Canadian Association for the Study of the Liver Single Topic Conference on Hepatitis B Virus: ‘Progress toward hepatitis B elimination in Canada’

Between 1973 and 1975, a serosurvey conducted across villages in Alaska revealed a 6.4% average HBV prevalence rate (ranging from 0% to 23%), particularly among indigenous populations (24,25). In response, a vaccine trial included the implementation of routine HBV vaccination for all infants starting at birth in 1984 (26). In addition, steps to eliminate HBV perinatal transmission have allowed the Alaska to reach the WHO HBV virus elimination goal, and as of 1998, no Alaska Native children have been identified as HBsAg positive. Furthermore, data from the same population have shown that an overwhelming majority of participants exhibit evidence of protection more than three decades after initial vaccination (27). In parallel, early surveys conducted in Arctic and sub-arctic Canada had revealed a high prevalence of HBV, but due to universal birth-dose vaccination programs since the mid-1980s, rates are greatly reduced (>3.0% to <0.1%) (28). Unfortunately, while more recent data are lacking, the strategies employed in Alaska and Canadian northern territories can act as a potential roadmap to achieve HBV eradication in remote communities in northern Canada (29).

In Canada, the latest surveillance and epidemiology study based on national notifiable data on HBV was conducted in 2021 and showed an overall total incidence rate of 9.2 per 100,000, with incidence of acute HBV of 0.3 per 100,000. The rates of reported chronic and unspecified hepatitis B cases in 2021 by province and territory are shown in Figure 1. Notably, there was a 38% reduction in the reported rate from 2019 to 2021 and a 19% decrease from 2020 to 2021, which was likely due to COVID-19 pandemic disruptions. This followed a period of relative stability from 2012 to 2019. Consistently higher rates among males than females were reported, with the highest rate occurring in the 40–59-year age group. Figure 2 illustrates the fluctuations in hepatitis B rates, both overall and by sex, in Canada from 2012 to 2021.

Figure 1: Rates of reported chronic and unspecified hepatitis B cases per 100,000 population by province and territory (Figure reproduced from “Hepatitis B in Canada: 2021 surveillances data”)

Figure 2: Rates of chronic and unspecified hepatitis B overall and by sex in Canada, 2012 to 2021

Between 2015 and 2021, a 30% reduction in reported cases was recorded, on track with WHO elimination targets. However, pre-pandemic data from 2015 to 2019 indicated a 1% increase in reported HBV cases. Unfortunately, comprehensive national data are currently unavailable. However, the childhood vaccination coverage among provinces having implemented the first dose of vaccine by 2 months of age, ranged between 83% and 89% in 2019, below the target of 90%. In terms of mortality, the 2020 target was a 10% reduction in deaths, but between 2015 and 2019, Canada observed only a 1% reduction. Out of the five targets for hepatitis B, only one has been met, and further insights are anticipated with the release of 2022 data.

Several initiatives are aimed at enhancing progress reporting on hepatitis and include the 2021 surveillance data publication, the recognition of the regional variation in hepatitis data across the country, a collaborative approach among all levels of government, and a more integrated approach encompassing both HBV and HCV. Additional updated data is expected to be released in 2024.

Comprehensive data obtained from the British Columbia Hepatitis Testers Cohort highlight gaps in vaccination programs, especially in addressing acute HBV, which is significantly linked to injection drug use and high-risk sexual behavior. In addition, the notable prevalence of HBV among individuals of East Asian ethnicity is evident in British Columbia, and this trend is expected to be similar in other provinces with a significant East Asian population. Consequently, there is a pressing need for screening, especially for immigrants arriving from highly endemic areas. However, screening is not commonly offered in primary care settings to immigrants from endemic countries and is usually limited to individuals with injection drug use or risky sexual behavior.

Co-infections with HCV and HIV are associated with an increased risk of both liver-related and non–liver-related complications. The prevalence of HBV/HIV co-infection is highest among men who have sex with men (MSM), whereas HBV/HCV co-infection is more prevalent among persons who inject drugs (PWID)s. Since there are highly effective treatments for HCV and for managing hepatitis B and HIV, this presents an opportunity to offer individuals these treatments to reduce the overall risk of adverse outcomes (30–34).

