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Georg Behrens Clinic for Immunology and Rheumatology Hannover Medical School, Germany

HAART to heart: HIV and cardiovascular disease. Georg Behrens Clinic for Immunology and Rheumatology Hannover Medical School, Germany. AIDS 2010. Overview. Epidemiology. 1. HIV therapy. 2. HIV infection. 3. Clinical care. 4. No. of patients/ No. of events. Event rate per 1,000 HIV+.

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Georg Behrens Clinic for Immunology and Rheumatology Hannover Medical School, Germany

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  1. HAART to heart:HIV and cardiovascular disease Georg BehrensClinic for Immunology and RheumatologyHannover Medical School, Germany AIDS 2010

  2. Overview Epidemiology 1 HIV therapy 2 HIV infection 3 Clinical care 4

  3. No. of patients/ No. of events Event rate per 1,000 HIV+ Event rate per 1,000 HIV- DAD I2 23,468/126 3.5 NA DAD I3 23,437/345 3.6 NA VA4 36,7667/1207 8.1 NA Kaiser 20025 4159/47 4.3 2.9 Kaiser 2007 5000/162 3.7 2.2 MGH6 3851/189 11.13 6.98 MediCal7 28512/294 4.12 3.32 Epidemiological data: CVD events in HIV-patients1 • Retrospective cohort studies • Prospective HIV cohort studies • Administrative/clinical databases • Randomized clinical trails of ART 1Currier Circulation 2008; 2Friis-Moller N Engl J Med 2003; 3 Friis-Moller N Engl J Med 2007; 4Bozette N Engl J Med 2003; 5Klein J AIDS 2002; 6Triant J Clin Endocrinol Metab 2007; 7Currier J AIDS 2003

  4. Role of traditional risk factors in HIV+ and HIV-1 % increase in risk per unit for each study HIV+ Unit Iloeje2 Friss-MØller3 HIV- Per 1 y  Age 9% 6% 6-9% Sex Male vs female NS 110% 110-160% Diabetes mellitus Yes vs No 260% 90% 140-252% Smoking Yes vs No 140% 290% 70-290% Hypertension Yes vs No 30% 80% 80-90% Per 1 mm/L  Total cholesterol … 26% 25-33% … HDL cholesterol Per 1 mm/L  -28% -52% 1Currier Circulation 2008; 2Iloeje HIV Med 2005; 3 Friis-Moller N Engl J Med 2007

  5. Cause of death in D:A:D 7.9 (ATCC)2 1Smith CROI 2009, #145; 2ATCC, Clin Infect Dis 2010

  6. Prevalence of cardiovascular risk factors in HIV Traditional risk factors • Smoking (47-71%) 1,2 • Obesity (40-60%) 3 • Hypertension (31%) 4 • Dyslipidemia (40-60%) 5 • Glucose intolerance • Type 2 diabetes 1Saves Clin Infect Dis 2003; 2Gritz Nicotine Tob Res 2004; 3Kaplan Clin Infect Dis 2007; 4Seaberg AIDS 2005; 5Samaras Diabetes Care 2007

  7. D:A:D: Traditional Risk Factors for CHD in an HIV-infected Population Better Worse RR: 1.32 (1.23-1.41) Age per 5 yrs older RR: 2.13 (1.29-3.52) Male sex RR: 4.64 (3.22-6.69) Previous CVD RR: 2.92 (2.04-4.18) Smoking RR: 1.40 (0.96-2.05) Family history RR: 1.86 (1.31-2.65) Diabetes (yes vs no) RR: 1.30 (0.99-1.72) Hypertension (yes vs no) 0.1 0.5 1 5 10 Relative Rate of MI (95% CI) Multivariable Poisson model adjusted for age, sex, BMI, HIV risk, cohort, calendar year, race, family history of CVD, smoking, previous CVD event, TC, HDL, hypertension, diabetes. Friis-Møller N et al.N Engl J Med. 2007;356:1723-1735.

  8. 10 Total world population 8 6 Population (Billion) German HIV+ > 60 years of age 60% 4 2 25% 4% 0 2015 HIV, HAART and aging: a rough estimate 22% 15% 10% Population over 60 years of age 2025 2050 2000

  9. Overview Epidemiology 1 HIV therapy 2 HIV infection 3 Clinical care 4

  10. Lipid profile before HIV infection Total cholesterol LDL cholesterol HDL cholesterol Triglycerides

  11. Lipid profile due to HIV infection Total cholesterol LDL cholesterol HDL cholesterol Triglycerides

  12. Lipid profile due HAART Total cholesterol LDL cholesterol HDL cholesterol Triglycerides

  13. HAART and cardiovascular disease Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG HAART CVD Central obesity Age, genetics, diet, hypertension, sedentery life style, renal disease…

  14. HAART and cardiovascular disease Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG HAART CVD Abacavir Didanosine Indinavir Lopinavir Central obesity Age, genetics, diet, hypertension, sedentery life style, renal disease…

