Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings
Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse area...
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Medicine Thomas B. Campbell Laura M. Smeaton N. Kumarasamy Timothy Flanigan Karin L. Klingman Cynthia Firnhaber Beatriz Grinsztejn Mina C. Hosseinipour Johnstone Kumwenda Umesh Lalloo Cynthia Riviere Jorge Sanchez Marineide Melo Khuanchai Supparatpinyo Srikanth Tripathy Ana I. Martinez Apsara Nair Ann Walawander Laura Moran Yun Chen Wendy Snowden James F. Rooney Jonathan Uy Robert T. Schooley Victor de Gruttola James Gita Hakim Edith Swann Ronald L. Barnett Barbara Brizz Yvette Delph Nikki Gettinger Ronald T. Mitsuyasu Susan Eshleman Steven Safren Susan A. Fiscus Adriana Andrade David W. Haas Farida Amod Vladimir Berthaud Robert C. Bollinger Yvonne Bryson David Celentano David Chilongozi Myron Cohen Ann C. Collier Judith Silverstein Currier Susan Cu-Uvin Joseph Eron Charles Flexner Joel E. Gallant Roy M. Gulick Scott M. Hammer Irving Hoffman Peter Kazembe Newton Kumwenda Javier R. Lama Jody Lawrence Chiedza Maponga Francis Martinson Kenneth Mayer Karin Nielsen Richard B. Pendame Bharat Ramratnam Ian Sanne Patrice Severe Thira Sirisanthana Suniti Solomon Steve Tabet Taha Taha Charles van der Horst Christine Wanke Joan Gormley Cheryl J. Marcus Beverly Putnam Smanga Ntshele Edde Loeliger Keith A. Pappa Nancy Webb David L. Shugarts Mark A. Winters Renard S. Descallar Joseph Steele Michael Wulfsohn Farideh Said Yue Chen John C. Martin Norbert Bischofberger Andrew Cheng Howard Jaffe Jabin Sharma S. Poongulali Sandra Wagner Cardoso Deise Lucia Faria Sima Berendes Kelly Burke Rosie Mngqibisa Cecelia Kanyama Virginia Kayoyo Wadzanai P. Samaneka Anthony Chisada Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings |
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Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136. © 2012. |
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Thomas B. Campbell Laura M. Smeaton N. Kumarasamy Timothy Flanigan Karin L. Klingman Cynthia Firnhaber Beatriz Grinsztejn Mina C. Hosseinipour Johnstone Kumwenda Umesh Lalloo Cynthia Riviere Jorge Sanchez Marineide Melo Khuanchai Supparatpinyo Srikanth Tripathy Ana I. Martinez Apsara Nair Ann Walawander Laura Moran Yun Chen Wendy Snowden James F. Rooney Jonathan Uy Robert T. Schooley Victor de Gruttola James Gita Hakim Edith Swann Ronald L. Barnett Barbara Brizz Yvette Delph Nikki Gettinger Ronald T. Mitsuyasu Susan Eshleman Steven Safren Susan A. Fiscus Adriana Andrade David W. Haas Farida Amod Vladimir Berthaud Robert C. Bollinger Yvonne Bryson David Celentano David Chilongozi Myron Cohen Ann C. Collier Judith Silverstein Currier Susan Cu-Uvin Joseph Eron Charles Flexner Joel E. Gallant Roy M. Gulick Scott M. Hammer Irving Hoffman Peter Kazembe Newton Kumwenda Javier R. Lama Jody Lawrence Chiedza Maponga Francis Martinson Kenneth Mayer Karin Nielsen Richard B. Pendame Bharat Ramratnam Ian Sanne Patrice Severe Thira Sirisanthana Suniti Solomon Steve Tabet Taha Taha Charles van der Horst Christine Wanke Joan Gormley Cheryl J. Marcus Beverly Putnam Smanga Ntshele Edde Loeliger Keith A. Pappa Nancy Webb David L. Shugarts Mark A. Winters Renard S. Descallar Joseph Steele Michael Wulfsohn Farideh Said Yue Chen John C. Martin Norbert Bischofberger Andrew Cheng Howard Jaffe Jabin Sharma S. Poongulali Sandra Wagner Cardoso Deise Lucia Faria Sima Berendes Kelly Burke Rosie Mngqibisa Cecelia Kanyama Virginia Kayoyo Wadzanai P. Samaneka Anthony Chisada |
author_facet |
Thomas B. Campbell Laura M. Smeaton N. Kumarasamy Timothy Flanigan Karin L. Klingman Cynthia Firnhaber Beatriz Grinsztejn Mina C. Hosseinipour Johnstone Kumwenda Umesh Lalloo Cynthia Riviere Jorge Sanchez Marineide Melo Khuanchai Supparatpinyo Srikanth Tripathy Ana I. Martinez Apsara Nair Ann Walawander Laura Moran Yun Chen Wendy Snowden James F. Rooney Jonathan Uy Robert T. Schooley Victor de Gruttola James Gita Hakim Edith Swann Ronald L. Barnett Barbara Brizz Yvette Delph Nikki Gettinger Ronald T. Mitsuyasu Susan Eshleman Steven Safren Susan A. Fiscus Adriana Andrade David W. Haas Farida Amod Vladimir Berthaud Robert C. Bollinger