Low-Density Lipoprotein Size and Lipoprotein-Associated Phospholipase A2 in HIV-Infected Patients Switching to Abacavir or Tenofovir

Abstract

Background

The aim of this study was to assess changes in the size and cholesterol content of low-density lipo-proteins (LDL) and changes in lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in HIV-infected patients switching to tenofovir + emtricitabine (TDF+FTC) or abacavir + lamivudine (ABC+3TC).

Methods

This was a substudy of a multicentre randomized trial comparing TDF+FTC with ABC+3TC-based regimens in patients with virological suppression. Fasting lipids and apolipoproteins (apo), LDL size and cholesterol content and Lp-PLA2 activity were measured at baseline and at week 48.

Results

A total of 62 patients, naive for the compared drugs, were included. At baseline, groups were comparable except for total Lp-PLA2 activity (P=0.047) and for a tendency towards the use of a major baseline thymidine analogue in the TDF+FTC arm (25 versus 18 patients; P=0.054). In the ABC+3TC arm a significant increase in total cholesterol (0.64 mmol/l; P=0.003), high-density lipoprotein cholesterol (HDL-c, 0.13 mmol/l; P=0.031), triglycerides (0.39 mmol/l; P=0.036), apo A-I (0.12 g/l; P=0.006), apo B (0.16 g/l; P=0.015) and non-HDL-c (0.50 mmol/l; P=0.009) concentrations was observed at week 48 compared with the TDF+FTC treatment arm. In addition, an increase in the cholesterol content of small, dense LDL subfractions (0.48 mmol/l; P=0.003) and a decrease in LDL size (-2.6 nm; P=0.011) was observed in the ABC arm without changes in the TDF patients. Total PLA2, LDL-PLA2 and HDL-PLA2 activity decreased in the TDF arm, but multivariate analysis showed baseline PLA2 values and previous use of thymidine analogues as the factors associated with these changes. Estimated cardiovascular risk did not change in either arm.

Conclusions

A more atherogenic LDL profile, including a decrease in LDL size, was found in the ABC group and not in TDF patients.

References

Kamin

D.S.

, Grinspoon

Cardiovascular disease in HIV-positive patients. AIDS 2005; 19: 641–652.

Aberg

J.A.

Cardiovascular complications in HIV management: past, present and future. J Acquir Immune Defic Syndr 2009; 50: 54–64.

Worm

S.W.

, Sabin

, Weber

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 Dis 2010; 201: 318–330.

The SMART/INSIGHT and the D:A:D study groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008; 22: F17–F24.

Martin

, Bloch

, Amin

Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine a randomized, 96-week, trial. Clin Infect Dis 2009; 49: 1591–1601.

Moyle

G.J.

, Sabin

C.A.

, Cartledge

RAVE (Randomized Abacavir versus Viread Evaluation) Group UK. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS 2006; 20: 2043–2050.

Martínez

, Arranz

J.A.

, Podzamczer

Bicombo Study Team. A simplification trial switching from nucleoside reverse transcriptase inhibitors to once-daily fixed-dose abacavir/lamivudine or tenofovir/emtricitabine in HIV-1-infected patients with virological suppression. J Acquir Immune Defic Syndr 2009; 51: 290–297.

Sax

P.E.

, Tierney

, Collier

A.C.

Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. N Engl J Med 2009; 361: 2230–2240.

Smith

K.Y.

, Patel

, Fine

Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS 2009; 23: 1547–1556.

10.

Virgili

, Fisac

, Martínez

, Ribera

, Gatell

J.M.

, Podzamczer

Proinflammatory cytokine changes in clinically stable, virologically suppressed, HIV-infected patients switching from protease inhibitors to abacavir. J Acquir Immune Defic Syndr 2009; 50: 552–553.

11.

Satchell

, O'Connor

, Peace

Platelet hyper-reactivity in HIV-1 infected patients on abacavir-containing ART. 16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, Canada. Abstract 151LB.

12.

McComsey

, Smith

, Patel

Similar reductions in markers of inflammation and endothelial activation of abacavir/lamivudine or tenofovir/emtricitabine: the HEAT study. 16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, Canada. Abstract 732.

13.

Palella

F.J.

, Gange

, Elion

Inflammatory biomarkers and abacavir use in the Women's Interagency HIV Study and the Multicenter AIDS Cohort Study. AIDS 2010; 24: 1657–1665.

14.

Martinez

, Larrousse

, Podzamczer

Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction. AIDS 2010; 24: F1–F9.

15.

Rizzo

, Berneis

Low-density lipoprotein size and cardiovascular risk assessment. QJM 2006; 99: 1–14.

16.

Gazi

I.F.

, Tsimihodimos

, Tselepis

A.D.

, Elisaf

, Mikhailidis

D.P.

