BACKGROUND & AIMS:Chronic hepatitis B (CHB) remains a leading cause of cirrhosis and hepatocellular carcinoma (HCC) worldwide, yet treatment uptake is suboptimal even in high-resource settings. This pan-Canadian study aimed to quantify treatment gaps within the Canadian Hepatitis B Network (CanHepB) Registry, compare characteristics of treatment-eligible but untreated patients to those receiving therapy, and assess patient and specialist perspectives on barriers to treatment. METHODS:A cross-sectional, retrospective analysis of 1983 adults with CHB followed in 18 Canadian hepatitis B specialty clinics between January 2018 and November 2024. Treatment eligibility was determined using the 2018 Canadian Association for the Study of the Liver guidelines. An anonymous survey captured patient-reported barriers and perspectives (n = 191), while a separate survey evaluated specialist perceptions (n = 54). RESULTS:Among 881 untreated patients, 46.4% (n = 409) were treatment eligible. Compared with the treatment group (n = 1087), the treatment-eligible but untreated patients were younger (median 47.3 vs. 54.5 years), more frequently female (54.2% vs. 39.7%), and more likely to be of Black/African/Caribbean origin (18.2% vs. 9.7%). They had a lower prevalence of cirrhosis (2.4% vs. 20.3%), HCC (0.7% vs. 9.3%), and hypertension (17.1% vs. 22.9%), but a higher prevalence of steatotic liver disease (36.4% vs. 24.6%) and dyslipidemia (14.7% vs. 10.8%). Among untreated respondents, concerns included side effects, the need for long-term therapy, and lack of curative options. Conversely, specialists identified cost as the primary barrier and side effects as the least concerning. CONCLUSION:This nationwide study reveals a significant treatment gap in CHB care, driven by demographic disparities and a mismatch between patient concerns and clinician perceptions.

BACKGROUND & AIMS:Stopping nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B can increase hepatitis B surface antigen (HBsAg) loss rates. However, long-term follow-up (FU) data after NA cessation in a multiethnic population are lacking. This study aimed to assess long-term outcomes after NA cessation in a large global cohort. METHODS:Extended FU data were collected from patients enrolled in the RETRACT-B cohort. New patients were added if they met the inclusion criteria (virally suppressed, HBeAg negative, and HBsAg positive at end of therapy [EOT]). The primary outcome was the 10-year off-treatment HBsAg loss rate. Secondary outcomes were retreatment and adverse events. RESULTS:In total, 2,029 patients were included. At EOT, mean age was 52 years; 81% were Asian, 15% White, and 4% Black/Other. Mean HBsAg at EOT was 2.7 log10 IU/ml (<100/100-1,000/≥1,000 IU/ml: 16/46/38%). Median FU was 65 [range 35-99] months. The 10-year off-treatment HBsAg loss rate was 17% (<100/100-1,000/≥1,000: 52/13/6%, p <0.001) and 59% were retreated (<100/100-1,000/≥1,000: 28/62/71%). HBsAg seroreversion was observed in 9 out of 171 (5.3%) patients, of whom 6 re-lost HBsAg. The 10-year risks of flares, hepatocellular carcinoma and decompensation were 30%, 3.9%, and 3.3%, respectively. A history of cirrhosis was associated with a higher risk of decompensation (10-year: 5.7% vs. 3.0%) and hepatocellular carcinoma (10-year: 12% vs. 2.4%), both p <0.001. CONCLUSION:At 10 years, 17% of patients achieved off-treatment HBsAg loss, whereas more than half were retreated. Patients with HBsAg levels <100 IU/ml benefit the most from NA cessation with a HBsAg loss rate of 52%. Based on our data, finite NA therapy is not recommended if HBsAg is ≥1,000 IU/ml or in patients with cirrhosis. IMPACT AND IMPLICATIONS:Based on our study, we can conclude that finite nucleos(t)ide analogue therapy can be considered in patients with hepatitis B surface antigen (HBsAg) levels <100 IU/ml when aiming for HBsAg loss, since they have the highest likelihood of achieving this endpoint (52%) and the lowest need for retreatment (28%) during long-term follow-up, but only when strict monitoring can be guaranteed. In contrast, finite therapy is not recommended in patients with HBsAg levels ≥1,000 IU/ml or those with a history of cirrhosis, especially as cirrhosis is a known risk factor for hepatic decompensation and hepatocellular carcinoma. In addition, our data can be used to further improve patient monitoring after finite nucleos(t)ide analogue therapy, especially in those who successfully remain off-therapy for 5 to 10 years.

