Coronary Artery Disease in HIV
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This document discusses coronary artery disease in HIV patients. It covers the relative magnitude of cardiovascular disease among HIV patients, current data on the association between HIV and coronary artery disease, known risk factors and how they may be modulated by HIV diagnosis, screening and prevention recommendations, and areas for future research. Key points include increased rates of myocardial infarction and atherosclerosis in HIV patients, traditional and HIV-specific risk factors, screening tools and their limitations, effects of antiretroviral therapy on risk, and lifestyle and medical interventions for prevention.
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Coronary Artery Disease in HIV
- 1. Coronary Artery Disease in HIV Patients Leonard Sowah, MBChB, MPH
- 2. Educational Objectives Relative Magnitude of CVS disease among HIV patients Discuss current data on association between HIV and Coronary Artery Disease Current known cardiovascular disease risk factors and how they may be modulated by HIV Dx Evaluation and Screening of HIV patients for CVS disease Prevention of Coronary Artery Disease in this population Areas of Future Research
- 3. Underlying Causes of Death Among Patients with a HIV Diagnosis AIDS-defining events (27% vrs 36% in 2005, 47% in 2000) Non-AIDS-defining and non-hepatitis-related cancers (24% vrs 17% in 2005 and 11% in 2000) Liver diseases (11%, 38% being hepatocellular carcinoma) Cardiovascular diseases (11%) Other Infections (10%, 50% of the respiratory tract) Suicide (5%) All Cancer types (37%) PhiliipeMorlat et al Paper #1130 - CROI 2012
- 4. Leading Categories of Underlying Causes of Non–HIV-Related Deaths in Persons with AIDS in New York City, 1999–2004 Ann Intern Med. 2006;145(6):397-406. Date of download: Copyright © The American College of Physicians. 6/18/2012 All rights reserved.
- 5. Evolution of Underlying Causes of Death in HIV PhiliipeMorlat et al Paper #1130 - CROI 2012
- 6. Common Causes of Death in HIV Patients in the HAART Era Clin Infect Dis. 2010; 50 (10): 1387-1396.
- 7. Percentage Distribution of the 10 Leading Causes of Death By Sex (USA)
- 8. Epidemiology of Atherosclerosis in HIV Myocardial Infarction Rates are 1.5 - 2 times higher among HIV positive individuals Incidence rate is about 11.13 per 1000 person yrs vrs 6.98 per 1000 person yrs in HIV negatives Relative Risk based on data from a large Health System in Massachusetts – 1.75 ( CI – 1.51 – 2.02; P < 0.0001) Relative Risk appears to be higher in women than for men – 2.98 ( CI – 2.33 – 3.75); P < 0.0001) compared to 1.40 (CI – 1.16 – 1.67; P <0.0003) for men 1. J Acquir Immune DeficSyndr. 2003;33:506 –512. 2. J Clin Endocrinology Metab, 2007, 92: 2506 – 2512
- 9. Epidemiology contd. In a Case Control study HIV positive patient were more likely to have 3 vessel disease compared to HIV negatives 76% vrs 30%1 DAD Study data suggests an RR of 1.26 per year of ART therapy (CI – 1.12 – 1.41; P < 0.001)2 The Relative Risk for MI in HIV positive patients 18 – 24 yrs – Ranges between 2.16 – 6.763 A study using data from the Danish HIV Cohort revealed an increase in risk of MI in first 90 days after initiating HAART RR – 7.44 (CI – 3.35 – 16.5)4 1. Arch Intern Med. 2003; 163(4): 457 – 460 2. N Engl J Med. 2003; 349: 1993 – 2003 3. J Acquir Immune DeficSyndr. 2003; 33:506-512 4. Clin Infect Dis. 2007; 44:1625-31
- 10. Incidents Rates of MI Across Cohorts and Databases Circulation 2008; 118: e29 – e35
- 11. CHD incidence per 100 PY among HIV-infected and non-HIV-infected men *Relative risk (HIV-infected versus non-HIV-infected), P < 0.01. JAIDS Journal of Acquired Immune Deficiency Syndromes. 33(4):506-512, August 1, 2003. © 2003 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2
