HIV and Cardiovascular/Lipid Disorders...HIV and Cardiovascular/Lipid Disorders Kenneth A. Lichtenstein, MD Director, HIV Clinical and Research Program National Jewish Health Denver,

HIV and Cardiovascular/Lipid Disorders

Kenneth A. Lichtenstein, MD

Director, HIV Clinical and Research Program

National Jewish Health

Denver, Colorado

Possible risk factors for atherosclerotic cardiovascular events in patients infected

with HIV are:

A. Traditional cardiovascular risk factors such as diabetes, hypertension, dyslipidemia, smoking, etc.

B. Some antiretroviral agents

C. HIV infection

D. A and B

E. A and C

F. A, B, and C

According to NCEP guidelines, which of the following lipid measurements are predictive of cardiovascular events?

A. Elevated LDL

B. Elevated non-HDL cholesterol

C. Total cholesterol

D. Elevated triglycerides

E. A, B, and D

F. A and D

G. A and B

H. A and C

Do you calculate the Framingham 10-year cardiovascular risk on your HIV-infected patients?

A. Yes. I use my computer or a portable device

B. No. I use a different calculation

C. No. I don’t know how

D. No. I don’t have time

E. None of the above

Learning Objectives Upon completion of this presentation,

learners should be better able to:

• Recognize that cardiovascular disease in HIV-infected individuals

occurs at younger ages and at a higher incidence than the general

population.

• Consider traditional, antiretroviral, and inflammatory risk factors

when managing cardiovascular disease prevention in patients

infected with HIV.

• Manage lipids according to IDSA/AACTG modified National

Cholesterol Education Program (NCEP) guidelines.

Faculty and Planning Committee

Disclosures Please consult your program book.

There will be no off-label/investigational

uses discussed in this presentation.

Off-Label Disclosure

Cardiovascular Disease in the

General Population

Projected Global Deaths

(All ages, 2005)

Death

s

World Health Organization.

Preventing Chronic Diseases 2005.

Available at:

http://www.who.int/chp/chronic_dis

ease_report. Accessed September

4, 2006.

2,830,000 1,607,000

883,000

7,586,000

4,057,000

1,125,000

17,528,000

0

10,000,000

20,000,000

HIV / AIDS

TB Malaria CVD Cancer Resp Diabetes

Infectious Diseases Chronic Diseases

The Magnitude of CAD

• 1 million Americans suffer an acute coronary event each year…over one half million Americans die each year from coronary disease

• 150,000 die from sudden cardiac death

• 63% of women and 50% of men had no known coronary artery disease

• 68% of AMI occur in patients without significant stenosis

American Heart Association/American Stroke

Association (2009). Heart and Stroke Statistical

Update


HIV-Infected Population

Smith C, et al. 16th CROI 2009;Abstract 145.

D:A:D (Data Collection on Adverse Drug Events of Anti-HIV Drugs)

Causes of Death Through October 2007

• HIV-infected patients followed from study entry until death or last follow-up

• There were 2192 deaths in

33,347 people followed for

158,959 person-years (PY);

Rate = 1.4/100 PY

• Risk factors for overall death were:

– Smoking

– Low BMI (<18 kg/m2)

– Diabetes

– HTN

– HBV/HCV co-infection

– Low current CD4

– Higher HIV RNA

AIDS-Related

32%

Liver-Related

14%

Non-AIDS

Cancer

12%

CVD-Related

11%

Other

31%

Overall Mortality and Causes of Death

Smith C, et al. AIDS. 2006;20:741-749.

Overall Mortality*

0

20

40

60

80

Pro

po

rtio

n (

%)

Years Since Seroconversion*

0 5 10 15

Pre-HAART

HAART

Causes of Death†

De

ath

s (

%)

Pre-HAART (n=1424)

HAART (n=514)

*N=7680 seroconverters from 22 cohorts, of whom 1938 died (26%; 1424 pre-HAART and 514 during HAART).

