hiv and cardiovascular disease - .: regency :. · r e c a d r i s k i n h i v ? yes ... hiv and...

HIV and

Cardiovascular Disease

Joseph Cofrancesco Jr. MD, MPH, FACPAssociate Professor of Medicine

Director, Institute for Excellence in Education

Johns Hopkins University School of Medicine

Objectives

• Detail the CV risk of HIV+ patients:

– HIV

– ARV Treatment

• ARV that may be associated with � CV risk

– Traditional Risk Factors

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

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

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

#1: Is th

ere�CAD ris

k

in HIV?

Yes

But,

by how much

is debatable.

• 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;2506-2512,2007.

Traint VA et al. J Clin Endocrinol Met 92;2506-2512,2007.

Results

• Cross sectional

• Outpatient

• n=220 HIV +

• Belo Horizonte,

Brazil

Moreira Guimaraes MM et al. Int J Clin Pract, May 2010, 64,6:739-745

Moreira Guimaraes MM et al. Int J Clin Pract, May 2010, 64,6:739-745

Results

• Prospective, recruited

cohort– 78 HIV +,

– 32 HIV – (similar

recruitment)

• Recruitment– 4 community centers in

Boston, and newspaper

advertisements

• 64-slice CT

(Sensations64)

AIDS. 2010 Jan 16;24(2):243-53.

Relative Risk CVD: HIV+ vs. HIV-

Islam FM, et. al. Relative risk of Cardiovascular …, HIV Medicine. 2012

• 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, 23:1841-1849

Pooled model

Grunfeld C et al. AIDS 2009, 23:1841-1849

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?

#2: Does contro

lling H

IV

eliminate th

e excess

risk?

No, not all of it

Why not?

Relative Risk CVD

HIV+

vs. HIV -

HIV+ and

ART

vs.

HIV -


CAD and Inflammation

• HIV+ without known CAD (n=27), well-controlled

disease – CD4 592±294 cells/mm3

– 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

CAD and Inflammation

• Arterial wall inflammation

– 18FDG-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)].


Results

Similar results subset (n = 22)

undetectable virus

(p = 0.0007)


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).


HIV and Cardiovascular Disease:

Recommendations for Evaluation

• 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

• Change modifiable risk factors

• Promote lifestyle changes

• Offer treatment options

• Follow-up as needed

Initial Subsequent

#3: How much does

specific ARV

contribute?

Lots of debate

CVD Relative Risk: ARV v. No ARV


ARV : � CAD Risk

• Indirectly, by � Traditional Risk Factors

– Lipids

– Glucose

– Body shape/fat

– ?Other inflammatory markers

• Directly

– Inflammation

– Arterial wall damage

– Coagulation factors

– Other

0

10

20

30

40

50

60

70

Fontas E, et al. J Infect Dis. 2004;189:1056-1074.

ART-naïveNRTI + NNRTINRTI + PINRTI + dual PI

Pati

en

ts (

%)

TotalCholesterol(>240 mg/dL)

LDL-C(>130 mg/dL)

HDL-C(<35 mg/dL)

Triglycerides(>200 mg/dL)

Prevalence of Abnormal Lipids2

Total Cholesterol HDL LDL Triglycerides

Protease Inhibitors

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):547-556.Hill A, Sawyer W, Gazzard B. Effects of first-line use of nucleoside analogues, efavirenz, and ritonavir-boosted 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):1056-1074.

PIs

Total Cholesterol HDL LDL Triglycerides

Non-nucleoside Reverse Transcriptase InhibitorEfavirenz ↑ ↑ ↑ ↑, ↑↑

Nevirapine ↑ ↑↑ ↑ ↑

Etravirine ↔ ↔ ↔ ↔

nNRTI


NRTIsTotal

Cholesterol HDL LDL TG

Nucleoside reverse transcriptase inhibitorsAbacavir ↑ ↑ ↔, ↑ ↔, ↑

Lamivudine ( & FTC) ↔ ↔ ↔ ↔

Tenofovir DF ↔ ↔ ↔ ↔

Stavudine ↑ ↔ ↑ ↑↑

Zidovudine ↑ ↔ ↔ ↔


OthersTotal

Cholesterol HDL LDL Triglyceride

sIntegrase strand transfer inhibitors

Raltegravir ↔ ↔ ↔ ↔

Entry Blockers

Maraviroc ↔ ↑, ↔ ↔ ↔

Enfuvirtide ↔ ↔ ↔ ↔

DeJesus E, et al 15th CROI, 2008; Boston # 929

ARV : � CAD Risk

• Indirectly, by � Traditional Risk Factors

– Lipids

– Glucose

– Body shape/fat

– ?Other inflammatory markers

• Directly

– Inflammation

– Arterial wall damage

– Coagulation factors

– Other

D:A:D Study Group. N Engl J Med. 2007;356:1723-1735.

Worm SW et al. JID 2010:201

CVD Relative Risk: PI v. non PI


Similar

plots NRTI

or

NNRTI:

NO signal

AbacavirAbc causes heart

attacks, Never use

it!

Abc is

totally safe,

Always use it!

Study Design CV Events Mostly Naïve v. Experienced at ABC initiation

Effect of ABC?

