METABOLIC CONSEQUENCES OF ANTIRETROVIRAL THERAPY

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DESCRIPTION: (Adapted from applicant's abstract) A new and poorly understood syndrome that may include central body fat redistribution, hyperlipidemia, and hyperglycemia has recently been recognized in individuals receiving highly active antiretroviral therapy (HAART) for HIV infection. It is likely that these metabolic changes, which resemble those seen in Cushing's syndrome, will significantly increase the risk for premature coronary artery disease in treated individuals. Although overt Cushing's syndrome has been excluded in affected individuals, there have been no reported studies based on actual measurement of cortisol production rates or tissue sensitivity to glucocorticoids in subjects receiving HAART. Similarly, it is not known whether HAART regimens may directly stimulate growth of abdominal adipocytes through an effect on PPAR gamma, a key transcriptional activator of preadipocyte differentiation. In this study, 180 HIV-infected individuals about to begin protease inhibitor therapy and 50 uninfected control subjects will be followed for one year with sensitive measurements of regional body composition, lipid and glucose metabolism, cortisol production, and adipocyte gene expression. The Specific Aims of this study are twofold: First, a case definition of the metabolic syndrome will be formulated based on identification of predisposing clinical factors and a comparison of changes in body composition, lipoprotein levels, ans glucose metabolism occurring in subjects over the course of the study. The atherogenicity of the hyperlipidemia associated with HAART will be fully defined by a detailed analysis of lipoprotein subfractions. The second aim of the study will be to test the hypotheses that (a) physiological hypercortisolemia + increased cortisol receptor expression, or (b) increased expression or activation of PPAR gamma is abdominal preadipocytes predict the subsequent development of metabolic abnormalities in subjects receiving HAART. The decision of investigate these two hypotheses was based on both the biological plausibility of the underlying mechanisms and the availability of drugs that might be used to specifically block glucococorticoid action (RU-486) or increase the activation of PPAR gamma in peripheral relative to abdominal preadipocytes (thiazolidenediones). Future trials of these medications, along with a great deal more basic research, are clearly justified by the increasing and sustained use of HAART to deal with the worldwide epidemic of HIV infection.