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, PEARLS study team of the ACTG, 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, Sharla Faesen, Suwat Chariyalertsak, Breno Santos, Rita Alves Lira, Anjali A Joglekar, Alberto La Rosa, Rosa Infante, Mamta Jain, Tianna Petersen, Sheela Godbole, Sampada Dhayarkar, Judith Feinberg, Jenifer Baer, Richard B Pollard, David Asmuth, Raman R Gangakhedkar, Asmita Gaikwad, M Graham Ray, Cathi Basler, Michael F Para, Kathy J Watson, Babafemi Taiwo, Donna McGregor, Henry H Balfour, Beth Mullan, Ge-Youl Kim, Michael K Klebert, Gary Matthew Cox, Martha Silberman, Donna Mildvan, Manuel Revuelta, Karen T Tashima, Helen Patterson, P Jan Geiseler, Bartolo Santos, Eric S Daar, Ruben Lopez, Laurie Frarey, David Currin, David H Haas, Vicki L Bailey, Pablo Tebas, Larisa Zifchak, Jolene Noel-Connor, Madeline Torres, Beverly E Sha, Janice M Fritsche, Michelle Cespedes, Janet Forcht, William A O'Brien, Cheryl Mogridge, Christine Hurley, Roberto Corales, Maria Palmer, Mary Adams, Amneris Luque, Luis Lopez-Detres, Todd Stroberg, 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, PEARLS study team of the ACTG, 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, Sharla Faesen, Suwat Chariyalertsak, Breno Santos, Rita Alves Lira, Anjali A Joglekar, Alberto La Rosa, Rosa Infante, Mamta Jain, Tianna Petersen, Sheela Godbole, Sampada Dhayarkar, Judith Feinberg, Jenifer Baer, Richard B Pollard, David Asmuth, Raman R Gangakhedkar, Asmita Gaikwad, M Graham Ray, Cathi Basler, Michael F Para, Kathy J Watson, Babafemi Taiwo, Donna McGregor, Henry H Balfour, Beth Mullan, Ge-Youl Kim, Michael K Klebert, Gary Matthew Cox, Martha Silberman, Donna Mildvan, Manuel Revuelta, Karen T Tashima, Helen Patterson, P Jan Geiseler, Bartolo Santos, Eric S Daar, Ruben Lopez, Laurie Frarey, David Currin, David H Haas, Vicki L Bailey, Pablo Tebas, Larisa Zifchak, Jolene Noel-Connor, Madeline Torres, Beverly E Sha, Janice M Fritsche, Michelle Cespedes, Janet Forcht, William A O'Brien, Cheryl Mogridge, Christine Hurley, Roberto Corales, Maria Palmer, Mary Adams, Amneris Luque, Luis Lopez-Detres, Todd Stroberg
Abstract
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.
Conflict of interest statement
TBC has received payments for lectures from, and served as a consultant for GlaxoSmithKline. TF has stock ownership in Abbot, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and has served as a consultant for Gilead Sciences. WS is an employee of GlaxoSmithKline. JFR is an employee and stockholder of Gilead Sciences. JU is an employee of Bristol-Myers Squibb. RTS has served as a consultant to GlaxoSmithKline, Gilead Sciences, Merck and Bristol-Myers Squibb. RTS has served as a member of Data and Safety Monitoring Boards for Gilead Sciences and had research contracts with Merck and Bristol-Myers Squibb. LMS, KLK, CF, BG, MCH, JK, UL, CR, JS, MM, KS, ST, AIM, AN, AW, LM, YC, VDG and JGH declare no conflicts of interest.
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References
- World Health Organization (2010) Treatment 2.0: Is this the future of treatment? World Health Organization. Available: . Accessed 8 August 2011
- Hirnschall G, Schwartlander B (2011) Treatment 2.0: catalysing the next phase of scale-up. Lancet 378: 209–211.
- World Health Organization (2010) Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach. Geneva: World Health Organization
- Staszewski S, Morales-Ramirez J, Tashima KT, Rachlis A, Skiest D, et al. (1999) Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults. Study 006 Team. N Engl J Med 341: 1865–1873.
- Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, et al. (2004) Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med 350: 1850–1861.
- Gallant JE, DeJesus E, Arribas JR, Pozniak AL, Gazzard B, et al. (2006) Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 354: 251–260.
- Squires K, Lazzarin A, Gatell JM, Powderly WG, Pokrovskiy V, et al. (2004) Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV. J Acquir Immune Defic Syndr 36: 1011–1019.
- Malan DR, Krantz E, David N, Wirtz V, Hammond J, et al. (2008) Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr 47: 161–167.
- Sanne I, Piliero P, Squires K, Thiry A, Schnittman S (2003) Results of a phase 2 clinical trial at 48 weeks (AI424-007): a dose-ranging, safety, and efficacy comparative trial of atazanavir at three doses in combination with didanosine and stavudine in antiretroviral-naive subjects. J Acquir Immune Defic Syndr 32: 18–29.
- Berenguer J, Gonzalez J, Ribera E, Domingo P, Santos J, et al. (2008) Didanosine, lamivudine, and efavirenz versus zidovudine, lamivudine, and efavirenz for the initial treatment of HIV type 1 infection: final analysis (48 weeks) of a prospective, randomized, noninferiority clinical trial, GESIDA 3903. Clin Infect Dis 47: 1083–1092.
