SPECIAL ARTICLE An update on the management of chronic hepatitis C: 2015 Consensus guidelines from the Canadian Association for the Study of the Liver Robert P Myers MD MSc1*, Hemant Shah MD MScCH HPTE2*, Kelly W Burak MD MSc1, Curtis Cooper MD3, Jordan J Feld MD MPH2* RP Myers, H Shah, KW Burak, C Cooper, JJ Feld. An update Mise à jour sur la prise en charge de l’hépatite C on the management of chronic hepatitis C: 2015 Consensus chronique : les lignes directrices consensuelles guidelines from the Canadian Association for the Study of the 2015 de l’Association canadienne pour l’étude Liver. Can J Gastroenterol Hepatol 2015;29(1):19-34. du foie Chronic hepatitis C remains a significant medical and economic bur- L’hépatite C chronique demeure un fardeau médical et économique den in Canada, affecting nearly 1% of the population. Since the last important au Canada, car il touche près de 1 % de la population. Canadian consensus conference on the management of chronic hepa- Depuis la dernière conférence consensuelle canadienne sur la prise en titis C, major advances have occurred that warrant a review of recom- charge de l’hépatite C chronique, on a réalisé des progrès marqués qui mended management approaches for these patients. Specifically, justifient une analyse des démarches de prise en charge recomman- direct-acting antiviral agents with dramatically improved rates of dées. Notamment, on a mis au point des antiviraux à action directe au virological clearance compared with standard therapy have been taux de clairance virologique bien supérieur à celui du traitement developed and interferon-free, all-oral antiviral regimens have been standard et on a homologué des antiviraux sans interféron par voie approved. In light of this new evidence, an update to the 2012 orale. À la lumière de ces nouvelles données probantes, l’Association Canadian Association for the Study of the Liver consensus guidelines canadienne pour l’étude du foie a mis à jour les lignes directrices con- on the management of hepatitis C was produced. The present docu- sensuelles 2012 sur la prise en charge de l’hépatite C. Le présent ment reviews the epidemiology of hepatitis C in Canada, preferred document traite de l’épidémiologie de l’hépatite C au Canada, des diagnostic testing approaches and recommendations for the treatment démarches et des recommandations favorisées pour traiter les patients of chronically infected patients with the newly approved antiviral atteints d’une infection chronique à l’aide des nouveaux antiviraux agents, including those who have previously failed peginterferon and homologués, y compris les patients qui n’avaient pas répondu à un ribavirin-based therapy. In addition, recommendations are made traitement à l’interféron pégylé et à la ribavirine. Il contient égale- regarding approaches to reducing the burden of hepatitis C in Canada. ment des recommandations sur les approches pour réduire le fardeau de l’hépatite C au Canada. Key Words: Dasabuvir; Direct-acting antivirals; Guideline; Hepatitis C; Interferon; Ledipasvir; Ombitasvir; Paritaprevir; Peginterferon; Simeprevir; Sofosbuvir; Ribavirin; Therapy; Treatment he present guidelines were written to assist physicians and other Since the last update of the CASL management guidelines for Thealth care professionals in the management of patients with chronic hepatitis C (CHC) in 2012 (3), major advances have chronic hepatitis C virus (HCV) infection. They were drafted by occurred including: the approval of novel direct-acting antiviral Canadian HCV experts at the request of the Executive Committee of agents (DAAs) used with pegylated interferon (PEG-IFN) that have the Canadian Association of the Study of the Liver (CASL). The docu- improved efficacy and tolerability compared with first-generation ment was made available for review by CASL members and a revised DAAs and/or standard PEG-IFN-based therapy (5-7); and the draft based on this feedback was submitted to the Executive Committee approval of all-oral, IFN-free, DAA combination therapies with of CASL for approval. The information contained within the present markedly improved efficacy and tolerability and activity beyond just guidelines represents a synthesis of evidence from the published litera- HCV genotype 1 (5,8-15). The current document was developed as ture and scientific abstract presentations available at the time of writing an update to previous guidelines with a focus on the management of with supplementation by the expert opinions of the authors. Any rec- HCV-infected patients rather than an exhaustive review of CHC or ommendations should be considered preferred approaches to care rather HCV screening. Future guidelines will include ‘special populations’ than strict