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Atherosclerotic Cardiovascular Disease and Anti-Retroviral Therapy

  • Complications of Antiretroviral Therapy (G McComsey, Section Editor)
  • Published:
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Abstract

In the current era of available therapy for human immunodeficiency virus (HIV), life expectancy for persons living with HIV (PLWH) nears that of the general population. Atherosclerotic cardiovascular disease (ASCVD) has become a particular burden for PLWH and society at large. PLWH have historically been shown to have an excess of cardiovascular risk and subsequent events when compared to the general population. Potential explanations include the increased prevalence of traditional risk factors, direct inflammatory and immunological effects from the HIV virus itself, and metabolic adverse effects of anti-retroviral therapy (ART). Over the past few years, there has been building evidence that chronic inflammation and immune activation independent of virologic suppression contribute significantly to excess ASCVD risk. Although independent agents and combination therapies have varying metabolic effects, the evidence from major randomized controlled trials (RCTs) supports the benefits of early initiation of ART. In this review, we will discuss the epidemiology of ASCVD in HIV-infected patients compared with the general population, give an overview of potential pathogenesis of high-risk plaque in HIV-infected patients, discuss different metabolic effects of individual anti-retrovirals, and discuss the limitations in current screening models for assessing cardiovascular disease (CVD) risk and future directions for treatment.

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References

  1. Samji H, Cescon A, Hogg RS, et al. Closing the gap: increases in life expectancy among treated HIV-positive individuals in the United States and Canada. PLoS One. 2013;8(12):e81355.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Wada N, Jacobson LP, Cohen M, French A, Phair J, Muñoz A. Cause-specific mortality among HIV-infected individuals, by CD4(+) cell count at HAART initiation, compared with HIV-uninfected individuals. AIDS (London, England). 2014;28(2):257–65.

    Article  CAS  Google Scholar 

  3. Miller V, Hodder S. Beneficial impact of antiretroviral therapy on non-AIDS mortality. AIDS (London, England). 2014;28(2):273–4.

    Article  Google Scholar 

  4. Richter A, Pladevall M, Manjunath R, et al. Patient characteristics and costs associated with dyslipidaemia and related conditions in HIV-infected patients: a retrospective cohort study. HIV Med. 2005;6(2):79–90.

    Article  CAS  PubMed  Google Scholar 

  5. Freiberg MS, Chang C-CH, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Currier JS, Taylor A, Boyd F, et al. Coronary heart disease in HIV-infected individuals. J Acquir Immune Defic Syndr 1999. 2003;33(4):506–12.

    Article  Google Scholar 

  7. Marcus JL, Leyden WA, Chao CR, et al. HIV infection and incidence of ischemic stroke. AIDS (London, England). 2014;28(13):1911–9.

    Article  CAS  Google Scholar 

  8. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Willerson JT, Ridker PM. Inflammation as a cardiovascular risk factor. Circulation. 2004;109(21 Suppl 1):II2–10.

    PubMed  Google Scholar 

  10. Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys. Ann Intern Med. 2015;162(5):335–44.

    Article  PubMed  Google Scholar 

  11. Wand H, Calmy A, Carey DL, et al. Metabolic syndrome, cardiovascular disease and type 2 diabetes mellitus after initiation of antiretroviral therapy in HIV infection. AIDS (London, England). 2007;21(18):2445–53.

    Article  CAS  Google Scholar 

  12. De Wit S, Sabin CA, Weber R, et al. Incidence and risk factors for new-onset diabetes in HIV-infected patients: the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study. Diabetes Care. 2008;31(6):1224–9.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Helleberg M, Afzal S, Kronborg G, et al. Mortality attributable to smoking among HIV-1-infected individuals: a nationwide, population-based cohort study. Clin Infect Dis. 2013;56(5):727–34.

    Article  PubMed  Google Scholar 

  14. Savès M, Chêne G, Ducimetière P, et al. Risk factors for coronary heart disease in patients treated for human immunodeficiency virus infection compared with the general population. Clin Infect Dis. 2003;37(2):292–8.

    Article  PubMed  Google Scholar 

  15. Kaplan RC, Kingsley LA, Sharrett AR, et al. Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis. 2007;45(8):1074–81.

    Article  PubMed  Google Scholar 

  16. Brown TT, Cole SR, Li X, et al. Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. Arch Intern Med. 2005;165(10):1179–84.

