Comparing the Safety, Effectiveness, and Tolerability of Three Anti-HIV Drug Regimens for Treatment-Naive Patients

A Phase III, Randomized, Open-Label Comparison of Lopinavir/Ritonavir Plus Efavirenz Versus Lopinavir/Ritonavir Plus 2 NRTIs Versus Efavirenz Plus 2 NRTIs as Initial Therapy for HIV-1 Infection

With new strategies and drugs available, many different regimens exist for the treatment of HIV. The purpose of this study is to compare three different anti-HIV drug regimens as first-time treatments for HIV infection.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Lamivudine; Drug: Stavudine; Drug: Zidovudine; Drug: Efavirenz; Drug: Lopinavir/ritonavir; Drug: Tenofovir disoproxil fumarate

Detailed Description

Numerous treatment options are available to HIV infected patients who are antiretroviral (ARV) therapy naive, but an optimal regimen has not yet been established. This study will compare a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, a ritonavir (RTV)-enhanced protease inhibitor (PI)-based regimen, and a nucleoside reverse transcriptase inhibitor (NRTI)-sparing regimen for the initial treatment of HIV infection.

Patients will be randomly assigned to one of three study arms. In Arm A, patients will receive lopinavir/ritonavir (LPV/r) twice daily and efavirenz (EFV) once daily before bed. Arm B patients will receive LPV/r twice daily, lamivudine (3TC) once daily, plus either stavudine extended release (d4T XR) once daily, zidovudine (ZDV) twice daily, or tenofovir disoproxil fumarate (TDF) once daily. Patients in Arm C will receive EFV once daily before bed and 3TC plus either d4T XR once daily before bed, ZDV twice daily, or TDF once daily before bed.

Study visits will occur every 4 weeks until Week 24, then every 8 weeks thereafter for a maximum of 96 weeks. Blood will be drawn at every visit and a urine sample will be collected every 8 weeks. Body measurements will be taken at Weeks 24, 48, 72, and 96. Whole body dual-energy x-ray absorptiometry (DEXA) scans will be done at Weeks 48 and 96. Patients must fast before study visits at Weeks 12, 24, 48, 72, and 96. Women in the study will have gynecological assessments every 24 weeks.

