One of the key features of chronic hepatitis B virus (HBV) infection is the inability to mount sufficient and coordinated adaptive immune responses against HBV. Recent studies on HBV-specific B cells and antibody to hepatitis B surface antigen (anti-HBs) have shed light on their role in the pathogenesis of chronic hepatitis B (CHB). Anti-HBs is recognized as a protective immune marker, both for HBV infection clearance and following vaccination, and it is also considered an important indicator of functional cure for CHB. Notably, functional impairment of HBV-specific B cells may be reversible. The restoration of HBV-specific B cell function, along with the induction of an anti-HBs antibody response, is regarded as pivotal for terminating chronic HBV infection and achieving functional cure. This article reviews the significance of anti-HBs in both the infection and clearance of HBV, and discusses the potential of neutralizing antibodies and therapeutic vaccines as promising future strategies.

Chronic hepatitis B (CHB) is a common cause of liver cirrhosis (LC), a condition associated with an unfavourable prognosis. Therefore, timely diagnosis of LC in CHB patients is crucial.

This study aimed to enhance the diagnostic accuracy of LC in CHB patients by integrating liver stiffness measurement (LSM) with traditional indicators.

The study participants were randomly divided into training and internal validation sets. Employing the least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) for feature selection, we developed both traditional logistic regression and five machine learning models (k-nearest neighbors, random forest (RF), artificial neural network, support vector machine and eXtreme Gradient Boosting). Performance evaluation included receiver operating characteristic curves, calibration curves and decision curve analysis. Shapley additive explanations (SHAP) was employed to improve the interpretability of the optimal model.

We retrospectively included 1609 patients with CHB, among whom 470 were diagnosed with cirrhosis. Cirrhosis was diagnosed based on histological confirmation or clinical assessment, supported by characteristic findings on abdominal ultrasound and corroborative evidence such as thrombocytopenia, varices or imaging from CT/MRI. In the internal validation, the RF model achieved an accuracy above 0.80 and an AUC above 0.80, with outstanding calibration ability and clinical net benefit. Additionally, the model exhibited excellent predictive performance in an independent external validation set. The SHAP analysis indicated that LSM contributed the most to the model. The model still showed strong discriminative power when using only LSM or traditional indicators alone.

Machine learning models, especially the RF model, can effectively identify LC in CHB patients. Integrating LSM with traditional indicators can enhance diagnostic performance.

This study evaluated the diagnostic and analytical performances of the Access anti-HBc IgM assay (Access assay) for use on the DxI 9000 Access Immunoassay Analyzer. Prospectively and retrospectively collected samples were tested with Access and a comparator assay with use of a second comparator for discrepant resolution to determine final anti-HBc IgM sample status. Specificity of Access was 100.00 % (99.65 - 100.00 %) on 1,098 anti-HBc IgM negative blood donor samples, 100.00 % (98.74 - 100.00 %) on 300 anti-HBc IgM negative hospitalized patient samples and 94.08 % (89.45 - 96.75 %) on 169 anti-HBc IgM negative acute/recent and chronic HBV infected patient samples. Sensitivity was 100.00 % (98.42 - 100.00 %) on 239 anti-HBc IgM positive acute/recent and chronic HBV infected patient samples. Seroconversion panels showed mean first day of detection 3.2 days earlier with Access than with the comparator assay. Maximum reproducibility on positive samples was 8.6 % coefficient of variance (CV) and 0.048 S/CO standard deviation (SD) on negative samples. The Access anti-HBc IgM assay demonstrated excellent diagnostic and analytical performances comparable to other current CE-marked anti-HBc IgM assays.

Hepatitis B virus reactivation (HBVr) can occur in patients with resolved hepatitis B virus (HBV) infection receiving immunosuppressive therapy. The class of immunosuppression influences HBV reactivation (HBVr) risk, with B-cell depleting agents such as Rituximab conferring a higher risk. The presence of hepatitis B surface antibodies (HBsAb) may be protective against HBVr.

To compare the rates of HBVr amongst individuals with resolved HBV infection receiving rituximab and non-rituximab immunosuppressive therapy, without chemoprophylaxis. Our secondary objective was to explore the role of HBsAb in risk stratification for HBVr.

We retrospectively collected the data of patients with resolved HBV infection receiving immunosuppressants between 2014 and 2022. HBVr rates amongst patients receiving rituximab and non-rituximab therapy were compared. Logistic regression analysis was performed to identify risk factors for HBVr.

148 patients with resolved HBV infection did not receive chemoprophylaxis. Of the 20 (13.5%) patients who developed HBVr, none developed HBV flare. 42 of the 148 (28.3%) patients received rituximab-based therapy. Patients who received rituximab had a higher risk of HBVr, 12(28.6%) vs 8(7.5%), P = 0.001. This was confirmed on multivariable analysis (OR 4.19 [C.I. 1.47-11.9], P = 0.007). HBsAb titres of above 100 mIU/ml were protective against HBVr (OR 0.04 [CI 0.001-0.84], P = 0.039) in the rituximab exposed cohort, but not in the non-rituximab exposed cohort.

The risk of HBVr was higher in patients receiving rituximab; however, no patient developed HBV flare. In patients with resolved HBV infection, the presence of HBsAb titres above 100 mIU/ml may confer additional protection against HBVr and can be used as part of risk stratification for HBVr. In such patients, close surveillance with on-demand therapy instead of chemoprophylaxis may be considered.