In 2023, the Center for Disease Analysis Foundation (CDAF), estimated that 255 million people are living with CHB, constituting 3.2% of the global population. Among them, 32% are considered treatment-eligible and 8% are currently on treatment. However, only 15% have been diagnosed. The majority of HBV infections are predominantly concentrated in low- and middle-income countries. However, in high-income countries, a large proportion of the HBV disease burden stems from immigration. In the USA, over 76% of all HBV infections are among the immigrant population (35,36).

Notably, there are significant variations in the cascade of care based on income groups, with high-income countries exhibiting the lowest prevalence (4.3%) but the highest treatment and diagnosis rates (25% and 45%, respectively). While the prevalence of HBV may only reach 13.3% in upper-middle-income countries compared to 44% prevalence in low-income, only 2% are treated and 7% diagnosed. (35,36). High-income countries experiencing an increased influx of immigration from HBV-endemic regions would benefit from culturally competent screening programs and linkage to care.

Significant progress has been achieved by adopting measures to reduce mother-to-child transmission (MTCT) and implementing early childhood vaccination. Consequently, there has been a substantial decrease in the prevalence of HBV among those aged 5 years and younger. The CDAF projects that 85 countries are poised to meet or exceed the 2023 targets, with a prevalence of <=0.1% in those aged <=5 years old. However, a considerable challenge persists in sub-Saharan Africa, attributed to the Global Alliance for Vaccines and Immunization's (GAVI) decision to support countries with a three-dose vaccination coverage without including a birth dose. In addition, while hepatitis B immunoglobulin is a highly effective intervention combined with a birth dose, administration remains challenging and expensive in many low-income countries. Therefore, exploring the possibility of using antiviral treatment for pregnant women and expanding the treatment criteria is one potential strategy to compensate for the lack of birth dose immunoprophylaxis. Moreover, the widespread absence of readily accessible HBV DNA (viral load testing by polymerase chain reaction) in most countries poses a challenge. There is an urgent need for a substantial scale-up of interventions in nearly all regions to effectively eliminate MTCT.

Currently, no countries are on track to achieve all the 2030 targets, with the programmatic goals of 90% diagnosis and 80% treatment proving particularly challenging. Projections indicate that 42 countries are on track to achieve or surpass the mortality target of four HBV-related deaths per 100,000 individuals by 2030, and 41 are expected to meet both the absolute incidence and mortality targets. However, for most countries, achieving both mortality and incidence targets remains a challenging task. Without a significant increase in treatment efforts, the incidence of liver-related deaths attributed to HBV is anticipated to rise.

Hepatitis delta virus (HDV) remains underdiagnosed, despite an estimated 4%–6% of individuals (∼12 millions) living with HBV who are also co-infected with HDV (37). The testing frequency for HDV is inadequate, and linking patients to care remains a significant challenge. The first European Association for the Study of the Liver (EASL) Clinical Practice Guidelines for HDV were released in 2023 and recommend that all individuals testing positive for HBsAg undergo screening for anti-HDV antibodies at least once, and HDV RNA quantification should be done in all anti-HDV-positive individuals using a polymerase chain reaction (PCR) to diagnose active HDV infection (38). Nonetheless, there is a critical need to make HDV testing practices worldwide more uniform and to create rapid or point-of-care (POC) tests for HDV on the global market.

Hepatitis delta virus infection remains one of the most severe forms of viral hepatitis, with accelerated progression of fibrosis, higher risk of HCC, and worse patient-reported patient outcomes than chronic HBV infection (39). Furthermore, persistent HDV viremia is associated with worse clinical outcomes including progression to cirrhosis or decompensation (40). There is a substantial need for novel therapies for HDV as the only available therapy, pegylated interferon (pegylated interferon alpha, PegIFNα) administered for 48 weeks, only achieves a maintained virologic response (undetectable HDV RNA 24 weeks post-therapy) in less than 25% of cases (41). Nonetheless, reduction of HDV RNA has been associated with clinical benefits and improved survival and > 2 log HDV RNA decline has been suggested as a surrogate clinical endpoint (42). Bulevirtide, an entry inhibitor, which mimics the HBV and HDV receptor binding domain, was approved by the European Medicines Agency in 2022 and is integrated in the EASL 2023 practice guidance. Clinical trials on long term efficacy or combination therapy with PegIFNα are still ongoing (43).