Yvonne Bryson David Celentano David Chilongozi Myron Cohen Ann C. Collier Judith Silverstein Currier Susan Cu-Uvin Joseph Eron Charles Flexner Joel E. Gallant Roy M. Gulick Scott M. Hammer Irving Hoffman Peter Kazembe Newton Kumwenda Javier R. Lama Jody Lawrence Chiedza Maponga Francis Martinson Kenneth Mayer Karin Nielsen Richard B. Pendame Bharat Ramratnam Ian Sanne Patrice Severe Thira Sirisanthana Suniti Solomon Steve Tabet Taha Taha Charles van der Horst Christine Wanke Joan Gormley Cheryl J. Marcus Beverly Putnam Smanga Ntshele Edde Loeliger Keith A. Pappa Nancy Webb David L. Shugarts Mark A. Winters Renard S. Descallar Joseph Steele Michael Wulfsohn Farideh Said Yue Chen John C. Martin Norbert Bischofberger Andrew Cheng Howard Jaffe Jabin Sharma S. Poongulali Sandra Wagner Cardoso Deise Lucia Faria Sima Berendes Kelly Burke Rosie Mngqibisa Cecelia Kanyama Virginia Kayoyo Wadzanai P. Samaneka Anthony Chisada |
author_sort |
Thomas B. Campbell |
title |
Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings |
title_short |
Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings |
title_full |
Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings |
title_fullStr |
Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings |
title_full_unstemmed |
Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings |
title_sort |
efficacy and safety of three antiretroviral regimens for initial treatment of hiv-1: a randomized clinical trial in diverse multinational settings |
publishDate |
2018 |
url |
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84865566725&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/51864 |
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th-cmuir.6653943832-518642018-09-04T06:10:46Z Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings Thomas B. Campbell Laura M. Smeaton N. Kumarasamy Timothy Flanigan Karin L. Klingman Cynthia Firnhaber Beatriz Grinsztejn Mina C. Hosseinipour Johnstone Kumwenda Umesh Lalloo Cynthia Riviere Jorge Sanchez Marineide Melo Khuanchai Supparatpinyo Srikanth Tripathy Ana I. Martinez Apsara Nair Ann Walawander Laura Moran Yun Chen Wendy Snowden James F. Rooney Jonathan Uy Robert T. Schooley Victor de Gruttola James Gita Hakim Edith Swann Ronald L. Barnett Barbara Brizz Yvette Delph Nikki Gettinger Ronald T. Mitsuyasu Susan Eshleman Steven Safren Susan A. Fiscus Adriana Andrade David W. Haas Farida Amod Vladimir Berthaud Robert C. Bollinger Yvonne Bryson David Celentano David Chilongozi Myron Cohen Ann C. Collier Judith Silverstein Currier Susan Cu-Uvin Joseph Eron Charles Flexner Joel E. Gallant Roy M. Gulick Scott M. Hammer Irving Hoffman Peter Kazembe Newton Kumwenda Javier R. Lama Jody Lawrence Chiedza Maponga Francis Martinson Kenneth Mayer Karin Nielsen Richard B. Pendame Bharat Ramratnam Ian Sanne Patrice Severe Thira Sirisanthana Suniti Solomon Steve Tabet Taha Taha Charles van der Horst Christine Wanke Joan Gormley Cheryl J. Marcus Beverly Putnam Smanga Ntshele Edde Loeliger Keith A. Pappa Nancy Webb David L. Shugarts Mark A. Winters Renard S. Descallar Joseph Steele Michael Wulfsohn Farideh Said Yue Chen John C. Martin Norbert Bischofberger Andrew Cheng Howard Jaffe Jabin Sharma S. Poongulali Sandra Wagner Cardoso Deise Lucia Faria Sima Berendes Kelly Burke Rosie Mngqibisa Cecelia Kanyama Virginia Kayoyo Wadzanai P. Samaneka Anthony Chisada Medicine Background:Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.Methods and Findings:1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure.An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007).Conclusion: EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are advantageous for use of this regimen for initial treatment of HIV-1 infection in resource-limited countries. ATV+DDI+FTC had inferior efficacy and is not recommended as an initial antiretroviral regimen.Trial Registration:http://www.ClinicalTrials.gov NCT00084136. © 2012. 2018-09-04T06:10:46Z 2018-09-04T06:10:46Z 2012-08-01 Journal 15491676 15491277 2-s2.0-84865566725 10.1371/journal.pmed.1001290 https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84865566725&origin=inward http://cmuir.cmu.ac.th/jspui/handle/6653943832/51864 |