Effect of boosted fosamprenavir or lopinavir-based combinations on whole-body insulin sensitivity and lipids in treatment-naive HIV-type-1-positive men.

BACKGROUND: Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals. METHODS: HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2. RESULTS: A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant. CONCLUSIONS: In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.

The effect of tenofovir disoproxil fumarate on whole-body insulin sensitivity, lipids and adipokines in healthy volunteers.

BACKGROUND: Certain antiretrovirals are known to affect lipid and glucose homeostasis. The aim of this study was to assess the effect on insulin sensitivity (determined by peripheral glucose uptake using a hyperinsulinaemic euglycaemic clamp) of tenofovir disoproxil fumarate (TDF) administration compared with placebo for 2 weeks in HIV-1-seronegative healthy male volunteers. Changes in lipids, adiponectin, leptin, plasminogen activator inhibitor 1 (PAI-1) and the adhesion molecules E-selectin and P-selectin were also assessed. METHODS: This was a single-centre, randomized, double-blinded, placebo-controlled study that used a two-sequence, two-period cross-over design. A total of 19 HIV-negative males were recruited to the study and randomized 1:1 to receive either 2 weeks of TDF (300 mg once daily) followed by 2 weeks of placebo or placebo initially followed by tenofovir. Clamps were performed at baseline, after 2 weeks and after 4 weeks. RESULTS: All three clamps were completed by 16 participants. During the euglycaemic clamp, there were no significant changes in insulin sensitivity after 2 weeks of TDF administration compared with placebo or baseline. There was a significant reduction in the mean total cholesterol (9.4%) and low-density lipoprotein (LDL; 8.1%) cholesterol following 2 weeks of TDF compared with placebo. Levels of adiponectin, leptin, PAI-1, P-selectin and E-selectin were not significantly altered. CONCLUSIONS: TDF use for 2 weeks does not affect insulin sensitivity, as assessed by the hyperinsulinaemic euglycaemic clamp in HIV-negative male volunteers. TDF use resulted in modest, but statistically significant, reductions in total and LDL cholesterol.

Antiretroviral therapy with or without protease inhibitors impairs postprandial TAG hydrolysis in HIV-infected men.

Mechanisms underlying the lipodystrophy syndrome associated with antiretroviral therapy (ART) for HIV infection are not completely understood. We investigated the effect of ART on blood lipid concentrations in the fasting state and after consumption of a meal containing [1-13C]palmitic acid in HIV-positive men receiving nucleoside reverse transcriptase inhibitors (NRTI, n 7), NRTI combined with protease inhibitors (PI; NRTIPI, n 6), in HIV-positive but therapy-naïve men (noART, n 5) and in HIV-seronegative men (controls, n 6). HIV-positive subjects had higher fasting TAG concentrations and resting energy expenditure than controls. Subjects receiving NRTIPI therapy had higher fasting NEFA concentrations than the other groups. There were no significant differences in postprandial lipid metabolism between noART subjects and controls. NRTI therapy impaired hydrolysis of meal-derived TAG, most evidently when combined with PI (the NRTIPI group). Accumulation of 13C-label in the NEFA fraction was not different between groups. In the NRTIPI group, fasting and postprandial NEFA concentrations were significantly higher than other groups. Postprandial glucose and insulin responses in HIV-positive subjects did not differ from controls. These findings suggest that ART dyslipidaemia is associated with impaired postprandial TAG clearance, which is exacerbated by NRTIPI therapy. If dyslipidaemia is to be minimised in ART, the specific adverse effects of particular combinations during the fed state should be considered.