Insight into the history of hepatitis C virus (HCV) infection; a cohort study of women infected postpartum with contaminated anti-D immunoglobulin in Ireland between 1977 and 1979 Patricia Garvey, EPIET fellow Health Protection Surveillance Centre, Ireland

HCV infection Acute and Chronic stages, with natural history still imperfectly understood Signs of liver disease (cirrhosis, hepatocellular carcinoma and liver-related death) take many decades to develop Cirrhosis rates -typically 5-20% after 20 years Risk groups in developed countries; IDU; people infected through unscreened blood products Antiviral treatment options have evolved (success measured as sustained virological response (SVR))

Anti-D 77-79 Cohort Group of women infected postpartum Via contaminated Anti-D immunoglobulin sourced from a single donora Infected between 1977-1979 After 17 years, 2% had developed cirrhosisb a) McGee et al. Department of Health and Children; 2000 b) Kenny-Walsh et al NEJM 1999

Objectives To describe the history of liver-related disease in the Anti-D 77-79 Cohort after c.36 years of infection To describe the outcomes of antiviral treatment To examine the effect of selected factors on disease progression To provide information for the planning of health services

Cohort study among Anti-D HCV infected women Longitudinal study (Retrospective-Prospective design) Database established by HPSC in 2004 Baseline data collected in 2005, and additional data at four time points since (to end 2013) Data extracted from medical records held at designated treatment centres Dataset includes: demographic characteristics; lifestyle factors; clinical signs of disease progression; treatment and outcomes Outcome measures: Cirrhosis, liver-related death

Data analyses Described characteristics of the cohort Reviewed cohort treatment history, and calculated % SVR Calculated cumulative incidence of adverse outcomes Examined the factors which affect development of cirrhosis using cox regression

Study population 863 women in cohort Database includes 82% (n=682) 55% chronically infected (n=374) Median age at infection 28 years (17-44)

Characteristics of 374 women with chronic HCV infection, Anti-D Cohort 77-79 % Genotype 1b 100 Proportion infected in 1977 96 HIV co-infection Hepatitis B co-infection 0.5 Diabetes mellitus 9.9 Obese/overweighta 70 Ever smoked 30 Ever high alcohol intake 5 a) Based on 229 observations only

Antiviral treatment courses and sustained virological response by year, Anti-D 77-79 Cohort IFN=interferon; Peg-IFN=pegyated interferon; RBN=ribavirin

Cumulative incidence selected disease outcomes, Anti-D Cohort 77-79 Year Cirrhosis Liver-related death 2003 25 (6.7%) 2 (0.5%) 2008 39 (10%) 9 (2.4%) 2013 72 (19%) 18 (4.8%) *Previously, 2% cirrhosis and no liver-related deaths reported in Anti-D 77-79 cohort 17 years after infection by Kenny-Walsh et al. NEJM 1999

Cumulative incidence cirrhosis by current status, Anti-D Cohort 77-79 Antiviral Treatment Group Cirrhosis Number % Untreated (n=222) 25 11 Treated SVR (n=55) 20 Non-SVR (n=76) 31 40 All* (n=374) 72 19 *includes 9 women for whom outcome of tx was not known at end of follow-up and 12 women who had late spontaneous resolution

Rate cirrhosis per 1000 person-years Risk Factors for CIRRHOSIS at 36 years (n=353), Irish Anti-D 77-79 HCV cohort Exposure Number cirrhosis Rate cirrhosis per 1000 person-years Adjusted HR (95% CI) Current status Non-SVR SVR Untreated 31 11 25 13 5.8 3.3 Ref 0.43 (0.21-0.89) 0.23 (0.13-0.40) Ever high alcohol intake No Yes 54 4.9 22 6.2 (3.2-12) Diabetes mellitus 47 20 4.4 19 4.5 (2.6-7.7) Age at infection (years) <35 ≥35 51 16 5.1 9.3 2.1 (1.2-3.9)

