1. Liver Injury is Associated with ASCVD, Stroke, and CHF
Including Among Those without Viral Hepatitis (B Or C), HIV, Alcohol Abuse and Obesity
K. So-Armah, J. Tate, J. Lim, V. Lo Re, V. Marconi, J. Samet, C. Gibert, D. Leaf, A. Butt, M. Goetz, D. Rimland, M. Rodriguez-Barradas, M. Budoff, C. Chang, A. Justice, M. Freiberg,

2. Traditional ASCVD Risk factors
Aging
Smoking
Hypertension
Dyslipidemia
Diabetes
People get atherosclerotic CVD (ASCVD) because
They smoke, have hypertension and other traditional risk factors leading to lipid accumulation in vessel walls, an inflammatory response to this accumulation, plaque formation, arterial narrowing and eventual thrombosis leading to clinical events

3. Excess ASCVD risk in certain groups
Compared to uninfected, HIV+ people have:
40-50% increased risk of AMI
17-40% increased risk of ischemic stroke
adjusting for multiple confounders
In some high risk groups (eg HIV) these risk factors do not explain the excess risk of ASCVD
HIV infected people have 40-50% increased AMI risk and up to 40% increased stroke risk compared to uninfected people adjusting for the risk factors we just talked about
Freiberg, JAMA IM 2013
Sico, Neurology 2014
Marcus, AIDS 2014

4. What Drives Excess ASCVD Risk in HIV?
Liver injury
Liver fibrosis
Liver cirrhosis
Immuno-metabolic alterations
Gut permeability & Microbial translocation
Inflammation & monocyte activation
Altered coagulation
CVD
Atherosclerosis
Clinical events
Heart failure
T-cell subsets imbalance
Current thinking points to changes in immunologic and metabolic processes associated with both HIV and atherosclerosis
For example persistent viremia may lead to systemic inflammaton and monocyte activation, which accentuates the inflammatory response to lipid accumulation in vessels driving atherosclerosis
Additionally, HIV is associated with increased gut permeability allowing microbes and microbial products into the portal and systemic circulation again driving inflammation
The T-cell is the main target for HIV and different T-cell subsets control inflammatory responses which we have just said is a driver of atherosclerosis.
For this study we wanted to look upstream of these immunologic processes since intervening earlier in the mechanism may be a more effective way to reduce CVD risk
Liver injury is common in HIV,
The liver regulates lipid metabolism, immune tolerance (T-cells), coagulation, and microbial translocation from portal to systemic circulation, processes associated with CVD risk

5. Hypothesis Liver injury CVD
Fibrosis
Cirrhosis
CVD
Atherosclerosis
Clinical events
Heart failure
Liver injury is independently associated with incident ASCVD events
Current thinking points to changes in immunologic and metabolic processes associated with both HIV and atherosclerosis
For example persistent viremia may lead to systemic inflammaton and monocyte activation, which accentuates the inflammatory response to lipid accumulation in vessels driving atherosclerosis
Additionally, HIV is associated with increased gut permeability allowing microbes and microbial products into the portal and systemic circulation again driving inflammation
The T-cell is the main target for HIV and different T-cell subsets control inflammatory responses which we have just said is a driver of atherosclerosis.
For this study we wanted to look upstream of these immunologic processes since intervening earlier in the mechanism may be a more effective way to reduce CVD risk
Liver injury is common in HIV,
The liver regulates lipid metabolism, immune tolerance (T-cells), coagulation, and microbial translocation from portal to systemic circulation, processes associated with CVD risk

6. VACS VC Overview & Study Design
VACS VC (N=133018)
Current Study (N=97979)
Prospective, observational cohort
Enrolled in VACS VC
Alive 4/1/2003 (baseline)
No prevalent CVD
Censor: 1st CVD event, death, 9/30/12
Cox proportional hazards
Median follow up 6.8 years
HIV+
HIV-
To test this hypothesis, we analzed data from the Veterans Aging Cohort Study Virtual cohort
This is a longitudinal prospective observational cohort of HIV+ Veterans each matched to 2 uninfected veterans on age, sex, race ethnicity and geographical location
In this analysis, participants alive and enrolled as of April 2003, free of CVD at baseline were followed until a CVD event, death or 9/30/2012
We used cox proportional hazards analysis
Matched on age, sex, race-ethnicity, geographical location
Fultz, Med Care 2006

