Efavirenz or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir Disoproxil Fumarate or Abacavir/Lamivudine in HIV Infected Treatment-Naive Adults
NCT ID: NCT00118898
Last Updated: 2018-10-12
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
1864 participants
INTERVENTIONAL
2005-09-30
2009-11-30
Brief Summary
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Detailed Description
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The treatment portion of this study will last 96 weeks after the last participant is enrolled. Participants will be randomly assigned to one of four arms:
* Arm 1 participants will receive EFV, FTC/TDF, and placebo for ABC/3TC.
* Arm 2 participants will receive EFV, ABC/3TC, and placebo for FTC/TDF.
* Arm 3 participants will receive ritonavir (RTV)-boosted ATV, FTC/TDF, and placebo for ABC/3TC.
* Arm 4 participants will receive RTV-boosted ATV, ABC/3TC and placebo for FTC/TDF.
NOTE: Lopinavir/ritonavir may be used in substitution of other drugs for certain participants.
Study visits will occur at study entry; Weeks 1, 2, 4, 8, 16, and 24; and every 12 weeks thereafter. A physical exam, blood collection, and urine collection will occur at most visits. Two pharmacokinetic blood samples will be collected from participants between Weeks 4 and 24. Participants will undergo adherence training at study entry and will be asked to complete adherence questionnaires at selected study visits. Some participants will be asked to participate in ACTG A5224s, a metabolic substudy of ACTG A5202.
The Data Safety Monitoring Board (DSMB) for A5202 met in January 2008 to review the study. After reviewing the study information, the DSMB noted that certain study regimens were significantly less effective than others. Specifically, ABC/3TC-containing regimens were not as effective in controlling the virus as TDF/FTC-containing regimens for participants entering the study with high viral loads. The DSMB also commented that participants assigned to ABC/3TC had a shorter time until they experienced side effects than participants assigned to TDF/FTC. The DSMB had no safety concerns for the other drug comparisons.
Based on DSMB review, in Feb 2008 participants who started the study with high viral loads were told whether they were taking ABC/3TC or TDF/FTC and offered the option to continue or change their NRTI study drug component, after discussion with their doctor. For participants who started the study with lower screening viral loads, study treatment continued without change.
For 74 participant the reason for first treatment modification was "unblinded and switched" as a consequence of the DSMB results (33 on EFV, ABC/3TC, and placebo FTC/TDF arm; 1 on RTV-boosted ATV, FTC/TDF, and placebo ABC/3TC arm; and 40 on RTV-boosted ATV, ABC/3TC, and placebo FTC/TDF arm).
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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EFV, FTC/TDF, and placebo ABC/3TC
Participants will receive EFV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
Efavirenz
600 mg tablet taken orally daily
Emtricitabine/Tenofovir disoproxil fumarate
200 mg emtricitabine/300 mg tenofovir disoproxil fumarate tablet taken orally daily
Abacavir/Lamivudine placebo
Placebo tablet taken orally daily
EFV, ABC/3TC and placebo FTC/TDF
Participants will receive EFV, ABC/3TC, and placebo for FTC/TDF for at least 96 weeks
Abacavir/Lamivudine
600 mg abacavir/300 mg lamivudine tablet taken orally daily
Efavirenz
600 mg tablet taken orally daily
Emtricitabine/Tenofovir disoproxil fumarate placebo
Placebo tablet taken orally daily
RTV-boosted ATV, FTC/TDF, and placebo ABC/3TC
Participants will receive RTV-boosted ATV, FTC/TDF, and placebo for ABC/3TC for at least 96 weeks
Atazanavir
300 mg tablet taken orally daily
Emtricitabine/Tenofovir disoproxil fumarate
200 mg emtricitabine/300 mg tenofovir disoproxil fumarate tablet taken orally daily
Ritonavir
100 mg tablet taken orally daily
Abacavir/Lamivudine placebo
Placebo tablet taken orally daily
RTV-boosted ATV, ABC/3TC, and placebo FTC/TDF
Participants will receive RTV-boosted ATV, ABC/3TC, and placebo for FTC/TDF for at least 96 weeks
Abacavir/Lamivudine
600 mg abacavir/300 mg lamivudine tablet taken orally daily
Atazanavir
300 mg tablet taken orally daily
Ritonavir
100 mg tablet taken orally daily
Emtricitabine/Tenofovir disoproxil fumarate placebo
Placebo tablet taken orally daily
Interventions
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Abacavir/Lamivudine
600 mg abacavir/300 mg lamivudine tablet taken orally daily
Atazanavir
300 mg tablet taken orally daily
Efavirenz
600 mg tablet taken orally daily
Emtricitabine/Tenofovir disoproxil fumarate
200 mg emtricitabine/300 mg tenofovir disoproxil fumarate tablet taken orally daily
Ritonavir
100 mg tablet taken orally daily
Abacavir/Lamivudine placebo
Placebo tablet taken orally daily
Emtricitabine/Tenofovir disoproxil fumarate placebo
Placebo tablet taken orally daily
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Antiretroviral naive, defined as 7 days or less of ARV treatment at any time prior to study entry. Participants who have received ARVs as part of postexposure prophylaxis or who have received an investigational drug that was not an NRTI, NNRTI, or PI are eligible for this study.
