HIV and Cardiovascular Disease

Transcription

1 HIV and Cardiovascular Disease Joseph Cofrancesco Jr. MD, MPH, FACP Associate Professor of Medicine Director, Institute for Excellence in Education Johns Hopkins University School of Medicine

2 Objectives Detail the CV risk of HIV+ patients: HIV ARV Treatment ARV that may be associated with CV risk Traditional Risk Factors

3 Case

4 George Bush 48 year old male new to your practice HIV+ 8 years and feels great PMH: Sometimes my blood pressure is high FH: I m adopted SH: Heterosexual, monogamous ( 1 slip ), works as government official Exercises 3x week Alcohol: None in >5 years (History of alcohol abuse) Smokes : 1+ ppd x 22 years No illicit drug use

5 GB Medication: ABC/3TC and LVP/r PE: Well appearing BMI 28, 148/94, pulse 62, afebrile (pain score 0) Normal exam Labs CD4= 538 cells/mm3 VL<20 copies Lipids: 210 mg/dl, HDL 38 mg/dl Glucose (fasting): 107 mg/dl Hep B Immune, Hep C negative Reminder: WNL

6 Q1: Is George at risk for CVD? 1. Yes, equal to HIV negative, matched, peers 2. Yes, higher than HIV negative, matched, peers Because of HIV infection 3. Yes, higher than HIV negative, matched, peers Because of HAART 4. No, HIV is protective

7 Yes But, by how much is debatable. #1: Is there CAD risk in HIV?

8 Health system wide cohort HIV+ = 3,851 HIV - = 1,044,589 October 1, 1996 June 20, 2004 MI: 189 HIV+, 26, 142 HIV- (Incomplete data on smoking) Traint VA et al. J Clin Endocrinol Met 92; ,2007.

9 Results Traint VA et al. J Clin Endocrinol Met 92; ,2007.

10 Cross sectional Outpatient n=220 HIV + Belo Horizonte, Brazil Moreira Guimaraes MM et al. Int J Clin Pract, May 2010, 64,6:

11 Results Moreira Guimaraes MM et al. Int J Clin Pract, May 2010, 64,6:

12 Prospective, recruited cohort 78 HIV +, 32 HIV (similar recruitment) Recruitment 4 community centers in Boston, and newspaper advertisements 64-slice CT (Sensations64) AIDS Jan 16;24(2):

13 Relative Risk CVD: HIV+ vs. HIV- Islam FM, et. al. Relative risk of Cardiovascular, HIV Medicine. 2012

14 HIV-infected participants: Diversity, 16 HIV/ ID clinics or cohorts geographic representative of US patients with HIV Control participants 2 centers, Coronary Artery Risk Development in Young Adults (CARDIA) study Birmingham, Alabama Oakland, California Grunfeld C et al. AIDS 2009, 23:

15 Pooled model Grunfeld C et al. AIDS 2009, 23:

16 But... Can you really fully adjust? Tobacco use in HIV 2-3 x higher Are we over adjusting Synergy of Risk Factors? Can you find true HIV negative comparators? Usual issues with Cohort studies, Retrospective studies MI still relatively rare event Is Hep B, C considered?

17 #2: Does controlling HIV eliminate the excess risk? No, not all of it Why not?

18 Relative Risk CVD HIV+ vs. HIV - HIV+ and ART vs. HIV - Islam FM, et. al. Relative risk of Cardiovascular, HIV Medicine. 2012

19 CAD and Inflammation HIV + without known CAD (n=27), well-controlled disease CD4 592±294 cells/mm 3 HIV RNA <48 copies/ml. On ART (duration 12±4 years) HIV neg (n = 27) matched for age, gender, and Framingham Score (FRS) no known CAD HIV neg, known CAD (n = 27) Subramanian et al. CROI 2012 #121

20 CAD and Inflammation Arterial wall inflammation 18 FDG-PET traditional and non-traditional risk markers including coronary calcium (CAC) marker of macrophage activation, scd163. Arterial inflammation prospectively determined ratio of FDG uptake in the arterial wall of the ascending aorta/blood background [target to background ratio (TBR)]. Subramanian et al. CROI 2012 #121

