Impact of Antiretroviral Therapy on Metabolic, Skeletal, and Cardiovascular Parameters

NCT00851799 | Completed Results

• 3 other identifiers: ACTG A5260s1U01AI068636ACTG A5257 metabolic substudy
• Study Type: observational
• Target: 334
• Locations: 1 country
• Sites: 26

Brief Summary

The U.S. Department of Health and Human Services (HHS) guidelines recommend that HIV-infected people who have never received anti-HIV therapy be treated with a triple drug regimen (commonly called combination antiretroviral therapy, cART). Since the introduction of cART, morbidity and mortality among HIV-infected patients has been dramatically reduced. However, metabolic, skeletal, and cardiovascular diseases have been increasingly reported among HIV-infected patients and may be attributable, in part, to the direct effects of cART. Much of our understanding of the development of these diseases, risk factors, and consequences of these disorders has been derived from clinical studies of HIV-infected persons receiving older antiretroviral agents. A5260s was designed to examine the contributions of HIV-disease related factors and impact of newer antiretroviral drugs on the development of metabolic (such as blood vessels, blood sugar, cholesterol), skeletal, and cardiovascular diseases in people who have never received anti-HIV therapy. A5260s is a prospective substudy of a phase III randomized clinical trial A5257 (see ClinicalTrials.gov identifier: NCT00811954). A5257 was designed to look at different combinations of anti-HIV drugs that do not contain the medication efavirenz (EFV) and how well these drug combinations work to decrease the amount of HIV in the blood and to allow immune system recovery in people who have never received anti-HIV therapy. A5257 also examined drug tolerability and safety for the various drug combinations.

Conditions

HIV Infection

Keywords

ART; Antiretroviral therapy; Treatment naive; Highly active antiretroviral therapy (HAART)

Outcome Measures

Primary Outcomes (2)

• Annual Rate of Change in Right Common Carotid Artery Intima-media Thickness (CIMT)

  Right common carotid artery intima-media thickness was measured by ultrasound scan at study entry and weeks 48, 96 and 144. The annual rate of change in right common carotid artery intima-media thickness (CIMT) was estimated over 144 weeks from study entry using mixed effects linear regression model that adjusted for screening HIV-1 RNA level and Framingham risk score stratification factors.

  Study entry, week 144

• Change in Brachial Artery (BA) Flow Mediated Dilation (FMD) From Study Entry to Week 24

  Brachial artery flow mediated dilation was measured by brachial artery reactivity tests. All results reflect measures captured from participants who reported fasting and not smoking for at least 8 hours prior to FMD assessments. The change from study entry to week 24 in brachial artery FMD (%) was defined as the maximum FMD (%) calculated from resting heart rate (RH) 60 seconds and RH 90 seconds, relative to resting brachial artery diameter.

  Study entry, week 24

Secondary Outcomes (25)

• Change in Brachial Artery Flow Mediated Dilation (FMD) From Study Entry to Weeks 4 and 48

  Study entry, weeks 4 and 48

• Change in Absolute Flow Mediated Dilation (FMD) From Study Entry to Weeks 4, 24 and 48

  Study entry, weeks 4, 24 and 48

• Percent Change in Bone Mineral Density (BMD) of the Hip From Study Entry to Week 96

  Study entry, week 96

• Percent Change in Bone Mineral Density (BMD) of the Lumber Spine From Study Entry to Week 96

  Study entry, week 96

• Percent Change in Bone Mineral Density (BMD) of the Total Body From Study Entry to Week 96

  Study entry, week 96

Study Arms (3)

Cohort A

ATV/RTV + FTC/TDF 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

Cohort B

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

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

Cohort C

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

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

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). Other Name: TDF/FTC

Cohort A; Cohort B; Cohort C

Ritonavir DRUG

100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV

Cohort A; Cohort B; Cohort C

Atazanavir DRUG

300 mg taken orally once daily. A protease inhibitor (PI). Other Name: ATV

Cohort A

Raltegravir DRUG

400 mg taken orally twice daily. An integrase inhibitor (INI). Other Name: RAL

Cohort B

Darunavir DRUG

100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV

Cohort C

Eligibility Criteria

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

Study Population

Antiretroviral naïve, HIV-infected men and women with HIV-1 RNA level \>1000 copies/ml initiating treatment for HIV-1 infection.

You may qualify if:

• Enrollment in A5257 and intent to enroll in A5001 (ALLRT)
• Signed informed consent

You may not qualify if:

• Diabetes mellitus, (fasting plasma glucose ≥ 126 mg/dL on two occasions or on hypoglycemic medications).
• Known cardiovascular disease (history of myocardial infarction \[MI\], coronary artery bypass graft surgery, percutaneous coronary intervention, stroke, transient ischemic attack, or peripheral arterial disease with ankle-brachial index of less than 0.9 or claudication)
• Uncontrolled hypothyroidism or hyperthyroidism which in the opinion of the site investigator would affect substudy participation
• Current use of statins, fish oil (greater than 2 grams per day), fibric acid derivatives, or niacin (more than 1000 mg per day) (NOTE: Current use of fish oil and niacin is defined as receiving treatment in the 8 weeks prior to study entry)
• Intention to start pharmacological or surgical intervention for weight loss
• Use of any ART in the 30 days before study entry

Sponsors & Collaborators

• Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (26)

USC CRS

Los Angeles, California, 90033, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90035, 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 (6101)