Chronic hepatitis B (CHB) remains a global health challenge, contributing to significant morbidity and mortality. While long-term nucleos(t)ide analogue (NA) therapy effectively suppresses viral replication, achieving a functional cure remains rare. Current treatment guidelines primarily recommend indefinite therapy. However, long-term NA use poses many challenges, prompting interest in finite therapy. Recent studies suggest that carefully selected patients may safely discontinue NAs, leading to a functional cure in some cases. This review evaluates the latest evidence on NA discontinuation, highlighting key factors influencing outcomes. This review synthesises established and emerging evidence on NA discontinuation in CHB. It explores early studies that identified quantitative HBsAg (qHBsAg) as a predictor of sustained response and HBsAg seroclearance, followed by systematic reviews and meta-analyses reinforcing finite therapy as a feasible approach. Advances in predictive modelling, incorporating biomarkers, have refined patient selection for safe NA withdrawal. Additionally, this review assesses the risks associated with NA discontinuation, highlighting the importance of identifying high-risk patients for hepatic decompensation. Ethnicity-specific qHBsAg cut-offs are also discussed, recognising variations in treatment response between Asian and Caucasian populations. Finite NA therapy is emerging as a viable approach for achieving functional cure. Future strategies should integrate liver fibrosis assessment to enhance patient selection before NA discontinuation. Optimising re-treatment approaches requires balancing timing, immune response, and qHBsAg kinetics to maximise HBsAg seroclearance. Clinical perspectives on NA discontinuation remain a key research priority, necessitating standardised guidelines and improved post-NA monitoring strategies to ensure safe and effective finite therapy in CHB management.

Pien Tze Huang (PTH), a well-established traditional Chinese medicine compound, has exhibited anti-hepatic fibrosis properties both in vitro and in vivo animal models, but the randomized clinical trials to evaluate anti-hepatic fibrosis efficacy of PTH are deficient. Chronic hepatitis B (CHB) is a leading cause of hepatic fibrosis in China. Although antiviral therapies have demonstrated significant effectiveness in arresting the progression of fibrotic disease, complete regression of established fibrosis is limited to only a subset of treated patients.

To assess the efficacy of PTH in improving hepatic fibrosis in CHB patients.

We conducted a randomized, double-blind, placebo-controlled clinical trial involving 144 CHB patients with hepatic fibrosis. This study was carried out from September 2020 to April 2023. (Clinical Trials Registration: ChiCTR2000035128) METHODS: CHB patients with an Ishak score of 2-5 points were recruited from ten hospitals across China. Participants were randomized in 1:1 ratio to receive either oral PTH (0.6 g per dose, three times/day) or placebo for 48 weeks, in addition to the standard treatment of entecavir (0.5 mg/day). The primary endpoint was the change in Ishak score. Secondary outcomes included changes in Knodell HAI score, liver stiffness measurement, AST- to -platelet ratio index, Fibrosis-4 index and hepatic function indices.

Of the 144 randomized patients, 142 patients (71 in the PTH group and 71 in the placebo group) were included in the primary analysis. The PTH group exhibited lower Ishak score compared to the control group (2.37 ± 0.94 vs. 2.87 ± 1.04, F = 6.072, p = 0.015). Notably, in treatment-naive patients, the PTH group showed significant improvement in Ishak score post-treatment compared with the control group (2.13 ± 0.72 vs. 2.74 ± 1.07, F = 6.336, p = 0.014). However, no significant changes were observed in these parameters among patients already receiving antiviral therapy.

The combination of PTH and entecavir demonstrates significant improvement in hepatic fibrosis among CHB patients, especially those who are treatment-naive patients.

Chronic hepatitis B virus remains a significant cause of liver disease in the developing world, leading to sequelae such as hepatocellular carcinoma. While entecavir (ETV) serves as a first-line treatment, its growing resistance rates underscore the need to explore viable alternatives. Tenofovir disoproxil fumarate (TDF) monotherapy and entecavir plus tenofovir (TDF + ETV) combination therapy are both employed as treatments, but one's efficacy over another is in question. This meta-analysis aims to investigate any primacy of either treatment.

We conducted a comprehensive literature search across PubMed/Medline, Embase, Cochrane Central, Web of Science, and China National Knowledge Infrastructure from inception till 7th October 2024. Studies comparing the safety and efficacy of TDF monotherapy versus TDF + ETV combination therapy in patients resistant to entecavir were considered. Data about the virologic response (VR), virologic breakthrough, HbeAg seroconversion, HbeAg/HbsAg seroclearance, and alanine aminotransferase normalization were extracted. Relative risks (RRs) and their corresponding 95% confidence intervals (CIs) were calculated, pooled, and analyzed in a random-effects model. P-value <0.05 was regarded as significant for all analyses.

Nine studies, comprising 335 patients undergoing monotherapy and 352 patients undergoing combination therapy, satisfied the criteria. TDF + ETV combination therapy was found slightly advantageous to TDF monotherapy, stimulating a VR at 48 weeks (RR 1.081 95% CI: [1.001-1.167] P = 0.046, I2 = 0%), along with the HbeAg seroconversion rate (RR 1.711 95% CI: [1.005-2.913] P = 0.048, I2 = 0%). There were no significant adverse events in individual studies to warrant a meta-analysis.

TDF + ETV shows slightly better efficacy to TDF monotherapy over a 48-week treatment regimen, with minimal safety concerns. However, further high-quality studies like randomized controlled trials are needed to further solidify conclusions, with this meta-analysis only achieving borderline significances.

This review is registered on the PROSPERO database (ID: CRD42024581443).

Hepatitis B and C infections are an underdiagnosed global health problem. Measurement of HBV DNA or HCV RNA levels using nucleic acid-based molecular diagnostic assays has been established as the standard of care for assessing diagnosis, guiding the treatment decision, and evaluating responses to antiviral therapy. In the present study, we examined the performance of the cobas 5800 System for HBV DNA and HCV RNA quantification in a large series of patients chronically infected. Specificity of the cobas HBV and HCV Tests on the 5800 System was high (99.1 % and 100 %, respectively). Linearity using the AcroMetrix panels was excellent. Repeatability and intermediate precision coefficients of variation were within 5 %. Of the 334 clinical specimens tested in parallel on the cobas 5800 and cobas 4800 Systems for HBV and the m2000 RealTime or Alinity m Systems for HCV, only 12 (3.6 %) yielded discrepant results that were at or near the limit of quantification of the cobas 5800 assays. The correlation between viral load results was extremely high, and only weak bias were observed across the entire range of concentrations tested without clinical impact in patients who are eligible for antiviral therapy. This comparison study demonstrated equivalent performance of the new cobas 5800 System compared with other molecular platforms widely used in clinical practice for HBV DNA and HCV RNA quantification. The cobas 5800 System can be confidently used in clinical practice. A few clinical specimens with low viral loads may be missed. Further studies are warranted to confirm or refute this finding.

