Clinical trial NCT00118898: Efavirenz or Atazanavir/Ritonavir Given With Emtricitabine/Tenofovir Disoproxil Fumarate or Abacavir/Lamivudine in HIV Infected Treatment-Naive Adults
Official title: A Phase IIIB, Randomized Trial of Open-Label Efavirenz or Atazanavir With Ritonavir in Combination With Double-Blind Comparison of Emtricitabine/Tenofovir or Abacavir/Lamivudine in Antiretroviral-Naive Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Treatment Naive
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2005-07-12
Enrollment: 1864
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Currently, the preferred anti-HIV regimens used in the United States consist of two nucleoside reverse transcriptase inhibitors (NRTIs) and the nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz (EFV). However, with new anti-HIV drugs being approved, alternative regimens need to be tested to determine if new drug combinations have increased effectiveness in treating HIV. The purpose of this study is to test the safety, tolerability, and effectiveness of four different regimens in HIV-infected adults who have never taken anti-HIV drugs.

Detailed description: Antiretroviral (ARV) treatment regimens consisting of EFV and two NRTIs are the most commonly prescribed regimens for the initial therapy of HIV-infected people in the United States. Such regimens are popular because the drugs are easy to administer, have overall excellent efficacy, and are well tolerated. However, because of concerns about long-term drug toxicity, the development of drug resistance, and potential complications in pregnant women, it is imperative that other drug combinations be investigated as possible alternative initial regimens. Drugs recently approved by the Food and Drug Administration (FDA) for HIV treatment include the protease inhibitor (PI) atazanavir (ATV) and the two NRTI coformulations emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and abacavir/lamivudine (ABC/3TC). Data are limited on the efficacy of these new drugs when part of anti-HIV drug regimens. This study will evaluate and compare the safety, tolerability, and efficacy of four different treatment regimens in HIV-infected treatment-naive adults.

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).

Eligibility criteria: Inclusion Criteria:

* HIV-infected. A resistance assay must be obtained if the participant has evidence of recent infection. More information on this criterion can be found in the protocol.
* 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:

* Immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Individuals receiving either stable physiologic glucocorticoid doses, corticosteroids for acute therapy for pneumocystis pneumonia, or a short course (2 weeks or less) of pharmacologic glucocorticoid therapy will not be excluded.
* 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.