    Article  PubMed  Google Scholar 

  17. Rotger M, Glass TR, Junier T, et al. Contribution of genetic background, traditional risk factors, and HIV-related factors to coronary artery disease events in HIV-positive persons. Clin Infect Dis. 2013;57(1):112–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guallar E, Banegas JR, Blasco-Colmenares E, et al. Excess risk attributable to traditional cardiovascular risk factors in clinical practice settings across Europe—The EURIKA Study. BMC Public Health. 2011;11:704.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Silverberg MJ, Leyden WA, Xu L, et al. Immunodeficiency and risk of myocardial infarction among HIV-positive individuals with access to care. J Acquir Immune Defic Syndr 1999. 2014;65(2):160–6.

    Article  CAS  Google Scholar 

  20. Hanna DB, Ramaswamy C, Kaplan RC, Kizer JR, Anastos K, Daskalakis D, Zimmerman R, Braunstein SL. Trends in Cardiovascular disease mortality among Persons with HIV in New York City, 2001–2012. Clin Infect Dis. 2016. doi:10.1093/cid/ciw470.

  21. Byrd KK, Furtado M, Bush T, Gardner L. Evaluating patterns in retention, continuation, gaps, and re-engagement in HIV care in a Medicaid-insured population, 2006–2012, United States. AIDS Care. 2015;27(11):1387–95.

    Article  PubMed  Google Scholar 

  22. Gardner EM, McLees MP, Steiner JF, Del Rio C, Burman WJ. The spectrum of engagement in HIV care and its relevance to test-and-treat strategies for prevention of HIV infection. Clin Infect Dis. 2011;52(6):793–800.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Prevalence of diagnosed and undiagnosed HIV infection—United States, 2008–2012 [Internet]. [cited 2016 Mar 1]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6424a2.htm

  24. Crowell TA, Gebo KA, Blankson JN, Korthuis PT, Yehia BR, Rutstein RM, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis. 2014.

  25. Krishnan S, Wilson EMP, Sheikh V, et al. Evidence for innate immune system activation in HIV type 1-infected elite controllers. J Infect Dis. 2014;209(6):931–9.

    Article  CAS  PubMed  Google Scholar 

  26. Wachira D, Lihana R, Okoth V, Maiyo A, Khamadi SA. Chemokine coreceptor-2 gene polymorphisms among HIV-1 infected individuals in Kenya. Dis Markers. 2015;2015:952067.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Westhorpe CLV, Maisa A, Spelman T, et al. Associations between surface markers on blood monocytes and carotid atherosclerosis in HIV-positive individuals. Immunol Cell Biol. 2014;92(2):133–8.

    Article  CAS  PubMed  Google Scholar 

  28. Van Lelyveld SFL, Gras L, Kesselring A, et al. Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort. AIDS (London, England). 2012;26(4):465–74.

    Article  CAS  Google Scholar 

  29. Lang S, Mary-Krause M, Simon A, et al. HIV replication and immune status are independent predictors of the risk of myocardial infarction in HIV-infected individuals. Clin Infect Dis. 2012;55(4):600–7.

    Article  CAS  PubMed  Google Scholar 

  30. Bucher HC, Richter W, Glass TR, et al. Small dense lipoproteins, apolipoprotein B, and risk of coronary events in HIV-infected patients on antiretroviral therapy: the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr 1999. 2012;60(2):135–42.

    Article  CAS  Google Scholar 

  31. Helleberg M, Kronborg G, Larsen CS, et al. CD4 decline is associated with increased risk of cardiovascular disease, cancer, and death in virally suppressed patients with HIV. Clin Infect Dis. 2013;57(2):314–21.

    Article  CAS  PubMed  Google Scholar 

  32. Drozd D, Nance R, Delaney J. Lower CD4 count and higher viral load are associated with increased risk of myocardial infarction. In Boston, MA; (March 3–6, 2014).

  33. Hanna DB, Post WS, Deal JA, et al. HIV infection is associated with progression of subclinical carotid atherosclerosis. Clin Infect Dis. 2015;61(4):640–50.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Mujawar Z, Rose H, Morrow MP, et al. Human immunodeficiency virus impairs reverse cholesterol transport from macrophages. PLoS Biol. 2006;4(11):e365.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Reingold J, Wanke C, Kotler D, et al. Association of HIV infection and HIV/HCV coinfection with C-reactive protein levels: the fat redistribution and metabolic change in HIV infection (FRAM) study. J Acquir Immune Defic Syndr 1999. 2008;48(2):142–8.

