Venous and Arterial Thromboembolic Complications Associated with HIV Infection and Highly Active Antiretroviral Therapy

 

 Buy Article Permissions and Reprints

Abstract

With the advent of highly active antiretroviral therapy (HAART), dramatic improvements have been made in the quality and length of life in people living with HIV/AIDS (PLWA). Complications that are seen with increasing frequency in this group include venous thromboembolism events (VTE) and cardiovascular disease. Recent epidemiologic studies suggest PLWA have a 2-fold to 10-fold greater risk of VTE compared with age-matched controls. Several mechanisms associated with HIV infection, coupled with traditional risk factors, including age, opportunistic infections, and lifestyle choices, may contribute to a heightened risk of VTE and cardiovascular disease. It has been challenging to discern which of these complications are related to HAART. Herein, we review the risk of VTE in the pre-HAART and current HAART era. We call attention to particular instances where components of HAART have been associated with acute myocardial infarction, noncirrhotic portal hypertension and portal vein thrombosis. We also highlight potential drug–drug interactions between HAART and anticoagulant therapy. Additional studies are needed to better understand the mechanisms and risks associated with long-term use of HAART and to what extent HAART contributes to or mitigates the risk of VTE and cardiovascular disease.

• References

• 1 Thompson MA, Aberg JA, Cahn P , et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA 2010; 304 (3) 321-333
  CrossrefPubMedGoogle Scholar
• 2 Panel on Antiretroviral Guidelines for Adults and Adolescents, Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf . Accessed September 17, 2012
  PubMedGoogle Scholar
• 3 Sterne JA, Hernán MA, Ledergerber B , et al. Long-term effectiveness of potent antiretroviral therapy in preventing AIDS and death: a prospective cohort study. Lancet 2005; 366 (9483) 378-384
  CrossrefPubMedGoogle Scholar
• 4 Walensky RP, Paltiel AD, Losina E , et al. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006; 194 (1) 11-19
  CrossrefPubMedGoogle Scholar
• 5 Aboulafia D. An update on HIV-associated venous thromboembolism in the era of highly active antiretroviral therapy. J Coagul Disord 2010; 2: 49-56
  PubMedGoogle Scholar
• 6 Crum-Cianflone NF, Weekes J, Bavaro M. Review: thromboses among HIV-infected patients during the highly active antiretroviral therapy era. AIDS Patient Care STDS 2008; 22 (10) 771-778
  CrossrefPubMedGoogle Scholar
• 7 Eyal A, Veller M. HIV and venous thrombotic events. S Afr J Surg 2009; 47 (2) 54-56
  PubMedGoogle Scholar
• 8 Cruciani M, Zanichelli V, Spelloni G , et al. Abacavir use and cardiovascular disease events: a meta-analysis of published and unpublished data. AIDS 2011; 25: 1993-2004
  CrossrefPubMedGoogle Scholar
• 9 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) 702-710
  CrossrefPubMedGoogle Scholar
• 10 Vispo E, Moreno A, Maida I , et al. Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings. AIDS 2010; 24 (8) 1171-1176
  CrossrefPubMedGoogle Scholar
• 11 Mallet VO, Varthaman A, Lasne D , et al. Acquired protein S deficiency leads to obliterative portal venopathy and to compensatory nodular regenerative hyperplasia in HIV-infected patients. AIDS 2009; 23 (12) 1511-1518
  CrossrefPubMedGoogle Scholar
• 12 Kovari H, Weber R. Influence of antiretroviral therapy on liver disease. Curr Opin HIV AIDS 2011; 6 (4) 272-277
  CrossrefPubMedGoogle Scholar
• 13 World Health Organization. Global HIV/AIDS response: epidemic update and health sector progress towards universal access: progress report 2011. Geneva, Switzerland: World Health Organization; 2011
  Google Scholar
• 14 Klein SK, Slim EJ, de Kruif MD , et al. Is chronic HIV infection associated with venous thrombotic disease? A systematic review. Neth J Med 2005; 63 (4) 129-136
  PubMedGoogle Scholar
