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 & 138 others 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, 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

Research output: Contribution to journalArticle

93 Citations (Scopus)

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:http://www.ClinicalTrials.gov NCT00084136.

Original languageEnglish (US)
Article numbere1001290
JournalPLoS Medicine
Volume9
Issue number8
DOIs
StatePublished - Aug 2012

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Lamivudine
HIV-1
Randomized Controlled Trials
Safety
Hazards
efavirenz
Treatment Failure
Tenofovir
Therapeutics
Didanosine
Zidovudine
HIV Infections
Labels
Monitoring

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Campbell, T. B., Smeaton, L. M., Kumarasamy, N., Flanigan, T., Klingman, K. L., Firnhaber, C., ... Stroberg, T. (2012). Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings. PLoS Medicine, 9(8), [e1001290]. https://doi.org/10.1371/journal.pmed.1001290

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; Ntshele, Smanga; 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.

In: PLoS Medicine, Vol. 9, No. 8, e1001290, 08.2012.

Research output: Contribution to journalArticle

Campbell, TB, Smeaton, LM, Kumarasamy, N, Flanigan, T, Klingman, KL, Firnhaber, C, Grinsztejn, B, Hosseinipour, MC, Kumwenda, J, Lalloo, U, Riviere, C, Sanchez, J, Melo, M, Supparatpinyo, K, Tripathy, S, Martinez, AI, Nair, A, Walawander, A, Moran, L, Chen, Y, Snowden, W, Rooney, JF, Uy, J, Schooley, RT, de Gruttola, V, Hakim, JG, 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 2012, 'Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings', PLoS Medicine, vol. 9, no. 8, e1001290. https://doi.org/10.1371/journal.pmed.1001290
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 ; Ntshele, Smanga ; 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. / Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1 : A Randomized Clinical Trial in Diverse Multinational Settings. In: PLoS Medicine. 2012 ; Vol. 9, No. 8.
@article{bac3fcf584d14980a284281e8df083f1,
title = "Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings",
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:http://www.ClinicalTrials.gov NCT00084136.",
author = "Campbell, {Thomas B.} and Smeaton, {Laura M.} and N. Kumarasamy and Timothy Flanigan and Klingman, {Karin L.} and Cynthia Firnhaber and Beatriz Grinsztejn and Hosseinipour, {Mina C.} and Johnstone Kumwenda and Umesh Lalloo and Cynthia Riviere and Jorge Sanchez and Marineide Melo and Khuanchai Supparatpinyo and Srikanth Tripathy and Martinez, {Ana I.} and Apsara Nair and Ann Walawander and Laura Moran and Yun Chen and Wendy Snowden and Rooney, {James F.} and Jonathan Uy and Schooley, {Robert T.} and {de Gruttola}, Victor and Hakim, {James Gita} and Edith Swann and Barnett, {Ronald L.} and Barbara Brizz and Yvette Delph and Nikki Gettinger and Mitsuyasu, {Ronald T.} and Susan Eshleman and Steven Safren and Fiscus, {Susan A.} and Adriana Andrade and Haas, {David W.} and Farida Amod and Vladimir Berthaud and Bollinger, {Robert C.} and Yvonne Bryson and David Celentano and David Chilongozi and Myron Cohen and Collier, {Ann C.} and Currier, {Judith Silverstein} and Susan Cu-Uvin and Joseph Eron and Charles Flexner and Gallant, {Joel E.} and Gulick, {Roy M.} and Hammer, {Scott M.} and Irving Hoffman and Peter Kazembe and Newton Kumwenda and Lama, {Javier R.} and Jody Lawrence and Chiedza Maponga and Francis Martinson and Kenneth Mayer and Karin Nielsen and Pendame, {Richard B.} and Bharat Ramratnam and Ian Sanne and Patrice Severe and Thira Sirisanthana and Suniti Solomon and Steve Tabet and Taha Taha and {van der Horst}, Charles and Christine Wanke and Joan Gormley and Marcus, {Cheryl J.} and Beverly Putnam and Smanga Ntshele and Edde Loeliger and Pappa, {Keith A.} and Nancy Webb and Shugarts, {David L.} and Winters, {Mark A.} and Descallar, {Renard S.} and Joseph Steele and Michael Wulfsohn and Farideh Said and Yue Chen and Martin, {John C.} and Norbert Bischofberger and Andrew Cheng and Howard Jaffe and Jabin Sharma and S. Poongulali and Cardoso, {Sandra Wagner} and Faria, {Deise Lucia} and Sima Berendes and Kelly Burke and Rosie Mngqibisa and Cecelia Kanyama and Virginia Kayoyo and Samaneka, {Wadzanai P.} and Anthony Chisada and Sharla Faesen and Suwat Chariyalertsak and Breno Santos and Lira, {Rita Alves} and Joglekar, {Anjali A.} and {la Rosa}, Alberto and Rosa Infante and Mamta Jain and Tianna Petersen and Sheela Godbole and Sampada Dhayarkar and Judith Feinberg and Jenifer Baer and Pollard, {Richard B.} and David Asmuth and Gangakhedkar, {Raman R.} and Asmita Gaikwad and Ray, {M. Graham} and Cathi Basler and Para, {Michael F.} and Watson, {Kathy J.} and Babafemi Taiwo and Donna McGregor and Balfour, {Henry H.} and Beth Mullan and Kim, {Ge Youl} and Klebert, {Michael K.} and Cox, {Gary Matthew} and Martha Silberman and Donna Mildvan and Manuel Revuelta and Tashima, {Karen T.} and Helen Patterson and Geiseler, {P. Jan} and Bartolo Santos and Daar, {Eric S.} and Ruben Lopez and Laurie Frarey and David Currin and Haas, {David H.} and Bailey, {Vicki L.} and Pablo Tebas and Larisa Zifchak and Jolene Noel-Connor and Madeline Torres and Sha, {Beverly E.} and Fritsche, {Janice M.} and Michelle Cespedes and Janet Forcht and O'Brien, {William A.} and Cheryl Mogridge and Christine Hurley and Roberto Corales and Maria Palmer and Mary Adams and Amneris Luque and Luis Lopez-Detres and Todd Stroberg",
year = "2012",
month = "8",
doi = "10.1371/journal.pmed.1001290",
language = "English (US)",
volume = "9",
journal = "Nature Methods",
issn = "1548-7091",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1