    Article  CAS  Google Scholar 

  36. Tien PC, Choi AI, Zolopa AR, et al. Inflammation and mortality in HIV-infected adults: analysis of the FRAM study cohort. J Acquir Immune Defic Syndr 1999. 2010;55(3):316–22.

    Article  CAS  Google Scholar 

  37. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207.

    Article  CAS  PubMed  Google Scholar 

  38. Albert MA, Danielson E, Rifai N, Ridker PM. PRINCE Investigators. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286(1):64–70.

    Article  CAS  PubMed  Google Scholar 

  39. Shikuma CM, Ribaudo HJ, Zheng Y, et al. Change in high-sensitivity c-reactive protein levels following initiation of efavirenz-based antiretroviral regimens in HIV-infected individuals. AIDS Res Hum Retroviruses. 2011;27(5):461–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. McComsey GA, Kitch D, Daar ES, et al. Inflammation markers after randomization to abacavir/lamivudine or tenofovir/emtricitabine with efavirenz or atazanavir/ritonavir. AIDS (London, England). 2012;26(11):1371–85.

    Article  CAS  Google Scholar 

  41. Kelesidis T, Tran TTT, Stein JH, et al. Changes in inflammation and immune activation with atazanavir-, raltegravir-, darunavir-based initial antiviral therapy: ACTG 5260s. Clin Infect Dis Off Publ Infect Dis Soc Am. 2015;61(4):651–60.

    Article  Google Scholar 

  42. Fichtenbaum CJ, Yeh T-M, Evans SR, Aberg JA. Treatment with pravastatin and fenofibrate improves atherogenic lipid profiles but not inflammatory markers in ACTG 5087. J Clin Lipidol. 2010;4(4):279–87.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy. J Acquir Immune Defic Syndr 1999. 2015;68(4):396–404.

    Article  CAS  Google Scholar 

  44. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008;5(10):e203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One. 2012;7(9):e44454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Armah KA, McGinnis K, Baker J, et al. HIV status, burden of comorbid disease, and biomarkers of inflammation, altered coagulation, and monocyte activation. Clin Infect Dis. 2012;55(1):126–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Longenecker CT, Jiang Y, Orringer CE, et al. Soluble CD14 is independently associated with coronary calcification and extent of subclinical vascular disease in treated HIV infection. AIDS (London, England). 2014;28(7):969–77.

    Article  CAS  Google Scholar 

  48. Subramanian S, Tawakol A, Burdo TH, et al. Arterial inflammation in patients with HIV. JAMA. 2012;308(4):379–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Burdo TH, Lo J, Abbara S, et al. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis. 2011;204(8):1227–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kelesidis T, Kendall MA, Yang OO, Hodis HN, Currier JS. Biomarkers of microbial translocation and macrophage activation: association with progression of subclinical atherosclerosis in HIV-1 infection. J Infect Dis. 2012;206(10):1558–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Francisci D, Giannini S, Baldelli F, et al. HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction. AIDS (London, England). 2009;23(5):589–96.

    Article  Google Scholar 

  52. Hulten E, Mitchell J, Scally J, Gibbs B, Villines TC. HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies. Heart Br Card Soc. 2009;95(22):1826–35.

    Article  CAS  Google Scholar 

  53. Grunfeld C, Delaney JAC, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS (London, England). 2009;23(14):1841–9.

    Article  Google Scholar 

  54. Hsue PY, Scherzer R, Hunt PW, Schnell A, Bolger AF, Kalapus SC, et al. Carotid intima-media thickness progression in HIV-infected adults occurs preferentially at the carotid bifurcation and is predicted by inflammation. J Am Heart Assoc. 2012. 1(2).

  55. Baker JV, Duprez D, Rapkin J, et al. Untreated HIV infection and large and small artery elasticity. J Acquir Immune Defic Syndr 1999. 2009;52(1):25–31.