Resistance-associated substitutions (RASs) are mutations within the hepatitis C (HCV) genome that may influence the likelihood of achieving a sustained virological response (SVR) with direct acting antiviral (DAA) treatment. Clinicians conduct RAS testing to adapt treatment regimens with the intent of improving the likelihood of cure. The Canadian Network Undertaking against Hepatitis C (CANUHC) prospective cohort consists of chronic HCV patients enrolled between 2015 and 2023 across 17 Canadian sites. Utilisation of RAS testing was assessed across demographics, clinical characteristics and years. SVR was described for the overall cohort and compared across populations of patients with historically negative predictors of SVR. The detection of key RASs and how this information influenced DAA selection were assessed. 2434 patients were identified with information on RAS testing. 98.3% achieved SVR. Out of the 227 patients tested for RAS, 147 (64.8%) had any detected RAS, and 84 (37.0%) had an NS5A RAS. The proportion of patients with SVR did not differ between RAS-tested (98.3%) and non-tested patients (98.3%; p = 0.99). SVR in those with an NS5a RAS was similar (98.6%) to the overall SVR proportion. Proportions with SVR did not differ between those with and without RAS testing in key subgroups (genotype 1a, genotype 3, prior treatment, cirrhosis). The specific DAA regimen and the addition of ribavirin were not associated with SVR outcome. RAS testing has a minimal influence on antiviral treatment selection. Going forward, there is a reduced role for RAS testing in most clinical scenarios.

Nucleos(t)ide analogs (NAs) provide prolonged viral suppression with favourable clinical outcomes in chronic hepatitis B (CHB) patients. Characterisation of adverse hepatic events after NA cessation leading to liver transplantation (LT) is vital to the improvement of patient management and safety considerations. This is a retrospective case series of CHB patients who developed hepatic decompensation due to NA discontinuation and were referred for LT. Patients with hepatocellular carcinoma or coinfection were excluded. Of 11 CHB patients included (81.8% clinical jaundice, 63.6% ascites, 54.5% hepatic encephalopathy and 18.2% variceal bleeding), 45.5% underwent LT, 36.4% were waitlisted (1 active, 1 died, 2 delisted of whom 1 died), and 18.2% died after referral during the assessment period. Median age was 55.1 years, 81.8% were male, and 72.7% had cirrhosis at NA cessation. Reasons for NA withdrawal included nonadherence (81.8%) and physician discretion (18.2%). Median time from NA cessation to a decompensating event was 3.2 months, and from the decompensating event to referral was 16.0 days. This study shows that most patients experience decompensations soon after NA cessation and reinforces that patients should not discontinue treatment themselves. Physicians should very carefully select non-cirrhotic, adherent patients for NA withdrawal, after which close monitoring and timely retreatment are crucial.

BACKGROUND:The impact of treatment on hepatitis C virus with direct-acting antivirals on 90-day postoperative outcomes, overall survival, and recurrence-free survival in patients after liver resection for hepatocellular carcinoma is unknown. METHODS:We conducted a multicenter retrospective study. Adults who underwent liver resection for hepatitis C virus-related hepatocellular carcinoma between January 2000 and December 2018 were included from 7 international institutions. Groups included direct-acting antiviral treated, non-direct-acting antiviral treated, and untreated hepatitis C virus infection. We used a multivariable model to evaluate the association between receipt of preoperative direct-acting antivirals and 90-day postoperative major complications (Clavien-Dindo class ≥III). RESULTS:We identified 738 patients, including 206 (28%) direct-acting antiviral treated, 241 (33%) non-direct-acting antiviral treated, and 291 (39%) untreated patients. The sustained virologic response rate was 92% in the direct-acting antiviral and 71% in the non-direct-acting antiviral treatment groups. The median follow-up was 7.6 years (95% confidence interval 6.1, 8.6) after surgery for the entire cohort. Patients who received direct-acting antiviral therapy had better 5-year overall and recurrence-free survival than those without antiviral therapy (adjusted hazard ratio [95% confidence interval]: 0.26 [0.19, 0.35] and 0.52 [0.43, 0.64], respectively). Patients who received direct-acting antiviral therapy had better 5-year overall and recurrence-free survival than those who received non-direct-acting antiviral therapy (adjusted hazard ratio [95% confidence interval]: 0.49 [0.36, 0.66] and 0.78 [0.63, 0.96], respectively). There was no significant association between preoperative direct-acting antiviral therapy and 90-day postoperative major complications (adjusted odds ratio 0.34, 95% confidence interval 0.08, 1.01). CONCLUSION:Direct-acting antiviral therapy is associated with improved 5-year overall and recurrence-free survival, without significantly increased risk of 90-day postoperative complications, in patients undergoing liver resection for hepatitis C virus-related hepatocellular carcinoma.

