Cardiovascular disease and HIV infection: Host, virus, or druas?

Current Opinion in Infectious Diseases

Volumn 22, Issue 1, 2009, Pages 28-34

  Martínez, Esteban ^a   Larrousse, María ^a   Gatell, José M ^a  

^a UNIVERSITY OF BARCELONA   (Spain)

Author keywords

Antiretroviral therapy; Cardiovascular disease; HIV; Host; Risk

Indexed keywords

ABACAVIR; ABACAVIR PLUS LAMIVUDINE; ATAZANAVIR; DIDANOSINE; EFAVIRENZ; EMTRICITABINE PLUS TENOFOVIR DISOPROXIL; INDINAVIR; LOPINAVIR PLUS RITONAVIR; NEVIRAPINE; PROTEINASE INHIBITOR; RITONAVIR; RITONAVIR PLUS SAQUINAVIR; RITONAVIR PLUS TIPRANAVIR; RNA DIRECTED DNA POLYMERASE INHIBITOR; STAVUDINE; ZIDOVUDINE;

BODY FAT; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CLINICAL TRIAL; DYSLIPIDEMIA; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE DEFICIENCY; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIPOATROPHY; MORBIDITY; MORTALITY; NONHUMAN; PREVALENCE; REVIEW; RISK FACTOR; SIDE EFFECT;

ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; CARDIOVASCULAR DISEASES; CASE MANAGEMENT; HIV INFECTIONS; HUMANS; RISK FACTORS;

EID: 58849145204     PISSN: 09517375     EISSN: None     Source Type: Journal    
DOI: 10.1097/QCO.0b013e328320a849     Document Type: Review

References (88)

