1. Impact of Alcohol Abuse and Dependence on Liver Fibrosis in HIV+/HIV- Veterans
VACS Scientific Meeting
October 15, 2008
Joseph K. Lim, M.D.
Assistant Professor of Medicine
Director, Yale Viral Hepatitis Program
Yale University School of Medicine

2. Background
Hepatocellular injury is common among individuals with HIV infection
This is frequently attributable to:
Chronic hepatitis B and/or C
Anti-retroviral therapy
Additive role of alcohol consumption is well-described
Quantitative impact of varying levels of alcohol consumption poorly defined
Decompensated cirrhosis represents the main clinical outcome of chronic liver disease (mainly due to hepatitis B and/or C as well as alcohol abuse).
It is clinical characterized by the presence of ascites, jaundice, variceal bleeding, hepatocellular carcinoma, and/or encephalopathy
In addition, according to the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) Study, decompensated cirrhosis due to hepatitis B and C is now the second leading cause of death in HIV-infected patients.

3. Progression of Liver Disease
No fibrosis
No fibrosis
ALCOHOL
To address these limitations and because of the importance of this outcome, this study aimed to: 1) establish a case definition of decompensated cirrhosis in the VACS, and 2) outline the process for ascertainment and classification of decompensated cirrhosis events among subjects in the VACS.
Cirrhosis
Cirrhosis

4. Hypothesis
Hazardous alcohol use and binge drinking is associated with greater liver injury, including inflammation and liver fibrosis, than abstinence or non-hazardous alcohol use
Hazardous alcohol use and binge drinking is associated with greater increases in liver injury among individuals with chronic liver disease (e.g. chronic HCV) and HIV infection
To address these limitations and because of the importance of this outcome, this study aimed to: 1) establish a case definition of decompensated cirrhosis in the VACS, and 2) outline the process for ascertainment and classification of decompensated cirrhosis events among subjects in the VACS.

5. Study Design Data derived from VACS-8 Observational cohort study
Setting:
Follows large number of HIV-infected and HIV-uninfected patients
8 sites: Atlanta, Baltimore, Bronx, Houston, Los Angeles, Manhattan, Pittsburgh, Washington, DC
Cohort populated with large number of patients with chronic liver disease
We conducted a retrospective observational cohort study among subjects in VACS-8. This was an ideal setting in which to conduct this study because: 1) the VACS follows large numbers of patients with chronic liver diseases, ensuring adequate sample sizes for epidemiologic studies, 2) data relevant to the diagnosis of decompensated cirrhosis can be collected from subjects (especially, availability of electronic medial records), and 3) follow-up within the VACS has been sufficiently long to allow for the development of outcomes.

6. Study Subjects Baseline enrollment June 2002-September 2004
Subjects enrolled from infectious disease or general medical clinics in age, race, and site-matched fashion
Additional HIV-infected subjects and age/race/gender/site-matched comparators enrolled since September 2004 to replace those whoo died or were lost to follow-up to avoid survival cohort effect
Standardized instruments used to obtain information on demographics, health status, substance use, AIDS-defining illness, administrative data, and telephone interviews
For this study, all VACS-8 patients were eligible.
Subjects were identified based on ICD-9 codes for decompensated cirrhosis. ICD-9 codes were recorded up to 1 yr before through 6 mo after VACS enrollment. All subjects with at least one ICD-9 code for decompensated cirrhosis were included in the study sample.

7. Assessment of Liver Injury
Liver injury was assessed along two domains:
Liver inflammation (AST, ALT, GGT)
Liver fibrosis (APRI, FIB-4)
APRI =
FIB-4 =
will be defined by Table 7. Diagnoses recorded in the medical record considered consistent
with end-stage liver disease.
Ascites
End-stage liver disease
Esophageal/gastric variceal bleeding
Hepatic encephalopathy
Hepatorenal syndrome
Liver failure
Hepatocellular carcinoma
Death (with 1 of the above conditions)
The primary outcome – hepatic decompensation – was defined by the presence of at least one of the following clinical diagnoses documented in the electronic medical record: ascites, esophageal and/or gastric variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, and/or hepatocellular carcinoma. These conditions are part of the standard definition of decompensated cirrhosis used in clinical practice.

