The updated EASL Clinical Practice Guidelines on the management of hepatitis B virus (HBV) infection provide comprehensive, evidence-based recommendations for its management. Spanning ten thematic sections, the guidelines address diagnostics, treatment goals, treatment indications, therapeutic options, hepatocellular carcinoma surveillance, management of special populations, HBV reactivation prophylaxis, post-transplant care, HBV prevention strategies, and finally address open questions and future research directions. Chronic HBV remains a global health challenge, with over 250 million individuals affected and significant mortality due to cirrhosis and hepatocellular carcinoma. These guidelines emphasise the importance of early diagnosis, risk stratification based on viral and host factors, and tailored antiviral therapy. Attention is given to simplified algorithms, vaccination, and screening to support global HBV elimination targets. The guidelines also discuss emerging biomarkers and evolving definitions of functional and partial cure. Developed through literature review, expert consensus, and a Delphi process, the guidelines aim to equip healthcare providers across disciplines with practical tools to optimise HBV care and outcomes worldwide.

Liver stiffness measurement (LSM) via vibration-controlled transient elastography accurately assesses fibrosis. We aimed to develop a universal risk score for predicting hepatocellular carcinoma (HCC) development in patients with chronic hepatitis.

We systematically selected predictors and developed the risk prediction model (HCC-LSM) in the hepatitis B virus (HBV) training cohort (n = 2251, median follow-up of 3.2 years). The HCC-LSM model was validated in an independent HBV validation cohort (n = 1191, median follow-up of 5.7 years) and a non-viral chronic liver disease (CLD) extrapolation cohort (n = 1189, median follow-up of 3.3 years). An HCC risk score was then constructed based on a nomogram. An online risk evaluation tool Liver Elastography-Based Hepatocellular Carcinoma Risk Score (LEBER) was developed using ChatGPT4.0.

Eight routinely available predictors were identified, with LSM levels showing a significant dose-response relationship with HCC incidence (P < .001 by log-rank test). The HCC-LSM model exhibited excellent predictive performance in the HBV training cohort (C-index = 0.866) and the HBV validation cohort (C-index = 0.852), with good performance in the extrapolation CLD cohort (C-index = 0.769). The model demonstrated significantly superior discrimination compared to 6 previous models across the 3 cohorts. Cut-off values of 87.2 and 121.1 for the HCC-LSM score categorized participants into low-, medium-, and high-risk groups. An online public risk evaluation tool (LEBER; http://ccra.njmu.edu.cn/LEBER669.html) was developed to facilitate the use of HCC-LSM.

The accessible, reliable risk score based on LSM accurately predicted HCC development in patients with chronic hepatitis, providing an effective risk assessment tool for HCC surveillance strategies.

Background and objectives: The efficacy of antiviral therapy in chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) is controversial. This study aimed to systematically review and analyze antiviral efficacy in ALT-normal CHB patients. Methods: PubMed, Embase, Web of Science, and the Cochrane Library databases from inception to 17 May 2024 were searched for retrieving relevant studies with antiviral efficacy of ALT-normal CHB patients. Results: Of 4992 records screened, 10 studies met the criteria for inclusion and had a low risk of bias. The pooled proportions of undetectable HBV DNA, HBeAg loss, HBeAg seroconversion, HBsAg loss, and HBsAg seroconversion in ALT-normal CHB patients with antiviral therapy were 87%, 35%, 19%, 16%, and 10%, respectively. Subgroup analysis suggested that the virological and serological responses were better in patients receiving IFN-based therapy or with a longer follow-up time. Compared with no treatment, antiviral therapy was associated with significant higher rates of undetectable HBV DNA (RR: 65.62, 95% CI: 16.65-258.57, and p < 0.01), HBeAg loss (RR: 14.97, 95% CI: 3.31-67.65, and p < 0.01), HBsAg loss (RR: 14.22, 95% CI: 4.10-49.29, and p < 0.01), and HBsAg seroconversion (RR: 24.65, 95% CI: 3.06-198.60, and p < 0.01). The normal ALT group and elevated ALT group had comparable antiviral efficacy including proportions of undetectable HBV DNA, HBeAg loss, and HBeAg seroconversion (p > 0.05). Conclusions: CHB patients with normal ALT could benefit from antiviral therapy, and the virological and serological responses were comparable to that of ALT-elevated ones.

This article reviews surveillance for the detection of early stage hepatocellular carcinoma, covering the rationale for surveillance, optimal selection of persons needing surveillance, methods and frequency of screening, strategies for addressing barriers to surveillance, and trends for future improvement in surveillance leading to more effective cancer control and improved patient outcomes. The importance of integrating liver cancer surveillance as a core component of national public health programs is emphasized. The impact of emerging technologies for identifying persons at risk, stratifying individual risk to improve the cost-effectiveness of surveillance programs, and improving the performance, accessibility, and convenience of surveillance are discussed.

The effects of acute kidney injury (AKI) on liver-related outcomes in patients with hepatitis B virus (HBV) infection remain unclear. The study aimed to evaluate the association between AKI with liver-related mortality and complications in patients with HBV infection.

The multicenter, retrospective cohort study included Chinese adults with HBV infection from 24 regional central hospitals between January 2000 and December 2022. AKI was defined as a ≥ 26.5 μmol/l increase in serum creatinine concentration within 48 h, or a ≥ 50% increase over the baseline within 7 days. The primary outcome was post-discharge liver-related mortality, while the secondary outcome was a composite of new-onset liver cirrhosis and hepatocellular carcinoma. Cox proportional hazard model was employed for analyses.