1. Khunnawat C, Mukerji S, Havlichek D, et al. Cardiovascular manifestations in human immunodeficiency virus-infected patients. Am J Cardiol 2008; 102:635-642.
2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3:e442.
3. Bhaskaran K, Hamouda O, Sannes M, et al. Changes in the risk of death after • HIV seroconversion compared with mortality in the general population. JAMA 2008; 300:51-59. The authors compared the mortality of HIV seroconverters within the CASCADE collaboration study with expected mortality from the adjusted general population. They found that mortality rates for HIV-infected persons had become closer to general mortality rates with the introduction of active ART in the first 5 years following infection, though mortality excess remains as duration of HIV-infection lengthens.
4. Martinez E, Milinkovic A, Buira E, et al. Incidence and causes of death in HIV-infected persons receiving highly active antiretroviral therapy compared with estimates for the general population of similar age and from the same geographical area. HIV Medicine 2007; 8:251 -258.
5. Lewden C, May T, Rosenthal E, et al. Changes in causes of death among adults infected by HIV between 2000 and 2005: the 'Mortalite 2000 and 2005' surveys (ANRS EN19 and Mortavic). J Acquir Immune Defic Syndr 2008; 48:590-598.
6. 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; 92:2506- 2512. The authors of this study show that both myocardial infarction and traditional cardiovascular disease risk factors are increased in those with HIV infection compared with uninfected controls, although smoking information was lacking.
7. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV- •• infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis 2007; 44:1625-1631. The authors of this study found a two-fold higher risk of ischemic heart disease in HIV-infected patients on ART compared with an adjusted uninfected population, although the risk did not increase over time. No increased risk was evident for antiretroviral- naïve HIV-infected patients.
8. Schuster I, Thöni GJ, Edérhy S, et al. Subclinical cardiac abnormalities in human immunodeficiency virus-infected men receiving antiretroviral therapy. Am J Cardiol 2008; 101:1213-1217.
9. 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; 109:1603-1608.
10. Mercie P, Thiebaut R, Aurillac-Lavignolle V, et al. Carotid intima-media thickness is slightly increased over time in HIV-1-infected patients. HIV Medicine 2005; 6:380-387.
11. Lekakis J, Tsiodras S, Ikonomidis I, et al. HIV-positive patients treated with PI have vascular changes resembling those observed in atherosclerotic cardiovascular disease. Clinical Science 2008; 115:189-196.
12. Lorenz MW, Stephan C, Harmjanz A, et al. Both long-term HIV infection and highly active antiretroviral therapy are independent risk factors for early carotid atherosclerosis. Atherosclerosis 2008; 196:720-726.
13. Palacios R, Alonso I, Hidalgo A, et al. Peripheral arterial disease in HIV patients older than 50 years of age. AIDS Res Human Retroviruses 2008; 8:1043-1046.
14. Periard D, Cavassini M, Taffé P, et al. High prevalence of peripheral arterial • disease in HIV-infected persons. Clin Infect Dis 2008; 46:761 -767. The previous two studies consistently show both an increase in peripheral arterial disease and traditional cardiovascular disease risk factors in HIV-infected patients compared with age-adjusted uninfected persons.
15. Melendez MM, McNurlan MA, Mynarcik DC, et al. Endothelial adhesion molecules are associated with inflammation in subjects with HIV disease. Clin Infect Dis 2008; 46:775-780.
16. Currier JS, Kendall MA, Henry WK, et al. Progression of carotid artery intima-media thickening in HIV-infected and uninfected adults. AIDS 2007; 21:1137-1145.
17. Lebech AM, Wiinberg N, Kristoffersen US, et al. Carotid intima-media thickness in HIV patients treated with antiretroviral therapy. Clin Physiol Funct Imaging 2007; 27:173-179.
18. Kingsley LA, Cuervo-Rojas J, Muñoz A, et al. Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study. AIDS 2008; 22:1589-1599.
19. McComsey GA, O'Riordan M, Hazen SL, et al. Increased carotid intima media thickness and cardiac biomarkers in HIV infected children. AIDS 2007; 21:921-927.
20. Giuliano ICB, de Freitas SFT, de Souza M, et al. Subclinic atherosclerosis and • cardiovascular risk factors in HIV-infected children: PERI study. Coron Artery Dis 2008; 19:167-172. The previous two studies consistently show both an increase in cardiovascular disease and traditional cardiovascular disease risk factors in HIV-infected children compared with age-adjusted uninfected children.
21. Miller TL, OravEJ, Lipshultz SE, et al. Risk factors for cardiovascular disease in children infected with human immunodeficiency virus-1. J Pediatr 2008; 153:491-497.