Individuals with chronic hepatitis B typically exhibit a lower metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence than the general population. Extensive cohort studies with follow-up data indicate that HBV infection correlates with a reduced incidence of MASLD, with odds ratios of 0.83 (95% CI 0.73–0.94) (44) and 0.70 (95% CI 0.64–0.76) (45). Moreover, MASLD seems to impede HBV replication and may contribute to the promotion of HBsAg seroconversion (46,47). Despite these observations, the coexistence of CHB and MASLD is increasing, and severe steatohepatitis could potentially worsen liver fibrosis or cirrhosis in patients with HBV (48). The impact of MASLD on the risk of HCC in patients with CHB remains (49–52).

Nonetheless, assessing CHB in the context of MASLD remains a clinical challenge, as elevation in transaminases may stem from either etiology. Persistent abnormalities in liver tests, non-invasive serum fibrosis markers, or vibration-controlled transient elastography (VCTE) results may serve as indicators for initiating antiviral treatment. However, liver biopsy can aid in making informed treatment decisions. Further, the presence of severe steatosis can hinder the effectiveness of ultrasound-based HCC screening in patients with CHB.

Exposure to HBV during infancy carries the highest risk (80%–90%) or chronicity, with mother to child transmission (MTCT) of HBV representing the major cause of CHB infections worldwide (1,35). To address this issue, the WHO and CDC have advocated for universal birth-dose vaccination since the 1990s. In Canada, as of 2021, 7 out of 13 jurisdictions offer a 3-dose HBV vaccination program for infants, covering approximately 40% of the Canadian population. The rationale for the absence of universal birth-dose HBV vaccination in Canada has been attributed to optimal perinatal screening and management programs. Nevertheless, studies have revealed gaps in prenatal hepatitis B screening and management in both the US (53) and Canada [i.e., Ontario (54), British Columbia (55), and Alberta (56)]. Addressing these gaps is essential to ensuring comprehensive protection against MTCT of hepatitis B and to enhance the overall effectiveness of vaccination programs in reducing the global burden of CHB.

Guidelines recommend that all pregnant patients be screened for HBV and HBsAg-positive pregnant patients be referred to a specialist for assessment. Infants born to HBsAg-positive mothers should receive the first dose of the HBV vaccine and hepatitis B immune globulin (HBIg) at birth, followed by two more doses of the HBV vaccine at the ages by 6 months to reduce the risk of MTCT of HBV by >90%. Nonetheless, failure of immunoprophylaxis can occur in cases of infants born to highly viremic HBV E antigen (HBeAg) -positive mothers. Thus, it is recommended that pregnant women with HBV-DNA >5.3 log IU/mL (200,000 IU/mL) receive nucelos(t)ide analog (NA) treatment, with tenofovir disoproxil fumarate (TDF) as the preferred option, in the third trimester (57–60) (Figure 3). In rural/remote as well as urban settings, implementing the extension for community healthcare outcomes (ECHO) model can bridge care gaps and address care disparities for some pregnant women.

Figure 3: Management of CHB in pregnancy to prevent infant immunoprophylaxis failure (WHO 2020)

There is no evidence that supports the modification of the mode of delivery for MTCT of HBV when appropriate passive and active immunoprophylaxis measures are employed. It is noteworthy that amniocentesis in mothers positive for HBsAg with HBV DNA levels of ≥7 log copies/mL increases the risk of MTCT. Mothers with HBV infection can breastfeed safely, and the use of TDF treatment during breastfeeding is also deemed safe (61,62).

