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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
- Campbell, Thomas B;
- Smeaton, Laura M;
- Kumarasamy, N;
- Flanigan, Timothy;
- Klingman, Karin L;
- Firnhaber, Cynthia;
- Grinsztejn, Beatriz;
- Hosseinipour, Mina C;
- Kumwenda, Johnstone;
- Lalloo, Umesh;
- Riviere, Cynthia;
- Sanchez, Jorge;
- Melo, Marineide;
- Supparatpinyo, Khuanchai;
- Tripathy, Srikanth;
- Martinez, Ana I;
- Nair, Apsara;
- Walawander, Ann;
- Moran, Laura;
- Chen, Yun;
- Snowden, Wendy;
- Rooney, James F;
- Uy, Jonathan;
- Schooley, Robert T;
- De Gruttola, Victor;
- Hakim, James Gita;
- Swann, Edith;
- Barnett, Ronald L;
- Brizz, Barbara;
- Delph, Yvette;
- Gettinger, Nikki;
- Mitsuyasu, Ronald T;
- Eshleman, Susan;
- Safren, Steven;
- Fiscus, Susan A;
- Andrade, Adriana;
- Haas, David W;
- Amod, Farida;
- Berthaud, Vladimir;
- Bollinger, Robert C;
- Bryson, Yvonne;
- Celentano, David;
- Chilongozi, David;
- Cohen, Myron;
- Collier, Ann C;
- Currier, Judith Silverstein;
- Cu-Uvin, Susan;
- Eron, Joseph;
- Flexner, Charles;
- Gallant, Joel E;
- Gulick, Roy M;
- Hammer, Scott M;
- Hoffman, Irving;
- Kazembe, Peter;
- Kumwenda, Newton;
- Lama, Javier R;
- Lawrence, Jody;
- Maponga, Chiedza;
- Martinson, Francis;
- Mayer, Kenneth;
- Nielsen, Karin;
- Pendame, Richard B;
- Ramratnam, Bharat;
- Sanne, Ian;
- Severe, Patrice;
- Sirisanthana, Thira;
- Solomon, Suniti;
- Tabet, Steve;
- Taha, Taha;
- van der Horst, Charles;
- Wanke, Christine;
- Gormley, Joan;
- Marcus, Cheryl J;
- Putnam, Beverly;
- Loeliger, Edde;
- Pappa, Keith A;
- Webb, Nancy;
- Shugarts, David L;
- Winters, Mark A;
- Descallar, Renard S;
- Steele, Joseph;
- Wulfsohn, Michael;
- Said, Farideh;
- Chen, Yue;
- Martin, John C;
- Bischofberger, Norbert;
- Cheng, Andrew;
- Jaffe, Howard;
- Sharma, Jabin;
- Poongulali, S;
- Cardoso, Sandra Wagner;
- Faria, Deise Lucia;
- Berendes, Sima;
- Burke, Kelly;
- Mngqibisa, Rosie;
- Kanyama, Cecelia;
- Kayoyo, Virginia;
- Samaneka, Wadzanai P;
- Chisada, Anthony;
- Faesen, Sharla;
- Chariyalertsak, Suwat;
- Santos, Breno;
- Lira, Rita Alves;
- Joglekar, Anjali A;
- La Rosa, Alberto;
- Infante, Rosa;
- Jain, Mamta;
- Petersen, Tianna;
- Godbole, Sheela;
- Dhayarkar, Sampada;
- Feinberg, Judith;
- Baer, Jenifer;
- Pollard, Richard B;
- Asmuth, David;
- Gangakhedkar, Raman R;
- Gaikwad, Asmita;
- Ray, M Graham;
- Basler, Cathi;
- Para, Michael F;
- Watson, Kathy J;
- Taiwo, Babafemi;
- McGregor, Donna;
- Balfour, Henry H;
- Mullan, Beth;
- Kim, Ge-Youl;
- Klebert, Michael K;
- Cox, Gary Matthew;
- Silberman, Martha;
- Mildvan, Donna;
- Revuelta, Manuel;
- Tashima, Karen T;
- Patterson, Helen;
- Geiseler, P Jan;
- Santos, Bartolo;
- Daar, Eric S;
- Lopez, Ruben;
- Frarey, Laurie;
- Currin, David;
- Haas, David H;
- Bailey, Vicki L;
- Tebas, Pablo;
- Zifchak, Larisa;
- Noel-Connor, Jolene;
- Torres, Madeline;
- Sha, Beverly E;
- Fritsche, Janice M;
- Cespedes, Michelle;
- Forcht, Janet;
- O'Brien, William A;
- Mogridge, Cheryl;
- Hurley, Christine;
- Corales, Roberto;
- Palmer, Maria;
- Adams, Mary;
- Luque, Amneris;
- Lopez-Detres, Luis;
- Stroberg, Todd
- Editor(s): Deeks, Steven G
- et al.
Published Web Location
https://doi.org/10.1371/journal.pmed.1001290Abstract
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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.
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