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Pathogenesis and biomarkers of cardiovascular disease in HIV-infected patients

Judith S Currier, MD
Section Editor
John G Bartlett, MD
Deputy Editor
Howard Libman, MD, FACP


As patients are living longer with HIV, cardiovascular disease has emerged as an important cause of morbidity and mortality. Even with effective antiretroviral therapy (ART), HIV-infected patients have a higher risk of myocardial infarction and cardiovascular death than age-matched uninfected controls. Although an increased prevalence of traditional risk factors, such as dyslipidemia and smoking, among HIV-infected patients likely contributes to this increased morbidity, growing evidence suggests that HIV infection and its treatment are directly linked to atherogenesis, endothelial dysfunction, and coagulation abnormalities, probably through inflammation and immune dysregulation.

Measures of subclinical cardiovascular disease and the pathogenesis of atherosclerosis in HIV-infected patients are discussed here. The epidemiology of cardiovascular morbidity and traditional risk factors and the management of dyslipidemia and cardiovascular risk in HIV-infected patients are addressed elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients" and "Management of cardiovascular risk (including dyslipidemia) in the HIV-infected patient".)


Cardiovascular disease has emerged as an important cause of death in HIV-infected patients, as illustrated by clinical studies evaluating such hard endpoints as stroke or myocardial infarctions (see "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients"). However, HIV patients are generally young and thus have overall low short-term cardiovascular risk and few events. Therefore, many clinical studies rely upon surrogate markers to indirectly assess the burden of cardiovascular disease. These studies have generally demonstrated an increased prevalence of subclinical atherosclerosis in HIV-infected compared with uninfected individuals. Such measurements include intima media thickness (IMT) and intraluminal arterial plaque as assessed by ultrasound and evaluation of coronary artery calcification and plaque by computed tomography (CT). These measurements have been moderately associated with coronary atherosclerosis and the future risk of a cardiovascular event in studies of uninfected adults [1]. (See "Overview of possible risk factors for cardiovascular disease", section on 'Arterial intima-media thickness' and "Overview of possible risk factors for cardiovascular disease", section on 'Coronary artery calcification'.)

Evidence of increased subclinical atherosclerosis among HIV-infected elite controllers compared with uninfected controls has also been observed, suggesting that an increased risk of atherosclerosis can occur in the absence of antiretroviral therapy (ART), detectable viremia, or overt immunodeficiency [2,3].

Intima media thickness — Most, but not all studies of IMT of the carotid artery and coronary arteries in asymptomatic adults have found an increase in measurement with HIV infection [2,4-13]. In a meta-analysis of observational studies evaluating subclinical atherosclerosis in HIV-infected patients, the following observations were noted [4]:

