The overall goal of this research proposal is to prospectively examine the impact of three modern antiretroviral therapy (ART) treatment strategies on the progression of atherosclerosis in treatment-na?ve individuals with human immunodeficiency virus (HIV) infection. The studies proposed will examine and quantify the contributions of ART, cardiovascular disease (CVD) risk factors, immune activation and inflammation on arterial injury and atherosclerosis progression in HIV-infected individuals. The co-principal investigators are an infectious disease specialist and a cardiologist with expertise in the investigation of CVD risk in patients with HIV. They have assembled a multidisciplinary team of investigators that includes two experts in the treatment of HIV, two cardiologists with expertise in atherosclerosis imaging and lipids, an endocrinologist, and an immunologist, and a cardiovascular basic scientist, who, in collaboration with the National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group AIDS Clinical Trials Group, will conduct a prospective substudy of A5257, "A Comparative Study of Three Compact, Non-Nucleoside Reverse Transcriptase Inhibitor Sparing Antiretroviral Regimens for the Treatment Naive HIV-1 Infected Volunteers." A5257 is a prospective, randomized clinical trial (RCT) of ART efficacy. Embedding analyses of structural and functional markers of arterial injury and their determinants in a prospective, randomized clinical trial within the ACTG is an efficient and cost-effective approach to understanding the contributions of traditional and HIV-related factors to atherosclerosis progression in individuals with HIV. The proposal includes the following clinical and mechanistic aims:
AIM 1 (Clinical): To examine the effects of three contemporary initial ART treatment strategies on atherosclerosis progression over three years.
AIM 2 (Mechanistic and clinical): To examine the magnitude and time course of the effects of three contemporary initial ART treatment strategies on endothelial function during the first year of therapy.
AIM 3 (Mechanistic): To examine the effects of ART-related metabolic changes on endothelial function and atherosclerosis progression.
AIM 4 (Mechanistic): To examine the effects of ART-related changes in immune function and inflammation on endothelial function and atherosclerosis progression.

Public Health Relevance

To Public Health Statement There are estimated to be 33 million people worldwide who are living with HIV infection. Treatment for HIV infection has improved dramatically over the past twenty years, however there is growing concern that HIV treatments and chronic HIV infection might increase the risk of cardiovascular disease in people living with HIV. The proposed research will help identify the factors that increase the risk of cardiovascular disease in HIV patients and determine the optimal treatment strategies to reduce long-term cardiovascular disease risk in the setting of HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095132-05
Application #
8312483
Study Section
Special Emphasis Panel (ZHL1-CSR-H (S1))
Program Officer
Mcdonald, Cheryl
Project Start
2008-09-25
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$679,219
Indirect Cost
$114,994
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Kelesidis, Theodoros; Jackson, Nicholas; McComsey, Grace A et al. (2016) Oxidized lipoproteins are associated with markers of inflammation and immune activation in HIV-1 infection. AIDS 30:2625-2633
Dirajlal-Fargo, Sahera; Moser, Carlee; Brown, Todd T et al. (2016) Changes in Insulin Resistance After Initiation of Raltegravir or Protease Inhibitors With Tenofovir-Emtricitabine: AIDS Clinical Trials Group A5260s. Open Forum Infect Dis 3:ofw174
Hanna, David B; Guo, Mengye; Bůžková, Petra et al. (2016) HIV Infection and Carotid Artery Intima-media Thickness: Pooled Analyses Across 5 Cohorts of the NHLBI HIV-CVD Collaborative. Clin Infect Dis 63:249-56
Kelesidis, Theodoros; Moser, Carlee; Stein, James H et al. (2016) Changes in Markers of T-Cell Senescence and Exhaustion With Atazanavir-, Raltegravir-, and Darunavir-Based Initial Antiviral Therapy: ACTG 5260s. J Infect Dis 214:748-52
Kelesidis, Theodoros; Tran, Thuy Tien T; Brown, Todd T et al. (2016) Changes in plasma levels of oxidized lipoproteins and lipoprotein subfractions with atazanavir-, raltegravir-, darunavir-based initial antiviral therapy and associations with common carotid artery intima-media thickness: ACTG 5260s. Antivir Ther :
McComsey, Grace A; Moser, Carlee; Currier, Judith et al. (2016) Body Composition Changes After Initiation of Raltegravir or Protease Inhibitors: ACTG A5260s. Clin Infect Dis 62:853-62
Stein, James H; Ribaudo, Heather J; Hodis, Howard N et al. (2015) A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness. AIDS 29:1775-83
Brown, Todd T; Moser, Carlee; Currier, Judith S et al. (2015) 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 212:1241-9
Kelesidis, Theodoros; Tran, Thuy Tien T; Stein, James H et al. (2015) Changes in Inflammation and Immune Activation With Atazanavir-, Raltegravir-, Darunavir-Based Initial Antiviral Therapy: ACTG 5260s. Clin Infect Dis 61:651-60
Kelesidis, Theodoros; Roberts, Christian K; Huynh, Diana et al. (2014) A high throughput biochemical fluorometric method for measuring lipid peroxidation in HDL. PLoS One 9:e111716

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