* HIV viral load greater than 1,000 copies/ml within 90 days prior to study entry
* Certain laboratory values obtained within 30 days prior to study entry. More information on this criterion can be found in the protocol
* Willing to use acceptable forms of contraception
* Parent or guardian able and willing to provide written informed consent, if applicable
* Hepatitis B surface antigen (HBsAg) negative at study entry
Exclusion Criteria
* Known allergy/sensitivity to study drugs or their formulations
* Active alcohol or drug use that, in the opinion of the investigator, would interfere with adherence to study requirements
* Serious illness requiring systemic treatment or hospitalization. Patients who have completed therapy or are clinically stable on therapy for at least 7 days prior to study entry are not excluded.
* Known clinically relevant cardiac conduction system disease
* Requirement for any current medications that are prohibited with any study treatment.
* Evidence of any major drug resistance-associated mutation on any genotype or evidence of significant resistance on any phenotype performed at any time prior to study entry.
* Current imprisonment or involuntary incarceration for psychiatric or physical (e.g., infectious disease) illness
* Breastfeeding. Women who become pregnant during the study will be unblinded and required to permanently discontinue their study regimens.
16 Years
ALL
No
Sponsors
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National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
NETWORK
Responsible Party
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Principal Investigators
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Eric Daar, MD
Role: STUDY_CHAIR
Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute
Paul Sax, MD
Role: STUDY_CHAIR
Division of Infectious Diseases, Brigham and Women's Hospital
Locations
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Moses H. Cone Memorial Hospital CRS (3203)
Greensboro, North Carolina, United States
Usc Crs (1201)
Los Angeles, California, United States
UCLA CARE Center CRS (601)
Los Angeles, California, United States
Stanford CRS (501)
Palo Alto, California, United States
Ucsd, Avrc Crs (701)
San Diego, California, United States
Ucsf Aids Crs (801)
San Francisco, California, United States
San Mateo County AIDS Program (505)
Stanford, California, United States
Willow Clinic (507)
Stanford, California, United States
Harbor-UCLA Med. Ctr. CRS (603)
Torrance, California, United States
University of Colorado Hospital CRS (6101)
Aurora, Colorado, United States
Georgetown University CRS (GU CRS) (1008)
Washington D.C., District of Columbia, United States
University of Miami AIDS CRS (901)
Miami, Florida, United States
Emory University
Atlanta, Georgia, United States
The Ponce de Leon Center CRS (5802)
Atlanta, Georgia, United States
Northwestern University CRS (2701)
Chicago, Illinois, United States
Cook County Hospital Core Center (2705)
Chicago, Illinois, United States
Rush Univ. Med. Ctr. ACTG CRS (2702)
Chicago, Illinois, United States
Indiana University Hospital (2601)
Indianapolis, Indiana, United States
Wishard Hospital (2603)
Indianapolis, Indiana, United States
Univ of Iowa Hosp and Clinic (1504)
Iowa City, Iowa, United States
IHV Baltimore Treatment CRS (4651)
Baltimore, Maryland, United States
Johns Hopkins Adult AIDS CRS (201)
Baltimore, Maryland, United States
Massachusetts General Hospital ACTG CRS (101)
Boston, Massachusetts, United States
Brigham and Women's Hosp. ACTG CRS (107)
Boston, Massachusetts, United States
Bmc Actg Crs (104)
Boston, Massachusetts, United States
Beth Israel Deaconess Med. Ctr., ACTG CRS (103)
Boston, Massachusetts, United States
Washington U CRS (2101)
St Louis, Missouri, United States
SUNY - Buffalo (Rochester) (1102)
Buffalo, New York, United States
Cornell CRS (7804)
New York, New York, United States
Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)
New York, New York, United States
NY Univ. HIV/AIDS CRS (401)
