| Recommendations for HBV screening and testing |
Universal one-time screening of all adults (>18 years) in Canada should be implemented. Screening should be conducted using a triple panel including testing for HBsAg, anti-HBs, and anti-HBc. In consultation with the patient, evidence of a new activity or persistent risk for HBV infection should prompt periodic re-testing if the patient is not immune (i.e., anti-HBs negative). Cost-effectiveness modelling is encouraged to support recommendations at provincial and national levels, and coordinated electronic records are recommended to enhance laboratory capacity and avoid repeat testing. (Strong recommendation; Level 5)
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| Recommendations for HDV screening and testing |
Universal reflex testing of HBsAg-positive individuals for antibody to HDV should be performed for patient samples with no history in the clinical laboratory system. For individuals having a negative result, follow-up testing for antibody to HDV is warranted for evidence of new activity or persistent risk for HDV, or a new clinical profile including HBV DNA <2,000 IU/mL and ALT > ULN*. (Strong recommendation; Level 3) Universal testing of antibody to HDV should be performed using an assay having diagnostic accuracy and performance characteristics of >90% sensitivity and >99% specificity. (Strong recommendation; Level 5) Universal reflex testing of HDV RNA in newly identified HDV seropositive samples should be performed by specialized or reference laboratories (i.e., the National Microbiology Laboratory). (Strong recommendation; Level 5).
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| Recommendations for HBV vaccination |
Universal infant (ideally at-birth) vaccination is recommended across all Canadian provinces and territories. (Strong recommendation; Level 1) Universal catch-up (adult) vaccination is recommended for all individuals not having received a full series of HBV vaccine doses or unsure of their vaccination history. (Strong recommendation; Level 3)
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| Recommendations for HBV laboratory assessment |
Quantitative HBV DNA testing is recommended to monitor treatment response. For NA treated patients, the recommendation is to test every 6 months, in order to confirm ongoing adherence. (Strong recommendation; Level 1) Quantitative measurement of HBsAg is recommended every one to two years to monitor treatment response and in determining functional cure. (Strong recommendation; Level 2) New biomarkers that are associated with cccDNA transcriptional activity (LHB and MHB expression, serum HBV RNA, HBcrAg, NRAg), or host immune activity (qAHBc) require standardized testing platforms (including analyte standards) or have not been fully studied for their utility in clinical management. Further research on the clinical utility and cost-effectiveness of new HBV biomarkers is required. Future testing algorithms will likely involve a combination of standard and new biomarker assays providing results that may provide a scoring system. (Weak recommendation; Level 4) Point-of-care tests for HBV screening are recommended for community-based testing, and resource-limited or remote regions to remove barriers to diagnosis and treatment uptake. (Strong recommendation; Level 4)
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| Recommendations for HBV treatment (Figure 1) |
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1.
HBsAg-positive patients with cirrhosis, those with a personal history of HCC, those about to receive highly potent immunosuppressive or immunomodulatory therapies (95), or those with extrahepatic HBV manifestations should receive oral antiviral treatment. (Strong recommendation; Level 1)
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2.
HBeAg-positive and HBeAg-negative patients with ALT > ULN* for 3–6 months or more and HBV DNA >2,000 IU/mL (HBeAg-positive chronic hepatitis and HBeAg-negative chronic hepatitis) should receive antiviral treatment. (Strong recommendation; Level 1)
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3.
HBeAg-positive patients over the age of 40 years with normal ALT and HBV DNA >2,000 IU/mL (HBeAg-positive chronic infection, formerly referred to as immune tolerant HBV) should receive antiviral treatment. (Strong recommendation; Level 2)
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4.
HBeAg-positive patients under the age of 40 years with normal ALT and HBV DNA >2,000 IU/mL (HBeAg-positive chronic infection, formerly referred to as immune tolerant HBV) who have a first-degree relative with a history of HCC or cirrhosis should be considered for antiviral treatment. They may also be considered for treatment on an individualized basis. (Strong recommendation; Level 2)
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5.