†No change in the following causes of death: AIDS-related malignancy, other infections, organ failure, and

unknown causes.

0

5

10

15

20

25

30

35

OIs Not Specified

Hepatitis/ Liver

Malig- nancy

CVD/ DM

AIDS-Related Non-AIDS-Related

31.7%

19.3%

10.0%

2.5% 3.2%

9.9%

2.5%

4.9%

1.3%

4.3% 6.5% 6.4%

Malig- nancy

Risk of MI While Admitted to Either of Two

Hospitals in Boston According to HIV Status

# of MI 189 26,142

A RR 1.75

p <0.0001

0

2

4

6

8

10

12

HIV Non-HIV

Eve

nts

Pe

r 1

00

0 P

Ys

B

0

20

40

60

80

100

18-34 35-44 45-54 55-64 65-74

Age Group (Years)

Eve

nts

Pe

r 1

00

0 P

Ys

Triant et al., JCEM, 2007, 92(7):2506-2512.

* Adjusted for age, gender, race, hypertension, diabetes and

dyslipidaemia.

n = 3,851 1,044,589

Contributing Factors to

Cardiovascular Disease

• General Population

– Traditional Cardiovascular Risk Factors

– The Role of Inflammation

• HIV-infected Population

– Traditional Cardiovascular Risk Factors

– Antiretroviral Therapy

– HIV-associated Inflammation

Traditional Cardiovascular Risk

Factors Management in the General

Population

CHD

Risk - -

Diabetes *Metabolic syndrome

Lipids*

Family

History

Abdominal

Obesity*

Hyper-

tension*

Cigarette

Smoking

Hyper-

glycemia Insulin

Resistance*

Inactivity,

Diet

Age

Gender

Brown = Modifiable

Red = Nonmodifiable

CHD Risk Factors

Major CHD Risk Factors

Modifiable

• Cigarette smoking

• Diabetes*

• Hypertension:

– BP ≥140/90 mm Hg or on

antihypertensive medication

(>130/80 if diabetic or CKD∞)

• Low HDL:

– Male <40 mg/dL

– Female < 50 mg/dL

Non-Modifiable

• Family history of premature

CHD (1st-degree relative):

– Male relative age <55 yrs

– Female relative age <65 yrs

• Age

– Male ≥45 years

– Female ≥55 years

*Diabetes is regarded as a CHD risk equivalent

∞ Chronic Kidney Disease NCEP/ATP III. JAMA. 2001;285:2486-2497.

10-Year CHD Risk Framingham Score

Age (years) Points

20 – 34 -7

35 – 39 -3

40 – 44 0

45 – 49 3

50 – 54 6

55 – 59 8

60 – 64 10

65 – 69 12

70 – 74 14

75 – 79 16

HDL

(mg/dL)

Points

≥60 -1

50 – 59 0

40 – 49 1

<40 2

Total

Cholesterol

(mg/dL)

Age

20 – 39

Age

40 – 49

Age

50 – 59

Age

60 – 69

Age

70 – 79

<160 0 0 0 0 0

160 – 199 4 3 2 1 1

200 – 239 8 6 4 2 1

240 – 279 11 8 5 3 2

≥280 13 10 7 4 2

Smoking Age

20 – 39

Age

40 – 49

Age

50 – 59

Age

60 – 69

Age

70 – 79

Nonsmoker 0 0 0 0 0

Smoker 9 7 4 2 1

Systolic BP (mm Hg) If Untreated If Treated

<120 0 0

120 – 129 1 3

130 – 139 2 4

140 – 159 3 5

≥160 4 6

10-Year CHD Risk Framingham Score Point Total 10-Year Risk %

<9 <1

9 1

10 1

11 1

12 1

13 2

14 2

15 3

16 4

17 5

18 6

19 8

20 11

21 14

22 17

23 22

24 27

≥25 ≥30

10-Year Risk: ___%

CHD Risk Prediction

High

Moderately High

Moderate

10%-20%

<10%

>20%, CHD, or DM

> 2 Risk Factors*

*If < 1 Risk Factors: 10 Year Risk < 10% and is Low Risk

LDL Cholesterol Goals (Triglycerides <200 mg/dL)