Aurora, Colorado, 80045, United States

Location

The Ponce de Leon Center

Atlanta, Georgia, 30308, United States

Location

Northwestern University CRS (2701)

Chicago, Illinois, 60611, United States

Location

Rush University Medical Center (2702)

Chicago, Illinois, 60612, United States

Location

Johns Hopkins Adult AIDS CRS

Baltimore, Maryland, 21287, United States

Location

Brigham and Women's Hosp. ACTG CRS

Boston, Massachusetts, 02115, United States

Location

Beth Israel Deaconess Med. Ctr., ACTG CRS

Boston, Massachusetts, 02215, United States

Location

Washington University CRS (2101)

St Louis, Missouri, 63110, United States

Location

New Jersey Medical School- Adult Clinical Research Ctr. CRS

Newark, New Jersey, 07103, United States

Location

NY Univ. HIV/AIDS CRS (401)

New York, New York, 10016, United States

Location

AIDS Care CRS

Rochester, New York, 14607, United States

Location

University of Rochester ACTG CRS

Rochester, New York, 14642, United States

Location

Unc Aids Crs

Chapel Hill, North Carolina, 27514, United States

Location

Duke Univ. Med. Ctr. Adult CRS (1601)

Durham, North Carolina, 27710, United States

Location

University of Cincinnati CRS (2401)

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 University AIDS CRS (2301)

Colombus, Ohio, 43210, United States

Location

Pitt CRS

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt Therapeutics CRS

Nashville, Tennessee, 37232, United States

Location

Houston AIDS Research Team CRS (31473)

Houston, Texas, 77030, United States

Location

University of Washington AIDS CRS (1401)

Seattle, Washington, 98104, United States

Location

Related Publications (11)

• 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 BACKGROUND

• 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 BACKGROUND

• Vardhanabhuti S, Ribaudo HJ, Landovitz RJ, Ofotokun I, Lennox JL, Currier JS, Olson LM, Haas DW. Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia. Open Forum Infect Dis. 2015 Jul 1;2(3):ofv085. doi: 10.1093/ofid/ofv085. eCollection 2015 Sep.

  PMID: 26180834 BACKGROUND

• Stein JH, Ribaudo HJ, Hodis HN, Brown TT, Tran TT, Yan M, Brodell EL, Kelesidis T, McComsey GA, Dube MP, Murphy RL, Currier JS. A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness. AIDS. 2015 Sep 10;29(14):1775-83. doi: 10.1097/QAD.0000000000000762.

  PMID: 26372383 RESULT

• 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 RESULT

• Brown TT, Moser C, Currier JS, Ribaudo HJ, Rothenberg J, Kelesidis T, Yang O, Dube MP, Murphy RL, Stein JH, McComsey GA. Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Atazanavir/Ritonavir, Darunavir/Ritonavir, or Raltegravir. J Infect Dis. 2015 Oct 15;212(8):1241-9. doi: 10.1093/infdis/jiv194. Epub 2015 May 5.

  PMID: 25948863 RESULT

• Stein JH, Brown TT, Ribaudo HJ, Chen Y, Yan M, Lauer-Brodell E, McComsey GA, Dube MP, Murphy RL, Hodis HN, Currier JS. Ultrasonographic measures of cardiovascular disease risk in antiretroviral treatment-naive individuals with HIV infection. AIDS. 2013 Mar 27;27(6):929-937. doi: 10.1097/QAD.0b013e32835ce27e.

  PMID: 23196938 RESULT

• Brown TT, Chen Y, Currier JS, Ribaudo HJ, Rothenberg J, Dube MP, Murphy R, Stein JH, McComsey GA. Body composition, soluble markers of inflammation, and bone mineral density in antiretroviral therapy-naive HIV-1-infected individuals. J Acquir Immune Defic Syndr. 2013 Jul 1;63(3):323-30. doi: 10.1097/QAI.0b013e318295eb1d.

  PMID: 23591634 RESULT

• 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

• Debroy P, Lake JE, Moser C, Olefsky M, Erlandson KM, Scherzinger A, Stein JH, Currier JS, Brown TT, McComsey GA. Antiretroviral Therapy Initiation Is Associated With Decreased Visceral and Subcutaneous Adipose Tissue Density in People Living With Human Immunodeficiency Virus. Clin Infect Dis. 2021 Mar 15;72(6):979-986. doi: 10.1093/cid/ciaa196.

  PMID: 32107532 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

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood and urine samples will be collected and stored

MeSH Terms

Conditions

HIV Infections

Interventions

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

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; Thiazoles; Sulfur Compounds; Azoles; Pyridines; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Pyrrolidinones; Pyrrolidines; Sulfonamides; Amides; Carbamates; Acids, Acyclic; Carboxylic Acids; Sulfones; Furans

Results Point of Contact

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

ACTGCT.Gov@s-3.com

(301) 628-3313

Study Officials

• Todd Brown, MD, PhD

  Johns Hopkins University

  STUDY CHAIR

• James Stein, MD

  University of Wisconsin, Madison

  STUDY CHAIR

• Grace McComsey, MD, FIDSA

  University Hospitals Cleveland Medical Center

  STUDY CHAIR

• Judith Currier, MD, MSc

  UCLA AIDS Prevention & Treatment CTU

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 24, 2009
• First Posted: February 26, 2009
• Study Start: June 1, 2009
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: January 13, 2016
• Results First Posted: January 13, 2016

Record last verified: 2015-12

Locations

US (26)