METABOLIC EFFECTS OF PROTEASE INHIBITORS IN HIV DISEASE

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DESCRIPTION: (Adapted from applicant's abstract). Reports of increased glucose triglyceride, and cholesterol levels in HIV-infected patients on protease inhibitors (PI) have prompter speculation that these agents have unique metabolic effects. Additionally, some HIV-infected patients have noted increased abdominal girth and buffalo humps that clinicians and patients attribute to the use of Pi's. In preliminary studies, we have observed significant increases in glucose, insulin, TG and total LDL cholesterol in a group of patients following initiation of therapy with a PI, whereas no such changes occurred in patients beginning therapy with lamivudine or maintaining constant regimen that did not include lamivudine or a PI. Because hyperglycemia, hypertriglyceridemia, hypercholesterolemia, and central obesity are associated with increased risk of cardiovascular disease, these effects may impact on the long-term prognosis in patients whose life expectancies are extended due to effective viral suppression. As yet, these metabolic and body composition changes have not been systematically characterized, nor is it known if these changes represent one year syndrome or are unrelated findings. Therefore,, to evaluate the scope of and mechanisms underling these changes in carbohydrate and lipid metabolism and their relationship, if any, to changes in body composition, e propose to perform intensive metabolic ward studies in which we prospectively evaluate changes in glucose and lipid metabolism and body composition in separate cohorts of HIV-infected men and women before and after beginning Pi therapy. These studies are designed to: (1) test the hypothesis that PI's induce insulin resistance (as assessed by oral glucose tolerance test, hyperinsulinemic, euglycemic clamp, stable isotope studies of hepatic glucose production, gluconeogenesis and glycogenesis); 2) test the hypothesis that PI's produce an atherogenic lipid profile (plasma lipids and lipoprotein composition, intravenous fat tolerance test, stable isotope studies of whole body lipolysis, de novo hepatic lipogenesis, and cholesterolgenesis); and (3) to determine whether patients uniformly develop changes in regional fat distribution while on PI therapy and the relationship, if any, or changes in glucose and lipid metabolism to changes in body composition (dual-energy X-ray absorptiometry, computed tomography)> The role of glucoregulatory, adrenal, and gonadal hormones in mediating these effects will also be evaluated.