Effect of DURATION OF INFECTION BEFORE SVR on development of CIRRHOSIS at 36 years among TREATED PARTICIPANTS* (n=108) Group Number cirrhosis Rate cirrhosis per 1000 person-years Crude HR (95% CI) Non-SVR SVR more than 30 years after infection SVR within 30 years of infection 16 2 1 7.7 2.7 1.1 Ref 0.25 (0.057-1.1) 0.13 (0.017-0.98) * those who had cirrhosis before last treatment are excluded

Overall status Anti-D HCV Cohort 77-79, end 2013 Cohort participants alive at end of 2013: 86% (321/374) Prevalence of cirrhosis among those alive: 15% (47/321) Prevalence of current chronic infection among those alive: 77% (247/321)

Conclusions Slow rate of development of cirrhosis and liver-related death in this cohort in first 20 years post infection, but disease progression is accelerating (doubled in last 5 years) Triple therapies were more effective than older therapies in this cohort Successful antiviral treatment associated with a lower rates of cirrhosis among treated participants Higher age at infection, diabetes mellitus and excess alcohol consumption associated with higher rates of cirrhosis A high proportion of original cohort is still alive and remain chronically infected

Limitations No longer possible to study natural history as many participants have received treatment Study partly retrospective –no input into what data might have been available prior to setting up of database Some variables (e.g. BMI) low level of completeness (and possibly biased data)

Recommendations With the advent of new HCV antiviral therapies with higher success rates, timely intervention could benefit a high proportion of this cohort Participants with chronic HCV infection should be advised of the additive harmful effect of alcohol and to maintain a healthy BMI Improve completeness of variables

Acknowledgements Staff from Health Protection Surveillance Centre Dr Lelia Thornton Ms. Niamh Murphy Ms. Paula Flanagan Ms. Margaret McIver Chair of the Hepatitis C Database Steering Committee Ms. Michelle Tait EPIET Supervisor Dr. Kostas Danis Other members of the National Hepatitis C Database Scientific and Technical Group Prof Billy Bourke, Our Lady’s Children’s Hospital, Crumlin Prof Garry Courtney, St Luke’s Hospital, Kilkenny Dr Orla Crosbie, Cork University Hospital Prof John Crowe, Mater Misericordiae University Hospital Prof John Hegarty, St Vincent’s University Hospital Dr John Lee, University College Hospital, Galway Ms Carol McNulty, St Vincent’s University Hospital Prof Frank Murray, Beaumont Hospital Dr Niamh Nolan, St Vincent’s University Hospital Prof Suzanne Norris, St James’s Hospital Prof Cliona O’Farrelly, Trinity College Dublin Dr Stephen Stewart, Mater Misericordiae University Hospital

Risk Factors for CIRRHOSIS at 36 years post infection (n=353) Number cirrhosis /person years Rate cirrhosis per 1000 person-years (95% CI) Crude HR (95% CI) Adjusted HR (95% CI) Current status Non-SVR SVR Untreated 31/2447.3 11/1890.6 25/7477.1 13 (8.9-18) 5.8 (3.2-11) 3.3 (2.3-4.9) Ref 0.40 (0.20-0.80) 0.24 (0.14-0.41) 0.010 <0.001 0.43 (0.21-0.89) 0.23 (0.13-0.40) 0.022 Ever high alcohol intake No Yes 54/11054.3 11/505.4 4.9 (3.7-6.4) 22 (12-39) 6.1 (3.2-12) 6.2 (3.2-12) Diabetes mellitus 47/10747.7 20/1067.2 4.4 (3.3-5.8) 19 (12-29) 5.4 (3.2-9.1) 4.5 (2.6-7.7) Age at infection <35 yrs >=35 years 51/10089.6 16/1725.4 5.1 (3.8-6.7) 9.3 (5.7-15.1) 2.1 (1.2-3.6) 0.012 2.1 (1.2-3.9) 0.015 BMI category Normal or underweight Overweight or obese 7/2296.5 31/5181.3 3.0 (1.5-6.4) 6.0 (4.2-8.5) 2.0 (0.86-4.4) 0.111  Ever smoked 46/8101.2 18/3422.7 5.7 (4.3-7.6) 5.3 (3.3-8.3) 1.0 (0.56-1.7) 0.905 - Hep B co-infection 62/10533.2 0/133.9 5.9 (4.6-7.5) 0.0 (---) Not calculable