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.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Intermediate-stage HCC is often treated with either transcatheter arterial chemoembolisation (TACE) or transcatheter arterial embolisation (TAE). Integrating machine learning (ML) offers the possibility of improving treatment outcomes through enhanced patient selection. This systematic review evaluates the effectiveness of ML models in improving the precision and efficacy of both TACE and TAE for intermediate-stage HCC. A comprehensive search of PubMed, EMBASE, Web of Science, and Cochrane Library databases was conducted for studies applying ML models to TACE and TAE in patients with intermediate-stage HCC. Seven studies involving 4,017 patients were included. All included studies were from China. Various ML models, including deep learning and radiomics, were used to predict treatment response, yielding a high predictive accuracy (AUC 0.90). However, study heterogeneity limited comparisons. While ML shows potential in predicting treatment outcomes, further research with standardised protocols and larger, multi-centre trials is needed for clinical integration.

Hepatocellular carcinoma (HCC) accounts for 75-85% of primary liver cancers, with its incidence continually rising, posing a threat to socio-economic development. Currently, liver resection is the standard treatment for HCC. However, post-hepatectomy liver failure (PHLF) is a severe and formidable postoperative complication that increases patients' medical expenses and mortality risk. Additionally, liver failure can occur at any stage of HCC development, severely affecting patients' quality of life and prognosis.

Using the Web of Science Core Collection, this bibliometric study analyzed English articles and reviews on HCC and liver failure from 2003 to 2023. Bibliometric tools like CiteSpace, VOSviewer, and R-studio were employed for data visualization and analysis, focusing on publication trends, citation metrics, explosive intensity, and collaborative networks. Use the Comparative Toxicogenomics and Genecards databases to screen for genes related to liver failure, and perform enrichment analyses using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and PubMed on the identified differentially expressed genes.

The study identified a significant increase in publications on HCC and liver failure, with key contributions from journals such as the World Journal of Gastroenterology and the Journal of Hepatology. The United States, China, and Japan were the leading countries in research output. Prominent authors and institutions, including Kudo Masatoshi and Sun Yat-sen University, were identified. Enrichment analysis showed drug metabolism, oxidative stress, lipid metabolism, and other pathways are closely related to this field. Research hotspots included risk prediction models and novel therapies.

This bibliometric analysis highlights the growing research interest and advancements in HCC and liver failure. Future research should focus on improving risk prediction, developing new therapies, and enhancing international collaboration to address these critical health issues.

Background/Objectives: Hepatitis B virus (HBV) is a virus that can cause chronic hepatitis B (CHB) in humans, leading to cirrhosis and hepatocellular carcinoma (HCC). In this study, we aimed to investigate the relationships between early ALT normalization (at 12 months), the virologic response in CHB patients, and the risk of HCC development. Methods: Data from a retrospective cohort study involving 616 chronic hepatitis B patients were used. The effects of ALT normalization and virologic response on the risk of developing HCC at 12 months of treatment were analyzed. Results: During a median treatment duration of 70.9 months, 36 (5.8%) HCC cases were detected in the total patient population. ALT normalization was detected in 68.83% of patients at 12 months of treatment. The rate of HCC in the group with early ALT normalization was lower than that in the group without ALT normalization, but this difference was not statistically significant (5% vs. 7.8%, p = 0.161). At the end of 12 months of treatment, virologic response was detected in 80.68% of the patients. The rate of patients developing HCC was significantly lower in the virologic response group (4.8% vs. 10.1%, p = 0.028). However, the risk of developing HCC was also significantly higher in the virologically unresponsive group, according to the virologic response at 12 months (p = 0.034). Conclusions: According to the results of this study, achieving virologic response at the end of 12 months in genotype D CHB patients treated with nucleos(t)ide analogs (NAs) reduces the risk of developing HCC.

Based on current practice guidelines, there are a substantial number of individuals who do not meet criteria for chronic hepatitis B (CHB) treatment eligibility but may be at risk of developing HCC. We sought to determine the estimated number of untreated patients with CHB in the Gray Zone or immune-tolerant phase who would develop HCC.

US epidemiologic data were obtained from the US Department of HHS. The literature was reviewed for studies that analyzed the distribution of phases of CHB patients including the Gray Zone and studies that determined the cumulative incidence of HCC over a set period unique to both the Gray Zone and the immune-tolerant phase populations. We modeled the projected number of patients in each group who would develop HCC in a period of 5 and 10 years.

There are about 880,000 to 1.89 million people living with CHB in the US. Based on our model, we estimated 1224-4146 patients and 6662-22,574 patients will likely develop HCC in 5 years and 10 years, respectively, if left untreated in the high viral load and normal liver enzyme Gray Zone. An estimated 356-1537 patients and 873-3774 patients will develop HCC in 5 years and 10 years, respectively, if left untreated in the immune-tolerant phase of CHB. Among patients who develop cirrhosis in the Gray Zone, approximately, 1615-5471 patients will develop HCC.

Current guidelines do not recommend hepatitis B antiviral therapy in patients in the Gray Zone and the immune-tolerant phase. Patients who fall into these categories are still at risk for HCC. By the numbers, the projected number of patients to develop HCC among these populations is in the order of thousands. Future guidelines should explore increasing treatment eligibility for potential mitigation of HCC burden in the US.

