HIV SYNDROME X & PROTEASE INHIBITORS: HUMAN STUDIES

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This proposal is based on the premise that insulin action varies widely in patients with HIV/AIDS, and that the untoward effects of protease inhibitors (Pis) occur in individuals with pre- existing insulin resistance. It is also postulated that type 2 diabetes, is more likely to develop in patients co-infected with hepatitis-C virus (HCV). To test these hypotheses we will determine glucose tolerance, lipoprotein, insulin action on muscle and adipose tissue, insulin secretory function, and plasma concentration of soluble cellular adhesion molecules in 150 individuals, 125 patients with HIV/AIDS (50 percent co-infected with HCV) in whom treatment with Pis is soon to be initiated, and 25 subjects with HCV only. The results of these studies will: 1) define the pre-treatment variation in insulin action and secretion in these patients; 2) test the hypothesis that pre- existing insulin resistance and hyperinsulinemia determines prevalence of risk factors for type 2 diabetes and coronary heart disease (CHD): and 3) compare risk factors for CHD and type 2 diabetes in HCV-positive and HCV-negative patients with HIV/AIDS. All baseline measurements will be repeated three months after treatment with Pis. These data will provide a prospective assessment of the effect of Pis on relevant variables, as well testing the hypotheses that: 1) the more insulin resistant and hyperinsulinemic an individual at baseline, the greater the untoward impact of PI: 2) the lipolytic effect of Pis results in day-long elevations in plasma FFA concentrations, that correlate closely with the decrease in insulin action and dyslipedemia in PI-treated patients; and 3) the increase in risk factors for type 2 diabetes will be accentuated in patients co-infected with HCV. Patients with HIV/AIDS will then be studied to see if replacing saturated fat (SF) with monounsaturated (MF)/polyunsaturated (PF), rather than carbohydrate (CHO), is more likely to maximally attenaute the abnormalities in PI-treated patients secondary to insulin resistance and hyperinsulinemia and lower LDL-cholesterol concentration. Specifically, patients will be studied after two randomly assigned dietary periods of four weeks (divided by a two-week washout period), consuming diets containing (as percent of calories) either 15 percent protein. 55 percent CHO and 30 percent fat, or, 15 percent, 40 percent CHO and 45 percent fat. SF will be less than 10 percent of calories in both diets, and the MF/PF ratio kept constant. Measurements will be made of fasting and postprandial plasma glucose, insulin, FFA, triglyceride, and lipoprotein at hourly intervals from 8 AM to 4 PM. It is postulated that all CHD risk factors will be accentuated on the 55 percent CHO diet. The results of these studies will help explain why untoward metabolic and clinical events occur with PI treatment, and define the diet most likely to decrease risk of type 2 diabetes and CHD in these patients.