Efficacy and safety of fluvastatin in hyperlipidemic protease inhibitor-treated HIV-infected patients.

Abstract

Protease inhibitor-treated HIV-infected patients appear to be at higher risk of cardiovascular diseases than HIV-negative patients. This higher risk may be related to the high prevalence of cardiovascular risk factors, in particular smoking, hyperlipidemia and diabetes. Accordingly, effective and safe modalities to prevent the development of atherosclerosis and cardiovascular diseases in this high-risk population are urgently needed. As a result of the higher risk of cardiovascular diseases apparently suffered by protease inhibitor-treated HIV-infected patients [1,2], possibly related to the high prevalence of cardiovascular risk factors, such as smoking, hyperlipidemia and diabetes [3,4], we undertook the present study. We assessed the efficacy and safety of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, in 16 hyperlipidemic HIV-infected protease inhibitor (PI)-treated patients, using a placebo-controlled, double-blind, randomized, cross-over design. Fluvastatin was chosen because, like other statins, it has been shown favourably to modify the atherogenic lipoprotein profile, to reduce the incidence of cardiovascular events, and to slow the progression of coronary and peripheral atherosclerosis in non-HIV-infected individuals [5]. Moreover, fluvastatin is preferentially metabolized through the CYP2C9 enzyme, thus reducing the risk of drug interactions. The mean age (± SEM) of the 16 participants (14 men and two women) was 40.5 ± 1.8 years, body mass index averaged 22.4 ± 0.8 kg/m2, waist-to-hip ratio was 0.90 ± 0.02 cm/cm, blood pressure was 118/77 ± 4/3 mmHg, HIV-RNA level was 10 780 ± 7031 copies/ml (median 65), CD4 cell count was 535 ± 63 cells/ml and the duration of PI therapy was 32 ± 3 months. Seven patients were treated with nelfinavir alone (n = 4) or in combination with saquinavir (n = 3), seven patients received ritonavir alone (n = 2) or in combination with saquinavir (n = 4) or indinavir (n = 1), whereas one patient was receiving indinavir alone. After a 2-week run-in period, fluvastatin 40 mg a day or placebo was administered for 4 weeks with a 2-week wash-out period. Fluvastatin 40 mg a day was well tolerated. Its effects on the plasma concentrations of lipids, nelfinavir and ritonavir (as markers for drug interactions) [6], liver and muscle enzyme activities (as markers for toxicity), and endothelial reactivity to sodium nitroprusside, acetylcholine and reactive hyperemia (as markers for endothelial function), are described in Table 1. The endothelial reactivity to iontophoretically mediated transdermal application of the vasoactive agents was measured non-invasively at the completion of each treatment phase using a recently developed laser Doppler-based flowmetry device [7].Table 1: Laboratory parameters and endothelial reactivity in 16 hyperlipidemic protease inhibitor-treated HIV-infected patients receiving fluvastatin 40 mg a day or placebo (mean ± SEM).No change in any of the parameters measured was observed during the placebo period. In contrast, fluvastatin significantly reduced plasma total cholesterol levels and the total : HDL-cholesterol ratio. The amplitude of this lipid-lowering effect, however, was limited because eight out of 16 patients (50%) still had plasma levels of total cholesterol or triglycerides greater than 7.0 and greater than 3.0 mmol/l, respectively, at completion of the fluvastatin period, compared with 10 out of 16 (62%, NS) at baseline. Plasma concentrations of ritonavir and nelfinavir, liver and muscle activities, and endothelial reactivity remained unchanged during the fluvastatin period. In summary, fluvastatin 40 mg/day administered for 4 weeks significantly and safely lowered plasma total cholesterol levels in 16 PI-treated hyperlipidemic HIV-infected patients. The amplitude of this lipid-lowering response (17%) was similar to that reported for HIV-negative individuals [5]. Fluvastatin in the present study had no effect on endothelial function in the skin microvascular bed, presumably as a result of the insufficient control of hyperlipidemia or the short duration of treatment. Larger and longer-term studies are obviously required to demonstrate unambiguously the safety of fluvastatin and confirm the potential benefits of this compound on cardiovascular events in this high-risk population. Acknowledgements Sponsorship: This study was funded by the Swiss National Foundation for Scientific Research (grants 44471.95 and 32-61623.00 to V.M.); the Octave Botnar and Placide Nicod Foundation, Lausanne, Switzerland; and Novartis Pharma Schweiz*, Switzerland.