Is there continued evidence for an association between abacavir usage and myocardial infarction risk in individuals with HIV? A cohort collaboration

Caroline A Sabin, Peter Reiss, Lene Ryom, Andrew N Phillips, Rainer Weber, Matthew Law, Eric Fontas, Amanda Mocroft, Stephane de Wit, Colette Smith, Francois Dabis, Antonella d'Arminio Monforte, Wafaa El-Sadr, Jens D Lundgren, D:A:D Study Group, Caroline A Sabin, Peter Reiss, Lene Ryom, Andrew N Phillips, Rainer Weber, Matthew Law, Eric Fontas, Amanda Mocroft, Stephane de Wit, Colette Smith, Francois Dabis, Antonella d'Arminio Monforte, Wafaa El-Sadr, Jens D Lundgren, D:A:D Study Group

Abstract

Background: In March 2008, the D:A:D study published results demonstrating an increased risk of myocardial infarction (MI) for patients on abacavir (ABC). We describe changes to the use of ABC since this date, and investigate changes to the association between ABC and MI with subsequent follow-up.

Methods: A total of 49,717 D:A:D participants were followed from study entry until the first of an MI, death, 1 February 2013 or 6 months after last visit. Associations between a person's 10-year cardiovascular disease (CVD) risk and the likelihood of initiating or discontinuing ABC were assessed using multivariable logistic/Poisson regression. Poisson regression was used to assess the association between current ABC use and MI risk, adjusting for potential confounders, and a test of interaction was performed to assess whether the association had changed in the post-March 2008 period.

Results: Use of ABC increased from 10 % of the cohort in 2000 to 20 % in 2008, before stabilising at 18-19 %. Increases in use pre-March 2008, and subsequent decreases, were greatest in those at moderate and high CVD risk. Post-March 2008, those on ABC at moderate/high CVD risk were more likely to discontinue ABC than those at low/unknown CVD risk, regardless of viral load (≤1,000 copies/ml: relative rate 1.49 [95 % confidence interval 1.34-1.65]; >1,000 copies/ml: 1.23 [1.02-1.48]); no such associations were seen pre-March 2008. There was some evidence that antiretroviral therapy (ART)-naïve persons at moderate/high CVD risk post-March 2008 were less likely to initiate ABC than those at low/unknown CVD risk (odds ratio 0.74 [0.48-1.13]). By 1 February 2013, 941 MI events had occurred in 367,559 person-years. Current ABC use was associated with a 98 % increase in MI rate (RR 1.98 [1.72-2.29]) with no difference in the pre- (1.97 [1.68-2.33]) or post- (1.97 [1.43-2.72]) March 2008 periods (interaction P = 0.74).

Conclusions: Despite a reduction in the channelling of ABC for patients at higher CVD risk since 2008, we continue to observe an association between ABC use and MI risk. Whilst confounding cannot be fully ruled out, this further diminishes channelling bias as an explanation for our findings.

Keywords: Abacavir; Cardiovascular disease; Channelling bias; Confounding; Myocardial infarction; Risk.

Figures

Fig. 1
Fig. 1
Changes to the use of ABC in the D:A:D cohort over time, overall and among groups stratified by CVD risk