Nucleos(t)ide analogues (NUCs) are first-line agents for chronic hepatitis B (CHB). Current guidelines provide recommendations for NUC initiation, yet the guidelines are complex and restrictive. Accumulating data on hepatitis B virus (HBV) replication and HBV integration suggests that there are no real quiescent disease phases in CHB, and treatment-ineligible patients in current guidelines still have substantial risks of cirrhosis and hepatocellular carcinoma. Expanding CHB treatment indications can effectively reduce the risks of liver-related complications. Furthermore, treatment indication expansion can be cost-effective, and can simplify care pathways to remove treatment barriers. Potential caveats for treatment expansion include risks of non-compliance, long-term side effects from NUCs, and poor patient acceptability. Nonetheless, these caveats are not insurmountable, and the benefits of treatment expansion outweigh the disadvantages. There is consensus among hepatologists in supporting treatment indication expansion, although expert panels have varying recommendations on treatment strategies. A treat-all approach, which involves treating all CHB patients, has also been proposed. A treat-all strategy is straightforward, and should yield the greatest benefits from a population health perspective. However, the feasibility of new treatment strategies, especially the treat-all approach, is influenced by multiple factors including local epidemiology, healthcare resource availability, and socioeconomic factors. A one-size-fits-all approach is not optimal, and treatment expansion strategies that are tailored based on local data should yield the greatest impact toward hepatitis elimination.

Hepatitis B virus (HBV) is a global health problem with over 250 million people affected worldwide. Nucleos(t)ide analogues remain the standard of care and suppress production of progeny virions; however, they have limited effect on the viral transcriptome and long-term treatment is associated with off-target toxicities. Promising results are emerging from clinical trials and several drug classes have been evaluated, including capsid assembly modulators and RNA interfering agents. Whilst peripheral biomarkers are used to monitor responses and define treatment endpoints, they fail to reflect the full reservoir of infected hepatocytes. Given these limitations, consideration should be given to the merits of sampling liver tissue, especially in the context of clinical trials. In this review article, we will discuss methods for profiling HBV in liver tissue and their value to the HBV cure programme.

To identify risk factors associated with liver complications in patients with chronic hepatitis B infection in an unselected cohort of hepatitis B patients in southern Spain.

A prospective open-cohort study was conducted on 437 patients with uncomplicated chronic hepatitis B infection in two hospitals in Málaga, southern Spain. The follow-up time ranged from 0.5 to 31.5 years (mean: 13.8±9.5 years; median: 11.4 years). The aim of this study was to evaluate the occurrence of the initial liver complication during follow-up, which is defined as the emergence of liver cancer or complications resulting from portal hypertension. Survival curves were obtained using a time-to-event method through Kaplan-Meier analysis. Multivariate Cox regression was conducted to estimate the hazard ratios of risk factors associated with complications after adjusting for multiple variables. The follow-up of the patients was carried out under conditions of usual clinical practice. Based on the weighted adjustment of these factors, we developed a Hepatitis B Complication Score (HBCS) from which it was possible to identify patients with low and high risk of complications during follow-up.

33 out of 437 patients (7.55%) experienced liver complications, 12 (36.3%) were secondary to portal hypertension, and 21 patients (63.7%) developed liver cancer. A Multivariate Cox regression identified the following independent risk factor: Age above 45 years: HR 7.10 (2.9-17.3); low platelet count: HR 4.88 (2.1-10.9); hepatitis C coinfection: HR 4.68 (2.0-10.9); Male gender: HR 4.64 (1.5-14.2); alkaline phosphatase above 147 UI/mL: HR 4.33 (2.0-8.9); and Child score above 5 points: HR 3.83 (1.7-8.4). The Risk of Complications Score (HBCS) was developed with a high predictive capacity AUROC 0.92 (0.87-0.97).

An HBCS score greater than 3.07 points identifies patients at high risk of developing complications and with an increased risk of liver and all-cause mortality.

This study aims to develop and validate a machine learning (ML) model predicting hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients after the first 5 years of entecavir (ETV) or tenofovir (TFV) therapy.

CHB patients treated with ETV/TFV for > 5 years and not diagnosed with HCC during the first 5 years of therapy were selected from two hospitals. We used 36 variables, including baseline characteristics (age, sex, cirrhosis, and type of antiviral agent) and laboratory values (at baseline, at 5 years, and changes between 5 years) for model development. Five machine learning algorithms were applied to the training dataset and internally validated using a test dataset. External validation was performed.

In years 5-15, a total of 279/5908 (4.7%) and 25/562 (4.5%) patients developed HCC in the derivation and external validation cohorts, respectively. In the training dataset (n = 4726), logistic regression showed the highest area under the receiver operating curve (AUC) of 0.803 and a balanced accuracy of 0.735, outperforming other ML algorithms. An ensemble model combining logistic regression and random forest performed best (AUC, 0.811 and balanced accuracy, 0.754). The results from the test dataset (n = 1182) verified the good performance of the ensemble model (AUC, 0.784 and balanced accuracy, 0.712). External validation confirmed the predictive accuracy of our ensemble model (AUC, 0.862 and balanced accuracy, 0.771). A web-based calculator was developed (http://ai-wm.khu.ac.kr/HCC/).

The proposed ML model excellently predicted HCC risk beyond year 5 of ETV/TFV therapy and, therefore, could facilitate individualised HCC surveillance based on risk stratification.

Plasma pregenomic hepatitis B virus RNA (pgRNA) is a novel biomarker in chronic hepatitis B infection (CHB). We aimed to describe the longitudinal profile of pgRNA and factors influencing its levels in CHB patients on nucleoside analogue (NUC).

Serial plasma samples from 1,354 CHB patients started on first-line NUC were evaluated. Time of NUC initiation was taken as baseline (year 0), followed by 1-year, 3-year and 5-year of NUC therapy. pgRNA was measured by Research Use Only RealTime HBV RNA v2.0 (0.2 mL) (Abbott Diagnostics) with lower limit of detection of 0.8 log U/mL (~20 copies/mL).

Among 1,354 subjects (median age at baseline 49.8 [interquartile range, IQR 40.2-57.3]) years, 65.2% male, 16.1% hepatitis B e antigen (HBeAg)-positive, 28.6% cirrhotic), baseline median HBV RNA was 3.68 (IQR 2.42-5.19) log U/mL. Upon NUC therapy, median pgRNA levels were 2.45 (IQR 1.82-3.62), 2.23 (IQR 1.67-3.05) and 2.14 (IQR 1.48-2.86) log U/mL at 1, 3 and 5 years, respectively, with the corresponding log U/mL reductions of 0.82, 1.20 and 1.54. Undetectable/ unquantifiable pgRNA was achieved in 13.5%, 15.9% and 20.1% of patients at 1, 3 and 5 years, respectively. Older age, male sex, HBeAg-negativity and high PAGE-B score were associated with lower pgRNA.

Plasma pgRNA declines are modest under NUC therapy, with only 16.3% achieving RNA undetectability after 5 years of first-line NUC indicating cccDNA silencing has not been achieved in the majority of patients. Clinical characteristics should be taken into consideration when interpreting the plasma pgRNA level.

We evaluated the diagnostic accuracy of various international guideline criteria for identifying HBeAg-positive chronic HBV infection patients with no significant liver disease. A total of 1108 HBeAg-positive CHB patients were retrospectively enrolled. The guidelines assessed included those from the European Association for the Study of the Liver (EASL) 2017, the American Association for the Study of the Liver Disease (AASLD) 2018, the Asian Pacific Association for the Study of the Liver (APASL) 2015 and the Chinese Society of Hepatology (CSH) 2022. The CSH criteria demonstrated a higher proportion of patients with G0-1 and S0-1 (82.9%) compared to the EASL (75.9%), AASLD (75.3%) and APASL groups (58.8%). Additionally, the CSH criteria exhibited a significantly higher predictive value (AUC 0.782, 95% CI 0.754-0.809) than the EASL (AUC 0.765, 95% CI 0.737-0.793), AASLD (AUC 0.749, 95% CI 0.720-0.778) and APASL (AUC 0.720, 95% CI 0.690-0.750) criteria for identifying G0-1 and S0-1. Adding quantitative HBsAg levels (> 104 IU/mL) to the EASL, AASLD and APASL criteria improved diagnostic performance. Consequently, the CSH guideline thresholds showed higher accuracy in identifying Chinese HBeAg-positive patients with no significant liver disease compared to EASL, AASLD and APASL criteria, emphasising the importance of considering quantitative HBsAg in the evaluation of HBeAg-positive chronic HBV infection.

Early assessment of hepatocellular carcinoma (HCC) risk could improve long-term outcomes in people with chronic hepatitis B virus (HBV) infection. Some existing HCC predictive scores are not easily implementable. We developed easy-to-use HCC predictive scores based on behavioural and routine bio-clinical data in people with chronic HBV infection.

Eight-year follow-up data was analysed from people with chronic HBV infection enrolled in the French ANRS CO22 HEPATHER cohort. Patients were randomly split into two samples (training/testing). A multivariable Cox model for time to HCC was estimated on the training sample. The HCC predictive score was computed by summing the points assigned to model predictors, normalising their coefficients over a 10-year age increment, and rounding to the nearest integer. The Youden index identified the score's optimal risk threshold. Comparisons with existing predictive scores were performed on the testing sample.

In the study population (N = 4370; 63% of men; 65% of < 50 years old), 56 HCC cases occurred during 25,900 follow-up person-years. Two HCC predictive scores were defined: SADAPTT (daily soft drink consumption, age, hepatitis Delta infection, unhealthy alcohol use, platelet count, heavy tobacco smoking, and HBV treatment) and ADAPTT (the same predictors except for daily soft drink consumption), with ranges 0-13 and 0-14, respectively, and values ≥ 3 indicating a high HCC risk. Their performances were similar to existing scores.

We developed two effective behaviour-based HCC predictive scores, implementable in many settings, including primary care and decentralised areas. Further studies are needed to validate these scores in other datasets.

Despite the expanding indications for laparoscopic liver resection (LLR), its role in hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains unclear. The aim of the current study is to compare the short- and long-term outcomes following LLR and open liver resection (OLR) for HCC with PVTT.

All HCC patients with PVTT registered for surgery between April 2015 and May 2022 were enrolled. Patients were divided into LLR and OLR groups, and postoperative recovery and oncological outcomes were analyzed.

Twenty-eight patients in the LLR group and one hundred seventeen patients in the OLR group were included for comparison. The blood loss was less and the postoperative hospital stay was shorter in LLR group compared to OLR group both before and after propensity score matching. The median recurrence-free survival (RFS) time did not significantly differ between the two groups (8.0 months [95% CI 3.1-13.0] vs. 7.5 months [95% CI 6.0-9.1]; P = 0.845). In stratified analysis, both the recurrence pattern and the median RFS time were comparable between the LLR group and the OLR group in type I PVTT (7.23 [95% CI 0.35-14.12] vs. 7.17 months [95% CI 3.49-10.85]; P = 0.794) and type II PVTT (8.96 [95% CI 0-19.56] vs. 7.60 months [95% CI 5.98-9.22], P = 0.651), respectively. The multivariate regression analysis showed that the tumor size ≥ 10 cm, AFP > 200 ng/ml, and HBV-DNA > 1000 copies/ml were independent risk factors for RFS.

