1. HIV infection and cardiovascular diseases Matthew S. Freiberg, MD, MSc University of Pittsburgh School of Medicine and Graduate School of Public Health Yale GIM Research in Progress September 8 th, 2011

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4. By 2015, what percentage of HIV infected people living in the U.S. will be 50 years of age or older 15% 25% 35% 50% http://www.cdc.gov/hiv/resources/factsheets/

5. By 2015, what percentage of HIV infected people living in the U.S. will be 50 years of age or older 15% 25% 35% 50% http://www.cdc.gov/hiv/resources/factsheets/

6. At the end of 2006, African Americans accounted for what percentage of all new HIV infection diagnoses 15% 35% 45% 50% http://www.cdc.gov/hiv/topics/aa/

7. At the end of 2006, African Americans accounted for what percentage of all new HIV infection diagnoses 15% 35% 45% 50% http://www.cdc.gov/hiv/topics/aa/

8. In 2006, the rate of new HIV infection for black women was nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women. 3 and 2 5 and 3 10 and 3 15 and 4 http://www.cdc.gov/hiv/topics/aa/

9. In 2006, the rate of new HIV infection for black women was nearly __ times as high as that of white women and nearly __ times that of Hispanic/Latina women. 3 and 2 5 and 3 10 and 3 15 and 4 http://www.cdc.gov/hiv/topics/aa/

10. Background HIV infection is associated with –Increased coronary calcium 1 –Progression of carotid IMT 2 –Endothelial dysfunction as measured by FMD 3 Antiretroviral therapy (ARV) is associated with AMI risk in observational studies 4 Intermittent ARV, however, is associated with a greater risk of AMI than continuous ARV for viral suppression 5 1. Lai et al. Archives of Internal Medicine 2005; 2. Hsue et al. Circulation 2004; 3. Solages et al. CID 2006; 4. DAD study group. NEJM 2007; 5. SMART study group. NEJM 2006.

11. 11 The SMART Study The Strategies for Management of ART (SMART) study is a RCT of 5472 HIV+ Participants who were assigned either to drug Conservation or viral suppression Participants were followed for 16 months Primary end points was opportunistic disease or death from any cause (n=167) Secondary endpoints were major CVD, renal, or hepatic disease (n=104 of which 79 were CVD)

12. 12 The SMART Study The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 2006;355:2283-2296

13. Important Questions Is HIV infection an independent risk factor for AMI? Does HIV infection increase the risk of other cardiovascular diseases? If HIV does increase the risk of CVD what is the mechanism? Do ARVs play a role? Do non-traditional risk factors play a role? If so, does the Framingham risk score apply to those with HIV infection?

14. Is HIV as an independent risk factor for AMI

15. Prior studies suggesting HIV is associated with a significant AMI risk Triant et al. 1 –AMI rate ratio=1.75 (95% CI=1.51-2.02, p<0.001) Klein et al. 2 –AMI rate ratio=1.4 (95% CI=1.3-1.7, p<0.001) Obel et al. 3 –IHD hospitalization RR=2.12 (95% CI=1.62-2.76) Currier et al. 4 –CHD RR=2.16 (95% CI=1.81-2.58) for men 25-34 –CHD RR=1.53 (95% CI=1.10-2.13) for women 25-34 1. Triant et al. J Clin Endo Metab 2007; 2. Klein et al. CROI. Boston, 2011; 3. Odell et al. CID. 2007 4. Currier et al. JAIDS 2003

16. Veterans Aging Cohort Study Virtual Cohort and Ischemic Heart Disease Quality Enhance Research Initiative Cohort of HIV+ and 1:2 matched age, gender, race/ethnicity, and clinical site matched Veterans All participants alive in 2003 eligible and free of baseline CVD (n=84,832, 33% HIV+) All AMI outcomes clinically confirmed by IHD QUERI Validated smoking data, blood pressure and lipid measurements were used

17. Freiberg et al. CROI. Boston, 2011

19. HIV and the risk of AMI in subpopulations Among never smokers (HR=2.82, 95% CI=1.60-2.38) Among those not on Statin therapy (HR=1.88, 95% CI=1.51-2.34) Among those without hepatitis C, renal disease, or obesity (HR=1.82, 95% CI=1.37- 2.40) Freiberg et al. CROI. Boston, 2011