Risk Category

LDL Goal

LDL Level -

Initiate TLC*

LDL Level -

Consider Drug

TX

LR

0-1 Risk Factor

<160 mg/dL ≥160 mg/dL ≥190 mg/dL

MR and MHR

>2 Risk Factors

(10 yr risk ≤20%)

<130 mg/dL ≥130 mg/dL

10-20%:

≥ 130 mg/dL

<10%:

≥ 160 mg/dL

HR

>2 Risk Factors or CRE

(10 yr risk >20%)

<100 mg/dL

Optional

< 70 mg/dL

≥100 mg/dL ≥ 130 mg/dL

Optional

< 100 mg/dL

*Therapeutic lifestyle changes NCEP/ATP III. JAMA. 2001;285:2486-2497.

Non-HDL Cholesterol Goals (Triglycerides >200 mg/dL)

Risk Category

N-HDL-C

Goal

N-HDL-C Initiate

TLC*

N-HDL-C

Consider Drug

TX

LR

0-1 Risk Factor

<190 mg/dL ≥190 mg/dL ≥190 mg/dL

MR and MHR

>2 Risk Factors

(10 yr risk ≤20%)

<160 mg/dL ≥160 mg/dL

<10%:

≥ 190 mg/dL

10-20%:

≥ 160 mg/dL

HR

>2 Risk Factors or CRE

(10 yr risk >20%)

<130 mg/dL

Optional

< 100 mg/dL

≥130 mg/dL ≥ 160 mg/dL

Optional

< 130 mg/dL

*Therapeutic lifestyle changes NCEP/ATP III. JAMA. 2001;285:2486-2497.

PROVE

AT

PROVE

PR A to Z

Tr

50 70 90 110 130 150 170 190 210

0

5

10

15

20

25

O´Keefe JH et al. J Am Coll Cardiol. 2004;43:2142-2146. LDL Cholesterol (mg/dL)

WOSCOPS-PL

WOSCOPS-Tr

CARE-PL

LIPID-PL

4S-PL

AFCAPS-PL AFCAPS-Tr

Secondary

Prevention

Primary

Prevention

1993 2001

2004

HPS-Tr

ASCOT-Tr

A to Z-PL TNT-AT80

LIPID-Tr

CARE-Tr

4S-Tr

HPS-PL

ASCOT-PL

TNT-AT10

Risk 0.5-fold

Risk 3-fold

Reduction of LDL-C Decreases

Risk of CVD

Lipid Management

• Therapeutic Lifestyle Changes

– Restriction of saturated fat (<7% of total calories) and cholesterol (<200 mg/day)1

– Promotion of daily physical activity and weight management1

– Increase in omega-3 fatty acid consumption2

– Smoking cessation1

• LDL-C Management3

– Statin therapy to meet NCEP/ATP III LDL Goals

– Statins are anti-inflammatory

– Statins lower LDL-C by increasing expression of LDL receptors

• Lovastatin and Simvastatin contraindicated

• Pravastatin contraindicated with darunavir

1NCEP/ATP III. JAMA. 2001;285:2486-2497. 2www.americanheart.org/presenter.jhtml?identifier=4632.

3Grundy S. Circulation. 2004;110:227-239.

Lipid Management

Triglyceride 200/500 Rule

• If TG level 200-499 mg/dL, adding a fibrate to statins is optional

– TG < 200 mg/dL: Apolipoprotein B ≈ LDL

– TG > 200 mg/dL: Apolipoprotein B ≈ non-HDL cholesterol

• Non-HDL cholesterol goal is 30 mg/dL higher than LDL-C goal

• If TG level ≥500 mg/dL, add a fibrate before starting LDL-lowering therapy

– TG > 500 mg/dL cannot be hydrolyzed off the Apolipoprotein B complex.