LLR for HCC patients with type I/II PVTT could be safely performed with superior short-term recovery and similar long-term survival compared to OLR. Larger tumor size, higher AFP, and elevated HBV-DNA levels contribute to worse RFS.

Identifying alpha-fetal protein (AFP)-negative focal hepatic lesions presents a significant challenge, particularly in China. We sought to develop an economically portable tool for the diagnosis of benign and malignant liver lesions with AFP-negative status, and explore its clinical diagnostic efficiency.

A retrospective study was conducted at Peking University Shenzhen Hospital from January 2017 to February 2023, including a total of 348 inpatients with AFP-negative liver space-occupying lesions. The study used a training set of 252 inpatients from January 2017 to September 2021 to establish a diagnostic model for differentiating benign and malignant AFP-negative liver space-occupying lesions. Additionally, a validation cohort of 96 inpatients from October 2021 to February 2023 was used to confirm the diagnostic performance of the model. From January 2017 to February 2023, patients at JingNing People's Hospital, Gansu Province were assigned to the external cohort (n = 78).

A predictive tool was established by screening age, gender, hepatitis B virus (HBV)/hepatitis C virus (HCV) infected, single lesion, alanine amino transferase (ALT), and lymphocyte-to-monocyte ratio (LMR) using multivariate logistic regression analysis and clinical practice. The area under the curve (AUC) of the model was 0.911 (95% CI [0.873-0.949]) in the training set and 0.882 (95% CI [0.815-0.949]) in the validation cohort. In addition, the model achieved an area under the curve of 0.811 (95% CI [0.687-0.935]) in the external validation cohort.

Our results demonstrated that the predictive tool has the characteristics of good diagnostic efficiency, economy and convenience, which is helpful for the clinical triage and decision-making of AFP-negative liver space-occupying lesions.

Liver cancer is the third leading cause of death globally, with hepatitis B virus (HBV) infection being identified as the primary risk factor for its development. The occurrence of HBV-related hepatocellular carcinoma (HCC) is attributed to various mechanisms, such as chronic inflammation and liver cell regeneration induced by the cytotoxic immune response triggered by the virus, abnormal activation of oncogenes arising from HBV DNA insertion mutations, and epigenetic alterations mediated by viral oncoproteins. The envelope protein of the HBV virus, known as hepatitis B surface antigen (HBsAg), is a key indicator of increased risk for developing HCC in HBsAg-positive individuals. The HBsAg seroclearance status is found to be associated with recurrence in HCC patients undergoing hepatectomy. Additional evidence indicates that HBsAg is essential to the entire process of tumor development, from initiation to advancement, and acts as an oncoprotein involved in accelerating tumor progression. This review comprehensively analyzes the extensive effects and internal mechanisms of HBsAg during the various stages of the initiation and progression of HCC. Furthermore, it highlights the importance and potential applications of HBsAg in the realms of HCC early diagnosis and personalized therapeutic interventions. An in-depth understanding of the molecular mechanism of HBsAg in the occurrence and development of HCC is provided, which is expected to develop more precise and efficient strategies for the prevention and management of HCC in the future.

We propose a causal mediation approach to semi-competing risks under left truncation sampling by considering an intermediate event as a mediator and a terminal event as an outcome. We focus on the causal relationship from exposure to the terminal outcome in relation to the intermediate event. In particular, we study the direct effect, the effect of exposure on the terminal event that is not through the intermediate event, and the indirect effect-the effect of exposure on the terminal event that is mediated through the intermediate event. We propose nonparametric and semiparametric methods, both accounting for left truncation. The nonparametric estimator can be viewed as a model-free time-varying Nelson-Aalen estimator that is robust to model misspecification. The semiparametric estimator calculated with the Cox proportional hazards model enjoys flexibility in adjusting for potential confounders as covariates. The asymptotic properties for both estimators, including uniform consistency and weak convergence, were established using the martingale theorem and functional delta method. The finite sample performance of the proposed estimators was evaluated through extensive numerical studies that investigated the influences of left truncation, confounding, and sample size. The utility of the proposed methods was illustrated using a hepatitis study.

In a population-based survey, Hepatitis B virus (HBV) infection status, associated risk factors and vaccine coverage among the 4006 Particularly Vulnerable Tribal Groups (PVTG) participants of Odisha Tribal Family Health Survey (OTFHS) were assessed using various viral markers. All the HBsAg-positive sera were screened for viral load estimation, envelopment antigen (HBeAg) identification and liver profile parameters. The overall prevalence of HBsAg was 5.73% and the Kutia Khond tribes showed highest prevalence (17.85%; 95% CI:17.41-18.29) of HBsAg. Only 2.7% of children born following the implementation of hepatitis B vaccination were HBsAg positive. Among the children between 0 and 36 months, the vaccination coverage was 91% and mean Anti-HBs titre was 142.56 mIU/ml. Tattooing and piercing were found to be positively associated with high HBsAg positivity. Abnormal liver function (high SGOT and SGPT) occurred more often in HBeAg positive with high viral loads (> 2000 IU/ml). Given the high prevalence of HBV DNA with active viral replication, a strategy for regular monitoring and treatment of these individuals combined with risk factor management and health education in this indigenous population is urgently needed.

