Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV (+) patients. However, such therapy is associated with a lipodystrophy syndrome characterized by marked loss of subcutaneous (sc) fat from the face and extremities but excess of sc fat around the neck, dorsocervical region and trunk. Such patients have increased propensity to insulin resistance, diabetes mellitus and dyslipidemia. The metabolic and molecular basis of lipodystrophy syndrome in HIV-infected patients is not known. Whether besides PIs, other antiretroviral drugs, HIV infection and reduction in viral load contribute to the development of lipodystrophy syndrome is not clear. The project therefore has the following aims: 1) to characterize metabolic abnormalities and changes in body fat distribution, 2) to develop objective criteria for defining the syndrome and to ascertain prognostic indicators and 3) to elucidate the molecular basis of the lipodystrophy syndrome in HIV-infected patients. To accomplish these aims, we will conduct a 2-year long prospective, randomized, double blind, placebo-controlled study in 200 asymptomatic HIV (+) patients to compare two equally effective antiretroviral regimens, one with and the other without a PI. We will study body fat distribution by anthropometry and magnetic resonance imaging and will measure insulin sensitivity (in a subset of patients), plasma lipoproteins, glucose tolerance and other metabolic variables. We will study expression of an array of adipocyte specific proteins/transcription factors involved in adipocyte differentiation, insulin action and lipoprotein metabolism in fat biopsy samples obtained before and after institution of therapy. Identification of the metabolic and molecular basis of lipodystrophy syndrome in HIV (+) patients may lead to better understanding of role of adipocyte-specific genes in insulin action and body fat distribution and may lead to discovery of other antiretroviral drugs that do not cause the lipodystrophy syndrome. Additionally, the study may prove effectiveness and reduced toxicity of alternative antiretroviral regimens without a PI.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK056583-01
Application #
6016990
Study Section
Special Emphasis Panel (ZRG1-AARR-6 (01))
Program Officer
Smith, Philip F
Project Start
1999-08-01
Project End
2003-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Shah, M; Tierney, K; Adams-Huet, B et al. (2005) The role of diet, exercise and smoking in dyslipidaemia in HIV-infected patients with lipodystrophy. HIV Med 6:291-8
Dinges, Warren L; Chen, Dali; Snell, Peter G et al. (2005) Regional body fat distribution in HIV-infected patients with lipodystrophy. J Investig Med 53:15-25
Chen, Dali; Misra, Anoop; Garg, Abhimanyu (2002) Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected patients. J Clin Endocrinol Metab 87:4845-56