– Failure to hydrolyze TGs traps LDL in the Apo B complex preventing release of LDL into the circulation for processing by LDL receptors (statins increase LDL receptor expression)

– This results in deposition of LDL into the intima media of the artery.

NCEP/ATP III. JAMA. 2001;285:2486-2497.

Traditional Cardiovascular Risk

Factors in HIV-Infection

D:A:D: Prevalence of Cardiac Risk Factors

in Cohort of HIV-Infected Patients

Friis-Møller N, et al. N Engl J Med. 2003;17:1179-1193.

0

10

20

30

40

50

60

FHx PHx Current orFormer

Smoking

BMI >30mg/m

HTN DM HC TG

2

% C

oh

ort

wit

h R

isk F

acto

r

at

Baselin

e

FHx = family history of CHD; PHx = previous history of CHD; BMI = body mass index;

HTN = hypertension; DM = diabetes mellitus; HC = hypercholesterolemia; TG = triglycerides

↑

N=23,468

Median age, yrs 39

Male, % 75.9

Median HIV-1 RNA, log10 c/mL 4.6

Median CD4 cell count, mm3 226

Median duration of HIV, yrs 3.5

Previous ART, % 80.8

Modifiable Risk Factors Increased Among

HIV vs. General Population

0

20

40

60

80

100

Smoking Hypertension HDL <40 mg/dL

APROCO Cohort (HIV+) MONICA Sample (HIV-)

Perc

en

t P

ati

en

ts

APROCO Cohort (N=223 HIV+ men on PI-containing regimen)

MONICA Sample (N=527 HIV- men)

Savès M, et al. Clin Infect Dis. 2003;37:292-298.

P<0.0001

P<0.01

P<0.0001

Law MG, et al. HIV Med. 2006;7:218-230.

0

1

2

3

4

5

6

7

8

Duration of cART Exposure (Years)

n=ART exposure

Rate

s P

er

Thousa

nd P

ers

on Y

ears

<1 1–2 2–3 3–4 4+

Observed

rates

Best

estimate of

predicted

rates

None

Observed and predicted MI rates according to ART exposure

(D:A:D Study; n=23,468)

D:A:D Study: Is the Framingham Risk

Estimation Valid in HIV-Infected Patients?

n=5,292 n=6,805 n=9,050 n=10,574 n=8,890 n=5,973

Incidence of MIs is low: 345 over 94,469 patient-years’ follow-up (3.7/1,000 patient-years)

HIV

Infection

ART

?

CHD

Risk - -

Lipids*

Family

History

Abdominal

Obesity*

Hyper-

tension*

Cigarette Smoking

Hyper-

glycemia

Insulin Resistance*

Inactivity,

Diet

Age

Gender

Brown = Modifiable

Red = Nonmodifiable

CHD Risk Factors in HIV-Infected Population

Antiretroviral Therapy and

Cardiovascular Disease

Friis-Møller N, et al. N Engl J Med. 2007;356:1723-1735.

An increase in incident CVD is associated with duration of

PI-containing combination antiretroviral therapy

Exposure to PI-Containing ART (years)

0

2

4

6

8

None

10

< 1 1-2 2-3 3-4 4-5 5-6 >6

D:A:D

PIs and Incidence of MI In

cid

en

ce o

f M

I p

er

1000

Pati

en

t-Y

ears

D:A:D Study:

NRTI Use and Risk of MI • D:A:D study

– 33,347 HIV patients on HAART

• 517 patients developed MI over 157,912 person-years of follow-up

– Recent didanosine use (n=124)

– Recent abacavir use (n=192)

– Recent other NRTI use (n=237)

• Recent use of abacavir and didanosine (but not cumulative or past use) associated with increased risk of MI

– Risk persists regardless of length of use

– Risk was reversible with discontinuation of drugs

– Most MIs occurred in patients with existing cardiovascular risk factors

Recent use Relative Risk

(95% CI)

P

Value

Zidovudine 0.97

(0.76- 1.25)