Current guidelines to prevent hepatocellular carcinoma (HCC) by chronic hepatitis B virus (HBV) infection are based on risk assessments that include age, sex, and virological and biochemical parameters. The study aim was to investigate the impact of predictive markers on long-term outcomes. The clinical outcomes of 100 patients with chronic hepatitis B were investigated 30 years after a baseline assessment that included liver biopsy. A favourable outcome-HBsAg loss or HBeAg-negative infection (ENI; previously termed 'inactive carrier')-was observed in 74% of all patients, whereas 7% developed HCC. HBsAg loss was observed in 75% of patients with genotype A, compared with 42%, 33% and 0% with genotypes D, B and C, respectively (p < 0.0001). HCC developed in 3 patients (33%) with genotype C as compared with 3 (17%), 1 (2%) and 0 patients with genotypes B, D and A, respectively (p < 0.0001). In multiple logistic regression analysis, both HBsAg loss and HCC were associated with HBV genotype and baseline HBV DNA level, and HCC also with histological score. The results suggest that genotyping and histological assessment may improve outcome prediction and help decisions about HCC screening, particularly in populations with HBV-infected individuals of mixed geographic origin.

Many evidences have confirmed that chromatin regulator factors (CRs) are involved in the progression of cancer, but its potential mechanism of affecting hepatitis B related hepatocellular carcinoma still needs to be studied. Our study detected the CRs that affect hepatitis B related hepatocellular carcinoma (HBV-HCC) through machine learning analysis, conducted the analysis of immune cells, constructed the relevant risk model and immune function infiltration, and predicted the potential therapeutic drugs. We found that these CRs were significantly related to the immune cells of Macrophages, B cells, CD8+T cells, etc., and PBK, AURKA, TOP2A and AURKB were the potential risk CRs of HBV-HCC. The expression levels of these four CRs increased in HepG2.2.15 cells and the liver of HBV-HCC patients, consistent with the predicted risk model. Subsequently, ten potential drugs closely related to the risk CRs were finally obtained, experimental research on resveratrol has shown that it can inhibit the proliferation of HepG2.2.15 cells and potentially inhibit the occurrence and development of HBV-HCC. Our study provides novel insights into the function of CRs in HBV-HCC and certain ideas for more accurate targeted therapy.

Our previous nested-case-control study demonstrated elevated adiponectin increased liver cirrhosis and HCC risk in HBV carriers. We extended the analysis to the whole REVEAL-HBV cohort to prospectively evaluate whether adiponectin directly affected end-stage liver diseases, or through affecting HBV progression.

Baseline plasma adiponectin was determined to investigate the association between adiponectin and subsequent HBeAg, HBsAg, and HBV DNA seroclearance, and the development of cirrhosis, HCC and liver-related death. Whether HBV characteristics modify the adiponectin-milestones associations was also examined.

Among 3,931 HBsAg(+)/anti-HCV(-) REVEAL-HBV participants, 3,684 had sufficient biosamples left for adiponectin assay. Elevated adiponectin was associated with a higher chance of HBeAg-seropositive, high HBV viral load (≥2 × 105 IU/mL) and high HBsAg titers (≥1,000 IU/mL) in a dose-response manner (OR = 2.25, 95% CI: 1.55-3.28; OR = 2.11, 95% CI: 1.47-3.04; and OR = 1.92, 95% CI: 1.47-2.52 for Q5 vs. Q1, respectively). Those with the highest quintile had a lower chance of achieving HBeAg (HR = 0.48, 95% CI: 0.27-0.85), HBsAg (HR = 0.69, 95% CI: 0.49-0.97), and HBV DNA seroclearance (HR = 0.63, 95% CI: 0.43-0.90) and a higher chance of developing liver cirrhosis (HR = 2.88, 95% CI: 1.98-4.20, HCC (HR = 2.38, 95% CI: 1.52-3.73), and died from liver-related causes (HR = 2.32, 95% CI: 1.51-3.54). HBV genotype significantly modified the adiponectin-HCC (Pinteraction = 0.005) and adiponectin-liver death associations (Pinteraction = 0.0157), with higher risk among genotype C.

Elevated adiponectin is consistently associated with all important chronic HBV infection milestones toward progression to liver cancer. The exact mechanism of how adiponectin mediates HBV infection toward carcinogenesis remains unclear and warrants further investigation. Disentangling this may help us in finding new HBV treatment target, biomarker in HBV surveillance to identify high-risk patients, or even cancer prevention.

Mother-to-child transmission (MTCT) is one of the main routes of transmission of HBV, and previous studies focused on the efficacy and safety of nucleoside analogues (NAs) in preventing MTCT. There are limited data on virologic changes of chronic hepatitis B (CHB) patients after discontinuing treatment postpartum and the efficacy of retreatment.

A retrospective-prospective real-world pilot cohort study on pregnant women with CHB was conducted. Biochemical and virological characteristics (HBsAg, HBeAg and HBV DNA) in patients received NAs treatment pre-pregnancy (n = 24), patients discontinued treatment after delivery (n = 88) and retreatment patients (n = 22) were collected during follow-up.

The incidences of HBeAg clearance, half decrease of HBsAg, 0.5 lg decrease of HBsAg and HBsAg < 1000 IU/mL in patients discontinuing treatment postpartum were 5.7% (4/70), 10.0% (8/48), 6.3% (3/48) and 1.6% (1/61), respectively. More significantly decreases of HBsAg, HBeAg and HBV DNA were observed in retreatment patients compared to patients received NAs treatment pre-pregnancy. Significantly higher cumulative incidences of half decrease of HBsAg, 0.5 lg decrease of HBsAg and HBsAg < 1000 IU/mL were achieved in retreatment patients compared to patients received NAs treatment pre-pregnancy. Long-term follow-up results indicated that it is safe for HBeAg positive pregnant patients to discontinue treatment after delivery.

