This K23 application proposes an integrated research and training plan to develop expertise in the assessment of whole-body glucose and lipid metabolism, and body composition in patients with HIV infection who are assigned one of three class-sparing Highly Active Anti-Retroviral Therapy (HAART) regimens. These regimens will consist of: 1) Lopinavir/Ritonavir + lamivudine + stavudine or zidovudine 2) Lopinavir/Ritonavir + efavirenz or 3) efavirenz + lamivudine + stavudine or zidovudine. HAART administration in subjects with HIV infection is associated with development of the """"""""HIV lipodystrophy"""""""" syndrome which is characterized by a combination of one or more of three characteristics: 1) impaired insulin sensitivity, possibly leading to diabetes mellitus, 2) accumulation of truncal, intraabdominal adipose tissue with or without loss of adipose tissue in the limbs and face, and 3) hypertriglyceridemia which is frequently severe. These characteristics impart an increased of cardiovascular disease such that heart disease may surpass HIV infection as the primary cause of mortality. The majority of prior human studies examining metabolic complications of antiretroviral therapy have been retrospective and to our knowledge there are no randomized prospective studies evaluating the metabolic effects of three different class-sparing regimens in patients with HIV infection who are naive to antiretroviral therapy. This project aims to a) evaluate the effects of these three HAART regimens on insulin secretion and insulin actions on skeletal muscle (glucose disposal), liver (glucose production) and adipose tissue (whole-body lipolysis), and glucose tolerance, b) evaluate the effects of these regimens on very low density lipoprotein-triglyceride (VLDL-TG) and apolipoprotein-B100 (apoB) production rates, c) evaluate regimen effects on body composition, and hepatic fat content, and d) evaluate the relationship between body composition, and hepatic fat content with insulin action, and VLDL-TG and VLDL-apoB production rates. Hypotheses will be evaluated by measuring: 1) whole-body glucose, lipid, VLDL-TG and VLDL-apoB kinetics using stable isotope tracer methodology, 2) body composition using dual energy x-ray absorptiometry and magnetic resonance imaging, hepatic fat content using magnetic resonance spectroscopy, and 3) glucose tolerance, prior to and after receiving 6 months of HAART in subjects na'l've to antiretroviral therapy.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23RR019508-03
Application #
7080413
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Wilde, David B
Project Start
2004-07-15
Project End
2009-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$113,103
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cade, William Todd; Overton, Edgar Turner; Mondy, Kristin et al. (2013) Relationships among HIV infection, metabolic risk factors, and left ventricular structure and function. AIDS Res Hum Retroviruses 29:1151-60
Cade, W Todd; Reeds, Dominic N; Overton, E Turner et al. (2013) Pilot study of pioglitazone and exercise training effects on basal myocardial substrate metabolism and left ventricular function in HIV-positive individuals with metabolic complications. HIV Clin Trials 14:303-12
Cade, W Todd; Reeds, Dominic N; Overton, E Turner et al. (2011) Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis. Cardiovasc Diabetol 10:111
Yarasheski, Kevin E; Cade, W Todd; Overton, E Turner et al. (2011) Exercise training augments the peripheral insulin-sensitizing effects of pioglitazone in HIV-infected adults with insulin resistance and central adiposity. Am J Physiol Endocrinol Metab 300:E243-51
Cade, W T; Reeds, D N; Mondy, K E et al. (2010) Yoga lifestyle intervention reduces blood pressure in HIV-infected adults with cardiovascular disease risk factors. HIV Med 11:379-88
Cade, W T; Reeds, D N; Lassa-Claxton, S et al. (2008) Post-exercise heart rate recovery in HIV-positive individuals on highly active antiretroviral therapy. Early indicator of cardiovascular disease? HIV Med 9:96-100
Reeds, Dominic N (2008) Metabolic syndrome risks of cardiovascular disease: differences between HIV-positive and HIV-negative? J Cardiometab Syndr 3:79-82
Cade, W Todd; Reeds, Dominic N; Mittendorfer, Bettina et al. (2007) Blunted lipolysis and fatty acid oxidation during moderate exercise in HIV-infected subjects taking HAART. Am J Physiol Endocrinol Metab 292:E812-9
Reeds, Dominic N; Cade, W Todd; Patterson, Bruce W et al. (2006) Whole-body proteolysis rate is elevated in HIV-associated insulin resistance. Diabetes 55:2849-55
Reeds, D N; Yarasheski, K E; Fontana, L et al. (2006) Alterations in liver, muscle, and adipose tissue insulin sensitivity in men with HIV infection and dyslipidemia. Am J Physiol Endocrinol Metab 290:E47-E53