With several drugs in use that inhibit the hepatitis B virus polymerases (nucleos(t)ide analogues (or NUCs)), some argue that new direct-acting antiviral drugs, and new NUCs in particular, are not necessary. Here, we make the counter-argument that additional direct-acting antiviral drugs that can potently suppress hepatitis B virus replication, ideally via distinct mechanisms, are still needed and can provide additional therapeutic benefits.

Background & Aims: Patients with chronic HBV (CHB) with advanced fibrosis are at high risk for hepatocellular carcinoma (HCC). Liver stiffness measurement (LSM) correlates with fibrosis in untreated patients, and is used to monitor changes in severity of liver disease. However, the association between on-treatment LSM and HCC risk is controversial. Methods: We conducted an international multicenter retrospective cohort study of patients with CHB with advanced fibrosis and assessed the association between on-treatment LSM, HCC development, and decompensation events. Results: We analyzed 562 patients (62.8% F4 LSM measurement, 69.2% Asian). During antiviral therapy, the on-treatment LSM decreased to <6 kPa in 209 (37.2%), to 6–9 kPa in 174 (31.0%), and remained >9 kPa in 179 (31.9%) patients. During a median follow-up of 6.8 years after the on-treatment LSM, 56 patients developed HCC and 18 (32.2%) had an on-treatment LSM <6 kPa. The 5-year cumulative HCC incidence was comparable across on-treatment LSM strata; 4.4% for <6 kPa, 5.5% for 6–9 kPa, and 5.8% for >9 kPa (p = 0.300). In multivariable analysis, older age (adjusted hazard ratio (aHR) 1.058, 95% CI 1.026–1.091, p <0.001) and lower platelet count (aHR 0.992, 95% CI 0.992–0.998, p = 0.005) were associated with HCC development, whereas on-treatment LSM was not (aHR 0.974, p = 0.974). By contrast, patients with an LSM decrease to ≤9 kPa had a negligible risk of decompensation (0% vs. 1.8% at 5 years, p = 0.017). Conclusions: Most patients with CHB with advanced fibrosis experienced a decrease in LSM during antiviral therapy. Although a decrease in liver stiffness was associated with a lower risk of decompensation, an improvement in liver stiffness was not associated with a reduction in HCC risk. Impact and implications: The majority of CHB patients with advanced fibrosis have a decrease in LSM during antiviral therapy. Although a decrease in LSM was associated with a lower risk of subsequent hepatic decompensation, an improvement in LSM was not associated with a reduction in HCC risk. HCC surveillance should therefore be continued in patients with advanced fibrosis at baseline regardless of LSM values obtained during therapy.

INTRODUCTION:Metabolic dysfunction and metabolic dysfunction-associated steatotic liver disease (MASLD) are associated with an increased risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to study risk factors for HCC and to assess the performance of the PAGE-B score in this population. METHODS:We included CHB patients with ≥ 1 metabolic comorbidity from nine centres. Steatosis was diagnosed by ultrasound, CAP, or histology. Risk factors were analysed by Cox regression, and the performance of the PAGE-B score was assessed in the overall population and across relevant subgroups. RESULTS:We included 1922 patients. 1730 (90.0%) were overweight, 434 (22.6%) had hypertension, 254 (13.2%) dyslipidemia, 230 (12.0%) diabetes and 732 (38.1%) MASLD. Presence of cirrhosis, older age, lower platelets and lower albumin were independent risk factors for HCC. The 5-year HCC risk was 0.1%/2.0%/12.4% patients with low/intermediate/high PAGE-B scores (p < 0.001). Consistent results were obtained in patients with MASLD (0/2.8/11.1% for low, intermediate and high PAGE-B scores (p < 0.001)). PAGE-B stratified risk in patients without cirrhosis (0% vs. 1.2% and 1.8%, p < 0.001). Among the subset of patients with cirrhosis, risks were 4.2% (low), 6.9% (intermediate) and 27.3% (high) (p < 0.001). CONCLUSIONS:CHB patients with metabolic dysfunction and/or MASLD are at significant risk of HCC. The PAGE-B score can be used to stratify HCC risk in this population, with negligible 5-year HCC incidence in those without cirrhosis and low PAGE-B scores. However, caution should be exercised in patients with cirrhosis in whom HCC risk remains significant even among those with a low PAGE-B score.