In the US, HBV prevalence among individuals aged 6–21 years decreased from 0.72% (1999–2004) to 0.27% (2011–2016) (63). In North America, the immune-tolerant (i.e., high replicative, non-inflammatory, or normal alanine transaminase [ALT]) phenotype is rare among children with CHB, and there is a decreasing trend in HBeAg positivity with age (64). Chronic hepatitis B leads to significant hepatic inflammation and fibrosis in childhood. As such, ALT levels serve as a strong indicator of the severity of hepatic fibrosis, whereas factors such as age, infection duration, HBV DNA levels, and HBV genotype do not show a correlation with fibrosis (65). Hepatocellular carcinoma occurs extremely rarely in young children. However, liver enzymes and alpha-fetoprotein (AFP) are normal upon presentation, and screening practices should be imaging-based (66).

Antiviral therapy, as opposed to no treatment, enhances viral suppression as well as HBeAg seroconversion and HBsAg clearance in children with CHB (67). Treatment threshold differs based on the magnitude of ALT elevation (>1.3 × upper limits of normal [ULN] according to AASLD and >1.5 × ULN according to CASL) and HBV DNA levels in HBeAg-positive children (68,69), with the ultimate aim of achieving sustained HBeAg seroconversion. Withholding treatment while monitoring transaminases for up to 6 months in the context of a hepatitis flare in a HBeAg-positive child can allow for natural progression to a HBeAg-negative state (70). Choice of antiviral treatment varies based on age (interferon alpha recommended for those over 1 year old, lamivudine and entecavir for children aged >2 years, and adefovir and TDF for those aged 12 years and older).

Screening for HBV should be performed in children with unexplained ALT elevations, notwithstanding their immunization status and risk profile, as well as children from endemic areas. In addition, counselling to minimize alcohol and metabolic-related comorbidities is advocated (70). Future studies should focus on treatment response predictors and therapy cessation points, cost-effectiveness of HCC screening, and advocate for the inclusion of children in trials for novel hepatitis B therapies targeting functional cure (70).

Hepatitis B virus-associated hepatocarcinogenesis can potentially occur in initial stages of HBV infection, characterized by a high-replication, low-inflammation state (formerly known as the immune-tolerant phase), with a significant occurrence of HBV-DNA integration and clonal hepatocyte expansion (71). HBV-DNA integration causes HCC through several mechanisms (Figure 4), including genome instability, mutations in proto-oncogenes and tumor suppressors, and expression of mutant viral proteins, including altered or truncated HBsAg, HBV core antigen (HBcAg), and HBx (72). Recent data revealed a significant mutational process in HBV-induced HCC, where viral DNA insertion into the tumor genome induces substantial structural changes, such as non-homologous chromosomal fusions, dicentric chromosomes, and mega base-size telomeric deletions. This aberrant mechanism, found in at least 8% of HCC tumors, drives essential rearrangements for cancer clone survival and growth, including the loss of crucial tumor suppressor genes. Real-time estimations indicate that certain HBV-mediated rearrangements can manifest as early as two decades before the diagnosis of cancer (73). The duration of CHB infection is associated with an increased risk of HCC. Even individuals with serological evidence of past HBV infection (indicating a natural cure) or CHB patients with complete antiviral-induced viral suppression (a functional cure) still face an increased risk of developing HCC (74–76). These findings suggest that hepatocarcinogenesis may be in progress even in individuals with early-stage CHB infection, highlighting the need to reconsider the timing of therapeutic interventions to minimize additional genetic damage to the hepatocytes.

