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.

The hepatitis B virus (HBV) chronically infects over 250 million people worldwide and is one of the leading causes of liver cancer and hepatocellular carcinoma. HBV persistence is due in part to the highly stable HBV minichromosome or HBV covalently closed circular DNA (cccDNA) that resides in the nucleus. As HBV replication requires the help of host transcription factors to replicate, focusing on host protein–HBV genome interactions may reveal insights into new drug targets against cccDNA. The structural details on such complexes, however, remain poorly defined. In this review, the current literature regarding host transcription factors’ interactions with HBV cccDNA is discussed.

The characterization of hepatitis B virus (HBV) quasispecies in different compartments in liver transplant (LT) recipients may be helpful in optimizing prophylaxis regimens. The aims of this study were to evaluate liver, peripheral blood mononuclear cells (PBMC), and plasma samples for HBV and to compare the quasispecies in hepatic and extrahepatic sites in LT recipients on long-term prophylaxis. For 12 patients followed for up to 15 years post-LT, liver, plasma, and PBMC samples [all HBV DNA–negative according to conventional polymerase chain reaction (PCR) assays] were evaluated for HBV DNA by a sensitive nested PCR method [covalently closed circular DNA (cccDNA) for liver and PBMC samples] and by the sequencing and phylogenetic analysis of polymerase quasispecies. For the 10 patients on prophylaxis with no clinical recurrence (median time post-LT = 15.5 months, range = 12–96 months), liver samples were HBV DNA–reactive in 9 of 10 cases, plasma samples were HBV DNA–reactive in 3 of 10 cases, and PBMC samples were HBV DNA–reactive in 2 of 7 cases (including 1 case with HBV cccDNA in PBMCs). The sequence analysis showed that all HBV clones had a wild-type (WT) sequence in the liver and PBMCs. In 2 patients with early HBV recurrence post-LT who were treated with nucleosides only, HBV DNA was detected in serum, PBMC, and liver samples, and HBV cccDNA was found in liver samples. An HBV lamivudine-resistant variant with an M204I mutation was identified in liver (70% and 18% of the clones) and plasma samples (100% of the clones), but a WT sequence was found in 70% and 100% of the PBMC clones. In conclusion, despite prophylaxis and the absence of HBV DNA in serum according to conventional assays, HBV is detectable in the serum, liver, and PBMCs of almost all patients, and this supports the use of continued anti-HBV therapy in this group. Antiviral drug–resistant variants are more frequent in the liver versus PBMCs, but both compartments are potential sources of reinfection. Liver Transpl 17:955–962, 2011. © 2011 AASLD.

Bepirovirsen, an antisense oligonucleotide, induces sustained reductions in hepatitis B surface antigen (HBsAg) and HBV DNA to below the lower limit of quantification (<LLOQ) in a subset of patients. The B-Together study investigated if sequential bepirovirsen and pegylated interferon-α-2a (Peg-IFN) therapy can reduce relapse rates and improve response rates. In this phase IIb, multicentre, open-label trial, participants on stable nucleos(t)ide analogue (NA) therapy were randomised 1:1 to bepirovirsen 300 mg once weekly (plus loading dose on Days 4 and 11) for 24 (Arm 1) or 12 (Arm 2) weeks followed by Peg-IFN 180 μg once weekly for up to 24 weeks, with up to 36 weeks follow-up. Participants continued NA therapy throughout. The primary outcome was the proportion of participants with HBsAg <0.05 IU/ml and HBV DNA <LLOQ for 24 weeks after planned end of Peg-IFN treatment, in the absence of newly initiated antiviral therapy. The intent-to-treat population included 108 participants (Arm 1, n = 55; Arm 2, n = 53). The primary outcome was achieved by 5 (9%) participants in Arm 1 and 8 (15%) in Arm 2. All responders had baseline HBsAg ≤3,000 IU/ml. Indirect comparison with the phase IIb study B-Clear indicates that sequential addition of Peg-IFN may reduce the relapse rates previously observed with bepirovirsen alone. The proportions of participants with adverse events and treatment-related adverse events in both treatment windows were similar between treatment arms. Sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective in participants with chronic HBV infection on stable NA therapy. This proof-of-concept trial demonstrates a potential strategy to extend responses to bepirovirsen by reducing relapse. This phase IIb study investigated whether sequential therapy with bepirovirsen followed by Peg-IFN could improve off-treatment response rates to bepirovirsen alone by converting partial bepirovirsen responders to full responders and/or reducing relapse rates in participants with chronic HBV. These data show that sequential therapy with bepirovirsen followed by Peg-IFN is tolerable and effective; in patients with a bepirovirsen response, sequential treatment with Peg-IFN may help to reduce off-treatment relapses in participants on stable NA. Participants had a similar response during bepirovirsen treatment as seen in B-Clear, with increased response rates in participants with lower baseline HBsAg; all responders to the sequential regimen had baseline HBsAg <3000 IU/mL. As the first study of antisense oligonucleotide-mediated RNA silencing followed by interferon immunomodulation in patients with chronic HBV infection, this study is an important proof-of-concept for sequential therapy, shedding light on the therapeutic potential of utilising immunomodulators following suppression of HBV antigens. NCT04676724.