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

HIV Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00851799
• Other study ID #: ACTG A5260s
• Secondary ID: 1U01AI068636ACTG
• Status: Completed
• Phase: N/A
• First received: February 24, 2009
• Last updated: December 9, 2015
• Start date: June 2009
• Est. completion date: June 2013

Study information

• Verified date: December 2015
• Source: AIDS Clinical Trials Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 334
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• HIV Infection

Intervention

Drug:
• 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
• Ritonavir
100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV
• Atazanavir
300 mg taken orally once daily. A protease inhibitor (PI). Other Name: ATV
• Raltegravir
400 mg taken orally twice daily. An integrase inhibitor (INI). Other Name: RAL
• Darunavir
100 mg taken orally once daily. A protease inhibitor (PI). Other Name: RTV

Locations

Country	Name	City	State
United States	The Ponce de Leon Center	Atlanta	Georgia
United States	University of Colorado Hospital CRS (6101)	Aurora	Colorado
United States	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Brigham and Women's Hosp. ACTG CRS	Boston	Massachusetts
United States	Unc Aids Crs	Chapel Hill	North Carolina
United States	Northwestern University CRS (2701)	Chicago	Illinois
United States	Rush University Medical Center (2702)	Chicago	Illinois
United States	University of Cincinnati CRS (2401)	Cincinnati	Ohio
United States	Case CRS	Cleveland	Ohio
United States	Metro Health CRS	Cleveland	Ohio
United States	The Ohio State University AIDS CRS (2301)	Colombus	Ohio
United States	Duke Univ. Med. Ctr. Adult CRS (1601)	Durham	North Carolina
United States	Houston AIDS Research Team CRS (31473)	Houston	Texas
United States	UCLA CARE Center CRS	Los Angeles	California
United States	USC CRS	Los Angeles	California
United States	Vanderbilt Therapeutics CRS	Nashville	Tennessee
United States	NY Univ. HIV/AIDS CRS (401)	New York	New York
United States	New Jersey Medical School- Adult Clinical Research Ctr. CRS	Newark	New Jersey
United States	Pitt CRS	Pittsburgh	Pennsylvania
United States	AIDS Care CRS	Rochester	New York
United States	University of Rochester ACTG CRS	Rochester	New York
United States	Ucsf Aids Crs	San Francisco	California
United States	University of Washington AIDS CRS (1401)	Seattle	Washington
United States	Washington University CRS (2101)	St. Louis	Missouri
United States	Harbor - UCLA Med. Ctr. CRS	Torrance	California

Sponsors (2)

Lead Sponsor	Collaborator
AIDS Clinical Trials Group	National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (8)

Brown TT, Chen Y, Currier JS, Ribaudo HJ, Rothenberg J, Dubé 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 — View Citation

Brown TT, Moser C, Currier JS, Ribaudo HJ, Rothenberg J, Kelesidis T, Yang O, Dubé MP, Murphy RL, Stein JH, McComsey GA. Changes in Bone Mineral Density After Initiation of Antiretroviral Treatment With Tenofovir Disoproxil Fumarate/Emtricitabine Plus Ata — View 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 I — View 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. Erratum in: Ann Intern Med. 2014 Nov 4;161(9):680. — View 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; 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. — View Citation

