Multidrug-Resistant Tuberculosis and Culture Conversion with Bedaquiline

被引:605
作者
Diacon, Andreas H. [1 ,2 ,3 ]
Pym, Alexander [4 ,5 ]
Grobusch, Martin P. [6 ]
de los Rios, Jorge M. [7 ]
Gotuzzo, Eduardo [8 ]
Vasilyeva, Irina [9 ]
Leimane, Vaira [10 ]
Andries, Koen [11 ]
Bakare, Nyasha [11 ]
De Marez, Tine [12 ]
Haxaire-Theeuwes, Myriam [11 ]
Lounis, Nacer [11 ]
Meyvisch, Paul [11 ]
De Paepe, Els [11 ]
van Heeswijk, Rolf P. G. [11 ]
Dannemann, Brian [12 ]
机构
[1] Univ Stellenbosch, Natl Res Fdn, Ctr Excellence Biomed TB Res, Div Med Physiol, Cape Town, South Africa
[2] Univ Stellenbosch, Natl Res Fdn, Ctr Excellence Biomed TB Res, Dept Sci & Technol, Cape Town, South Africa
[3] Univ Stellenbosch, MRC, Ctr TB Res, Fac Med & Hlth Sci, Cape Town, South Africa
[4] MRC, Durban, South Africa
[5] Kwazulu Res Inst TB & HIV, Durban, South Africa
[6] Univ Amsterdam, Acad Med Ctr, Div Internal Med, Ctr Trop Med & Travel Med,Dept Infect Dis, NL-1105 AZ Amsterdam, Netherlands
[7] Hosp Maria Auxiliadora, Serv Neumol, Ctr Excelencia El Control TB Nino Jesus, Lima, Peru
[8] Univ Peruana Cayetano Heredia, Inst Med Trop Alexander von Humboldt, Lima, Peru
[9] Russian Acad Med Sci, Cent TB Res Inst, Moscow 109801, Russia
[10] Riga East Univ Hosp, Ctr TB & Lung Dis, Riga, Latvia
[11] Janssen Infect Dis, Beerse, Belgium
[12] Janssen Res & Dev, Titusville, NJ 08560 USA
关键词
EARLY BACTERICIDAL ACTIVITY; MYCOBACTERIUM-TUBERCULOSIS; DIARYLQUINOLINE TMC207;
D O I
10.1056/NEJMoa1313865
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.)
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收藏
页码:723 / 732
页数:10
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