8. Assessment of Liver Injury
Definitions of advanced fibrosis or cirrhosis (F3-F4):
APRI > 1.5
FIB-4 > 3.25
Definitions of no significant fibrosis (F0-F1):
APRI < 0.5
FIB-4 < 1.45
will be defined by Table 7. Diagnoses recorded in the medical record considered consistent
with end-stage liver disease.
Ascites
End-stage liver disease
Esophageal/gastric variceal bleeding
Hepatic encephalopathy
Hepatorenal syndrome
Liver failure
Hepatocellular carcinoma
Death (with 1 of the above conditions)
The primary outcome – hepatic decompensation – was defined by the presence of at least one of the following clinical diagnoses documented in the electronic medical record: ascites, esophageal and/or gastric variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, and/or hepatocellular carcinoma. These conditions are part of the standard definition of decompensated cirrhosis used in clinical practice.

9. Assessment of Alcohol Use
Prospective characterization and quantification of alcohol consumption through:
AUDIT-C
CIDI
30-day Time Line Follow-Back
Abstinence, non-hazardous, hazardous, and binge drinking patterns defined by above instruments
Alcohol abuse and dependence defined by survey criteria or administrative ICD-9 diagnosis
will be defined by Table 7. Diagnoses recorded in the medical record considered consistent
with end-stage liver disease.
Ascites
End-stage liver disease
Esophageal/gastric variceal bleeding
Hepatic encephalopathy
Hepatorenal syndrome
Liver failure
Hepatocellular carcinoma
Death (with 1 of the above conditions)
The primary outcome – hepatic decompensation – was defined by the presence of at least one of the following clinical diagnoses documented in the electronic medical record: ascites, esophageal and/or gastric variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, and/or hepatocellular carcinoma. These conditions are part of the standard definition of decompensated cirrhosis used in clinical practice.

10. Other Co-Variates Demographics (age, gendar, race, body mass)
Medical conditions (HIV, HCV, HBV, other chronic liver diseases)
Medications (HAART, hepatotoxic drugs)
will be defined by Table 7. Diagnoses recorded in the medical record considered consistent
with end-stage liver disease.
Ascites
End-stage liver disease
Esophageal/gastric variceal bleeding
Hepatic encephalopathy
Hepatorenal syndrome
Liver failure
Hepatocellular carcinoma
Death (with 1 of the above conditions)
The primary outcome – hepatic decompensation – was defined by the presence of at least one of the following clinical diagnoses documented in the electronic medical record: ascites, esophageal and/or gastric variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, and/or hepatocellular carcinoma. These conditions are part of the standard definition of decompensated cirrhosis used in clinical practice.

11. Results 6,090 VACS Subjects 4726 Subjects (77%) had complete data
-1 yr through +6 mo
after VACS enrollment
Subjects selection is noted on the slide.
2713 HIV+
1965 HIV-

12. Patient Demographics Characteristic All Subjects (n=4678) HIV+
Median Age (years) 50 49
Male sex (%)
95.2
97.5
91.9
African-American (%)
White (%)
Hispanic (%)
66.0
23.5
5.4
68.0
21.9
5.2
63.3
25.7
5.6
Hepatitis C
Hepatitis B
Other liver disease
Diabetes mellitus
Obesity (BMI ≥ 30)
CD4 count
Statin use
HCV antiviral therapy
HIV anti-retroviral therapy
25.6
4.1
1.5
18.3
23.0
n/a
13.9
2.4
31.1
5.8
1.6
13.1
12.3
362
11.0
2.7
73.6
17.9
1.8
1.4
25.3
37.9
18.0
2.1
Subjects characteristics are reported on this slide. The majority of subjects were coinfected with HIV and chronic hepatitis C.

13. Alcohol Consumption and Liver Injury
Clinical Variable
All Subjects
(n=4678)
HIV+
(n=1965)
HIV-
(n=2713)
Alcohol Consumption
None
Non-hazardous
Hazardous
Binge Drinking
Abuse or dependence
2.4%
51.2%
13.3%
10.7%
21.1%
2.5%
53.6%
13.4%
10.9%
18.1%
2.3%
47.9%
13.1%
10.5%
25.2%
Serum ALT
Normal (<52)
1-2x Normal (52-104)
2-3x Normal ( )
3-10x Normal ( )
>10x Normal (520+)
80.33%
15.2%
3.2%
1.2%
0.1%
77.5%
16.6%
4.3%
1.5%
84.2%
13.2%
1.7%
0.8%
Subjects characteristics are reported on this slide. The majority of subjects were coinfected with HIV and chronic hepatitis C.

