Comparison of Three Different Initial Treatments Without Protease Inhibitors for HIV Infection

Phase III, Randomized, Double-Blind Comparison of Three Protease Inhibitor-Sparing Regimens for the Initial Treatment of HIV Infection

The purpose of this study is to compare the effectiveness, safety, and tolerability of 3 anti-HIV combination treatments that do not use protease inhibitors (PIs).

The current rule for starting treatment of HIV infection is to combine members from different classes of anti-HIV drugs, such as 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either a PI or a nonnucleoside reverse transcriptase inhibitor (NNRTI). However, these combinations can be complicated and difficult to take, can cause a number of side effects, and may become ineffective. Combinations that are simpler, better tolerated, and more effective are needed. Because PIs can cause long-term side effects and because HIV can become resistant to many of them at the same time, anti-HIV combination treatments that do not use PIs are being tested.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Nevirapine; Drug: Lamivudine; Drug: Stavudine; Drug: Zidovudine; Drug: Didanosine; Drug: Abacavir sulfate; Drug: Efavirenz; Drug: Atazanavir; Drug: Lamivudine/Zidovudine; Drug: Abacavir sulfate, Lamivudine and Zidovudine

Detailed Description

Current treatment guidelines recommend combination regimens of 2 nucleoside analogues with either a PI or an NNRTI for the initial treatment of HIV infection. However, the efficacy of current regimens is limited by their complexity, pharmacokinetic characteristics, short- and long-term side effects, and drug-resistance profiles at the time of virologic failure. Consequently, the identification of new initial regimens that are simpler, better tolerated, preserve treatment options in the event of failure, and improve antiretroviral potency is needed. In addition, recent concern over the long-term toxicities of PIs and the extensive cross-resistance among the available PIs have led to the testing of PI-sparing regimens.

Participants will be in this study for a minimum of 120 weeks and a maximum of approximately 4 years. In Step 1, patients are randomly selected to receive 1 of 3 blinded treatment regimens: abacavir (ABC)/lamivudine (3TC)/zidovudine (ZDV)/efavirenz (EFV), ABC/3TC/ZDV, or 3TC/ZDV/EFV. Patients with confirmed virologic failure on Step 1 and two successive plasma HIV RNA levels of 10,000 copies/ml or greater must register to Step 2. Patients with confirmed virologic failure on Step 1 and whose plasma HIV RNA is under 10,000 copies/ml may remain on Step 1 or register to Step 2. [AS PER AMENDMENT 04/11/03: Discontinuation of Arm B was recommended. Consequently, Arms A and C were unblinded to EFV but not to ABC. A number of options are available for patients originally randomized to Arm B.]

Step 2 is open label. Regimens include 2 or 3 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with EFV, atazanavir (ATZ), ritonavir-boosted ATZ, or tenofovir disoproxil fumarate (TDF). Patients on Arm B treatment who have an HIV RNA level less than 200 copies/ml within the past 8 weeks are eligible for randomization to open-label intensification of Arm B on Step 3.

Step 3 regimens include ABC/3TC/ZDV plus either EFV or TDF. Patients with evidence of treatment-limiting toxicity to Step 3 study drugs have the option of substituting d4T for ZDV, ddI for ABC or TDF, and/or NVP for EFV. Patients with confirmed virologic failure on Step 3 and whose plasma HIV RNA is less than 10,000 copies/ml may either remain on Step 3 or register to Step 4. Patients with two successive plasma HIV RNA levels of 10,000 copies/ml or greater on Step 3 must register to Step 4.

Step 4 is open label. Regimens include two or three NRTIs plus EFV, ATV, ritonavir-boosted ATV, or TDF. Clinical assessments and laboratory evaluations are done at entry, at Weeks 2, 4, 6, 8, 12, 16, 20, 24, and then every 8 weeks thereafter for the duration of the study. Evaluations are also required when a protocol-allowed drug substitution is made.

In addition, 3 substudies are being conducted: a neurology substudy for efavirenz, a pharmacology substudy for atazanavir, and a viral dynamics substudy.

