By Erika Duffell, presented at the International Liver Congress, 12 April 2019

1. Erika Duffell, European Centre for Disease Prevention and Control
International Liver Congress
Vienna, Austria, 12 April 2019
The attributable fraction of deaths due to viral hepatitis:
results from a sentinel surveillance pilot and lessons
learnt for future clinical-public health partnerships

2. Overview of presentation
1. Background to the project
2. Estimation of mortality due to viral hepatitis in EU/EEA countries
using existing estimates of the attributable fraction
3. Sentinel pilot to develop up-to-date estimates of the attributable
fraction

3. The WHO impact targets for hepatitis
Source: Global Health Sector Strategy on Viral Hepatitis 2016 – 2021 . Geneva: World Health Organization; 2016

4. Global mortality from viral hepatitis, HIV,
tuberculosis and malaria, 2000 – 2015
Source: Global Hepatitis Report 2017. Geneva: World Health Organization; 2017.

5. WHO Monitoring framework for viral hepatitis
Source: Monitoring and evaluation for viral hepatitis B and C: recommended indicators and framework.
Geneva: World Health Organization; 2016.
Hepatitis related mortality is
not straightforward to
measure:
• Previous estimates focused on
deaths from acute infections
but mortality mostly from
cirrhosis and hepatocellular
carcinoma (HCC)
• Viral hepatitis status usually
missing from death
certificates of patients with
cirrhosis and HCC

6. WHO reference method for estimating
mortality related to viral hepatitis
1. NATIONAL MORTALITY
STATISTICS
2. ATTRIBUTABLE FRACTION ESTIMATES*
Deaths from cirrhosis and HCC
HCC and cirrhosis deaths
from chronic HBV and HCV infections
Mortality
envelope
Source: Slide adapted from slide by Yvan Hutin, WHO.
* http://ghdx.healthdata.org/gbd-results-tool
HBV
29%
HCV
26%
Other
45%
Cirrhosis
HBV
40%
HCV
29%
Other
31%
HCC
GBD
estimates

7. WHO reference method for estimating
mortality related to viral hepatitis
1. NATIONAL MORTALITY
STATISTICS
2. ATTRIBUTABLE FRACTION ESTIMATES*
Deaths from cirrhosis and HCC
HCC and cirrhosis deaths
from chronic HBV and HCV infections
Mortality
envelope
Source: Slide adapted from slide by Yvan Hutin, WHO.
* http://ghdx.healthdata.org/gbd-results-tool
HBV
29%
HCV
26%
Other
45%
Cirrhosis
HBV
40%
HCV
29%
Other
31%
HCC
GBD
estimates

8. Defining the mortality envelope: ICD10 codes
for liver disease related to viral hepatitisB18 Chronic viral hepatitis
B18.0 Chronic viral hepatitis B with delta-agent
B18.1 Chronic viral hepatitis B without delta-agent CVH
B18.2 Chronic viral hepatitis C
B18.8 Other chronic viral hepatitis
B18.9 Chronic viral hepatitis, unspecified
C22 Malignant neoplasm of liver and intrahepatic bile ducts
C22.0 Liver cell carcinoma WHO HCC
C22.1 Intrahepatic bile duct carcinoma
C22.2 Hepatoblastoma
C22.3 Angiosarcoma of liver
C22.4 Other sarcomas of liver
C22.7 Other specified carcinomas of liver
C22.8 Malignant neoplasm of liver, primary, unspecified as to type
C22.9 Malignant neoplasm of liver, not specified as primary or secondary
K70-K77 Diseases of liver
K70 Alcoholic liver disease
K71 Toxic liver disease
K72 Hepatic failure, not elsewhere classified WHO CLD
K72.0 Acute and subacute hepatic failure
K72.1 Chronic hepatic failure
K72.9 Hepatic failure, unspecified
K73 Chronic hepatitis, not elsewhere classified
K73.0 Chronic persistent hepatitis, not elsewhere classified
K73.1 Chronic lobular hepatitis, not elsewhere classified
K73.2 Chronic active hepatitis, not elsewhere classified
K73.8 Other chronic hepatitis, not elsewhere classified
K73.9 Chronic hepatitis, unspecified
K74 Fibrosis and cirrhosis of liver
K74.0 Hepatic fibrosis
K74.1 Hepatic sclerosis
K74.2 Hepatic fibrosis with hepatic sclerosis
K74.3 Primary biliary cirrhosis WHO Cirrhosis
K74.4 Secondary biliary cirrhosis
K74.5 Biliary cirrhosis, unspecified
K74.6 Other and unspecified cirrhosis of liver
K75 Other inflammatory liver diseases
K75.0 Abscess of liver
K75.1 Phlebitis of portal vein
K75.2 Nonspecific reactive hepatitis
K75.3 Granulomatous hepatitis, not elsewhere classified
K75.4 Autoimmune hepatitis
K75.8 Other specified inflammatory liver diseases
K75.9 Inflammatory liver disease, unspecified
K76 Other diseases of liver
ICD codes
proposed by WHO
ICD codes
used by ECDC