• Study Type: Interventional
• Enrollment: 775
• Phase: Phase 3

Contacts and Locations

Study Locations

• South Africa
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa
      • Durban Adult HIV CRS
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35924
      • Alabama Therapeutics CRS
  • California
    • Los Angeles, California, United States, 90033-1079
      • USC CRS
    • Los Angeles, California, United States, 90095-1793
      • UCLA CARE Center CRS
    • Palo Alto, California, United States, 94305-5107
      • 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, 94305-5107
      • Santa Clara Valley Med. Ctr.
    • San Mateo, California, United States, 94305-5107
      • San Mateo County AIDS Program
    • Torrance, California, United States, 90502-2052
      • Harbor-UCLA Med. Ctr. CRS
  • Colorado
    • Aurora, Colorado, United States, 80262-3706
      • 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, 33136
      • 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, 60611-3015
      • Northwestern University CRS
    • Chicago, Illinois, United States, 60612
      • Cook County Hosp. CORE Ctr.
    • Chicago, Illinois, United States, 60612-3806
      • Rush Univ. Med. Ctr. ACTG CRS
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana Univ. School of Medicine, Wishard Memorial
    • Indianapolis, Indiana, United States, 46202-5250
      • Indiana Univ. School of Medicine, Infectious Disease Research Clinic
    • Indianapolis, Indiana, United States, 46202-1261
      • Methodist Hosp. of Indiana
  • Iowa
    • Iowa City, Iowa, United States, 52242-1201
      • Univ. of Iowa Healthcare, Div. of Infectious Diseases
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Adult AIDS CRS
    • Baltimore, Maryland, United States, 21201
      • IHV Baltimore Treatment 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, 02215
      • Brigham and Women's Hosp. ACTG CRS
    • Fall River, Massachusetts, United States
      • SSTAR, Family Healthcare Ctr.
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455-0392
      • University of Minnesota, ACTU
  • Missouri
    • Saint Louis, Missouri, United States, 63108-2138
      • Washington U CRS
    • Saint Louis, Missouri, United States, 63108-2138
      • St. Louis ConnectCare, Infectious Diseases Clinic
  • Nebraska
    • Omaha, Nebraska, United States, 68198-5130
      • 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
      • Weill Med. College of Cornell Univ., The Cornell CTU
    • New York, New York, United States, 10021
      • Cornell CRS
    • New York, New York, United States, 10016-6481
      • NY Univ. HIV/AIDS CRS
    • New York, New York, United States
      • HIV Prevention & Treatment CRS
    • New York, New York, United States, 10032-3784
      • Columbia Univ., HIV Prevention and Treatment Medical Ctr.
    • Rochester, New York, United States, 14642-0001
      • 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, 27514
      • Unc Aids Crs
    • Durham, North Carolina, United States, 27710
      • Duke Univ. Med. Ctr. Adult CRS
    • Raleigh, North Carolina, United States
      • Wake County Health and Human Services CRS
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0405
      • Univ. of Cincinnati CRS
    • Cleveland, Ohio, United States, 44106-5083
      • Case CRS
    • Cleveland, Ohio, United States, 44109-1998
      • MetroHealth CRS
    • Cleveland, Ohio, United States, 44109-5083
      • Cleveland Clinic Foundation, Div. of Medicine, Infectious Diseases
    • Columbus, Ohio, United States, 43210-1282
      • The Ohio State Univ. AIDS CRS
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Univ. of Pennsylvania Health System, Presbyterian Med. Ctr.
    • Philadelphia, Pennsylvania, United States, 19401
      • Hosp. of the Univ. of Pennsylvania CRS
    • Pittsburgh, Pennsylvania, United States, 15213-2582
      • Pitt CRS
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hosp. ACTG CRS
    • Providence, Rhode Island, United States, 02906
      • 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: 13 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria for Step 1:

• HIV infected
• HIV viral load of 2000 copies/ml or greater within 60 days prior to study entry
• Willing to use acceptable means of contraception
• d4T XR, TDF, or ZDV chosen as part of an initial regimen prior to randomization to a study arm
• Coenrolled in ACTG A5152s

Exclusion Criteria for Step 1:

• On ARV therapy for 7 days or more any time prior to study entry
• NNRTIs or 3TC at any time prior to study entry
• Current peripheral neuropathy of Grade 2 or higher
• Pregnancy or breastfeeding
• Immunomodulators, vaccines, or investigational therapies within 30 days of study entry. Patients taking a stable or tapering dose of prednisone at less than 10 mg are not excluded.
• Human growth hormone within 30 days prior to study entry
• Initiation of testosterone or anabolic steroids within 30 days prior to study entry
• Certain other medications within 30 days of study entry
• Hypersensitivity to components of the study drug formulations
• Drug or alcohol use or dependence that would interfere with adherence to study requirements
• Acute therapy for serious medical illnesses requiring systemic treatment and/or hospitalization within 14 days prior to study entry
• Recent infection with drug-resistant HIV

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time from study entry to virologic failure
time from study entry to regimen completion

Secondary Outcome Measures

Outcome Measure	Time Frame
20 % or more loss in peripheral fat
increase in lactic acid levels at least 2-4old above the upper limit of normal (ULN)
20 % or more increase in truncal fat accumulation
fasting cholesterol level equal to or greater than 240 mg/dl
Grade 3 or greater elevation in fasting triglyceride levels
change from baseline in insulin resistance	at Weeks 24, 48 and 96
change from baseline of whole-body bone density and whole-body bone mineral content	at Weeks 48 and 96
time to confirmed virologic failure while on Steps I (initial randomized regimen) or II (within class substitutes for initial regimen toxicity) OR treatment-limiting toxicity on Steps I or II
number of antiretroviral classes with resistance mutations at virologic failure
number of missed medication doses	4 days prior
change from baseline in self-reported symptoms OR occurrence of reporting an increase in symptoms	at Weeks 4, 48, 72 and 96
change from baseline in body image OR occurrence of reporting body image distress	at Weeks 24, 48, 72 and 96
time until treatment-limiting toxicity OR occurrence of Grades 3 or 4 toxicity