Of the 86,204 inpatients with HBV infection and without liver cancer or cirrhosis at baseline, 4407(5.1%) patients experienced AKI. During a mean follow-up of 4.6 ± 2.4 years, 334 (0.4%) patients died of liver-related events. After adjustment, AKI during hospitalization was significantly associated with a higher risk of liver-related mortality after discharge (adjusted hazard ratio (HR), 1.78; 95% confidence intervals (CI), 1.26-2.51, P = 0.001), especially in those with severe AKI. Similarly, AKI was associated with a higher risk of cirrhosis or new-onset hepatocellular carcinoma (adjusted HR, 1.33; 95%CI, 1.10-1.60, P = 0.004). The association between AKI and liver-related outcomes remained consistent across different subgroups.

AKI during hospitalization was associated with substantial increased risk of liver-related mortality and incident liver-related complication. Our findings highlight the importance of monitoring AKI in patients with HBV infection for tailoring personalized treatments.

Risk prediction models can identify individuals at high risk of chronic liver disease (CLD), but there is limited evidence on the performance of various models in diverse populations. We aimed to systematically review CLD prediction models, meta-analyze their performance, and externally validate them in 0.5 million Chinese adults in the China Kadoorie Biobank (CKB).

Models were identified through a systematic review and categorized by the target population and outcomes (hepatocellular carcinoma [HCC] and CLD). The performance of models to predict 10-year risk of CLD was assessed by discrimination (C-index) and calibration (observed vs predicted probabilies).

The systematic review identified 57 articles and 114 models (28.4% undergone external validation), including 13 eligible for validation in CKB. Models with high discrimination (C-index ≥ 0.70) in CKB were as follows: (1) general population: Li-2018 and Wen 1-2012 for HCC, CLivD score (non-lab and lab) and dAAR for CLD; (2) hepatitis B virus (HBV) infected individuals: Cao-2021 for HCC and CAP-B for CLD. In CKB, all models tended to overestimate the risk (O:E ratio 0.55-0.94). In meta-analysis, we further identified models with high discrimination: (1) general population (C-index ≥ 0.70): Sinn-2020, Wen 2-2012, and Wen 3-2012 for HCC, and FIB-4 and Forns for CLD; (2) HBV infected individuals (C-index ≥ 0.80): RWS-HCC and REACH-B IIa for HCC and GAG-HCC for HCC and CLD.

Several models showed good discrimination and calibration in external validation, indicating their potential feasibility for risk stratification in population-based screening programs for CLD in Chinese adults.

Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of "partial cure" in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.

Expanding antiviral therapy to people with chronic hepatitis B virus (HBV) infection who are ineligible to receive treatment under current international criteria has been increasingly debated. Evidence to support this approach is scarce, especially in Africa. We aimed to address this knowledge gap by analysing the clinical outcomes of people with chronic hepatitis B in The Gambia who were untreated and ineligible for antiviral therapy at diagnosis.

Between Dec 7, 2011, and Jan 24, 2014, we implemented the prospective PROLIFICA cohort study in The Gambia. Participants with chronic hepatitis B aged 16 years or older were recruited after large-scale, community-based HBV screening; blood bank-based HBV screening in Edward Francis Small Teaching Hospital, Banjul; and prospective follow-up of HBsAg-positive individuals via historical, population-based HBsAg serosurveys in two rural villages (Keneba and Manduar). Participants underwent HBV serology and other laboratory tests, fasting FibroScan, and abdominal ultrasound. Survival data were collected between Dec 7, 2011, and Aug 17, 2021. Between Oct 9, 2018, and Aug 17, 2021, all HBsAg-positive participants enrolled in the 2011-14 cohort were invited for a reassessment. For this analysis, we included HBsAg-positive people and excluded all participants who were eligible for treatment according to the 2012 European Association for the Study of the Liver (EASL) criteria at baseline and those who were treated irrespective of treatment eligibility. The primary outcome was all-cause mortality, assessed in all treatment-ineligible and treatment-naive participants with follow-up data. The secondary outcome, analysed in those who were reassessed, was disease progression, defined as becoming eligible for antivirals per 2017 EASL criteria; having an increase in liver fibrosis of at least one stage; or having a clinical diagnosis of hepatic decompensation or hepatocellular carcinoma.

943 HBsAg-positive people with chronic hepatitis B were recruited to the PROLIFICA study. Of these 943, 58 (6%) fulfilled 2012 EASL treatment eligibility criteria at baseline, 35 (4%) were ineligible for treatment but received antiviral therapy, and 44 (5%) were immediately lost to follow-up. Thus, 806 (85%) participants were analysed for the primary outcome (486 [60%] were male and 320 [40%] were female). After a median follow-up of 6·11 years (IQR 5·34-6·80), 708 (88%) participants were confirmed to be alive at last surveillance, 71 (9%) were lost to follow-up and were censored, and 27 (3%) died, giving an all-cause mortality rate of 582 per 100 000 person-years (95% CI 399-849). Of the 27 people who died, five (19%) had liver-related deaths. Of 708 participants confirmed to be alive, 544 (77%) attended follow-up and were assessed for the secondary outcome. Disease progression occurred in 36 (7%) participants: five (1%) became newly eligible for antiviral therapy per EASL 2017 criteria without liver fibrosis progression; 18 (3%) had liver fibrosis progression alone; 13 (2%) had liver fibrosis progression and newly fulfilled the treatment criteria; and none had hepatic decompensation or developed hepatocellular carcinoma. In multivariable analysis adjusted for sex and age, only a baseline HBV DNA of 20 000 IU/mL or more, compared with the baseline HBV DNA of 2000 IU/mL or lower as the reference, was significantly associated with liver disease progression (odds ratio 5·39, 95% CI 1·37-21·23).