References

    1. Sabin C, Worm S, Weber R, El-Sadr W, Reiss P, Thiebaut R, et al. Do thymidine analogues, abacavir, didanosine and lamivudine contribute to the risk of myocardial infarction? The D:A:D Study. Poster 957c. 15th Conference on Retroviruses and Opportunistic Infections, Boston, 3–6 February 2008.
    1. D:A:D Study Group. Sabin CA, Worm SW, Weber R, Reiss P, El-Sadr W, et al. 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;371:1417–26. doi: 10.1016/S0140-6736(08)60423-7.
    1. Strategies for Management of Anti-Retroviral Therapy/INSIGHT; DAD Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS. 2008;22:F17–24.
    1. Martin A, Bloch M, Amin J, Baker D, Cooper DA, Emery S, et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-lamivudine: a randomized, 96 week trial. Clin Infect Dis. 2009;49:1591–601. doi: 10.1086/644769.
    1. Obel N, Farkas DK, Kronborg G, Larsen CS, Pedersen G, Riis A, et al. Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study. HIV Med. 2010;11:130–6. doi: 10.1111/j.1468-1293.2009.00751.x.
    1. Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL. Association between HIV infection, antiretroviral therapy, and risk of myocardial infarction: a cohort and nested case-control study using Québec's public health insurance database. J Acquir Immune Defic Syndr. 2011;57:245–53. doi: 10.1097/QAI.0b013e31821d33a5.
    1. Choi AI, Vittinghoff E, Deeks SG, Weekley CC, Li Y, Shlipak MG. Cardiovascular risks associated with abacavir and tenofovir exposure in HIV-infected persons. AIDS. 2011;25:1289–98. doi: 10.1097/QAD.0b013e328347fa16.
    1. Palella FJ, Althoff KN, Moore R, Zhang J, Kitahata M, Gange SJ, et al. Abacavir use and risk for myocardial infarction in the NA-ACCORD. Poster 749LB. 22nd Conference on Retroviruses and Opportunistic Infections, Seattle, 23–26 February 2015.
    1. Young J, Xiao Y, Moodie EEM, Abrahamowicz M, Klein MB, Bernasconi E, et al. Effect of cumulating exposure to abacavir on the risk of cardiovascular disease events in patients from the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 2015;69:413–21.
    1. Triant VA, Regan S, Lee H, Sax PE, Meigs JB, Grinspoon SK. Association of immunologic and virologic factors with myocardial infarction rates in a US healthcare system. J Acquir Immune Defic Syndr. 2010;55:615–9. doi: 10.1097/QAI.0b013e3181f4b752.
    1. Brothers CH, Hernandez JE, Cutrell AG, Curtis L, Ait-Khaled M, Bowlin SJ, et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immun Defic Syndr. 2009;51:20–8. doi: 10.1097/QAI.0b013e31819ff0e6.
    1. Ribaudo HJ, Benson CA, Zheng Y, Koletar SL, Collier AC, Lok JJ, et al. 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;52:929–40. doi: 10.1093/cid/ciq244.
    1. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al. Impact of individual antiretroviral drugs on the risk of myocardial infarction in human immunodeficiency virus-infected patients. Arch Int Med. 2010;170:1228–38. doi: 10.1001/archinternmed.2010.197.
    1. Bedimo RJ, Westfall AO, Brechsler 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;53:84–91. doi: 10.1093/cid/cir269.
    1. Ding X, Andraca-Carrera E, Cooper C, Miele P, Kornegay C, Soukup M, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Aquir Immun Defic Syndr. 2012;61:441–7. doi: 10.1097/QAI.0b013e31826f993c.
    1. Cruciani M, Zanichelli V, Serpelloni G, Bosco O, Malena M, Mazzi R, et al. Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data. AIDS. 2011;25:1993–2004. doi: 10.1097/QAD.0b013e328349c6ee.
    1. Satchell CS, O’Halloran JA, Cotter AG, Peace AJ, O’Connor EF, Tedesco AF, et al. Increased platelet reactivity in HIV-1-infected patients receiving abacavir-containing antiretroviral therapy. J Infect Dis. 2011;204:1202–10. doi: 10.1093/infdis/jir509.
    1. Baum PD, Sullam PM, Stoddart CA, McCune JM. Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase. AIDS. 2011;25:2243–8. doi: 10.1097/QAD.0b013e32834d3cc3.
    1. Falcinelli E, Francisci D, Belfiori B, Petito E, Guglielmini G, Malincarne L, et al. In vivo platelet activation and platelet hyperreactivity in abacavir-treated HIV-infected patients. Thromb Haemost. 2013;110:349–57. doi: 10.1160/TH12-07-0504.