    Article  Google Scholar 

  56. Torriani FJ, Komarow L, Parker RA, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: the ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol. 2008;52(7):569–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Schuetz A, Deleage C, Sereti I, et al. Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation. PLoS Pathog. 2014;10(12):e1004543.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Yukl SA, Shergill AK, Girling V, et al. Site-specific differences in T cell frequencies and phenotypes in the blood and gut of HIV-uninfected and ART-treated HIV+ adults. PLoS One. 2015;10(3):e0121290.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Mavigner M, Cazabat M, Dubois M, et al. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest. 2012;122(1):62–9.

    Article  CAS  PubMed  Google Scholar 

  60. Vyboh K, Jenabian M-A, Mehraj V, Routy J-P. HIV and the gut microbiota, partners in crime: breaking the vicious cycle to unearth new therapeutic targets. J Immunol Res. 2015;2015:614127.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Sandler NG, Wand H, Roque A, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis. 2011;203(6):780–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hunt PW, Sinclair E, Rodriguez B, et al. Gut epithelial barrier dysfunction and innate immune activation predict mortality in treated HIV infection. J Infect Dis. 2014;210(8):1228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hsue PY, Hunt PW, Sinclair E, et al. Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS (London, England). 2006;20(18):2275–83.

    Article  Google Scholar 

  64. Sacre K, Hunt PW, Hsue PY, et al. A role for cytomegalovirus-specific CD4+CX3CR1+ T cells and cytomegalovirus-induced T-cell immunopathology in HIV-associated atherosclerosis. AIDS (London, England). 2012;26(7):805–14.

    Article  CAS  Google Scholar 

  65. DAD Study Group, Friis-Møller N, Reiss P, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007;356(17):1723–35.

    Article  Google Scholar 

  66. Friis-Møller N, Sabin CA, Weber R, d’ Arminio Monforte A, El-Sadr WM, Reiss P, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003;349(21):1993–2003.

    Article  PubMed  Google Scholar 

  67. Bozzette SA, Ake CF, Tam HK, Chang SW, Louis TA. Cardiovascular and cerebrovascular events in patients treated for human immunodeficiency virus infection. N Engl J Med. 2003;348(8):702–10.

    Article  CAS  PubMed  Google Scholar 

  68. INSIGHT START Study Group, Lundgren JD, Babiker AG, et al. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373(9):795–807.

    Article  CAS  Google Scholar 

  69. ANRS TEMPRANO 12136 Study Group, Danel C, Moh R, Gabillard D, Badje A, Le Carrou J, et al. A trial of early antiretrovirals and isoniazid preventive therapy in Africa. N Engl J Med. 2015;373(9):808–22.

    Article  CAS  Google Scholar 

  70. HIV/AIDS guidelines—adult_oi.pdf [Internet]. [cited 2015 Dec 27]. Available from: https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf

  71. Labhardt ND, Cheleboi M, Faturyiele O, et al. Higher rates of metabolic syndrome among women taking zidovudine as compared to tenofovir in rural Africa: preliminary data from the CART-1 study. J Int AIDS Soc. 2014;17(4 Suppl 3):19552.

    PubMed  PubMed Central  Google Scholar 

  72. Domingo P, del Gutierrez M, Gallego-Escuredo JM, et al. Effects of switching from stavudine to raltegravir on subcutaneous adipose tissue in HIV-infected patients with HIV/HAART-associated lipodystrophy syndrome (HALS). A clinical and molecular study. PloS One. 2014;9((2).

  73. Hammond E, McKinnon E, Nolan D. Human immunodeficiency virus treatment-induced adipose tissue pathology and lipoatrophy: prevalence and metabolic consequences. Clin Infect Dis. 2010;51(5):591–9.

    Article  PubMed  Google Scholar 

  74. Worm SW, Sabin C, Weber R, et al. 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(3):318–30.

    Article  CAS  PubMed  Google Scholar 

  75. Strategies for Management of Antiretroviral Therapy (SMART) Study Group, El-Sadr WM, Lundgren JD, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96.

    Article  Google Scholar 

  76. Martin A, Bloch M, Amin J, et al. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir-Lamivudine: a randomized, 96-week trial. Clin Infect Dis. 2009;49(10):1591–601.

    Article  CAS  PubMed  Google Scholar 

  77. 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 (London, England). 2011;25(10):1289–98.

    Article  CAS  Google Scholar 

  78. 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 (London, England). 2008;22(14):F17–24.

    Article  CAS  Google Scholar 

  79. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108(17):2154–69.

