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. 2018 Dec 25;1(4):156-217.
doi: 10.3138/canlivj.2018-0008. eCollection 2018 Fall.

Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada

Carla S Coffin  1 , Scott K Fung  2 , Fernando Alvarez  3 , Curtis L Cooper  4 , Karen E Doucette  5 , Claire Fournier  6 , Erin Kelly  7 , Hin Hin Ko  8 , Mang M Ma  9 , Steven R Martin  10 , Carla Osiowy  11 , Alnoor Ramji  12 , Edward Tam  13 , Jean Pierre Villeneuve  6
Affiliations

Management of Hepatitis B Virus Infection: 2018 Guidelines from the Canadian Association for the Study of Liver Disease and Association of Medical Microbiology and Infectious Disease Canada

Carla S Coffin et al. Can Liver J. .

Abstract

Hepatitis B virus (HBV) infection is an important public health problem in Canada. In keeping with evolving evidence and understanding of HBV pathogenesis, the Canadian Association for the Study of Liver Disease periodically publishes HBV management guidelines. The goals of the 2018 guidelines are to (1) highlight the public health impact of HBV infection in Canada and the need to improve diagnosis and linkage to care, (2) recommend current best-practice guidelines for treatment of HBV, (3) summarize the key HBV laboratory diagnostic tests, and (4) review evidence on HBV management in special patient populations and include more detail on management of HBV in pediatric populations. An overview of novel HBV tests and therapies for HBV in development is provided to highlight the recent advances in HBV clinical research. The aim and scope of these guidelines are to serve as an up-to-date, comprehensive resource for Canadian health care providers in the management of HBV infection.

Keywords: Association of Medical Microbiology and Infectious Disease (AMMI) Canada; Canadian Association for the Study of Liver Disease (CASL); guidelines; hepatitis B.

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Conflict of interest statement

Scott Fung reports speaking and teaching fees from Gilead, Merck, and Abbvie and advisory board and consulting roles with Gilead, Merck, Abbvie and Lupin. Carla Coffin reports investigator initiated research grant/research materials from GSK, Gilead Sciences, Arbutus Biopharma, and Bristol-Myers Squibb; educational grants from Merck, Gilead Sciences, and Janssen Inc.; advisory board roles with Merck, Gilead Sciences, and GSK; CTPC committee role with Springbank Pharmaceuticals; and local site PI participation in Clinical Trials with Gilead Sciences, Springbank Pharmaceuticals, and Transgene. Curtis Cooper reports Speaker fees from Gilead Sciences, Merck, and ABBVIE; advisor role with Gilead Sciences, Merck, and ABBVIE; and research/program support from Gilead Sciences, Merck, and ABBVIE. Karen Doucette reports clinical trials with Gilead, Merck, AbbVie, BMS, and Pfizer; speaker honorarium from Merck and Gilead; and educational grants from Merck, Gilead, BMS, and Astellas. Claire Fournier reports local site PI/sub-investigator participation in clinical trials for Transgene, Beckmann, Gilead, Bristol-Myers Squibb Canada, and Immune carta. Erin Kelly reports speaking fees from Lupin, Intercept, and Gilead and advisory board role with Intercept. Hin Hin Ko reports speaker fees from Merck, Intercept, Lupin, Allergan, and Procter and Gamble; advisory board role with Intercept and Lupin; and subinvestigator for studies role with Gilead, Merck, and Intercept. Mang Ma reports clinical investigator role with AbbVie, Gilead, Transgene, Sillagen, and BTG International and advisory board role with AbbVie, Gilead, and Merck. Alnoor Ramji reports clinical investigator role with Abbvie, Allergan, BMS, Gilead, Janssen, Intercept, Norvartis, and Merck; consultant role with Abbvie, Gilead, Intercept, and Lupin; speaker fees from Abbvie, Intercept, Gilead, and Merck; grants from Abbvie, Gilead, Intercept, and Merck. Edward Tam reports clinical investigator role with AbbVie, Allergan, BMS, Boehringer Ingelheim, Genfit, Gilead, Intercept, Janssen, Merck, Novartis, Roche, and Shire; advisory board role with AbbVie, BMS, Boehringer Ingelheim, Gilead, Intercept, Janssen, Lupin, Merck, PendoPharm, and Roche; and speaker honoraria from AbbVie, BMS, Gilead, Intercept, Merck, PenoPharm, and Roche. Jean Pierre Villeneuve reports clinical investigator role with Transgene, and Immune carta.

