Evaluation of cardiovascular biomarkers in HIV-infected patients switching to abacavir or tenofovir based therapy

Thomas A Rasmussen, Martin Tolstrup, Jesper Melchjorsen, Christian A Frederiksen, Ulla S Nielsen, Bente L Langdahl, Lars Østergaard, Alex L Laursen, Thomas A Rasmussen, Martin Tolstrup, Jesper Melchjorsen, Christian A Frederiksen, Ulla S Nielsen, Bente L Langdahl, Lars Østergaard, Alex L Laursen

Abstract

Background: Our objective was to evaluate and compare the effect of abacavir on levels of biomarkers associated with cardiovascular risk.

Methods: In an open-label randomized trial, HIV-infected patients were randomized 1:1 to switch from zidovudine/lamivudine to abacavir/lamivudine or tenofovir/emtricitabine. In the present analysis, we measured levels of interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin, and myeloperoxidase (MPO) at baseline and 4, 12, and 48 weeks after randomization. D-dimer and fasting lipids were measured at baseline and weeks 12 and 48. Levels of biomarkers at all time points and changes from baseline were compared across study arms using Wilcoxon rank sum test.

Results: Of 40 included patients, 35 completed 48 weeks of randomized therapy and follow up. Levels of E-selectin (P=0.004) and sVCAM-1 (P=0.041) increased transiently from baseline to week 4 in the abacavir arm compared with the tenofovir arm, but no long-term increases were detected. We found no significant differences between study arms in the levels or changes in the levels of sICAM-1, MPO, d-dimer, IL-6, or hs-CRP. Levels of total cholesterol and high density lipoprotein (HDL) increased in the abacavir arm relative to the tenofovir arm, but no difference was found in total cholesterol/HDL ratio.

Conclusion: In patients randomized to abacavir-based HIV-treatment transient increases were seen in the plasma levels of E-selectin and sVCAM-1 compared with treatment with tenofovir, but no difference between study arms was found in other biomarkers associated with endothelial dysfunction, inflammation, or coagulation. The clinical significance of these findings is uncertain. TRIAL REGESTRATION: Clinicaltrials.gov identifier: NCT00647244.

Figures

Figure 1
Figure 1
Flow chart of inclusion and follow up. No figure legends.
Figure 2
Figure 2
Median levels of cardiovascular biomarkers and fasting lipids during study treatment according to study arm. Hs-CRP = high sensitivity C-reactive protein; IL-6 = interleukin 6; sVCAM-1 = soluble vascular adhesion molecule-1; slCAM-1 = soluble intercellular adhesion molecule-1; MPO = myeloperoxidase; LDL = low density lipoprotein; HDL = high density lipoprotein. Whiskers indicate interquartile ranges. * P < 0.05 for ABC/3TC compared with TDF/FTC arm at the specific time point using Wilcoxon rank sum test.
Figure 3
Figure 3
Proportion with hs-CRP > 1 mg/L according to study arm. The proportion of patients with hs-CRP > 1 mg/L is shown for each treatment arm at the various time points. At each time point, the two study arms are compared using χ2;-test; corresponding P-values are indicated above the graphs. Hs-CRP = high sensitivity C-reactive protein.