- Molina JM, Journot V, Morand-Joubert L, Yeni P, Rozenbaum W, et al. (2005) Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a protease inhibitor-based regimen: a randomized trial. J Infect Dis 191: 830–839.
- Molina JM, Journot V, Furco A, Palmer P, De CN, et al. (2007) Five-year follow up of once-daily therapy with emtricitabine, didanosine and efavirenz (Montana ANRS 091 trial). Antivir Ther 12: 417–422.
- Sanchez-Conde M, Palacios R, Sanz J, Rodriguez-Novoa S, Rivas P, et al. (2007) Efficacy and safety of a once daily regimen with efavirenz, lamivudine, and didanosine, with and without food, as initial therapy for HIV Infection: the ELADI study. AIDS Res Hum Retroviruses 23: 1237–1241.
- Saag MS, Cahn P, Raffi F, Wolff M, Pearce D, et al. (2004) Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial. JAMA 292: 180–189.
- Division of AIDS (2004; 2010) Table for grading the severity of adult and pediatric adverse events Available: . Accessed 12 January 2011.
- US Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (2002) Guidance for industry: antiretroviral drugs using plasma HIV RNA measurements - clinical considerations for accelerated and traditional approval. Available: . Accessed 13 October 2010.
- Xu X, Tian L, Wei LJ (2003) Combining dependent tests for linkage or association across multiple phenotypic traits. Biostatistics 4: 223–229.
- Fletcher CV, Jiang H, Brundage RC, Acosta EP, Haubrich R, et al. (2004) Sex-based differences in saquinavir pharmacology and virologic response in AIDS Clinical Trials Group Study 359. J Infect Dis 189: 1176–1184.
- King JR, Kakuda TN, Paul S, Tse MM, Acosta EP, et al. (2007) Pharmacokinetics of saquinavir with atazanavir or low-dose ritonavir administered once daily (ASPIRE I) or twice daily (ASPIRE II) in seronegative volunteers. J Clin Pharmacol 47: 201–208.
- Pai MP, Schriever CA, az-Linares M, Novak RM, Rodvold KA (2004) Sex-related differences in the pharmacokinetics of once-daily saquinavir soft-gelatin capsules boosted with low-dose ritonavir in patients infected with human immunodeficiency virus type 1. Pharmacotherapy 24: 592–599.
- Richman DD, Fischl MA, Grieco MH, Gottlieb MS, Volberding PA, et al. (1987) The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 317: 192–197.
- Jacobson MA, Liu RC, Davies D, Cohen PT (1997) Human immunodeficiency virus disease-related neutropenia and the risk of hospitalization for bacterial infection. Arch Intern Med 157: 1825–1831.
- Moore RD, Keruly JC, Chaisson RE (1995) Neutropenia and bacterial infection in acquired immunodeficiency syndrome. Arch Intern Med 155: 1965–1970.
- Hermans P, Sommereijns B, Van CN, Clumeck N (1999) Neutropenia in patients with HIV infection: a case control study in a cohort of 1403 patients between 1982 and 1993. J Hematother Stem Cell Res 8 Suppl 1: S23–S32.
- Kuritzkes DR, Parenti D, Ward DJ, Rachlis A, Wong RJ, et al. (1998) Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. AIDS 12: 65–73.
- Pozniak AL, Gallant JE, DeJesus E, Arribas JR, Gazzard B, et al. (2006) Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes–a 96-week analysis. J Acquir Immune Defic Syndr 43: 535–540.
- Joint United Nations Programme on HIV/AIDS (UNAIDS) (2010) Global report: UNAIDS report on the global AIDS epidemic 2010. Available: . Accessed 14 September 2011.
- d'Arminio MA, Gonzalez L, Haberl A, Sherr L, Ssanyu-Sseruma W, et al. (2010) Better mind the gap: addressing the shortage of HIV-positive women in clinical trials. AIDS 24: 1091–1094.
- Moore RD, Fortgang I, Keruly J, Chaisson RE (1996) Adverse events from drug therapy for human immunodeficiency virus disease. Am J Med 101: 34–40.
- Currier JS, Spino C, Grimes J, Wofsy CB, Katzenstein DA, et al. (2000) Differences between women and men in adverse events and CD4+ responses to nucleoside analogue therapy for HIV infection. The AIDS Clinical Trials Group 175 Team. J Acquir Immune Defic Syndr 24: 316–324.
- Clark R (2005) Sex differences in antiretroviral therapy-associated intolerance and adverse events. Drug Saf 28: 1075–1083.
- Nielsen-Saines K, Komarow L, Cu-Uvin S, Jourdain G, Klingman K, et al. (2012) Assessment of safety and toxicity following maternal antiretroviral exposure in infants born To HIV-infected women enrolled in antiretroviral treatment protocols in diverse areas of the world. Eighteen month results of AIDS Clinical Trials Group (ACTG) Study 5190/Pediatric AIDS Clinical Trials Group (PACTG) 1054. Pediatrics 129: e1525–e1532.
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