Comparative Study of Three NNRTI-Sparing HAART Regimens

NCT00811954 | Completed Phase 3 Results DMC

• 2 other identifiers: ACTG A52571U01AI068636
• Study Type: interventional
• Target: 1,814
• Locations: 2 countries
• Sites: 57

Brief Summary

The U.S. Department of Health and Human Services (HHS) guidelines recommend that HIV infected patients who have never received anti-HIV therapy be treated with a triple drug regimen. The most commonly prescribed and successful regimen contains the medication efavirenz (EFV). However, this regimen may not be an option for everyone, hence alternative regimens are needed. This study was designed to look at how well different combinations of anti-HIV drugs work to decrease the amount of HIV in the blood (viral load) of and allow immune system recovery in people who have never received anti-HIV therapy. This study also examined drug tolerability and safety for the various drug combinations.

Conditions

HIV Infection

Keywords

Treatment naive; Treatment inexperienced

Outcome Measures

Primary Outcomes (2)

• Cumulative Probability of First Virologic Failure by Week 96

  The Kaplan-Meier estimate of the cumulative probability of virologic failure by week 96. Time to virologic failure was defined as the first time from study entry to the first of two consecutive HIV-1 RNA \>1000 copies/mL at or after week 16 and before week 24, or \>200 copies/mL at or after week 24. Week 16 is defined to occur between 14 (98 days) and 18 weeks (126 days) after study entry, week 24 is defined to occur between 22 (154 days) and 26 (182 days) after study entry, and week 96 is defined to occur between 88 (616 days) and 104 (728 days) after study entry.

  From study entry to week 96

• Cumulative Incidence of Discontinuation of the RAL or PI Component of Randomized Treatment for Toxicity by Week 96

  The cumulative incidence of discontinuation for toxicity by week 96 was estimated using competing risks with treatment discontinuation for other reasons considered as a competing event; participants completing the study on the RAL or PI component of their randomized regimen were considered censored at the earliest of the date of last patient contact and off study date.

  From study entry to week 96

Secondary Outcomes (17)

• Cumulative Incidence of First Adverse Event by Week 96

  From study entry to week 96

• Cumulative Probability of Time to Loss of Virologic Response (TLOVR) by Week 96

  From study entry to week 96

• Presence of Mutations Associated With NRTI Resistance

  At the virologic failure at any time throughout the study (up to 213 weeks)

• Presence of Mutations Associated With ATV/RTV or DRV/RTV Resistance

  At the virologic failure at any time throughout the study (up to 213 weeks)

• Presence of Mutations Associated With INI Resistance

  At the virologic failure at any time throughout the study (up to 213 weeks)

Study Arms (3)

Arm A: ATV/RTV + FTC/TDF

EXPERIMENTAL

Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), ritonavir (RTV), and atazanavir (ATV) to be taken orally, once daily.

Drug: Emtricitabine/tenofovir disoproxil fumarate; Drug: Ritonavir; Drug: Atazanavir

Arm B: RAL + FTC/TDF

EXPERIMENTAL

FTC/TDF orally, once daily, and raltegravir (RAL) orally, twice daily.

Drug: Emtricitabine/tenofovir disoproxil fumarate; Drug: Raltegravir

Arm C: DRV/RTV + FTC/TDF

EXPERIMENTAL

FTC/TDF, darunavir (DRV), and RTV, orally, once daily.

Drug: Emtricitabine/tenofovir disoproxil fumarate; Drug: Darunavir; Drug: Ritonavir

Interventions

Emtricitabine/tenofovir disoproxil fumarate DRUG

200 mg emtricitabine/300 mg tenofovir disoproxil fumarate taken orally daily. A combination drug of two nucleoside reverse transcriptase inhibitors (NRTIs).

Also known as: TDF/FTC

Arm A: ATV/RTV + FTC/TDF; Arm B: RAL + FTC/TDF; Arm C: DRV/RTV + FTC/TDF

Raltegravir DRUG

400 mg taken orally twice daily. An integrase inhibitor (INI).

Also known as: RAL

Arm B: RAL + FTC/TDF

Darunavir DRUG

800 mg taken orally once daily. A protease inhibitor (PI).

Also known as: DRV

Arm C: DRV/RTV + FTC/TDF

Ritonavir DRUG

100 mg taken orally once daily. A protease inhibitor (PI).

