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Session 34 Oral Abstract Session Late Breakers II Session Time: Thursday, 9:30 am - 11:45 am Room 4B

9:45   LB10. Effect of Indinavir (IDV) Monotherapy on Endothelial Function in Men without HIV Infection M. P. Dubé*, S. Shankar, J. M. Vanderluitgaren, C. M. Leffler, A. D. Baron, and H. O. Steinberg Indiana Univ., Indianapolis Background: Protease inhibitor-based regimens have been associated with endothelial dysfunction, an early step in atherogenesis that predicts cardiovascular events. Possible mediators of endothelial dysfunction include dyslipidemia, insulin resistance, hypertension, or direct drug effects. Methods: 6 healthy, non-obese, normotensive, HIV-seronegative men with mean age 41 years were evaluated before and after 4 weeks of IDV 800 mg TID. Subjects did not change diet or exercise habits during study. Hyperglycemic clamps (plasma glucose levels ~200 mg/dL for 240 minutes) and direct, invasive measurements of leg blood-flow were performed in basal conditions and during intra-arterial infusion of vasoactive compounds. Results: Mean (±SEM) BMI was 23.8±1.3 kg/m2. Subjects lost a mean of 0.7 kg (p = 0.3, paired t-test) over 4 weeks. The increase in leg blood-flow (LBF) during femoral artery infusion of the endothelium-dependent vasodilator methacholine (Mch) at maximal doses (15 ?g/minute), expressed as percentage of change from pre-Mch basal values, were markedly impaired after 4 weeks of IDV: +227±45 pre-IDV, +82±18 post-IDV, p = 0.003. The response to the endothelium-independent vasodilator nitroprusside, an exogenous source of nitric oxide (NO), did not change. The expected reduction in LBF after infusion of the NO synthase antagonist L-NMMA, expressed as the percentage of change from pre-LNMMA values, was abolished with IDV: -30.4±8.9 pre-IDV vs +7.2±9.2 post-IDV, p = 0.03. HOMA-IR increased significantly: 1.15±0.23 pre-IDV, 1.52±0.34 post-IDV, p = 0.03. During hyperglycemic clamp, steady-state plasma glucose was similar: 201±1 mg/dL pre-IDV, 196±3 mg/dL post-IDV, as were glucose infusion rates: 16.1±1.5 pre-IDV, 15.4±2.2 mg/kg/minute post-IDV. Steady-state insulin concentrations during hyperglycemia were increased during treatment: 43.3±9.3 muU/mL pre-IDV, 54.4±7.5 muU/mL post-IDV, p = 0.06. Mean blood pressure, cholesterol, and triglycerides did not change. Conclusions: IDV induces endothelial dysfunction when administered as monotherapy for 4 weeks to healthy, HIV seronegative men. This does not appear to be mediated by dyslipidemia or changes in blood pressure. Endogenous NO-mediated vasodilation appears to be impaired, although other mechanisms may also be involved. Insulin resistance, and perhaps other drug-related effects, may contribute to endothelial dysfunction from IDV.

©2002 9th Conference on Retroviruses and Opportunistic Infections