HBeAg-negative patients over age 40 years with normal ALT and HBV DNA >2,000 IU/mL (HBeAg-negative chronic infection) should receive antiviral treatment to reduce the risk of HCC. (Strong recommendation; Level 2)
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6.
HBeAg-negative patients under the age of 40 years with normal ALT and HBV DNA >2,000 IU/mL (HBeAg-negative chronic infection) who have a first-degree relative with a history of HCC or cirrhosis should be considered for antiviral treatment. (Strong recommendation; Level 2)
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7.
HBeAg-negative patients with normal ALT and HBV DNA <2,000 IU/mL (formerly referred to as inactive HBV carriers) should be monitored on a regular basis but may be considered for antiviral treatment on an individualized basis. (Strong recommendation; Level 3)
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8.
HBeAg-negative patients with ALT > ULN* and HBV DNA <2,000 IU/mL should be investigated for causes of elevated ALT other than HBV infection but may also be considered for antiviral treatment on an individualized basis. (Strong recommendation; Level 3)
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9.
The importance of treatment adherence should be reinforced. If patients experience treatment interruptions (due to loss of medication coverage, etc.), but have not achieved the usual treatment endpoints (i.e., HBeAg seroconversion, low level qHBsAg) they should be counselled about the risk and the importance of regular monitoring for severe rebound flares and relapse of HBV (see Endpoints section).
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| Recommendations for first-line HBV therapy |
TAF, TDF, or ETV are recommended as first-line monotherapy in HBeAg-positive chronic hepatitis and HBeAg-negative chronic HBV patients. (Strong recommendation; Level 1) TDF or TAF with or without pegylated interferon-alpha may be used in both HBeAg-positive and -negative chronic hepatitis patients. (Strong recommendation; Level 1)
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| Recommendations for endpoints of HBV therapy |
For patients with HBeAg-positive chronic hepatitis who are noncirrhotic, treatment should continue until confirmed HBeAg loss or seroconversion followed by an additional 12–18 months of consolidation therapy. (Strong recommendation; Level 1) For patients with HBeAg-negative chronic hepatitis who are noncirrhotic, treatment should continue until confirmed HBsAg loss or quantitative HBsAg <100 IU/mL for Asian patients or quantitative HBsAg <1,000 IU/mL for White patients followed by an additional 12 months of consolidation therapy (47). (Strong recommendation; Level 2) All HBsAg-positive patients should be monitored closely after stopping NA (i.e., ALT and HBV DNA monthly for 3 months, then once every 3 months for one year, then once every 6 months, as per usual standard of care) to exclude severe HBV relapse (Strong recommendation; Level 2) For patients with HBV cirrhosis, treatment is of indefinite duration or until HBsAg loss followed by regular monitoring. (Strong recommendation; Level 2)
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| Recommendations for HCC surveillance |
HCC surveillance is recommended even in patients who are on antiviral therapy due to residual risk. Abdominal ultrasound and AFP screening every 6 months is recommended in the following patients with chronic infection. (Strong recommendation; Level 3)
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(1)
All patients with cirrhosis, irrespective of age (even those who clear HBsAg).
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(2)
Men aged 40 years or older.
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(3)
Women aged 50 years or older.
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(4)
Persons of African (Black) ancestry aged 30 years or older (due to risk associated with certain African HBV genotypes and environmental factors including aflatoxin exposure).
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(5)
First-degree family history of HCC (starting at age 40 or 10 years before affected first-degree family member, whichever is sooner).
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(6)
All HIV-coinfected patients (starting at age 40).
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(7)
All HBV/HDV coinfected individuals (starting at age 40, or earlier if advanced >F3 [stage 3] fibrosis).
Risk calculators (i.e., REACH-B, PAGE-B, mPAGE-B) may be useful to support clinical practice and identification of patients who may benefit from HCC screening.