    1. Katlama C, Fenske S, Gazzard B, Lazzarin A, Clumeck N, Mallolas J, et al. TRIZAL study: switching from successful HAART to Trizivir (abacavir-lamivudine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. HIV Med. 2003;4:79–86. doi: 10.1046/j.1468-1293.2003.00139.x.
    1. Sabin CA, Worm S, Phillips AN, Lundgren JD. Abacavir and increased risk of myocardial infarction. Authors’ reply. Lancet. 2008;372:804–5. doi: 10.1016/S0140-6736(08)61332-X.
    1. British HIV Association British HIV Association Guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2012. HIV Med. 2014;15 Suppl 1:1–85.
    1. European AIDS Clinical Society. Guidelines. Version 7.0. 2013. . Accessed 14 Oct 2014.
    1. Antoniou T, Gillis J, Loutfy MR, Cooper C, Hogg RS, Klein MB, et al. Impact of the Data Collection on Adverse Events of Anti-HIV Drugs cohort study on abacavir prescription among treatment-naïve, HIV-infected patients in Canada. J Int Assoc Prov AIDS Care. 2014;13:153–9. doi: 10.1177/2325957413495565.
    1. DAD Study Group. Friis-Møller N, Reiss P, Sabin CA, Weber R, Monforte AD, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356:1723–35. doi: 10.1056/NEJMoa062744.
    1. Tunstall-Pedoe H, Kuulasmaa K, Amouyel P, Arveiler D, Rajakangas AM, Pamak A. Myocardial infarction and coronary deaths in the World Health Organization MONICA Project registration procedures, event rates, and case-fatality rates in 38 populations from 21 countries in four continents. Circulation. 1994;90:583–612. doi: 10.1161/01.CIR.90.1.583.
    1. Friis-Moller N, Thiebaut R, Reiss P, Weber R, Monforte AD, de Wit S, et al. Predicting the risk of cardiovascular disease in HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J Cardiovasc Prev Rehabil. 2010;17:491–501. doi: 10.1097/HJR.0b013e328336a150.
    1. Mallon PW. Impact of nucleoside reverse transcriptase inhibitors on coronary heart disease. Rev Cardiovasc Med. 2014;15(Suppl 1):S21–9.
    1. Bavinger C, Bendavid E, Niehaus K, Olshen RA, Olkin I, Sundaram V, et al. Risk of cardiovascular disease from antiretroviral therapy for HIV: a systematic review. PLoS One. 2013;8:e59551. doi: 10.1371/journal.pone.0059551.
    1. Desai M, Joyce V, Bendavid E, Olshen RA, Hlatky M, Chow A, et al. Risk of cardiovascular events associated with current exposure to HIV antiretroviral therapies in a US Veteran population. Clin Infect Dis. 2015;61:445–52. doi: 10.1093/cid/civ316.
    1. Marcus JL, Neugebauer RS, Leyden WA, Chao CR, Xu L, Quesenberry CP, Jr, et al. Use of abacavir and risk of cardiovascular disease among HIV-infected individuals. J Acquir Immune Defic Syndr. 2016;71(4):413–9. doi: 10.1097/QAI.0000000000000881.
    1. Brouwer ES, Napravnik S, Eron JJ, Stalzer B, Floris-Moore M, Simpson RJ, et al. Effects of combination antiretroviral therapies on the risk of myocardial infarction among HIV patients. Epidemiology. 2014;25:406–17. doi: 10.1097/EDE.0000000000000041.
    1. Martin A, Amin J, Cooper DA, Carr A, Kelleher AD, Bloch M, et al. Abacavir does not affect circulating levels of inflammatory or coagulopathic biomarkers in suppressed HIV: a randomized clinical trial. AIDS. 2010;24:2657–63. doi: 10.1097/QAD.0b013e32833f147f.
    1. Ford ES, Grenwald JH, Richterman AG, Rupert A, Dutcher L, Badralmaa Y, et al. Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS. 2010;24:1509–17. doi: 10.1097/QAD.0b013e32833ad914.
    1. Kaplan RC, Landay AL, Hodis HN, Gange SJ, Norris PJ, Young M, et al. Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment. J Acquir Immun Defic Syndr. 2012;60:359–68. doi: 10.1097/QAI.0b013e31825b03be.
    1. McComsey GA, Kitch D, Daar ES, Tierney C, Jahed NC, Melbourne K, et al. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AIDS. 2012;26:1371–85. doi: 10.1097/QAD.0b013e328354f4fb.
    1. Rasmussen TA, Tolstrup M, Melchjorsen J, Frederiksen CA, Nielsen US, Langdahl BL, et al. Evaluation of cardiovascular biomarkers in HIV-infected persons switching to abacavir or tenofovir based therapy. BMC Infect Dis. 2011;11:267. doi: 10.1186/1471-2334-11-267.
