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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. et al. | Date Issued: 2012
Author
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
PEARLS study team
Affilliation
University of Colorado School of Medicine. Department of Medicine. Division of Infectious Diseases. Aurora, United States of America.
Harvard School of Public Health. Center for Biostatistics in AIDS Research. Boston, Massachusetts, United States of America.
YRG Centre for AIDS Research & Education. Chennai, India.
Brown Medical School. Providence, Rhode Island, United States of America.
National Institutes of Health. Bethesda, Maryland, United States of America.
University of the Witwatersrand. Faculty of Health Sciences. Department of Medicine. Clinical HIV Research Unit. Johannesburg, South Africa.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
Kamuzu Central Hospital. Lilongwe, Malawi.
College of Medicine. Department of Medicine. Blantyre, Malawi.
Nelson R. Mandela School of Medicine. Durban, South Africa.
Institut Nacional de laboratoire et de Recherches. Port-au-Prince, Haiti.
Asociación Civil Impacta Salud y Educación. Lima, Peru.
Hospital Nossa Senhora da Conceição-GHC. Serviço de Infectologia. Porto Alegre, Brasil.
Chiang Mai University. Department of Medicine and Research Institute for Health Sciences. Chiang Mai, Thailand.
National AIDS Research Institute. Pune, India.
National Institutes of Health. Bethesda, Maryland, United States of America.
Frontier Science & Technology Research Foundation. Amherst, Massachusetts, United States of America.
Frontier Science & Technology Research Foundation. Amherst, Massachusetts, United States of America.
Social & Scientific Systems, Inc. Silver Spring, Maryland, United States of America.
Harvard School of Public Health. Center for Biostatistics in AIDS Research. Boston, Massachusetts, United States of America.
GlaxoSmithKline, Research Triangle Park. North Carolina, United States of America.
Gilead Sciences, Inc. Foster City, California, United States of America.
Bristol-Myers Squibb Company. Plainsboro, New Jersey, United States of America.
University of California San Diego. San Diego, United States of America.
Harvard School of Public Health. Center for Biostatistics in AIDS Research. Boston, Massachusetts, United States of America.
University of Zimbabwe College of Health Sciences. Harare, Zimbabwe.
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.
Citation
CAMPBELL, T. B. et al. Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings. PLoS medicine, v. 9, n. 8, p. e1001290, 2012.
DOI
10.1371/journal.pmed.1001290
ISSN
1549-1277
Notes
Colaboradores: Swann E, Barnett RL, Brizz B, Delph Y, Gettinger N, Mitsuyasu RT, Eshleman S, Safren S, Fiscus SA, Andrade A, Haas DW, Amod F, Berthaud V, Bollinger RC, Bryson Y, Celentano D, Chilongozi D, Cohen M, Collier AC, Currier JS, Cu-Uvin S, Eron J, Flexner C, Gallant JE, Gulick RM, Hammer SM, Hoffman I, Kazembe P, Kumwenda N, Lama JR, Lawrence J, Maponga C, Martinson F, Mayer K, Nielsen K, Pendame RB, Ramratnam B, Sanne I, Severe P, Sirisanthana T, Solomon S, Tabet S, Taha T, van der Horst C, Wanke C, Gormley J, Marcus CJ, Putnam B, Ntshele S, Loeliger E, Pappa KA, Webb N, Shugarts DL, Winters MA, Descallar RS, Steele J, Wulfsohn M, Said F, Chen Y, Martin JC, Bischofberger N, Cheng A, Jaffe H, Sharma J, Poongulali S, Cardoso SW, Faria DL, Berendes S, Burke K, Mngqibisa R, Kanyama C, Kayoyo V, Samaneka WP, Chisada A, Faesen S, Chariyalertsak S, Santos B, Lira RA, Joglekar AA, La Rosa A, Infante R, Jain M, Petersen T, Godbole S, Dhayarkar S, Feinberg J, Baer J, Pollard RB, Asmuth D, Gangakhedkar RR, Gaikwad A, Ray MG, Basler C, Para MF, Watson KJ, Taiwo B, McGregor D, Balfour HH, Mullan B, Kim GY, Klebert MK, Cox GM, Silberman M, Mildvan D, Revuelta M, Tashima KT, Patterson H, Geiseler PJ, Santos B, Daar ES, Lopez R, Frarey L, Currin D, Haas DH, Bailey VL, Tebas P, Zifchak L, Noel-Connor J, Torres M, Sha BE, Fritsche JM, Cespedes M, Forcht J, O'Brien WA, Mogridge C, Hurley C, Corales R, Palmer M, Adams M, Luque A, Lopez-Detres L, Stroberg T.