1. 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

2. 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))

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

4. Objectives
To describe the history of liver-related disease in the Anti-D 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

5. 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

6. 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

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

8. 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

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

10. 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 cohort 17 years after infection by Kenny-Walsh et al. NEJM 1999

11. 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

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

13. 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 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 ( )
0.13 ( )
* those who had cirrhosis before last treatment are excluded

14. 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)

15. 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

16. 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)

17. 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

18. 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

19. Risk Factors for CIRRHOSIS at 36 years post infection (n=353)
Number cirrhosis /person years
Rate cirrhosis per 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 ( )
Ref
0.40 ( )
0.24 ( )
0.010
<0.001
0.43 ( )
0.23 ( )
0.022
Ever high alcohol intake No
Yes
54/
11/505.4
4.9 ( )
22 (12-39)
6.1 (3.2-12)
6.2 (3.2-12)
Diabetes mellitus
47/
20/1067.2
4.4 ( )
19 (12-29)
5.4 ( )
4.5 ( )
Age at infection
<35 yrs
>=35 years
51/
16/1725.4
5.1 ( )
9.3 ( )
2.1 ( )
0.012
2.1 ( )
0.015
BMI category
Normal or underweight
Overweight or obese
7/2296.5
31/5181.3
3.0 ( )
6.0 ( )
2.0 ( )
0.111 
Ever smoked
46/8101.2
18/3422.7
5.7 ( )
5.3 ( )
1.0 ( )
0.905 -
Hep B co-infection
62/
0/133.9
5.9 ( )
0.0 (---)
Not calculable