Stein JH, Brown TT, Ribaudo HJ, Chen Y, Yan M, Lauer-Brodell E, McComsey GA, Dubé MP, Murphy RL, Hodis HN, Currier JS. Ultrasonographic measures of cardiovascular disease risk in antiretroviral treatment-naive individuals with HIV infection. AIDS. 2013 Ma — View 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):1775-8 — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	Change in Brachial Artery Flow Mediated Dilation (FMD) From Study Entry to Weeks 4 and 48	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 weeks 4 and 48 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, weeks 4 and 48	No
Secondary	Change in Absolute Flow Mediated Dilation (FMD) From Study Entry to Weeks 4, 24 and 48	The change in absolute FMD was defined as the maximum absolute FMD from the RH 60 and 90 second measurements, from study entry to weeks 4, 24, and 48 (unit of measure millimeters). All results reflect measures captured from participants who reported fasting and not smoking for at least 8 hours prior to FMD assessments.	Study entry, weeks 4, 24 and 48	No
Secondary	Percent Change in Bone Mineral Density (BMD) of the Hip From Study Entry to Week 96	Bone mineral density (BMD) of the hip was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and study week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	Percent Change in Bone Mineral Density (BMD) of the Lumber Spine From Study Entry to Week 96	Bone mineral density (BMD) of the lumber spine was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and study week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	Percent Change in Bone Mineral Density (BMD) of the Total Body From Study Entry to Week 96	Bone mineral density (BMD) of the total body was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and study week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	Percent Change in Total Limb Fat From Study Entry to Week 96	Total limb fat was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	Percent Change in Trunk Fat From Study Entry to Week 96	Trunk fat was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	Percent Change in Lean Mass From Study Entry to Week 96	Lean mass was evaluated by dual-energy x-ray absorptiometry (DXA) scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	Percent Change in Visceral Abdominal Fat (VAT) From Study Entry to Week 96	Visceral abdominal fat (VAT) was evaluated by single slice abdominal computerized tomography scans at study entry and week 96. The percent change was calculated as as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	Percent Change in Subcutaneous Abdominal Fat (SAT) From Study Entry to Week 96	Subcutaneous abdominal fat (SAT) was evaluated by single slice abdominal computerized tomography scans at study entry and week 96. The percent change was calculated as ((week 96 value - study entry value) / study entry value)) x 100.	Study entry, week 96	No
Secondary	CD4+ T-cell Count at Study Entry and Weeks 24, 48, 96 and 144	The absolute levels of CD4+ T-cell counts (cells/mm^3) measured at study entry and weeks 24, 48, 96 and 144.	Study entry, weeks 24, 48, 96 and 144	No
Secondary	Change in CD4+ T-cell Count From Study Entry to Weeks 24, 48, 96 and 144	Change was calculated as (CD4+ T-cell count at week 24, 48, 96, or 144) - (CD4+ T-cell count at study entry).	Study entry to weeks 24, 48, 96, and 144	No
Secondary	Change in Fasting Total Cholesterol (TC) From Study Entry to Weeks 4, 24, 48 and 96	Total cholesterol (TC, unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in TC was calculated as (week 4, 24, 48 or 96 result) - (study entry result).	Study entry, weeks 4, 24, 48 and 96	No
Secondary	Change in Fasting Triglyceride (TG) From Study Entry to Weeks 4, 24, 48 and 96	Triglyceride (TG, unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in TG was calculated as (week 4, 24, 48 or 96 result) - (study entry result).	Study entry, weeks 4, 24, 48 and 96	No
Secondary	Change in Fasting High-density Lipoprotein Cholesterol (HDL-C) From Study Entry to Weeks 4, 24, 48 and 96	HDL cholesterol (unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in HDL-C was calculated as (week 4, 24, 48 or 96 result) - (study entry result).	Study entry, weeks 4, 24, 48 and 96	No
Secondary	Change in Fasting Calculated Low-density Lipoprotein Cholesterol (LDL-C) From Study Entry to Weeks 4, 24, 48 and 96	Calculated LDL-C (unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96 from participants who reported fasting for at least 8 hours prior to assessment; all results were centrally laboratory tested in batch. Change in calculated LDL-C was calculated as (week 4, 24, 48 or 96 result) - (study entry result).	Study entry, weeks 4, 24, 48 and 96	No
Secondary	Change in Fasting Glucose Level From Study Entry to Weeks 4, 24, 48 and 96	Glucose (unit of measure mg/dL) was measured at study entry and weeks 4, 24, 48 and 96; all results reflect measures captured from participants who reported fasting for at least 8 hours prior to assessment. Change was calculated as (fasting result during at week 4, 24, 48 or 96) - (fasting result at study entry).	Study entry, weeks 4, 24, 48 and 96	No
Secondary	Change in Fasting Insulin Level From Study Entry to Weeks 4, 24, 48 and 96	Insulin (unit of measure uIU/dL) was measured at study entry and weeks 4, 24, 48 and 96; all results reflect measures captured from participants who reported fasting for at least 8 hours prior to assessment. Change was calculated as (fasting result during at week 4, 24, 48 or 96) - (fasting result at study entry).	Study entry, weeks 4, 24, 48 and 96	No
Secondary	Fold Change in D-dimer From Study Entry to Weeks 48 and 96	D-dimer was measured at study entry and weeks 48 and 96 (unit of measure ug/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay.	Study entry, weeks 48 and 96	No
Secondary	Fold Change in High Sensitivity C-reactive Protein (hsCRP) From Study Entry to Weeks 48 and 96	hsCRP was measured at study entry and weeks 48 and 96 (unit of measure ug/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay.	Study entry, weeks 48 and 96	No
Secondary	Fold Change in Interleukin-6 (IL-6) From Study Entry to Weeks 48 and 96	IL-6 was measured at study entry and weeks 48 and 96 (unit of measure pg/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay.	Study entry, weeks 48 and 96	No
Secondary	Fold Change in Soluble CD14 From Study Entry to Weeks 48 and 96	Soluble CD14 was measured at study entry and weeks 48 and 96 (unit of measure ng/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay.	Study entry, weeks 48 and 96	No
Secondary	Fold Change in Soluble CD163 From Study Entry to Weeks 48 and 96	Soluble CD163 was measured at study entry and weeks 48 and 96 (unit of measure ng/ml). Fold change from study entry to week 48 or week 96 was calculated as (week 48 value or week 96 value) / (study entry value). Results identified above or below the limit of quantification were imputed at the quantification limit of the respective assay.	Study entry, weeks 48 and 96	No
Secondary	Fold Change in Percent Expression of CD38+HLADR+ on CD4+ (Percent) From Study Entry to Weeks 24 and 96	Percent expression of CD38+HLADR+ on CD4+ was measured at study entry and weeks 24 and 96 (unit of measure percent). Fold change from study entry to week 24 or week 96 was calculated as (week 24 value or week 96 value) / (study entry value).	Study entry, weeks 24 and 96	No
Secondary	Fold Change in Percent Expression of CD38+HLADR+ on CD8+ (Percent) From Study Entry to Weeks 24 and 96	Percent expression of CD38+HLADR+ on CD8+ was measured at study entry and weeks 24 and 96 (unit of measure percent). Fold change from study entry to week 24 or week 96 was calculated as (week 24 value or week 96 value) / (study entry value).	Study entry, weeks 24 and 96	No