Figures

Figure 1:
Figure 1:
Rates of reported cases of acute (A) and chronic (B) hepatitis B virus infection in Canada by age group in 2013, according to the Canadian Notifiable Disease Surveillance System. Government of Canada. 2017. Report on hepatitis B and C in Canada: 2014. https://www.canada.ca/en/services/health/publications/diseases-conditions/report-hepatitis-b-c-canada-2014.html
Figure 2:
Figure 2:
Summary of the HBV lifecycle. Key steps include the formation of intranuclear HBV minichromosome (HBV cccDNA) that is not targeted by current NA therapy. The HBV replicates through an error-prone reverse transcription of an RNA intermediate that lacks proofreading, leading to frequent mutations in the viral genome. HBV persistence is due to ineffective antiviral immune response and resilient HBV cccDNA template. cccDNA = covalently closed circular DNA; HBV = hepatitis B virus; NA = nucleos(t)ide analogue; NTCP = sodium taurocholate cotransporting polypeptide; pgRNA = pregenomic RNA; RC-DNA = relaxed circular DNA.
Figure 3:
Figure 3:
Natural history of CHB infection based on conventional definitions (A). Recent data suggest that the immune-tolerant phase is a misnomer because many patients have active HBV-specific immune responses and unrecognized hepatic necroinflammatory activity. A new classification system has been proposed, differentiating only between chronic infection versus chronic hepatitis (B). *The risk of cirrhosis and HCC is higher in patients with high HBV DNA levels and ongoing hepatic inflammation (ie, elevated ALT) ALT = alanine aminotransferase; anti-HBs = antibody to HBsAg; CHB = chronic hepatitis B; HBeAg = HBV e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCC = hepatocellular carcinoma
Figure 4:
Figure 4:
Proposed clinical algorithm for selecting HBV patients for antiviral therapy. In general, patients at risk for liver disease and needing therapy have persistently elevated ALT (normal, < 25 U/L in women, < 35 U/L in men) and elevated HBV DNA. However, normal ALT may not rule out liver disease risk and can fluctuate over time. Because of increased HCC risk with age, some experts are suggesting treating older patients (aged > 35 or 40 years) with high viral load regardless of ALT levels or fibrosis status. Any person with significant fibrosis regardless of ALT level should be considered for treatment, as per recommendation #16. ALT = alanine aminotransferase; HBV = hepatitis B virus
Figure 5:
Figure 5:
Relative potencies of different hepatitis B oral antivirals at 48–52 weeks of therapy. LAM has been compared with ETV and with TBV in two separate randomized controlled trials. ADV has not been compared directly with the other agents. TDF was compared with TAF. * For TDF and TAF, results reported as HBV DNA < 29 IU/ml ADV = adefovir dipivoxil; ETV = entecavir; LAM = lamivudine; TAF = tenofovir alafenamide; TBV = telbivudine; TDF = tenofovir disoproxil fumarate.
Figure 6:
Figure 6:
Algorithm for selection of specific agents for hepatitis B. The recommended first-line oral nucleos(t)ide analogue therapy is TDF, TAF, or ETV if patients have no pre-existing resistance to lamivudine. TAF or ETV may be considered in selected populations that have or are at risk for renal disease or metabolic bone disease. In selected HBeAg-positive patients (high ALT, genotype A or B, HBV DNA) may respond to finite therapy with PEG-IFN. ALT = alanine aminotransferase; HBeAg = HBV e antigen; HBV = hepatitis B virus; ETV = entecavir; PEG-IFN = pegylated interferon; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.
Figure 7:
Figure 7:
Suggested algorithm for management of patients with hepatitis B viral cirrhosis. Cirrhotic patients are at high risk of hepatic decompensation with virological and biochemical (hepatic) flares and progression to HCC. Thus, potent nucleos(t)ide analogue therapy is recommended with TDF or ETV (if there is no history of lamivudine resistance). Some studies indicate that initiating combination therapy is beneficial to rapidly suppress viral load in patients with cirrhosis. ETV = entecavir; HBV = hepatitis B virus; HCC = hepatocellular carcinoma; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.
Figure 8:
Figure 8:
Rates of resistance to antiviral agents by duration of therapy. In treatment-naïve patients, resistance rates are low with entecavir and tenofovir disoproxil fumarate. Patients with lamivudine resistance are at risk of cross-resistance and treatment failure with entecavir.
Figure 9:
Figure 9:
Algorithm for management of hepatitis B in immunosuppressed patients. All patients should be screened for HBV and offered vaccination if at risk. HBsAg-positive patients should receive prophylaxis with most regimens. HBsAg-negative, anti-HBc-positive patients with immunosuppression may be treated with first-generation NA (LAM) because of the lower risk of resistance in those with undetectable HBV DNA. In patients that are HBsAg negative, anti-HBc positive with high anti-HBs titres (>100 IU/L) on low-moderate risk IMS, monitoring may be acceptable. anti-HBc = antibody to HBV core; anti-HBs = antibody to HBsAg; ETV = entecavir; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; IS = immunosuppression; LAM = lamivudine; NA = nucleos(t)ide analogue; NACI = National Advisory Committee on Immunization; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate.
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