- 12. Kaplan Meier curves for time from HAART initiation to first verified hospitalization with ischemic heart disease in HIV-infected patients and control subjects. Obel N et al. Clin Infect Dis. 2007;44:1625-1631 © 2007 Infectious Diseases Society of America
- 13. RISK FACTORS OF CVS DISEASE IN HIV PATIENTS Traditional risk factors; age, family history, male sex, diabetes, hypertension, hyperlipidemia, smoking, obesity CD4 count of < 200 after > 24mths of stable ART (RR - 1.66 CI – 1.14 – 1.85)3 High level viremia ( RR- 1.37, CI 1.04 – 1.81)1, 2 Duration of Protease Inhibitors therapy ( RR- 1.16 CI -1.10 – 1.23)2 Lipodystrophy or body fat redistrubution4 Micro-albuminuria5 1. N Engl J Med 2006; 355:2283 – 2296 2. N Engl J Med 2007;356:1723-1735 3. AIDS 2012; 26 (4) 465 - 474 4. J Acquir Immune DeficSyndr 2005; 39:44-54) 5. Nephrol. Dial. Transplant. 2008; 23 (10) : 3130 -3137
- 14. RISK FACTORS & MARKERS OF ELEVATED RISK Contd Coronary Artery Calcium1 Vitamin D deficiency2 Carotid Artery Intimal Medial Thickness3 C-Reactive Protein/high sensitivity CRP2 Soluble Tumor Necrosis Factor α Receptor 1 (sTNFα1)2 1. Fitch K, Abbara S, Lee H et al, AIDS 2012, 26:587–597 2. Legeai L, Vigourox C, Souberbiele JC et al; paper 883 CROI 2012 3. AIDS 2009, 23:1841–1849
- 15. Long-term complications in patients with poor immunologic outcomes on suppressed ART Dutch ATHENA cohort. AIDS. 26(4):465-474, February 20, 2012. DOI: 10.1097/QAD.0b013e32834f32f8
- 16. Impact of HAART Therapy on CVS Risk Circulation 2008; 118: e29 – e35
- 17. Effects of ART therapy on Lipids J Acquir Immune DeficSyndr 2009, 50: 54 -64
- 18. Relative Risk of MI by PI exposure Currier J S et al. Circulation 2008;118:e29-e35 Copyright © American Heart Association
- 19. Atherogenesis in HIV T-Cell activation Cytokine dysregulation causing dyslipidemia Metabolic effects of HIV therapy (insulin resistance) Increased visceral adiposity Inflammatory effects of HIV related Opportunistic Infections Increased proliferation of smooth muscle cells in the intima The Journal of Infectious Diseases 2012;205:S368–74
- 20. CARDIOVASCULAR DISEASE IN HIV HIV Viral Replication Anti- retroviral Immune Therapy activation Insulin Inflammation Resistance & Diabetes Macrophage Dyslipidemia Recruitment Atherosclerosis Endothelial Dysfunction Hypertensio Genetics Smoking n Modified from: Currier J.S., Topics in HIV Medicine, 2009, 17(3); 98-103
- 21. Cellular Mechanisms of Atherosclerosis Nature 2011; 473:317–25
- 22. Relative increase in Risk of Cardiovascular Disease By Different Risk Factors among HIV Patients 4 3.5 3 2.5 2 1.5 1 0.5 0 Increase in Risk of Cadiovascular Disease The DAD Study Group. N Engl J Med 2007; 356:1723 - 1735
- 23. Relationship between Cardiovascular Risk Factors and the Rate of Myocardial Infarction in HIV Patients Cardiovascular Risk Relative Risk of Heart p-value Factor Attack Protease Inhibitor use per 1.10 (1.04 – 1.18) 0.002 additional year Age per additional 5 yrs 1.32 ( 1.23 – 1.41) < 0.001 BMI > 30 1.34 (0.86 – 2.09) 0.19 Family History of Heart Dx 1.40 (0.92 – 1.91) 0.08 Current Smoker 2.92 (2.04 – 4.18) < 0.001 Former Smoker 1.63 (1.07 – 2.48) 0.02 Previous CVS event 4.64 (3.22 – 6.69) < 0.001 Diabetes 1.86 (1.31 – 2.65) < 0.001 Hypertension 1.30 (0.99 – 1.72) 0.06 Total Cholesterol per mmol 1.26 (1.19 – 1.35) < 0.001 HDL per mmol 0.65 (0.48 -0.88) 0.05 The DAD Study Group. N Engl J Med 2007;356:1723-1735
- 24. From: Acute Myocardial Infarction in Human Immunodeficiency Virus–Infected Patients Arch Intern Med. 2003;163(4):457-460. doi:10.1001/archinte.163.4.457 Copyright © 2012 American Medical Date of download: 6/14/2012 Association. All rights reserved.