Among people with chronic hepatitis B who were ineligible for antiviral therapy in The Gambia, all-cause mortality and liver disease progression were low. The clinical benefit of expanding antiviral therapy in this subgroup of patients remains uncertain.

European Commission, Medical Research Council UK Research and Innovation, and Gilead Sciences.

The construction of a robust healthcare information system is fundamental to enhancing countries' capabilities in the surveillance and control of hepatitis B virus (HBV). Making use of China's rapidly expanding primary healthcare system, this innovative approach using big data and machine learning (ML) could help towards the World Health Organization's (WHO) HBV infection elimination goals of reaching 90% diagnosis and treatment rates by 2030. We aimed to develop and validate HBV detection models using routine clinical data to improve the detection of HBV and support the development of effective interventions to mitigate the impact of this disease in China.

Relevant data records extracted from the Family Medicine Clinic of the University of Hong Kong-Shenzhen Hospital's Hospital Information System were structuralized using state-of-the-art Natural Language Processing techniques. Several ML models have been used to develop HBV risk assessment models. The performance of the ML model was then interpreted using the Shapley value (SHAP) and validated using cohort data randomly divided at a ratio of 2:1 using a five-fold cross-validation framework.

The patterns of physical complaints of patients with and without HBV infection were identified by processing 158,988 clinic attendance records. After removing cases without any clinical parameters from the derivation sample (n = 105,992), 27,392 cases were analysed using six modelling methods. A simplified model for HBV using patients' physical complaints and parameters was developed with good discrimination (AUC = 0.78) and calibration (goodness of fit test p-value >0.05).

Suspected case detection models of HBV, showing potential for clinical deployment, have been developed to improve HBV surveillance in primary care setting in China. (Word count: 264).

Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed.

In 2023, the US Centers for Disease Control and Prevention recommended universal screening for hepatitis B virus (HBV); however, the proportion of US adults screened before implementing this recommendation is unknown. We analysed nationally representative data from the National Health Interview Survey (2013-2017) on self-reported HBV testing among noninstitutionalized US adults ≥18 years. We employed Poisson logistic regression to identify factors associated with self-reported testing, using a conceptual framework that included four overarching factors: sociodemographic characteristics, healthcare access, health-seeking behaviours and experiences, and access to internet-based health information. Among 149,628 survey respondents, the self-reported HBV testing rate was 27.2% (95% CI 26.2-28.7) and increased by 1.7% from 2013 to 2017 (p = .006). In adjusted analysis, health-seeking behaviours and experiences had the strongest associations of self-reported testing including a history of hepatitis (AOR 2.68, 95% CI 1.92-3.73), receipt of hepatitis B vaccination (AOR 5.11, 95% CI 4.61-5.68) and prior testing for hepatitis C (AOR 9.14, 95% CI 7.97-10.48) and HIV (AOR 2.69, 95% CI 2.44-2.97). Other factors associated with testing included being male (AOR 1.14, 95% CI 1.03-1.26), ages 30-44 years (AOR 1.37, 95% CI 1.17-1.61), 45-60 years (AOR 1.55, 95% CI 1.30-1.80) and ≥60 years (AOR 1.53, 95% CI 1.28-1.84), residence in the Western US region (AOR 1.23, 95% CI 1.06-1.43), and access to internet-based health information (AOR 1.32, 95% CI 1.18-1.47). Being Hispanic was associated with lower odds of testing (AOR 0.80, 95% CI 0.66-0.97). These findings may help guide optimal HBV screening in the universal testing era.

New antiviral approaches that target multiple aspects of the HBV replication cycle to improve rates of functional cure are urgently required. HBV RNA represents a novel therapeutic target. Here, we programmed CRISPR-Cas13b endonuclease to specifically target the HBV pregenomic RNA and viral mRNAs in a novel approach to reduce HBV replication and protein expression.

Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pregenomic RNA. Mammalian cells transfected with replication competent wild-type HBV DNA of different genotypes, a HBV-expressing stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-BFP (blue fluorescent protein) and crRNA plasmids, and the impact on HBV replication and protein expression was measured. Wild-type HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and serum HBsAg was measured. PspCas13b mRNA and crRNA were also delivered to a HBsAg-expressing stable cell line via lipid nanoparticles and the impact on secreted HBsAg determined.

Our HBV-targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p <0.0001). HBV protein expression was also reduced in a HBV-expressing stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p <0.0001) in vivo. Lipid nanoparticle-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p = 0.0168) in a HBsAg-expressing stable cell line.

Together, these results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection.

Owing to the limitations of current antiviral therapies for hepatitis B, there is an urgent need for new treatments that target multiple aspects of the HBV replication cycle to improve rates of functional cure. Here, we present CRISPR-Cas13b as a novel strategy to target HBV replication and protein expression, paving the way for its development as a potential new treatment option for patients living with chronic hepatitis B.

Hepatitis B remains a significant global health challenge, contributing to substantial morbidity and mortality. Approximately 254 million people worldwide live with Chronic hepatitis B (CHB), with the majority of cases occurring in sub-Saharan Africa and the Western Pacific regions. Alarmingly, only about 13.4% of the individuals infected with this disease have been diagnosed, and awareness of hepatitis B virus (HBV) infection status is as low as 1% in sub-Saharan Africa. In 2022, CHB led to 1.1 million deaths globally. The World Health Organization (WHO) has set a target of eliminating hepatitis B as a public health concern by 2030; however, this goal appears increasingly unattainable due to multiple challenges. These challenges include low vaccination coverage; a large number of undiagnosed cases; a low proportion of patients eligible for treatment under current guidelines; limited access to healthcare; and the costs associated with lifelong treatment. Treatment of HBV can yield significant clinical benefits within a long window of opportunity. However, the benefits of therapy are markedly diminished when the disease is detected at the advanced cirrhosis stage. This editorial aim to highlight the current challenges in hepatitis care and the necessary steps to achieve the WHO's hepatitis elimination goals for 2030.