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: Richard Haubrich, MD, University of California, San Diego, Division of Infectious Diseases

Publications and helpful links

General Publications

• Bronke C, Almeida CM, McKinnon E, Roberts SG, Keane NM, Chopra A, Carlson JM, Heckerman D, Mallal S, John M. HIV escape mutations occur preferentially at HLA-binding sites of CD8 T-cell epitopes. AIDS. 2013 Mar 27;27(6):899-905. doi: 10.1097/QAD.0b013e32835e1616.
• 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.
• Saint-Marc T, Partisani M, Poizot-Martin I, Rouviere O, Bruno F, Avellaneda R, Lang JM, Gastaut JA, Touraine JL. Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS. 2000 Jan 7;14(1):37-49. doi: 10.1097/00002030-200001070-00005.
• DiRienzo AG, DeGruttola V. Design and analysis of clinical trials with a bivariate failure time endpoint, with application to AIDS Clinical Trials Group Study A5142. Control Clin Trials. 2003 Apr;24(2):122-34. doi: 10.1016/s0197-2456(02)00321-5.
• Von Burg R, Stout T. Paraldehyde. J Appl Toxicol. 1991 Oct;11(5):379-81. doi: 10.1002/jat.2550110515. No abstract available.
• Haubrich RH, Riddler SA, DiRienzo AG, Komarow L, Powderly WG, Klingman K, Garren KW, Butcher DL, Rooney JF, Haas DW, Mellors JW, Havlir DV; AIDS Clinical Trials Group (ACTG) A5142 Study Team. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS. 2009 Jun 1;23(9):1109-18. doi: 10.1097/QAD.0b013e32832b4377.
• Gazzard B, Balkin A, Hill A. Analysis of neuropsychiatric adverse events during clinical trials of efavirenz in antiretroviral-naive patients: a systematic review. AIDS Rev. 2010 Apr-Jun;12(2):67-75.
• Simpson KN, Dietz B, Baran RW, Garren KW, Riddler SA, Bhor M, Haubrich RH. Economic modeling of the combined effects of HIV-disease, cholesterol and lipoatrophy based on ACTG 5142 trial data. Cost Eff Resour Alloc. 2011 May 8;9:5. doi: 10.1186/1478-7547-9-5.
• Hulgan T, Haubrich R, Riddler SA, Tebas P, Ritchie MD, McComsey GA, Haas DW, Canter JA. European mitochondrial DNA haplogroups and metabolic changes during antiretroviral therapy in AIDS Clinical Trials Group Study A5142. AIDS. 2011 Jan 2;25(1):37-47. doi: 10.1097/QAD.0b013e32833f9d02.
• Riddler SA, Haubrich R, DiRienzo AG, Peeples L, Powderly WG, Klingman KL, Garren KW, George T, Rooney JF, Brizz B, Lalloo UG, Murphy RL, Swindells S, Havlir D, Mellors JW; AIDS Clinical Trials Group Study A5142 Team. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008 May 15;358(20):2095-106. doi: 10.1056/NEJMoa074609.

Study record dates

Study Major Dates

• Study Completion (Actual): March 1, 2006

Study Registration Dates

• First Submitted: December 30, 2002
• First Submitted That Met QC Criteria: December 31, 2002
• First Posted (Estimate): January 1, 2003

Study Record Updates

• Last Update Posted (Actual): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Drug Therapy, Combination; Reverse Transcriptase Inhibitors; HIV-1; HIV Protease Inhibitors; Treatment Naive; Delayed Action Preparations
• Additional Relevant MeSH Terms: Infections; 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 CYP3A 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; Tenofovir; Ritonavir; Lopinavir; Lamivudine; Zidovudine; Stavudine; Efavirenz
• Other Study ID Numbers: A5142; A5152s; 10085 (DAIDS ES); ACTG A5142; A5160s