    Article  PubMed  Google Scholar 

  80. Chronic Kidney Disease Prognosis Consortium, Matsushita K, van der Velde M, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet Lond Engl. 2010;375(9731):2073–81.

    Article  Google Scholar 

  81. Marcus JL, Neugebauer RS, Leyden WA, et al. Use of abacavir and risk of cardiovascular disease among HIV-infected individuals. J Acquir Immune Defic Syndr. 2016;71(4):413–9.

    Article  CAS  PubMed  Google Scholar 

  82. Martin A, Amin J, Cooper DA, et al. Abacavir does not affect circulating levels of inflammatory or coagulopathic biomarkers in suppressed HIV: a randomized clinical trial. AIDS (London, England). 2010;24(17):2657–63.

    Article  CAS  Google Scholar 

  83. Palella FJ, Gange SJ, Benning L, et al. Inflammatory biomarkers and abacavir use in the Women’s Interagency HIV Study and the Multicenter AIDS Cohort Study. AIDS (London, England). 2010;24(11):1657–65.

    Article  CAS  Google Scholar 

  84. Hsue PY, Hunt PW, Wu Y, et al. Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. AIDS (London, England). 2009;23(15):2021–7.

    Article  CAS  Google Scholar 

  85. 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 (London, England). 2010;24(9):1259–66.

    Google Scholar 

  86. Abacavir increases platelet reactivity via competitive inhibition of soluble guanylyl cyclase. - PubMed - NCBI [Internet]. [cited 2015 Dec 27]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/?term=Baum+P+et+al.+Abacavir+increases+platelet+reactivity+via+competitive+inhibition+of+soluble+guanylyl+cyclase.+AIDS+2011

  87. Ribaudo HJ, Benson CA, Zheng Y, 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(7):929–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Brothers CH, Hernandez JE, Cutrell AG, et al. Risk of myocardial infarction and abacavir therapy: no increased risk across 52 GlaxoSmithKline-sponsored clinical trials in adult subjects. J Acquir Immune Defic Syndr 1999. 2009;51(1):20–8.

    Article  CAS  Google Scholar 

  89. Cruciani M, Zanichelli V, Serpelloni G, et al. Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data. AIDS (London, England). 2011;25(16):1993–2004.

    Article  CAS  Google Scholar 

  90. 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.

    Article  CAS  PubMed  Google Scholar 

  91. Ding X, Andraca-Carrera E, Cooper C, et al. No association of abacavir use with myocardial infarction: findings of an FDA meta-analysis. J Acquir Immune Defic Syndr 1999. 2012;61(4):441–7.

    Article  CAS  Google Scholar 

  92. Crane HM, Grunfeld C, Willig JH, et al. Impact of NRTIs on lipid levels among a large HIV-infected cohort initiating antiretroviral therapy in clinical care. AIDS (London, England). 2011;25(2):185–95.

    Article  CAS  Google Scholar 

  93. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr 1999. 2014;67(1):52–8.

    Article  CAS  Google Scholar 

  94. Mills A, Arribas JR, Andrade-Villanueva J, DiPerri G, Van Lunzen J, Koenig E, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study. Lancet Infect Dis. 2015.

  95. Fontas E, van Leth F, Sabin CA, Friis-Møller N, Rickenbach M, d’ Arminio Monforte A, et al. Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? J Infect Dis. 2004;189(6):1056–74.

    Article  CAS  PubMed  Google Scholar 

  96. Tebas P, Sension M, Arribas J, et al. Lipid levels and changes in body fat distribution in treatment-naive, HIV-1-infected adults treated with rilpivirine or Efavirenz for 96 weeks in the ECHO and THRIVE trials. Clin Infect Dis. 2014;59(3):425–34.

    Article  CAS  PubMed  Google Scholar 

  97. Negredo E, Ribalta J, Ferré R, et al. Efavirenz induces a striking and generalized increase of HDL-cholesterol in HIV-infected patients. AIDS (London, England). 2004;18(5):819–21.

    Article  CAS  Google Scholar 

  98. Pereira SA, Branco T, Côrte-Real RM, et al. Long-term and concentration-dependent beneficial effect of efavirenz on HDL-cholesterol in HIV-infected patients. Br J Clin Pharmacol. 2006;61(5):601–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med. 2005;352(1):48–62.