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Literature review current through: Dec 2017. | This topic last updated: Oct 03, 2017.
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  1. Bots ML, Baldassarre D, Simon A, et al. Carotid intima-media thickness and coronary atherosclerosis: weak or strong relations? Eur Heart J 2007; 28:398.
  2. Hsue PY, Scherzer R, Hunt PW, 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.
  3. Pereyra F, Lo J, Triant VA, et al. Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers. AIDS 2012; 26:2409.
  4. Hulten E, Mitchell J, Scally J, et al. HIV positivity, protease inhibitor exposure and subclinical atherosclerosis: a systematic review and meta-analysis of observational studies. Heart 2009; 95:1826.
  5. Grunfeld C, Delaney JA, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS 2009; 23:1841.
  6. Mercié P, Thiébaut R, Aurillac-Lavignolle V, et al. Carotid intima-media thickness is slightly increased over time in HIV-1-infected patients. HIV Med 2005; 6:380.
  7. Currier JS, Kendall MA, Henry WK, et al. Progression of carotid artery intima-media thickening in HIV-infected and uninfected adults. AIDS 2007; 21:1137.
  8. Kaplan RC, Kingsley LA, Gange SJ, et al. Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men. AIDS 2008; 22:1615.
  9. Hsue PY, Hunt PW, Schnell A, et al. Role of viral replication, antiretroviral therapy, and immunodeficiency in HIV-associated atherosclerosis. AIDS 2009; 23:1059.
  10. Hsue PY, Lo JC, Franklin A, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation 2004; 109:1603.
  11. Bongiovanni M, Casana M, Cicconi P, et al. Predictive factors of vascular intima media thickness in HIV-positive subjects. J Antimicrob Chemother 2008; 61:195.
  12. Fitch KV, Looby SE, Rope A, et al. Effects of aging and smoking on carotid intima-media thickness in HIV-infection. AIDS 2013; 27:49.
  13. Hanna DB, Post WS, Deal JA, et al. HIV Infection Is Associated With Progression of Subclinical Carotid Atherosclerosis. Clin Infect Dis 2015; 61:640.
  14. Hanna DB, Guo M, Bůžková P, et al. HIV Infection and Carotid Artery Intima-media Thickness: Pooled Analyses Across 5 Cohorts of the NHLBI HIV-CVD Collaborative. Clin Infect Dis 2016; 63:249.
  15. Stein JH, Ribaudo HJ, Hodis HN, et al. A prospective, randomized clinical trial of antiretroviral therapies on carotid wall thickness. AIDS 2015; 29:1775.
  16. Lo J, Abbara S, Shturman L, et al. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS 2010; 24:243.
  17. Fitch KV, Lo J, Abbara S, et al. Increased coronary artery calcium score and noncalcified plaque among HIV-infected men: relationship to metabolic syndrome and cardiac risk parameters. J Acquir Immune Defic Syndr 2010; 55:495.
  18. Fitch KV, Srinivasa S, Abbara S, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis 2013; 208:1737.
  19. Post WS, Budoff M, Kingsley L, et al. Associations between HIV infection and subclinical coronary atherosclerosis. Ann Intern Med 2014; 160:458.
  20. Kingsley LA, Deal J, Jacobson L, et al. Incidence and progression of coronary artery calcium in HIV-infected and HIV-uninfected men. AIDS 2015; 29:2427.
  21. 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:e52.
  22. Subramanian S, Tawakol A, Burdo TH, et al. Arterial inflammation in patients with HIV. JAMA 2012; 308:379.
  23. 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 2008; 48:142.
  24. 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 2010; 55:316.
  25. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr 2009; 51:268.
  26. Aslangul E, Fellahi S, Assoumou LK, et al. High-sensitivity C-reactive protein levels fall during statin therapy in HIV-infected patients receiving ritonavir-boosted protease inhibitors. AIDS 2011; 25:1128.
  27. Arildsen H, Sørensen KE, Ingerslev JM, et al. Endothelial dysfunction, increased inflammation, and activated coagulation in HIV-infected patients improve after initiation of highly active antiretroviral therapy. HIV Med 2013; 14:1.
  28. Hileman CO, Wohl DA, Tisch DJ, et al. Short communication: 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 Retroviruses 2012; 28:1561.
  29. Martínez E, D'Albuquerque PM, Llibre JM, et al. Changes in cardiovascular biomarkers in HIV-infected patients switching from ritonavir-boosted protease inhibitors to raltegravir. AIDS 2012; 26:2315.
  30. Hileman CO, Kinley B, Scharen-Guivel V, et al. Differential Reduction in Monocyte Activation and Vascular Inflammation With Integrase Inhibitor-Based Initial Antiretroviral Therapy Among HIV-Infected Individuals. J Infect Dis 2015; 212:345.
  31. Bastard JP, Fellahi S, Couffignal C, et al. Increased systemic immune activation and inflammatory profile of long-term HIV-infected ART-controlled patients is related to personal factors, but not to markers of HIV infection severity. J Antimicrob Chemother 2015; 70:1816.