• 15 Sullivan PS, Dworkin MS, Jones JL, Hooper WC. Epidemiology of thrombosis in HIV-infected individuals. The adult/adolescent spectrum of HIV disease project. AIDS 2000; 14 (3) 321-324
  CrossrefPubMedGoogle Scholar
• 16 Fultz SL, McGinnis KA, Skanderson M, Ragni MV, Justice AC. Association of venous thromboembolism with human immunodeficiency virus and mortality in veterans. Am J Med 2004; 116 (6) 420-423
  CrossrefPubMedGoogle Scholar
• 17 Saber AA, Aboolian A, LaRaja RD, Baron H, Hanna K. HIV/AIDS and the risk of deep vein thrombosis: a study of 45 patients with lower extremity involvement. Am Surg 2001; 67 (7) 645-647
  PubMedGoogle Scholar
• 18 Malek J, Rogers R, Kufera J, Hirshon JM. Venous thromboembolic disease in the HIV-infected patient. Am J Emerg Med 2011; 29 (3) 278-282
  CrossrefPubMedGoogle Scholar
• 19 Copur AS, Smith PR, Gomez V, Bergman M, Homel P. HIV infection is a risk factor for venous thromboembolism. AIDS Patient Care STDS 2002; 16 (5) 205-209
  CrossrefPubMedGoogle Scholar
• 20 Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIV-infected patients. AIDS Patient Care STDS 2001; 15 (6) 311-320
  CrossrefPubMedGoogle Scholar
• 21 Jenkins RE, Peters BS, Pinching AJ. Thromboembolic disease in AIDS is associated with cytomegalovirus disease. AIDS 1991; 5 (12) 1540-1542
  CrossrefPubMedGoogle Scholar
• 22 Hassell KL, Kressin DC, Neumann A, Ellison R, Marlar RA. Correlation of antiphospholipid antibodies and protein S deficiency with thrombosis in HIV-infected men. Blood Coagul Fibrinolysis 1994; 5 (4) 455-462
  PubMedGoogle Scholar
• 23 Laing RB, Brettle RP, Leen CL. Venous thrombosis in HIV infection. Int J STD AIDS 1996; 7 (2) 82-85
  CrossrefPubMedGoogle Scholar
• 24 George SL, Swindells S, Knudson R, Stapleton JT. Unexplained thrombosis in HIV-infected patients receiving protease inhibitors: report of seven cases. Am J Med 1999; 107 (6) 624-630
  CrossrefPubMedGoogle Scholar
• 25 Howling SJ, Shaw PJ, Miller RF. Acute pulmonary embolism in patients with HIV disease. Sex Transm Infect 1999; 75 (1) 25-29
  CrossrefPubMedGoogle Scholar
• 26 Matta F, Yaekoub AY, Stein PD. Human immunodeficiency virus infection and risk of venous thromboembolism. Am J Med Sci 2008; 336 (5) 402-406
  CrossrefPubMedGoogle Scholar
• 27 Rasmussen LD, Dybdal M, Gerstoft J , et al. HIV and risk of venous thromboembolism: a Danish nationwide population-based cohort study. HIV Med 2011; 12 (4) 202-210
  CrossrefPubMedGoogle Scholar
• 28 Ahonkhai AA, Gebo KA, Streiff MB, Moore RD, Segal JB. Venous thromboembolism in patients with HIV/AIDS: a case-control study. J Acquir Immune Defic Syndr 2008; 48 (3) 310-314
  CrossrefPubMedGoogle Scholar
• 29 Louw S, Jacobson BF, Büller H. Human immunodeficiency virus infection and acute deep vein thromboses. Clin Appl Thromb Hemost 2008; 14 (3) 352-355
  CrossrefPubMedGoogle Scholar
• 30 Jansen JM, Lijfering WM, Sprenger HG, van der Meer J, van Pampus MG. Venous thromboembolism in HIV-positive women during puerperium: a case series. Blood Coagul Fibrinolysis 2008; 19 (1) 95-97
  CrossrefPubMedGoogle Scholar
• 31 Nagaraja V, Terriquez JA, Gavini H, Jha L, Klotz SA. Pulmonary embolism mimicking pneumonia in a HIV patient. Case Report Med 2010; June14: DOI: 10.1155/2010/394546. [Epub ahead of print]
  PubMedGoogle Scholar
• 32 Jacobson MC, Dezube BJ, Aboulafia DM. Thrombotic complications in patients infected with HIV in the era of highly active antiretroviral therapy: a case series. Clin Infect Dis 2004; 39 (8) 1214-1222
  CrossrefPubMedGoogle Scholar
• 33 Jong E, Louw S, Meijers JC , et al. The hemostatic balance in HIV-infected patients with and without antiretroviral therapy: partial restoration with antiretroviral therapy. AIDS Patient Care STDS 2009; 23 (12) 1001-1007
  CrossrefPubMedGoogle Scholar
• 34 Kiser KL, Badowski ME. Risk factors for venous thromboembolism in patients with human immunodeficiency virus infection. Pharmacotherapy 2010; 30 (12) 1292-1302
  CrossrefPubMedGoogle Scholar
• 35 Baker JV, Lundgren JD. Cardiovascular implications from untreated human immunodeficiency virus infection. Eur Heart J 2011; 32 (8) 945-951