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| Recommendations for management of individuals of childbearing age and pregnancy |
All HBsAg-positive persons of child-bearing age planning pregnancy in near future should be assessed (HBV DNA, HBeAg, anti-HBe, ALT, fibrosis) and counselled about HBV management. (Strong recommendation; Level 1) All pregnant persons should be screened for HBsAg in the first trimester of pregnancy. (Strong recommendation; Level 1) HBsAg-positive pregnant persons should undergo additional assessment for HBeAg, anti-HBe, HBV DNA, and ALT and be referred to a provider with expertise in HBV management. (Strong recommendation; Level 1) TDF or TAF should be given as the drug of choice for pregnant persons and those of child-bearing potential who require immediate treatment for HBV. (Strong recommendation; Level 1) HBsAg-positive persons planning to become pregnant in the near future (1-2 years), especially if over age 30 and HBV DNA >200,000 IU/mL, may be considered for immediate treatment, rather than waiting for future pregnancy. (Strong recommendation; Level 2) HBsAg-positive pregnant persons with HBV DNA of more than 200,000 IU/mL should initiate antiviral therapy as soon as possible and no later than the second trimester to reduce the risk of vertical transmission and to ensure treatment is tolerated.Earlier treatment may be considered in high-risk pregnancies and potential pre-term delivery. (Strong recommendation; Level 2) TDF or TAF may be continued up to 12 weeks post-partum if given strictly to prevent MTCT. (Strong recommendation; Level 1) If antiviral treatment is started to reduce MTCT risk, on a case-by-case basis, treatment may be continued until all family planning is completed. (Strong recommendation; Level 5) After stopping TDF or TAF post-partum, persons should be monitored for ALT flares, with ALT testing every 4 weeks for the first 3 months and then at 6 months, followed by routine monitoring thereafter. (Strong recommendation; Level 2) All infants born to HBsAg-positive pregnant persons should receive immunoprophylaxis with HBIG and HBV vaccine as soon as possible after birth, and completion of second and third HBV vaccine doses before 6 months. (Strong recommendation; Level 1) Infants should be tested for HBsAg and anti-HBs between 1 and 4 months after the last dose of vaccine (by age 1 year) to confirm that they are uninfected and immune to HBV. (Strong recommendation; Level 1) Breastfeeding while receiving TDF or TAF is not contraindicated. (Strong recommendation; Level 1)
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| Recommendations for management of HBV and HDV coinfection |
All HBsAg-positive/HDV antibody positive individuals should be considered for anti-HBV NA therapy, regardless of HBV DNA levels or fibrosis stage, but especially if there is detectable viremia. NA are not directly active against HDV but in theory will block residual HBV replication which may reduce liver disease risk. (Strong recommendation; Level 2) PEG-IFN therapy (180 µg once weekly) for 48 weeks should be considered in individuals without contraindications to IFN treatment. (Strong recommendation; Level 1) As novel HDV therapies (Bulevirtide) are expected to become available in Canada, they should be prioritized for HBV/HDV coinfected individuals, particularly those with advanced liver disease with or without IFN combination therapy. (Strong recommendation; Level 1) Due to the high risk of rapid disease progression, all HBV/HDV coinfected individuals should be followed by a specialist and monitored closely with HBV DNA, HDV RNA, ALT every 6–12 months, HCC surveillance starting at age 40 (see above), and fibrosis assessment yearly. Late HDV RNA relapse has been described even in those who suppress HDV RNA on PEG-IFN. (Strong recommendation; Level 2)
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| Recommendations for management of HBV and HCV coinfection |
All HCV patients should be tested for HBsAg and anti-HBc prior to initiating HCV DAA therapy. (Strong recommendation; Level 2) All HBsAg-positive patients, especially in those with advanced fibrosis or cirrhosis, should initiate oral anti-HBV NA treatment while undergoing HCV DAA therapy. Empiric NA treatment is recommended given possible delays in HBV DNA testing in some regions. (Strong recommendation; Level 3) HBsAg-negative and anti-HBc positive (with or without anti-HBs) patients should be monitored for ALT and HBsAg while on HCV DAA until 24-weeks post-treatment.HBsAg and HBV DNA should be measured if ALT fails to normalize or increases during or after completion of DAA treatment. HBV antiviral therapy should be initiated promptly in those with emergence of HBsAg or detectable HBV DNA with elevated ALT. (Strong recommendation; Level 3)
