georg behrens clinic for immunology and rheumatology hannover medical school, germany haart to...
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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
Total cholesterol Triglycerides
LDL cholesterol
HDLcholesterol
Lipid profile due HAART
Total cholesterol Triglycerides
LDL cholesterol
HDLcholesterol
HAART and cardiovascular disease
Insulin resistanceType 2 diabetes
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
Central obesityCentral obesity
HAARTHAART
Age, genetics, diet, hypertension, sedentery life style, renal disease…
CVD
Insulin resistanceType 2 diabetes
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
Central obesityCentral obesity
HAARTHAARTCVD
Age, genetics, diet, hypertension, sedentery life style, renal disease…
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
Lipid profile due HAART
Insulin resistanceType 2 diabetes
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
Central obesityCentral obesity
HAARTHAARTCVD
Inflammation ?Inflammation ?
AbacavirDidanososineIndinavir Lopinavir
Age, genetics, diet, hypertension, sedentery life style, renal disease…
Lipid profile due HAART
Insulin resistanceType 2 diabetes
Insulin resistanceType 2 diabetes
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
DyslipidemiaHigh FFA
Small dense LDLLow HDLHigh TG
Central obesityCentral obesity
HAARTHAARTCVD
Inflammation ?Inflammation ?HIV
Age, genetics, diet, hypertension, sedentery life style, renal disease…
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%
Drug treatment if:Established CVD or
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%)
Drug treatment if:Established CVD or
T2D or 10 year CVD risk 20%
Drug treatment if:Established CVD or
T2D or 10 year CVD risk 20%
Assess CVD risk in the next 10 yearsAssess CVD risk in the next 10 years
Advise on diet and lifestyle in all patientsConsider ART modification, if 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
EACS Guideline for non-infectious Co-Morbidities in HIV
EACS Guideline for non-infectious Co-Morbidities in HIV, 2009 www.eacs.com
SmokingSmoking
GlucoseGlucoseCoagulationCoagulationBlood pressureBlood pressure LipidsLipids
Assess CVD risk in the next 10 yearsAssess CVD risk in the next 10 years
Advise on diet and lifestyle in all patientsConsider ART modification, if 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
EACS Guideline for non-infectious Co-Morbidities in HIV, 2009 www.eacs.com
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)
EACS Guideline for non-infectious Co-Morbidities in HIV
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: