1. What is the contribution of alcohol to liver disease in the hepatitis C infected population. The epidemiological evidence Hamish Innes Research Fellow Blood Borne Virus Epidemiology Group

2. Excess liver mortality in individuals diagnosed with HCV antibodies CountryExcess liver mortality relative to general population Scotland25 times greater Sweden36 times greater Australia16 times greater U.S27 times greater Canada25 times greater Is this excess mortality a consequence of hepatitis C alone? FOREWORD

3. Heavy alcohol consumption in infected individuals is common CountryData SourceSelf-reported consumption Scotland Survey of People Who Inject Drugs 22% of HCV infected PWIDs have current consumption >50 units/wk (versus 4-9% in general population) Individuals attending HCV specialist care 33% have ever sustained >50 units/wk for ≥ 6 months U.S Survey of general population HCV+ve 4 times more likely to report 3+ drinks a day than HCV-ve Individuals attending HCV specialist care 31% of individuals ever been in alcohol abuse treatment; 41% ever drank ≥5 drinks a day (~>60-70 units/wk)

4. Heavy alcohol consumption is associated with liver disease progression Many studies show that heavy alcohol use is associated with disease progression and liver mortality What does “association” mean? ONE CASE STUDY OF OUR OWN* We examined 1620 individuals new attendees at specialist liver clinics in Scotland for presence of liver cirrhosis. We examined the frequency of liver cirrhosis according to whether the patient had a history of heavy alcohol use Heavy alcohol use defined as drinking >50 units/wk for at least six months (equivalent to ~5 bottles of wine a week) * See: Innes et al, Hepatology 2013

5. HCV+ ALCOHOL- HCV+ ALCOHOL+ Cirrhosis No cirrhosis Odds of liver cirrhosis at index appt are >3 times higher in those with history of heavy alcohol versus those without. Based on the size of this association and the prevalence of this exposure- we calculated that 36% of all liver cirrhosis cases are attributable to heavy alcohol use ODDS= 5:1ODDS= 17:1 Heavy alcohol consumption is associated with liver disease progression (cont.)

6. Number of cases Alcohol considered by clinical team to be a contributing factor in ~40% of cases Alcohol NOT involved New cases of liver failure in persons with hepatitis C antibodies, according to alcohol involvement Alcohol involved

7. Using spontaneous resolvers as a benchmark group Exposure to the HCV virus Develop chronic infection Spontaneously resolve (in 2-3 months) 25% 75% Alcohol consumption is hard to measure. Preferable to not rely completely on self-reported intake. The natural history of infection affords us an alternative! Premise = Similar alcohol consumption/ lifestyle profile between these two groups

8. Using spontaneous resolvers as a benchmark group (cont.) – a hypothetical example 2.5 5 7.5 10 Mortality rate 25% not attributable to CHC (would have occurred anyway) 75% attributable to CHC (would not have occurred without CHC) Chronic Infection Spontaneous resolver

9. Fraction of liver death attributable to HCV, in Scotland and Denmark 0 20 40 60 80 100 DENMARKSCOTLAND Fraction of death attributable to Chronic infection (%) Completely attributable to infection Not attributable to infection at all 68% 55% Innes et al, 2015; Under review with GUT

10. Post-SVR liver mortality? Generally there is limited information on liver disease occurring after SVR But some early data from Scotland * – Among 560 patients treated in 1996-2007 who attained SVR, the subsequent rate of liver-related hospitalisation remained 10 times higher than the general population – Specifically among SVR patients without cirrhosis who are routinely discharged from care, the subsequent rate of liver-related hospitalisation was 6 times greater than the general population – Could alcohol be the cause of this continued increase? More data is required- routine surveillance of this outcome is justified. * See: Innes et al, Hepatology 2011

11. Strands of evidence STRAND #Brief Summary 1 Heavy alcohol use is common in individuals with infection (more so that in the general population) 2 Heavy alcohol use is associated with liver cirrhosis in hepatitis C patients. We estimate that 36% of cirrhosis cases present at first liver clinic appt wouldn’t have occurred in the absence of alcohol. 3 In 40% of hep C + Liver failure cases, alcohol is listed as a primary or contributing cause 4 Using spontaneous resolvers as a benchmark group suggests 45% of liver death in chronic patients, would have occurred any way regardless of chronic infection. 5 After attaining SVR, there is a some evidence that liver related morbidity remains higher than the general population

12. AFTERWORD The epidemiological evidence presented has not been translated into public health action. Just one handful of studies exploring the impact of alcohol intervention in patients with hepatitis C High rates of liver disease in the hepatitis C population is a compound problem; it demands a compound solution + REVERSAL OF MORTALITY EXCESSANTIVIRAL THERAPY A PLAN THAT ADDRESSES ALCOHOL

13. Acknowledgements Prof. Sharon Hutchinson and Prof. David Goldberg Colleagues from HPS and GCU (in particular, Alison Potts) Members of the Clinical Database Monitoring committee and data entry staff