9. WHO reference method for estimating
mortality related to viral hepatitis
1. NATIONAL MORTALITY
STATISTICS
2. ATTRIBUTABLE FRACTION ESTIMATES*
Deaths from cirrhosis and HCC
HCC and cirrhosis deaths
from chronic HBV and HCV infections
Mortality
envelope
Source: Slide adapted from slide by Yvan Hutin, WHO.
* http://ghdx.healthdata.org/gbd-results-tool
HBV
29%
HCV
26%
Other
45%
Cirrhosis
HBV
40%
HCV
29%
Other
31%
HCC
GBD
estimates

10. Estimating the attributable fraction (AF)
AF = Proportion exposed (Pe) x (Risk ratio – 1)
(Risk ratio)
When the risk ratio is high AF ≈ Pe
Attributable mortality = AF x number deaths
Source: Perz JF et al, Journal of Hepatology 2006 and Mokdad AA et al, BMC Medicine 2014

11. Applying attributable fraction estimates to
estimate the mortality due to viral hepatitis
in EU/EEA countries
Source: Mardh O et al, (Paper in preparation).
*Global Burden of Disease Collaborative Network. Global Burden of Disease Study 2016 (GBD 2016) Results. Available from http://ghdx.healthdata.org/gbd-results-tool
** Global Burden of Disease Liver Cancer Collaboration. The burden of primary liver cancer and underlying aetiologies from 1990 to 2015 at the global, regional, and
national level: results from the Global Burden of Disease Study 2015. 2017. JAMA Oncology.
Chronic liver disease Liver cancer CVH
Total mortality
attributable to
hep B/C
(ICD-10 K72-K75) (ICD-10 C22)
(ICD-10 B180-
B182)
Deaths AF GBD*
Mortality
attributable to
hep B/C (deaths x
AF GBD*)
Deaths AF GBD**
Mortality
attributable to
hep B/C (deaths x
AF GBD**)
Deaths
(a) (b) (c) (a+b+c)
Austria 826 0.87 722 929 0.45 418 262 1402
Belgium 770 0.81 622 948 0.44 417 34 1073
Bulgaria 1748 0.71 1244 677 0.48 325 8 1577
Croatia 464 0.68 315 495 0.36 178 60 553
Cyprus 36 0.87 31 51 0.58 30 4 65
Czech Republic 643 0.61 395 818 0.39 319 26 740

12. Deaths from HIV, tuberculosis and viral
hepatitis* in EU/EEA countries, 2015
0
10000
20000
30000
40000
50000
60000
70000
80000
HIV Tuberculosis Viral hepatitis
Numberofdeaths
Source: Eurostat and Mardh O et al, (paper in preparation).
2 320 4 441
68 062
*Deaths from chronic liver disease (K72 - K75) + primary liver cancer (C22) attributable to HBV and HCV and deaths from chronic viral hepatitis (B18.0 - B18.2)

13. The need for better estimates of the
attributable fraction in Europe
• Few recent attributable fraction estimates from EU/EEA countries
• Estimates from GBD imputed for many countries which may not be
appropriate in Europe
• Evidence of changes in attributable fraction estimates over time
Older HCV
outbreak in
Italy
More recent
HCV outbreak
in Germany
Source: De Martel et al. Hepatology, 2015
HCC attributable to HBV and HCV in selected countries, before and after 2000