21 Results Similar results subset (n = 22) undetectable virus (p = ) Subramanian et al. CROI 2012 #121

22 In addition Aortic TBR remained significantly higher restricted to Zero calcium, FRS <10, LDL <100 mg/dl (p 0.01). Aortic TBR was associated scd163 (r = 0.53, p = 0.03) Not with C-reactive protein (CRP) or D-dimer (p >0.05). Subramanian et al. CROI 2012 #121

23 HIV and Cardiovascular Disease: Recommendations for Evaluation Initial Part of initial patient visit Obtain baseline fasting lipid profile LDL-C, total cholesterol, HDL- C, triglycerides Assess risk factors Family history, smoking, diabetes, hypertension, obesity, exercise Identify comorbidities and/or pre-existing conditions Pancreatitis, CAD, etc Subsequent Change modifiable risk factors Promote lifestyle changes Offer treatment options Follow-up as needed

24 Lots of debate #3: How much does specific ARV contribute?

25 CVD Relative Risk: ARV v. No ARV Islam FM, et. al. Relative risk of Cardiovascular, HIV Medicine. 2012

26 ARV : CAD Risk Indirectly, by Traditional Risk Factors Lipids Glucose Body shape/fat?other inflammatory markers Directly Inflammation Arterial wall damage Coagulation factors Other

27 ARV : CAD Risk Indirectly, by Traditional Risk Factors Lipids Glucose Body shape/fat?other inflammatory markers Directly Inflammation Arterial wall damage Coagulation factors Other

28 Prevalence of Abnormal Lipids ART-naïve NRTI + NNRTI NRTI + PI NRTI + dual PI Patients (%) Total Cholesterol (>240 mg/dl) LDL-C (>130 mg/dl) HDL-C (<35 mg/dl) Triglycerides (>200 mg/dl) Fontas E, et al. J Infect Dis. 2004;189:

29 Protease Inhibitors PIs Total Cholesterol HDL LDL Triglycerides Atazanavir (unboosted) / Atazanavir/ritonavir Darunavir/ritonavir Fosamprenavir/ritonavir Lopinavir/ritonavir Nelfinavir Saquinavir/ritonavir Tipranavir/ritonavir Malvestutto CD, Aberg JA. Coronary heart disease in people infected with HIV. Cleve Clin J Med 2010; 77(8): Hill A, Sawyer W, Gazzard B. Effects of first-line use of nucleoside analogues, efavirenz, and ritonavirboosted protease inhibitors on lipid levels. HIV Clin Trials 2009; 10(1):1-12. Fontas E, van LF, Sabin CA, Friis- Moller N, Rickenbach M, d'arminio MA, et al. Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? J Infect Dis 2004; 189(6):

30 nnrti Total Cholesterol HDL LDL Triglycerides Non-nucleoside Reverse Transcriptase Inhibitor Efavirenz, Nevirapine Etravirine Malvestutto CD, Aberg JA. Coronary heart disease in people infected with HIV. Cleve Clin J Med 2010; 77(8): Hill A, Sawyer W, Gazzard B. Effects of first-line use of nucleoside analogues, efavirenz, and ritonavirboosted protease inhibitors on lipid levels. HIV Clin Trials 2009; 10(1):1-12. Fontas E, van LF, Sabin CA, Friis- Moller N, Rickenbach M, d'arminio MA, et al. Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? J Infect Dis 2004; 189(6):

31 NRTIs Total Cholesterol HDL LDL TG Nucleoside reverse transcriptase inhibitors Abacavir,, Lamivudine ( & FTC) Tenofovir DF Stavudine Zidovudine Malvestutto CD, Aberg JA. Coronary heart disease in people infected with HIV. Cleve Clin J Med 2010; 77(8): Hill A, Sawyer W, Gazzard B. Effects of first-line use of nucleoside analogues, efavirenz, and ritonavirboosted protease inhibitors on lipid levels. HIV Clin Trials 2009; 10(1):1-12. Fontas E, van LF, Sabin CA, Friis- Moller N, Rickenbach M, d'arminio MA, et al. Lipid profiles in HIV-infected patients receiving combination antiretroviral therapy: are different antiretroviral drugs associated with different lipid profiles? J Infect Dis 2004; 189(6):

32 Others Total Cholesterol HDL LDL Triglyceride s Integrase strand transfer inhibitors Raltegravir Entry Blockers Maraviroc, Enfuvirtide DeJesus E, et al 15th CROI, 2008; Boston # 929