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| Recommendations for management of HBV and HIV co-infection |
All people living with HIV should be screened for HBV infection and immunity. If anti-HBs and anti-HBc negative, then HBV immunization should be pursued. (Strong recommendation; Level 1) HIV treatment with HBV-active antivirals should be initiated once the diagnosis of HIV and HBV is established and irrespective of CD4+ T cell count. (Strong recommendation; Level 1) On-treatment monitoring of HBV is the same as in HBV monoinfection. (Strong recommendation; Level 5) Patients who have interruptions in HIV therapy that included any HBV active antivirals should be monitored for HBV reactivation if unable to continue with anti-HBV antiviral. (Strong recommendation; Level 4) All HIV-HBV co-infected patients starting or switching to cabotegravir / rilpivirine intramuscular injection treatment for HIV should ensure that HBV antiviral therapy is concurrently initiated or continued. (Strong recommendation; Level 5)
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| Recommendations for management of HBV in pediatric patients |
There is no strong evidence at present for treatment of children without complications in the high replicative/non-inflammatory phase (formerly referred to as immune tolerant) and HBeAg-negative chronic HBV infection with normal ALT* and low level HBV DNA (<2,000 IU/mL) (formerly referred to as inactive chronic carrier phase). (Moderate recommendation; Level 4) Due to the long-term safety profile of NA, the potential development of curative treatments in the next decade, as well as novel predictive biomarkers of HBV in the liver, on an individualized basis regardless of ALT levels, taking into account concomitant MASLD and diabetes, a strong family history of HCC or cirrhosis, and infection with genotype C, treatment may be considered in adolescence in patients with very high HBV viral load (high replicative / non-inflammatory phase, formerly referred to as immune tolerant phase), under the care of a specialist. (Moderate recommendation; Level 3) Children with chronic HBV infection, either HBeAg-positive or -negative, should be followed once a year by ultrasound examination of the liver (ideally with elastography) and serum AFP, in addition to ALT and HBV DNA. (Moderate recommendation; Level 3) In HBeAg-positive children with serum ALT more than 1.3–2 times the normal values, monitoring every 3 months for at least 1 year, to document decreasing or low levels of serum HBV DNA, is recommended before considering treatment to account for possible spontaneous seroconversion. (Strong recommendation; Level 1) In HBeAg-negative children ALT > ULN* on 2 occasions measured 6 months apart and HBV DNA >2,000 IU/mL should be considered for treatment (Strong recommendation, Level 1) Treatment should be initiated for children with advanced fibrosis and cirrhosis (based on clinical findings or non-invasive tests) to lower HCC risk. (Strong recommendation; Level 3) Treatment should be considered for children with extrahepatic disease and co-infection (i.e., HIV, HDV, HCV). (Strong recommendation; Level 2) All pediatric patients undergoing immunosuppression should be assessed regarding need for HBV treatment (similar to adults). (Strong recommendation; Level 1) ETV, TDF and TAF are drugs that are orally administered and exhibit a high genotypic barrier to resistance and a favorable side effect profile. NAs should be continued for 1 year after the disappearance of HBeAg and the appearance of anti-HBe (seroconversion) before attempting cessation. (Strong recommendation; Level 1) After seroconversion, whether spontaneous or treatment induced, children should be followed every 3 months for at least 1 year. After confirmation of immune inactive status (persistently normal ALT, HBV DNA < 2,000 IU/mL), monitoring should be continued every 6 months. (Strong recommendation; Level 2)
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