There are limited recent data on the burden of chronic hepatitis B (CHB) in the North American general population. We aimed to identify the CHB burden from a Canadian population-based perspective.

Using a retrospective cohort design, we searched Alberta Analytics administrative databases including the Provincial Laboratory database, to describe CHB epidemiology and natural history in Alberta, Canada between fiscal years 2012-2020. We analyzed incidence and prevalence trends using a Poisson regression model and conducted Kaplan-Meier analyses to examine the incident cohort's survival.

The age/sex-adjusted incidence of CHB between 2015-2020 was 27.1/100,000 person/years (29.6/100,000 in males and 24.5/100,000 in females) and was highest among individuals aged 45-64 years. Despite a decrease in annual incidence of CHB from 36.4 to 13.4/100,000 between 2015-2020, prevalence increased from 98.9 to 210.3/100,000 in the same period. Of 6,860 incident cases, 2.1% died, and 0.2% underwent liver transplantation during a median follow-up of 3.6 years (interquartile range 2.0-4.9 years). CHB patients had significantly lower survival rates compared to age/sex-matched Canadians, with a standardized mortality ratio of 3.9 (95% confidence interval [CI] 3.3-4.6). Male sex (hazard ratio [HR] 1.7; 95% CI 1.2-2.5), older age at diagnosis (HR, 1.08; 95% CI 1.07-1.09) independently predicted mortality.

CHB incidence decreased in Alberta, which is consistent with nationwide trends. Males and individuals aged 45-64 had higher CHB incidence and prevalence. CHB patients' lower survival rates emphasize the need to address barriers to guideline recommended HBV care linkage.

Point-of-care (PoC) hepatitis B virus (HBV) DNA viral load (VL) assays represent an alternative to laboratory-based standard-of-care (SoC) VL assays to accelerate diagnosis and treatment. We evaluated the impact of using PoC versus SoC approaches on the uptake of VL testing, treatment, and turnaround times from testing to treatment across the HBV care cascade.

We searched 5 databases, 6 conference websites, and contacted manufacturers for unpublished reports, for articles with or without a comparator (SoC VL testing), and had data on the uptake of VL testing, treatment, or turnaround times between hepatitis B surface antigen (HBsAg) testing, VL testing, and treatment in the cascade. We performed a random-effects meta-analysis on rates of VL testing and treatment initiation.

Six studies, composing 9 arms, were included. Three PoC arms reported less than 1 day between screening for HBsAg positivity and VL testing, and the other one (2 arms) reported it between 7 and 11 days. Five arms reported the time to available VL test results (<1 day). Three studies reported 1-8 days between VL testing results and treatment initiation. Two studies reported the turnaround times between a positive HBsAg screening and treatment initiation (the same day and 27 days). Overall, 84.1% of those with HBsAg positivity were tested for DNA VL and 88.3% of eligible people initiated treatment.

HBV PoC DNA testing appears to be associated with a turnaround time of <1 day for receipt of VL results and appears associated with high rates of DNA testing and initiation of treatment among those eligible.

PROSPERO CRD42023398440.

Management of chronic hepatitis delta (CHD) requires reliable tests for HDV RNA quantification. The aim of the study was to compare two extraction methods for the quantification of HDV RNA in untreated and bulevirtide (BLV)-treated CHD patients.

Frozen sera from untreated and BLV-treated CHD patients were tested in a single-centre study for HDV RNA levels (Robogene 2.0, Roboscreen GmbH, Leipzig, Germany; LOD 6 IU/mL) with two extraction methods: manual (INSTANT Virus RNA/DNA kit; Roboscreen GmbH, Leipzig, Germany) versus automated (EZ1 DSP Virus Kit; Qiagen, Hilden, Germany). BLV-treated patients were sampled at baseline and during therapy.

Two hundred sixty-four sera collected from 157 CHD (139 untreated, 18 BLV-treated) patients were analysed: age 51 (28-78), 59% males, 90% of European origin, 60% cirrhotics, ALT 85 (17-889) U/L, HBsAg 3.8 (1.7-4.6) Log IU/mL, 81% HBV DNA undetectable, 98% HDV genotype 1. Median HDV RNA was 4.53 (.70-8.10) versus 3.77 (.70-6.93) Log IU/mL by manual versus automated extraction (p < .0001). Manual extraction reported similar HDV RNA levels in 31 (20%) patients, higher in 119 (76%) [+.5 and +1 log10 in 60; > +1 log10 in 59] and lower in 7 (4%). Among 18 BLV-treated patients, rates of HDV RNA < LOD significantly differed between the two assays at Weeks 16 and 24 (0% vs. 22%, p = .02; 11% vs. 44%, p = .03), but not at later timepoints. By contrast, virological response rates were similar.

Quantification of HDV RNA by Robogene 2.0 is influenced by the extraction method, the manual extraction being 1 Log more sensitive.

This study aimed to investigate the role of immunocompetence in chronic hepatitis B (CHB) patients with normal alanine transaminase (ALT) levels and negative hepatitis B e antigen (HBeAg) in the risk assessments of the progression of liver fibrosis.