0.82

Stavudine 1.00

(0.76-1.32)

0.93

Lamivudine 1.25

(0.96-1.62)

Abacavir 1.90

(1.47-2.45)

0.001

Didanosine 1.49

(1.14-1.95)

0.003

Sabin CA, Worm SW, Weber R et al. Lancet. April 26, 2008. 371(9622):1417-26

Implications:

Use caution in the interpretation of these preliminary findings and await further studies

D:A:D Study:

NRTI Use and Risk of MI • D:A:D study

– 33,347 HIV patients on HAART

• 517 patients developed MI over 157,912 person-years of follow-up

– Recent didanosine use (n=124)

– Recent abacavir use (n=192)

– Recent other NRTI use (n=237)

• Recent use of abacavir and didanosine (but not cumulative or past use) associated with increased risk of MI

– Risk persists regardless of length of use

– Risk was reversible with discontinuation of drugs

– Most MIs occurred in patients with existing cardiovascular risk factors

Recent use Relative Risk

(95% CI)

P

Value

Zidovudine 0.97

(0.76- 1.25)

0.82

Stavudine 1.00

(0.76-1.32)

0.93

Lamivudine 1.25

(0.96-1.62)

Abacavir 1.90

(1.47-2.45)

0.001

Didanosine 1.49

(1.14-1.95)

0.003

Sabin CA, Worm SW, Weber R et al. Lancet. April 26, 2008. 371(9622):1417-26

Implications:

Use caution in the interpretation of these preliminary findings and await further studies

SMART Study Design • Randomized, controlled study of treatment interrruption

• Primary endpoint: development of OI or death from any cause

• Secondary endpoint: development of major CV, renal, or hepatic disease

Patients with CD4+ >350 cells/mm3

(n=5472)

Virologic Suppression

(VS) Strategy

Drug Conservation

(DC) Strategy

Immediate or

Continued ART

Deferred ART*

(until CD4+ <250 cells/mm3)

* Patients in the deferred ART arm initiated therapy when CD4+ count decreased

to <250 cells/mm3, until CD4+ count increased to >350 cells/mm3 with repeated

interruptions and re-initiation at CD4+ cell counts of >350 and <250 cells/mm3,

respectively. The SMART Study Group, N Engl J Med 2006;355:2283-96

SMART Study Results:

HIV and Clinical Events

Viral Suppression Group

Drug Conservation Group

44 40 36 32 28 24 20 16 12 8 4 0

Months

0.00

0.05

0.10

0.15

0.20

Hazard ratio, 2.6; 95% CI, 1.9-3.7; P<0.001

Cu

mu

lati

ve P

rob

abili

ty o

f E

ven

t

Opportunistic Disease or Death from Any Cause

No. at Risk

162 280 372 444 540 689 870 1040 1301 1666 2074 2720

173 288 388 474 572 724 906 1077 1310 1695 2081 2752

Drug conservation

Viral suppression

Drug Conservation Group

44 40 36 32 28 24 20 16 12 8 4 0

Months

0.00

0.05

0.10

0.15

0.20

Hazard ratio, 1.7; 95% CI, 1.1-2.5; P=0.009

157 273 375 443 543 693 867 1041 1292 1663 2074 2720

165 282 380 462 563 713 899 1070 1307 1692 2077 2752

Major Cardiovascular, Renal or Hepatic Disease

Viral Suppression Group

SMART Study Group NEJM 2006;355:2283-2296

XXXX Study: Drug A + Versus

Drug B in HAART Regimen:

• Open-label, non-inferiority study: ART-naïve, HIV+ patients randomized to

Drug A or Drug B

• Primary end points: proportion of patients achieving HIV-1 RNA <400 c/mL

at Week 48 and treatment discontinuations because of an adverse event

Drug A BL

Drug A BL

Drug A BL

Drug A BL

Drug A Wk 48

Drug A Wk 48

Drug A Wk 48

Drug A Wk 48

Drug B BL

Drug B BL

Drug B BL

Drug B BL

Drug B Wk 48

Drug B Wk 48

Drug B Wk 48

Drug B Wk 48

0

50

100

150

200

250

TC LDL-C HDL-C TG

Fa

stin

g L

ipid

Leve

ls (

mg

/dL)

Fasting Lipid Levels at Week 48

Total Cholesterol LDL HDL Triglyerides

MACS Cohort: Mean Lipid Values Before and After HIV Infection (Treated and Untreated)

Riddler SA, et al. JAMA. 2003;289:2978-2982.

