Synoposis

SYNOPSIS

Review of Update on the management of chronic hepatitis C: 2018 consensus guidelines from the Canadian Association for the Study of the Liver

Requestor: Public Health Unit request Request prepared by: Michelle Murti, Jennifer Pritchard Date: 07/09/2018 Contact information: michelle.murti@oahpp.ca

Article citation: Shah H, Bilodeau M, Burak KW, Cooper C, Klein M, Ramji A, et al. The management of

chronic hepatitis C: 2018 guideline update from the Canadian Association for the Study of the Liver.

CMAJ. 2018;190(22):E677-E687. Available at: http://www.cmaj.ca/content/190/22/E677

Key Messages of Synopsis o Hepatitis C virus (HCV) has a high prevalence with national estimates of approximately 1% of

the overall Canadian population being anti-HCV-positive, between 0.64% to 0.71% living with

chronic HCV infection, and approximately 44% of those living with chronic HCV infection

remaining undiagnosed.1

o Risk-factor based screening is universally recommended to identify undiagnosed infection in

those at elevated risk of HCV. Recent Canadian guidelines have disagreed in terms of whether

birth cohort population-based screening for Baby Boomers should be added to risk-factor

screening.

o The recent 2018 guideline from the Canadian Association for the Study of the Liver (CASL) by

Shah et al, has recommended population-based screening for Baby-Boomers in addition to

risk-factor based screening to address the burden of illness and under-diagnosis in this age

cohort.2

o This synopsis is a summary and critical appraisal of the strengths and limitations of the Baby-

Boomer screening recommendation by Shah et al.

Synopsis: HCV screening recommendations 2

Background on HCV Screening

There are approximately 3,500 newly reported cases of HCV annually in Ontario, and in a 2010

burden of illness report, it was the highest burden reportable infectious agent in Ontario based on

potential years of life lost.3 National estimates by the Public Health Agency of Canada (PHAC), using a

back-calculation methodology, estimated that 0.64% to 0.71% % of the Canadian population has

chronic HCV, and this was highest among those born between 1955-1959 (1.5%), followed by those

born in 1950-1954 (1.25%).1 The same model estimated that 44% of those with chronic HCV were

unaware of their infection.1 Early identification of HCV exposure and current infectious status

through testing for HCV RNA are necessary steps to ensure timely engagement in care and treatment

in order to prevent long-term complications (such as cirrhosis, liver cancer and death) and to reduce

the risk of transmission to others. In recent years, treatment options, such as direct acting antivirals

(DAAs), have become highly effective as well as safer and more tolerable, affordable and accessible.2

In 2018, the Canadian Association for the Study of the Liver (CASL) published guidelines on the

management of chronic hepatitis C which recommended population-based screening for those born

between 1945-1975 in addition to risk-factor based screening.2 Public Health Ontario’s (PHOs)

objective was to conduct a critical appraisal of the population-based screening recommendation

included in the guideline, including both the published manuscript and the online Appendix. It should

be noted the CASL guideline also addressed treatment recommendations which are not covered in

this synopsis.

In addition to the CASL guideline, there have been a number of other recent relevant guidelines from

Canadian jurisdictions regarding HCV screening, including the following:

o Nationally, the Public Health Agency of Canada recommends screening individuals for hepatitis C

using a risk-based approach.4

o This recommendation is based on the 2017 Canadian Task Force on Preventive Health

Care recommendation against screening for hepatitis C in asymptomatic Canadian adults

unless they are at risk for hepatitis C infection (strong recommendation, very low quality

evidence).5

o The 2016 Canadian Liver Foundation’s Hepatitis C Screening and Testing Quick Reference Guide

included a recommendation for birth cohort screening of all adults born between 1945-1975.6

This Guide is an infographic listed in the Clinical Practice Guidelines section of the Canadian Liver

Foundation’s website. It does not describe the basis of this recommendation or have a reference

to a guideline on which this recommendation is based.

o A 2017 guideline from Quebec did not find the data to be sufficiently compelling to justify a

systematic screening program for those born between 1950 to 1969, but recommended

considering offering one-time opportunistic screening of those born between 1950 and 1969

regardless of other risk factors.7

Synopsis: HCV screening recommendations 3

Summary of 2018 CASL Guideline The CASL recommendation under ‘screening and linkage to care’ was:

To increase the identification of the large proportion of persons living with undiagnosed HCV, we

recommend that screening be both risk-based and target the birth cohort of individuals born from

1945 to 1975, which currently encompasses the majority of persons chronically infected with HCV

in Canada. (Class 2a – weight of evidence or opinion is in favour of usefulness or efficacy, Level C –

only consensus opinions of experts, case studies, or standard of care).