Also known as: RTV

Arm A: ATV/RTV + FTC/TDF; Arm C: DRV/RTV + FTC/TDF

Atazanavir DRUG

300 mg taken orally once daily. A protease inhibitor (PI).

Also known as: ATV

Arm A: ATV/RTV + FTC/TDF

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infected
• No prior anti-HIV therapy. More information on this criterion can be found in the study protocol.
• Viral load is 1000 copies/mL or higher, as measured within 90 days prior to study entry
• Certain laboratory values obtained within 60 days prior to study entry
• Ability to obtain RTV by prescription
• Completed cardiovascular risk assessment. More information on this criterion can be found in the study protocol.
• Must agree to use acceptable forms of contraception while receiving study drugs and for 6 weeks after stopping the medications. More information on this criterion is available in the protocol.
• Negative pregnancy test within 72 hours before initiating antiretroviral medication
• Participating in research at any AIDS Clinical Trial Group (ACTG) clinical research site or select International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group sites
• Ability and willingness of subject or legal guardian/representative to give written informed consent

You may not qualify if:

• Use of immunomodulators, HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry. Those using stable physiologic glucocorticoid doses, a short course of pharmacologic glucocorticoid, corticosteroids for acute therapy treating an opportunistic infection, inhaled or topical corticosteroids, or granulocyte-colony stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) will not be excluded.
• Known allergy or sensitivity to study drugs or their ingredients. A history of sulfa allergy is not excluded.
• Any condition that, in the opinion of the investigator, would compromise the participant's ability to participate in the study
• Serious illness requiring systemic treatment and/or hospitalization until participant either completes therapy or is clinically stable on therapy, in the opinion of the investigator, for at least 7 days prior to study entry
• Requirement for any current medications that are prohibited with any study drugs
• Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical illness
• Any prior use of entecavir for treatment of hepatitis B for greater than 8 weeks while the participant was known to be HIV infected
• Presence of decompensated cirrhosis
• Pregnant or breastfeeding

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Bristol-Myers Squibb: collaborator
• Gilead Sciences: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Tibotec Therapeutics, a Division of Ortho Biotech Products, L.P., USA: collaborator

Study Sites (57)

Alabama Therapeutics CRS

Birmingham, Alabama, 35294-2050, United States

Location

Miller Children's Hospital

Long Beach, California, 90806, United States

Location

USC CRS

Los Angeles, California, 90033, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90035, United States

Location

Stanford CRS

Palo Alto, California, 94304, United States

Location

Ucsd, Avrc Crs

San Diego, California, 92103, United States

Location

Ucsf Aids Crs

San Francisco, California, 94110, United States

Location

Harbor-UCLA Med. Ctr. CRS

Torrance, California, 90502, United States

Location

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Denver Public Health CRS

Denver, Colorado, 80204, United States

Location

Georgetown University CRS (GU CRS)

Washington D.C., District of Columbia, 20007, United States

Location

Howard Univ. Washington DC NICHD CRS

Washington D.C., District of Columbia, 20060, United States

Location

South Florida Childrens Diagnostic & Treatment Cen (5055)

Fort Lauderdale, Florida, 33316, United States

Location

University of Florida Jacksonville (5051)

Jacksonville, Florida, 32209, United States

Location

Univ. of Miami AIDS CRS

Miami, Florida, 33136, United States

Location

The Ponce de Leon Center CRS

Atlanta, Georgia, 30308, United States

Location

Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Rush Univ. Med. Ctr. ACTG CRS

Chicago, Illinois, 60612, United States

Location

Tulane University New Orleans NICHD CRS (5095)