0

50

100

150

200

250

0 2 4 6 8 10 12 14

Years

Mean

mg

/dL

TC

LDL

HDL

Pre-HAART

Preseroconversion HAART

Non-fasting values Recommended NCEP values

Incidence of CVD events by select factors at baseline* and during observation among 2,005 HOPS patients, January 2002- September 2009.

Cumulative antiretroviral exposures since HIV

diagnosis

# of

persons

CVD incidence

per 100 py

p-value

Exposure to NRTI

Yes 1,941 1.36 0.029

No 64 3.39 referent

Exposure to NNRTI

Yes 1,470 1.24 0.023

No 535 1.89 referent

Exposure to PI

Yes 1,602 1.38 0.88


Exposure to zidovudine

Yes 1,309 1.38 0.93

No 696 1.43 referent Lichtenstein KA, Buckner K, et al. Clin Infect Dis. 51(4)435-47. 2010.

Incidence of CVD events by select factors at baseline* and during observation among 2,005 HOPS patients, January 2002- September 2009.

Cumulative antiretroviral exposures since HIV

diagnosis

# of

persons

CVD incidence

per 100 py

p-value

Exposure to "d-drug"

Yes 1,222 1.37 0.78


Exposure to abacavir

Yes 909 1.29 0.44

No 1,096 1.49 referent

Exposure to tenofovir

Yes 1,363 0.92 <0.001


Exposure to HAART

Yes 1,931 1.36 0.10

No 74 2.72 referent

Lichtenstein KA, Buckner K, et al. Clin Infect Dis. 51(4)435-47. 2010.

Inconsistent Results: From major studies on CVD risk in

HIV-infected and HAART-treated patients Study N Study Event ARV Effect Traditional risk factors

VA1 36,766 R 1,207

CHD

HAART or PI No Not evaluated

HOPS8 1807 P 84 CV

events

specific ARVs No Age >40 y, diabetes, HTN

SMART9

5472 p 63 CHD intermittent

HAART

No – stopping

therapy led to

complication

Age

Kaiser3 4408 R 86 MI PIs Risk of HIV+ vs. HIV-

No risk on PI

Not evaluated

Medi-Cal4 28,513 R NA ART Risk with ART in 18–

33 year olds

Not evaluated

DAD2 23,490 P 345 MI cART and PI Yes Smoking, age, gender, HTN, DM

French5 34,976 R 49 MI PI Yes Age

Johns

Hopkins6

2671 Case

control

43 CHD HIV+ vs. HIV- Yes Age, HTN, DM

Frankfurt7 4993 R 29 MI HAART Yes Age >40

1. Bozzette SA, New Eng J Med. 2003;348:702–10

2. Friis-Møller N, 13th CROI, Denver 2006, #144

3. Klein D,13th CROI, Denver 2006, #737

7. Rickerts V, Eur J Med Res. 2000;5:329–33

8. Lichtenstein K, 13th CROI, Denver 2006, #735

9. El-Sadr W, et al. 13th CROI, Denver 2006, #106LB

4. Currier JS, JAIDS. 2003;33:506–12

5. Mary-Krause M, AIDS. 2003;21:2479–86

6. Moore RD, 10th CROI, Boston 2003, #132

Obtain fasting lipid profile,

prior to starting ARVS and

within 3 to 6 months of starting

new regimen

Adapted with permission from Dube MP, et al. Clin Infect Dis. 2003;37:613-627. Figure 1. Publisher: University of Chicago Press. © 2003 The Infectious Diseases Society of America. All rights reserved.

