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Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Thomas Campbell,Laura Smeaton,N. Kumarasamy,Timothy P. Flanigan,Karin L. Klingman,Cynthia Firnhaber,Beatriz Grinsztejn,Mina C. Hosseinipour,Johnstone Kumwenda,Umesh Lalloo,Cynthia Riviere,Jorge Sánchez,Marineide Melo,Khuanchai Supparatpinyo,Srikanth Tripathy,Ana Martı́nez,Apsara Nair,Ann Walawander,Laura Moran,Yun Chen,Wendy Snowden,James F. Rooney,Jonathan Uy,Robert T. Schooley,Victor De Gruttola,James Hakim,Edith Swann,Ronald L. Barnett,Barbara Brizz,Yvette Delph,Nikki Gettinger,Ronald T. Mitsuyasu,Susan H. Eshleman,Steven A. Safren,Susan A. Fiscus,Adriana Andrade,David W. Haas,Farida Amod,Vladimir Berthaud,Robert C. Bollinger,Yvonne J. Bryson,David D. Celentano,David Chilongozi,Myron S. Cohen,Ann C. Collier,Judith S. Currier,Susan Cu‐Uvin,Joseph J. Eron,Charles Flexner,Joel E. Gallant,Roy M. Gulick,Scott M. Hammer,Irving Hoffman,Peter N. Kazembe,Newton Kumwenda,Javier R. Lama,Jody Lawrence,Charles C. Maponga,Francis Martinson,Kenneth H. Mayer,Karin Nielsen,Richard Pendame,Bharat Ramratnam,Ian Sanne,Patrice Sévère,Thira Sirisanthana,Suniti Solomon,Steve Tabet,Taha E. Taha,Charles van der Horst,Christine Wanke,Joan Gormley,Cheryl Marcus,Beverly Putnam,Smanga Ntshele,Edde Loeliger,Keith A. Pappa,Nancy R. Webb,David Shugarts,Mark A. Winters,Renard S. Descallar,J. C.H. Steele,Michael Wulfsohn,Farideh Said,Yue Chen,John Martin,Norbert Bischofberger,Andrew Cheng,Howard S. Jaffe,Jabin Sharma,Selvamuthu Poongulali,Sandra Wagner Cardoso,Deise Lucia Faria,Sima Berendes,Kelly P. Burke,Rosie Mngqibisa,Cecilia Kanyama,Virginia Kayoyo,Wadzanai Samaneka,Anthony Chisada,Sharla Faesen,Suwat Chariyalertsak,Breno Santos,Rita Alves Lira,A. A. Joglekar,Alberto La Rosa,Rosa Infante,Mamta K. Jain,Tianna Petersen,Sheela Godbole,Sampada Dhayarkar,Judith Feinberg,Jenifer Baer,Richard B. Pollard,David M. Asmuth,Raman Gangakhedkar,Asmita Gaikwad,Michelle Ray,Cathi Basler,Michael F. Para,Kathy J. Watson,Babafemi Taiwo,Donna V McGregor,Henry H. Balfour,Beth Mullan,Ge Youl Kim,Michael K. Klebert,Gary M. Cox,Martha Silberman,Donna Mildvan,Manuel Revuelta,Karen T. Tashima,Helen Patterson,P. Jan Geiseler,Bartolo Santos,Eric S. Daar,R. Cortes Lopez,Laurie Frarey,D. Currin,Vicki Bailey,Pablo Tebas,Larisa Zifchak,Jolene Noel-Connor,M. Farrero Torres,Beverly E. Sha,Janice M. Fritsche,Michelle Cespedes,Janet Forcht,William A. O’Brien,Cheryl Mogridge,Christine Hurley,Roberto Corales,Maria Palmer,M. Jacob Adams,Amneris E. Luque,Luis Lopez-Detres,Todd Stroberg

Efavirenz

Emtricitabine

Medicine

2012

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 www.ClinicalTrials.gov NCT00084136 Please see later in the article for the Editors' Summary.

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“Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings” is a paper by Thomas Campbell Laura Smeaton N. Kumarasamy Timothy P. Flanigan Karin L. Klingman Cynthia Firnhaber Beatriz Grinsztejn Mina C. Hosseinipour Johnstone Kumwenda Umesh Lalloo Cynthia Riviere Jorge Sánchez Marineide Melo Khuanchai Supparatpinyo Srikanth Tripathy Ana Martı́nez Apsara Nair Ann Walawander Laura Moran Yun Chen Wendy Snowden James F. Rooney Jonathan Uy Robert T. Schooley Victor De Gruttola James Hakim Edith Swann Ronald L. Barnett Barbara Brizz Yvette Delph Nikki Gettinger Ronald T. Mitsuyasu Susan H. Eshleman Steven A. Safren Susan A. Fiscus Adriana Andrade David W. Haas Farida Amod Vladimir Berthaud Robert C. Bollinger Yvonne J. Bryson David D. Celentano David Chilongozi Myron S. Cohen Ann C. Collier Judith S. Currier Susan Cu‐Uvin Joseph J. Eron Charles Flexner Joel E. Gallant Roy M. Gulick Scott M. Hammer Irving Hoffman Peter N. Kazembe Newton Kumwenda Javier R. Lama Jody Lawrence Charles C. Maponga Francis Martinson Kenneth H. Mayer Karin Nielsen Richard Pendame Bharat Ramratnam Ian Sanne Patrice Sévère Thira Sirisanthana Suniti Solomon Steve Tabet Taha E. Taha Charles van der Horst Christine Wanke Joan Gormley Cheryl Marcus Beverly Putnam Smanga Ntshele Edde Loeliger Keith A. Pappa Nancy R. Webb David Shugarts Mark A. Winters Renard S. Descallar J. C.H. Steele Michael Wulfsohn Farideh Said Yue Chen John Martin Norbert Bischofberger Andrew Cheng Howard S. Jaffe Jabin Sharma Selvamuthu Poongulali Sandra Wagner Cardoso Deise Lucia Faria Sima Berendes Kelly P. Burke Rosie Mngqibisa Cecilia Kanyama Virginia Kayoyo Wadzanai Samaneka Anthony Chisada Sharla Faesen Suwat Chariyalertsak Breno Santos Rita Alves Lira A. A. Joglekar Alberto La Rosa Rosa Infante Mamta K. Jain Tianna Petersen Sheela Godbole Sampada Dhayarkar Judith Feinberg Jenifer Baer Richard B. Pollard David M. Asmuth Raman Gangakhedkar Asmita Gaikwad Michelle Ray Cathi Basler Michael F. Para Kathy J. Watson Babafemi Taiwo Donna V McGregor Henry H. Balfour Beth Mullan Ge Youl Kim Michael K. Klebert Gary M. Cox Martha Silberman Donna Mildvan Manuel Revuelta Karen T. Tashima Helen Patterson P. Jan Geiseler Bartolo Santos Eric S. Daar R. Cortes Lopez Laurie Frarey D. Currin Vicki Bailey Pablo Tebas Larisa Zifchak Jolene Noel-Connor M. Farrero Torres Beverly E. Sha Janice M. Fritsche Michelle Cespedes Janet Forcht William A. O’Brien Cheryl Mogridge Christine Hurley Roberto Corales Maria Palmer M. Jacob Adams Amneris E. Luque Luis Lopez-Detres Todd Stroberg published in 2012. It has an Open Access status of “gold”. You can read and download a PDF Full Text of this paper here.