The online Appendix version of the recommendation is similar except that the birth cohort years

included are from 1945 to 1970.

The authors listed four reasons for supporting birth cohort screening:

1. HCV prevalence is highest in the Baby Boomer birth cohort and that the burden of liver

disease is expected to increase in this population. Supporting evidence for this statement

included an Ontario laboratory serosurvey study and a national modeling estimate study.

o The Ontario study was a serosurvey of laboratory samples of individuals born between 1945

and 1974 where seroprevalence rates, based on anti-HCV antibodies, were highest in those

born between 1950-54 and 1960-64 (1.98% each), followed by those born in 1955-1959

(1.80%), 1965-1969 (1.38%), 1970-74 (1.14%) and 1945-1950 (1.02%).8

o The PHAC modeling study estimated chronic HCV prevalence in Canada between 1991 and

2011. Based on estimates for 2011, they found that those born between 1955 and 1959 had

the highest prevalence of chronic HCV (1.5%), followed by those born in 1950-54 (1.25%),

1960-64 (1.2%), 1965-69 (1.1%) and 1970-74 (0.8%).1

2. Approximately 44-70% of HCV-infected Canadians are unaware of their infection. Supporting

evidence for this statement includes two studies.

o The upper estimate (70%) is based on an analysis from the 2007-2009 and 2009-2011

Canadian Health Measures Survey comparing seroprevalence of anti-HCV antibody to

participant’s (14-79 years old) awareness of their infection status, and found that 69.5%

(95%CI: 49.3% to 84.3%) were unaware of their infection.9

o The lower estimate (44%) is a based on the PHAC modeling estimate described above.1

o The CASL recommendation also noted that risk-based strategies perpetuate stigma

associated with HCV, whereas population-based screening normalizes the process.

Synopsis: HCV screening recommendations 4

3. New lowered pricing for HCV treatment makes screen-and-treat strategies even more cost-

effective than previously estimated.

o Previous cost-effectiveness estimates include a 2015 Canadian study that concluded “in

Canada, a 1-time program to screen for and treat HCV infection, aimed at birth cohort

populations (25-64 years or 45-64 years of age) is likely to be cost-effective.”10 The ages for

one-time screening in this cost-effectiveness analysis translate into birth cohorts of 1951-

1990 or 1951-1971.

4. Canada will not meet World Health Organization 2030 HCV elimination targets without birth

cohort screening.

The authors also listed five rebuttals to the 2017 CTFPHC Guideline that recommended against Baby

Boomer screening, indicating that in the CTFPHC Guideline document:

I. There was an overemphasis on harms of screening

II. Benefits of screening were under-valued

III. Costs of therapy used were inaccurate and misleading, and included mention of

outdated treatment regimens

IV. Costs of no therapy for patients with HCV were not included

V. Concerns about the diagnostic accuracy of HCV testing are inaccurate and outdated

Study Methodological Rigour and Transparency Two PHO reviewers assessed the CASL population-based screening recommendation using a modified

approach to the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. The

recommendation was assessed broadly within the six domains of the AGREE II instrument without

assigning numeric scoring to each domain and without a numeric score to the overall assessment.

The reviewers also did not provide a statement on whether they would recommend the use of this

guideline. An overall assessment was determined based on the overall quality of the

recommendation after consideration of the six domains; this assessment involves judgement by the

reviewers and is subjective.11 The synopsis was reviewed by all contributors.

1. Scope and Purpose

This guideline updates previous guidance from CASL published in 2015.12 The 2015 version of

this guideline did not include specific screening recommendations, and the stated scope of

the 2018 guideline document did not include making recommendations on screening. The

Synopsis: HCV screening recommendations 5

scope of the 2018 guideline was “to support clinical practice, it makes recommendations on

the assessment, evaluation and management of HCV-infected persons.” The specific health

question and target population of this guideline is the clinical management of HCV-infected

persons. Nonetheless, the 2018 guideline documents do make screening recommendations

for the Baby Boomer cohort.