New York, New York, United States
HIV Prevention & Treatment CRS (30329)
New York, New York, United States
Harlem ACTG CRS (31483)
New York, New York, United States
AIDS Community Health Ctr. ACTG CRS (1108)
Rochester, New York, United States
University of Rochester ACTG CRS (1101)
Rochester, New York, United States
Unc Aids Crs (3201)
Chapel Hill, North Carolina, United States
Wake County Department of Health (30076)
Chapel Hill, North Carolina, United States
Duke University Medical Center Adult CRS (1601)
Durham, North Carolina, United States
University of Cincinnati CRS (2401)
Cincinnati, Ohio, United States
Case CRS (2501)
Cleveland, Ohio, United States
Metro Health CRS (2503)
Cleveland, Ohio, United States
The Ohio State Univ. AIDS CRS (2301)
Columbus, Ohio, United States
Presbyterian Medical Center - Univ. of PA (6206)
Norristown, Pennsylvania, United States
Hosp. of the Univ. of Pennsylvania CRS (6201)
Philadelphia, Pennsylvania, United States
Pitt CRS (1001)
Pittsburgh, Pennsylvania, United States
The Miriam Hosp. ACTG CRS (2951)
Providence, Rhode Island, United States
Vanderbilt Therapeutics CRS (3652)
Nashville, Tennessee, United States
Peabody Health Center CRS (31443)
Dallas, Texas, United States
University of Texas, Galveston (6301)
Galveston, Texas, United States
University of Washington AIDS CRS (1401)
Seattle, Washington, United States
University of Washington General Clinical Research (1403)
Seattle, Washington, United States
Puerto Rico-AIDS CRS (5401)
San Juan, , Puerto Rico
Countries
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References
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Kress KD. HIV update: emerging clinical evidence and a review of recommendations for the use of highly active antiretroviral therapy. Am J Health Syst Pharm. 2004 Oct 1;61 Suppl 3:S3-14; quiz S15-6. doi: 10.1093/ajhp/61.suppl_3.S3.
Robbins GK, De Gruttola V, Shafer RW, Smeaton LM, Snyder SW, Pettinelli C, Dube MP, Fischl MA, Pollard RB, Delapenha R, Gedeon L, van der Horst C, Murphy RL, Becker MI, D'Aquila RT, Vella S, Merigan TC, Hirsch MS; AIDS Clinical Trials Group 384 Team. Comparison of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003 Dec 11;349(24):2293-303. doi: 10.1056/NEJMoa030264.
Shafer RW, Smeaton LM, Robbins GK, De Gruttola V, Snyder SW, D'Aquila RT, Johnson VA, Morse GD, Nokta MA, Martinez AI, Gripshover BM, Kaul P, Haubrich R, Swingle M, McCarty SD, Vella S, Hirsch MS, Merigan TC; AIDS Clinical Trials Group 384 Team. Comparison of four-drug regimens and pairs of sequential three-drug regimens as initial therapy for HIV-1 infection. N Engl J Med. 2003 Dec 11;349(24):2304-15. doi: 10.1056/NEJMoa030265.
Li B, Veturi Y, Verma A, Bradford Y, Daar ES, Gulick RM, Riddler SA, Robbins GK, Lennox JL, Haas DW, Ritchie MD. Tissue specificity-aware TWAS (TSA-TWAS) framework identifies novel associations with metabolic, immunologic, and virologic traits in HIV-positive adults. PLoS Genet. 2021 Apr 26;17(4):e1009464. doi: 10.1371/journal.pgen.1009464. eCollection 2021 Apr.
Anderson PL. Pharmacologic perspectives for once-daily antiretroviral therapy. Ann Pharmacother. 2004 Nov;38(11):1924-34. doi: 10.1345/aph.1E036. Epub 2004 Oct 12.
Leonard MA, Cindi Z, Bradford Y, Bourgi K, Koethe J, Turner M, Norwood J, Woodward B, Erdem H, Basham R, Baker P, Rebeiro PF, Sterling TR, Hulgan T, Daar ES, Gulick R, Riddler SA, Sinxadi P, Ritchie MD, Haas DW. Efavirenz Pharmacogenetics and Weight Gain Following Switch to Integrase Inhibitor-Containing Regimens. Clin Infect Dis. 2021 Oct 5;73(7):e2153-e2163. doi: 10.1093/cid/ciaa1219.
Bednasz CJ, Venuto CS, Ma Q, Daar ES, Sax PE, Fischl MA, Collier AC, Smith KY, Tierney C, Acosta EP, Mager DE, Morse GD; AIDS Clinical Trials Group Study A5202 Team. Race/Ethnicity and Protease Inhibitor Use Influence Plasma Tenofovir Exposure in Adults Living with HIV-1 in AIDS Clinical Trials Group Study A5202. Antimicrob Agents Chemother. 2019 Mar 27;63(4):e01638-18. doi: 10.1128/AAC.01638-18. Print 2019 Apr.