Figure 4: HBV-associated hepatocarcinogenesis

Geographical variability in practice guidance reflects local practices but it also reflects access to diagnostic and therapeutic agents. The 2018 AASLD practice guidelines recommend treatment in active chronic HBV (i.e., ALT ≥2 × ULN and an HBV DNA >20,000 IU/mL if HBeAg positive or HBV DNA <2,000 if HBeAg positive), advanced fibrosis/cirrhosis, and in special populations (68). In contrast, Chinese guidelines recommend treating CHB patients who are positive for HBV DNA, regardless of ALT level and HBeAg status, if they meet any of the following criteria: family history of hepatitis B, cirrhosis, or HCC; age >30 years; non-invasive testing or liver biopsy indicating fibrosis (≥F2); or HBV-related extrahepatic manifestations (77). Therefore, the complexity of AASLD Guidelines can contribute to undertreatment of HBV. Groups potentially benefiting from expanded treatment criteria include immune tolerant or “gray zone” patients (with elevations in either HBV DNA and/or ALT levels not meeting treatment thresholds). Initiating treatment in all “immune tolerant” patients can be justified through the availability of safe and well-tolerated therapy, a reduction in the risk of transmission, a favourable impact on risk of HCC development, and potential cost-effectiveness. Nonetheless, adherence to lifelong therapy is a challenge. A functional cure is not attainable with current agents, with additional pharmacotherapy potentially required, and data on magnitude of reduction in hepatocarcinogenesis is lacking. Therefore, while data are lacking in support of treatment to prevent liver-related complications in this patient population, redefining the immune-tolerant phase is warranted (78–80). Expansion and simplification of treatment guidelines for HBeAg-positive patients to include HBeAg-positive patients with HBV DNA ≥10⁴ IU/mL will be considered in the near future.

At the time of initial presentation, “gray zone” or intermediate patients account for ∼40%–50% of cases and represent around 30% of the CHB patient population (81). Notably, the majority (∼75%) of these patients are HBeAg-negative and a similar percentage (73.9%) maintain their intermediate status over a 5-year follow-up period (81,82). However, patients with HBV DNA levels between 2,000 and 10,000 IU/mL exhibited the highest risk of transitioning, whereas those with lower viral loads demonstrated a lower risk of such transition (83). In addition, antiviral therapy showed a significant reduction in HCC risk (70%) in non-cirrhotic “gray zone” patients during a 6-year follow-up (84). Novel biomarkers might allow for improved management in this patient population as a hepatitis B core-related antigen (HBcrAg) level ≥10,000 U/mL has been associated with an HCC risk comparable to that of individuals with immune-active disease, while levels below that threshold represent a risk similar to inactive CHB (85). In summary, in “gray zone” patients, treatment should be considered for those with HBV DNA levels ≥10,000 IU/mL. For patients with HBV DNA levels between 2,000 and 10,000 IU/mL, treatment is recommended for males, those aged ≥50 years, or individuals with significant fibrosis. Otherwise, monitoring for reactivation is advised. Figure 5 provides a summary of the expanded approach for treating patients with chronic hepatitis B, as proposed by Dr Norrah Terrault.

Figure 5: Expanded approach for treating patients with chronic hepatitis B (presented by Dr. N Terrault)

Figure 6: The mechanism of action for compounds under investigation for hepatitis B treatment

Despite the availability of effective oral medications to manage CHB, the HBV mortality rate has remained consistent over the past two decades due to barriers to linkage to care for individuals at the patient, provider, and healthcare system levels. The complexity of guidelines poses a significant barrier for primary care providers. In addition, testing remains resource intensive, with implementation of point-of-care (POC) testing still lacking in comparison to hepatitis C. Improved electronic medical record (EMR) integration across clinics can prevent discontinuity of patient care during transitions, as has been shown in efforts to link patients to hepatitis C care.

The stigma associated with hepatitis B particularly impacts individuals who are socially marginalized and already face challenges in accessing care. It is essential to integrate strategies that address stigma, discrimination, infectivity, and quality of life issues into patient education and our decision-making processes and guidelines. Patient advocacy groups, such as the Hepatitis B Foundation, play a crucial role in promoting awareness (86). Cultural competence is crucial for delivering HBV-directed care that is customized to individual patients. Using positive messaging to convey a hopeful future with additional treatment options and a potential functional cure can be encouraging for patients.

While there are several already approved therapies for prevention and treatment of HBV infection, additional drugs are at various stages in clinical and pre-clinical trials (https://www.hepb.org/treatment-and-management/clinical-trials/). These agents target various aspects of the HBV life cycle—broadly neutralizing antibodies, capsid assembly modulators, nucleic acid polymerases (NAP), agents targeting HBV gene expression, inhibitors of covalently closed circular DNA (cccDNA) transcription, host-targeting anti-HBV agents, immune modulators, and therapeutic vaccines Figure 6.