IDSA Recommendations for Dyslipidemia

Management in HIV-Infected Patients Count number of cardiovascular disease (CVD)

risk factors and determine level of risk. If ≥2

risk factors, perform a 10-year risk calculation,

based on Framingham

Intervene for modifiable nonlipid risk factors

such as diet and smoking

If lipids remain above threshold based on risk group

despite vigorous lifestyle interventions,

consider altering ARV therapy or using lipid-lowering drugs

Serum LDL cholesterol above threshold, or

TG 200-500 mg/dL with

elevated non-HDL cholesterol:

STATIN

Serum TG >500 mg/dL:

FIBRATE

LIPID-LOWERING DRUG THERAPY IS NECESSARY IF:

OR

Inflammation and


General Population

Age (yrs)

P=.001 for trend toward increasing prevalence with age in coronary arteries.

Early Appearance of Atherosclerosis

Prevalence of Fibrous Plaque Lesions in Coronary Arteries

2–15 16–20 21–25 26–39 0

20

40

60

80

%

Berenson J, et al. N Engl J Med. 1998;338:1650-1656

Endothelial Dysfunction in

Atherosclerosis

NEJM.1999;340:115-126

Fatty-Streak Formation in

Atherosclerosis

NEJM.1999;340:115-126

Formation of an Advanced,

Complicated

Lesion of Atherosclerosis

NEJM.1999;340:115-126

Zipes,Libby,Bonow,Braunwald. Braunwald’s Heart Disease. 7th edition. Elsevier/Saunders, 2005

Evolution of the Atherosclerotic Plaque


Increased States of Inflammation Weaken the Fibrous Cap


Increased States of Inflammation Weaken the Fibrous Cap

“In states characterized by heightened

inflammation, the fibrous cap is under

double attack”

Unstable Fibrous Plaques

in Atherosclerosis

NEJM.1999;340:115-126

Molecular Factors Involved in

Plaque Evolution

J Nucl Med 2007; 48:1800–1815

It’s the doughnut, not the hole

Inflammation and


HIV-Infected Population

D:A:D Study: Risk Factors for CHD in an HIV+ Population

Friis-Moller N, Sabin CA, Weber R, et al. N Engl J Med 2003;349:1993-2003.

Relative Rate of Myocardial Infarction (95% CI)

Adjusted for BMI, HIV risk, cohort, calendar year and race

Diabetes mellitus (yes versus no)

Hypertension (yes versus no)

Better Worse

0.1 0.5 1 5 10

Family history

Previous CVD

Male gender

Age per 5 years older

Smoking

Drug class: not sufficient # of events to examine yet

cART Therapy RR 1.17 (1.08-1.26)

HIV Outpatient Study (HOPS)

Lichtenstein KA, et al. Abstract CROI, Denver, 2006

Relative Rate of Cardiovascular Event (95% CI)

Multivariable Poisson regression model

Hypertension

Diabetes mellitus

Better Worse

0.1 0.5 1 5 10

Baseline CD4 <350 cells/mm3

HDL <40 mg/dL

LDL/non-HDL-C > Goal


Smoking


RR 1.99 (1.32-3.01)

RR 1.95 (1.27-2.98)

RR 1.29 (1.18-2.13)

RR 1.07 (1.05-1.10)

RR 1.78 (1.22-2.58)

RR 1.56 (1.02-2.39)

RR 1.63 (1.08-2.46)

HIV Outpatient Study (HOPS)

Lichtenstein KA, et al. Abstract CROI, Denver, 2006

Relative Rate of Cardiovascular Event (95% CI)

Multivariable Poisson regression model

Hypertension

Diabetes mellitus

Better Worse

0.1 0.5 1 5 10

Baseline CD4 <350 cells/mm3

HDL <40 mg/dL

LDL/non-HDL-C > Goal


Smoking


RR 1.99 (1.32-3.01)

