Lipid disorders are frequent in HIV-1-infected patients taking combination antiretroviral therapy (cART) that includes protease inhibitors (PIs). The presence of small dense low-density lipoprotein particles might be an important predictive marker of cardiovascular disease in this setting. This cross-sectional substudy of the ANRS 126 trial was designed to identify variables influencing LDL diameter.
Methods
We studied 81 stable HIV-1-infected patients with dyslipidaemia (LDL-cholesterol >4.1 mmol/l, triglycerides <8.8 mmol/l) receiving PI-including cART regimens and no lipid-lowering drugs. LDL diameter was assessed by gradient gel electrophoresis. Relationships between LDL diameter and demographic, metabolic and HIV-related variables were identified by using non-parametric univariate tests and multiple linear regression models.
Results
In univariate analysis, LDL diameter was related to demographic variables, triglyceride (TG) levels, high-density lipoprotein cholesterol (HDL-c) levels, and the numbers and duration of exposure to nucleoside reverse transcriptase inhibitors and PIs. In multivariable linear regression analysis, LDL diameter was negatively associated with the TG level (P<0.0001) and positively associated with the HDL-c level (P<0.0001). For each 1-mmol/l increase in TG, LDL diameter fell by 0.281 nm. Conversely, for each 1-mmol/l increase in HDL-c, LDL diameter rose by 1.175 nm.
Conclusions
Higher TG and lower HDL-c levels are associated with smaller LDL particle diameter. Small-diameter LDL particles could contribute to early atherogenic processes in HIV-1-infected patients on cART.
References
1.
GrunfeldC., MiyinP., DoerrlerW., ShigenagaJ.K., JensenP., FeingoldP.R.Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab1992; 74: 1045–1052.
2.
KhovidhunkitW., KimM.S., MemonR.A.Effects of infection and inflammation on lipid and lipoprotein metabolism: mechanisms and consequences to the host. J Lipid Res2004; 45: 1169–1196.
3.
FeingoldK.R., KraussR.M., PangM.The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. J Clin Endocrinol Metab1993; 76: 1423–1427.
4.
SamarasK.Metabolic consequences and therapeutic options in highly active antiretroviral therapy in human immunodeficiency virus-1 infection. J Antimicrob Chemother2008; 61: 238–245.
5.
Mary-KrauseM., CotteL., SimonA.Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS2003; 17: 2479–2486.
6.
SteinJ.H., KleinM.A., BellehumeurJ.L.Use of human immunodeficiency virus-1 protease inhibitors is associated with atherogenic lipoprotein changes and endothelial dysfunction. Circulation2001; 104: 257–262.
7.
BadiouS., Merle De BoeverC., DupuyA.M., BaillatV., CristolJ.P., ReynesJ.Decrease in LDL size in HIV-positive adults before and after lopinavir/ritonavir-containing regimen: an index of atherogenicity?Atherosclerosis2003; 168: 107–113.
8.
Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) Final Report. Circulation2002; 106: 3143–3421.
9.
ChapmanM.J., GuerinM., BruckertE.Atherogenic, dense low-density lipoproteins. Physiopathology and new therapeutic approaches. Eur Heart J1998; 19: A24–A30.
ObelN., ThomsenH., KronborgG.Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis2007; 44: 1625–1631.
12.
AslangulE., AssoumouK.L., BittarR.Rosuvastatin versus pravastatin in dyslipidemic HIV-infected patients receiving protease inhibitors; the ANRS 126 randomized trial. AIDS2010; 24: 77–83.
13.
1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep1992; 41: 1–19.
14.
FossatiP., PrencipeL.Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem1982; 28: 2077–2080.
15.
AllainC.C., PoonL.S., ChanC.S.G.Enzymatic determination of total serum cholesterol. Clin Chem1974; 20: 470–475.
16.
EgloffM., LegliseD., DuvillardL.Multicenter evaluation on different analysers of three methods for direct HDL-cholesterol assays. Ann Biol Clin (Paris)1999; 57: 561–572.
17.
BayerP., VeinbergF., CoudercC.Multicenter evaluation of four homogenous LDL-cholesterol assays. Ann Biol Clin (Paris)2005; 63: 27–41.
18.
BlancheP.J., GongE.L., ForteT.M.Characterization of human-high-density lipoproteins by gradient gel electrophoresis. Biochim Biophys Acta1981; 665: 408–419.
19.