HBsAg is an important drug target in chronic HBV infection, as HBsAg loss reflects immune control. A broadly neutralizing antibody, VIR-3434, has been shown to effectively reduce circulating HBsAg in human liver-chimeric mice, and clinical trials are currently underway (87,88).

The HBV core antigen (HBcAg), responsible for the packaging of pgRNA into the core particle and import of rcDNA and dslDNA into the nucleus of hepatocytes, is another potential target. Capsid assembly modulators (CAMs) target the core antigen with several compounds, progressing up to phase II of clinical trials, having been developed, including ABI-H0731 (89), RO7049389 (90), JNJ-56136379 (91), ALG-000184 (92), and GLS4 (93). A substantial HBV DNA reduction of 2–3 logs IU/mL with a 28-day dosing regimen has been observed and HBV DNA suppression is magnified when combined with NAs or PegIFN. However, these compounds do not impact HBsAg levels, and discontinuation of treatment leads to rapid viral rebound. Moreover, concerns about the emergence of drug-resistant mutants persist, although in vivo evidence is limited due to the short treatment duration. Further exploration in phase III studies holds the potential to provide valuable insights into drug resistance patterns.

Nucleic acid polymers (NAP) target viral assembly, focusing on HBsAg, with an exact mechanism of action that remains unclear. In a phase II trial (REP2139/2165+PegIFN+NA), the addition of NAP to the combination of TDF + PEG-INF markedly enhanced the rates of HBsAg loss and HBsAg seroconversion during treatment, leading to functional cure post-therapy. Notably, ALT flares, reaching levels of up to 800 U/L, were common and correlated with the decline in HBsAg levels (94,95).

Targeting HBV gene expression through approaches, such as small interfering RNA (siRNA) and antisense therapies, aim at inhibiting HBV transcription. These agents have shown promise in early clinical phase trials with drugs, such as JNJ3989, VIR02218, AB-729, and RG-6346, and the ASO (i.e., Bepirovirsen) currently in phase III development. These trials exhibited promising results with significant reduction in HBsAg levels in NA-treated patients, showcasing antiviral effect. Notably, there is potential for the restoration of HBV-specific immune responses, particularly with AB-729. Additionally, combinations with immune modulators, such as PEG-IFN in the case of VIR02218, have been investigated, introducing further avenues for exploring comprehensive antiviral strategies (96).

Developing curative treatments for hepatitis B by targeting cccDNA remains the most challenging aspect of therapy. Promising approaches involve genetic editing and epigenetic modification to suppress cccDNA transcription. These methods are currently in the pre-clinical stage, presenting exciting possibilities for advancing hepatitis B treatment. The focus on host-targeting antivirals arises from the limited number of viral targets in Hepatitis B, whereas various host factors have been demonstrated to be essential for productive infection. The potential success of targeting cccDNA in hepatitis B may necessitate involvement with host factors, offering a promising avenue for further research.

Interferons (i.e., alpha, beta, gamma, and lambda), along with interleukin-12 (IL-12), have been tested in HBV with limited clinical effects. Currently, toll-like receptors (TLR), specifically TLR-7 or TLR-8 agonists, are intriguing targets due to their diverse antiviral effects, activating interferon and other cytokines, while also modulating cell-mediated immune responses (97,98). Early clinical trials with NA-treated patients showed induction of innate and adapted immune responses against HBV, with limited effects on HBsAg level (99). The latest generation of TLR-8 agonist (GS-9688) showed some clinical benefits, though further observation is needed to confirm their effectiveness (100).

The therapeutic vaccine strategy for chronic HBV infections seeks to counter the depletion of HBV-specific T cells in CHB patients. The core concept involves restoring or replacing anti-HBV immunity to eradicate viral infection. Various candidates, including protein-based and viral vector-based vaccines, have been tested. While they generally induce some HBV-specific response, it tends to be weak, potentially insufficient for achieving a curative therapy, and of limited clinical benefit has been demonstrated in clinical trials (101–104).