Longenecker CT, Kitch D, Sax PE, Daar ES, Tierney C, Gupta SK, McComsey GA; AIDS Clinical Trials Group Study A5224s Team. Reductions in Plasma Cystatin C After Initiation of Antiretroviral Therapy Are Associated With Reductions in Inflammation: ACTG A5224s. J Acquir Immune Defic Syndr. 2015 Jun 1;69(2):168-77. doi: 10.1097/QAI.0000000000000557.
Mollan KR, Smurzynski M, Eron JJ, Daar ES, Campbell TB, Sax PE, Gulick RM, Na L, O'Keefe L, Robertson KR, Tierney C. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014 Jul 1;161(1):1-10. doi: 10.7326/M14-0293.
Sax PE, Zolopa A, Brar I, Elion R, Ortiz R, Post F, Wang H, Callebaut C, Martin H, Fordyce MW, McCallister S. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014 Sep 1;67(1):52-8. doi: 10.1097/QAI.0000000000000225.
Erlandson KM, Kitch D, Tierney C, Sax PE, Daar ES, Melbourne KM, Ha B, McComsey GA. Impact of randomized antiretroviral therapy initiation on glucose metabolism. AIDS. 2014 Jun 19;28(10):1451-61. doi: 10.1097/QAD.0000000000000266.
Erlandson KM, Kitch D, Tierney C, Sax PE, Daar ES, Tebas P, Melbourne K, Ha B, Jahed NC, McComsey GA. Weight and lean body mass change with antiretroviral initiation and impact on bone mineral density. AIDS. 2013 Aug 24;27(13):2069-79. doi: 10.1097/QAD.0b013e328361d25d.
Smith KY, Tierney C, Mollan K, Venuto CS, Budhathoki C, Ma Q, Morse GD, Sax P, Katzenstein D, Godfrey C, Fischl M, Daar ES, Collier AC; AIDS Clinical Trials Group 5202 Study Team. Outcomes by sex following treatment initiation with atazanavir plus ritonavir or efavirenz with abacavir/lamivudine or tenofovir/emtricitabine. Clin Infect Dis. 2014 Feb;58(4):555-63. doi: 10.1093/cid/cit747. Epub 2013 Nov 18.
McComsey GA, Daar ES, O'Riordan M, Collier AC, Kosmiski L, Santana JL, Fichtenbaum CJ, Fink H, Sax PE, Libutti DE, Gerschenson M. Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202. J Infect Dis. 2013 Feb 15;207(4):604-11. doi: 10.1093/infdis/jis720. Epub 2012 Nov 29.
Mollan K, Daar ES, Sax PE, Balamane M, Collier AC, Fischl MA, Lalama CM, Bosch RJ, Tierney C, Katzenstein D; AIDS Clinical Trials Group Study A5202 Team. HIV-1 amino acid changes among participants with virologic failure: associations with first-line efavirenz or atazanavir plus ritonavir and disease status. J Infect Dis. 2012 Dec 15;206(12):1920-30. doi: 10.1093/infdis/jis613. Epub 2012 Nov 12.
McComsey GA, Kitch D, Sax PE, Tebas P, Tierney C, Jahed NC, Myers L, Melbourne K, Ha B, Daar ES. Peripheral and central fat changes in subjects randomized to abacavir-lamivudine or tenofovir-emtricitabine with atazanavir-ritonavir or efavirenz: ACTG Study A5224s. Clin Infect Dis. 2011 Jul 15;53(2):185-96. doi: 10.1093/cid/cir324.
McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Tebas P, Myers L, Melbourne K, Ha B, Sax PE. Bone mineral density and fractures in antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. J Infect Dis. 2011 Jun 15;203(12):1791-801. doi: 10.1093/infdis/jir188.
Daar ES, Tierney C, Fischl MA, Sax PE, Mollan K, Budhathoki C, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Pappa KA, Woodward WC, Patterson K, Bolivar H, Benson CA, Collier AC; AIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011 Apr 5;154(7):445-56. doi: 10.7326/0003-4819-154-7-201104050-00316. Epub 2011 Feb 14.
Sax PE, Tierney C, Collier AC, Fischl MA, Mollan K, Peeples L, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Ha B, Woodward WC, Koletar SL, Johnson VA, Geiseler PJ, Daar ES; AIDS Clinical Trials Group Study A5202 Team. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med. 2009 Dec 3;361(23):2230-40. doi: 10.1056/NEJMoa0906768. Epub 2009 Dec 1.
Other Identifiers
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ACTG 5224s
Identifier Type: OTHER
Identifier Source: secondary_id
ACTG A5202
Identifier Type: -
Identifier Source: org_study_id
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