  32. Hsue PY, Deeks SG, Hunt PW. Immunologic basis of cardiovascular disease in HIV-infected adults. J Infect Dis 2012; 205 Suppl 3:S375.
  33. 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; 55:126.
  34. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008; 5:e203.
  35. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation, coagulation and cardiovascular disease in HIV-infected individuals. PLoS One 2012; 7:e44454.
  36. Baker J, Quick H, Hullsiek KH, et al. Interleukin-6 and d-dimer levels are associated with vascular dysfunction in patients with untreated HIV infection. HIV Med 2010; 11:608.
  37. Borges ÁH, O'Connor JL, Phillips AN, et al. Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection. J Infect Dis 2016; 214:408.
  38. 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 2010; 24:2657.
  39. Palella FJ Jr, 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 2010; 24:1657.
  40. Longenecker CT, Funderburg NT, Jiang Y, et al. Markers of inflammation and CD8 T-cell activation, but not monocyte activation, are associated with subclinical carotid artery disease in HIV-infected individuals. HIV Med 2013; 14:385.
  41. Merlini E, Luzi K, Suardi E, et al. T-cell phenotypes, apoptosis and inflammation in HIV+ patients on virologically effective cART with early atherosclerosis. PLoS One 2012; 7:e46073.
  42. Kaplan RC, Sinclair E, Landay AL, et al. T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women. J Infect Dis 2011; 203:452.
  43. Kaplan RC, Sinclair E, Landay AL, et al. T cell activation predicts carotid artery stiffness among HIV-infected women. Atherosclerosis 2011; 217:207.
  44. 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; 204:1227.
  45. Kelesidis T, Kendall MA, Yang OO, et al. Biomarkers of microbial translocation and macrophage activation: association with progression of subclinical atherosclerosis in HIV-1 infection. J Infect Dis 2012; 206:1558.
  46. Ross AC, Judd S, Kumari M, et al. Vitamin D is linked to carotid intima-media thickness and immune reconstitution in HIV-positive individuals. Antivir Ther 2011; 16:555.
  47. Hearps AC, Maisa A, Cheng WJ, et al. HIV infection induces age-related changes to monocytes and innate immune activation in young men that persist despite combination antiretroviral therapy. AIDS 2012; 26:843.
  48. Baker JV, Hullsiek KH, Singh A, et al. Immunologic predictors of coronary artery calcium progression in a contemporary HIV cohort. AIDS 2014; 28:831.
  49. McKibben RA, Margolick JB, Grinspoon S, et al. Elevated levels of monocyte activation markers are associated with subclinical atherosclerosis in men with and those without HIV infection. J Infect Dis 2015; 211:1219.
  50. 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; 52:569.
  51. Murphy R, Costagliola D. Increased cardiovascular risk in HIV infection: drugs, virus and immunity. AIDS 2008; 22:1625.
  52. Baker JV, Duprez D, Rapkin J, et al. Untreated HIV infection and large and small artery elasticity. J Acquir Immune Defic Syndr 2009; 52:25.
  53. van Wijk JP, de Koning EJ, Cabezas MC, et al. Functional and structural markers of atherosclerosis in human immunodeficiency virus-infected patients. J Am Coll Cardiol 2006; 47:1117.
  54. Schillaci G, De Socio GV, Pirro M, et al. Impact of treatment with protease inhibitors on aortic stiffness in adult patients with human immunodeficiency virus infection. Arterioscler Thromb Vasc Biol 2005; 25:2381.
  55. Shankar SS, Dubé MP, Gorski JC, et al. Indinavir impairs endothelial function in healthy HIV-negative men. Am Heart J 2005; 150:933.
  56. Dubé MP, Shen C, Greenwald M, Mather KJ. No impairment of endothelial function or insulin sensitivity with 4 weeks of the HIV protease inhibitors atazanavir or lopinavir-ritonavir in healthy subjects without HIV infection: a placebo-controlled trial. Clin Infect Dis 2008; 47:567.
  57. Hsue PY, Hunt PW, Wu Y, et al. Association of abacavir and impaired endothelial function in treated and suppressed HIV-infected patients. AIDS 2009; 23:2021.
  58. Graham SM, Rajwans N, Jaoko W, et al. Endothelial activation biomarkers increase after HIV-1 acquisition: plasma vascular cell adhesion molecule-1 predicts disease progression. AIDS 2013; 27:1803.
  59. Francisci D, Giannini S, Baldelli F, et al. HIV type 1 infection, and not short-term HAART, induces endothelial dysfunction. AIDS 2009; 23:589.
  60. Baker JV, Neuhaus J, Duprez D, et al. HIV replication, inflammation, and the effect of starting antiretroviral therapy on plasma asymmetric dimethylarginine, a novel marker of endothelial dysfunction. J Acquir Immune Defic Syndr 2012; 60:128.
  61. de Gaetano Donati K, Rabagliati R, Tumbarello M, et al. Increased soluble markers of endothelial dysfunction in HIV-positive patients under highly active antiretroviral therapy. AIDS 2003; 17:765.