• Study Type: Interventional
• Enrollment: 1125
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 009365067
    • Puerto Rico-AIDS CRS
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Alabama Therapeutics CRS
  • California
    • Los Angeles, California, United States, 90095
      • UCLA CARE Center CRS
    • Los Angeles, California, United States, 900331079
      • USC CRS
    • Palo Alto, California, United States
      • Stanford CRS
    • Sacramento, California, United States, 95814
      • UC Davis Medical Center
    • Sacramento, California, United States
      • Univ. of California Davis Med. Ctr., ACTU
    • San Diego, California, United States, 92103
      • Ucsd, Avrc Crs
    • San Francisco, California, United States, 94110
      • Ucsf Aids Crs
    • San Jose, California, United States
      • Santa Clara Valley Med. Ctr.
    • San Mateo, California, United States, 943055107
      • San Mateo County AIDS Program
    • San Mateo, California, United States
      • Willow Clinic A0507 CRS
    • Torrance, California, United States, 90502
      • Harbor-UCLA Med. Ctr. CRS
  • Colorado
    • Aurora, Colorado, United States, 80262
      • University of Colorado Hospital CRS
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University CRS (GU CRS)
  • Florida
    • Miami, Florida, United States, 331361013
      • Univ. of Miami AIDS CRS
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • The Ponce de Leon Ctr. CRS
  • Hawaii
    • Honolulu, Hawaii, United States, 96816
      • Univ. of Hawaii at Manoa, Leahi Hosp.
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University CRS
    • Chicago, Illinois, United States, 60612
      • Rush Univ. Med. Ctr. ACTG CRS
    • Chicago, Illinois, United States
      • Cook County Hosp. CORE Ctr.
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Methodist Hosp. of Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana Univ. School of Medicine, Wishard Memorial
    • Indianapolis, Indiana, United States, 462025250
      • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Univ. of Iowa Healthcare, Div. of Infectious Diseases
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Adult AIDS CRS
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital ACTG CRS
    • Boston, Massachusetts, United States, 02118
      • Bmc Actg Crs
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Med. Ctr., ACTG CRS
    • Boston, Massachusetts, United States
      • Brigham and Women's Hosp. ACTG CRS
    • Fall River, Massachusetts, United States
      • SSTAR, Family Healthcare Ctr.
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota, ACTU
  • Missouri
    • St. Louis, Missouri, United States
      • St. Louis ConnectCare, Infectious Diseases Clinic
    • St. Louis, Missouri, United States
      • Washington U CRS
  • Nebraska
    • Omaha, Nebraska, United States, 681985130
      • Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
  • New York
    • Buffalo, New York, United States, 14215
      • SUNY - Buffalo, Erie County Medical Ctr.
    • New York, New York, United States, 10003
      • Beth Israel Med. Ctr., ACTU
    • New York, New York, United States, 10016
      • NY Univ. HIV/AIDS CRS
    • New York, New York, United States, 10021
      • Cornell CRS
    • New York, New York, United States
      • HIV Prevention & Treatment CRS
    • New York, New York, United States, 10011
      • Weill Med. College of Cornell Univ., The Cornell CTU
    • New York, New York, United States, 10032
      • Columbia Univ., HIV Prevention and Treatment Medical Ctr.
    • Rochester, New York, United States, 14642
      • Univ. of Rochester ACTG CRS
    • Rochester, New York, United States
      • AIDS Care CRS
    • Rochester, New York, United States
      • McCree McCuller Wellness Ctr. at the Connection, Infectious Disease Unit
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275997215
      • Unc Aids Crs
    • Durham, North Carolina, United States, 27710
      • Duke Univ. Med. Ctr. Adult CRS
    • Greensboro, North Carolina, United States, 27401
      • Regional Center for Infectious Disease, Wendover Medical Center CRS
  • Ohio
    • Cincinnati, Ohio, United States, 452670405
      • Univ. of Cincinnati CRS
    • Cleveland, Ohio, United States, 44106
      • Case CRS
    • Cleveland, Ohio, United States, 441091998
      • MetroHealth CRS
    • Columbus, Ohio, United States, 432101228
      • The Ohio State Univ. AIDS CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States
      • Hosp. of the Univ. of Pennsylvania CRS
    • Philadelphia, Pennsylvania, United States, 19104
      • Philadelphia Veterans Admin. Med. Ctr. A6205 CRS
    • Philadelphia, Pennsylvania, United States, 19104
      • Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.
    • Pittsburgh, Pennsylvania, United States, 15213
      • Pitt CRS
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hosp. ACTG CRS
    • Providence, Rhode Island, United States
      • Rhode Island Hosp.
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt Therapeutics CRS
  • Washington
    • Seattle, Washington, United States, 98104
      • University of Washington AIDS CRS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Patients may be eligible for this study if they:

