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

NCT ID: NCT00851799

Last Updated: 2016-01-13

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Total Enrollment

334 participants

Study Classification

OBSERVATIONAL

Study Start Date

2009-06-30

Study Completion Date

2013-06-30

Brief Summary

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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.

Detailed Description

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A5260s is the optional, metabolic substudy of a phase III, prospective, randomized clinical trial (A5257). For complete details about the parent study A5257, please see ClinicalTrials.gov identifier NCT00811954.

Some participants in study A5257 were asked to participate in substudy A5260s. Not all participants were asked since A5260s only took place at a subset of A5257 sites. Participants who agreed to participate in substudy A5260s were enrolled at the same time as their enrollment in A5257. No interventions were given as part of A5260s, but all A5260s participants underwent blood draws, self-administered questionnaire responses (related to physical activity and body image), ultrasound scans to measure the thickness of the carotid artery in the neck and brachial artery flow mediated dilation in the arm, and computerized topography (CT) and dual-energy x-ray absorptiometry (DEXA) scans to measure bone mineral density and body fat.

The duration of A5260s study was between 2 and 3 years (96 and 144 weeks), depending on when the participant enrolled. The study was designed to enroll a total of 330 participants with at least 110 per a group; each group represented a different randomized drug combination as defined and assigned by the main study A5257.

Cohort A: Atazanavir (ATV) + Ritonavir (RTV) + Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)

Cohort B: Raltegravir (RAL) + FTC/TDF

Cohort C: Darunavir (DRV) + RTV + FTC/TDF

All participants were asked to return for A5260s clinic visits at weeks 4, 24, 48 96 and 144 and participated in all clinical evaluations. No clinical evaluation was restricted to a subset of A5260s participants. If a participant chose to discontinue participation in the substudy, the participant was able to continue in study A5257. However, a participant discontinuing participation from A5257 was also removed from A5260s. Additionally, a participant's decision to discontinue or switch study drugs in the main study did not impact participation and follow-up clinic visits in A5260s.

Conditions

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HIV Infection

Study Design

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Observational Model Type

COHORT

Study Time Perspective

PROSPECTIVE

Study Groups

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Cohort A

ATV/RTV + FTC/TDF

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

Emtricitabine/tenofovir disoproxil fumarate

Intervention Type 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

Ritonavir

Intervention Type DRUG

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

Other Name: RTV

Atazanavir

Intervention Type DRUG

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

Other Name: ATV

Cohort B

RAL + FTC/TDF

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

Emtricitabine/tenofovir disoproxil fumarate

Intervention Type 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

Ritonavir

Intervention Type DRUG

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

Other Name: RTV

Raltegravir

Intervention Type DRUG

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

Other Name: RAL

Cohort C

DRV/RTV + FTC/TDF

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

Emtricitabine/tenofovir disoproxil fumarate

Intervention Type 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

Ritonavir

Intervention Type DRUG

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

Other Name: RTV

Darunavir

Intervention Type DRUG

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

Other Name: RTV

Interventions

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Emtricitabine/tenofovir disoproxil fumarate

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

Intervention Type DRUG

Ritonavir

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

Other Name: RTV

Intervention Type DRUG

Atazanavir

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

Other Name: ATV

Intervention Type DRUG

Raltegravir

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

Other Name: RAL

Intervention Type DRUG

Darunavir

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

Other Name: RTV

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

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

Exclusion Criteria

* 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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role collaborator

Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections

NETWORK

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Todd Brown, MD, PhD

Role: STUDY_CHAIR

Johns Hopkins University

James Stein, MD

Role: STUDY_CHAIR

University of Wisconsin, Madison

Grace McComsey, MD, FIDSA

Role: STUDY_CHAIR

University Hospitals Cleveland Medical Center

Judith Currier, MD, MSc

Role: STUDY_CHAIR

UCLA AIDS Prevention & Treatment CTU

Locations

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USC CRS

Los Angeles, California, United States

Site Status

UCLA CARE Center CRS

Los Angeles, California, United States

Site Status

Ucsf Aids Crs

San Francisco, California, United States

Site Status

Harbor - UCLA Med. Ctr. CRS

Torrance, California, United States

Site Status

University of Colorado Hospital CRS (6101)

Aurora, Colorado, United States

Site Status

The Ponce de Leon Center

Atlanta, Georgia, United States

Site Status

Northwestern University CRS (2701)

Chicago, Illinois, United States

Site Status

Rush University Medical Center (2702)

Chicago, Illinois, United States

Site Status

Johns Hopkins Adult AIDS CRS

Baltimore, Maryland, United States

Site Status

Brigham and Women's Hosp. ACTG CRS

Boston, Massachusetts, United States

Site Status

Beth Israel Deaconess Med. Ctr., ACTG CRS

Boston, Massachusetts, United States

Site Status

Washington University CRS (2101)

St Louis, Missouri, United States

Site Status

New Jersey Medical School- Adult Clinical Research Ctr. CRS

Newark, New Jersey, United States

Site Status

NY Univ. HIV/AIDS CRS (401)

New York, New York, United States

Site Status

AIDS Care CRS

Rochester, New York, United States

Site Status

University of Rochester ACTG CRS

Rochester, New York, United States

Site Status

Unc Aids Crs

Chapel Hill, North Carolina, United States

Site Status

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

Durham, North Carolina, United States

Site Status

University of Cincinnati CRS (2401)

Cincinnati, Ohio, United States

Site Status

Case CRS

Cleveland, Ohio, United States

Site Status

Metro Health CRS

Cleveland, Ohio, United States

Site Status

The Ohio State University AIDS CRS (2301)

Colombus, Ohio, United States

Site Status

Pitt CRS

Pittsburgh, Pennsylvania, United States

Site Status

Vanderbilt Therapeutics CRS

Nashville, Tennessee, United States

Site Status

Houston AIDS Research Team CRS (31473)

Houston, Texas, United States

Site Status

University of Washington AIDS CRS (1401)

Seattle, Washington, United States

Site Status

Countries

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United States

References

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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.

Reference Type BACKGROUND
PMID: 25285539 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 25767256 (View on PubMed)

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.

Reference Type BACKGROUND
PMID: 26180834 (View on PubMed)

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.

Reference Type RESULT
PMID: 26372383 (View on PubMed)

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.

Reference Type RESULT
PMID: 25904376 (View on PubMed)

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.

Reference Type RESULT
PMID: 25948863 (View on PubMed)

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.

Reference Type RESULT
PMID: 23196938 (View on PubMed)

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.

Reference Type RESULT
PMID: 23591634 (View on PubMed)

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.

Reference Type DERIVED
PMID: 35179037 (View on PubMed)

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.

Reference Type DERIVED
PMID: 32107532 (View on PubMed)

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.

Reference Type DERIVED
PMID: 26797215 (View on PubMed)

Other Identifiers

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1U01AI068636

Identifier Type: NIH

Identifier Source: secondary_id

View Link

ACTG A5257 metabolic substudy

Identifier Type: -

Identifier Source: secondary_id

ACTG A5260s

Identifier Type: -

Identifier Source: org_study_id

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