We collected the clinical data of 57 patients with CHB, with normal ALT levels and negative HBeAg from December 2020 to December 2022. With hepatitis B virus (HBV) DNA > 20 IU/mL and ALT ≤ 40 U/L, these patients had never undergone antiviral therapy. The levels of CD4+ , CD4+ CD25+ , CD8+ , and CD4+ CD25+ CD127LOW regulatory T cells (Tregs) in the patients were detected using flow cytometry; the liver stiffness measurement (LSM) values of the patients were detected using Fibroscan.

There was a statistically significant difference between the levels of fibrosis-4 (FIB-4) and hepatitis B surface antigen (HBsAg) when the cutoff point was HBsAg ≥ 1500 (p < .001). FIB-4 was negatively correlated with HBsAg (R = -0.291, p = .028) and positively correlated with age (R = 0.787, p < .001). LSM was negatively correlated with Treg but this correlation was not statistically significant (p > .05). Findings based on the analysis using logistic regression were as follows: (i) age was the independent risk factor when FIB-4 was used as the indicator for assessing liver fibrosis; (ii) Treg was the independent risk factor when LSM was used as the indicator for assessing liver fibrosis. When Treg was used to predict liver fibrosis, the cutoff value, diagnostic efficacy, area under the receiver operating characteristic (ROC) curve, and p value of the ROC curve were 6.875, 0.641, 0.84, and .027, respectively.

Age and Treg are independent risk factors for progressive liver fibrosis. The cutoff value of Treg > 6.81 indicates the need for timely antiviral treatment and can serve as an indicator for evaluating liver fibrosis.

The present study aimed to develop and validate a new nomogram for predicting the incidence of hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients receiving antiviral therapy from real-world data.

The nomogram was established based on a real-world retrospective study of 764 patients with HBV from October 2008 to July 2020. A predictive model for the incidence of HCC was developed by multivariable Cox regression, and a nomogram was constructed. The predictive accuracy and discriminative ability of the nomogram were assessed by the concordance index (C-index), calibration curves, and decision curve analysis (DCA). Risk group stratification was performed to assess the predictive capacity of the nomogram. The nomogram was compared to three current commonly used predictive models.

A total of 764 patients with HBV were recruited for this study. Age, family history of HCC, alcohol consumption, and Aspartate aminotransferase-to-Platelet Ratio Index (APRI) were all independent risk predictors of HCC in CHB patients. The constructed nomogram had good discrimination with a C-index of 0.811. The calibration curve and DCA also proved the reliability and accuracy of the nomogram. Three risk groups (low, moderate, and high) with significantly different prognoses were identified (p < 0.001). The model's performance was significantly better than that of other risk models.

The nomogram was superior in predicting HCC risk among CHB patients who received antiviral treatment. The model can be utilized in clinical practice to aid decision-making on the strategy of long-term HCC surveillance, especially for moderate- and high-risk patients.

We set out to characterise chronic hepatitis B (CHB) in the primary care population in England and investigate risk factors for progression to hepatocellular carcinoma (HCC).

Retrospective cohort study.

We identified 8039 individuals with CHB in individuals aged ≥18 years between 1999 and 2019 in the English primary care database QResearch. HCC risk factors were investigated using Cox proportional hazards modelling.

Most of those with a record of CHB were males (60%) of non-White ethnicity (>70%), and a high proportion were in the most deprived Townsend deprivation quintile (44%). Among 7029 individuals with longitudinal data, 161 HCC cases occurred. Increased HCC hazards were significantly associated with male sex (adjusted hazards ratio [aHR] 3.17, 95% confidence interval [95% CI] 1.92-5.23), in the fifth deprivation quintile as compared to the third quintile (aHR 1.69, 95% CI 1.01-2.84), with older age (for age groups 56-65 and ≥66 years, compared to 26-35 years, aHRs 2.82 [95% CI 1.45-5.46] and 3.76 [95% CI 1.79-7.9], respectively), Caribbean ethnicity (aHR 3.32, 95% CI 1.43-7.71, compared to White ethnicity), ascites (aHR 3.15, 95% CI 1.30-7.67), cirrhosis (aHR 6.55, 95% CI 4.57-9.38) and peptic ulcer disease (aHR 2.26, 95% CI 1.45-3.51).

Targeting interventions and HCC surveillance at vulnerable groups is essential to improve CHB outcomes and to support progress towards international goals for the elimination of hepatitis infection as a public health threat.

Recent studies reported that moderate HBV DNA levels are significantly associated with hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-positive, non-cirrhotic patients with chronic hepatitis B (CHB). We aimed to develop and validate a new risk score to predict HCC development using baseline moderate HBV DNA levels in patients entering into HBeAg-positive CHB from chronic infection.

This multicenter cohort study recruited 3,585 HBeAg-positive, non-cirrhotic patients who started antiviral treatment with entecavir or tenofovir disoproxil fumarate at phase change into CHB from chronic infection in 23 tertiary university-affiliated hospitals of South Korea (2012-2020). A new HCC risk score (PAGED-B) was developed (training cohort, n = 2,367) based on multivariable Cox models. Internal validation using bootstrap sampling and external validation (validation cohort, n = 1,218) were performed.

