
|
Medline
3. Guidelines for the programmatic management of drug-resistant tuberculosis: emergency update. Geneva: World Health Organization, 2008.
4. Notice to readers: revised definition of extensively
drug-resistant tuberculosis.
JAMA 2006;296:2792-2792
Web of Science
5. Guidance for industry — pulmonary tuberculosis: developing drugs for treatment. Rockville, MD: Food and Drug Administration, November 2013.
