Multidrug-resistant tuberculosis and culture conversion with bedaquiline
Andreas H Diacon, Alexander Pym, Martin P Grobusch, Jorge M de los Rios, Eduardo Gotuzzo, Irina Vasilyeva, Vaira Leimane, Koen Andries, Nyasha Bakare, Tine De Marez, Myriam Haxaire-Theeuwes, Nacer Lounis, Paul Meyvisch, Els De Paepe, Rolf P G van Heeswijk, Brian Dannemann, TMC207-C208 Study Group, Valeria Rolla, Margreth Dalcomo, Karla Gripp, Rodrigo Escada, Isabel Tavares, Liamar Borga, Aleyamma Thomas, Banu Rekha, Dina Nair, Chockalingam Chandrasekar, Ramavaran Thiruvengadaraj Parthasarathy, Gomathi Sekhar, Krishnamoorthy Ganesh, Krishnakumar Rajagopalan, Gangadevi Rajapandian, Rajendran Dorairajalu, Surendra Kumar Sharma, Jayant Banavaliker, Tamilarasu Kadhiravan, Vinay Gulati, Hanif Mahmud, Arvind Gupta, Anuj Bhatnagar, Vipin Jain, Smriti Hari, Yogesh Kumar Gupta, Ashok Vaid, Vaira Leimane, Andra Cirule, Gunta Dravniece, Vija Skripconoka, Liga Kuksa, Edite Kreigere, Eduardo Gotuzzo, Carlos Rafael Seas Ramos, Ivan Arapovic Amat y Leon, Jorge Antonio Centeno Huaman, Roy German Duenas Carbajal, Christian Andres Yoshiyama Sasaki, Maria Angelica Garcia Yllanes, Mario Vilcahauman Izzara, Porfirio Fortunato Changa Campos, Luis Enrique Bustinza Oviedo, Leslie Levano Zavala, Cinthia Salome Hurtado Esquen, Carlos Eduardo Zamudio Fuertes, Gabriela Carriquiry Carrefio, Isaias Manuel Rolando Castañeda, Jesus Renato Ayala, Eduardo Romulo Ticona Chavez, Wilfredo Vargas Onofre, Juan Genaro Sosa Paucar, Elias Rodrigo Aliaga Herrera, Jamie Ismael Soria Medina, José Carlos Masciotti Barraza, Domingo Elias Gómez-Sanchez Mateo, Ruben Marino Azañero Reyna, Jorge de los Rios Senmache, Christian Juan Galvez Vasquez, Zully Haydee Ruiz Vargas, Blanca Luz Parra Galvan, Karin Marlene Reyes Aparcana, Dina Vera Diaz, Joven Roque Gonong, Lawrence Raymond, Roxas Lee Llacer, Aileen Alvarez-Tiu, Vladislav Erokhin, Olga Demikhova, Irina Vasilyeva, Tatevik Bagdasarian, Svetlana Gorlova, Alexey Tikhonov, Andreas Diacon, Madeleine Hanekom, Zoja Noveljic, Ramonde Patientia, Sweetness Siwendu, Alexander Pym, Roxana Rustomjee, Carl Reddy, Lancelot Garth Osburn, Aruna Ramjee, Sbongile Pumzile Ntshanga, Lerato Gabela, Shivani Chirkut, Melony C Fortuin-De Smidt, Ronelle Narasimooloo, John Richard Yarr Quantrill, Iqbal Haroon Master, Thulani Bethwell Gumede, Sunitha Chotoo, Francesca Conradie, Martin P Grobusch, N Russel Mahanyele, Alicja Dziewiecki, Collin N Menezes, Ian Mathias Sanne, Melanie-Anne John, Jean Michel Kayumba, Liesl Page-Shipp, Dawid Kruger, Irene Schroeder, Louwrens L Leeuwner, Cathryn Louise O'Reilly, Myrtle Joubert, Corlia Coetzee, Stephanie Rene Krause, Reinard McPherson, Louise Muller, Charoen Chuchottaworn, Piamplarp Sangsayunh, Kittima Bangpattanasiri, Tawatchai Wiwatworapan, Tanakorn Anantasetagoon, Andreas