Clinical trial NCT00851799: Impact of Antiretroviral Therapy on Metabolic, Skeletal, and Cardiovascular Parameters
Official title: Cardiovascular, Anthropometric, and Skeletal Effects of Antiretroviral Therapy (ART) Initiation With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Plus Atazanavir/Ritonavir (ATV/r), Darunavir/Ritonavir (DRV/r), or Raltegravir (RAL): Metabolic Substudy of A5257
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HIV Infection
Keywords: ART
Antiretroviral therapy
Treatment naive
Highly active antiretroviral therapy (HAART)
Lead sponsor: Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections
Sponsor class: NETWORK
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2009-02-26
Enrollment: 334
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Enrollment in A5257 and intent to enroll in A5001 (ALLRT)
* Signed informed consent
* For A5257 inclusion criteria, please see ClinicalTrials.gov identifier NCT00811954

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
* For A5257 exclusion criteria, please see ClinicalTrials.gov identifier NCT00811954

Primary outcomes:
measure: Annual Rate of Change in Right Common Carotid Artery Intima-media Thickness (CIMT)
timeFrame: Study entry, week 144
measure: Change in Brachial Artery (BA) Flow Mediated Dilation (FMD) From Study Entry to Week 24
timeFrame: Study entry, week 24
Secondary outcomes:
measure: Change in Brachial Artery Flow Mediated Dilation (FMD) From Study Entry to Weeks 4 and 48
timeFrame: Study entry, weeks 4 and 48
measure: Change in Absolute Flow Mediated Dilation (FMD) From Study Entry to Weeks 4, 24 and 48
timeFrame: Study entry, weeks 4, 24 and 48
measure: Percent Change in Bone Mineral Density (BMD) of the Hip From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: Percent Change in Bone Mineral Density (BMD) of the Lumber Spine From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: Percent Change in Bone Mineral Density (BMD) of the Total Body From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: Percent Change in Total Limb Fat From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: Percent Change in Trunk Fat From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: Percent Change in Lean Mass From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: Percent Change in Visceral Abdominal Fat (VAT) From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: Percent Change in Subcutaneous Abdominal Fat (SAT) From Study Entry to Week 96
timeFrame: Study entry, week 96
measure: CD4+ T-cell Count at Study Entry and Weeks 24, 48, 96 and 144
timeFrame: Study entry, weeks 24, 48, 96 and 144
measure: Change in CD4+ T-cell Count From Study Entry to Weeks 24, 48, 96 and 144
timeFrame: Study entry to weeks 24, 48, 96, and 144
measure: Change in Fasting Total Cholesterol (TC) From Study Entry to Weeks 4, 24, 48 and 96
timeFrame: Study entry, weeks 4, 24, 48 and 96
measure: Change in Fasting Triglyceride (TG) From Study Entry to Weeks 4, 24, 48 and 96
timeFrame: Study entry, weeks 4, 24, 48 and 96
measure: Change in Fasting High-density Lipoprotein Cholesterol (HDL-C) From Study Entry to Weeks 4, 24, 48 and 96
timeFrame: Study entry, weeks 4, 24, 48 and 96
measure: Change in Fasting Calculated Low-density Lipoprotein Cholesterol (LDL-C) From Study Entry to Weeks 4, 24, 48 and 96
timeFrame: Study entry, weeks 4, 24, 48 and 96
measure: Change in Fasting Glucose Level From Study Entry to Weeks 4, 24, 48 and 96
timeFrame: Study entry, weeks 4, 24, 48 and 96
measure: Change in Fasting Insulin Level From Study Entry to Weeks 4, 24, 48 and 96
timeFrame: Study entry, weeks 4, 24, 48 and 96
measure: Fold Change in D-dimer From Study Entry to Weeks 48 and 96
timeFrame: Study entry, weeks 48 and 96
measure: Fold Change in High Sensitivity C-reactive Protein (hsCRP) From Study Entry to Weeks 48 and 96
timeFrame: Study entry, weeks 48 and 96
measure: Fold Change in Interleukin-6 (IL-6) From Study Entry to Weeks 48 and 96
timeFrame: Study entry, weeks 48 and 96
measure: Fold Change in Soluble CD14 From Study Entry to Weeks 48 and 96
timeFrame: Study entry, weeks 48 and 96
measure: Fold Change in Soluble CD163 From Study Entry to Weeks 48 and 96
timeFrame: Study entry, weeks 48 and 96
measure: Fold Change in Percent Expression of CD38+HLADR+ on CD4+ (Percent) From Study Entry to Weeks 24 and 96
timeFrame: Study entry, weeks 24 and 96
measure: Fold Change in Percent Expression of CD38+HLADR+ on CD8+ (Percent) From Study Entry to Weeks 24 and 96
timeFrame: Study entry, weeks 24 and 96
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: USC CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor - UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS (6101)
state: Colorado
city: Atlanta
country: United States
facility: The Ponce de Leon Center
state: Georgia
city: Chicago
country: United States
facility: Northwestern University CRS (2701)
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center (2702)
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hosp. ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: St. Louis
country: United States
facility: Washington University CRS (2101)
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School- Adult Clinical Research Ctr. CRS
state: New Jersey
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS (401)
state: New York
city: Rochester
country: United States
facility: AIDS Care CRS
state: New York
city: Rochester
country: United States
facility: University of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS (1601)
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati CRS (2401)
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: Metro Health CRS
state: Ohio
city: Colombus
country: United States
facility: The Ohio State University AIDS CRS (2301)
state: Ohio
city: Pittsburgh
country: United States
facility: Pitt CRS
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Therapeutics CRS
state: Tennessee
city: Houston
country: United States
facility: Houston AIDS Research Team CRS (31473)
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS (1401)
state: Washington
Study officials:
affiliation: Johns Hopkins University
name: Todd Brown, MD, PhD
role: STUDY_CHAIR
affiliation: University of Wisconsin, Madison
name: James Stein, MD
role: STUDY_CHAIR
affiliation: University Hospitals Cleveland Medical Center
name: Grace McComsey, MD, FIDSA
role: STUDY_CHAIR
affiliation: UCLA AIDS Prevention & Treatment CTU
name: Judith Currier, MD, MSc
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.