2. Stakeholder Involvement

o Stakeholder input was received from nine CASL members including physicians and allied

health workers.

o Persons with lived experience of HCV and persons who are born between 1945 and 1975

were not included in the guideline development or review.

3. Rigour of Development

o The methodology included a focused literature search of published and unpublished English-

language literature in MEDLINE from January 15, 2015 up to October 17, 2017 using search

terms: hepatitis C, hepatitis and treatment.

o The primary section author reviewed the previous 2015 guideline, added the new

recommendations and graded the evidence. The secondary author reviewed the

recommendations and supporting evidence and disagreements were resolved by consensus.

o The entire guideline panel reviewed the recommendations with support from two-thirds of

the members required for recommendation inclusion and grading. The panel used the same

grading system (class of evidence levels 1-3 and grade of evidence A-C) as their 2015

recommendations.12

o The literature review did not specifically include ‘screening’ as part of the search strategy.

The results of the search strategy and the papers reviewed in developing the

recommendation are not published in the manuscript or the Appendix.

o There is no description of critical appraisal tools used to assess the quality of studies included

as supporting literature.

o The methods did not describe whether any established framework13 or methodology, such as

procedures used by the CTFPHC14, the United States Preventive Services Task Force15, or

Public Health England16, was used in the process of developing this screening

recommendation.

4. Clarity of Presentation

o There is inconsistency between the published manuscript and the online Appendix in terms

of the birth cohort years included in the recommendation, and it is unclear which cohort

Synopsis: HCV screening recommendations 6

(1945-75 in the published manuscript vs. 1945-70 in the Appendix) is the intended/preferred

option.

o There is inconsistency between the supporting literature for the HCV prevalence and cost-

effectiveness and the recommendation in terms of the years chosen for inclusion as the Baby

Boomer cohort.

In the referenced PHAC modeling study, the birth cohort between 1955 to 1979 had

an increasing prevalence of chronic HCV from 1991 to 2011, whereas the birth cohort

between 1945 to 1954 had a decreasing prevalence in that time frame.1 While the

prevalence in the 1945 to 1954 cohort was still higher than the overall prevalence in

the population, it is unclear how the authors of the CASL guideline assessed these

declining trends in their determination of which cohorts to recommend for screening.

The guideline does not establish a specific chronic HCV prevalence threshold above

which screening is considered cost-effective. Without a threshold to assess each five-

year birth cohort within the 1945 to 1975 birth years, it is unclear why the entire 30

years range was included in the recommendation.

o The referenced 2015 Canadian cost-effectiveness study used a baseline scenario of screening

in those born between 1951 and 1990 or 1951 and 1971.10 The guideline does not discuss the

applicability of these results to their recommendation of the 1945 to 1975 birth cohort.

5. Applicability

o The two main supporting articles on population prevalence referenced by the CASL

recommendation are based on national modeling estimates and Ontario seroprevalence.1,8

Because of the inclusion of Ontario data, these estimates have greater applicability to

Ontario than to the rest of Canada.

o The article cited as the source for the upper end estimate of the undiagnosed fraction of HCV

infected Canadians (70%) is based on a national survey from 2007 to 2011, and may not

reflect more recent efforts to raise awareness and testing of HCV with the advent of new

therapies.9

o The cost-effectiveness study cited by the CASL recommendation likely had a higher cost per

quality of life years saved than are expected to result from current cost-effectiveness

analyses given recent decreases in HCV treatment pricing and improvement in outcomes

associated with treatment.10

o The authors of the CASL recommendation have not included feasibility considerations for the

implementation of a one-time population-based birth cohort screening program, such as:

o The clinical, social and ethical acceptability to patients and providers

Synopsis: HCV screening recommendations 7

o An assessment of the benefits and harms from screening

o An assessment of the health care system capabilities for offering accessible testing

and provision of care and treatment for newly diagnosed patients

6. Editorial Independence

o The guideline panel consisted of co-chairs appointed by the CASL Executive Committee and

six selected panel members. Members of the guideline panel disclosed financial relationships

with HCV treatment pharmaceutical companies and were not excluded from voting on

recommendations.

o The authors declared that no funding, direct or in-kind, was provided to the guideline panel

for the guideline development.

o CASL membership vetted the guideline for the presence of commercial bias. The financial

relationships of the CASL members who vetted the guidelines were not included.