Immigrants are the largest subgroup living with chronic hepatitis B (HBV) infection in the United States. It is not well understood how immigration and associated social and cultural factors impact adherence to HBV monitoring.

We conducted a multicentre multilingual survey among foreign-born adults with chronic HBV between 7/2021 and 4/2023. Participants were surveyed regarding (1) immigration factors, (2) acculturation and language preferences, (3) social determinants of health and (4) HBV-related clinical factors. The primary outcome was optimal adherence, defined as 100% of the time with at least annual testing of HBV DNA, ALT and ultrasound while under care. Logistic regression was used to examine survey factors associated with the outcome.

Two hundred and seventy-four foreign-born patients with HBV (median 57 years, 57% male) from 32 birth countries were included. Thirteen per cent had immigrated within the past 10 years, and 62% were US citizens. Nearly all (92%) reported seeing a specialist for HBV, with 72% currently on treatment. 44% of participants had optimal adherence to monitoring over a median of 6 years (2-7) under care. Factors associated with more optimal adherence on multivariate testing included non-English survey language (OR 2.32, 95% CI 1.15-4.66), non-US citizens (OR 2.05, 95% CI 1.01-4.15) and higher education (college vs. high school or less: OR 2.39, 95% CI 1.09-5.24). Medicare insurance (vs. private) was associated with less optimal adherence (OR 0.42, 95% CI 0.19-0.94).

Adherence to long-term monitoring is suboptimal among a diverse cohort of immigrants with chronic HBV. More efforts to engage and retain immigrants in care are needed.

Serum HBV RNA and hepatitis B core-related antigen (HBcrAg) levels have been proposed as useful biomarkers in the management of patients with HBV; however, their role in chronic hepatitis delta (CHD) is currently unknown.

Consecutive untreated patients with CHD were enrolled in a cross-sectional study in three EU centers. Clinical and virological characteristics were collected. Serum HBV RNA and HBcrAg levels were quantified by an automated real-time investigational assay (Cobas® 6800, Roche Diagnostics, Pleasanton, Ca, USA) and by LUMIPULSE® G HBcrAg assay (Fujirebio Europe), respectively. In 18 patients with available liver biopsies, intrahepatic analyses were performed.

Overall, 240 patients with HDV were enrolled: median age 46 years, 62% male, 53% with cirrhosis, 57% nucleos(t)ide analogue treated, median ALT 70 U/L, median HBsAg 3.8 log10 IU/ml, 88% HBeAg negative, and median HDV RNA 4.9 log10 IU/ml. HBV RNA was positive (>10 copies/ml) in only 8% of patients (median 40 [13-82,000] copies/ml), whereas HBcrAg was ≥3 log10 U/ml in 77% (median 4.2 [3.0-8.0] log10 U/ml). By combining these biomarkers, three categories were identified: 23% double negative (HBV RNA/HBcrAg), 9% double positive (HBV RNA/HBcrAg) and 68% HBV RNA negative/HBcrAg positive. HBV RNA levels positively correlated with male sex and detectable HBV DNA, while positive HBcrAg correlated with higher HBsAg levels. Double-positive patients were younger, non-European, with elevated ALT and HDV RNA levels and detectable HBV DNA. Intrahepatic HDV RNA and HBV RNA were positive in most samples, while intrahepatic levels of covalently closed circular DNA were low.

In untreated CHD, most patients had undetectable HBV RNA but quantifiable HBcrAg ("divergent pattern") in the absence of HBeAg. Additional studies aiming to unravel the molecular mechanisms underlying these findings are warranted.

Serum HBV RNA and HBcrAg (hepatitis B core-related antigen) are promising biomarkers of the transcriptional activity of covalently closed circular DNA in chronic HBV infection; however, their role in patients with HBV-HDV coinfection is unknown. At variance with what is commonly observed in HBV-monoinfected patients, HBV RNA was undetectable and HBcrAg detectable in the serum of most patients with HDV ("divergent pattern"). The understanding of the viral interplay between HBV and HDV is crucial to dissect the pathogenic mechanisms associated with the distinct phenotypes of patients with HDV.

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

The hepatitis B virus (HBV) remains a global problem despite effective tools to prevent, diagnosis, and control it. Unmet needs are identifiable across its clinical care cascade, underlining the challenges providers face in delivering effective care for patients with chronic hepatitis B. The review herein will focus on three timely clinical issues in HBV. This includes efforts to optimize delivery of perinatal HBV care, improve HBV-related hepatocellular carcinoma risk stratification models, and clarify the role of finite therapy in the HBV treatment algorithm. Important developments within these three topics will be addressed with the goal to motivate further investigation and optimization of these treatment strategies for HBV.

Despite having the highest Hepatitis B Virus (HBV)-related mortality globally, sub-Saharan Africa (SSA) has been slow in its disease elimination campaign. We describe a 5-year experience in HBV management at a large facility in Uganda and how it can inform future management strategies. HBV-related patient data were abstracted from clinic records. Of 2664 patients, 1828 (68.6 %) had documented chronic HBV infection. Participants were young, mean age (±SD) 31.3 (±10.6) and equally split by gender. Overall, 423 (23.1 %) were on antiviral medications including 158/229 (69.0 %) with a sonographic diagnosis of cirrhosis and 130/282 (46.1 %) with Aspartate aminotransferase to Platelet Ratio Index (APRI) score ≥0.5.48/1828 (2.6 %) had Hepatocellular Carcinoma (HCC). In multivariable analysis, APRI score ≥0.5 [OR (95 % CI) = 1.76 (1.26-2.46), p < 0.01], elevated alanine aminotransferase (ALT) [OR (95 % CI) = 2.25 (1.35-4.47), p = 0.04], and HBV viral load ≥2,000IU/mL [OR (95 % CI) = 2.97 (1.68-5.22), p < 0.01] were predictors of cirrhosis/HCC. Also, an APRI score of ≥0.5 [OR (95 % CI) = 1.62 (1.19-2.22), p = 0.01], elevated ALT [OR (95 % CI) = 2.60 (1.23-5.49), p = 0.02], cirrhosis [OR (95 % CI) = 21.65 (9.26-50.59), p < 0.01], and viral load ≥2,000IU/mL [OR (95 % CI) = 6.62 (3.93-11.15), p < 0.01] were associated with antiviral use. Cirrhosis/HCC apparently occur at lower APRI scores in SSA suggesting need for urgent adoption of the 2024 WHO guidelines which provide for earlier initiation of anti-HBV therapy.

Circulating HBsAg, HBV RNA, and hepatitis B core-related antigen (HBcrAg) are potential biomarkers for the response to nucleos(t)ide analog (NA) treatment discontinuation in patients with chronic hepatitis B (CHB). We retrospectively investigated the long-term kinetics of HBsAg, HBV RNA, and HBcrAg in HBeAg-negative patients treated with NA for up to 14 years in a prospective cohort study.

Ninety-six patients (mean age 65 y, 77% male, 52% with cirrhosis, all HBV genotype D) who were undergoing first (n=33, group A) or second-line (n=63, group B) treatment with tenofovir disoproxil fumarate were included. HBV biomarkers collected during tenofovir disoproxil fumarate treatment were measured in 384 serum samples stored at -20 °C. The combined biomarker endpoints associated with functional cure following NA discontinuation included HBsAg <1000 IU/mL, HBV RNA <54 copies/mL, and HBcrAg <2 log U/mL.

Before NA treatment, HBV RNA and HBcrAg were detectable in 85% (mean 3.9±2.3 [range, 0-9.2] log10 copies/mL) and 80% (mean 4.3±1.9 [2-8.9] log10 U/mL), respectively, of the patients in group A. In groups A and B, the percentages of patients with detectable HBV RNA levels decreased to 53% and 34%, respectively, during years 8-10 of NA treatment, and to 29% in group B during years 11-14 to 29%. HBcrAg could be quantified in 2% of patients in group B NA treatment years 8-10. Combined biomarker endpoints were met at baseline and at years 1-4, 5-7, 8-10, and 11-14 of treatment by 3.3%, 12% and 14%, 13% and 38%, 26% and 29%, and 41% of patients, respectively.

HBV biomarker endpoints are associated with functional cure after the discontinuation of NA increase during long-term NA treatment.

HDV infection is the most severe form of chronic hepatitis. However, studies on outcomes and causes of death in a US-born population, with primarily horizontal transmission of HDV, are lacking. The aim of this study was to conduct a national study of patients with hepatitis D to understand the natural history and outcomes compared to patients with HBV infection.

In a national cohort of 4817 veterans infected with HBV tested for HDV (99.6% US-born, 3.3% HDV-positive) over a 23-year period, we used multivariable models to identify the factors associated with a composite outcome of HCC, decompensation, and liver-related mortality, and all-cause mortality of patients with HDV compared to HBV mono-infection. HDV coinfection (vs. HBV mono-infection) was associated with a significantly higher incidence of composite liver-related outcomes at both 5 (23.84 vs. 7.98, p < 0.001) and 10 years (19.14 vs. 10.18, p < 0.001), respectively. The most common cause of death was liver-related (33.8% for HDV vs. 24.7% for HBV), followed by nonhepatic malignancies (15.6% vs. 14.8%), cardiac (11.7% vs. 15.2%), and lung disease (5.2% vs. 3.7%). In multivariable models, HDV was associated with an increased risk of composite liver outcomes (adjusted hazard ratio: 2.57, 95% CI: 1.87-3.52, p < 0.001) and all-cause mortality (adjusted hazard ratio: 1.52, 95% CI: 1.20-1.93, p < 0.001).

In a predominantly US-born cohort of veterans, HDV coinfection was associated with an increased risk of liver-related outcomes and all-cause mortality. Our findings support widespread testing for early identification of HDV.

Hepatitis D virus (HDV) affects nearly 5% of people globally who are chronically infected with hepatitis B virus, according to the World Health Organisation. The prevalence of HDV in the United States is considered lower than in other countries. However, HDV seroprevalence studies of the US population are limited, and reported seroprevalences vary. To improve diagnoses, universal HDV testing of hepatitis B surface antigen (HBsAg)-positive specimens has been proposed. The objective of this study was to estimate the prevalence of HDV infection within the United States in HBsAg-positive specimens. Unique deidentified remnant HBsAg-positive specimens submitted for routine clinical testing to Quest Diagnostics, representing all 10 Health and Human Services (HHS) regions, were included. Reflex testing of HBsAg-positive specimens for HDV antibody testing, and further testing of positive specimens for HDV RNA, was conducted from July 2023 to June 2024 for 5251 HBsAg-positive specimens. The cohort was 45% female, with mean ages of 50.8 (M) and 49.4 (F) years. The seroprevalence of anti-HDV was 2.2% [95% CI: 1.8%-2.6%; range: 2.5%-4.1%]. Of 107 anti-HDV-positive specimens, 28% were positive for HDV RNA (viral load range: 94-7,480,000 IU/mL: n = 23; Detected < 40 IU/mL: n = 7). This is the first nationwide seroprevalence study examining HBsAg-positive samples collected from 10 HHS regions across the United States, which offers an overview of the prevalence of HDV in the United States through the use of HbsAg-positive remnant specimens in proportion to regional population sizes. Expanded screening for HDV would help identify patients who may benefit from HDV-related interventions.