- 25. PREVENTION Circulation July 8, 2008 vol. 118 no. 2 e41-e47
- 26. Framingham Risk This is useful in HIV infected patients but may underestimate CAD risk1,2 Does not include information on lipodystrophy currently identified to be independently associated with CAD risk The is no accounting for PI exposure suggested to increase risk from 11-16 % per year of exposure No consideration for poor immunologic response on HAART Therapy another marker of likelihood of CAD event Does not include CD4 nadir 1. J Acquir Immune DeficSyndr 2009; 52 (2) 303 -304 2. HIV Medicine (2010) 11, 225 -231 3. Eur J PrevCardiol. 2012 Jun 20
- 27. Correlation between Framingham, DAD and SCORE with cIMT Villar S. et al 2012, European Journal of Preventive Cardiology, Epubahed of print.
- 28. Adding HIV Related Variables to the D.A.D risk Equation Villar S. et al 2012, European Journal of Preventive Cardiology, Epubahed of print.
- 29. Modified Framingham for HIV Framingham Risk Calculator The DAD Five Year Risk Equation Source: Copenhagen HIV Program, http://www.chip.dk/TOOLS/tabid/282/Default.aspx Acessed: 6/18/2012
- 30. Interventions Early ART therapy Careful choice of ART regimen Lifestyle modification and diet Smoking Cessation Metformin therapy for those with insulin resistance or evidence of metabolic syndrome Statin Therapy Vitamin D supplementation
- 31. Lifestyle Modification and Metformin 1. Fitch K, Abbara S, Lee H et al, AIDS 2012, 26:587–597
- 32. Metabolic Effects of Metformin in HIV Patients Int. J ClinPract. 2007; 60 (3) 463 - 472
- 33. Statin Therapy Statins lower lower LDL and hsCRP and TNFα in HIV patients1,3 Statins lower lower hsCRP and TNFα in HIV patients1 Statin use reduced mortality by 67% in suppressed patients 2 Statins may reverse PI mediated premature vascular senescence in HIV-infected patients4 Statin use reduces markers of immune activation in HIV positive cells without any effect on viral load.5 1. HIV Clin Trials. 2012 May-Jun;13(3):153-61 2. Moore RD, Bartlett JG, Gallant JE PLoS ONE:2011 vol:6 iss:7 pg:e21843 -e21843 3. J ClinLipidol. 2010 Jul-Aug;4(4):279-87. 4. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010; 30: 2611-2620 5. J Infect Dis. (2011) 203 (6): 756-764. doi: 10.1093/infdis/jiq115
- 34. Future Research Does using Ace-Inhibitors and Angiotension Receptor Blockers in HIV patients with early CAD improve outcome ? Will the use of lipid neutral and metabolic neutral ART agents have significant impact on CVS outcomes ? Will patients with erratic medication adherence have poorer CVS outcomes on the long term ? Does the practice on induction of virologic suppression with high genetic barrier for resistance regimens with switch to less metabolic and lipid neutral agents for maintenance confer any long term benefit ?
Editor's Notes
- This data represents a large European and North American Cohort of Patients. These are patients are individuals who initiated ART therapy from 1996 – 2006. Total of 39,272 patients from 13 different HIV positive Cohorts.
- The relative risk calculated was after adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. There was no adjustment for smoking since the database had a lot of incomplete data on smoking.The risk associated with lipodystrophy and other HIV related body fat redistribution may be more significant in HIV positive women. ( J Acquir Immune DeficSyndr 2005; 39:44-54)
- The case control study on MI incidences was from a Los Angeles Cedars-Sinai Medical Center. HIV patients have a higher incidence of recurrent coronary and atherothrombotic events (re-infarction or unstable angina) over a 15month follow up period. (Small study 24 HIV positive matched to 48 HIV negatives)Data from DAD Study Group from 1996 – 2001 from about 23, 437 patients median age 39yrs 34 – 45 IQR.Based on data from MediCal population 1994 - 2000 large study 3,083,209 individuals with 28,513 persons being HIV positive. Several limitations including lack of good data on smoking and family history to help adjust for these risk factors. There is an obvious likelihood of Medical Surveillance bias as HIV positive patients in care have more opportunities to have CHD diagnosed on account of them having more frequent visits.Danish Study included 4252 Residents of Denmark with a HIV diagnosis prior to January 2005; the Data was from the Danish HIV Cohort Study and 373, 856 controls. The Danish National Hospital Registry and the Danish Civil Registration System was the source of the controls. Mean CD4 count at treatment onset was 182 (74 – 290) IQR
- The data for this table was derived from 5 different cohorts DAD study data from 2003 and 2006. Bozzette data is from the VA Cohort from 1993 - 2001 which is predominantly male and has limitations for generalizability. Klein used data from the Kaiser Permanente Database for his studies the 2002 paper was for data from January 1996 to June 2001. The second estimate was from 2001 – 2006 the late HAART period and was presented at CROI 2007. The Triant data was from the Mass General Hospital and Brigham and Women Hospital between Oct 1996 – June 2004. Currier et al used data from Medi-Cal ( The California Medicaid Claims database) data was drawn from claims with HIV specific ICD codes from July 1994 – June 2000.
