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.