    Article  CAS  PubMed  Google Scholar 

  100. Monforte AD, Reiss P, Ryom L, El-Sadr W, Dabis F, De Wit S, et al. Atazanavir is not associated with an increased risk of cardio- or cerebrovascular disease events. AIDS (London, England). 2013;27(3):407–15.

    Article  CAS  Google Scholar 

  101. Möbius U, Lubach-Ruitman M, Castro-Frenzel B, et al. Switching to atazanavir improves metabolic disorders in antiretroviral-experienced patients with severe hyperlipidemia. J Acquir Immune Defic Syndr 1999. 2005;39(2):174–80.

    Google Scholar 

  102. Ofotokun I, Na LH, Landovitz RJ, et al. Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis. 2015;60(12):1842–51.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Aberg JA, Tebas P, Overton ET, et al. Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treatment-naive, HIV type 1-infected subjects over 48 weeks. AIDS Res Hum Retroviruses. 2012;28(10):1184–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Martinez E, Gonzalez-Cordon A, Ferrer E, et al. Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: a randomized clinical trial. Clin Infect Dis. 2015;60(5):811–20.

    Article  PubMed  Google Scholar 

  105. Mary-Krause M, Cotte L, Simon A, Partisani M, Costagliola D. Clinical Epidemiology Group from the French Hospital Database. Increased risk of myocardial infarction with duration of protease inhibitor therapy in HIV-infected men. AIDS (London, England). 2003;17(17):2479–86.

    Article  Google Scholar 

  106. Wang X, Sato R, Brown MS, Hua X, Goldstein JL. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell. 1994;77(1):53–62.

    Article  CAS  PubMed  Google Scholar 

  107. Caron M, Auclair M, Sterlingot H, Kornprobst M, Capeau J. Some HIV protease inhibitors alter lamin A/C maturation and stability, SREBP-1 nuclear localization and adipocyte differentiation. AIDS (London, England). 2003;17(17):2437–44.

    Article  CAS  Google Scholar 

  108. Murata H, Hruz PW, Mueckler M. Investigating the cellular targets of HIV protease inhibitors: implications for metabolic disorders and improvements in drug therapy. Curr Drug Targets Infect Disord. 2002;2(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  109. Chow WA, Guo S, Valdes-Albini F. Nelfinavir induces liposarcoma apoptosis and cell cycle arrest by upregulating sterol regulatory element binding protein-1. Anticancer Drugs. 2006;17(8):891–903.

    Article  CAS  PubMed  Google Scholar 

  110. Miserez AR, Muller PY, Spaniol V. Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations. AIDS (London, England). 2002;16(12):1587–94.

    Article  CAS  Google Scholar 

  111. Lee GA, Schwarz J-M, Patzek S, et al. The acute effects of HIV protease inhibitors on insulin suppression of glucose production in healthy HIV-negative men. J Acquir Immune Defic Syndr 1999. 2009;52(2):246–8.

    Article  CAS  Google Scholar 

  112. Rudich A, Ben-Romano R, Etzion S, Bashan N. Cellular mechanisms of insulin resistance, lipodystrophy and atherosclerosis induced by HIV protease inhibitors. Acta Physiol Scand. 2005;183(1):75–88.

    Article  CAS  PubMed  Google Scholar 

  113. Mulligan K, Grunfeld C, Tai VW, et al. Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr 1999. 2000;23(1):35–43.

    Article  CAS  Google Scholar 

  114. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem. 2000;275(27):20251–4.

    Article  CAS  PubMed  Google Scholar 

  115. Rudich A, Vanounou S, Riesenberg K, et al. The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes. Diabetes. 2001;50(6):1425–31.

    Article  CAS  PubMed  Google Scholar 

  116. Ben-Romano R, Rudich A, Török D, et al. Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors. AIDS (London, England). 2003;17(1):23–32.

    Article  CAS  Google Scholar 

  117. Bastard JP, Caron M, Vidal H, et al. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet Lond Engl. 2002;359(9311):1026–31.

    Article  CAS  Google Scholar 

  118. Noor MA, Flint OP, Maa J-F, Parker RA. Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically. AIDS (London, England). 2006;20(14):1813–21.

    Article  CAS  Google Scholar 

  119. Noor MA, Parker RA, O’Mara E, et al. The effects of HIV protease inhibitors atazanavir and lopinavir/ritonavir on insulin sensitivity in HIV-seronegative healthy adults. AIDS (London, England). 2004;18(16):2137–44.