22. Data Collection on Adverse Events of Anti-HIV Drugs Study Group. Changes •• over time in risk factors for cardiovascular disease and use of lipid-lowering drugs in HIV-infected individuals and impact on myocardial infarction. Clin Infect Dis 2008; 46:1101 -1110. This study indicates that the risk of cardiovascualr disease in the D :A :D study has not increased over time. In fact, the adjusted risk has decreased probably due to increasing specific inteventions.
23. Lundgren JD, Battegay M, Behrens G, et al. European AIDS Clinical Society •• (EACS) guidelines on the prevention and management of metabolic diseases in HIV. HIV Medicine 2008; 9:72-81. These are not the only existing metabolic guidelines for HIV-infected patients, but they are the most complete and updated. They are written in a practical way so they may be useful in the standard of care of HIV-infected patients.
24. DAD Study Group. Class of antiretroviral drugs and the risk of myocardial • infarction. N Engl J Med 2007; 356:1723-1735. This study gave evidende of a higher risk of myocardial infarction in HIV-infected patients treated with protease inhibitors compared with NNRTIs. Nevertheless, the absolute risk was low and the risk attributed to protease inhibitors was due at least in part to lipid changes.
25. 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; 37:292-298.
26. Currier JS, Lundgren JD, Carr A, et al. Epidemiological evidence for cardio-•• vascular disease in HIV-infected patients and relationship to highly active antiretroviral therapy. Circulation 2008; 118:e29-e35. This is one of the series reviewing the state of current evidence on cardiovascular disease in HIV-infected patients. It is a must-read paper.
27. Mondy KE, de las Fuentes L, Waggoner A, et al. Insulin resistance predicts endothelial dysfunction and cardiovascular risk in HIV-infected persons on long-term highly active antiretroviral therapy. AIDS 2008; 22:849-856.
28. Bongiovanni M, Casana M, Cicconi P, et al. Predictive factors of vascular intima media thickness in HIV-positive subjects. J Antimicrob Chemother 2008; 61:195-199.
29. Lai S, Fishman EK, Lai H, et al. Long-term cocaine use and antiretroviral therapy are associated with silent coronary artery disease in African Americans with HIV infection who have no cardiovascular symptoms. Clin Infect Dis 2008; 46:600-610.
30. Arnedo M, Taffé P, Sahli R, et al. Contribution of 20 single nucleotide • polymorphisms of 13 genes to dyslipemia associated with antiretroviral therapy. Pharmacogenet Genomics 2007; 17:755-764. This complex article provides evidence that genetic factors may influence the risk of dyslipidemia when HIV-infected patients are exposed to certain ART drugs.
31. Tarr PE, Telenti A. Toxicogenetics of antiretroviral therapy: genetic factors that contribute to metabolic complications. Antivir Ther 2007; 12:999-1013.
32. Alonso-Villaverde C, Coll B, Parra S, et al. Atherosclerosis in patients infected with HIV is influenced by a mutant monocyte chemoattractant protein-1 allele. Circulation 2004; 110:2204-2209.
33. 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; 22:1615-1624.
34. Baker JV, Peng G, Rapkin J, et al. Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases. J Acquir Immune Defic Syndr 2008; 48:541 -546.
35. Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS 2008; 22:841 -848.
36. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Major clinical outcomes in antiretroviral therapy (ART)-naïve participants and in those not receiving ART at baseline in the SMART Study. J Infect Dis 2008; 197:1133-1144.
37. Hammer SM, Eron JJ Jr, Reiss P, et al. Antiretrovirfal treatment of adult HIV •• infection: 2008 recommendations of the Inernational AIDS Society-USA Panel. JAMA 2008; 300:555-570. This is an update of the classical guidelines, probably the ones most influential throughout the world. It suggests for the first time that ART should be initiated earlier in patients with high cardiovascular risk.
38. Mattila KJ, Valtonen VV, Nieminen MS, et al. Role of infection as a risk factor for atherosclerosis, myocardial infarction, and stroke. Clin Infect Dis 1998; 26:719-734.
39. Smeeth L, Thomas SL, Hall AJ, et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N Engl J Med 2004; 351:2611-2618.
40. Sung J, Song YM, Choi YH, et al. Hepatitis B virus seropositivity and the risk of stroke and myocardial infarction. Stroke 2007; 38:1436-1441.
41. Vassalle C, Masini S, Bianchi F, et al. Evidence for an association between hepatitis C virus seropositivity and coronary artery disease. Heart 2004; 90:565-566.
42. van Leuven SI, Franssen R, Kastelein JJ, et al. Systemic inflammation as a risk • factor for atherothrombosis. Rheumatology 2008; 47:3-7. A nice review on the pathophysiological mechanisms of chronic inflammation involved in the development of cardiovascular disease.