Sixty (1.7%) patients developed HCC (median follow-up, 5.4 years). In the training cohort, age, gender, platelets, diabetes and moderate HBV DNA levels (5.00-7.99 log10 IU/ml) were independently associated with HCC development; the PAGED-B score (based on these five predictors) showed a time-dependent AUROC of 0.81 for the prediction of HCC development at 5 years. In the validation cohort, the AUROC of PAGED-B was 0.85, significantly higher than for other risk scores (PAGE-B, mPAGE-B, CAMD, and REAL-B). When stratified by the PAGED-B score, the HCC risk was significantly higher in high-risk patients than in low-risk patients (sub-distribution hazard ratio = 8.43 in the training and 11.59 in the validation cohorts, all p <0.001).

The newly established PAGED-B score may enable risk stratification for HCC at the time of transition into HBeAg-positive CHB.

In this study, we developed and validated a new risk score to predict hepatocellular carcinoma (HCC) development in patients entering into hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) from chronic infection. The newly established PAGED-B score, which included baseline moderate HBV DNA levels (5-8 log10 IU/ml), improved on the predictive performance of prior risk scores. Based on a patient's age, gender, diabetic status, platelet count, and moderate DNA levels (5-8 log10 IU/ml) at the phase change into CHB from chronic infection, the PAGED-B score represents a reliable and easily available risk score to predict HCC development during the first 5 years of antiviral treatment in HBeAg-positive patients entering into CHB. With a scoring range from 0 to 12 points, the PAGED-B score significantly differentiated the 5-year HCC risk: low <7 points and high ≥7 points.

Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and represents a global health challenge. Liver cancer ranks third in cancer-related mortality with 830,000 deaths and sixth in incidence with 906,000 new cases annually worldwide. HCC most commonly occurs in patients with underlying liver disease, especially chronic hepatitis B virus (HBV) infection in highly endemic areas. Predicting HCC risk based on scoring models for patients with chronic liver disease is a simple, effective strategy for identifying and stratifying patients to improve the early diagnosis rate and prognosis of HCC. We examined 23 HCC risk scores published worldwide in CHB patients with (n=10) or without (n=13) antiviral treatment. We also described the characteristics of the risk score's predictive performance and application status. In the future, higher predictive accuracy could be achieved by combining novel technologies and machine learning algorithms to develop and update HCC risk score models and integrated early warning and diagnosis systems for HCC in hospitals and communities.

The purpose of this study was to develop an effective and non-invasive nomogram for evaluating liver obvious inflammation in untreated HBeAg positive patients with chronic hepatitis B virus (HBV) infection. A nomogram was established on a model cohort of 292 treatment-naïve HBeAg positive patients with normal alanine aminotransferase (ALT ≤40 U/L) at Beijing Ditan Hospital from January 2008 to March 2018. Then the nomogram was prospectively validated in a cohort of 88 patients from July 2019 to May 2021. Calibration curves and Concordance index were used to evaluate the accuracy of prediction and identification performance of the model. In untreated HBeAg positive chronic hepatitis B virus infection patients with normal ALT, the formula for predicting liver inflammation was Logit (P) =-0.91-0.41×log10 (qHBeAg)+0.11×AST-0.01×PLT. The nomogram had C-index of 0.751 (95% CI, 0.688-0.815), indicating a good consistency between prediction and real observation on the model cohort. The validation cohort confirmed its good performance. In this study, liver inflammation nomograms based on HBeAg, AST, and PLT were established and verified in treatment-naïve HBeAg positive chronic HBV patients with normal ALT.

To facilitate the achieving of the goal of "eliminating viral hepatitis as a major public health threat by 2030" set by the World Health Organization, the Chinese Society of Hepatology together with the Chinese Society of Infectious Diseases (both are branches of the Chinese Medical Association) organized a panel of experts and updated the guidelines for prevention and treatment of chronic hepatitis B in China (version 2022). With the support of available evidence, this revision of the guidelines focuses on active prevention, large scale testing, and expansion of therapeutic indication of chronic hepatitis B with the aim of reducing the hepatitis B related disease burden.

Representatives from academia, industry, regulatory agencies, and patient advocacy groups convened under the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) in June 2022 with the primary goal of achieving consensus on chronic HBV and HDV treatment endpoints to guide clinical trials aiming to "cure" HBV and HDV. Conference participants reached an agreement on some key points. The preferred primary endpoint for phase II/III trials evaluating finite treatments for chronic hepatitis B (CHB) is a "functional" cure, defined as sustained HBsAg loss and HBV DNA less than the lower limit of quantitation (LLOQ) 24 weeks off-treatment. An alternate endpoint would be "partial cure" defined as sustained HBsAg level <100 IU/mL and HBV DNA Collapse

The clinical and histological features of chronic hepatitis B (CHB) patients who fall into the "grey zone (GZ)" and do not fit into conventional natural phases are unclear.

To explore the impact of varying the threshold of alanine aminotransferase (ALT) levels in identifying significant liver injury among GZ patients.

This retrospective analysis involved a cohort of 1617 adult patients diagnosed with CHB who underwent liver biopsy. The clinical phases of CHB patients were determined based on the European Association for the Study of the Liver 2017 Clinical Practice Guidelines. GZ CHB patients were classified into four groups: GZ-A (HBeAg positive, normal ALT levels, and HBV DNA ≤ 107 IU/mL), GZ-B (HBeAg positive, elevated ALT levels, and HBV DNA < 104 or > 107 IU/mL), GZ-C (HBeAg negative, normal ALT levels, and HBV DNA ≥ 2000 IU/mL), and GZ-D (HBeAg negative, elevated ALT levels, and HBV DNA ≤ 2000 IU/mL). Significant hepatic injury (SHI) was defined as the presence of notable liver inflammation (≥ G2) and/or significant fibrosis (≥ S2).