Clinical importance and therapeutic modulation of small dense low-density lipoprotein particles. Expert Opin Biol Ther 2007; 7: 53–72.

17.

Garza

C.A.

, Montori

V.M.

, McConnell

J.P.

Association between lipoprotein-associated phospholipase A₂ and cardiovascular disease: a systematic review. Mayo Clin Proc 2007; 82: 159–165.

18.

Noto

, Hara

, Karasawa

Human plasma platelet-activating factor acetylhydrolase binds to all the murine lipoproteins conferring protection against oxidative stress. Arterioscler Thromb Vasc Biol 2003; 23: 829–835.

19.

Negredo

, Ribalta

, Paredes

Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine. AIDS 2002; 16: 1383–1389.

20.

Badiou

, Merle De Boever

, Dupuy

A.M.

, Baillat

, Cristol

J.P.

, Reynes

Decrease in LDL size in HIV-positive adults before and after lopinavir/ritonavir-containing regimen: an index of atherogenicity?

Atherosclerosis 2003; 168: 107–113.

21.

Riddler

S.A.

, Li

, Otvos

Antiretroviral therapy is associated with and atherogenic lipoprotein phenotype among HIV-1-infected men in the multicenter AIDS Cohort Study. J Acquir Immune Defic Syndr doi:10.1097/QAI.0b013e31817bbbf0.

22.

Duprez

D.A.

, Kuller

L.H.

, Tracy

Lipoprotein particle subclasses, cardiovascular disease and HIV infection. Atherosclerosis 2009; 207: 524–529.

23.

National Cholesterol Education Program. Third report of the expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Circulation 2002; 106: 3143–3421.

24.

Wilson

P.W.F.

, D'Agostino

R.B.

, Levy

Prediction of coronary heart disease using risk factor categories. Circulation 1998; 97: 1837–1847.

25.

Hoefner

D.M.

, Hodel

S.D.

, O'Brien

J.F.

Development of a rapid, quantitative method for LDL subfractionation with use of the Quantimetrix Lipoprint LDL System. Clin Chem 2001; 47: 266–274.

26.

Benítez

, Sánchez-Quesada

J.L.

, Ribas

Platelet-activating factor acetylhydrolase is mainly associated with electronegative low-density lipoprotein subfraction. Circulation 2003; 108: 92–96.

27.

Hodges

J.R.

, Lehmann

E.L.

Confidence interval for the difference between two medians by Hodges-Lehmann method: ‘Estimates of location based on rank tests'. Ann Math Statist 1963; 34: 598–611.

28.

Benson

, Ribaudo

, Zheng

No association of abacavir use with risk of myocardial infarction or severe cardiovascular disease events: results from ACTG A5001. 16th Conference on Retroviruses and Opportunistic Infections. 8–11 February 2009, Montreal, Canada. Abstract 721.

29.

Bedimo

, Westfall

, Drechsler

Abacavir use and risk of acute myocardial infarction and cerebrovascular disease in the HAART era. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. 18–22 July 2009, Cape Town, South Africa. Abstract MOAB202.

30.

Lang

, Mary-Krause

, Cotte

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 datebase on HIV ANRS Cohort CO4. Arch Intern Med 2010; 170: 1228–1238.

31.

Behrens

G.M.

, Reiss

Abacavir and cardiovascular risk. Curr Opin Infect Dis 2010; 23: 9–14.

32.

Sacks

F.M.

, Campos

Clinical review 163: Cardiovascular endocrinology: Low-density lipoprotein size and cardiovascular disease: a reappraisal. J Clin Endocrinol Metab 2003; 88: 4525–4532.

33.

Furnkranz

, Schober

, Bochkov

V.N.

Oxidized phospholipids trigger atherogenic inflammation in murine arteries. Arterioscler Thromb Vasc Biol 2005; 25: 633–638.

34.

Superko

H.R.

, Krauss

R.M.

Differential effects of nicotinic acid in subjects with different LDL subclass patterns. Atherosclerosis 1992; 95: 69–76.

35.

Tellis

C.C.

, Tselepis

A.D.

The role of lipoprotein-associated phospholipase A₂ in atherosclerosis may depend on its lipoprotein carrier in plasma. Biochim Biophys Acta 2009; 1791: 327–338.

36.

Persson

, Nilsson

J.A.

, Nelson

J.J.

, Hedblad

, Berglund

The epidemiology of Lp-PLA2: distribution and correlation with cardiovascular risk factors in a population-based cohort. Atherosclerosis 2007; 190: 388–396.

37.

Corson

M.A.

, Jones

P.H.

, Davidson

M.H.

Review of the evidence for the clinical utility of lipoprotein-associated phospholipase A2 as a cardiovascular risk marker. Am J Cardiol 2008; 101: 41F–50F.