43. Takano Y, Shimokado K, Hata Y, et al. HIV envelope protein gp120-triggered CD4+ T-cell adhesion to vascular endothelium is regulated via CD4 and CXCR4 receptors. Biochim Biophys Acta 2007; 1772:549-555.
44. Kline ER, Kleinhenz DJ, Liang B, et al. Vascular oxidative stress and nitric oxide depletion in HIV-1 transgenic rats are reversed by glutathione restoration. Am J Physiol Heart Circ Physiol 2008; 294:H2792-H2804.
45. Mu H, Chai H, Lin PH, et al. Current update on HIV-associated vascular disease and endothelial dysfunction. World J Surg 2007; 31:632-643.
46. Eugenin EA, Morgello S, Klotman ME, et al. Human immunodeficiency virus •• (HIV) infects human arterial smooth muscle cells in vivo and in vitro: implications for the pathogenesis of HIV-mediated vascular disease. Am J Pathol 2008; 172:1100-1111. A proof of evidence that HIV infects endothelial cells and promotes local inflammation that could contribute to the development of atherosclerosis.
47. Torriani FJ, Komarow L, Parker RA, et al. Endothelial function in human •• immunodeficiency virus-infected antiretroviral-naïve subjects before and after starting potent antiretroviral therapy. J Am Coll Cardiol 2008; 52:569-576. A simple and consistent study proving that HIV infection is associated with endothelial dysfunction, and that ART irrespective of the regimen used restores HIV-damaged endothelial function.
48. Schilaci G, De Socio GVL, Pucci G, et al. Aortic stiffness in untreated adult patients with human immunodeficiency virus infection. Hypertension 2008; 52:308-313.
49. Carr A, Ory D. Does HIV cause cardiovascular disease? PLoS Med 2006; 3:e496.
50. Rose H, Woolley J, Hoy J, et al. HIV infection and high-density lipoprotein: the effect of the disease vs. the effect of treatment. Metabolism 2006; 55:90-95.
51. Rose H, Hoy J, Woolley J, et al. HIV infection and high density lipoprotein metabolism. Atherosclerosis 2008; 199:79-86.
52. Bernal E, Masiá M, Padilla S, et al. High-density lipoprotein cholesterol in HIV-infected patients: evidence for an association with HIV-1 viral load, antiretroviral therapy status, and regimen compositon. AIDS Patient Care and STDs 2008; 22:569-575.
53. Mujawar Z, Rose H, Morrow MP, et al. Human immunodeficiency virus impairs reverse cholesterol transport from macrophages. PLoS Biol 2006; 4:e365.
54. Bukrinsky M, Svidirov D. HIV and cardiovascular disease: contribution of HIV-infected macrophages to the development of atherosclerosis. PloS Med 2007; 4:e43.
55. Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006; 355:2283-2296.
56. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Inferior clinical outcome of the CD4+ cell count-guided antiretroviral treatment interruption strategy in the SMART Study: role of CD4+ cell counts and HIV RNA levels during follow-up. J Infect Dis 2008; 197:1145-1155.
57. Phillips AN, Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther 2008; 13:177-187.
58. Tebas P, Henry WK, Matining R, et al. Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk. PloS ONE 2008; 3:e2021.
59. Papasavvas E, Azzoni L, Pistilli M, et al. Increased soluble vascular adhesion molecule-1 plasma levels and soluble intercellular adhesion molecule-1 during antiretroviral therapy interruption and retention of elevated soluble vascular cellular adhesion molecule-1 levels following resumption of antiretroviral therapy. AIDS 2008; 22:1153-1161.
60. Seoane E, Resino S, Micheloud D, et al. Lipid and apoprotein profile in HIV-1 - infected patients after CD4-guided treatment interruption. J Acquir Immune Defic Syndr 2008; 48:455-459.
61. Grunfeld C, Kotler DP, Arnett DK, et al. Contribution of metabolic and •• anthropometric abnormalities to cardiovascular disease risk factors. Circulation 2008; 118:e20-e28. This is another one of the series reviewing the state of current evidence on cardiovascular disease in HIV-infected patients. It is a must-read paper.
62. Riddler SA, Smit E, Cole SR, et al. Impact of HIV infection and HAART on serum lipids in men. JAMA 2003; 289:2978-2982.
63. Madden E, Lee G, Kotler DP, et al. Association of antiretroviral therapy with fibrinogen levels in HIV-infection. AIDS 2008; 22:707-715.
64. Masiá M, Padilla S, Bernal E, et al. Influence of antiretroviral therapy on oxidative stress and cardiovascular risk: a prospective cross-sectional study in HIV-infected patients. Clin Ther 2007; 29:1448-1455.
65. Murata H, Hruz PW, Mueckler M. The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 2000; 275:20251 - 20254.
66. Noor MA, Lo JC, Mulligan K, et al. Metabolic effects of indinavir in healthy HIV seronegative men. AIDS 2001; 15:F11 -F18.
67. Noor MA, Seneviratne T, Aweeka FT, et al. Indinavir acutely inhibits insulin-stimulated glucose disposal in humans: a randomized, placebo-controlled study. AIDS 2002; 29:F1 -F8.
68. 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 2004; 18:2137-2144.