References

    1. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, Dabis F, De WS, Law M, D'Arminio MA, Friis-Moller N, Kirk O, Pradier C, Weller I, Phillips AN, Lundgren JD. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multi-cohort collaboration. Lancet. 2008;371(9622):1417–1426.
    1. Ribaudo HJ, Benson CA, Zheng Y, Koletar SL, Collier AC, Lok JJ, Smurzynski M, Bosch RJ, Bastow B, Schouten JT. No risk of myocardial infarction associated with initial antiretroviral treatment containing abacavir: short and long-term results from ACTG A5001/ALLRT. Clin Infect Dis. 2011;52(7):929–940. doi: 10.1093/cid/ciq244.
    1. Bedimo RJ, Westfall AO, Drechsler H, Vidiella G, Tebas P. Abacavir use and risk of acute myocardial infarction and cerebrovascular events in the highly active antiretroviral therapy era. Clin Infect Dis. 2011;53(1):84–91. doi: 10.1093/cid/cir269.
    1. Obel N, Farkas DK, Kronborg G, Larsen CS, Pedersen G, Riis A, Pedersen C, Gerstoft J, Sorensen HT. Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study. HIVMed. 2010;11(2):130–136.
    1. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, Boccara F, Costagliola D. 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 Med. 2010;170(14):1228–1238. doi: 10.1001/archinternmed.2010.197.
    1. Brothers CH, Hernandez JE, Cutrell AG, Curtis L, Ait-Khaled M, Bowlin SJ, Hughes SH, Yeo JM, Lapierre DH. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. JAcquirImmuneDeficSyndr. 2009;51(1):20–28.
    1. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22(14):F17–F24.
    1. Martin A, Bloch M, Amin J, Baker D, Cooper DA, Emery S, Carr A. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-Lamivudine: a randomized, 96-week trial. ClinInfectDis. 2009;49(10):1591–1601.
    1. Martinez E, Arranz JA, Podzamczer D, Lonca M, Sanz J, Barragan P, Ribera E, Knobel H, Roca V, Gutierrez F, Blanco JL, Mallolas J, Llibre JM, Clotet B, Dalmau D, Segura F, Arribas JR, Cosin J, Barrufet P, Casas E, Ferrer E, Curran A, Gonzalez A, Pich J, Cruceta A, Arnaiz JA, Miro JM, Gatell JM. 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. JAcquirImmuneDeficSyndr. 2009;51(3):290–297.
    1. Sax PE, Tierney C, Collier AC, Fischl MA, Mollan K, Peeples L, Godfrey C, Jahed NC, Myers L, Katzenstein D, Farajallah A, Rooney JF, Ha B, Woodward WC, Koletar SL, Johnson VA, Geiseler PJ, Daar ES. Abacavir-lamivudine versus tenofovir-emtricitabine for initial HIV-1 therapy. NEnglJMed. 2009;361(23):2230–2240. doi: 10.1056/NEJMoa0906768.
    1. Smith KY, Patel P, Fine D, Bellos N, Sloan L, Lackey P, Kumar PN, Sutherland-Phillips DH, Vavro C, Yau L, Wannamaker P, Shaefer MS. Randomized, double-blind, placebo-matched, multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23(12):1547–1556. doi: 10.1097/QAD.0b013e32832cbcc2.
    1. Ding A-CE X, Cooper C, Miele P, Kornegay C, Soukup M, Marcus K. 18th Conference on Retroviruses and Opportunistic Infections. Boston; 2011. No Association of Myocardial Infarction with Abacavir Use. Abstract # O-1004.
    1. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, Wensley F, Higgins JP, Lennon L, Eiriksdottir G, Rumley A, Whincup PH, Lowe GD, Gudnason V. Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoSMed. 2008;5(4):e78.
    1. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. NEnglJMed. 2004;350(14):1387–1397. doi: 10.1056/NEJMoa032804.
    1. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. NEnglJMed. 2000;342(12):836–843. doi: 10.1056/NEJM200003233421202.
    1. Hammond E, McKinnon E, Mallal S, Nolan D. Longitudinal evaluation of cardiovascular disease-associated biomarkers in relation to abacavir therapy. AIDS. 2008;22(18):2540–2543. doi: 10.1097/QAD.0b013e328319807f.
    1. Jong E, Meijers JC, van Gorp EC, Spek CA, Mulder JW. Markers of inflammation and coagulation indicate a prothrombotic state in HIV-infected patients with long-term use of antiretroviral therapy with or without abacavir. AIDS ResTher. 2010;7:9.
    1. Martinez E, Larrousse M, Podzamczer D, Perez I, Gutierrez F, Lonca M, Barragan P, Deulofeu R, Casamitjana R, Mallolas J, Pich J, Gatell JM. Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction. AIDS. 2010;24(3):F1–F9. doi: 10.1097/QAD.0b013e32833562c5.
    1. Kristoffersen US, Kofoed K, Kronborg G, Benfield T, Kjaer A, Lebech AM. Changes in biomarkers of cardiovascular risk after a switch to abacavir in HIV-1-infected individuals receiving combination antiretroviral therapy. HIVMed. 2009;10(10):627–633.
    1. Humphries A, Amin J, Cooper D, Carr A, Kelleher A, Bloch M. Paper #718, 17th Conference on Retroviruses and Oppertunistic Infections. San Francisco, USA; 2010. Changes in Cardiovascular Biomarkers with Abacavir: A Randomized, 96-week trial.
    1. Wilson PW, D'Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97(18):1837–1847.
    1. Pearson TA, Bazzarre TL, Daniels SR, Fair JM, Fortmann SP, Franklin BA, Goldstein LB, Hong Y, Mensah GA, Sallis JF, Smith S, Stone NJ, Taubert KA. American Heart Association guide for improving cardiovascular health at the community level: a statement for public health practitioners, healthcare providers, and health policy makers from the American Heart Association Expert Panel on Population and Prevention Science. Circulation. 2003;107(4):645–651. doi: 10.1161/01.CIR.0000054482.38437.13.
    1. Sabatine MS, Morrow DA, Jablonski KA, Rice MM, Warnica JW, Domanski MJ, Hsia J, Gersh BJ, Rifai N, Ridker PM, Pfeffer MA, Braunwald E. Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease. Circulation. 2007;115(12):1528–1536. doi: 10.1161/CIRCULATIONAHA.106.649939.
    1. Padilla S, Masia M, Garcia N, Jarrin I, Tormo C, Gutierrez F. Early changes in inflammatory and pro-thrombotic biomarkers in patients initiating antiretroviral therapy with abacavir or tenofovir. BMC Infect Dis. 2011;11(1):40. doi: 10.1186/1471-2334-11-40.
    1. De PC, Orden S, Apostolova N, Blanquer A, Esplugues JV, Alvarez A. Abacavir and didanosine induce the interaction between human leukocytes and endothelial cells through Mac-1 upregulation. AIDS. 2010;24(9):1259–1266.
    1. Mulvihill NT, Foley JB, Murphy R, Crean P, Walsh M. Evidence of prolonged inflammation in unstable angina and non-Q wave myocardial infarction. JAmCollCardiol. 2000;36(4):1210–1216.
    1. Blankenberg S, Rupprecht HJ, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J. Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation. 2001;104(12):1336–1342. doi: 10.1161/hc3701.095949.
    1. Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis. 2003;170(2):191–203. doi: 10.1016/S0021-9150(03)00097-2.
    1. Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM, Boerwinkle E. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation. 1997;96(12):4219–4225.
    1. Melchjorsen J, Risor MW, Sogaard OS, O'Loughlin K L, Chow S, Paludan SR, Ellermann-Eriksen S, Hedley DW, Phd HM, Ostergaard L, Phd MT. Tenofovir selectively regulates production of inflammatory cytokines and shifts the IL-12/IL-10 balance in human primary cells. J Acquir Immune Defic Syndr. 2011.

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