33 ARV : CAD Risk Indirectly, by Traditional Risk Factors Lipids Glucose Body shape/fat?other inflammatory markers Directly Inflammation Arterial wall damage Coagulation factors Other

34 D:A:D Study Group. N Engl J Med. 2007;356:

35 Worm SW et al. JID 2010:201

36 CVD Relative Risk: PI v. non PI Similar plots NRTI or NNRTI: NO signal Islam FM, et. al. Relative risk of Cardiovascular, HIV Medicine. 2012

37 Abc causes heart attacks, Never use it! Abacavir Abc is totally safe, Always use it!

38 Study Design CV Events Mostly Naïve v. Experienced at ABC initiation D:A:D [1] (N = 33347) FHDH [2] (N = 1173) SMART [3] (N = 2752) Observational cohort Case control study RCT, observational analyses Prospective, predefined Prospective, MI retrospectively validated Prospective, predefined Experienced Experienced Experienced Effect of ABC? Yes Yes Yes -> NO STEAL [4] (N = 357) RCT Prospective Experienced Yes Yes GSK analysis [5] (N = 14174) 54 RCTs Retrospective database search Naïve No ALLRT ACTG A5001 [6] (N = 3205) 5 RCTs Retrospective by 2 independent reviewers Naive No ACTG 5202 (N = 1857) RCT Not principle outcome Naïve No FDA MetaAnalysis No Lundgren JD, et al. CROI Abstract 44LB. 2. Lang S, et al. CROI Abstract 43LB. 3. SMART. AIDS. 2008;22:F17-F Carr A, et al. CROI Abstract Cutrell A, et al. IAC Abstract WEAB Benson C, et al. CROI Abstract 721. MODELED AFTER PETER REISS

39 Study Design CV Events Mostly Naïve v. Experienced at ABC initiation D:A:D [1] (N = 33347) FHDH [2] (N = 1173) SMART [3] (N = 2752) Observational cohort Case control study RCT, observational analyses Prospective, predefined Prospective, MI retrospectively validated Prospective, predefined Experienced Experienced Experienced Effect of ABC? STEAL [4] (N = 357) RCT Prospective Experienced Yes Yes Yes Yes GSK analysis [5] (N = 14174) 54 RCTs Retrospective database search Naïve No ALLRT ACTG A5001 [6] (N = 3205) 5 RCTs Retrospective by 2 independent reviewers Naive No ACTG 5202 (N = 1857) RCT Not principle outcome Naïve No FDA MetaAnalysis No Lundgren JD, et al. CROI Abstract 44LB. 2. Lang S, et al. CROI Abstract 43LB. 3. SMART. AIDS. 2008;22:F17-F Carr A, et al. CROI Abstract Cutrell A, et al. IAC Abstract WEAB Benson C, et al. CROI Abstract 721. MODELED AFTER PETER REISS

40 CVD Relative Risk: ABC Islam FM, et. al. Relative risk of Cardiovascular, HIV Medicine. 2012

41 Q2: If you could address only 1 issue, which has greatest impact on reducing CVD risk? 1. Change LVP/r EFV 2. Change ABC/3TC AZT/3TC 3. Have him quit smoking 4. Lower his total cholesterol to 170 mg/dl 5. Change his gender

42 Traditional Risk Factors Relative Risk vs ARV Absolute Risk #4: Traditional Risk Factors

43 CAD Risk Factors Modifiable/Controllable Cigarette smoking HTN Dyslipidemia Diabetes mellitus Obesity Physical inactivity (Psychosocial) Not modifiable Gender M. more MIs, at older ages, F more likely to die from MI Advancing age Males >55 Females >65 FH premature CHD <55 years in men <65 years in women CKD Microabluminuria GFR <60 ml/min

44 George Bush 48 year old Male HIV+ Smokes : 1 ppd x 12 years BP = 148/94 TC: 210 mg/dl, HDL 38 mg/dl

45 Framingham Risk: Baseline And, he s only 48years old, I m concerned about the next 50 years! Does NOT take into account: - DM (= CVD risk equivalent) - FH - HIV

46 Framingham Risk: Female Baseline Risk = 17%

47 Framingham Risk: BP Controlled Baseline Risk = 17%

48 JNC 7 (JNC 8 expected Spring 2012) Treat patients with CKD or DM to BP goal of <130/80 mmhg. JNC 7: U. S. Department of Health and Human Services, National Institutes of Health National Heart, Lung, and Blood Institute