- This study by Currier J et all is based on a nested case control study from the Medi-Cal database and may not be very representative of the general population. Medicaid patients without HIV may on average by sicker, this may not apply to HIV patients who may have been enrolled in medicaid on account of their HIV status.
- Low level viremia in the study of the Athena cohort patients was defined as 50 – 400, and high level viremia as viral load > 400 copies. The SMART study also produced overwhelming data in support of the fact that plasma viremia does have a deleterious effect on cardiovascular endpoints.
- 2. Paper presented at CROI 2012 a group from the French National Agency for Research on AIDS and Viral Hepatitis reported an association between vitamin D levels and CD4 counts < 100 cells. In this study the HIV positive patients with the lowest tertile of 25(OH) Vitamin D level had higher mean levels of inflammatory markers hsCRP (P = 0.047), sTNFR1 (P = 0.02). In subgroup analysis they found an association between vitamin D levels and insulin resistance in white patients this association was not found for black patients. The consisted of 355 treatment naïve patients, 204 white and 151 black mostly Africans from the continent, 30% of the patients where women. Another paper presented at CROI found a strong association between Vitamin D and adiponectin levels in HIV patients small study sample size 103. 3. A secondary data analysis of the FRAM (Fat Redistribution and Metabolic Changes in HIV Study and MESA (Multi-Ethnic Study of Atherosclerosis) shows a strong association between HIV and cIMT and HIV similar to the association between cIMT and smoking in men and 4x the association seen in smoking and cIMT in women.
- The normal muscular artery and the cell changes that occur during disease progression to thrombosis are shown. a, The normal artery contains three layers. The inner layer, the tunica intima, is lined by a monolayer of endothelial cells that is in contact with blood overlying a basement membrane. In contrast to many animal species used for atherosclerosis experiments, the human intima contains resident smooth muscle cells (SMCs). The middle layer, or tunica media, contains SMCs embedded in a complex extracellular matrix. Arteries affected by obstructive atherosclerosis generally have the structure of muscular arteries. The arteries often studied in experimental atherosclerosis are elastic arteries, which have clearly demarcated laminae in the tunica media, where layers of elastin lie between strata of SMCs. The adventitia, the outer layer of arteries, contains mast cells, nerve endings and microvessels. b, The initial steps of atherosclerosis include adhesion of blood leukocytes to the activated endothelial monolayer, directed migration of the bound leukocytes into the intima, maturation of monocytes (the most numerous of the leukocytes recruited) into macrophages, and their uptake of lipid, yielding foam cells. c, Lesion progression involves the migration of SMCs from the media to the intima, the proliferation of resident intimalSMCs and media-derived SMCs, and the heightened synthesis of extracellular matrix macromolecules such as collagen, elastin and proteoglycans. Plaque macrophages and SMCs can die in advancing lesions, some by apoptosis. Extracellular lipid derived from dead and dying cells can accumulate in the central region of a plaque, often denoted the lipid or necrotic core. Advancing plaques also contain cholesterol crystals and microvessels. d, Thrombosis, the ultimate complication of atherosclerosis, often complicates a physical disruption of the atherosclerotic plaque. Shown is a fracture of the plaque's fibrous cap, which has enabled blood coagulation components to come into contact with tissue factors in the plaque's interior, triggering the thrombus that extends into the vessel lumen, where it can impede blood flow.
- 1. Compared corellation between Framingham Risk and Coronary Artery Calcium, Sample was 330 HIV positive patients 69.4% men. 2
- 5. Of 24 randomized participants, 22 completed the study. Although HIV-1 RNA level was unaffected by the intervention (–0.13 log10 copies/mL; P = .85), atorvastatin use resulted in reductions in circulating proportions of CD4+ HLA-DR+ (–2.5%; P = .02), CD8+ HLA-DR+ (–5%; P = .006), and CD8+ HLA-DR+ CD38+ T cells (–3%; P = .03).