Current international guidelines recommend close monitoring and evaluation of patients with chronic hepatitis B (CHB) in the indeterminate phase, and treatment of patients at high risk of adverse outcomes. Clinical outcomes and the effect of antiviral therapy on the indeterminate phase remain unclear. We performed a systematic review and meta-analysis to study the incidence of adverse clinical outcomes including hepatocellular carcinoma (HCC), cirrhosis, and hepatic decompensation, and the effect of antiviral therapy, in the indeterminate phase.

Two investigators independently searched Embase, MEDLINE, Web of Science and China National Knowledge Infrastructure from 1/1/2007 to 31/12/2023. Three investigators independently assessed study eligibility and quality. We included cohort studies and a randomised-controlled trial, allowing for calculation of the incidence rate of adverse clinical outcomes, and cross-sectional studies that reported the prevalence of moderate-to-severe inflammation and different degrees of fibrosis. Incidence rates and prevalence were pooled using generalised linear mixed-effects models and random-effects models, respectively.

One hundred and three studies (70 case-control studies [18,739 patients], 32 cohort studies [15,118 patients], and one RCT [160 patients]) were included. The annual incidence rate of HCC in patients in the indeterminate phase was 0.32% (95% CI 0.21-0.48%, I2 = 85.7%), and those of cirrhosis and hepatic decompensation were 0.67% (95% CI 0.30-1.49%, I2 = 94.3%) and 0.34% (95% CI 0.17-0.69%, I2 = 51.8%), respectively. The pooled prevalence of moderate-to-severe liver inflammation, significant fibrosis, advanced fibrosis, and cirrhosis was 40.7%, 39.7%, 17.9%, and 7.2%, respectively. Use of antiviral therapy was associated with a lower risk of HCC in patients in the indeterminate phase (adjusted incidence rate ratio 0.38, 95% CI 0.18-0.79, p = 0.009).

Patients in the indeterminate phase are at risk of developing advanced liver disease and HCC. Although inherent heterogeneity across studies limited the evidence to support expanding treatment to all patients in the indeterminate phase, antiviral therapy may reduce the risk of HCC development in high-risk subgroups.

Current international guidelines recommend close monitoring and evaluation of patients with chronic hepatitis B (CHB) in the indeterminate phase, in whom antiviral treatment is not always indicated. Based on the systematic review and meta-analysis with significant heterogeneity across studies, patients in the indeterminate phase are at risk of developing hepatocellular carcinoma, cirrhosis, and hepatic decompensation. Meta-regression findings on platelet count, positive HBeAg, and age highlighted the importance of liver fibrosis assessment, accurate phase classification, and timely detection of phase transition to identify antiviral treatment indications, supporting current guideline recommendations. Antiviral treatment may reduce the risk of hepatocellular carcinoma in the high-risk subgroups of patients in the indeterminate phase.

CRD42024537095.

Viral hepatitis poses a significant public health challenge. Five types (A, B, C, D, E) have distinct transmission, prognosis, and management. Hepatitis A (HAV), spread through fecal-oral contamination, is typically self-limiting with supportive therapy. Hepatitis B (HBV) is sexually transmitted but may also be spread perinatally. HBV can progress into cirrhosis or hepatocellular carcinoma. Hepatitis C (HCV), a bloodborne virus, can also cause chronic infection and severe liver disease. Vaccination can prevent HAV and HBV; HCV is curable with antiviral therapy but lacks a vaccine. Pregnant patients and those with HIV require special management considerations. Here, we review the pathogenesis, diagnosis, treatment, and prevention of viral hepatitis.

Hepatitis B virus (HBV) reactivation in patients with HBV/hepatitis C virus (HCV) co-infection due to direct-acting antiviral agent (DAA) therapy is a growing concern. This study focused on 47 patients with chronic hepatitis C (CHC) and positivity for HBV surface antigen (HBsAg) who were treated with interferon (IFN)-based therapy, DAA, or DAA after IFN-based therapy failure and followed for a median of 53 months. Here, we aimed to determine HBV reactivation rates and associated factors, the incidence of HBV and liver-related events, and the rate of sustained virologic response (SVR) for HCV. Fifteen (15/47, 31.9%) patients experienced HBV reactivation during or after HCV treatment. This reactivation occurred significantly more frequently in patients who received DAA treatment after IFN-based treatment failure than in those who received IFN-based treatment (IFN-based vs. DAA vs. DAA treatment after IFN-based treatment failure 11.8% vs. 35.3% vs. 53.8%, respectively; p = 0.046). The interval from HCV treatment initiation to HBV reactivation was shortest in the DAA group (4.2 months), followed by the DAA after IFN-based treatment failure group (6.4 months) and the IFN-based treatment group (44.5 months) (p < 0.001). One case of HBV-related hepatitis spontaneously resolved after 4 weeks. The rate of SVR for the entire cohort was 87.2%, with no significant difference in this regard among the IFN-based treated, DAA-treated, and DAA-treated after IFN-based treatment failure arms at 82.4%, 88.2%, and 92.3%, respectively. HBV reactivation in HBsAg-positive CHC patients is more common and occurs earlier in those who receive DAA treatment after IFN-based treatment failure than in those with IFN-based treatment. Therefore, all patients with CHC should be tested for HBV exposure prior to DAA treatment. In addition, HBsAg positive patients, especially those among whom have previously experienced IFN-based treatment failure, should be closely monitored for HBV reactivation during DAA therapy.