  CrossrefPubMedGoogle Scholar
• 36 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 (2) 161-167
  CrossrefPubMedGoogle Scholar
• 37 Musselwhite LW, Sheikh V, Norton TD , et al. Markers of endothelial dysfunction, coagulation and tissue fibrosis independently predict venous thromboembolism in HIV. AIDS 2011; 25 (6) 787-795
  CrossrefPubMedGoogle Scholar
• 38 Koppel K, Bratt G, Schulman S, Bylund H, Sandström E. Hypofibrinolytic state in HIV-1-infected patients treated with protease inhibitor-containing highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2002; 29 (5) 441-449
  CrossrefPubMedGoogle Scholar
• 39 Carr A, Samaras K, Burton S , et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998; 12 (7) F51-F58
  CrossrefPubMedGoogle Scholar
• 40 Carr A. HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. AIDS 2003; 17 (Suppl. 01) S141-S148
  CrossrefPubMedGoogle Scholar
• 41 Grinspoon S, Carr A. Cardiovascular risk and body-fat abnormalities in HIV-infected adults. N Engl J Med 2005; 352 (1) 48-62
  CrossrefPubMedGoogle Scholar
• 42 Barbaro G. Heart and HAART: two sides of the coin for HIV-associated cardiology issues. World J Cardiol 2010; 2 (3) 53-57
  CrossrefPubMedGoogle Scholar
• 43 Calmy A, Gayet-Ageron A, Montecucco F , et al. HIV increases markers of cardiovascular risk: results from a randomized, treatment interruption trial. AIDS 2009; 23 (8) 929-939
  CrossrefPubMedGoogle Scholar
• 44 Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost 1997; 78 (1) 1-6
  PubMedGoogle Scholar
• 45 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) 569-576
  CrossrefPubMedGoogle Scholar
• 46 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 (1) 12-19
  CrossrefPubMedGoogle Scholar
• 47 Friis-Møller N, Reiss P, Sabin CA , et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007; 356 (17) 1723-1735
  CrossrefPubMedGoogle Scholar
• 48 Dubé MP, Lipshultz SE, Fichtenbaum CJ , et al. Effects of HIV infection and antiretroviral therapy on the heart and vasculature. Circulation 2008; 118 (2) e36-e40
  CrossrefPubMedGoogle Scholar
• 49 Durand M, Sheehy O, Baril JG, Lelorier J, Tremblay CL. Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Québec's public health insurance database. J Acquir Immune Defic Syndr 2011; 57 (3) 245-253
  CrossrefPubMedGoogle Scholar
• 50 Obel N, Farkas DK, Kronborg G , 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 (2) 130-136
  CrossrefPubMedGoogle Scholar
• 51 Sabin CA, Worm SW, Weber R , 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 (9622) 1417-1426
  CrossrefPubMedGoogle Scholar
• 52 Podzamczer D, Ferrer E, Sanchez P , et al. Less lipoatrophy and better lipid profile with abacavir as compared to stavudine: 96-week results of a randomized study. J Acquir Immune Defic Syndr 2007; 44 (2) 139-147
  CrossrefPubMedGoogle Scholar
• 53 Fätkenheuer G, Duvivier C, Rieger A , et al. Lipid profiles for etravirine versus efavirenz in treatment-naive patients in the randomized, double-blind SENSE trial. J Antimicrob Chemother 2012; 67 (3) 685-690
  CrossrefPubMedGoogle Scholar
• 54 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 (14) F17-F24
  CrossrefPubMedGoogle Scholar
• 55 Lang S, Mary-Krause M, Cotte L , et al. 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
  CrossrefPubMedGoogle Scholar
• 56 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
  CrossrefPubMedGoogle Scholar
• 57 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 2009; 51 (1) 20-28
  CrossrefPubMedGoogle Scholar
• 58 Padilla S, Masiá M, García N, Jarrin I, Tormo C, Gutiérrez F. Early changes in inflammatory and pro-thrombotic biomarkers in patients initiating antiretroviral therapy with abacavir or tenofovir. BMC Infect Dis 2011; 11: 40
  CrossrefPubMedGoogle Scholar
• 59 Ding X, Andraca-Carrera E, Cooper C , et al. No association of myocardial infarction with ABC use: an FDA meta-analysis. 18th Conference on Retroviruses and Opportunistic Infections 2011;paper #808.