20. HIV and HCV Co-infection and the Risk of Incident CHD * Incidence rates are age and race/ethnicity adjusted per 1000 person-years Model 1 adjusted for age, race/ethnicity, education, BMI, traditional CHD risk factors, and substance use Model 2 adjusted for all in model 1 plus competing risk of death Freiberg et al. Circ Cardiovascular Quality and Outcomes, in press

21. HCV, ARV, and the risk of AMI among HIV infected men ‡Models adjusted for age, race/ethnicity, education, BMI, traditional CHD risk factors, and substance use Class of ARV (either duration or recent use), HIV viral load, CD4 count, and adjustment for death as a Censoring event or a competing risk Freiberg et al. Circ Cardiovascular Quality and Outcomes, in press

22. Does HIV infection increase the risk of other cardiovascular diseases?

23. 2 Increasing incidence of ischemic stroke in patients with HIV Figure 1 Trends in stroke hospitalization by type among persons with a diagnosis of HIV in the United States population 1997-2006(A) Ischemic stroke: trend p value p value = 0.27. (C) Intracerebral hemorrhage: trend p value = 0.88. Ovbiagele et al. Neurology 2011

24. Alcohol Abuse or Dependence, HIV, and the Risk of Incident Ischemic Stroke Incidence rates are age and race/ethnicity adjusted per 1000 person-years Model adjusted for age, race/ethnicity, education, CVD risk factors, hepatitis C; and DX of cocaine abuse or dependence Freiberg et al. Research Society on Alcoholism Conference, San Antonio, 2010

25. Which of the following is NOT true about HIV and failure HIV is associated with a nearly two fold increased risk of heart failure Ongoing HIV viral replication may play a role HIV is not associated with heart failure after adjusting for CHD, ischemic cardiomyopathy, and hazardous alcohol consumption

26. Which of the following is NOT true about HIV and failure HIV is associated with a nearly two fold increased risk of heart failure Ongoing HIV viral replication may play a role HIV is not associated with heart failure after adjusting for CHD, ischemic cardiomyopathy, and hazardous alcohol consumption

27. HIV and the Risk of Heart Failure Butt et al. Archives of Internal Medicine, 2011

28. HIV and the Risk of Heart Failure by viral load status Butt et al. Archives of Internal Medicine, 2011

29. Echocardiographic Parameters by HIV Status Hsue et al. Circ Heart Failure 2010

30. HIV infection is associated with diastolic dysfunction Hsue et al. Circ Heart Failure 2010

31. If HIV does increase the risk of CVD what is the mechanism? Do ARVs play a role?

32. Conceptual Model for HIV and Vascular Risk Baker et al. European Heart Journal 2011

33. Chronic HIV infection and microbial translocation Brenchley et al. Nature Medicine 2006

34. Microbial translocation and mortality among HIV infected people* Sandler et al. JID. 2011 *No adjustment for liver disease or alcohol

35. Biomarkers associated with Fatal and Non-Fatal CVD from the SMART Study Hs CRP HR=1.6 (95% CI=0.8-3.1) p=0.20 IL-6 HR=2.8 (95% CI=1.4-5.5) p=0.003 Amyloid A HR=1.6 (95% CI=0.9-2.9) p=0.12 Amyloid P HR=2.8 (95% CI=1.4-5.3) p=0.002 D-dimer HR=2.0 (95% CI=1.0-3.9) p=0.06 Kuller et al. CROI. Boston, 2008

36. 2 Biomarkers associated with CVD risk among those chronically infected with HIV Ford et al. AIDS 2010

37. 2 ART Use, Viral Suppression, and CD4 Change Over Follow-Up Baker et al. JAIDS 2011

38. 2 Median levels of hsCRP (A), IL-6 (B), and D-dimer (C) are presented for VS and DC groups at each visit. Error bars represent the interquartile range (IQR). *P values represent the difference between treatment groups in the change from baseline (on loge scale) and are adjusted for baseline biomarker level. Baker et al. JAIDS 2011

39. Average change to 1 month in the DC versus VS group in total, large, medium and small HDL-p (μmol/L) by treatment group among HIV infected people. Duprez et al. Atherosclerosis 2009

40. ARV Therapy and Levels of Inflammatory Biomarkers Baker et al. CROI. Boston, 2011

41. Do non-traditional risk factors play a role?

42. The role of alcohol, hepatitis C, and HIV and the risk of AMI Freiberg and Kraemer. Alcohol Research and Health. 2010