  15. D:A:D: Recent and/or cumulative antiretroviral exposure and risk of MI PI† NNRTI 1.2 RR of cumulative exposure/year 95% CI 1.13 1.1 1.0 0.9 IDV NFV LPV/r SQV NVP EFV # PYFU: 68,469 56,529 37,136 44,657 61,855 58,946# MI: 298 197 150 221 228 221 *Current or within last 6 months. †Approximate test for heterogeneity: P = 0.02 Only >30,000 PY of follow up Lundgren JD, et al. CROI 2009. Abstract 44LB; DAD Study Group Lancet 2008

  16. D:A:D: Recent and/or cumulative antiretroviral exposure and risk of MI NRTI 1.9 1.9 1.5 1.5 RR of recent* exposure yes/no 95% CI RR of cumulative exposure/year 95% CI 1.2 1.2 1.0 1.0 0.8 0.8 0.6 0.6 ZDV ddI ddC d4T 3TC ABC TDF # PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157# MI: 523 331 148 40 554 221 139 *Current or within last 6 months. †Approximate test for heterogeneity: P = 0.02 Only >30,000 PY of follow up Lundgren JD, et al. CROI 2009. Abstract 44LB; DAD Study Group Lancet 2008

  17. Abacavir and myocardial infarction Behrens & Reiss Curr Opin Infect Dis 2010

  18. Amyloid A Amyloid P (µg/L) D-dimer (µg/ml) F1.2 (pmol/l) (mg/l) Abacavir and inflammation (SMART) Adjusted mean differences in biomarker levels at study entry for using »ABC (no ddI)« or »ddI (w/wo ABC)« versus »Other NRTI« ABC (no ddI) 30 * ddI (w/wo ABC) 25 20 * Percent adjusted difference from „other NRTI“ 15 10 5 0 hsCRP IL-6 (pg/ml) n=791 (µg/ml) SMAT+DAD AIDS 2008

  19. ABC in patients: • STEAL Study4 • WIHS and HOPS Cohort5 • BICOMBO Study6 • HEAT Study7 No differences in biomarkers (hsCRP, IL-6, D-dimer, MCP-1…) ABC + inflammation: More data, more questions? Mac-1 Leukocytes Endothelial cells Platelets ICAM-1 ABC in vitro: • induces Mac-1 on leukocytes, which interacts with ICAM-1 on endothelial cells1 • increases platelet activity through inhibition of soluble guanylyl cyclase2 • facilitates collagen-induced platelet aggregation3 1de Pablo CROI 2010 #716; 2Baum CROI 2010 #717; 3 Satchell CROI 2009 #151LB7; 4Martin CROI 2010, #718; 5Palella AIDS 2010; 6Martinez AIDS 2010; 7McComsey CROI 2009 # 732

  20. Lipid profile due HAART Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG HAART CVD Abacavir Didanososine Indinavir Lopinavir Central obesity Inflammation ? Age, genetics, diet, hypertension, sedentery life style, renal disease…

  21. Lipid profile due HAART Insulin resistance Type 2 diabetes Dyslipidemia High FFA Small dense LDL Low HDL High TG HAART CVD Central obesity Inflammation ? HIV Age, genetics, diet, hypertension, sedentery life style, renal disease…

  22. Overview Epidemiology 1 HIV therapy 2 HIV infection 3 Clinical care 4

  23. Risk of major CVD events* by study arm in SMART DC = drug conservation arm VS = viral suppression arm 5 Relative hazard: 1.57 (1.00-2.46) p = 0.05 DC** 4 3 VS** % with a major CVD event* 2 1 0 0 0.5 1 1.5 2 2.5 3 3.5 4 Years from Randomization Number at risk DC 2,752 1,306 713 379 10 VS 2,720 1,292 696 377 10 *Death from CVD, silent or clinical MI, stroke, CAD requiring invasive procedure. Phillips A et al. (SMART Study Group). 14th CROI2007; Los Angeles, CA. Abstract 41.

  24. Changes in immune activation with treatment interruption (ATG 5102) Soluble TNFR II CD8+/HLA-DR+/CD38+ STEP 2(off ART) STEP 1(on ART) STEP 2(off ART) 50 6000 * 40 5000 * 30 4000 ng/mL % Δ from BL 20 3000 10 2000 0 1000 -10 0 0 16 2 4 48 0 14 Weeks Weeks Conclusion for treatment interruption: Lipids , immune activation  Tebas P PLoS ONE 2008

  25. Preclinical atherosclerosis in HIV-patients (FRAM) IMT: Multivariable analysis of associated factors IMT: Intima media thickness BP: Blood pressure * p<0.01 ** p<0.001 *** p<0.0001 Grunfeld CROI 2009, Grunfeld AIDS 2010

  26. Preclinical atherosclerosis in HIV-patients (FRAM) IMT: Multivariable analysis of associated factors * p<0.01 ** p<0.001 *** p<0.0001 BP: Blood pressure Grunfeld CROI 2009, Grunfeld AIDS 2009