7. Exposure: Liver Injury
Fibrosis
Cirrhosis
ICD9 codes
FIB4= Age x AST
Platelets x ALT0.5
FIB4<1.45
No advanced fibrosis (83% NPV vs. biopsy)
Moderate fibrosis
FIB4>3.25
Advanced fibrosis (71% PPV vs. biopsy)
To define liver injury,
We used FIB4 is an index calculated from Age, aspartate and alanine transaminases and platelet count
Cirrhosis was identified by ICD9 codes
FIB4<1.45: 83% probability of no advanced fibrosis (NPV); 74% sensitivity
FIB4>3.25: 71% probability of having advanced fibrosis (PPV)
CVD was defined using ICD9 codes for acute myocardial infarction (AMI), coronary heart disease, ischemic stroke and heart failure
For Jan – expanded FIB4 to include alt, ast, plt within 180 days of each other and alt within 180 days of baseline
Am J Gastroenterol Aug;103(8):

8. Outcomes: ASCVD + CHF Prevalent - EXCLUDED Incident AMI CHD Stroke
Unstable angina
Revascularization
Stroke
Congestive heart failure
AMI
CHD
Ischemic stroke
Congestive heart failure
ASCVD
We excluded people with prevalent CVD including AMI, CHD, ischemic or hemorrhagic stroke or heart failure
We defined ASCVD to include AMI, CHD and ischemic stroke and examined CHF separately
ICD-9 codes from VA, Medicare, VA Fee for Service

9. Baseline Characteristics
Liver fibrosis (no cirrhosis)
Cirrhosis
(N=1635)
Minimal
(N=57423)
Moderate
(N=16067)
Advanced
(N=2910)
Mean age (SD)
47 (9)
54 (9)
53 (8)
52 (7)
Female 4 2 1
Race
Black 47 53 55 36
White 40 35 33 49
HCV 13 60 68
HIV 29 50 64 44
Alcohol abuse 24 31 46
Heres what the cohort looked like
Mean age in the predominantly male cohort was 49.
Over half the participants were black
Increasing severity of liver injury was associated with greater prevalence of HCV and HIV, and alcohol abuse
Missing FIB4 =19926

10. Baseline Characteristics
Liver fibrosis (no cirrhosis)
Cirrhosis
(N=1635)
Minimal
(N=57423)
Moderate
(N=16067)
Advanced
(N=2910)
Current smoker 37 38 46 48
Diabetes 13 15 27
BMI>30 kg/m2 34 22 14
Hypertension 61 67 66 81
LDL≥160 mg/dl 10 6 3
Triglycerides ≥200 mg/dl 21 20 16
HDL<40 mg/dl 39
Those with cirrhosis had greater prevalence of smoking diabetes, hypertension but lower LDL and triglycerides

11. Liver fibrosis (no cirrhosis)
Number of Events
Incident CVD events
Liver fibrosis (no cirrhosis)
Cirrhosis
(N=1635)
Minimal
(N=57423)
Moderate
(N=16067)
Advanced
(N=2910)
ASCVD
2786
1131
196
104
CHF
2248
1059
222
132

12. Liver Injury, CVD & Mortality (crude rates)
Left axist has incident CVD rates while the right axis has mortality rates
Blue bars represent ASCVD, red bars represent CHF and the white line is mortality
ASCVD and CHF rates were highest among those with advanced fibrosis or cirrhosis despite the fact that risk of death was highest in these two groups
Given the proximity in rates for advanced fibrosis and cirrhosis, and smaller sample sizes in these groups, subsequent analyses will lump them togehter

13. Liver Injury & CVD Risk Liver injury N=97397 ASCVD
Hazard ratio, HR (95% CI)
CHF
HR (95% CI)
Age, race adjusted
Fully adjusted*
Fully Adjusted*
Fibrosis (no cirrhosis)
Minimal
Ref
Moderate
1.1 ( )
1.0 ( )
1.15 ( )
Advanced
1.4 ( )
1.1 ( )
1.5 ( )
Cirrhosis
Yes
1.6 ( )
1.2 ( )
1.8 ( )
To orient you, the first 2 columns lists liver injury categories
The next two show age, race adjusted and fully adjusted hazard ratios for ASCVD risk
The last shows fully adjusted hazard ratios for CHF
The fully adjusted analyses were adjusted for age, race-ethnicity, HIV, HCV, HBV, alcohol abuse/dependence, hypertension, diabetes, LDL, HDL, triglycerides, smoking, statin, renal disease, anemia, BMI, cocaine, aFib
Increasing severity of liver injury was associated with ASCVD risk in a stepwise fashion in age, race adjusted models
After adjustment for confounders these associations were attenuated and no longer statistically significant
Liver injury was associated with heart failure in fully adjusted models
*Adjusted for age, race-ethnicity, HIV, HCV, HBV, alcohol abuse/dependence, hypertension, diabetes, LDL, HDL, triglycerides, smoking, statin, renal disease, anemia, BMI, cocaine, aFib