HBeAg positive patients received NAs treatment during pregnancy and discontinued it postpartum can benefit from NAs retreatment because of unexpected decrease of HBsAg, which may be helpful for achieve the goal of functional cure. Trial registration number ClinicalTrials.gov (No.ChiCTR2100054116).

There are several meta-analyses about the comparison of tenofovir disoproxil fumarate (TDF) versus entecavir (ETV) for preventing hepatocellular carcinoma in patients with chronic HBV infection published in recent years. However, the conclusions vary considerably. This umbrella review aims to consolidate evidence from various systematic reviews to evaluate differences in hepatocellular carcinoma prevention between two drugs. Systematic searches were conducted using PubMed, Embase, and Web of Science to identify original meta-analyses. Finally, twelve studies were included for quantitative analyses. We found that TDF treatment was associated with a significantly lower risk of HCC than ETV (hazard ratio, 0.80; 95% CI 0.75-0.86, p < 0.05). The lower risk of HCC in patients given TDF compared with ETV persisted in subgroup analyses performed with propensity score-matched cohorts, cirrhosis cohorts, nucleos(t)ide naïve cohorts and Asian cohorts. In the cohorts of non-Asia and patients without cirrhosis, there was no difference exhibited between these two drugs. Subsequent analyses showed TDF treatment was also associated with a lower incidence of death or transplantation than patients receiving ETV. Overall, the preventive effect of these two drugs on HCC has been studied in several published meta-analyses, but few were graded as high-quality evidence, meanwhile, most of which had high overlap. Thus, future researchers should include updated cohorts or conduct prospective RCTs to further explore this issue.

Hepatocellular carcinoma (HCC) risk persists in patients with chronic hepatitis B (CHB) despite antiviral therapy. The relationship between pre-treatment baseline hepatitis B virus (HBV) viral load and HCC risk during antiviral treatment remains uncertain.

This multinational cohort study aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in 20,826 noncirrhotic, hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with baseline HBV DNA levels ≥2000 IU/mL (3.30 log10 IU/mL) who initiated entecavir or tenofovir treatment. The primary outcome was on-treatment HCC incidence, stratified by baseline HBV viral load as a categorical variable.

In total, 663 patients developed HCC over a median follow-up of 4.1 years, with an incidence rate of 0.81 per 100 person-years (95% confidence interval [CI], 0.75-0.87). Baseline HBV viral load was significantly associated with HCC risk in a non-linear parabolic pattern, independent of other factors. Patients with baseline viral load between 6.00 and 7.00 log10 IU/mL had the highest on-treatment HCC risk (adjusted hazard ratio, 4.28; 95% CI, 2.15-8.52; P < .0001) compared with those with baseline viral load ≥8.00 log10 IU/mL, who exhibited the lowest HCC risk.

Baseline viral load showed a significant, non-linear, parabolic association with HCC risk during antiviral treatment in noncirrhotic patients with CHB. Early initiation of antiviral treatment based on HBV viral load may help prevent irreversible HCC risk accumulation in patients with CHB.

To investigate sex differences in liver disease development and prognosis in individuals with HIV and HBV co-infection. This study comprised 752 HIV/HBV co-infected people who were diagnosed with HIV and started on combination antiretroviral therapy (cART) between January 31st, 2015 and January 31st, 2023. Their clinical data, including CD4+ T lymphocyte counts, HBV-DNA, and FIB-4 scores, were tracked once a year. The prognosis was determined during the long-term surveillance period. Risk factors related with the progression of liver diseases were included in both univariable and multivariable logistic regression. Then, sex differences in CD4+ T lymphocyte counts, HBV-DNA, FIB-4 scores, changes in liver fibrosis levels, and prognosis were investigated. Multivariable logistic regression analysis identified male as an independent risk factor for liver disease progression. Compared to the male group, the female group had a significantly greater decline of HBV DNA levels at years 1, 2, 3, 3-5, and > 5 post-cART. At each assessment point, the female group showed a significantly greater rise in CD4+ T lymphocyte counts than the male group based on their respective baseline values. Furthermore, females had greater CD4+ T lymphocyte counts and a lower prevalence of liver cirrhosis than males throughout the study period. Compared to female, higher incidence of end-stage-liver disease (1.190/100 person-years vs 0.714/100 person-years), higher all-cause mortality (0.440/100 person-years vs 0.148/100 person-years) and higher mortality associated with end-stage-liver diseases (0.273/100 person-years vs 0.074/100 person-years) were found in male. Among individuals with HIV and HBV coinfection, males had a worse therapeutic effect of HBV-active therapy and poorer prognosis than females.

Hepatitis B virus (HBV) infection is a global health concern. The current sequential endpoints for the treatment of HBV infection include viral suppression, hepatitis B e antigen (HBeAg) seroconversion, functional cure, and covalently closed circular DNA (cccDNA) clearance. Serum hepatitis B core-related antigen (HBcrAg) is an emerging HBV marker comprising three components: HBeAg, hepatitis B core antigen, and p22cr. It responds well to the transcriptional activity of cccDNA in the patient's liver and is a promising alternative marker for serological testing. There is a strong correlation, and a decrease in its level corresponds to sustained viral suppression. In patients with chronic hepatitis B (CHB), serum HBcrAg levels are good predictors of HBeAg seroconversion (both spontaneous and after antiviral therapy), particularly in HBeAg-positive patients. Both low baseline HBcrAg levels and decreasing levels early in antiviral therapy favored HBsAg seroconversion, which may serve as a good surrogate option for treatment endpoints. In this review, we summarize the role of serum HBcrAg in the treatment of CHB. Therefore, long-term continuous monitoring of serum HBcrAg levels contributes to the clinical management of patients with CHB and optimizes the choice of treatment regimen, making it a promising marker for monitoring HBV cure.