Overall, the main strength of the CASL recommendation for population-based screening is the

authors’ identification of the high prevalence of chronic HCV in this population and the undiagnosed

burden of illness. The authors also include important considerations of the new lower costs

associated with treatment, new evidence on health benefits of treatment, and the potential for

stigma associated with risk-based screening. The main limitation is the absence of a described

methodological framework for guiding the development of this recommendation, and thereby to

assess the validity of the recommendation. This also includes absence of a feasibility assessment for

implementing population-based screening from which to assess applicability. There is a lack of clarity

in application of findings from supporting literature and potential for bias based on stakeholder

involvement and editorial independence. As such, the overall quality of this screening

recommendation was assessed as relatively low.

Ontario Applicability The treatment of HCV has been significantly improved with the advent of DAAs which are safe, better

tolerated and highly effective treatment options. Ontario has recently updated the drug formulary

such that DAA treatment is available to essentially all patients with chronic HCV infection.17

Interpretation of the recent recommendation to include population-based screening for HCV for

those born between 1945 and 1975 should consider the strengths and limitations of this guideline

recommendation and its applicability at the individual and population levels.

Synopsis: HCV screening recommendations 8

References

1. Trubnikov M, Yan P, Archibald C. Estimated prevalence of Hepatitis C Virus infection in Canada,

2011. CCDR 2014;40-19; 429-436. Available from: https://www.canada.ca/en/public-

health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-

issue/2014-40/ccdr-volume-40-19-december-18-2014/ccdr-volume-40-19-december-18-2014-

2.html

2. Shah H, Bilodeau M, Burak KW, Cooper C, Klein M, Ramji A, et al. The management of chronic

hepatitis C: 2018 guideline update from the Canadian Association for the Study of the Liver.

CMAJ. 2018;190(22):E677-87. Available from: http://www.cmaj.ca/content/190/22/E677

3. Kwong JC, Crowcroft NS, Campitelli MA, Ratnasingham S, Daneman N, Deeks SL, et al. Ontario

Burden of Infectious Disease Study Advisory Group; Ontario Burden of Infectious Disease Study

(ONBOIDS): An OAHPP/ICES Report. Toronto, ON: Ontario Agency for Health Protection and

Promotion, Institute for Clinical Evaluative Sciences; 2010. Available from:

http://www.ontla.on.ca/library/repository/mon/24012/306590.pdf

4. Government of Canada. For Health Professionals: Hepatitis C [Internet]. Ottawa, ON: PHAC; 2016-

03-16. Available from: https://www.canada.ca/en/public-health/services/diseases/hepatitis-

c/health-professionals-hepatitis-c.html#a2

5. Canadian Task Force on Preventive Health Care. Recommendations on hepatitis C screening for

adults. CMAJ 2017;189(16):E594-604. Available from: http://www.cmaj.ca/content/189/16/E594

6. Canadian Liver Foundation (CLF). Hepatitis C in Canada: Primary care physicians are the 1st point

of screening [Infographic]. Ontario, Canada: CLF; 2016. Available from: https://www.liver.ca/wp-

content/uploads/2017/09/CLF_HepC_Screening_Infographic_FINAL_ENG.pdf

7. Noël L, Drouin MC. Avis sur la pertinence d’un dépistage du VHC chez les baby-boomers au

Québec. Québec : Institut national de santé publique du Québec; 2018. Available from:

https://www.inspq.qc.ca/sites/default/files/publications/2333_pertinence_depistage_vhc_baby_

boomers.pdf

8. Bolotin S, Feld JJ, Garber G, Wong WW, Guerra FM, Mazzulli T. Population-based estimate of

hepatitis C virus prevalence in Ontario, Canada. PloS One. 2018;13(1):e0191184. Available from:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191184

9. Rotermann M, Langlois K, Andonov A, et al. Seroprevalence of hepatitis B and C virus infections:

results from the 2007 to 2009 and 2009 to 2011 Canadian Health Measures Survey. Health Rep