RainwaterD.L., AndresD.W., FordA.L.Production of polyacrylamide gradient gels for the electrophoretic resolution of lipoproteins. J Lipid Res1992; 33: 1876–1881.
20.
KraussR.M., BlancheP.J.Detection and quantification of LDL subfractions. Curr Opin Lipidol1992; 3: 377–383.
21.
VekicJ., ZeljkovicA., Jelic-IvanovicZ.Small, dense LDL and apolipoprotein B: relationship with serum lipids and LDL size. Atherosclerosis2009; 207: 496–501.
22.
WilliamsP.T., SuperkoH.R., HaskellW.L.Smallest LDL particles are most strongly related to coronary disease progression in men. Arterioscler Thromb Vasc Biol2003; 23: 314–321.
23.
KraussR.M., BurkeD.J.Identification of multiple subclasses of plasma low density lipoproteins in normal humans. J Lipid Res1982; 23: 97–104.
24.
FriedlanderY., KidronM., CasalkeM.Low density lipoprotein particle size and risk factors of insulin resistance syndrome. Atherosclerosis2000; 148: 141–149.
25.
BerneisK., JeanneretC., MuserJ.Low density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes. Metabolism2005; 54: 227–234.
26.
RizzoM., BerneisK.Who needs to care about small, dense low-density lipoproteins?Int J Clin Pract2007; 61: 1949–1956.
27.
AustinM.A., KingM.C., VranizanK.M.Atherogenic lipoprotein phenotype. A proposed genetic marker for coronary heart disease risk. Circulation1990; 82: 495–506.
28.
RiddlerS.A., LiX., OtvosJ.Antiretroviral therapy is associated with an atherogenic lipoprotein phenotype among HIV-1-infected men in the Multicenter Aids Cohort Study. J Acquir Immune Defic Syndr2008; 48: 281–288.
29.
WormS.W., SabinC., WeberR.Risk of myocardial infarction in patients with HIV infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis2010; 201: 318–330.
30.
LangS., Mary-KrauseM., CotteL.Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients: a case-control study nested within the French Hospital Database on HIV ANRS cohort CO4. Arch Intern Med2010; 170: 1228–1238.
31.
TriantV.A., LeeH., HadiganC., GrinspoonS.K.Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human deficiency virus disease. J Clin Endocrinol Metab2007; 92: 2506–2512.
32.
LangS., Mary-KrauseM., CotteL.Increased risk of myocardial infarction in HIV-infected patients in France, relative to the general population. AIDS2010; 24: 1228–1230.
33.
SaumoyM., OrdoñezJ., MartinezE.Comprehensive lipid evaluation in patients switching from PI/r-based cART to a Ral-based cART: The SPIRAL Substudy.18th Conference on Retroviruses and Opportunistic Infections. 27 February – 2 March, 2011, Boston, MA, USA. Abstract 820.
34.
TienP.C., SchneiderM.F., CoxC.HIV, HAART, and lipoprotein particle concentrations in Women's Interagency HIV Study. AIDS2010; 24: 2809–2817.
35.
ShahmaneshM., DasS., StolinskiM.Antiretroviral treatment reduces very-low-density lipoprotein and intermediate-density lipoprotein apolipoprotein B fractional catabolic rate in human immunodeficiency virus-infected patients with mild dyslipidemia. J Clin Endocrinol Metab2005; 90: 755–760.
36.
UmplebyA.M., DasS., StolinskiM.Low density lipoprotein apolipoprotein B metabolism in treatment-naive HIV patients and patients on antiretroviral therapy. Antivir Ther2005; 10: 663–670.
37.
DasS., ShahmaneshM., StolinskiM.In treatment-naive and antiretroviral-treated subjects with HIV, reduced plasma adiponectin is associated with a reduced fractional clearance rate of VLDL, IDL and LDL apolipoprotein B-100. Diabetologia2006; 49: 538–542.
38.
RoseH., HoyJ., WoolleyI.HIV infection and high density metabolism. Atherosclerosis2008; 199: 79–86.
39.
DuprezD.A., KullerL.H., TracyR.Lipoprotein particle subclasses, cardiovascular disease and HIV infection. Atherosclerosis2009; 207: 524–529.
40.
EnsignW., HillN., HewardC.B.Disparate LDL phenotypic classification among 4 different methods assessing LDL particle characteristics. Clin Chem2006; 52: 1722–1727.