Entecavir (ETV) may have limited antiviral efficacy in chronic hepatitis B (CHB) patients with a high baseline viral load, especially in cases of partial virologic response (PVR). This study evaluated the outcomes of prolonged ETV monotherapy, given the lack of clear evidence favoring continuation or combination therapy in such scenarios. We included 188 treatment-naïve patients on ETV 0.5 mg and compared antiviral responses between high viral load (HVL, ≥7 log10 IU/mL) and non-HVL groups for over up to 120 months in this study. Compared to the non-HVL group, the HVL group exhibited a lower cumulative virologic response (VR, <20 IU/mL) during the 10-year therapy period (p < 0.01). Antiviral resistance to entecavir (rtS202G + rtM204V + rtL180M) developed in three out of 90 patients in the HVL group. Patients with complete response at 6 months had a 100% likelihood of achieving VR, while 83.9% of patients with PVR at 6 months achieved VR by month 120 (p < 0.01). Multivariate analysis revealed that baseline HVL was a significant predictor of long-term VR at 120 months. In conclusion, CHB patients with baseline HVL and PVR at 6 months are prone to ETV resistance and inadequate response, warranting a modification in treatment strategy.

Background/Objectives: Atezolizumab and bevacizumab combination therapy has been established as a standard of care for first-line treatment; however, its efficacy and safety have not been fully evaluated for patients previously treated with systemic therapy. Methods: In this phase II trial, patients with advanced hepatocellular carcinoma previously treated with lenvatinib were enrolled to receive a dose of 1,200 mg of atezolizumab and 15 mg/kg of bevacizumab every 3 weeks. The primary endpoint was progression-free survival. The secondary endpoints included overall survival, objective response rate, disease control rate, subsequent therapy, and frequency of adverse events. The threshold and expected progression-free survival were 3 and 6.8 months, respectively. Considering a one-sided significance level of 0.05 and a statistical power of 80%, the minimum required sample size was 26 patients. Results: The median progression-free survival from the start of treatment was 9.70 [90% confidence interval, 5.10-14.24] months, and the lower limit of the 90% CI was above the predefined threshold. The objective response and disease control rates were 34.6% and 73.1%, respectively. Sixteen patients (61.5%) received subsequent therapies, and the median overall survival was 17.23 [90% confidence interval, 13.18-27.85] months. Severe adverse events, adverse events leading to treatment delays, and adverse events leading to treatment discontinuation occurred in eight (30.8%), fourteen (53.8%), and five (19.2%) patients, respectively, and no treatment-related deaths occurred. Conclusions: Atezolizumab and bevacizumab combination therapy is effective and can safely be administered to patients with advanced HCC previously treated with lenvatinib.

We herein report a 40-year-old Japanese man with chronic hepatitis B genotype C (viral load 6.7 Log copies/mL) who developed hepatocellular carcinoma (HCC) despite achieving undetectable hepatitis B virus (HBV)-DNA levels with nucleos(t)ide analog (NA) treatment (entecavir). Notably, his hepatitis B surface antigen (HBsAg) level remained elevated at 388.4 IU/mL. Given the continued risk of carcinogenesis associated with HBsAg positivity, we initiated pegylated interferon (PEG-IFN) therapy one month after HCC surgery. Following three periods of PEG-IFN treatment, HBsAg seroclearance (HBsAg-negative state) was achieved.

Hepatitis C virus (HCV) infection is a systemic disease. However, the relative contribution of intrahepatic and extrahepatic diseases to mediating HCV-induced mortality is unclear, albeit critical in resource allocation for reducing preventable deaths. To this end, this study comprehensively quantified the extent to which intrahepatic and extrahepatic diseases mediate HCV-induced mortality.

A community-based cohort study with >25 years of follow-up was conducted in Taiwan. HCV infection was profiled by antibodies against HCV and HCV RNA in participants' serum samples. The cohort data were linked to Taiwan's National Health Insurance Research Database to determine the incidences of potential mediating diseases and mortality. We employed causal mediation analyses to estimate the mediation effects of HCV on mortality in relation to the incidences of 34 candidate diseases.

In 18,972 participants with 934 HCV infection, we observed that 54.1% of HCV-induced mortality was mediated by intrahepatic diseases, such as liver cirrhosis and liver cancer, and 45.9% of mortality was mediated by extrahepatic diseases. The major extrahepatic mediating diseases included septicemia (estimated proportion of HCV-induced mortality mediated through the disease: 25.2%), renal disease (16.7%), blood/immune diseases (12.2%), gallbladder diseases (9.7%), and endocrine diseases (9.6%). In women, hypertension (20.0%), metabolic syndrome (18.9%), and type 2 diabetes (17.0%) also mediated HCV-induced mortality. A dose-response relationship of HCV viral load was further demonstrated for the mediation effect.

Both intrahepatic and extrahepatic manifestations mediated approximately half of HCV-induced mortality. The mediation mechanisms are supported by a dose-response relationship of HCV viral load.