Tenofovir alafenamide (TAF) is recommended for chronic hepatitis B (CHB) treatment in international guidelines according to its efficacy and safety. However, in phase III study, an increased LDL-c was observed in those who were switched from Tenofovir disoproxil fumarate (TDF) to TAF. Limited data exists on whether lipid profiles change only in individuals who switched to TAF from TDF or from any nucleoside/nucleotide analogues (NUC). We investigated how switching to TAF affected lipid and cardiovascular outcomes in Thai CHB patients.

We conducted a prospective observational study including CHB patients who had to switch from their prior NUC to TAF according to the national reimbursement policy in late 2022. All enrolled patients had lipid tests and transient elastography (TE) done at 0 and 48-week post-switch to TAF. Demographic data, prior NUC, liver biochemistry, controlled attenuated parameter (CAP) and liver stiffness (elastic modulus; E) data measured by TE were collected. The changes in lipid, Thai cardiovascular (CV) risk score, and TE results between 0 and 48-week were compared.

A total of 110 patients who were switched to TAF and completed 48-week follow-up were analyzed. The prior NUCs were as follows: 47 Lamivudine (LAM), 22 Entecavir (ETV), and 41 TDF-based. Baseline characteristics were similar between the three groups except for underlying hypertension was more frequent and baseline total cholesterol was lower in the TDF-based group. At 48-week post-switch, the median LDL-c changes were -2.45, -5.9 and +8.8 mg/dL (p<0.001), and total cholesterol changes were -4.5, -4 and +17 mg/dL (p<0.001), in the ETV, LAM, and TDF-based group, respectively. Whereas the changes in hepatic steatosis (measured by CAP), and liver stiffness (measured by E) as well as Thai CV risk score were not significantly different. No cardiovascular events occurred during follow-up.

Significant increase in LDL-c and total cholesterol after switching to TAF were observed only in patients with prior TDF, but not in those with prior ETV or LAM. Careful monitoring of lipids after the switch may not be universally needed. Data regarding long-term cardiovascular outcomes are warrant.

To identify clinical and viral indicators for the development of a new model to accurately differentiate the stages of chronic hepatitis B virus (HBV) infection based on histopathological changes in the liver.

Clinical and liver pathology data from chronic hepatitis B (CHB) patients who underwent liver biopsy were retrospectively collected. The patients were allocated into test and validation groups. The area under the receiver operating characteristic (ROC) curve (AUC) was calculated to idneitfy the optimal diagnostic value for differentiating the stages of chronic HBV infection.

A total of 118 patients and 73 patients who met the diagnostic and inclusion criteria were selected as the test group and validation group, respectively. Multivariate analysis revealed that HBeAg was independently correlated with the IT and IC stages. The cutoff value of HBeAg used to quantitatively differentiate between IT and IC was 1335 S/CO. The AUC values were 0.921 (95% confidence interval (CI): 0.836-0.971) and 0.846 (95% CI: 0.726-0.967) in the test and validation groups, respectively. A new prediction model of the IT stage was established by using three indicators, namely, HBeAg, HBsAg and HBV DNA. The AUC values were 0.923 (95% CI: 0.864-0.982, p < 0.001) and 0.89 (95% CI: 0.787-0.994, p < 0.01) in the test and validation groups, respectively, when this prediction model was used. For the new model, CMA guidelines (2019 version), EASL guidelines (2017 version) and AASLD guidelines (2018 version), the error rates in the test group were 4.65%, 11.62%, 23.26%, and 46.51%, respectively, while the errors rates in the validation group were 20.0%, 25.0%, 40.0%, and 45.0%, respectively.

High levels of HBeAg, rather than HBeAg positivity, may serve as a predictor of the IT stage. A predictive model for the immune tolerance stage was established by combining three indicators. Compared with the recommended standards from multiple current guidelines, the new prediction model has a significantly lower error rate.

Drug pricing is a major driver of healthcare spending in the United States (US) and the cost of medications in the US is up to three time higher than other countries. This cross-sectional study aims to investigate the current price differences between hepatitis B (HBV) and hepatitis C (HCV) antiviral therapies in the US as compared to peer high-income countries.

Publicly available drug formularies for Canada, UK, Japan, France, Germany, Italy, and Australia were used to collect 2024 prices for seven HBV medications (lamivudine, adefovir, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate, entecavir, peginterferon alfa-2a, emtricitabine/TDF) and seven HCV medications (sofosbuvir/velpatasvir, sofosbuvir/ledipasvir, sofosbuvir, ribavirin, elbasvir/grazoprevir, glecaprevir/pibrentasvir, sofosbuvir/velpatasvir/voxilaprevir). US prices were obtained from UpToDate®'s listed representative average wholesale price and Medicare Part D 2022 drug prices.

US prices for HBV originator medications were on average 4.71x (range 1.99-6.17x) the prices in the peer countries. US generic HBV drug prices for TDF, entecavir, and emtricitabine/TDF were on average 45% cheaper or 0.55x less than the average generic prices in peer countries (range 0.48-0.66x). US originator prices for HCV medications were on average 1.83x the prices in peer countries (range 0.63-2.66x).

HBV and HCV originator medications cost significantly more in the US compared to seven other major industrial countries. However, the introduction of HBV generic medications has lowered the cost of treatment for patients in the US. Future adoption of international reference pricing may help bridge remaining pricing disparities.

