9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 19-21 July 2007, Sydney, Australia

EFFECTS OF 4 WEEKS OF ATAZANAVIR, LOPINAVIR/RITONAVIR OR PLACEBO ON ENDOTHELIAL FUNCTION AND INSULIN SENSITIVITY IN HEALTHY MEN

ANTIVIRAL THERAPY 2007; 12(Suppl. 2):L14 (abstract no. O-17)

MP Dubé, C Shen, ML Greenwald and K Mather
Indiana University School of Medicine, Indianapolis, IN, USA

AIM: Vascular endothelial dysfunction plays a critical role in atherosclerosis and thrombosis. Dyslipidaemia alone does not fully explain the observed increase in cardiovascular events in patients receiving PI-based antiretroviral treatment. Some HIV-1 protease inhibitors (PIs), such as indinavir, directly induce endothelial dysfunction, an effect that may mediate the portion of the increase in cardiovascular events that is not attributable to dyslipidaemia.

METHODS: Thirty healthy, non-obese, HIV seronegative men had invasive evaluation of vascular function and hyperinsulinaemic, euglycaemic clamps before and after randomization to atazanavir (ATV) 400 mg once daily plus lopinavir/ritonavir (LPV/r) placebo (n=9), LPV/r 400/100 mg twice daily plus ATV placebo (n=9) or placebos for both drugs (n=12) for 4 weeks. Subjects were studied after an overnight fast and abstinence from smoking. Subjects who smoked (67%) maintained their usual smoking habits during the study.

RESULTS: Median age (36 years) and mean body mass index (23.4 ±2.6 kg/m²) did not differ between groups. Endothelium-dependent vasodilation (EDV) did not change after 4 weeks of treatment in any group. EDV, assessed as the leg blood flow response to intrafemoral artery infusion of 15 µg/min of the endothelium-dependent vasodilator methacholine, was 154 ±102% above basal at baseline and 242 ±254% at week 4 with ATV (P=0.7), 82 ±63% and 76 ±79% at week 4 with LPV/r (P=0.8), and 109 ±84% and 127 ±153% at week 4 with placebo (P=0.8; between groups P=0.9). The leg blood flow response to infusion of the endothelium-independent vasodilator nitroprusside was not different at week 4 in any group, nor was insulin-mediated vasodilation (the increase in leg blood flow during hyperinsulinaemia), whole-body insulin-mediated glucose uptake (M) or leg glucose uptake (all P-values >0.1).

CONCLUSIONS: Unlike the dramatic impairment seen with indinavir, the newer PIs atazanavir and lopinavir-ritonavir do not induce endothelial dysfunction in healthy subjects. Thus, endothelial dysfunction does not appear to be a PI class effect. The cause of the non-lipid-mediated increase in cardiovascular events reported with PIs remains unclear.

Acknowledgements: This work was supported by the NHLBI (grant R01 HL72711), NCRR (grant RR-00750), and drug was provided by Abbott and Bristol-Myers- Squibb.

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2007-07-24
O-17

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