standards. In some cases, off-label use of regimens are recom- with CHC, including people who use injection drugs (PWIDs), incar- mended based on the authors’ opinions. To more fully characterize the cerated individuals, patients with decompensated cirrhosis, those quality of evidence supporting these recommendations, we have pre- or post-transplantation, and patients with HIV/HCV coinfection assigned a class (reflecting benefit versus risk) and level (assessing (for whom relevant guidelines have recently been published by the strength of certainty) of evidence as adapted from the American College Canadian Institute of Health Research HIV Trials Network) (16). of Cardiology and the American Heart Association Practice Guidelines Due to the rapidity of advances in this field, recommendations in the (1,2), and as used in similar practice guidelines of CASL (3) and the present document will be updated regularly as new information emer- American Association for the Study of Liver Diseases (4) (Table 1). No ges and novel agents are approved. funding was provided to the authors for this work. *Authors who contributed equally to this work. 1Liver Unit, Division of Gastroenterology and Hepatology, University of Calgary, Calgary, Alberta; 2Toronto Western Hospital Liver Centre, University of Toronto, Toronto; 3Division of Infectious Diseases, University of Ottawa, Ottawa, Ontario Correspondence: Dr Jordan J Feld, Toronto Western Hospital Liver Centre, University Health Network, McLaughlin-Rotman Centre for Global Health, Telephone 416-603-6230, fax 416-603-5472, e-mail [email protected] Received for publication December 17, 2014. Accepted December 18, 2014 Can J Gastroenterol Hepatol Vol 29 No 1 January/February 2015 ©2015 Pulsus Group Inc. All rights reserved 19 Myers et al TABLE 1 Grading system for recommendations Classification Description Class of evidence Class 1 Conditions for which there is evidence and/or general agreement that a given diagnostic evaluation, procedure or treatment is beneficial, useful and effective Class 2 Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a diagnostic evaluation, procedure or treatment Class 2a Weight of evidence/opinion is in favour of usefulness/efficacy Class 2b Usefulness/efficacy is less well established by evidence/opinion Class 3 Conditions for which there is evidence and/or general agreement that a diagnostic evaluation, procedure/treatment is not useful/effective and in some cases may be harmful Grade of evidence Level A Data derived from multiple randomized clinical trials or meta-analyses Level B Data derived from a single randomized trial, or nonrandomized studies Level C Only consensus opinions of experts, case studies or standard-of-care EPIDEMIOLOGY OF HEPATITIS C IN CANADA CHC remains a significant medical and economic burden in Canada (17-19). In the Canadian Health Measures Survey (20), Statistics Canada and the Public Health Agency of Canada reported an esti- mated anti-HCV prevalence of 0.5% (95% CI 0.3% to 0.9%) or approximately 138,600 (95% CI 55,800 to 221,300) anti-HCV-positive individuals in Canada. However, these figures are likely underesti- mates because the Canadian Health Measures Survey excluded several high-risk populations including incarcerated individuals, Aboriginals and PWIDs (20). In fact, a recent modelling study suggests that approximately 252,000 Canadians (uncertainty interval 178,000 to 315,000) were chronically infected in 2013 (18). The peak preva- lence was estimated to have occurred in 2003, with approximately 260,000 infected individuals. It has been estimated that approxi- mately 60% of HCV cases in Canada are among current or former PWIDs, 20% are among infected immigrants and 11% have received Figure 1) Modelled incidence of hepatitis C-related sequelae in Canada, contaminated blood products (21). Of the nearly 8000 incident cases 1950 to 2035. Estimates are not mutually exclusive. Reproduced with per- in Canada in 2007, approximately 80% likely occurred via sharing of mission from Myers et al (18). Decomp Decompensated; HCC injecting equipment, and most of the remainder among immigrants Hepatocellular carcinoma from endemic countries (21). There is wide variation in estimates of the number of HCV-infected individuals who remain undiagnosed. Modelling data from the Public Health Agency of Canada estimated Recommendations: that 79% of individuals were diagnosed in 2003 (21); however, the 1. A large population-based seroprevalence survey should be CMHS found that only 30% of anti-HCV-positive individuals were conducted to accurately define the prevalence of hepatitis C in aware of their infection (20). Canada. The design of the study should include populations Genotype 1 infection is the most prevalent