    1. Hileman CO, Wohl DA, Tisch DJ, Debanne SM, McComsey GA. Initiation of an abacavir-containing regimen in HIV-infected adults is associated with a smaller decrease in inflammation and endothelial activation markers compared to non-abacavir-containing regimens. AIDS Res Hum Retrovir. 2012;28:1561–4. doi: 10.1089/aid.2012.0034.
    1. Hsue PY, Hunt PW, Wu Y, Schnell A, Jo JE, Hatano H, et al. Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. AIDS. 2009;23:2021–7. doi: 10.1097/QAD.0b013e32832e7140.
    1. McComsey GA, Kitch D, Sax PE, Tierney C, Jahed NC, Melbourne K, et al. Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202. J Acquir Immune Defic Syndr. 2014;65:167–74. doi: 10.1097/01.qai.0000437171.00504.41.
    1. Hammond E, McKinnon E, Mallal S, Nolan D. Longitudinal evaluation of cardiovascular disease-associated biomarkers in relation to abacavir therapy. AIDS. 2008;22:2540–3. doi: 10.1097/QAD.0b013e328319807f.
    1. Wohl DA, Arnoczy G, Fichtenbaum CJ, Campbell T, Taiwo B, Hicks C, et al. Comparison of cardiovascular disease risk markers in HIV-infected patients receiving abacavir and tenofovir: the nucleoside inflammation, coagulation and endothelial function (NICE) study. Antiviral Ther. 2014;19:141–7. doi: 10.3851/IMP2681.
    1. Patel P, Bush T, Overton T, Baker J, Hammer J, Kojic E, et al. Effect of abacavir on acute changes in biomarkers associated with cardiovascular dysfunction. Antiviral Ther. 2012;17:755–61. doi: 10.3851/IMP2020.
    1. Martinez E, Larrousse M, Podzamczer D, Perez I, Gutierrez F, Lonca M, et al. Abacavir-based therapy does not affect biological mechanisms associated with cardiovascular dysfunction. AIDS. 2010;24:F1–9. doi: 10.1097/QAD.0b013e32833562c5.
    1. De Luca A, de Gaetano Donati K, Cozzi-Lepri A, Colafigli M, de Curtis A, Capobianchi MR, et al. Exposure to abacavir and biomarkers of cardiovascular disease in HIV-1-infected patients on suppressive antiretroviral therapy: a longitudinal study. J Acquir Immun Defic Syndr. 2012;60:e98–e100. doi: 10.1097/QAI.0b013e318259875b.
    1. De Pablo C, 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;24:1259–66.
    1. De Pablo C, Orden S, Peris JE, Barrachina MD, Esplugues JV, Alvarez A. Profile of leukocyte-endothelial cell interactions induced in venules and arterioles by nucleoside reverse-transcriptase inhibitors in vivo. J Infect Dis. 2013;208:1448–53. doi: 10.1093/infdis/jit340.
    1. De Pablo C, Orden S, Calatayud S, Marti-Cabrera M, Esplugues JV, Alvarez A. Differential effects of tenofovir/emtricitabine and abacavir/lamivudine on human leukocyte recruitment. Antivir Ther. 2012;17:1615–9. doi: 10.3851/IMP2357.
    1. Papakonstantinou VD, Chini M, Mangafas N, Stamatakis GM, Tsogas N, Tsoupras AB, et al. In vivo effect of two first-line ART regimens on inflammatory mediators in male HIV patients. Lipids Health Dis. 2014;13:90. doi: 10.1186/1476-511X-13-90.
    1. Piconi S, Parisotto S, Rizzardini G, Passerini S, Meraviglia P, Schiavini M, et al. Atherosclerosis is associated with multiple pathogenic mechanisms in HIV-infected antiretroviral-naive or treated individuals. AIDS. 2013;27:381–9. doi: 10.1097/QAD.0b013e32835abcc9.
    1. Chini M, Tsoupras AB, Mangafas N, Tsogas N, Papakonstantinou VD, Fragopoulou E, et al. Effects of highly active antiretroviral therapy on platelet activating factor metabolism in naïve HIV-infected patients: ii) study of the abacavir/lamivudine/Efavirenz HAART regimen. Int J Immunopathol Pharmacol. 2012;25:247–58.
    1. Haugaard AK, Lund TT, Birch C, Fonsholt F, Troseid M, Ullum H, et al. Discrepant coagulation profile in HIV infection: elevated D-dimer but impaired platelet aggregation and clot initiation. AIDS. 2013;27:2749–58. doi: 10.1097/01.aids.0000432462.21723.ed.
    1. Danaei G, Tavakkoli M, Hernán MA. Bias in observational studies of prevalent users: lessons for comparative effectiveness research from a meta-analysis of statins. Am J Epidemiol. 2012;175:250–62. doi: 10.1093/aje/kwr301.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere