georg behrens clinic for immunology and rheumatology hannover medical school, germany haart to...

Georg BehrensClinic for Immunology and RheumatologyHannover Medical School, Germany

HAART to heart:HIV and cardiovascular disease

AIDS 2010

Overview

1

2

3

4

Epidemiology

HIV therapy

HIV infection

Clinical care

Epidemiological data: CVD events in HIV-patients1

• Retrospective cohort studies• Prospective HIV cohort studies• Administrative/clinical databases• Randomized clinical trails of ART

DAD I2

DAD I3

23,468/12623,437/345

3.53.6

No. of patients/No. of events

36,7667/1207

Event rate per1,000 HIV+

Event rate per1,000 HIV-

VA4

Kaiser 20025

Kaiser 2007

MGH6

MediCal7

4159/475000/162

3851/189

28512/294

4.33.7

8.1

11.13

4.12

NANA

2.92.2

NA

6.98

3.32

1Currier Circulation 2008; 2Friis-Moller N Engl J Med 2003; 3 Friis-Moller N Engl J Med 2007; 4Bozette N Engl J Med 2003;5Klein J AIDS 2002; 6Triant J Clin Endocrinol Metab 2007; 7Currier J AIDS 2003

Role of traditional risk factors in HIV+ and HIV- 1

1Currier Circulation 2008; 2Iloeje HIV Med 2005; 3 Friis-Moller N Engl J Med 2007

Age Per 1 y 9%

Unit

Male vs female

Iloeje2 Friss-MØller3

Sex

Diabetes mellitus

Smoking

Hypertension

Total cholesterol

Yes vs No

Yes vs No

Yes vs No

Per 1 mm/L

260%

140%

NS

30%

…

6%

90%

290%

110%

80%

26%

HDL cholesterol Per 1 mm/L … -28%

HIV-

6-9%

140-252%

70-290%

110-160%

80-90%

25-33%

-52%

HIV+

% increase in risk per unitfor each study

Cause of death in D:A:D

7.9 (ATCC)2

1Smith CROI 2009, #145; 2ATCC, Clin Infect Dis 2010

Cause of death Percentage

AIDS-related 32

Liver-ralated 14

Non-AIDS cancers 12

CVD-related 11

Non-natural 9

Bacterial infections 7

Renal 1

Lactic acidosis/pancreatitis 1

Others/Unknown 1

Prevalence of cardiovascular risk factors in HIV

Traditional risk factors

• Smoking (47-71%) 1,2

• Obesity (40-60%) 3

• Hypertension (31%) 4

• Dyslipidemia (40-60%) 5

• Glucose intolerance• Type 2 diabetes

1Saves Clin Infect Dis 2003; 2Gritz Nicotine Tob Res 2004; 3Kaplan Clin Infect Dis 2007; 4Seaberg AIDS 2005; 5Samaras Diabetes Care 2007

Multivariable Poisson model adjusted for age, sex, BMI, HIV risk, cohort, calendar year, race, family history of CVD, smoking, previous CVD event, TC, HDL, hypertension, diabetes.

Relative Rate of MI (95% CI)

WorseBetter

0.1 0.5 1 5 10

RR: 1.86 (1.31-2.65)Diabetes (yes vs no)

RR: 1.30 (0.99-1.72)Hypertension (yes vs no)

Family history

Previous CVD

Male sex

Age per 5 yrs older

Smoking

RR: 1.40 (0.96-2.05)

RR: 2.92 (2.04-4.18)

RR: 2.13 (1.29-3.52)

RR: 4.64 (3.22-6.69)

RR: 1.32 (1.23-1.41)

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

D:A:D: Traditional Risk Factors for CHD in anHIV-infected Population

Population over 60 years of age

2000 2025 2050

Total world population

2

4

6

8

10

0

Po

pu

lati

on

(B

illio

n)

10%15%

22%

4%

2015

25%

60%German HIV+

> 60 years of age

HIV, HAART and aging: a rough estimate

Overview

1

2

3

4

Epidemiology

HIV therapy

HIV infection

Clinical care

Total cholesterol Triglycerides

LDL cholesterol

HDLcholesterol

Lipid profile before HIV infection

Lipid profile due to HIV infection


LDL cholesterol

HDLcholesterol

Lipid profile due HAART


LDL cholesterol

HDLcholesterol

HAART and cardiovascular disease

Insulin resistanceType 2 diabetes


DyslipidemiaHigh FFA

Small dense LDLLow HDLHigh TG



Central obesityCentral obesity

HAARTHAART

Age, genetics, diet, hypertension, sedentery life style, renal disease…

CVD








HAARTHAARTCVD


HAART and cardiovascular disease

AbacavirDidanosineIndinavir Lopinavir

Lundgren JD, et al. CROI 2009. Abstract 44LB; DAD Study Group Lancet 2008

# PYFU: 68,469 56,529 37,136 44,657 61,855 58,946# MI: 298 197 150 221 228 221

IDV NFV LPV/r SQV NVP EFV

PI† NNRTI

1.21.13

1.0

1.1

0.9

*Current or within last 6 months. †Approximate test for heterogeneity: P = 0.02

Only >30,000 PY of follow up

D:A:D: Recent and/or cumulative antiretroviral exposure and risk of MI

RR

of

cum

ula

tive

exp

osu

re/y

ear

95%

CI

# PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157# MI: 523 331 148 40 554 221 139

1.9

1.51.2

1.00.8

0.6ZDV ddI ddC d4T 3TC ABC TDF

1.9

1.5

1.2

1.0

0.8

0.6

NRTI

*Current or within last 6 months. †Approximate test for heterogeneity: P = 0.02

D:A:D: Recent and/or cumulative antiretroviral exposure and risk of MI

RR

of

rece

nt*

exp

osu

reye

s/n

o 9

5% C

I

RR

of

cum

ula

tive

exp

os

ure

/yea

r 95

% C

I

Lundgren JD, et al. CROI 2009. Abstract 44LB; DAD Study Group Lancet 2008 Only >30,000 PY of follow up

Study Design Event Ascertainment

Patients (n=) MI (n=)

Abacavir-effect?

D:A:D Prospective observ. cohort

Prospective predefined

33,347 580 Yes

FHDB Case control in observ. cohort

Prospective, MI retrospectively validated

289 cases 884 control

289 Yes, first year of exposure

SMART RCT, Oberserv. analysis Prospective predefined 2,752 19 Yes

STEAL RTC Prospective 357 3 Yes

QPHID Case control in observ. cohort

ICD 9 code acute MI Not validated

142 cases 1,420 controls

142 Yes

GSK Analysis

RCT (n=54) Retrospective Data base search 14,174 11 No

ALLRT ACTG

Long term follow up of 5 RCT

Retrospective 2 independent reviewer 3,205 27 No

VACCRRetrospective observ. cohort

ICD 9 code acute MI Not validated

19,424 278 No

Behrens & Reiss Curr Opin Infect Dis 2010

Abacavir and myocardial infarction

0

5

10

15

20

25

30

hsCRP(µg/ml)

IL-6(pg/ml)

Per

cent

adj

uste

d di

ffere

nce

from

„ot

her

NR

TI“

n=791

*

*

Adjusted mean differences in biomarker levels at study entry for using »ABC (no ddI)« or »ddI (w/wo ABC)« versus »Other NRTI«

ABC (no ddI)

ddI (w/wo ABC)

Amyloid A(mg/l)

Amyloid P(µg/L)

D-dimer(µg/ml)

F1.2(pmol/l)

Abacavir and inflammation (SMART)

SMAT+DAD AIDS 2008

ABC + inflammation: More data, more questions?

Mac-1

ICAM-1

1de Pablo CROI 2010 #716; 2Baum CROI 2010 #717; 3 Satchell CROI 2009 #151LB7; 4Martin CROI 2010, #718; 5Palella AIDS 2010; 6Martinez AIDS 2010; 7McComsey CROI 2009 # 732

• induces Mac-1 on leukocytes, which interacts with ICAM-1 on endothelial cells1

• increases platelet activity through inhibition of soluble guanylyl cyclase2

• facilitates collagen-induced platelet aggregation3

ABC in vitro:

ABC in patients:• STEAL Study4

• WIHS and HOPS Cohort5

• BICOMBO Study6

• HEAT Study7

No differences in biomarkers(hsCRP, IL-6, D-dimer, MCP-1…)

PlateletsEndothelial cells

Leukocytes









HAARTHAARTCVD

Inflammation ?Inflammation ?

AbacavirDidanososineIndinavir Lopinavir










HAARTHAARTCVD

Inflammation ?Inflammation ?HIV


Overview

2

3

4

HIV therapy

HIV infection

Clinical care

1 Epidemiology

*Death from CVD, silent or clinical MI, stroke, CAD requiring invasive procedure.

Number at risk

DC 2,752 1,306 713 379 10

VS 2,720 1,292 696 377 10

% w

ith a

ma

jor

CV

D e

ven

t*

Years from Randomization

VS**

DC**Relative hazard:1.57 (1.00-2.46)p = 0.05

0

1

2

3

4

5

0 0.5 1 1.5 2 2.5 3 3.5 4

Phillips A et al. (SMART Study Group). 14th CROI 2007; Los Angeles, CA. Abstract 41.

DC = drug conservation armVS = viral suppression arm

Risk of major CVD events* by study arm in SMART

Tebas P PLoS ONE 2008

CD8+/HLA-DR+/CD38+CD8+/HLA-DR+/CD38+

0

-10

10

20

30

40

50

% Δ

from

BL

0 16Weeks

24 48

STEP 1(on ART)

STEP 2(off ART)

Soluble TNFR IISoluble TNFR II

1000

0

2000

3000

4000

5000

6000

ng/m

L

0Weeks

14

Conclusion for treatment interruption: Lipids , immune activation

**

Changes in immune activation with treatment interruption (ATG 5102)

STEP 2(off ART)

Preclinical atherosclerosis in HIV-patients (FRAM)

IMT: Multivariable analysis of associated factors

Grunfeld CROI 2009, Grunfeld AIDS 2010

IMT:Intima mediathickness

BP: Blood pressure* p<0.01** p<0.001*** p<0.0001

Preclinical atherosclerosis in HIV-patients (FRAM)

IMT: Multivariable analysis of associated factors

Grunfeld CROI 2009, Grunfeld AIDS 2009

* p<0.01** p<0.001*** p<0.0001BP: Blood pressure

HIV and cardiovascular risk

HIV induces

• Apoptosis in endothelial cells (gp120, Tat)1-3

• Endothelial dysfunction4

• Leukocyte activation5

• HDL , IL-6 , sICAM , D-dimer • MCP-1-CCR2 axis activation6

• MCP-1 polymorphism associated with atherosclerosis in HIV7

• a distinct (inflammatory) atherosclerosis process?8

1Sudano, Am Heart J 2006; 2Huang, J AIDS 2001; 3Jia, Biochem Biophys Res Commun 2001; 4Solages, CID 2006; 5de Gaetano,Lancet Infect Dis 2004; 6Park Blood 2001; 7Alonso-Villaverde Circulation 2004; 8Mehta, Angiology 2003, Baker CID 2010

MCP-1: Monocyte chemotactic protein-1

HIV as a risk factor

• HIV+HCV: - sICAM-1 + sVCAM-1 1

- endothelial dysfunction1

- increased risk for MI2

• Low CD4 count is risk factor for MI3 and carotid leasons

• Low CD4 nadir is associated with reduced arterial stiffness4

• HAART improves FMD, but not to normal (ACTG 5152s)5

• HIV is an independent predictor of increased carotid IMT6,7

• HIV increases tissue factor expression on monocytes8

1Castro, AIDS 2010; 2Bedimo, HIV Med 2010; 3Lichentstein, Clin Infect Dis 2010; 4Ho, AIDS 2010; 5Torriani Am J Coll Cardiaol 2008;6Hsu, Circulation 2004; 7Grunfeld AIDS 2009; 8Funderburg Blood 2010

HIV and cardiovascular risk

FMD: Flow-mediated dilatation

Baenziger et al. Blood 2008; Chang & Altfeld Blood 2009

Microbial translocation and low-level inflamation

Disruption of lymph node architectureImmune activation

MØ

pDC

TLR7HIV

IFNα

TLR4

LPS

TNFαLumen

Gut mucosa

GALT

CD4

CD4CD4

pDC

Modified from Hansson & Libby. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006

Atherosclerosis and immune cells

Atherosclerosis and immune cells

InflammationCoagulationApoptosis

Modified from Hansson & Libby. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 2006

Atheroma formationand growth

Plaque instability and ruptur

Hyper-coagulability

LipidsGlucose

Fat tissue HIV-therapy

Age♂♀

NicotineHypertension

ObesityLipids

Glucose

HIV

Inflammation

Behrens & Reiss Curr Opin Infect Dis 2010

Overview

2

3

4

HIV therapy

HIV infection

Clinical care

1 Epidemiology

Viral load

Inflammation

Risk formyocardial infarction 105% 2%

HAART

VL<50 copies

Clinical care

HAART, lipodystrophy,lipids, insulin resistence,

type 2 diabetes…

5%

7%

HAART

VL<50 copies

Clinical care

Viral load

Inflammation

Risk formyocardial infarction

VL<50 copies

10%

15%

HAART

Clinical care

HAART, lipodystrophy,lipids, insulin resistence,

type 2 diabetes…

Viral load

Inflammation

Risk formyocardial infarction

EACS Guideline for non-infectious Co-Morbidities in HIV

Assess CVD risk in the next 10 yearsAssess CVD risk in the next 10 years

EACS Guideline for non-infectious Co-Morbidities in HIV, 2009 www.eacs.com

SmokingSmoking

GlucoseGlucoseCoagulationCoagulationBlood pressureBlood pressure LipidsLipids

Confirm DMand treat

Confirm DMand treat

Drug treatment if:Established CVD or

Age 50 and 10 yearCVD risk 20%


Age 50 and 10 yearCVD risk 20%

Drug treatment if:SBP140 or

DBP90 mmHg(especially if 10 year

CVD risk 20%)

Drug treatment if:SBP140 or

DBP90 mmHg(especially if 10 year

CVD risk 20%)


T2D or 10 year CVD risk 20%


T2D or 10 year CVD risk 20%


Advise on diet and lifestyle in all patientsConsider ART modification, if 10 year CVD risk 20%


Identify key modifiable risk factorsIdentify key modifiable risk factors



SmokingSmoking

GlucoseGlucoseCoagulationCoagulationBlood pressureBlood pressure LipidsLipids




Identify key modifiable risk factorsIdentify key modifiable risk factors


Target

If T2D or prior CVD or CKD +

proteinuria

Others

SBP<130 <140

DBP<80 <90

Target

N/A

Consider to treat with acetylsalicylic acid

75-150mg

Consider to treat with acetylsalicylic acid

75-150mg

Target

HbA1c <6.5-7%

TargetBest Standard

TC 4(155)

5(190)

LDL 2(80)

3(115)


HIV + is not only about myocardial infarction!

• ECG evidence of asymptomatic IHD1

• Diastolic dysfunction2,3

• QT-Prolongation:- High prevalence in HIV (20%)4

- Associated with HIV-drugs5

• Pericardial tuberculosis, pericardial effusion6

• Dilated cardiomyopathy6

• …

1 Carr AIDS 2008; 2Hsue Circ Heart Fail 2010 ; 3Thöni AIDS 2008; 4Reinsch HIV Clin Trial 2009; 5FDA: Ongoing safety review of Invirase and possible association with abnormal heart rhythms, Feb. 2010; Ntsekhe Nat Clin Pract Cardiovasc Med 2009

Other cardiac manifestations of HIV infection:

georg behrens clinic for immunology and rheumatology hannover medical school, germany haart to...

Documents

hiv risk

german hiv

iloeje hiv med

hiv infectionlipid profile

hiv event rate per1

friismoller n engl j

currier j aids

bozette n engl j med