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
Cardiovascular Disease in the
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
No 403 1.46 referent
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
No 783 1.46 referent
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
No 642 2.65 referent
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
Cardiovascular Disease in the
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
Zipes,Libby,Bonow,Braunwald. Braunwald’s Heart Disease. 7th edition. Elsevier/Saunders, 2005
Increased States of Inflammation Weaken the Fibrous Cap
Zipes,Libby,Bonow,Braunwald. Braunwald’s Heart Disease. 7th edition. Elsevier/Saunders, 2005
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
Cardiovascular Disease in the
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
Age per 5 years older
Smoking
cART Therapy RR 1.00 (0.53-1.34)
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
Age per 5 years older
Smoking
cART Therapy RR 1.00 (0.53-1.34)
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?