D:A:D[1] (N = 33347)Observational

cohortProspective, predefined

Experienced Yes

FHDH[2] (N = 1173)Case control

study

Prospective, MI retrospectively

validatedExperienced Yes

SMART[3] (N = 2752)RCT,

observational analyses

Prospective, predefined

Experienced Yes

STEAL[4] (N = 357) RCT Prospective Experienced 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

reviewersNaive No

ACTG 5202(N = 1857)

RCTNot principle

outcomeNaïve No

FDA MetaAnalysis No

Lundgren JD, et al. CROI 2009. Abstract 44LB. 2. Lang S, et al. CROI 2009. Abstract 43LB. 3. SMART. AIDS. 2008;22:F17-F24. 4. Carr A, et al. CROI 2009. Abstract 576. 5. Cutrell A, et al. IAC 2008. Abstract

WEAB0106. 6. Benson C, et al. CROI 2009. Abstract 721. MODELED AFTER PETER REISS


study


validatedExperienced Yes -> NO

Study Design CV Events Mostly Naïve v. Experienced at ABC initiation

Effect of ABC?

D:A:D[1] (N = 33347)Observational

cohortProspective, predefined

Experienced Yes


study


validatedExperienced Yes

SMART[3] (N = 2752)RCT,

observational analyses

Prospective, predefined

Experienced Yes

STEAL[4] (N = 357) RCT Prospective Experienced 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

reviewersNaive No

ACTG 5202(N = 1857)

RCTNot principle

outcomeNaïve No

FDA MetaAnalysis No

Lundgren JD, et al. CROI 2009. Abstract 44LB. 2. Lang S, et al. CROI 2009. Abstract 43LB. 3. SMART. AIDS. 2008;22:F17-F24. 4. Carr A, et al. CROI 2009. Abstract 576. 5. Cutrell A, et al. IAC 2008. Abstract

WEAB0106. 6. Benson C, et al. CROI 2009. Abstract 721. MODELED AFTER PETER REISS

CVD Relative Risk: ABC


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

#4: Traditio

nal Risk

Factors

Relative Risk

vs

Absolute Risk

Traditional Risk

Factors

ARV

CAD Risk Factors

Modifiable/Controllable

• Cigarette smoking

• HTN

• Dyslipidemia

• Diabetes mellitus

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

• Obesity

• Physical inactivity

• (Psychosocial)• CKD

• Microabluminuria

• GFR <60 mL/Min

George Bush• 48 year old

• Male

• HIV+

• Smokes : 1 ppd x 12 years

• BP = 148/94

• TC: 210 mg/dL, HDL 38 mg/dL

Framingham Risk: Baseline

Does NOT take into account:- DM (= CVD risk equivalent)- FH- HIV

And, he’s only 48years old, I’m

concerned about the next 50 years!

Framingham Risk: Female

Baseline Risk = 17%

Framingham Risk: BP Controlled

Baseline Risk = 17%

JNC 7 (JNC 8 expected Spring 2012)

JNC 7: U . S . Department of Health and Human Services , National Institutes

of Health National Heart, Lung, and Blood Institute

‡ Treat patients with CKD or DM to BP goal of <130/80 mmHg.

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

Framingham Risk: Lipids Controlled

Baseline Risk = 17%

NCEP

http://circ.ahajournals.org/cgi/content/full/106/25/3143

http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf

NCEP ATP III LDL Targets

mg/dL

CHD + CHD risk equivalent <100 (<70)

Multiple (2+) RF <130

-if 10 year risk > 20% <100

0-1 RF <160

Should HIV count as an additional RF?

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

Lipid-Lowering Agents and PIs:

Drug-Drug Interactions

*AUC ↑↑↑with DRV

FibratesFluvastatin

Pravastatin*Ezetimibe

Fish oil

Use cautiously

Statin + fibrateAtorvastatin

Rosuvastatin

Niacin

LovastatinSimvastatin

Contraindicated

Low interactionpotential

Fitchenbaum CJ, et al. AIDS. 2002;16:569-577. Hsue PH, et al. Antimicrob Agents Chemother. 2001;45:3445-

3450. Gerber J, et al. IAS 2003. Abstract 870. Carr RA, et al. ICAAC 2000. Abstract 1644. Telzir [package insert];

2003. Gerber JG, et al. CROI 2004. Abstract 603. Reyataz [package insert]; 2005. Aptivus [package insert]; 2005.

Prezista [package insert]; 2006.

Framingham Risk: BP and Lipids

Controlled

Baseline Risk = 17%

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)

4. 6% (akin to gender effect)

5. 4%

Baseline Risk =

17%

Framingham Risk: No Smoking

Baseline Risk = 17%

• Cessation of tobacco smoking : ⇓ risk of MI, CHD and CVD

• No association of time since smoking cessation and mortality risk

Petoumenos K, et al. HIV Med 2011 (Epub ahead of print)

*Adjusted for: age, cohort, calendar yr, antiretroviral treatment, family history of

CVD, diabetes, time-updated lipids and blood pressure assessments.

Never Smoked Previous Current

Baseline Smoking

< 1 yr 1-2 yrs 2-3 yrs 3+ yrs

Stopped Smoking During Follow-up

5

IRR

of

MI*

1

0.5

1.73

3.403.73

3.00 2.622.07

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

http://www.uptodate.com/contents/smoking-cessation

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

Framingham Risk: No Smoking, BP

and Lipid Control

Baseline Risk = 17%

• 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: 396-404

Conclusions

HIV

ARV

Traditional Risk

Factors

CardiovascularDisease

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

No Smoking

hiv and cardiovascular disease - .: regency :. · r e c a d r i s k i n h i v ? yes ... hiv and...

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