  27. HIV and cardiovascular risk HIV induces • Apoptosis  in endothelial cells (gp120, Tat)1-3 • Endothelial dysfunction4 • Leukocyte activation5 • HDL , IL-6 , sICAM , D-dimer  • MCP-1-CCR2 axis activation6 • MCP-1 polymorphism associated with atherosclerosis in HIV7 • a distinct (inflammatory) atherosclerosis process?8 MCP-1: Monocyte chemotactic protein-1 1Sudano, Am Heart J 2006; 2Huang, J AIDS 2001; 3Jia, Biochem Biophys Res Commun 2001; 4Solages, CID 2006; 5de Gaetano, Lancet Infect Dis 2004; 6Park Blood 2001; 7Alonso-Villaverde Circulation 2004; 8Mehta, Angiology 2003, Baker CID 2010

  28. HIV and cardiovascular risk HIV as a risk factor • HIV+HCV: - sICAM-1 + sVCAM-1 1 • - endothelial dysfunction1 • - increased risk for MI2 • Low CD4 count is risk factor for MI3 and carotid leasons • Low CD4 nadir is associated with reduced arterial stiffness4 • HAART improves FMD, but not to normal (ACTG 5152s)5 • HIV is an independent predictor of increased carotid IMT6,7 • HIV increases tissue factor expression on monocytes8 FMD: Flow-mediated dilatation 1Castro, AIDS 2010; 2Bedimo, HIV Med 2010; 3Lichentstein, Clin Infect Dis 2010; 4Ho, AIDS 2010; 5Torriani Am J Coll Cardiaol 2008; 6Hsu, Circulation 2004; 7Grunfeld AIDS 2009; 8Funderburg Blood 2010

  29. TLR7 HIV pDC  LPS IFNα TLR4 MØ TNFα Immune activation Disruption of lymph node architecture Microbial translocation and low-level inflamation GALT CD4 CD4 pDC CD4 Lumen Gut mucosa Baenziger et al. Blood 2008; Chang & Altfeld Blood 2009

  30. Atherosclerosis and immune cells Modified from Hansson & Libby. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006

  31. Atherosclerosis and immune cells Inflammation Coagulation Apoptosis Modified from Hansson & Libby. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006

  32. HIV Nicotine Hypertension Obesity Lipids Glucose Age ♂♀ Lipids Glucose Fat tissue HIV-therapy Atheroma formation and growth Plaque instability and ruptur Hyper- coagulability Inflammation Behrens & Reiss Curr Opin Infect Dis 2010

  33. Overview Epidemiology 1 HIV therapy 2 HIV infection 3 Clinical care 4

  34. Clinical care Viral load Inflammation Risk for myocardial infarction 10 5% 2% HAART VL<50 copies

  35. Clinical care Viral load Inflammation HAART, lipodystrophy, lipids, insulin resistence, type 2 diabetes… 7% Risk for myocardial infarction 5% HAART VL<50 copies

  36. Clinical care Viral load Inflammation HAART, lipodystrophy, lipids, insulin resistence, type 2 diabetes… 15% Risk for myocardial infarction 10% HAART VL<50 copies

  37. EACS Guideline for non-infectious Co-Morbidities in HIV Assess CVD risk in the next 10 years EACS Guideline for non-infectious Co-Morbidities in HIV, 2009 www.eacs.com

  38. Smoking Blood pressure Coagulation Glucose Lipids Drug treatment if: SBP140 or DBP90 mmHg (especially if 10 year CVD risk 20%) Drug treatment if: Established CVD or Age  50 and 10 year CVD risk 20% Confirm DM and treat Drug treatment if: Established CVD or T2D or 10 year CVD risk 20% EACS Guideline for non-infectious Co-Morbidities in HIV Assess CVD risk in the next 10 years Advise on diet and lifestyle in all patients Consider ART modification, if 10 year CVD risk 20% Identify key modifiable risk factors EACS Guideline for non-infectious Co-Morbidities in HIV, 2009 www.eacs.com

  39. EACS Guideline for non-infectious Co-Morbidities in HIV Assess CVD risk in the next 10 years Advise on diet and lifestyle in all patients Consider ART modification, if 10 year CVD risk 20% Smoking Identify key modifiable risk factors Blood pressure Coagulation Glucose Lipids Consider to treat with acetylsalicylic acid 75-150mg EACS Guideline for non-infectious Co-Morbidities in HIV, 2009 www.eacs.com

  40. HIV +  is not only about myocardial infarction! Other cardiac manifestations of HIV infection: • ECG evidence of asymptomatic IHD1 • Diastolic dysfunction2,3 • QT-Prolongation: • High prevalence in HIV (20%)4 • Associated with HIV-drugs5 • Pericardial tuberculosis, pericardial effusion6 • Dilated cardiomyopathy6 • … 1 Carr AIDS 2008; 2Hsue Circ Heart Fail 2010 ;3Thöni AIDS 2008;4Reinsch HIV Clin Trial 2009; 5FDA: Ongoing safety review of Invirase and possible association with abnormal heart rhythms, Feb. 2010; Ntsekhe Nat Clin Pract Cardiovasc Med 2009

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