H Diacon, Alexander Pym, Martin P Grobusch, Jorge M de los Rios, Eduardo Gotuzzo, Irina Vasilyeva, Vaira Leimane, Koen Andries, Nyasha Bakare, Tine De Marez, Myriam Haxaire-Theeuwes, Nacer Lounis, Paul Meyvisch, Els De Paepe, Rolf P G van Heeswijk, Brian Dannemann, TMC207-C208 Study Group, Valeria Rolla, Margreth Dalcomo, Karla Gripp, Rodrigo Escada, Isabel Tavares, Liamar Borga, Aleyamma Thomas, Banu Rekha, Dina Nair, Chockalingam Chandrasekar, Ramavaran Thiruvengadaraj Parthasarathy, Gomathi Sekhar, Krishnamoorthy Ganesh, Krishnakumar Rajagopalan, Gangadevi Rajapandian, Rajendran Dorairajalu, Surendra Kumar Sharma, Jayant Banavaliker, Tamilarasu Kadhiravan, Vinay Gulati, Hanif Mahmud, Arvind Gupta, Anuj Bhatnagar, Vipin Jain, Smriti Hari, Yogesh Kumar Gupta, Ashok Vaid, Vaira Leimane, Andra Cirule, Gunta Dravniece, Vija Skripconoka, Liga Kuksa, Edite Kreigere, Eduardo Gotuzzo, Carlos Rafael Seas Ramos, Ivan Arapovic Amat y Leon, Jorge Antonio Centeno Huaman, Roy German Duenas Carbajal, Christian Andres Yoshiyama Sasaki, Maria Angelica Garcia Yllanes, Mario Vilcahauman Izzara, Porfirio Fortunato Changa Campos, Luis Enrique Bustinza Oviedo, Leslie Levano Zavala, Cinthia Salome Hurtado Esquen, Carlos Eduardo Zamudio Fuertes, Gabriela Carriquiry Carrefio, Isaias Manuel Rolando Castañeda, Jesus Renato Ayala, Eduardo Romulo Ticona Chavez, Wilfredo Vargas Onofre, Juan Genaro Sosa Paucar, Elias Rodrigo Aliaga Herrera, Jamie Ismael Soria Medina, José Carlos Masciotti Barraza, Domingo Elias Gómez-Sanchez Mateo, Ruben Marino Azañero Reyna, Jorge de los Rios Senmache, Christian Juan Galvez Vasquez, Zully Haydee Ruiz Vargas, Blanca Luz Parra Galvan, Karin Marlene Reyes Aparcana, Dina Vera Diaz, Joven Roque Gonong, Lawrence Raymond, Roxas Lee Llacer, Aileen Alvarez-Tiu, Vladislav Erokhin, Olga Demikhova, Irina Vasilyeva, Tatevik Bagdasarian, Svetlana Gorlova, Alexey Tikhonov, Andreas Diacon, Madeleine Hanekom, Zoja Noveljic, Ramonde Patientia, Sweetness Siwendu, Alexander Pym, Roxana Rustomjee, Carl Reddy, Lancelot Garth Osburn, Aruna Ramjee, Sbongile Pumzile Ntshanga, Lerato Gabela, Shivani Chirkut, Melony C Fortuin-De Smidt, Ronelle Narasimooloo, John Richard Yarr Quantrill, Iqbal Haroon Master, Thulani Bethwell Gumede, Sunitha Chotoo, Francesca Conradie, Martin P Grobusch, N Russel Mahanyele, Alicja Dziewiecki, Collin N Menezes, Ian Mathias Sanne, Melanie-Anne John, Jean Michel Kayumba, Liesl Page-Shipp, Dawid Kruger, Irene Schroeder, Louwrens L Leeuwner, Cathryn Louise O'Reilly, Myrtle Joubert, Corlia Coetzee, Stephanie Rene Krause, Reinard McPherson, Louise Muller, Charoen Chuchottaworn, Piamplarp Sangsayunh, Kittima Bangpattanasiri, Tawatchai Wiwatworapan, Tanakorn Anantasetagoon
Abstract
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.).
Source: PubMed