49 Treatment Lifestyle Low sodium diet Weight loss if obese Aerobic exercise EtOH: > 2/day, 1.5 to 2-fold incidence (v. nondrinkers), esp at > 5/day Moderate alcohol intake CAD ABCDs of Pharmacology ACE Inhibitor, ARB B. blocker Calcium channel blocker, Diuretic (Thiazide) Patients with BP > 20/10 above goal will need combination therapy

50 Framingham Risk: Lipids Controlled Baseline Risk = 17%

51 NCEP

52 NCEP ATP III LDL Targets mg/dl CHD + CHD risk equivalent <100 (<70) Multiple (2+) RF <130 -if 10 year risk > 20% < RF <160 Should HIV count as an additional RF?

53 Comparing Statins Retrospective Cohort, 2 clinics (n=700) Results: (compared to Pravastatin (N=280): Atorvastatin (N=303) and Rosuvastatin (N =95) Greater LDL and non HDL cholesterol Higher likelihood of reaching NCEP LDL targets Rosuvastatin also higher likelihood of reaching non HDL target Toxicities: similar Singh S et al. CID 2011: 52

54 Lipid-Lowering Agents and PIs: Drug-Drug Interactions *AUC with DRV Fibrates Fluvastatin Pravastatin* Ezetimibe Fish oil Statin + fibrate Atorvastatin Rosuvastatin Niacin Lovastatin Simvastatin Low interaction potential Use cautiously Contraindicated Fitchenbaum CJ, et al. AIDS. 2002;16: Hsue PH, et al. Antimicrob Agents Chemother. 2001;45: Gerber J, et al. IAS Abstract 870. Carr RA, et al. ICAAC Abstract Telzir [package insert]; Gerber JG, et al. CROI Abstract 603. Reyataz [package insert]; Aptivus [package insert]; Prezista [package insert]; 2006.

55 Framingham Risk: BP and Lipids Controlled Baseline Risk = 17%

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57 Q3: What do you think the 10 year risk will be if he was a nonsmoker? 1. 20% (Stress of smoking cessation s risk) 2. 16% (akin to BP control) 3. 11% (akin to lipid control) Baseline Risk = 17% 4. 6% (akin to gender effect) 5. 4%

58 Framingham Risk: No Smoking Baseline Risk = 17%

59 Cessation of tobacco smoking : risk of MI, CHD and CVD No association of time since smoking cessation and mortality risk IRR of MI* Never Smoked Previous Current Baseline Smoking < 1 yr 1-2 yrs 2-3 yrs 3+ yrs Stopped Smoking During Follow-up *Adjusted for: age, cohort, calendar yr, antiretroviral treatment, family history of CVD, diabetes, time-updated lipids and blood pressure assessments. Petoumenos K, et al. HIV Med 2011 (Epub ahead of print)

60 Cigarette Cessation Offer treatment at each visit Most smokers make many attempts Specialty clinic or smoking cessation program Unwilling to quit: 5 R's" motivational Relevance, Risks, Rewards, Roadblocks, and Repetition Willing to quit: 5 A's" Ask, Advise, Assess, Assist, and Arrange Practical counseling: Problem solving/skills training; social support Person-to-person contact

61 Pharmacotherapy + Other Nicotene replacement Transdermal patch Gum Lozenge Inhaer Spay Medication Bupropion Varenicline Hypnosis Acupunture Most smokers make many attempts Specialty clinic or smoking cessation program

62 Framingham Risk: No Smoking, BP and Lipid Control Baseline Risk = 17%

63 Men 45-79, when potential benefit MI > potential harm of of GI bleed. (A recommendation) Women 55-79, when the potential benefit ischemic strokes > potential harm of of GI bleed. (A recommendation) Ann Int Med. 2009;150:

64 Conclusions

65 HIV Traditional Risk Factors ARV Cardiovascular Disease

66 Conclusions CVD will be an increasing issue for our patients Providers need to be aware Controlling HIV Risk Selecting ARV may be better than others Focus on Traditional RF Tobacco use Lipids, HTN, glucose control ASA where appropriate High level of suspicion for CAD

67 No Smoking

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