44. Current Alcohol Consumption and HIV VL and Levels of sCD14, IL-6, D-dimer, and Fib4 Score All values are median (25 th,75 th percentiles) Freiberg et al. ISBRA Conference. Paris, 2010

45. HCV Status and Levels of sCD14, IL-6, D-dimer, and FIB4 Score Median values for all biomarkers, p values ≤ 0.001 for all ng/mlpg/ml ug/ml Freiberg et al. ISBRA Conference. Paris, 2010

46. FIB4 Score and Levels of sCD14, IL-6, and D- dimer Freiberg et al. ISBRA Conference. Paris, 2010

47. The association between HIV and HCV viral load and biomarkers in the HIV LIVE Study Viral Load (VL) Biomarker Category HIV+ HCV+ N=127 HIV+ HCV- N=122 HIV- HCV+ N=53 HIV- HCV- N=59 P value Percentage of participants with >75 th percentile of Biomarker IL-632.316.042.512.5<0.01 CRP21.326.825.624.00.81 Cystatin C40.717.023.312.0<0.01 SSA26.222.219.526.10.78 TNF alpha35.222.320.96.0<0.01 MCP-123.226.823.418.00.67 IL-1037.023.225.66.0<0.01 INF gamma11.116.118.612.00.56 Samet et al. ISBRA Conference. Paris, 2010

48. Correlation between D-dimer, sCD14, IL-6 biomarkers in the VACS* * All associations are significant p<0.001

49. So, what might you predict next….

50. Characteristics of SMART, CARDIA, and MESA Study Participants. Neuhaus J et al. J Infect Dis. 2010.

51. Median Levels and Interquartile Ranges (IQRs) of Biomarkers for SMART, CARDIA, and MESA Study Participants. Neuhaus J et al. J Infect Dis. 2010.

52. Biomarkers Levels in SMART Study Participants Receiving Antiretroviral Therapy (ART) Who Had an HIV RNA Level ≤400 Copies/mL and Percentage Differences in Levels Versus CARDIA and MESA Study Participants Neuhaus J et al. J Infect Dis. 2010.

53. HIV + HIV - D-dimer sCD14 IL-6 The association between biomarkers and HIV status in the VACS

54. Does the Framingham risk score apply to those with HIV infection? Yes but it probably overestimates the risk Yes but it probably underestimates the risk No, because middle aged Caucasians from Framingham, Massachusetts cannot generalize to an HIV population I have no idea

55. Does the Framingham risk score apply to those with HIV infection? Yes but it probably overestimates the risk Yes but it probably underestimates the risk No, because middle aged Caucasians from Framingham, Massachusetts cannot generalize to an HIV population I have no idea

56. Freiberg et al. CROI. Boston, 2011

57. Additional Framingham Risk Score Data Median Baseline Framingham Risk score –HIV+ 6.0 –uninfected 6.0 HIV infected Veterans have an increased risk of AMI ( HR=1.95, 95% CI=1.60-2.38) This risk persisted among never smokers This risk persisted among those without HCV, renal disease, or obesity

58. Predicting MI with the Framingham risk equation Law et al. HIV Med 2006

59. Important Questions Is HIV infection an independent risk factor for AMI? Does HIV infection increase the risk of other cardiovascular diseases? If HIV does increase the risk of CVD what is the mechanism? Do ARVs play a role? Do non-traditional risk factors play a role? If so, does the Framingham risk score apply to those with HIV infection?

60. Acknowledgements Veteran Aging Cohort Study (VACS) Participants Mentors –Amy Justice, MD, PHD –Lewis Kuller, MD, Dr.PH Project Officers –Cheryl McDonald, MD, NHLBI –Kendal Bryant, PhD, NIAAA NHLBI HL095136-03; 03S1; 03S2 NIAAA AA0159136-06S1 Project Coordinators: Carol Rogina and Glory Koerbel Collaborators: –Jason Baker MD, MPH, University of Minnesota –Russ Tracy, PhD, University of Vermont –Jeffrey Samet, MD, MA, MPH, Boston University

61. 2 Cardiovascular and metabolic markers before and after a median of 8 months of combination antiretroviral therapy and their correlation with HIV-RNA before combination antiretroviral therapy. Calmy et al. AIDS 2009.

62. Correlation of Lipid Measures with Human Immunodeficiency Virus (HIV) RNA and Biomarkers among HIV-Infected Participants. Baker J et al. J Infect Dis. 2010.