Emerging biomarkers, particularly viral gene products such as the hepatitis B virus core-related antigen (HBcrAg), HBV RNA, and various HBsAg isoforms, are under examination. The HBcrAg consists of three pre-core/core proteins: HBcAg, HBeAg, and a core-related protein (p22cr), with HBeAg being the predominant component. The HBcrAg level is significantly higher in HBeAg-positive patients compared to HBeAg-negative patients. The HBcrAg is a surrogate marker of both intrahepatic cccDNA and its transcriptional activity (105–107). The HBcrAg predicts spontaneous ALT flare, HBeAg loss, and HBsAg loss. However, its incorporation into the baseline predictive model (which includes age, sex, ethnicity, ALT, antiviral therapy, and HBV DNA) with acceptable-excellent accuracy yielded only minor improvements in predictive ability (108). Lower serum HBcrAg levels correlate with an increased likelihood of HBsAg seroclearance over time. For patients with HBsAg levels >1000 IU/mL, the clearance of HBcrAg may serve as an early biomarker for subsequent HBsAg seroclearance (i.e., 10–14 years later) (109). The HBcrAg assay showed high diagnostic performance in identifying patients with HBeAg-negative CHB, regardless of the HBV genotype (110). In HBeAg-negative patients with normal ALT, higher HBcrAg levels are linked to an increased risk of cirrhosis. Conversely, among those with an intermediate viral load, HBcrAg levels <10 KU/mL categorize them as a low-risk group for disease progression (111).

Circulating HBV RNA, primarily composed of pregenomic RNA (pgRNA), is found in the blood of individuals with chronic HBV infection, mainly as virus-like particles. Detection methods include in-house real-time PCR assays and commercial real-time PCR assays, although it is important to note that these assays are often validated using a DNA standard and that an international HBV RNA standard is not yet available. HBV RNA cannot distinguish the source from cccDNA versus integrated DNA (112). The relevance of HBV RNA in the natural history of HBV infection is not well-understood, but there is some potential for HBV RNA to serve as a predictor of therapeutic outcomes on nucleos(t)ide analogs (113–116). The most robust predictor of HBeAg seroconversion was the reduction in HBV RNA levels at months 3 and 6 of treatment, compared to HBV DNA, HBsAg, ALT, as well as factors such as HBV genotype, age, and sex (115). HBV RNA was also found to be a predictor for post-treatment ALT flare and viremic relapse (116).

The HBsAg isoforms consist of large, middle, and small forms, with the small HBsAg being the major component circulating in the blood. A potentially distinct kinetic pattern in HBsAg loss is evident, where a decline in large and middle isoforms precedes the reduction in the small HBsAg antigen. This observation suggests that large and middle isoforms hold promise as novel biomarker candidates for predicting the cure of HBV infection. HBsAg isoforms cannot distinguish the source from cccDNA versus integrated DNA. There is currently no commercially available test for HBsAg isoforms (117,118). An overview of classic and new/emerging biomarkers to guide management, and assessing novel therapies aimed at achieving an HBV cure is provided in Figure 7.

Figure 7: An overview of classic and new/emerging biomarkers to guide management and assessing novel therapies aimed at achieving an HBV cure

In conclusion, there are numerous biomarkers currently in use or under development that are relevant to the natural history and treatment of HBV. While some encouraging data on HBcrAg, HBV RNA, and others are emerging, additional studies are needed. Moreover, the importance of existing traditional markers persists. Further exploration into comorbid risk factors is also necessary to understand their impact on the natural history and treatment outcomes of HBV infection (119).

The Public Health Agency of Canada (PHAC) led a pilot POC HCV testing project through the Health Canada Special Access program. Rapid antibody and molecular testing through fingerstick assay yield results within an hour, compared to the 2 to 4 weeks required by a laboratory. This potentially transformative approach, allowing for single-visit tests and treatment, could thereby minimize loss to follow-up and increase linkage to care in underserved populations. A similar strategy could be employed for HBV screening using a rapid HBsAg test followed by a molecular test. Decentralized testing will be vital in meeting public health targets for sexually transmitted blood borne infections (STBBIs), and other diseases identified as PHAC strategic priorities. In addition, by building point-of-care testing capacity and by supporting community-led diagnostics, Canada will be better positioned for future outbreaks and pandemics to protect historically underserved and undiagnosed populations.

