ABSTRACT
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.
Subject(s)
Anti-HIV Agents/adverse effects , Carbamates/pharmacokinetics , HIV Infections/drug therapy , HIV-1 , Insulin Resistance , Lipids/blood , Organophosphates/pharmacokinetics , Sulfonamides/pharmacokinetics , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/pharmacokinetics , Adenine/therapeutic use , Adipose Tissue/drug effects , Adult , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Blood Glucose/drug effects , Blood Glucose/metabolism , Carbamates/adverse effects , Carbamates/therapeutic use , Confidence Intervals , Drug Administration Schedule , Drug Combinations , Dyslipidemias/chemically induced , Furans , HIV Infections/complications , HIV Infections/metabolism , Humans , Insulin/blood , Insulin Resistance/physiology , Lamivudine/adverse effects , Lamivudine/pharmacokinetics , Lamivudine/therapeutic use , Lopinavir , Male , Organophosphates/adverse effects , Organophosphates/therapeutic use , Organophosphonates/adverse effects , Organophosphonates/pharmacokinetics , Organophosphonates/therapeutic use , Pyrimidinones/adverse effects , Pyrimidinones/pharmacokinetics , Pyrimidinones/therapeutic use , Ritonavir/adverse effects , Ritonavir/pharmacokinetics , Ritonavir/therapeutic use , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , TenofovirABSTRACT
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.