  62. Chai H, Yang H, Yan S, et al. Effects of 5 HIV protease inhibitors on vasomotor function and superoxide anion production in porcine coronary arteries. J Acquir Immune Defic Syndr 2005; 40:12.
  63. Fu W, Chai H, Yao Q, Chen C. Effects of HIV protease inhibitor ritonavir on vasomotor function and endothelial nitric oxide synthase expression. J Acquir Immune Defic Syndr 2005; 39:152.
  64. de Gaetano Donati K, Rabagliati R, Iacoviello L, Cauda R. HIV infection, HAART, and endothelial adhesion molecules: current perspectives. Lancet Infect Dis 2004; 4:213.
  65. Panigrahi S, Freeman ML, Funderburg NT, et al. SIV/SHIV Infection Triggers Vascular Inflammation, Diminished Expression of Krüppel-like Factor 2 and Endothelial Dysfunction. J Infect Dis 2016; 213:1419.
  66. Baliga RS, Chaves AA, Jing L, et al. AIDS-related vasculopathy: evidence for oxidative and inflammatory pathways in murine and human AIDS. Am J Physiol Heart Circ Physiol 2005; 289:H1373.
  67. Martin S, Tesse A, Hugel B, et al. Shed membrane particles from T lymphocytes impair endothelial function and regulate endothelial protein expression. Circulation 2004; 109:1653.
  68. Schecter AD, Berman AB, Yi L, et al. HIV envelope gp120 activates human arterial smooth muscle cells. Proc Natl Acad Sci U S A 2001; 98:10142.
  69. Paladugu R, Fu W, Conklin BS, et al. Hiv Tat protein causes endothelial dysfunction in porcine coronary arteries. J Vasc Surg 2003; 38:549.
  70. Seigneur M, Constans J, Blann A, et al. Soluble adhesion molecules and endothelial cell damage in HIV infected patients. Thromb Haemost 1997; 77:646.
  71. Blann AD, Seigneur M, Constans J, et al. Soluble P-selectin, thrombocytopenia and von Willebrand factor in HIV infected patients. Thromb Haemost 1997; 77:1221.
  72. Karmochkine M, Ankri A, Calvez V, et al. Plasma hypercoagulability is correlated to plasma HIV load. Thromb Haemost 1998; 80:208.
  73. Ford ES, Greenwald JH, Richterman AG, et al. Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS 2010; 24:1509.
  74. Hsue PY, Scherzer R, Grunfeld C, et al. HIV infection is associated with decreased thrombin generation. Clin Infect Dis 2012; 54:1196.
  75. Madden E, Lee G, Kotler DP, et al. Association of antiretroviral therapy with fibrinogen levels in HIV-infection. AIDS 2008; 22:707.
  76. Funderburg NT, Mayne E, Sieg SF, et al. Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation. Blood 2010; 115:161.
  77. Barska K, Kwiatkowska W, Knysz B, et al. The role of the tissue factor and its inhibitor in the development of subclinical atherosclerosis in people living with HIV. PLoS One 2017; 12:e0181533.
  78. Lichtner M, Cicconi P, Vita S, et al. Cytomegalovirus coinfection is associated with an increased risk of severe non-AIDS-defining events in a large cohort of HIV-infected patients. J Infect Dis 2015; 211:178.
  79. 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 2006; 20:2275.
  80. Parrinello CM, Sinclair E, Landay AL, et al. Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. J Infect Dis 2012; 205:1788.
  81. Hechter RC, Budoff M, Hodis HN, et al. Herpes simplex virus type 2 (HSV-2) as a coronary atherosclerosis risk factor in HIV-infected men: multicenter AIDS cohort study. Atherosclerosis 2012; 223:433.
  82. de Castro IF, Micheloud D, Berenguer J, et al. Hepatitis C virus infection is associated with endothelial dysfunction in HIV/hepatitis C virus coinfected patients. AIDS 2010; 24:2059.
  83. Freiberg MS, Chang CC, Skanderson M, et al. The risk of incident coronary heart disease among veterans with and without HIV and hepatitis C. Circ Cardiovasc Qual Outcomes 2011; 4:425.
  84. Bedimo R, Westfall AO, Mugavero M, et al. Hepatitis C virus coinfection and the risk of cardiovascular disease among HIV-infected patients. HIV Med 2010; 11:462.
  85. Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study Group, Weber R, Sabin C, et al. HBV or HCV coinfections and risk of myocardial infarction in HIV-infected individuals: the D:A:D Cohort Study. Antivir Ther 2010; 15:1077.
  86. Lai H, Gerstenblith G, Fishman EK, et al. Vitamin D deficiency is associated with silent coronary artery disease in cardiovascularly asymptomatic African Americans with HIV infection. Clin Infect Dis 2012; 54:1747.
  87. Choi AI, Lo JC, Mulligan K, et al. Association of vitamin D insufficiency with carotid intima-media thickness in HIV-infected persons. Clin Infect Dis 2011; 52:941.
  88. Shikuma CM, Seto T, Liang CY, et al. Vitamin D levels and markers of arterial dysfunction in HIV. AIDS Res Hum Retroviruses 2012; 28:793.
  89. Longenecker CT, Hileman CO, Carman TL, et al. Vitamin D supplementation and endothelial function in vitamin D deficient HIV-infected patients: a randomized placebo-controlled trial. Antivir Ther 2012; 17:613.
  90. Eckard AR, Raggi P, O'Riordan MA, et al. Effects of vitamin D supplementation on carotid intima-media thickness in HIV-infected youth. Virulence 2017; :1.