T2 - A Randomized Clinical Trial in Diverse Multinational Settings

AU - Campbell, Thomas B.

AU - Smeaton, Laura M.

AU - Kumarasamy, N.

AU - Flanigan, Timothy

AU - Klingman, Karin L.

AU - Firnhaber, Cynthia

AU - Grinsztejn, Beatriz

AU - Hosseinipour, Mina C.

AU - Kumwenda, Johnstone

AU - Lalloo, Umesh

AU - Riviere, Cynthia

AU - Sanchez, Jorge

AU - Melo, Marineide

AU - Supparatpinyo, Khuanchai

AU - Tripathy, Srikanth

AU - Martinez, Ana I.

AU - Nair, Apsara

AU - Walawander, Ann

AU - Moran, Laura

AU - Chen, Yun

AU - Snowden, Wendy

AU - Rooney, James F.

AU - Uy, Jonathan

AU - Schooley, Robert T.

AU - de Gruttola, Victor

AU - Hakim, James Gita

AU - Swann, Edith

AU - Barnett, Ronald L.

AU - Brizz, Barbara

AU - Delph, Yvette

AU - Gettinger, Nikki

AU - Mitsuyasu, Ronald T.

AU - Eshleman, Susan

AU - Safren, Steven

AU - Fiscus, Susan A.

AU - Andrade, Adriana

AU - Haas, David W.

AU - Amod, Farida

AU - Berthaud, Vladimir

AU - Bollinger, Robert C.

AU - Bryson, Yvonne

AU - Celentano, David

AU - Chilongozi, David

AU - Cohen, Myron

AU - Collier, Ann C.

AU - Currier, Judith Silverstein

AU - Cu-Uvin, Susan

AU - Eron, Joseph

AU - Flexner, Charles

AU - Gallant, Joel E.

