1. Georg Behrens Clinic for Immunology and Rheumatology Hannover Medical School, Germany HAART to heart: HIV and cardiovascular disease AIDS 2010

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

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

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

5. Cause of death in D:A:D 7.9 (ATCC) 2 1 Smith CROI 2009, #145; 2 ATCC, Clin Infect Dis 2010 Cause of deathPercentage AIDS-related32 Liver-ralated14 Non-AIDS cancers12 CVD-related11 Non-natural9 Bacterial infections7 Renal1 Lactic acidosis/pancreatitis1 Others/Unknown1

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 1 Saves Clin Infect Dis 2003; 2 Gritz Nicotine Tob Res 2004; 3 Kaplan Clin Infect Dis 2007; 4 Seaberg AIDS 2005; 5 Samaras Diabetes Care 2007

7. 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. Relative Rate of MI (95% CI) WorseBetter 0.10.51510 RR: 1.86 (1.31-2.65) Diabetes (yes vs no) RR: 1.30 (0.99-1.72) Hypertension (yes vs no) Family history Previous CVD Male sex Age per 5 yrs older Smoking RR: 1.40 (0.96-2.05) RR: 2.92 (2.04-4.18) RR: 2.13 (1.29-3.52) RR: 4.64 (3.22-6.69) RR: 1.32 (1.23-1.41) Friis-Møller N et al. N Engl J Med. 2007;356:1723-1735. D:A:D: Traditional Risk Factors for CHD in an HIV-infected Population

8. Population over 60 years of age 2000 20252050 Total world population 2 4 6 8 10 0 Population (Billion) 10% 15% 22% 4% 2015 25% 60% German HIV + > 60 years of age HIV, HAART and aging: a rough estimate

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

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

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

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

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

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

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

16. # PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 # MI: 523 331 148 40 554 221 139 1.9 1.5 1.2 1.0 0.8 0.6 ZDVddIddCd4T3TCABCTDF 1.9 1.5 1.2 1.0 0.8 0.6 NRTI *Current or within last 6 months. † Approximate test for heterogeneity: P = 0.02 D:A:D: Recent and/or cumulative antiretroviral exposure and risk of MI RR of recent* exposure yes/no 95% CI RR of cumulative exposure/year 95% CI Lundgren JD, et al. CROI 2009. Abstract 44LB; DAD Study Group Lancet 2008 Only >30,000 PY of follow up

17. StudyDesign Event Ascertainment Patients (n=)MI (n=) Abacavir- effect? D:A:D Prospective observ. cohort Prospective predefined 33,347580 Yes FHDB Case control in observ. cohort Prospective, MI retrospectively validated 289 cases 884 control 289 Yes, first year of exposure SMART RCT, Oberserv. analysis Prospective predefined 2,75219 Yes STEAL RTCProspective3573 Yes QPHID Case control in observ. cohort ICD 9 code acute MI Not validated 142 cases 1,420 controls 142 Yes GSK Analysis RCT (n=54) Retrospective Data base search 14,17411 No ALLRT ACTG Long term follow up of 5 RCT Retrospective 2 independent reviewer 3,20527 No VACCR Retrospective observ. cohort ICD 9 code acute MI Not validated 19,424278 No Behrens & Reiss Curr Opin Infect Dis 2010 Abacavir and myocardial infarction

18. 0 5 10 15 20 25 30 hsCRP (µg/ml) IL-6 (pg/ml) Percent adjusted difference from „other NRTI“ n=791 * * 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) ddI (w/wo ABC) Amyloid A (mg/l) Amyloid P (µg/L) D-dimer (µg/ml) F1.2 (pmol/l) Abacavir and inflammation (SMART) SMAT+DAD AIDS 2008

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

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

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

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

23. *Death from CVD, silent or clinical MI, stroke, CAD requiring invasive procedure. Number at risk DC 2,752 1,306 713 379 10 VS 2,720 1,292 696 377 10 % with a major CVD event* Years from Randomization VS** DC** Relative hazard: 1.57 (1.00-2.46) p = 0.05 0 1 2 3 4 5 00.511.522.533.54 Phillips A et al. (SMART Study Group). 14th CROI 2007; Los Angeles, CA. Abstract 41. DC = drug conservation arm VS = viral suppression arm Risk of major CVD events * by study arm in SMART

24. Tebas P PLoS ONE 2008 CD8 + /HLA-DR+/CD38+ 0 -10 10 20 30 40 50 % Δ from BL 016 Weeks 2448 STEP 1 (on ART) STEP 2 (off ART) Soluble TNFR II 1000 0 2000 3000 4000 5000 6000 ng/mL 0 Weeks 14 Conclusion for treatment interruption: Lipids , immune activation  * * Changes in immune activation with treatment interruption (ATG 5102) STEP 2 (off ART)

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

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

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

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

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

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

31. InflammationCoagulationApoptosis Modified from Hansson & Libby. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006

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

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

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

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

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

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 Glucose Coagulation Blood pressure Lipids Confirm DM and treat Confirm DM and treat Drug treatment if: Established CVD or Age  50 and 10 year CVD risk  20% Drug treatment if: Established CVD or Age  50 and 10 year CVD risk  20% Drug treatment if: SBP  140 or DBP  90 mmHg (especially if 10 year CVD risk  20%) Drug treatment if: SBP  140 or DBP  90 mmHg (especially if 10 year CVD risk  20%) Drug treatment if: Established CVD or T2D or 10 year CVD risk  20% Drug treatment if: Established CVD or T2D or 10 year CVD risk  20% 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% 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 EACS Guideline for non-infectious Co-Morbidities in HIV, 2009 www.eacs.com

39. Smoking Glucose Coagulation Blood pressure Lipids 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% 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 Target If T2D or prior CVD or CKD + proteinuria Others SBP<130<140 DBP<80<90 Target N/A Consider to treat with acetylsalicylic acid 75-150mg Consider to treat with acetylsalicylic acid 75-150mg Target HbA1c <6.5-7% Target BestStandard TC  4 (155)  5 (190) LDL  2 (80)  3 (115) EACS Guideline for non-infectious Co-Morbidities in HIV

40. HIV + is not only about myocardial infarction! ECG evidence of asymptomatic IHD 1 Diastolic dysfunction 2,3 QT-Prolongation: - High prevalence in HIV (20%) 4 - Associated with HIV-drugs 5 Pericardial tuberculosis, pericardial effusion 6 Dilated cardiomyopathy 6 … 1 Carr AIDS 2008; 2 Hsue Circ Heart Fail 2010 ; 3 Thöni AIDS 2008; 4 Reinsch HIV Clin Trial 2009; 5 FDA: Ongoing safety review of Invirase and possible association with abnormal heart rhythms, Feb. 2010; Ntsekhe Nat Clin Pract Cardiovasc Med 2009 Other cardiac manifestations of HIV infection: