Small dense LDL and atherogenic lipid profile in HIV-positive adults

Abstract

In order to characterize the influence of a lopinavir/ritonavir-containing regimen on the lipoprotein profile, lipid parameters and LDL size, as an index of atherogenicity, were determined in 24 HIV-infected adults before and after the initiation of lopinavir/ritonavir treatment. At baseline an abnormal prevalence of small dense LDL was observed. One month of lopinavir/ritonavir use enhanced triglyceride and apolipoprotein CIII levels and reduced LDL size, suggesting an increase in atherogenicity. The changes in the lipid metabolism of HIV patients have raised clinical concern with respect to the atherogenic risk [1,2]. As well as cholesterol, hypertriglyceridemia appears to be an independent risk factor partly by the occurrence of small dense LDL [3]. Indeed, small dense LDL have a greater capacity to infiltrate the arterial wall, a reduced affinity for the LDL receptors and an increased susceptibility to ex-vivo oxidation [4]. Recently, a high prevalence of small dense LDL in HIV patients was reported [5]. The determination of LDL size could thus be a useful tool to assess the atherogenic risk in HIV patients. A lopinavir/ritonavir-containing regimen was initiated in 24 consecutive HIV-infected adults who were in virological failure or therapeutic intolerance. All the patients were evaluated before the initiation of lopinavir/ritonavir and at one month thereafter. Fourteen HIV-uninfected controls matched for age and body mass index were enrolled. All individuals provided inform consent and none took lipid-lowering drugs. Venous blood samples were collected after an overnight fast. Total cholesterol and triglyceride levels were measured using routine enzymatic methods. Apolipoprotein (apo) A1, B and CIII measurements were performed using an immunonephelometric assay. The size of the predominant LDL subfraction was determined by plasma electrophoretic migration in polyacrylamide gradient gels. Most patients (88%) were in the symptomatic stage, none had acute opportunistic infections, and 58% were suffering from lipodystrophy. All patients were treatment-experienced, with a mean duration of 60 months’ exposure to highly active antiretroviral therapy (HAART) and 28 months’ exposure to protease inhibitors (PI). Fourteen patients were in therapeutic interruption of at least 2 months, motivated by virological failure. The remaining 10 patients were currently receiving HAART. Significantly higher triglyceride levels, lower apoA1 levels and a smaller mean LDL size were observed in HIV patients when compared with controls (Table 1). No difference was observed between patients with or without lipodystrophy. The presence of small dense LDL (< 25.5 nm) was observed in 75% of HIV patients compared with 7% in the control group. One month of a lopinavir/ritonavir-containing regimen resulted in a significant increase in total cholesterol, triglyceride, apoA1, B and CIII levels, associated with a significant reduction in LDL size. The prevalence of hypertriglyceridemia (> 2 mmol/l) increased from 54% at baseline to 79%. An elevation of triglyceride levels was correlated with an increase in apoCIII (r = 0.84).Table 1: Lipid parameters and LDL size.Evidence is emerging that the incidence of cardiovascular events has increased over the past few years in HIV-infected adults [6,7], and HAART-induced or worsened dyslipidemia has been suggested to be an independent risk factor [1,8]. In our study an atherogenic lipid profile including a high prevalence of small dense LDL was evidenced at baseline. This atherogenic profile appears to be majored under a lopinavir/ritonavir-containing regimen by a more reduced LDL size. The mechanisms involved in HAART-induced hypertriglyceridemia remain unclear but apoCIII, an endogenous inhibitor of lipoprotein lipase, seems to play a pivotal role. Under PI administration, an increase in apoCIII levels and more particularly apoCIII associated with apoB-containing lipoparticles, was previously described [9]. In agreement with these data, we observed a global positive correlation between triglyceride levels and apoCIII levels (r = 0.88). The impairment of lipoprotein lipase leads to VLDL accumulation, hypertriglyceridemia and the occurrence of the atherogenic small dense LDL [10], which were previously reported in HIV patients [5]. Few data have been published on lipid and lipoprotein changes during lopinavir/ritonavir therapy. In antiretroviral-naive and PI-experienced patients a significant increase in mean cholesterol and triglyceride levels was described, but without respect to fasting [11–13]. In our study, a lopinavir/ritonavir-containing regimen accentuated HIV-induced dyslipidemia by an important increase in triglyceride and apoCIII levels associated with a reduction in LDL size, leading to an atherogenic profile. As fibrates lower triglyceride and apoCIII levels [9], and increase LDL size [14], they appear to be a logical option to manage HAART-induced dyslipidemia.