2013;24:3-13. Available from:

https://www.researchgate.net/publication/258824951_Seroprevalence_of_hepatitis_B_and_C_v

Synopsis: HCV screening recommendations 9

irus_infections_Results_from_the_2007_to_2009_and_2009_to_2011_Canadian_Health_Measur

es_Survey

10. Wong WW, Tu HA, Feld JJ, Wong T, Krahn M. Cost-effectiveness of screening for hepatitis C in

Canada. CMAJ. 2015;187(3):E110-E121. Available from:

http://www.cmaj.ca/content/cmaj/early/2015/01/12/cmaj.140711.full.pdf

11. Brouwers M, Kho ME, Browman GP, Cluzeau F, Feder G, Fervers B et al. on behalf of the AGREE

Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in

healthcare. CMA J. 2010; 182:E839-842. Available from: http://www.agreetrust.org/wp-

content/uploads/2013/10/AGREE-II-Users-Manual-and-23-item-

Instrument_2009_UPDATE_2013.pdf

12. Myers RP, Shah H, Burak KW, Cooper C, Feld JJ. An update on the management of chronic

hepatitis C: 2015 consensus guidelines from the Canadian Association for the Study of the Liver.

Canadian Journal of Gastroenterology and Hepatology. 2015;29(1):19-34. Available from:

https://www.liver.ca/wp-

content/uploads/2017/09/CASL_Hep_C_Consensus_Guidelines_Update_-_Jan_2015.pdf

13. Wilson JMG, Jungner G. Principles and practice of screening for disease. Public Health Papers.

1968;34. Geneva: World Health Organization. Available from:

http://apps.who.int/iris/bitstream/handle/10665/37650/WHO_PHP_34.pdf;sequence=17

14. Canadian Task Force on Preventive Health Care. Canadian Task Force on Preventive Health Care

procedure manual. 2014. Available from: https://canadiantaskforce.ca/wp-

content/uploads/2016/12/procedural-manual-en_2014_Archived.pdf

15. U.S. Preventive Services Task Force. Standards for guideline development. Rockville, MD: Agency

for Healthcare Research and Quality.2017. Available from:

https://www.uspreventiveservicestaskforce.org/Page/Name/standards-for-guideline-

development

16. Public Health England. Criteria for appraising the viability, effectiveness and appropriateness of a

screening programme. London, UK: Public Health England. 2015. Available from:

https://www.gov.uk/government/publications/evidence-review-criteria-national-screening-

programmes/criteria-for-appraising-the-viability-effectiveness-and-appropriateness-of-a-

screening-programme

17. Ontario Ministry of Health and Long-Term Care. Notice from the Executive Officer: Funding of

hepatitis C drug products under the Ontario Drug Benefit program. Ottawa, ON: Queen’s Printer

for Ontario; 2017. Available from:

http://www.health.gov.on.ca/en/pro/programs/drugs/opdp_eo/notices/exec_office_20170227.p

df

Synopsis: HCV screening recommendations 10

Contributors Bryna Warshawsky, Medical Director, Communicable Diseases, Emergency Preparedness and

Response, Public Health Ontario

Karin Hohenadal, Manager, Communicable Diseases, Emergency Preparedness and Response, Public

Health Ontario

Lee Goneau, Clinical Microbiologist, Public Health Ontario Laboratories, Public Health Ontario

Shelley Deeks, Chief, Communicable Diseases, Emergency Preparedness and Response, Public Health

Ontario

Disclaimer This document was developed by Public Health Ontario (PHO). PHO provides scientific and technical

advice to Ontario’s government, public health organizations and health care providers. PHO’s work is

guided by the current best available evidence at the time of publication.

The application and use of this document is the responsibility of the user. PHO assumes no liability

resulting from any such application or use.

This document may be reproduced without permission for non-commercial purposes only and

provided that appropriate credit is given to PHO. No changes and/or modifications may be made to

this document without express written permission from PHO.

Citation:

Ontario Agency for Health Protection and Promotion (Public Health Ontario). Synopsis: Article

review: The management of chronic hepatitis C: 2018 guideline update from the Canadian

Association for the Study of the Liver. Toronto, ON: Queen’s Printer for Ontario; 2018.

Synopsis: HCV screening recommendations 11

Public Health Ontario acknowledges the financial support of the Ontario Government.