The results showed that 50.22% of patients were classified as GZ, and 63.7% of GZ patients developed SHI. The study also found that lowering the ALT treatment thresholds to the American Association for the Study of Liver Diseases 2018 treatment criteria (35 U/L for men and 25 U/L for women) can more accurately identify patients with significant liver damage in the GZ phases. In total, the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 64.86% [(221 + 294)/794]. When we lowered the ALT treatment threshold to the new criteria (30 U/L for men and 19 U/L for women), the same outcome was revealed, and the proportion of patients with ALT ≤ 40 U/L who required antiviral therapy was 75.44% [(401 + 198)/794]. Additionally, the proportion of SHI was 49.1% in patients under 30 years old and increased to 55.3% in patients over 30 years old (P = 0.136).

These findings suggest the importance of redefining the natural phases of CHB and using new ALT treatment thresholds for better diagnosis and management of CHB patients in the GZ phases.

HBV functional cure is an optimal treatment goal for chronic hepatitis B (CHB) at present and numerous new drugs aiming for HBV functional cure are in development. We carried out an internet-based survey to understand the treatment status, unmet needs, awareness of HBV functional cure and attitude toward related clinical trials among CHB patients in China.

An internet-based anonymous survey was conducted on CHB patients who reside in mainland China. Determinants of awareness and attitude were identified by logistic regression models.

Of the 1220 CHB patients who completed the survey questionnaire, 11.1% (135/1220) were aware of HBV functional cure and 50.2% (612/1220) answered "definitely will" to participate in related clinical trials. Participants who knew their HBsAg level (HBsAg<1500 IU/mL: OR=3.03, 95% CI: 1.87-4.92; HBsAg≥1500 IU/mL: OR=2.57, 95% CI: 1.35-4.88), who expected to achieve HBsAg loss with treatment (OR=1.63, 95% CI: 1.07-2.50) and who were dissatisfied with current treatment due to the failure of achieving HBsAg loss (OR=1.67, 95% CI: 1.10-2.53) had better awareness of HBV functional cure. Participants who had HBsAg level less than 1500 IU/mL (OR=1.45, 95% CI: 1.05-1.99), treatment with pegylated interferon alpha with or without nucleos(t)ide (OR=1.68, 95% CI: 1.11-2.53) and better awareness of HBV functional cure (OR=1.62, 95% CI: 1.01-2.61) were more likely to say "definitely will" to participate in related clinical trials.

Chinese CHB patients reported a low awareness of HBV functional cure. Although CHB patients in China reported a low rate of HBV functional cure awareness, they had a high acceptance of related clinical trials.

Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.

Hepatitis B (HB) vaccination effectively reduces the risks of chronic infection with the hepatitis B virus (HBV). It is unknown whether there is a common genetic determinant for response to the HB vaccine and susceptibility to chronic HBV infection. This case-control study, which included 193 chronic HBV carriers and 495 non-carriers, aimed to explore the effects of the most significant single nucleotide polymorphisms (SNPs) in response to the HB vaccine on the risks of chronic HBV infection. Out of 13 tested SNPs, the genotype distributions of four SNPs at the human leukocyte antigen (HLA) class II region, including rs34039593, rs614348, rs7770370, and rs9277535, were significantly different between HBV carriers and non-carriers. The age-sex-adjusted odds ratios (OR) of chronic HBV infection for rs34039593 TG, rs614348 TC, rs7770370 AA, and rs9277535 AA genotypes were 0.51 (95% confidence interval [CI], 0.33-0.79; p = 0.0028), 0.49 (95% CI, 0.32-0.75; p = 6.5 × 10^-4), 0.33 (95% CI, 0.18-0.63; p = 7.4 × 10^-4), and 0.31 (95% CI, 0.14-0.70; p = 0.0043), respectively. Multivariable analyses showed that rs614348 TC and rs7770370 AA genotypes were significantly independent protectors against chronic HBV infection. The multivariable-adjusted ORs for subjects with none, either one, or both of the protective genotypes were 1.00 (referent), 0.47 (95% CI: 0.32-0.71; p = 3.0 × 10^-4), and 0.16 (95% CI: 0.05-0.54; p = 0.0032), respectively. Among eight HBeAg-positive carriers, only one of them carried a protective genotype. This study shows that response to the HB vaccine and susceptibility to chronic HBV infection share common genetic determinants and indicates that HLA class II members are the main responsible host genetic factors.

We aim to investigate the impact of different clinical phases' definitions of chronic hepatitis B (CHB) infection on the profiles of grey zone, based on HBV guidelines set by the Chinese Society of Hepatology and Chinese Society of Infectious Diseases (CSH/CSID, 2022 version) and guidelines set by the American Association for the Study of Liver Diseases (AASLD, 2018 version). We retrospectively examined untreated CHB patients enrolled in the China Registry of Hepatitis B database. Patients' clinical phases were determined as per CSH/CSID and AASLD. Liver fibrosis was estimated by FIB-4 and/or APRI. Among 3462 CHB patients, 56.9% and 41.7% fell into the grey zone based on AASLD and CSH/CSID. Compared with grey zone patients as per AASLD, those under CSH/CSID guidelines showed lower levels of median ALT (26.0 vs. 37.0 U/L, p < 0.001), AST (25.0 vs. 29.4 U/L, p < 0.001) and APRI (0.3 vs. 0.4, p < 0.001), and lower rates of advanced fibrosis estimated by APRI (7.9% vs. 11.4% p = 0.001), but comparable rates by FIB-4 (13.0% vs. 14.1%, p = 0.389). With the stepwise lowering of ALT upper limits of normal (ULN) values from 50/40 U/L for males/females to 40/40 U/L, 35/25 U/L and 30/19 U/L, the proportions of grey zone patients as per CSH/CSID declined from 46.7% to 41.7%, 34.3% and 28.8%, respectively, whereas they remained stable (55.7%, 56.2%, 56.9% and 57.0%) as per AASLD. Compared with the AASLD guidelines, CSH/CSID guidelines leave fewer and less severe patients in the grey zone. Lowering ALT ULN values reduces the number of grey zone patients as per CSH/CSID, but not under AASLD guidelines.