We aimed to explore the effectiveness of CTH as a serum inflammation biomarker for HCC. Enzyme-linked immunosorbent assay was used to detect serum levels of CTH, interleukin-6 (IL-6), C-reactive protein (CRP), and IL-10. The Scheuer scoring system was used to assess the liver inflammation grading (significant liver inflammation: ≥ G2 grade). CTH levels in the HCC group were significantly elevated (P < 0.0001). Of 146 patients, 58.22% exhibited significant liver inflammation. CTH levels in patients with significant liver inflammation were significantly higher than those in patients with no or mild liver inflammation (< G 2) (p < 0.0001). The area under the Receiver Operating Characteristic (ROC) curve for CTH in predicting significant hepatitis was 0.77 (sensitivity, 81.2%; specificity,62.3%). There was a significant positive correlation (r = 0.50, p < 0.05) between serum CTH levels and histopathological parameter G. The area under the ROC curve for CTH in predicting hepatocellular carcinoma was 0.83 (sensitivity, 64.6%; specificity, 83.3%). CTH and AFP improved the diagnostic accuracy of HCC. CTH levels significantly decreased 6 months post-operation (p < 0.05). The recurrence of HCC caused significant increases in CTH levels. Thus, CTH can serve as a serum inflammation marker for HCC.

Chronic hepatitis B (CHB) is a significant global health challenge, with tenofovir disoproxil fumarate (TDF) widely used as an effective treatment option. Despite TDF's efficacy in suppressing hepatitis B virus (HBV) DNA, it rarely achieves functional cure, requiring hepatitis B surface antigen (HBsAg) clearance or seroconversion, which are an optimal goal of CHB treatment. This study aimed to evaluate the long-term effects of TDF monotherapy on HBsAg clearance rates through a systematic review and meta-analysis, combined with a longitudinal modeling analysis to investigate HBsAg dynamics.

Eligible studies published between January 1st, 2008, and September 28th, 2023, in PubMed, EMBASE, and Web of Science were included in the systematic review and meta-analysis. The longitudinal model was developed based on data from 123 subjects in a Phase III trial cohort.

Twenty-three studies were selected for meta-analysis. The summarized HBsAg clearance rate was near zero and unlikely to increase with extended treatment. The longitudinal model of HBsAg dynamic in CHB patients receiving TDF monotherapy showed a good fitting performance and extrapolation predictive ability. Model-based simulation confirmed that HBsAg clearance remained unlikely with prolonged therapy, with median HBsAg levels reducing by 21% after 168 weeks.

The consistency between meta-analysis and model simulation outcomes indicated that TDF monotherapy can achieve a limited reduction in HBsAg levels but did not result in functional cure, which reinforced the limited role of TDF monotherapy in comprehensive CHB management.

Chronic hepatitis B (CHB) with indeterminate phase comprises a heterogeneous group of patients. We determined the prevalence of indeterminate CHB overall and characterised novel types and phase transition probabilities of novel types of indeterminate CHB.

CHB patients were enrolled retrospectively from 24 centres (9 countries/regions). Indeterminate phase was defined based on the AASLD 2018 guidance.

The cohort included 8375 patients with a mean age of 45.0 ± 13.7 years, 22.5% HBeAg-positive, and median ALT and HBV DNA of 30 U/L and 4.3 ± 2.2 log10IU/mL, respectively. Of the total cohort, half (47.2%) were in the indeterminate phase; and of these, the most prevalent group among HBeAg-positive patients was Type 2 (ALT 1-2 × ULN, HBV DNA≥ 20,000 IU/mL; 12.6%), while in HBeAg-negative patients it was Type 6 (ALT

CONCLUSIONS

Indeterminate CHB can be classified into 10 types, with the most prevalent type being those with HBeAg-negative, HBV DNA ≥ 2000 IU/mL and ALT Collapse

Key Words

• HBV
• grey zone
• longitudinal
• long‐term follow‐up
• phase transition
• prevalence

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Affiliation(s)

Rui Huang Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
Ai-Thien Do Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA Digestive Health Associates of Texas, Dallas, Texas, USA The University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA
Hidenori Toyoda Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
Jie Li Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
Satoshi Yasuda Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Ogaki, Japan
Pei-Chien Tsai Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
Ming-Lun Yeh Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Huy Trinh San Jose Gastroenterology, San Jose, California, USA
Angela Chau Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA Weill Cornell Medical College, New York, New York, USA
Daniel Q Huang Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Eiichi Ogawa Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, Japan
Takanori Ito Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Ritsuzo Kozuka Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
Masanori Atsukawa Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
Sebastián Marciano Liver Unit Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
Takashi Honda Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Tsunamasa Watanabe Division of Gastroenterology and Hepatology, St. Marianna University School of Medicine, Kawasaki, Japan
Norio Itokawa Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
Carmen Monica Preda Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, University of Medicine and Pharmacy "Carol Davila", Romania
Cheng-Hao Tseng Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
Ana Barreira Liver Unit, Hospital Universitari Valle D'hebron and Universitat Autònoma de Barcelona, Barcelona, and CIBEREHD del Instituto Carlos III, Spain
Kaori Inoue Liver Center, Saga University Hospital, Saga, Japan
Hirokazu Takahashi Liver Center, Saga University Hospital, Saga, Japan Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
Haruki Uojima Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan Genome Medical Sciences Project, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
Keigo Kawashima National Institute of Infectious Diseases, Tokyo, Japan
Yao-Chun Hsu Division of Gastroenterology and Hepatology, Department of Internal Medicine, E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
Raluca Ioana Marin Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, University of Medicine and Pharmacy "Carol Davila", Romania
Irina Sandra Department of Gastroenterology and Hepatology, Clinic Fundeni Institute, University of Medicine and Pharmacy "Carol Davila", Romania
Masatoshi Ishigami Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
Jiayi Li Palo Alto Medical Foundation, Mountain View Division, Mountain View, California, USA
Jian Zhang Chinese Hospital, San Francisco, California, USA
Son Do The University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, USA
Mayumi Maeda Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA
Dong-Hyun Lee Division of Gastroenterology, Department of Internal Medicine, Good Gang-An Hospital, Busan, South Korea
Wan-Long Chuang Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Chia-Yen Dai Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Jee-Fu Huang Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Chung-Feng Huang Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Ramsey Cheung Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA Gastroenterology and Hepatology, The Palo Alto Veterans Affairs Health Care System, Palo Alto, California, USA
Maria Buti Liver Unit, Hospital Universitari Valle D'hebron and Universitat Autònoma de Barcelona, Barcelona, and CIBEREHD del Instituto Carlos III, Spain
Yasuhito Tanaka Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
Man-Fung Yuen Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong, China State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong, China
Masaru Enomoto Department of Hepatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan Department of Transfusion Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
Adrian Gadano Liver Unit Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
Seng Gee Lim Director of Hepatology, Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
Ming-Lung Yu Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan Hepatitis Research Center, College of Medicine and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University, Kaohsiung, Taiwan
Chao Wu Department of Infectious Disease, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, China Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, China
Mindie H Nguyen Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California, USA Department of Epidemiology and Population Health, Stanford University, Stanford, California, USA