Background:Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major causes of morbidity and mortality worldwide. Measuring the epidemiological burden of HCV and HBV in Canada is essential to measure progress towards global elimination targets and to ultimately eliminate viral hepatitis as a public health concern. Objective:This study aimed to provide the first national estimates of HBV prevalence and unawareness, and to update estimates of HCV incidence, prevalence, and unawareness in the general population and key populations in Canada for 2021. Progress towards elimination targets for 2025, namely incidence, awareness, mortality, and HBV vaccination, was also assessed. Methods:A combination workbook method and mathematical modelling was used to estimate the prevalence and unawareness of chronic hepatitis B (CHB), prevalence and incidence of anti-HCV antibodies, and the prevalence and unawareness of chronic hepatitis C (CHC). Results:The estimated prevalence of CHB was 0.68% (plausible range: 0.40%-0.97%) or 262,000 (152,000-371,000) people in the general population, of whom 42.5% (33.9%-51.0%) were unaware of their infection. Immigrants from countries where HBV is common had the highest prevalence at 4.2% (1.9%-5.6%). An estimated 8,212 new HCV infections occurred in 2021, and the estimated prevalence of CHC was 0.56% (0.15%-0.97%) or 214,000 (58,500-369,000) people, of whom 41.5% (34.3%-48.8%) were unaware of their infection. People who inject drugs had the highest prevalence and largest proportion who were unaware at 36.9% (12.6%-55.1%) and 49.9% (29.0%-70.2%), respectively. Conclusion:While the overall viral hepatitis burden is low in the general Canadian population, these estimates indicate that certain populations and communities remain disproportionately affected. Although Canada has met some of the 2025 targets, more work is needed. To this end, efforts to obtain and standardize provincial and national data will be required to measure progress towards all elimination targets.

Chronic liver injury triggers the activation and recruitment of immune cells, causing antigen-independent tissue damage and liver disease progression. Tissue inflammation can reshape macrophage composition through monocyte replacement. Replacement of tissue macrophages with monocytes differentiating in an inflammatory environment can potentially imprint a phenotype that switches the liver from an immune-tolerant organ to one predisposed to tissue damage. We longitudinally sampled the liver of patients with chronic hepatitis B who had active liver inflammation and were starting antiviral therapy. Antiviral therapy suppressed viral replication and liver inflammation, which coincided with decreased myeloid activation markers. Single-cell RNA-Seq mapped peripheral inflammatory markers to a monocyte-derived macrophage population, distinct from Kupffer cells, with an inflammatory transcriptional profile. The inflammatory macrophages (iMacs) differentiated from blood monocytes and were unique from macrophage found in healthy or cirrhotic liver. iMacs retained their core transcriptional signature after inflammation resolved, indicating inflammation-mediated remodeling of the macrophage population in the human liver that may affect progressive liver disease and immunotherapy.

The natural history and response to therapy in chronic hepatitis B (CHB) infection have been defined by a combination of serological and virological biomarkers along with liver biochemistry and/or histology. A number of novel biomarkers, including HBV RNA, hepatitis B core-related antigen, hepatitis B core antigen, and quantitative HBsAg, have been developed and evaluated in different clinical settings. Novel immunological biomarkers have also been studied but have been less well characterized. In addition to providing insights into HBV biology, these novel biomarkers may significantly aid in the design, development, and assessment of novel antiviral strategies aiming for the cure of chronic hepatitis B. Biomarkers can be used to confirm the mechanism of action or target engagement of a novel agent but also may be used for patient selection for trials and clinical use. Ideally, biomarkers can be used to more accurately define stages of chronic hepatitis B, particularly degrees of virological control. In this review, the serological, virological, and immunological biomarkers are described with a focus on how they can be used to guide the development of HBV cure strategies. New terminology is proposed for clinical endpoints, including sustained control to replace the concept of partial cure and resolved chronic infection to replace functional cure, reserving the term cure for clearance or silencing of all covalently closed circular DNA and integrated HBV DNA.