• Are HIV-positive.
• Have a viral load of at least 400 copies/ml within 90 days prior to study entry.
• Are at least 16 years old.
• Weigh at least 40 kg.
• Have a negative pregnancy test within 48 hours before starting study drugs, if female and able to have children.
• Agree to use 2 effective methods of birth control while taking, and for 3 months after stopping, the study medications.
• Provide written consent of a parent or guardian, if under 18 years of age.

Exclusion Criteria

Patients will not be eligible for this study if they:

• Have taken anti-HIV drugs in the past.
• Are allergic to any of the study drugs or ingredients.
• Are pregnant or breast-feeding.
• Have taken any of the following drugs within 14 days prior to study entry: amiodarone, astemizole, bepridil, cisapride, ergot or ergot derivatives, systemic itraconazole, systemic ketoconazole, midazolam, propoxyphene, quinidine, rifampin, terfenadine, thalidomide, triazolam, or St. John's wort.
• Have taken drugs that influence the immune system, HIV or other vaccines, or investigational drugs within 30 days prior to study entry. Prednisone at a dose of 10 mg or less daily is allowed.
• Have taken drugs or been hospitalized for serious infections or medical illnesses within 14 days prior to study entry.
• Have growths or tumors that require drug therapy.
• Have Pneumocystis carinii pneumonia that is not clinically stable and whose treatment is not completed at least 7 days prior to study entry.
• Have infections or medical illnesses that are not under control or that have not received complete treatment before study entry.
• Have any condition that, in the opinion of the investigator, would prevent them from properly participating in the study.
• Abuse drugs or alcohol.
• This study has been updated to exclude patients who are receiving systemic itraconazole and rifabutin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Roy Gulick, MD; Study Chair: Cecilia Shikuma, MD