69. Noor MA, Flint OP, Maa JF, et al. Effects of atazanavir/ritonavir and lopinavir/ritonavir on glucose uptake and insulin sensitivity: demonstrable differences in vitro and clinically. AIDS 2006; 20:1813-1821.
70. Dube MP, Shen C, Greenwald M, et al. 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; 47:567-574. A study that gives further support to the contention that protease inhibitors do not contribute to endothelial dysfunction. Therefore, this mechanism cannot be considered as responsible for the nonlipid effects of protease inhibitor on the risk for cardiovascular disease.
71. Lee GA, Seneviratne T, Noor MA, et al. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS 2004; 18:641 -649.
72. Blümer RM, van Vonderen MG, Sutinen J, et al. Zidovudine/lamivudine •• contributes to insulin resistence within 3 months of starting combination antiretroviral therapy. AIDS 2008; 22:227-236. This study shows that lopinavir/ritonavir is not associated with insulin resistance when it is accompanied by nevirapine but is when it is accompanied by zidovudine and lamivudine, therefore supporting the role of thymidine NRTIs and not of protease inhibitors in the development of insulin resistance. Insulin resistance appeared early and therefore this effect cannot be attributed to body fat changes.
73. th International AIDS Society Conference on HIV pathogenesis, Treatment and Prevention. Sydney, Australia, 2007: abstract TUPE B079.
74. Van der Lugt J, Ruxrungtham K, Autar S, et al. Metabolic changes in a Thai treatment-naïve population starting double-boosted protease inhibitor therapy. 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Sydney, Australia, 2007 (Abstract).
75. Carr A, Zajdenverg R, Workman C, et al. Effects of tipranavir/r (500/200 or 500/100 mg BID) in comparison with lopinavir/r (400/100 mg BID) on changes in body composition and metabolic parameters in ARV-naïve patients over 48 weeks. 9th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. Sydney, Australia, 2007 (Abstract).
76. Shlay JC, Bartsch G, Peng G, et al. Long-term body composition and metabolic changes in antiretroviral naive persons randomized to protease inhibitor-, nonnucleoside reverse transcriptase inhibitor-, or protease inhibitor plus nonnucleoside reverse transcriptase inhibitor-based strategy. J Acquir Immune Defic Syndr 2007; 44:506-517.
77. Fleischman A, Johnsen S, Systrom DM, et al. Effects of a nucleoside reverse • transcriptase inhibitor, stavudine, on glucose disposal and mitochondrial function in muscle of healthy adults. Am J Physiol Endocrinol Metab 2007; 292:E1666-E1673. This is a proof that short-term stavudine causes both insulin resistance and mitochondrial dysfunction.
78. Brown TT, Li X, Cole SR, et al. Cumulative exposure to nucleoside analogue reverse transcriptase inhibitors is associated with insulin resistance markers in the Multicenter AIDS Cohort Study. AIDS 2005; 19:1375-1383.
79. Ledergerber B, Furrer H, Rickenbach M, et al. Factors associated with the incidence of type 2 diabetes mellitus in HIV-infected participants in the Swiss HIV Cohort Study. Clin Infect Dis 2007; 45:111-119.
80. 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; 31:1224-1229.
81. Wang X, Chai H, Yao Q, et al. Molecular mechanism of HIV protease inhibitor-induced endothelial dysfunction. J Acquir Immune Defic Syndr 2007; 44:493-499.
82. Bozzette SA, Ake CF, Tarn HK, et al. Long-term survival and serious cardiovascular events in HIV-infected patients treated with highly active antiretroviral therapy. J Acquir Immune Defic Syndr 2008; 47:338-341.
83. Murphy R, Costagliola D. Increased cardiovascular risk in HIV infection: drugs, virus and immunity. AIDS 2008; 22:1625-1627.
84. D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study: a multicohort collaboration. Lancet 2008; 371:1417-1426.
85. The SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside • reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS 2008; 22: F17-F24. The previous two studies are controversial because they suggest that recent use of abacavir is associated with a higher risk of developing myocardial infarction in HIV-infected patients. They do not prove causality. Their findings need to be confirmed in other independent clinical and experimental studies.
86. Goicoechea M, McCutchan A. Abacavir and increased risk of myocardial infarction. Lancet 2008; 372:803-804.
87. Cutrell A, Hernandez J, Brothers C, et al. Is abacavir (ABC)-containing combination antiretroviral therapy (CART) associated with myocardial infarction (Ml)? No association identified in pooled summary of 54 clinical trials. XVII International AIDS Conference. Mexico City, August 2008 (Abstract).
88. Smith KY, Fine D, Patel P, et al. Similarity in efficacy and safety of abacavir/ lamivudine compared to tenofovir/emtricitabine in combination with QD lopinavir/ritonavir (LPV/r) over 96 weeks in the HEAT study. XVII International AIDS Conference. Mexico City, August 2008: abstract LBPE1138.