14. Alcohol Consumption and Liver Injury
Clinical Variable
All Subjects
(n=4678)
HIV+
(n=1965)
HIV-
(n=2713)
Serum AST
Normal (<34)
1-2x Normal (34-68)
2-3x Normal (68-102)
3-10x Normal ( )
>10x Normal (340+)
64.3%
25.5%
5.7%
4.3%
0.3%
55.6%
31.0%
7.3%
5.9%
76.3%
18.0%
3.5%
2.0%
0.2%
Liver Fibrosis
APRI > 1.5
FIB-4 > 3.25
9.0%
8.9%
12.1%
4.7%
4.5%
Subjects characteristics are reported on this slide. The majority of subjects were coinfected with HIV and chronic hepatitis C.

15. Advanced Fibrosis or Cirrhosis By Alcohol Consumption
Clinical Variable
HIV+
(n=1965)
HIV-
(n=2713)
p-value
APRI > 1.5
No alcohol use
Non-hazardous
Hazardous
Binge Drinking
Abuse or dependence
2.5%
8.4%
12.6%
14.2%
22.4%
0.0%
1.8%
2.7%
7.2%
10.7%
<0.001
FIB-4 > 3.25
1.0%
8.6%
11.0%
13.9%
22.0%
2.1%
3.9%
Subjects characteristics are reported on this slide. The majority of subjects were coinfected with HIV and chronic hepatitis C.

16. Predictors of Advanced Fibrosis or Cirrhosis
Clinical Variable
Odds Ratio (OR)
95% CI
p-value
Age > 50 years
Female
Black
Diabetes mellitus
Obesity (BMI > 30)
Alcohol abuse
Hepatitis B
Hepatitis C
HIV
1.40
0.46
0.74
1.15
0.62
2.19
1.79
3.74
2.69
0.009
0.098
0.007
0.353
0.006
<0.001
0.005
Subjects characteristics are reported on this slide. The majority of subjects were coinfected with HIV and chronic hepatitis C.

17. Impact of Alcohol Dependence on Liver Fibrosis* *
The most common ICD-9 codes were for end-stage liver disease, ascites, variceal bleed, and encephalopathy. *
* p<0.001

18. Conclusions
Alcohol use is common among individuals with advanced fibrosis or cirrhosis
97.6% reported any alcohol use
38.7% had alcohol use or dependence
Alcohol use contributed to approximately 50% higher proportion of advanced fibrosis in HIV+ and HIV- individuals with or without HCV
HIV alone (5.6% vs. 8.6%)
HCV alone (9.0% vs. 13.8%)
HCV/HIV (20.8% vs. 31.8%
Step-wise increases in proportion of advanced fibrosis or cirrhosis was observed with incremental increases in alcohol consumption (none, non-hazardous, hazardous, binge drinking, abuse or dependence)
Multivariate regression analyses demonstrated that after controlling for HCV and HIV infection, alcohol represented the strongest predictor for advanced fibrosis or cirrhosis (OR 2.19)
Conclusions

19. Limitations
Cohort bias selecting U.S. veterans from 8 sites within the national VA system
Advanced fibrosis or cirrhosis defined by non-invasive serum fibrosis markers
Cross-sectional design fails to address temporal relationships of cumulative alcohol consumption on liver injury
Could not control for potential impact of drug therapy for HCV or HIV on liver injury

20. Final Thoughts
Future studies will focus on longitudinal analyses of prospective cohort to characterize the quantitative impact of non-hazardous alcohol consumption on liver fibrosis progression
Data provides rationale and informs future interventional studies on alcohol modification strategies

21. Acknowledgements VACS Liver Group: Amy Justice Joseph Goulet
Shawn Fultz
Kendall Bryant
David Fiellin
Joseph Conigliaro
Adam Gordon
Cynthia Gibert
Yale/VA HCRC:
Guadalupe Garcia-Tsao
Carol Eggers
NIH/NIAAA R21