AU - Gulick, Roy M.

AU - Hammer, Scott M.

AU - Hoffman, Irving

AU - Kazembe, Peter

AU - Kumwenda, Newton

AU - Lama, Javier R.

AU - Lawrence, Jody

AU - Maponga, Chiedza

AU - Martinson, Francis

AU - Mayer, Kenneth

AU - Nielsen, Karin

AU - Pendame, Richard B.

AU - Ramratnam, Bharat

AU - Sanne, Ian

AU - Severe, Patrice

AU - Sirisanthana, Thira

AU - Solomon, Suniti

AU - Tabet, Steve

AU - Taha, Taha

AU - van der Horst, Charles

AU - Wanke, Christine

AU - Gormley, Joan

AU - Marcus, Cheryl J.

AU - Putnam, Beverly

AU - Ntshele, Smanga

AU - Loeliger, Edde

AU - Pappa, Keith A.

AU - Webb, Nancy

AU - Shugarts, David L.

AU - Winters, Mark A.

AU - Descallar, Renard S.

AU - Steele, Joseph

AU - Wulfsohn, Michael

AU - Said, Farideh

AU - Chen, Yue

AU - Martin, John C.

AU - Bischofberger, Norbert

AU - Cheng, Andrew

AU - Jaffe, Howard

AU - Sharma, Jabin

AU - Poongulali, S.

AU - Cardoso, Sandra Wagner

AU - Faria, Deise Lucia

AU - Berendes, Sima

AU - Burke, Kelly

AU - Mngqibisa, Rosie

AU - Kanyama, Cecelia

AU - Kayoyo, Virginia

AU - Samaneka, Wadzanai P.

AU - Chisada, Anthony

AU - Faesen, Sharla

AU - Chariyalertsak, Suwat

AU - Santos, Breno

AU - Lira, Rita Alves

AU - Joglekar, Anjali A.

AU - la Rosa, Alberto

AU - Infante, Rosa

AU - Jain, Mamta

AU - Petersen, Tianna

AU - Godbole, Sheela

AU - Dhayarkar, Sampada

AU - Feinberg, Judith

AU - Baer, Jenifer

AU - Pollard, Richard B.

AU - Asmuth, David

AU - Gangakhedkar, Raman R.

AU - Gaikwad, Asmita

AU - Ray, M. Graham

AU - Basler, Cathi

AU - Para, Michael F.

AU - Watson, Kathy J.

AU - Taiwo, Babafemi

AU - McGregor, Donna

AU - Balfour, Henry H.

AU - Mullan, Beth

AU - Kim, Ge Youl

AU - Klebert, Michael K.

AU - Cox, Gary Matthew

AU - Silberman, Martha

AU - Mildvan, Donna

AU - Revuelta, Manuel

AU - Tashima, Karen T.

AU - Patterson, Helen

AU - Geiseler, P. Jan

AU - Santos, Bartolo

AU - Daar, Eric S.

AU - Lopez, Ruben

AU - Frarey, Laurie

AU - Currin, David

AU - Haas, David H.

AU - Bailey, Vicki L.

AU - Tebas, Pablo

AU - Zifchak, Larisa

AU - Noel-Connor, Jolene

AU - Torres, Madeline

AU - Sha, Beverly E.

AU - Fritsche, Janice M.

AU - Cespedes, Michelle

AU - Forcht, Janet

AU - O'Brien, William A.

AU - Mogridge, Cheryl

AU - Hurley, Christine

AU - Corales, Roberto

AU - Palmer, Maria

AU - Adams, Mary

AU - Luque, Amneris

AU - Lopez-Detres, Luis

AU - Stroberg, Todd

PY - 2012/8

Y1 - 2012/8

N2 - 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.

AB - 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.

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U2 - 10.1371/journal.pmed.1001290

DO - 10.1371/journal.pmed.1001290

M3 - Article

VL - 9

JO - Nature Methods

JF - Nature Methods

SN - 1548-7091

IS - 8

M1 - e1001290

ER -