    Article  CAS  Google Scholar 

  120. Collot-Teixeira S, De Lorenzo F, Waters L, et al. Impact of different low-dose ritonavir regimens on lipids, CD36, and adipophilin expression. Clin Pharmacol Ther. 2009;85(4):375–8.

    Article  CAS  PubMed  Google Scholar 

  121. Carey D, Amin J, Boyd M, Petoumenos K, Emery S. Lipid profiles in HIV-infected adults receiving atazanavir and atazanavir/ritonavir: systematic review and meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2010;65(9):1878–88.

    Article  CAS  PubMed  Google Scholar 

  122. Molina J-M, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet Lond Engl. 2008;372(9639):646–55.

    Article  CAS  Google Scholar 

  123. De Saint-Martin L, Bressollette L, Perfezou P, et al. Impact of atazanavir-based HAART regimen on the carotid intima-media thickness of HIV-infected persons: a comparative prospective cohort. AIDS (London, England). 2010;24(18):2797–801.

    Article  CAS  Google Scholar 

  124. Stein JH, Ribaudo HJ, Hodis HN, et al. A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness. AIDS (London, England). 2015;29(14):1775–83.

    Article  CAS  Google Scholar 

  125. Rockstroh JK, Lennox JL, Dejesus E, et al. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis. 2011;53(8):807–16.

    Article  CAS  PubMed  Google Scholar 

  126. Stribild package insert, Gilead sciences. https://www.gilead.com/~/media/files/pdfs/medicines/hiv/stribild/stribild_pi.pdf?la=en (accessed on January 3rd, 2016).

  127. MacInnes A, Lazzarin A, Di Perri G, et al. Maraviroc can improve lipid profiles in dyslipidemic patients with HIV: results from the MERIT trial. HIV Clin Trials. 2011;12(1):24–36.

    Article  CAS  PubMed  Google Scholar 

  128. Cooper DA, Cordery DV, Reiss P, et al. The effects of enfuvirtide therapy on body composition and metabolic parameters over 48 weeks in the TORO body imaging substudy. HIV Med. 2011;12(1):31–9.

    Article  CAS  PubMed  Google Scholar 

  129. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of The 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). JAMA. 2001. 285(19):2486–97.

  130. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–934.

    Article  PubMed  Google Scholar 

  131. Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015;9(6 Suppl):S1–122.e1.

    Article  PubMed  Google Scholar 

  132. Zanni MV, Fitch KV, Feldpausch M, et al. 2013 American College of Cardiology/American Heart Association and 2004 Adult Treatment Panel III cholesterol guidelines applied to HIV-infected patients with/without subclinical high-risk coronary plaque. AIDS (London, England). 2014;28(14):2061–70.

    Article  CAS  Google Scholar 

  133. Begovac J, Dragović G, Višković K, et al. Comparison of four international cardiovascular disease prediction models and the prevalence of eligibility for lipid lowering therapy in HIV infected patients on antiretroviral therapy. Croat Med J. 2015;56(1):14–23.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Friis-Møller N, Thiébaut R, Reiss P, 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(5):491–501.

    Article  PubMed  Google Scholar 

  135. Marcus JL et al. Presented at CROI 2016, Feb. 22–25, Boston. Abstract 54.

  136. Keith A, Dong Y, Shuter J, Himelhoch S. Behavioral interventions for tobacco use in HIV-infected smokers: a meta-analysis. J Acquir Immune Defic Syndr 1999. 2016.

  137. Thompson-Paul AM, Wei SC, Mattson CL, et al. Obesity among HIV-infected adults receiving medical care in the United States: data from the cross-sectional Medical Monitoring Project and National Health and Nutrition Examination Survey. Medicine (Baltimore). 2015;94(27):e1081.

    Article  Google Scholar 

  138. Fysekidis M, Cohen R, Bekheit M, et al. Sleeve gastrectomy is a safe and efficient procedure in HIV patients with morbid obesity: a case series with results in weight loss, comorbidity evolution, CD4 count, and viral load. Obes Surg. 2015;25(2):229–33.

    Article  PubMed  Google Scholar 

  139. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333(20):1301–7.

    Article  CAS  PubMed  Google Scholar 

  140. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615–22.

    Article  CAS  PubMed  Google Scholar 

  141. Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58(1):1–10.