Hepatitis B virus (HBV) is a life-threatening infectious virus associated with the risk of liver failure and hepatocellular carcinoma (HCC). Regarding HBV treatment, the recent development of nucleoside/nucleotide analogs (NUC), HBV reverse transcriptase inhibitors, enabled favorable viral control as well as improved prognosis in patients with chronic hepatitis B. However, NUC fails to clear HBV because the formation of covalently closed circular DNA or HBV surface antigen occurs upstream of the point of action of NUC. Recently, we found that acyclic nucleoside phosphonates (ANP) such as adefovir or tenofovir, but not lamivudine or entecavir, induced IFN-λ3 productions in the gastrointestinal tract and modulated lipopolysaccharide (LPS)-mediated cytokine profiles in peripheral blood mononuclear cells, such as interleukin (IL)-12p70 induction and IL-10 inhibition, which are immunologically favorable cytokine profiles for HBV elimination. Furthermore, IFN-α, in combination with ANP, showed additional and synergistic effects on IFN-λ3 and IL-12p70 production, respectively, while not affecting IL-10 levels. Mechanistic analyses of the cytokine modulation by ANP revealed that ANP blocked the mammalian target of the rapamycin (mTOR) pathway by inhibiting Akt translocation to the plasma membrane, thereby inhibiting Akt phosphorylation. As it has been reported that IFN-λ inhibits tumor growth directly or indirectly and the mTOR pathway is generally activated in most cancer cells, ANP might have potential anti-HCC effects. Our in vitro and ex vivo findings might stir the debate on whether types of NUC affect the risk of HBV-related HCC incidence.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths globally. The risk factors for HCC include chronic hepatitis B and C virus infections, excessive alcohol consumption, obesity, metabolic disease, and aflatoxin exposure. In addition to these viral and environmental risk factors, individual genetic predisposition is a major determinant of HCC risk. Familial clustering of HCC has been observed, and a hereditary factor likely contributes to the risk of HCC development. The familial aggregation may depend on a shared environment and genetic background as well as the interactions of environmental and genetic factors. Genome-wide association studies (GWASs) are one of the most practical tools for mapping the patterns of inheritance for the most common form of genomic variation, single nucleotide polymorphisms. This approach is practical for investigating genetic variants across the human genome, which is affected by thousands of common genetic variants that do not follow Mendelian inheritance. This review article summarizes the academic knowledge of GWAS-identified genetic loci and their association with HCC. We summarize the GWASs in accordance with various chronic hepatitis virus infection statuses. This genetic profiling could be used to identify candidate biomarkers to refine HCC screening and management by enabling individual risk-based personalization and stratification. A more comprehensive understanding of the genetic mechanisms underlying individual predisposition to HCC may lead to improvements in the prevention and early diagnosis of HCC and the development of effective treatment strategies.

This study aimed to evaluate the predictive performance of pre-existing well-validated hepatocellular carcinoma (HCC) prediction models, established in patients with HBV-related cirrhosis who started potent antiviral therapy (AVT). We retrospectively reviewed the cases of 1339 treatment-naïve patients with HBV-related cirrhosis who started AVT (median period, 56.8 months). The scores of the pre-existing HCC risk prediction models were calculated at the time of AVT initiation. HCC developed in 211 patients (15.1%), and the cumulative probability of HCC development at 5 years was 14.6%. Multivariate Cox regression analysis revealed that older age (adjusted hazard ratio [aHR], 1.023), lower platelet count (aHR, 0.997), lower serum albumin level (aHR, 0.578), and greater LS value (aHR, 1.012) were associated with HCC development. Harrell’s c-indices of the PAGE-B, modified PAGE-B, modified REACH-B, CAMD, aMAP, HCC-RESCUE, AASL-HCC, Toronto HCC Risk Index, PLAN-B, APA-B, CAGE-B, and SAGE-B models were suboptimal in patients with HBV-related cirrhosis, ranging from 0.565 to 0.667. Nevertheless, almost all patients were well stratified into low-, intermediate-, or high-risk groups according to each model (all log-rank p < 0.05), except for HCC-RESCUE (p = 0.080). Since all low-risk patients had cirrhosis at baseline, they had unneglectable cumulative incidence of HCC development (5-year incidence, 4.9−7.5%). Pre-existing risk prediction models for patients with chronic hepatitis B showed suboptimal predictive performances for the assessment of HCC development in patients with HBV-related cirrhosis.

Hepatocellular carcinoma (HCC) is a major public health problem worldwide for which the incidence and mortality are similar, pointing to the lack of effective treatment options. Knowing the different issues involved in the management of HCC, from risk factors to screening and management, is essential to improve the prognosis and quality of life of affected individuals. This document summarises the current state of knowledge and the unmet needs for all the different stakeholders in the care of liver cancer, meaning patients, relatives, physicians, regulatory agencies and health authorities so that optimal care can be delivered to patients. The document was commissioned by the International Liver Cancer Association and was reviewed by senior members, including two ex-presidents of the Association. This document lays out the recommended approaches to the societal management of HCC based on the economic status of a given region.