Emerging evidence indicates a robust association between internal RNA N7-methylguanosine (m7G) modification and hepatocarcinogenesis. However, the precise implications of altered internal m7G modifications within mRNA on the progression of Hepatitis B Virus (HBV)-induced Hepatocellular Carcinoma (HCC) remain inadequately elucidated.

This study utilized a previously published dataset from the Gene Expression Omnibus (GEO) that includes samples of normal liver tissue, HBV positive (HP) liver tissue, and HP HCC tissue to investigate the profiling of mRNA internal m7G methylation. The STRING database and in vitro experiments were employed for the screening and validation of key m7G-related genes. The Cancer Genome Atlas cohorts were utilized to analyze the association of these key genes with the prognosis of HCC patients.

Comparative analyses revealed internal m7G modification alterations in 1546 mRNAs between HP liver and normal liver tissues, and in 3424 mRNAs between HP HCC and HP liver tissues. Following Protein-Protein Interaction (PPI) network analyses, validation experiments confirmed sustained high levels of internal m7G methylation modifications in EZH2, SMARCA4, and YY1. Furthermore, these genes were found to exhibit m7G modification-dependent expression changes during the transition from HBV infection to HCC, and were closely associated with the prognosis of HCC patients.

This study provides validation of substantial dynamic alternations in mRNA internal methylation profiles during the HBV infection to HCC. EZH2, SMARCA4, and YY1 emerge as promising molecular targets within this intricate regulatory landscape, offering avenues for further research and potential therapeutic exploration.

This study aims to investigate the impact of comorbidity with chronic hepatitis B (CHB) on the survival rates and incidence of liver cancer in patients with alcohol-related liver disease (ARLD).

Patients with ARLD and those with ARLD co-morbid with CHB were included in this study and designated as the ARLD group and the ARLD + HBV group, respectively. Propensity score matching (PSM) was then employed to compare survival rates and liver cancer development between these two groups.

Among the 404 patients, 254 were in the ARLD group and 150 in the ARLD + HBV group. After propensity score matching, each group comprised 67 patients. Initially, the ARLD + HBV group exhibited lower 5-year survival rates compared to the ARLD group (51.3% vs. 70.1%, p < 0.001). However, PSM mitigated this difference, with survival rates now comparable (61.2% vs. 60.9%, p = 0.390). Notably, the ARLD + HBV group showed a higher incidence of liver-specific mortality after matching (32.6% vs. 6.2%, p = 0.018). Furthermore, although a higher proportion of patients in the ARLD + HBV group developed liver cancer post-matching, the difference was not statistically significant compared to the ARLD group (15.7% vs. 9.8%, p = 0.170).

Co-morbidity with CHB in ARLD patients elevates the risk of liver-related mortality.

Primary liver cancers are tumors that develop from different liver cells. Hepatocellular carcinoma (HCC), which develops from hepatocytes, accounts for approximately 75-85% of primary liver cancers.HCC is the 6th leading cause of cancer worldwide and the 3rd leading cause of cancer-related death. Its incidence is low in northern Europe, but high in sub-Saharan Africa and the Far East, where both hepatotropic viruses and exposure to mycotoxins are. It complicates cirrhosis in over 90% of cases and is predominantly male.The prevalence of HCC is increasing due to improved diagnostic techniques and criteria, but also to the persistence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in adults. A worldwide increase in the incidence of steatopathy makes it the leading cause of liver disease worldwide, associated with alcohol abuse and/or steatohepatitis associated with metabolic dysfunction (MASH), including type 2 diabetes.Chronic hepatotropic viral infections, cirrhosis and chemical carcinogens combine to produce an annual incidence of 2-5% of hepatocellular carcinoma arising from cirrhosis. This justifies biannual surveillance of known cirrhosis, without which late diagnosis limits therapeutic options.Major advances have been made in curative treatment (liver transplantation, surgery, radiodestruction) and palliative treatment (chemo- or radioembolization, sorafenib chemotherapy or immunotherapy), depending on how early HCC is diagnosed (size, number of hepatic or extrahepatic lesions) and the severity of underlying liver disease and associated comorbidities.

To identify risk factors associated with the development of hepatocellular carcinoma (HCC) in an unselected cohort of patients with chronic B virus infection (CHB) in Spain. A predictive model was developed to assess the risk of HCC.

A prospective open-cohort study recruited 446 unselected patients with chronic hepatitis B infection from two hospitals in Málaga (Spain). The follow-up time ranged from 0.5 to 31.5 years (mean: 13.8; SD: 9.5; median: 11.4 years). We used a Cox proportional hazard model to estimate the multivariable-adjusted hazard ratios of risk factors associated with the development of liver cancer and developed a clinical score, (HCCB score) to determine the risk of liver cancer, that categories patients into two risk levels for the development of HCC. We compared the diagnostic accuracy of our model with other previously published.

During the follow-up period, 4.80% of the patients developed liver cancer (21 out of 437), 0.33 cases per 100 patient-years. Multivariate Cox regression analysis revealed that age >45 years, male gender, hepatitis C coinfection, alkaline phosphatase >147IU/L, Child score >5 points, glucose >126mg/dL, and a viral load >4.3 log10 IU/mL were independent risk factors. A risk score has been developed with a high predictive capacity for identifying patients at high risk of developing hepatocellular carcinoma. AUROC 0.87 (95% CI: 0.79-0.95).

An HCCB score greater than 5.42 points identifies a subgroup of chronic hepatitis B patients at high risk of developing liver cancer, who could benefit from screening measures for the early diagnosis of HCC.