New Orleans, Louisiana, 70112, United States

Location

IHV Baltimore Treatment CRS

Baltimore, Maryland, 21201, United States

Location

Johns Hopkins Adult AIDS CRS

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital CRS

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hosp. ACTG CRS

Boston, Massachusetts, 02115, United States

Location

Bmc Actg Crs

Boston, Massachusetts, 02118, United States

Location

Beth Israel Deaconess Med. Ctr., ACTG CRS

Boston, Massachusetts, 02215, United States

Location

Wayne State Univ. CRS

Detroit, Michigan, 48201, United States

Location

Henry Ford Hosp. CRS

Detroit, Michigan, 48202, United States

Location

Washington U CRS

St Louis, Missouri, 63110, United States

Location

Cooper Univ. Hosp. CRS

Camden, New Jersey, 08103, United States

Location

New Jersey Medical School- Adult Clinical Research Ctr. CRS

Newark, New Jersey, 07103, United States

Location

Cornell CRS

New York, New York, 10011, United States

Location

NY Univ. HIV/AIDS CRS

New York, New York, 10016, United States

Location

Metropolitan Hospital

New York, New York, 10029, United States

Location

HIV Prevention & Treatment CRS

New York, New York, 10032, United States

Location

AIDS Care CRS

Rochester, New York, 14607, United States

Location

Univ. of Rochester ACTG CRS

Rochester, New York, 14642, United States

Location

SUNY Stony Brook NICHD CRS (5040)

Stony Brook, New York, 11794, United States

Location

Bronx-Lebanon Hosp. Ctr. CRS

The Bronx, New York, 10457, United States

Location

Unc Aids Crs

Chapel Hill, North Carolina, 27514, United States

Location

Duke Univ. Med. Ctr. Adult CRS

Durham, North Carolina, 27710, United States

Location

Regional Center for Infectious Disease, Wendover Medical Center CRS (3203)

Greensboro, North Carolina, 27401, United States

Location

Univ. of Cincinnati CRS

Cincinnati, Ohio, 45267, United States

Location

Case CRS

Cleveland, Ohio, 44106, United States

Location

Metro Health CRS

Cleveland, Ohio, 44109, United States

Location

The Ohio State Univ. AIDS CRS

Columbus, Ohio, 43210, United States

Location

The Research & Education Group- Portland CRS (31474)

Portland, Oregon, 97209, United States

Location

Hosp. of the Univ. of Pennsylvania CRS

Philadelphia, Pennsylvania, 19104, United States

Location

Pitt CRS

Pittsburgh, Pennsylvania, 15213, United States

Location

The Miriam Hosp. ACTG CRS

Providence, Rhode Island, 02906, United States

Location

St. Jude/UTHSC CRS

Memphis, Tennessee, 38105-2794, United States

Location

Vanderbilt Therapeutics CRS

Nashville, Tennessee, 37203, United States

Location

Trinity Health and Wellness Center

Dallas, Texas, 75208, United States

Location

Houston AIDS Research Team CRS

Houston, Texas, 77030, United States

Location

Virginia Commonwealth Univ. Medical Ctr. CRS

Richmond, Virginia, 23219, United States

Location

University of Washington AIDS CRS

Seattle, Washington, 98104, United States

Location

San Juan City Hosp. PR NICHD CRS

Rio Piedras, 00927, Puerto Rico

Location

Puerto Rico-AIDS CRS

San Juan, 00935, Puerto Rico

Location

Related Publications (11)

• Bartlett JA, Chen SS, Quinn JB. Comparative efficacy of nucleoside/nucleotide reverse transcriptase inhibitors in combination with efavirenz: results of a systematic overview. HIV Clin Trials. 2007 Jul-Aug;8(4):221-6. doi: 10.1310/hct0804-221.

  PMID: 17720662 BACKGROUND

• Duvivier C, Ghosn J, Assoumou L, Soulie C, Peytavin G, Calvez V, Genin MA, Molina JM, Bouchaud O, Katlama C, Costagliola D; ANRS 121 study group. Initial therapy with nucleoside reverse transcriptase inhibitor-containing regimens is more effective than with regimens that spare them with no difference in short-term fat distribution: Hippocampe-ANRS 121 Trial. J Antimicrob Chemother. 2008 Oct;62(4):797-808. doi: 10.1093/jac/dkn278. Epub 2008 Jul 18.

  PMID: 18641035 BACKGROUND

• Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Gilde LR, Wan H, Miller MD, Wenning LA, Teppler H; Protocol 004 Part II Study Team. Rapid and durable antiretroviral effect of the HIV-1 Integrase inhibitor raltegravir as part of combination therapy in treatment-naive patients with HIV-1 infection: results of a 48-week controlled study. J Acquir Immune Defic Syndr. 2007 Oct 1;46(2):125-33. doi: 10.1097/QAI.0b013e318157131c.