    Article  PubMed  Google Scholar 

  142. ACTG Drug Interactions Database. http://tprc.pharm.buffalo.edu/home (last accessed 12/15/15 ).

  143. McNicholl I. Database of Antiretroviral Drug Interactions. In: Coffey S, Volberding PA, eds. HIV InSite. San Francisco: UCSF Center for HIV Information; 2008. http://hivinsite.ucsf.edu/insite?page=ar-00-02 (Last accessed December 15th, 2015).

  144. Pitavastatin package insert. http://www.kowapharma.com/documents/livalo_pi_current.pdf (last accessed January 3rd, 2016).

  145. Dubé MP. Will statins be an effective anti-inflammatory intervention for prevention of cardiovascular disease in patients with HIV? J Infect Dis. 2014;209(8):1149–50.

    Article  PubMed  Google Scholar 

  146. Lo J, Lu MT, Ihenachor EJ, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015;2(2):e52–63.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Nakanjako D, Ssinabulya I, Nabatanzi R, et al. Atorvastatin reduces T-cell activation and exhaustion among HIV-infected cART-treated suboptimal immune responders in Uganda: a randomised crossover placebo-controlled trial. Trop Med Int Health. 2015;20(3):380–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hileman CO, Turner R, Funderburg NT, Semba RD, McComsey GA. Changes in oxidized lipids drive the improvement in monocyte activation and vascular disease after statin therapy in HIV. AIDS (London, England). 2016;30(1):65–73.

    CAS  Google Scholar 

  149. Nou E, Lu MT, Looby SE, et al. Serum oxidized low-density lipoprotein decreases in response to statin therapy and relates independently to reductions in coronary plaque in patients with HIV. AIDS (London, England). 2016;30(4):583–90.

    Article  CAS  Google Scholar 

  150. Reprieve trial website. Reprievetrial.org (last accessed January 3rd, 2016).

  151. O’Brien M, Montenont E, Hu L, et al. Aspirin attenuates platelet activation and immune activation in HIV-1-infected subjects on antiretroviral therapy: a pilot study. J Acquir Immune Defic Syndr 1999. 2013;63(3):280–8.

    Article  CAS  Google Scholar 

  152. D’ Ettorre G, Ceccarelli G, Giustini N, et al. Probiotics reduce inflammation in antiretroviral treated, HIV-infected individuals: results of the “Probio-HIV” clinical trial. PloS One. 2015;10(9):e0137200.

    Article  CAS  Google Scholar 

  153. Srinivasa S, Fitch KV, Wong K, et al. RAAS activation is associated with visceral adiposity and insulin resistance among HIV-infected patients. J Clin Endocrinol Metab. 2015;100(8):2873–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lake JE, Tseng C-H, Currier JS. A pilot study of telmisartan for visceral adiposity in HIV infection: the metabolic abnormalities, telmisartan, and HIV infection (MATH) trial. PLoS One. 2013;8(3):e58135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Goodwin SR, Reeds DN, Royal M, Struthers H, Laciny E, Yarasheski KE. Dipeptidyl peptidase IV inhibition does not adversely affect immune or virological status in HIV infected men and women: a pilot safety study. J Clin Endocrinol Metab. 2013;98(2):743–51.

    Article  CAS  PubMed  Google Scholar 

  156. Grundeken MJ, Wykrzykowska JJ, Ishibashi Y, Garg S, de Vries T, Garcia-Garcia HM, et al. First generation versus second generation drug-eluting stents for the treatment of bifurcations: 5-year follow-up of the LEADERS all-comers randomized trial. Catheter Cardiovasc Interv Off J Soc Card Angiogr Interv. 2015.

  157. Heredia A, Le N, Gartenhaus RB, et al. Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice. Proc Natl Acad Sci U S A. 2015;112(30):9412–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Stock PG, Barin B, Hatano H, et al. Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients. Am J Transplant. 2014;14(5):1136–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1090, New York, NY, 10029, USA

    Emma Kaplan-Lewis, Judith A. Aberg & Mikyung Lee

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Judith A. Aberg reports personal fees for advisory work with Janssen, Merck, and ViiV.

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Kaplan-Lewis, E., Aberg, J.A. & Lee, M. Atherosclerotic Cardiovascular Disease and Anti-Retroviral Therapy. Curr HIV/AIDS Rep 13, 297–308 (2016). https://doi.org/10.1007/s11904-016-0331-y

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