  PubMedGoogle Scholar
• 60 European AIDS Clinical Society. EACS HIV guidelines. PARIS, France: European AIDS Clinical Society; 2011. Available at: http://www.europeanaidsclinicalsociety.org . Accessed September 17, 2012
  PubMedGoogle Scholar
• 61 Behrens GM. Abacavir and myocardial infarctions: the benefit of doubt?. AIDS 2011; 25 (16) 2043-2045
  CrossrefPubMedGoogle Scholar
• 62 Maida I, Garcia-Gasco P, Sotgiu G , et al. Antiretroviral-associated portal hypertension: a new clinical condition? Prevalence, predictors and outcome. Antivir Ther 2008; 13 (1) 103-107
  PubMedGoogle Scholar
• 63 Bihl F, Janssens F, Boehlen F, Rubbia-Brandt L, Hadengue A, Spahr L. Anticoagulant therapy for nodular regenerative hyperplasia in a HIV-infected patient. BMC Gastroenterol 2010; 10: 6
  CrossrefPubMedGoogle Scholar
• 64 Scourfield A, Waters L, Holmes P , et al. Non-cirrhotic portal hypertension in HIV-infected individuals. Int J STD AIDS 2011; 22 (6) 324-328
  CrossrefPubMedGoogle Scholar
• 65 Mendizabal M, Craviotto S, Chen T, Silva MO, Reddy KR. Noncirrhotic portal hypertension: another cause of liver disease in HIV patients. Ann Hepatol 2009; 8 (4) 390-395
  PubMedGoogle Scholar
• 66 Soriano V, Puoti M, Garcia-Gascó P , et al. Antiretroviral drugs and liver injury. AIDS 2008; 22 (1) 1-13
  CrossrefPubMedGoogle Scholar
• 67 Fihn SD, McDonell M, Martin D , et al. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993; 118 (7) 511-520
  CrossrefPubMedGoogle Scholar
• 68 Goldstein K, Gluckman S, Mounzer K. Challenge of co-administering antiretroviral therapy and oral anticoagulants in HIV-positive patients. AIDS Read 2008; 18 (9) 480-482 , 486–489
  PubMedGoogle Scholar
• 69 Welzen ME, van den Berk GE, Hamers RL, Burger DM. Interaction between antiretroviral drugs and acenocoumarol. Antivir Ther 2011; 16 (2) 249-252
  CrossrefPubMedGoogle Scholar
• 70 Holbrook AM, Pereira JA, Labiris R , et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10) 1095-1106
  CrossrefPubMedGoogle Scholar
• 71 Liedtke MD, Rathbun RC. Warfarin-antiretroviral interactions. Ann Pharmacother 2009; 43 (2) 322-328
  CrossrefPubMedGoogle Scholar
• 72 Thompson III GR, Lawrence VA, Crawford GE. HIV infection increases the risk of heparin-induced thrombocytopenia. Clin Infect Dis 2007; 45 (10) 1393-1396
  CrossrefPubMedGoogle Scholar
• 73 Racoosin JA, Kessler CM. Bleeding episodes in HIV-positive patients taking HIV protease inhibitors: a case series. Haemophilia 1999; 5 (4) 266-269
  CrossrefPubMedGoogle Scholar
• 74 Pollmann H, Richter H, Jürgens H. Platelet dysfunction as the cause of spontaneous bleeding in two haemophilic patients taking HIV protease inhibitors. Thromb Haemost 1998; 79 (6) 1213-1214
  PubMedGoogle Scholar
• 75 Graff J, von Hentig N, Kuczka K , et al. Significant effects of tipranavir on platelet aggregation and thromboxane B2 formation in vitro and in vivo. J Antimicrob Chemother 2008; 61 (2) 394-399
  PubMedGoogle Scholar
• 76 Becattini C, Agnelli G, Schenone A , et al; WARFASA Investigators. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012; 366 (21) 1959-1967
  CrossrefPubMedGoogle Scholar
• 77 Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172 (5) 397-402
  CrossrefPubMedGoogle Scholar
• 78 Hsue PY, Scherzer R, Grunfeld C , et al. HIV infection is associated with decreased thrombin generation. Clin Infect Dis 2012; 54 (8) 1196-1203
  CrossrefPubMedGoogle Scholar