Publications and helpful links

General Publications

• H Ribaudo, D Clifford, R Gulick, C Shikuma, K Klingman, S Snyder, and E Acosta. Relationships between Efavirenz Pharmacokinetics, Side Effects, Drug Discontinuation, Virologic Response, and Race: Results from ACTG A5095/A5097s. CROI 2004. Abstract 132.
• Feinberg J. Meeting notes from the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Trizivir vs. efavirenz: results from ACTG 5095. AIDS Clin Care. 2003 Sep;15(9):78-9.
• Gulick RM, Ribaudo HJ, Shikuma CM, Lustgarten S, Squires KE, Meyer WA 3rd, Acosta EP, Schackman BR, Pilcher CD, Murphy RL, Maher WE, Witt MD, Reichman RC, Snyder S, Klingman KL, Kuritzkes DR; AIDS Clinical Trials Group Study A5095 Team. Triple-nucleoside regimens versus efavirenz-containing regimens for the initial treatment of HIV-1 infection. N Engl J Med. 2004 Apr 29;350(18):1850-61. doi: 10.1056/NEJMoa031772.
• Clifford DB, Evans S, Yang Y, Acosta EP, Goodkin K, Tashima K, Simpson D, Dorfman D, Ribaudo H, Gulick RM. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med. 2005 Nov 15;143(10):714-21. doi: 10.7326/0003-4819-143-10-200511150-00008.
• Gulick RM, Ribaudo HJ, Shikuma CM, Lalama C, Schackman BR, Meyer WA 3rd, Acosta EP, Schouten J, Squires KE, Pilcher CD, Murphy RL, Koletar SL, Carlson M, Reichman RC, Bastow B, Klingman KL, Kuritzkes DR; AIDS Clinical Trials Group (ACTG) A5095 Study Team. Three- vs four-drug antiretroviral regimens for the initial treatment of HIV-1 infection: a randomized controlled trial. JAMA. 2006 Aug 16;296(7):769-81. doi: 10.1001/jama.296.7.769.
• Ribaudo HJ, Kuritzkes DR, Schackman BR, Acosta EP, Shikuma CM, Gulick RM. Design issues in initial HIV-treatment trials: focus on ACTG A5095. Antivir Ther. 2006;11(6):751-60.
• Kuritzkes DR, Ribaudo HJ, Squires KE, Koletar SL, Santana J, Riddler SA, Reichman R, Shikuma C, Meyer WA 3rd, Klingman KL, Gulick RM; ACTG A5166s Protocol Team. Plasma HIV-1 RNA dynamics in antiretroviral-naive subjects receiving either triple-nucleoside or efavirenz-containing regimens: ACTG A5166s. J Infect Dis. 2007 Apr 15;195(8):1169-76. doi: 10.1086/512619. Epub 2007 Mar 6.
• Schackman BR, Ribaudo HJ, Krambrink A, Hughes V, Kuritzkes DR, Gulick RM. Racial differences in virologic failure associated with adherence and quality of life on efavirenz-containing regimens for initial HIV therapy: results of ACTG A5095. J Acquir Immune Defic Syndr. 2007 Dec 15;46(5):547-54. doi: 10.1097/qai.0b013e31815ac499.
• Paredes R, Lalama CM, Ribaudo HJ, Schackman BR, Shikuma C, Giguel F, Meyer WA 3rd, Johnson VA, Fiscus SA, D'Aquila RT, Gulick RM, Kuritzkes DR; AIDS Clinical Trials Group (ACTG) A5095 Study Team. Pre-existing minority drug-resistant HIV-1 variants, adherence, and risk of antiretroviral treatment failure. J Infect Dis. 2010 Mar;201(5):662-71. doi: 10.1086/650543.
• 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.
• 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.
• 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. Erratum In: Ann Intern Med. 2014 Aug 19;161(4):308.
• Lok JJ, Hunt PW, Collier AC, Benson CA, Witt MD, Luque AE, Deeks SG, Bosch RJ. The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy. AIDS. 2013 Aug 24;27(13):2101-10. doi: 10.1097/QAD.0b013e32836191b1.
• Schouten JT, Krambrink A, Ribaudo HJ, Kmack A, Webb N, Shikuma C, Kuritzkes DR, Gulick RM. Substitution of nevirapine because of efavirenz toxicity in AIDS clinical trials group A5095. Clin Infect Dis. 2010 Mar 1;50(5):787-91. doi: 10.1086/650539.

Study record dates

Study Major Dates

• Study Completion (Actual): June 1, 2005

Study Registration Dates

• First Submitted: March 16, 2001
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Estimate): May 21, 2012
• Last Update Submitted That Met QC Criteria: May 17, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Nevirapine; Reverse Transcriptase Inhibitors; Anti-HIV Agents; HIV-1; Stavudine; Lamivudine; RNA, Viral; Viral Load; Efavirenz; Didanosine; Zidovudine; Treatment Naive; Combivir; BMS 232632
• Additional Relevant MeSH Terms: Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Disease Attributes; Slow Virus Diseases; HIV Infections; Infections; Communicable Diseases; Acquired Immunodeficiency Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Protease Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; HIV Protease Inhibitors; Viral Protease Inhibitors; Cytochrome P-450 CYP2B6 Inducers; Cytochrome P-450 CYP2C9 Inhibitors; Cytochrome P-450 CYP2C19 Inhibitors; Nevirapine; Lamivudine; Zidovudine; Stavudine; Didanosine; Atazanavir Sulfate; Efavirenz; Abacavir; Dideoxynucleosides; Lamivudine, zidovudine drug combination
• Other Study ID Numbers: A5095; 10212 (Other Identifier: CTEP); ACTG A5095; AACTG A5095; Substudy ACTG A5097s; Substudy AACTG 5107s; Substudy AACTG 5166s; Substudy ACTG A5166s; Substudy AACTG 5097s; Substudy ACTG A5107s; 5K24AI051966-03 (U.S. NIH Grant/Contract)