BACKGROUND & AIMS:Sustained virological response (SVR) improves prognosis in patients with chronic hepatitis C virus (HCV) with compensated cirrhosis, but whether a similar benefit can be obtained in decompensated patients is controversial. We studied the association between SVR and liver-related events (LREs) in patients with decompensated HCV cirrhosis. METHODS:We included patients with decompensated HCV cirrhosis (Child-Turcotte-Pugh [CTP] ≥7 and/or history of decompensation) treated with direct-acting antivirals. The association between SVR and LREs, and between SVR-related change in Model for End-stage Liver Disease (MELD) score and LREs were assessed. RESULTS:In total, 914 patients were included, with a median age of 54.7 years; 45% had alcohol use disorder, 87% CTP-B, and the median MELD score was 12.1. SVR was achieved in 834 patients (91.2%), with a median follow-up of 28 months. The 3-year cumulative incidence of LREs was 47.5% in patients with SVR compared with 58.6% in those without (P < .001). Findings were consistent in multivariable analysis (adjusted hazard ratio [aHR], 0.692; P = .011). SVR was associated with a reduced risk of LREs in patients with a pretreatment MELD <15 (44.4% vs 57.6%; aHR, 0.601; P = .004), but not among patients with MELD ≥15 (62.8% vs 58.9%; aHR, 0.936; P = .801). Among patients with SVR, a ≥2-point decrease in MELD was observed in 23.4% and was not associated with a reduced risk of LREs (52.1% vs 50.7%; P = .473). Findings were consistent in multivariable analysis (aHR, 0.730; P = .122), and in patients with a pretreatment MELD score ≥15. CONCLUSIONS:SVR was associated with a reduced risk of LREs in patients with decompensated HCV cirrhosis with a MELD score <15, whereas no clinical benefit was observed in those with higher MELD scores despite an SVR-associated MELD decrease.

Background:Canada's Sexually Transmitted and Blood-borne Infections (STBBI) Action Plan and the Global Health Sector Strategies on STBBI highlight the importance of putting people at the centre of the health system response. Several key populations are disproportionately affected by viral hepatitis, including immigrants. However, there is a limited body of evidence on the burden of viral hepatitis among immigrants in Canada. We seek to address this gap by estimating the prevalence of hepatitis B (HBV) and C (HCV) infections among immigrants in Canada. Methods:Using country- and region-specific publicly available data on the prevalence of HBV and HCV, we estimated the number of immigrants with chronic HBV (CHB), HCV antibodies, and chronic HCV (CHC) by multiplying the number of immigrants from Statistics Canada's 2021 census of population data by the corresponding publicly available country or region-of-origin prevalence, including lower and upper bounds. Each country was categorized as low (<2%) or intermediate-to-high (≥2%) based on published prevalence. To capture changes over time, estimates were stratified by time-period, where possible. Results:In 2021, the estimated prevalence of viral hepatitis among all immigrants was 4.03% for CHB, 1.43% for HCV antibodies, and 0.78% for CHC. The estimated prevalence of CHB, HCV antibodies, and CHC was 0.91%, 0.96% and 0.52%, respectively, among immigrants from low-prevalence countries (<2%). It was 5.57%, 4.04%, and 2.20%, respectively, among immigrants from intermediate-to-high-prevalence countries (≥2%). Conclusion:This is the first study to estimate the burden of HBV and HCV among immigrants at the national level in Canada. The results show that the prevalence of viral hepatitis among immigrants is higher than the general Canadian population. However, grouping all immigrants into one category masks important variation, and potentially over-estimates the burden of HBV and HCV among immigrants. Strengthening our understanding of hepatitis prevalence among immigrants can improve our ability to connect those in need to care and treatment services.

The immune-tolerant (IT) phase of chronic hepatitis B is a distinct stage of infection, characterized by high HBV replication, normal ALT levels, and minimal liver inflammation. Despite its classification as a benign phase, growing evidence challenges this notion, revealing immune activation, HBV DNA integration, and potential oncogenic processes even in the absence of elevated ALT. The IT phase's prolonged high viral replication raises concerns about its implications for HCC risk. Histological studies show that significant inflammation and fibrosis may exist in patients meeting IT criteria, suggesting that the current definitions may underestimate disease activity. Treatment during the IT phase remains controversial, with international guidelines largely recommending against antiviral therapy due to its limited efficacy and potential risks. However, subsets of IT patients may benefit from early intervention. The risks and benefits of therapy in IT chronic hepatitis B are not fully understood, and the lack of consensus regarding treatment thresholds further complicates clinical decision-making. This review highlights the importance of redefining IT chronic hepatitis B to include virological and histological parameters and calls for long-term studies to clarify the role of therapy in reducing fibrosis progression and HCC risk. A more precise understanding of the IT phase is essential to balance the risks of treatment against its potential benefits and to inform future therapeutic strategies.