TY - JOUR
T1 - Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline
AU - Diacon, Andreas H.
AU - Pym, Alexander
AU - Grobusch, Martin P.
AU - de Los Rios, Jorge M.
AU - Gotuzzo, Eduardo
AU - Vasilyeva, Irina
AU - Leimane, Vaira
AU - Andries, Koen
AU - Bakare, Nyasha
AU - de Marez, Tine
AU - Haxaire-Theeuwes, Myriam
AU - Lounis, Nacer
AU - Meyvisch, Paul
AU - de Paepe, Els
AU - van Heeswijk, Rolf P. G.
AU - Dannemann, Brian
AU - AUTHOR GROUP
AU - Rolla, Valeria
AU - Dalcomo, Margreth
AU - Gripp, Karla
AU - Escada, Rodrigo
AU - Tavares, Isabel
AU - Borga, Liamar
AU - Thomas, Aleyamma
AU - Rekha, Banu
AU - Nair, Dina
AU - Chandrasekar, Chockalingam
AU - Parthasarathy, Ramavaran Thiruvengadaraj
AU - Sekhar, Gomathi
AU - Ganesh, Krishnamoorthy
AU - Rajagopalan, Krishnakumar
AU - Rajapandian, Gangadevi
AU - Dorairajalu, Rajendran
AU - Sharma, Surendra Kumar
AU - Banavaliker, Jayant
AU - Kadhiravan, Tamilarasu
AU - Gulati, Vinay
AU - Mahmud, Hanif
AU - Gupta, Arvind
AU - Bhatnagar, Anuj
AU - Jain, Vipin
AU - Hari, Smriti
AU - Gupta, Yogesh Kumar
AU - Vaid, Ashok
AU - Cirule, Andra
AU - Dravniece, Gunta
AU - Skripconoka, Vija
AU - Kuksa, Liga
AU - Kreigere, Edite
AU - Ramos, Carlos Rafael Seas
AU - Amat y Leon, Ivan Arapovic
PY - 2014
Y1 - 2014
N2 - BACKGROUND Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. RESULTS Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P <0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P = 0.008) and at 120 weeks (62% vs. 44%, P = 0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P = 0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident. CONCLUSIONS The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.)
AB - BACKGROUND Bedaquiline (Sirturo, TMC207), a diarylquinoline that inhibits mycobacterial ATP synthase, has been associated with accelerated sputum-culture conversion in patients with multidrug-resistant tuberculosis, when added to a preferred background regimen for 8 weeks. METHODS In this phase 2b trial, we randomly assigned 160 patients with newly diagnosed, smear-positive, multidrug-resistant tuberculosis to receive either 400 mg of bedaquiline once daily for 2 weeks, followed by 200 mg three times a week for 22 weeks, or placebo, both in combination with a preferred background regimen. The primary efficacy end point was the time to sputum-culture conversion in liquid broth. Patients were followed for 120 weeks from baseline. RESULTS Bedaquiline reduced the median time to culture conversion, as compared with placebo, from 125 days to 83 days (hazard ratio in the bedaquiline group, 2.44; 95% confidence interval, 1.57 to 3.80; P <0.001 by Cox regression analysis) and increased the rate of culture conversion at 24 weeks (79% vs. 58%, P = 0.008) and at 120 weeks (62% vs. 44%, P = 0.04). On the basis of World Health Organization outcome definitions for multidrug-resistant tuberculosis, cure rates at 120 weeks were 58% in the bedaquiline group and 32% in the placebo group (P = 0.003). The overall incidence of adverse events was similar in the two groups. There were 10 deaths in the bedaquiline group and 2 in the placebo group, with no causal pattern evident. CONCLUSIONS The addition of bedaquiline to a preferred background regimen for 24 weeks resulted in faster culture conversion and significantly more culture conversions at 120 weeks, as compared with placebo. There were more deaths in the bedaquiline group than in the placebo group. (Funded by Janssen Pharmaceuticals; TMC207-C208 ClinicalTrials.gov number, NCT00449644.)
U2 - https://doi.org/10.1056/NEJMoa1313865
DO - https://doi.org/10.1056/NEJMoa1313865
M3 - Article
C2 - 25140958
SN - 0028-4793
VL - 371
SP - 723
EP - 732
JO - New England journal of medicine
JF - New England journal of medicine
IS - 8
ER -