14. Sentinel study* to measure AF
Aim:
• To obtain a local estimate of the attributable fraction of cirrhosis
and HCC patients caused by HBV and HCV
Key objectives:
• To recruit a sample of patients with cirrhosis and HCC
• To assess the HBV and HCV status of these patients, as well as
the status of other non-viral causes including alcohol and NASH
*WHO protocol available at https://apps.who.int/iris/bitstream/handle/10665/280097/WHO-CDS-HIV-19.4-eng.pdf

15. Key elements of the study protocol*
1. Population under surveillance:
Patients with cirrhosis or hepatocellular carcinoma in clinical centres
2. Investigators:
Clinicians functioning as investigators
3. Case definitions:
Clinical criteria/ICD-10 codes
4. Data collection:
• Retrospective review of patients’ records
• Data collected on outcome and exposures
Source: Source: Slide adapted from slide by Yvan Hutin, WHO.
*Protocol available at https://apps.who.int/iris/bitstream/handle/10665/280097/WHO-CDS-HIV-19.4-eng.pdf

16. European pilot of the study protocol
1. Collaboration between ECDC, EASL and WHO
2. Methodological approaches
• Bulgaria: All patients (602 total) with cirrhosis and HCC
presenting to national reference centre in Sofia 2016-7
Portugal: 1st 100 sequential patients with cirrhosis and 1st 100
with HCC presenting to national reference centre in
Lisbon 2015-6
• Patients diagnosed with both cirrhosis and HCC classified as ‘HCC’
• HCV-RNA used to define the prevailing infection in patients
co-infected with HBV and HCV

17. European pilot: results
Cirrhosis HCC
Lisbon Sofia Lisbon Sofia
HBV 6% 18% 9% 37%
HCV 25% 16% 37% 25%
Alcohol 56% 46% 46% 8%
NAFLD 6% 4% 3% 8%
None identified 7% 16% 5% 21%
Proportion of clinical cases of cirrhosis and HCC in each pilot site with risk factors

18. European pilot: results
*Global Burden of Disease Liver Cancer Collaboration, JAMA Oncol 2017
**GBD Results Tool cause-specific mortality estimates for deaths. Available from:
http://ghdx.healthdata.org/gbd-results-tool
Cirrhosis HCC
Lisbon Sofia Lisbon Sofia
HBV
6%
8%**
18%
23%**
9%
18%*
37%
18%*
HCV
25%
18%**
16%
20%**
37%
36%*
25%
30%*
Proportion of clinical cases of cirrhosis and HCC in each pilot site with risk factors

19. Outcomes from the pilot
1. Possibility to improve local mortality estimates using simple and
transparent method
2. Lessons learnt for extension of the project to other countries
3. Partnership created between clinical teams and public health

20. Limitations of the methodology
• Assigning morbidity findings to mortality data
• Representativeness of selected ‘sentinel’ sites
• Simplification of issue around overlapping risks
• Assumptions regarding cases with cirrhosis/HCC and HBV/HCV
• Fitting the AF estimate to the “mortality envelope”

21. Future perspectives
1. Pilot in Norway exploring differences across case-mix
2. Validation of results against cross-linked mortality data
3. Refinement of methodology following pilot studies
• Simplification of data collection process
• Selection of sentinel sites
• Sampling of cases
4. Building on success of sentinel sites to develop system for collection
enhanced surveillance and continuum of care data

22. Conclusions
• Accurate measurement of hepatitis related mortality is needed to
determine progress towards elimination targets
• Up-to-date empirical data on the attributable fraction of end stage
liver disease due to hepatitis important
• Pilot study in sentinel sites demonstrated feasibility of methodology
to obtain empirical data
• Clinical-public health partnerships important in improving quality
and availability of viral hepatitis data

23. Acknowledgements
Bulgaria: Tanja Hadzhiolova, Krum Katzarov, Slava Pavlova, Marietta
Simonova
Portugal: Helena Cortez Pinto, Carolina Simões
European Centre for Disease Prevention and Control: Andrew
Amato-Gauci, Otilia Mardh, Lina Nerlander, Anastasia Pharris, Chantal
Quinten
EASL: Fiona Godfrey, Francesco Negro
WHO: Yvan Hutin, Antons Mozalevskis