Primary outcomes:
measure: Time From Randomization to Virologic Failure
timeFrame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
measure: Time From Treatment Dispensation to a Grade 3/4 Safety Event
timeFrame: All follow-up while on initially assigned regimen; the median (25th, 75th percentile) follow-up while on initial regimen was 120 (54, 156) weeks and the range was 0 to 205 weeks.
measure: Time From Treatment Dispensation to Treatment Modification
timeFrame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
Secondary outcomes:
measure: Time From Treatment Dispensation to Regimen Failure (First Occurrence of Virologic Failure or Treatment Modification)
timeFrame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
measure: The Number of Participants With HIV-1 RNA Levels Less Than 50 Copies/mL
timeFrame: At Weeks 48 and 96
measure: Number of Participants With HIV-1 RNA Levels Less Than 200 Copies/mL
timeFrame: At Weeks 48 and 96
measure: Change in CD4 Count (Cells/mm3) From Baseline
timeFrame: At Weeks 48 and 96
measure: Number of Participants With Virologic Failure and Emergence of Major Resistance
timeFrame: Follow-up time was variable,median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
measure: Number of Participants Experiencing Certain Targeted Clinical Events, Including Death, AIDS-defining Illness, and HIV-1 Related Events.
timeFrame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
measure: Change in Fasting Total Cholesterol Level From Baseline
timeFrame: At Weeks 48 and 96
measure: Change in Fasting High-density Lipoprotein (HDL) Cholesterol Level From Baseline
timeFrame: At Weeks 48 and 96
measure: Change in Fasting Non-high Density Lipoprotein (Non-HDL) Cholesterol Level From Baseline
timeFrame: At Weeks 48 and 96
measure: Change in Fasting Triglyceride Level From Baseline
timeFrame: At Weeks 48 and 96
Other outcomes:
measure: Amount of Study Follow-up
timeFrame: Follow-up time was variable, median follow-up was 138 weeks
measure: Number of Participants With Virologic Failure
timeFrame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
measure: Cumulative Probability of Not Experiencing Virologic Failure
timeFrame: At week 48 and 96
measure: Number of Participants With a Grade 3/4 Safety Event
timeFrame: Over all study follow-up while on initially assigned treatment, median follow-up was 120 weeks
measure: Cumulative Probability of Not Experiencing a Grade 3/4 Safety Event
timeFrame: At week 48 and 96
measure: Number of Participants With Treatment Modification
timeFrame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
measure: Cumulative Probability of Not Experiencing Treatment Modification
timeFrame: At week 48 and 96
measure: Number of Participants With Regimen Failure
timeFrame: Follow-up time was variable, median follow-up was 138 weeks; see 'Amount of study follow-up' outcome for details
measure: Cumulative Probability of Not Experiencing Regimen Failure
timeFrame: At week 48 and 96
Locations:
city: Los Angeles
country: United States
facility: Usc Crs (1201)
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS (601)
state: California
city: Palo Alto
country: United States
facility: Stanford CRS (501)
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs (701)
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs (801)
state: California
city: Stanford
country: United States
facility: San Mateo County AIDS Program (505)
state: California
city: Stanford
country: United States
facility: Willow Clinic (507)
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS (603)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Washington
country: United States
facility: Georgetown University CRS (GU CRS) (1008)
state: District of Columbia
city: Miami
country: United States
facility: University of Miami AIDS CRS (901)
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Atlanta
country: United States
facility: The Ponce de Leon Center CRS (5802)
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Cook County Hospital Core Center (2705)
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS (2702)
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Hospital (2601)
state: Indiana
city: Indianapolis
country: United States
facility: Wishard Hospital (2603)
state: Indiana
city: Iowa City
country: United States
facility: Univ of Iowa Hosp and Clinic (1504)
state: Iowa
city: Baltimore
country: United States
facility: IHV Baltimore Treatment CRS (4651)
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS (201)
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS (101)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS (107)
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs (104)
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS (103)
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington U CRS (2101)
state: Missouri
city: Buffalo
country: United States
facility: SUNY - Buffalo (Rochester) (1102)
state: New York
city: New York
country: United States
facility: Cornell CRS (7804)
state: New York
city: New York
country: United States
facility: Weill Med. College of Cornell Univ., The Cornell CTU -Chelsea (7803)
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS (401)
state: New York
city: New York
country: United States
facility: HIV Prevention & Treatment CRS (30329)
state: New York
city: New York
country: United States
facility: Harlem ACTG CRS (31483)
state: New York
city: Rochester
country: United States
facility: AIDS Community Health Ctr. ACTG CRS (1108)
state: New York
city: Rochester
country: United States
facility: University of Rochester ACTG CRS (1101)
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs (3201)
state: North Carolina
city: Chapel Hill
country: United States
facility: Wake County Department of Health (30076)
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center Adult CRS (1601)
state: North Carolina
city: Greensboro
country: United States
facility: Moses H. Cone Memorial Hospital CRS (3203)
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS (2501)
state: Ohio
city: Cleveland
country: United States
facility: Metro Health CRS (2503)
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS (2301)
state: Ohio
city: Norristown
country: United States
facility: Presbyterian Medical Center - Univ. of PA (6206)
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS (6201)
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Pitt CRS (1001)
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hosp. ACTG CRS (2951)
state: Rhode Island
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS (3652)
state: Tennessee
city: Dallas
country: United States
facility: Peabody Health Center CRS (31443)
state: Texas
city: Galveston
country: United States
facility: University of Texas, Galveston (6301)
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
city: Seattle
country: United States
facility: University of Washington General Clinical Research (1403)
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS (5401)
Study officials:
affiliation: Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute
name: Eric Daar, MD
role: STUDY_CHAIR
affiliation: Division of Infectious Diseases, Brigham and Women's Hospital
name: Paul Sax, MD
role: STUDY_CHAIR
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citation: 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.
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.