RR 1.95 (1.27-2.98)

RR 1.29 (1.18-2.13)

RR 1.07 (1.05-1.10)

RR 1.78 (1.22-2.58)

RR 1.56 (1.02-2.39)

RR 1.63 (1.08-2.46)

Attributable Risk for CVD

49.1

34.6

26.7 25.6

21 20.5

12.7

2.3

0

10

20

30

40

50

60

Risk Factor

Perc

en

t A

ttri

bu

tab

le R

isk

Age > 42 Hypertension Smoker CD4 < 500 LDL/non-HDL-C

> NCEP Goal

HDL < 40 M

HDL < 50 F

Male Diabetes

Lichtenstein, et al. Clin Infect Dis 2010, 51(4):435-47.

Attributable Risk for CVD

57.7

47.1

26.4 25.6

0

10

20

30

40

50

60

70

NCEP Risk Category

Perc

en

t A

ttri

bu

tab

le R

isk

High Risk Moderately High Risk Moderate Risk CD4 < 500

Lichtenstein, et al. Clin Infect Dis 2010, 51(4):435-47.

Improved immune function decreases the risk of non–HIV-related death

• n=23,000+

• 1,248 (5.3%) deaths 2000 -2004 (1.6/100 person-years)

– Of these, 82% on ART

• Incidence of CV-related mortality lower than other non–HIV-related deaths Monforte A, Abrams D, Pradier C, et al. AIDS. 2008 Oct 18;22(16):2143-53

D:A:D Study: Relative Risk of Death According to Immune Function and Specific Cause

Latest CD4+ count (cells/mm3)

100

>500

1.0

10

<50 50–99 100–199 200–349 350–499

Rela

tive R

isk o

f

Death

HIV

Liver

Malignancy

Heart

FRAM: The Effects of HIV on

CHD/Death Results

Modrich L, et al. 16th CROI 2009;Abstract 706.

• Comparing mortality risk in 468 HIV-infected vs 278 controls, ages

33-45: 7X higher death risk in the HIV group (P<0.0001)

• After adjusting for traditional CV risk factors: the death risk remained

3.4X higher in people with HIV (P = 0.009)

• Current smoking (but not past smoking) nearly tripled the death risk

(HR = 2.73, P = 0.0001)

• Every added 10 years of age raised the risk more than 60% (HR =

1.61, P<0.0001)

• Every doubling of the baseline CD4 cell count lowered the risk 35%

(HR = 0.65, P<0.0001)

FRAM = Fat Redistribution and Metabolic Change in HIV Infection Study

FRAM: Fat Redistribution and

Metabolic Change in HIV Infection Study

• HIV itself emerged as a mortality risk factor as

potent as:

– Age

– Male gender

– Smoking

– Diabetes

Modrich L, et al. 16th CROI 2009;Abstract 146.

Summary Contributors to CVD Risk

Traditional CVD

Risk Factors

Antiretroviral Therapy

HIV Infection

ICAM

VCAM IL-6

RANTES CCR2

CCR5 HDL TGs

TNF-alpha Fibroblasts

Metalloproteinases

Collagenases Oxidized LDL

IL-1 CD4 Cells Glycated LDL

MCP-1 Interferon-gamma IL-2

Foam Cells Smooth Muscle Cells

Summary Goal: Reduction of CHD Risk

Risk Factor Intervention

Untreated HIV Initiate HAART

Traditional risk factors Lifestyle modifications (TLC) ±

pharmacologic therapy (NCEP

Guidelines)

Lipid effects of HAART Avoid specific anti-retrovirals if

lipid-lowering therapy and TLCs

are ineffective

Mate, doesn’t HIV infection add at least some additional risk for cardiovascular disease?

Questions?

Documents

HIV and Cardiovascular/Lipid Disorders...HIV and Cardiovascular/Lipid Disorders Kenneth A. Lichtenstein, MD Director, HIV Clinical and Research Program National Jewish Health Denver,