  PMID: 17721395 BACKGROUND

• Molina JM, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, David N, Moyle G, Mancini M, Percival L, Yang R, Thiry A, McGrath D; CASTLE Study Team. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008 Aug 23;372(9639):646-55. doi: 10.1016/S0140-6736(08)61081-8.

  PMID: 18722869 BACKGROUND

• Hughey CM, Vuong BW, Ribaudo HB, Mitchell CCK, Korcarz CE, Hodis HN, Currier JS, Stein JH. Grayscale Ultrasound Texture Features of Carotid and Brachial Arteries in People With HIV Infection Before and After Antiretroviral Therapy. J Am Heart Assoc. 2022 Mar;11(5):e024142. doi: 10.1161/JAHA.121.024142. Epub 2022 Feb 18.

  PMID: 35179037 DERIVED

• 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.

  PMID: 33901188 DERIVED

• Bares SH, Smeaton LM, Scott SE, Smith BA, Godfrey C, McComsey GA. The Association Between Weight Gain, Sex, and Immune Activation Following the Initiation of Antiretroviral Therapy. J Infect Dis. 2021 Nov 22;224(10):1765-1774. doi: 10.1093/infdis/jiab210.

  PMID: 33870433 DERIVED

• McComsey GA, Moser C, Currier J, Ribaudo HJ, Paczuski P, Dube MP, Kelesidis T, Rothenberg J, Stein JH, Brown TT. Body Composition Changes After Initiation of Raltegravir or Protease Inhibitors: ACTG A5260s. Clin Infect Dis. 2016 Apr 1;62(7):853-62. doi: 10.1093/cid/ciw017. Epub 2016 Jan 20.

  PMID: 26797215 DERIVED

• Kelesidis T, Tran TT, Stein JH, Brown TT, Moser C, Ribaudo HJ, Dube MP, Murphy R, Yang OO, Currier JS, McComsey GA. Changes in Inflammation and Immune Activation With Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy: ACTG 5260s. Clin Infect Dis. 2015 Aug 15;61(4):651-60. doi: 10.1093/cid/civ327. Epub 2015 Apr 22.

  PMID: 25904376 DERIVED

• Ofotokun I, Na LH, Landovitz RJ, Ribaudo HJ, McComsey GA, Godfrey C, Aweeka F, Cohn SE, Sagar M, Kuritzkes DR, Brown TT, Patterson KB, Para MF, Leavitt RY, Villasis-Keever A, Baugh BP, Lennox JL, Currier JS; AIDS Clinical Trials Group (ACTG) A5257 Team. Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis. 2015 Jun 15;60(12):1842-51. doi: 10.1093/cid/civ193. Epub 2015 Mar 12.

  PMID: 25767256 DERIVED

• Lennox JL, Landovitz RJ, Ribaudo HJ, Ofotokun I, Na LH, Godfrey C, Kuritzkes DR, Sagar M, Brown TT, Cohn SE, McComsey GA, Aweeka F, Fichtenbaum CJ, Presti RM, Koletar SL, Haas DW, Patterson KB, Benson CA, Baugh BP, Leavitt RY, Rooney JF, Seekins D, Currier JS; ACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014 Oct 7;161(7):461-71. doi: 10.7326/M14-1084.

  PMID: 25285539 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Raltegravir Potassium; Darunavir; Ritonavir; Atazanavir Sulfate

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Tenofovir; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Emtricitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Drug Combinations; Pharmaceutical Preparations; Pyrrolidinones; Pyrrolidines; Sulfonamides; Amides; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Sulfur Compounds; Furans; Thiazoles; Azoles; Pyridines; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social & Scientific Systems, Inc.

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Jeffrey L. Lennox, MD

  Emory HIV/AIDS CTU

  STUDY CHAIR

• Judith Silverstein Currier, MD, MSc

  UCLA AIDS Prevention & Treatment CTU

  STUDY CHAIR

• Raphael Landovitz, MD, MSc

  UCLA AIDS Prevention & Treatment CTU

  STUDY CHAIR

• Igho Ofotokun, MD

  Emory HIV/AIDS CTU

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2008
• First Posted: December 19, 2008
• Study Start: May 1, 2009
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: September 5, 2014
• Results First Posted: September 5, 2014

Record last verified: 2014-09

Locations

US (55); PR (2)