14. Liver Injury & ASCVD Risk
Liver status N=97397
Fully adjusted* Hazard Ratio (95% confidence interval)
AMI
CHD
Isch. Stroke
Fibrosis (no cirrhosis)
Minimal
Ref
Moderate
1.0 ( )
1.03 ( )
Advanced
1.0 ( )
1.1 ( )
1.3 ( )
Cirrhosis
Yes
1.0 ( )
1.0 ( )
1.4 ( )
When we look separately at different types of ASCVD,
We found no association of liver njury with AMI or CHD but did find a significant association with the risk of ischemic stroke in fully adjusted models
*Adjusted for age, race-ethnicity, HIV, HCV, HBV alcohol abuse/dependence, hypertension, diabetes, LDL, HDL, triglycerides, smoking, statin, renal disease, anemia, BMI, cocaine, (aFib)

15. Analyses Excluding : HIV, HCV, HBV, Alcohol abuse, Obesity
Lastly, to get a better sense of whether the association between liver injury and CVD was independent of confounding, we performed a sensitivity analysis excluding people with HIV, hepatitis C, alcohol abuse/dependence diagnosis, or BMI>30
With this limited sample, we still saw trends where advanced fibrosis or cirrhosis was associated with ACVD, stroke and CHF

16. Limitations & Next Steps
Indirect measure of liver fibrosis
Non-adjudicated outcomes
Limited generalizability to women
Competing risk of non-CVD death
Important limitations include our assessment of liver injury only at baseline and the low number of women in the cohort, which may limit the generalizability of these findings.
The next step will be to account for competing risk of death

17. Summary Liver injury Atherosclerosis Fibrosis AMI, CHD Stroke
Cirrhosis
Atherosclerosis
Stroke
Heart failure
AMI, CHD
In summary, Stroke and heart failure risk increase with severity of liver injury
Despite competing risk of mortality

18. Acknowledgements VACS Mentors Funding support Participants Amy Justice
Janet Tate
Chuck Alcorn
Mentors
Matthew Freiberg
Jeffrey Samet
Joseph Lim
Joyce Chang
Funding support
NIAAA U01-AA U24-AA022001
NHLBI R01-HL R01-HL095136

19. Thank you

20. CVD & Mean Time to Event (MTTE)
Incident CVD
Liver fibrosis (no cirrhosis)
Cirrhosis
(N=1783)
Minimal
(N=57342)
Moderate
(N=16036)
Advanced
(N=2893)
ASCVD (#)
2786
1131
196
104
MTTE (SD)
4.6 (2.4)
4.4 (2.4)
4.3 (2.3)
4.2 (2.4)
CHF (#)
2248
1059
222
132
4.5 (2.3)
4.1 (2.3)
4.0 (2.4)

21. Baseline Characteristics
Liver fibrosis (no cirrhosis)
Cirrhosis
(N=1635)
Minimal
(N=57423)
Moderate
(N=16067)
Advanced
(N=2910)
Mean age (SD)
47 (9)
54 (9)
53 (8)
52 (7)
Female 4 2 1
Race
Black 47 53 55 36
White 40 35 33 49
HCV 13 60 68
HIV 29 50 64 44
VL≥500 copies/ml 14 27 38 17
CD4<500 /mm3 16 25
Heres what the cohort looked like
Mean age in the predominantly male cohort was 49.
Over half the participants were black
Increasing severity of liver injury was associated with greater prevalence of HCV and HIV, particularly poorly conrolled HIV
Missing FIB4 =19926

22. Baseline Characteristics
Liver fibrosis (no cirrhosis)
Cirrhosis
(N=1783)
Minimal
(N=57342)
Moderate
(N=16036)
Advanced
(N=2893)
BMI>30 kg/m2 34 22 14
Renal disease 4 7 8
Alcohol abuse 24 31 46 68
Cocaine 15 21 25
Statin 30
ART 39 51
This with cirrhosis or advanced fbrosis were less obese, had a greater prevalence of renal disease, alcohol abuse, cocaine in the past year.

23. Summary CVD rates increase with severity of liver injury
Despite competing risk of mortality
CVD risk increases with severity of liver injury
Largely driven by congestive heart failure (CHF)
Stroke risk is elevated with severe liver injury
Increased CVD, CHF, and stroke risk with liver injury may be independent of hepatic-comorbidities
HIV, HCV, alcohol abuse/dependence, obesity