The evolution of the hepatitis B vaccination program in Quebec includes the following key milestones: In 1983, the focus was on high-risk groups, encompassing a maternal screening program and passive-active immunoprophylaxis for newborns of HBsAg-positive mothers. Since then, the hepatitis B immunization program in Quebec has dynamically evolved. In 1994, a pre-adolescent school program was implemented, transitioning in 2003 to two pediatric doses of the combined hepatitis A (HA)-Hepatitis B (HB) vaccine. The program underwent further changes in 2013 with the introduction of an infant program, involving three doses of hexavalent vaccine administered at 2, 4, and 18 months. Notably, in 2019, a modified schedule included hexavalent doses at 2 and 4 months, with an additional dose of the HA-HB vaccine at 18 months. Studies consistently support the program's adaptability, demonstrating that modifications in schedule or dosage can be implemented without compromising protection (120–124).

While the school vaccination program led to a significant reduction of acute cases in children from targeted cohorts, the infant program achieved higher vaccine coverage than the school program. With the implementation of the new schedule, the program can now efficiently immunize children against hepatitis A, utilizing a single dose administered at 18 months of age. Ongoing research explores the feasibility of using only two doses of the hepatitis B vaccine in infants (i.e., one dose of hexavalent vaccine at 2 months and another of the combined HA-HB vaccine at 18 months). While results are pending, there is optimism that this simplified schedule may perform well in providing hepatitis B and A protection.

Addressing the unique healthcare needs of Alaska Native individuals with CHB presents with unique challenges of providing care to those in remote communities. Compliance to regularly scheduled encounters for blood draws, biannual ultrasound exams, or assessment of liver fibrosis are all challenges. The Alaska Native Tribal Health Consortium (ANTHC) Hepatitis Registry oversees the follow-up of patients with chronic HBV, a population that comprises 1,181 individuals, with an average care duration of 33 years. All but eight patients, who declined further follow-up, have been successfully linked to care. Nonetheless, challenges to linkage to care remain as only 25% of patients undergo blood testing every 6 months. However, 65% have these tests at least once a year. The frequency of liver ultrasound is lower, with only 10% undergoing this examination every six months and 60% having it at least once a year.

Despite the success in halting HBV transmission and curing over 1,000 Alaska Natives with HCV, the rate of HCC has doubled in the Alaska Native population since the 1970s. While HCC due to HBV in the Alaska Native population has significantly decreased, cases of HCC due to HCV and MASLD have seen a significant increase. The overall incidence of HCC in Alaska is 8.4 cases per 100,000 individuals. The Hepatitis B Alaska Study identified HBV genotype as a significant risk factor during HCC surveillance for individuals with chronic HBV infection. Higher HCC risk was observed for genotypes F (risk ration [RR], 12.7, 95% CI, 6.1–26.4), C (RR, 10.6, 95% CI, 4.3–26.0), and A (RR, 2.9, 95% CI, 1.0–8.0) compared to genotypes B and D. Genotype F shows the highest incidence among men <40 years and women <50 years and replicons of Genotype F produce more oncogenic genes in animal models (125,126).

The Government of Canada has adopted an integrated approach, tailoring programs to address the complexity and interrelated nature of risk factors and transmission routes for STBBI. It has also endorsed the WHO and United Nations Program on HIV/AIDS (UNAIDS) global targets to eliminate STBBI, including viral hepatitis, as public health concerns by 2030, which is outlined in the 2018 Pan-Canadian STBBI Framework for Action (127 ) and the 2019 Government of Canada Five-Year Action Plan on STBBI (128). The Government of Canada's Renewed Action Plan will endorse new global targets for 2030, including HBV and HCV, and leverage lessons learned from the COVID-19 pandemic. Table 2 presents an overview of the diverse roles by the federal government toward hepatitis B elimination. The renewal of the Action Plan underscores the importance of collaboration with key stakeholders, partners, and populations. This collaborative approach is essential in shaping policies and guidelines, and working together serves to accelerate efforts toward the elimination of viral hepatitis and STBBI in Canada.

Table 2: An overview of the diverse roles by the federal government toward hepatitis B elimination