VACS Scientific Meeting October 15, 2008 Joseph K. Lim, M.D.

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Presentation transcript:

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

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.

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

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.

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.

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.

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.

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.

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.

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.

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-

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.

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 (104-156) 3-10x Normal (156-520) >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.

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 (102-340) >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.

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.

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 1.12-1.73 0.19-1.15 0.59-0.93 0.86-1.53 2.09-3.48 1.74-2.77 1.23-2.61 2.99-4.67 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.

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

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

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

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

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