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The long-term clinical benefits of interferon (IFN)-based therapy compared to nucleos(t)ide analogue (NA) monotherapy in HBeAg-positive chronic hepatitis B (CHB) have not been well defined. This study aimed to evaluate the cumulative incidence of new-onset cirrhosis, serological responses, and hepatocellular carcinoma (HCC) development between these treatment strategies.

Two independent cohorts of non-cirrhotic, HBeAg-positive CHB patients were analyzed: a treatment-naïve cohort (n = 686) and an NA-experienced cohort (n = 531). Patients received either IFN-based therapy or NA monotherapy. Propensity score matching (PSM) was employed to minimize intergroup heterogeneity. The primary endpoint was the cumulative incidence of new-onset cirrhosis.

After PSM, the 10-year cumulative incidence of new-onset cirrhosis was significantly lower in the IFN-based therapy group compared to the NA monotherapy group in both the treatment-naïve (3.3 % vs 20.0 %, p = 0.005) and NA-experienced (4.9 % vs 20.9 %, p = 0.034) cohorts. IFN-based therapy also resulted in significantly higher serological response rates across both cohorts, including HBeAg loss (treatment-naïve: 84.7 % vs 55.6 %; NA-experienced: 60.4 % vs 43.6 %, both p < 0.001) and HBsAg loss (treatment-naïve: 14.3 % vs 5.7 %, p = 0.006; NA-experienced: 10.2 % vs 1.3 %, p < 0.001). Subgroup analysis showed that patients receiving IFN-based therapy who achieved HBeAg loss within 96 weeks had the greatest long-term benefits, with lower cirrhosis incidence and higher HBsAg loss rates. Although the incidence of HCC was lower in the IFN-based group, the difference did not reach statistical significance (both p > 0.05).

IFN-based therapy provides superior long-term benefits over NA monotherapy in reducing cirrhosis risk and enhancing serological responses in HBeAg-positive CHB patients.

The role of alanine aminotransferase (ALT) dynamics during nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) is unclear. We aimed to evaluate the correlation between ALT dynamics and liver-related events (LRE), and explore the optimal threshold of ALT during NA treatment.

We enrolled 18,129 NA-treated patients, comprising 3104 patients from the Search-B study (NCT02167503) and 15,025 patients from a real-world cohort in Hong Kong. Latent-class mixed model (LCMM) was adopted to identify trajectory patterns of ALT during treatment. ALT value at the 95th percentile of the trajectory group with the lowest LRE risk was obtained as the optimal threshold.

During a median follow-up of 53.3 months, 1164 patients developed LRE with a 7-year cumulative incidence of 9.9%. In the Search-B cohort, LCMM recognised 3 trajectory groups with progressively increasing ALT levels, which were positively associated with LRE risk. Subsequently, the optimal thresholds for ALT were obtained as 23 U/L for men and 16 U/L for women. The 7-year cumulative incidence of LRE was 5.5% for ALT ≤ 23 or 16 U/L, significantly lower than that for ALT > 23 or 16 U/L but ≤ 40 U/L (10.8%; aHR = 2.0, p < 0.001), and ALT > 40 U/L (15.1%; aHR = 3.4, p < 0.001). Similarly, in the Hong Kong cohort, ALT > 23 or 16 U/L but < 40 U/L and ALT > 40 U/L also increased the LRE risk, with aHRs of 2.0 (p = 0.003) and 6.1 (p < 0.001), respectively.

On-treatment ALT levels were significantly correlated with the prognosis of CHB. ALT ≤ 23 U/L for men and ≤ 16 U/L for women were identified as the optimal thresholds during NA treatment, suggesting that CHB patients should strive for a lower ALT level beyond the traditional normal range.

Hepatitis B surface antigen (HBsAg) clearance is an achievable treatment endpoint for chronic hepatitis B virus (HBV)-infected patients. Pegylated interferon-α (PEG-IFN-α) induces higher rate of HBsAg clearance than nucleos(t)ide analogues. However, the influencing factors associated with HBsAg recurrence have not been fully elucidated. The aim of this study was to evaluate the risk factors for recurrence in chronic HBV-infected patients who achieved functional cure with PEG-IFN-α-2b-based treatment.

A multicenter retrospective study was conducted. All patients received PEG-IFN-α-2b-based therapy, achieved HBV DNA negativity and HBsAg clearance, and were followed-up for at least 48 weeks after discontinuation of medications. The demographic data, as well as virological, serological, and biochemical indicators, were collected at baseline, therapy cessation, and during followed-up. Logistic regression analysis was subsequently performed.

A total of 101 chronic HBV-infected patients who achieved HBsAg loss with PEG-IFN-α-2b-based therapy were enrolled. The median treatment time was 24.00 (14.50, 37.50) weeks, and the median consolidation time was 11.00 (0.00, 24.00) weeks. HBsAg recurrence was found in 16 patients after a median 70.00 (48.00, 96.00) week follow-up, with a cumulative recurrence rate of 15.84%. A higher platelet count was associated with a slightly increased HBsAg recurrence risk at therapy cessation, whereas a shorter consolidation time was associated with an elevated HBsAg recurrence risk during followed-up. The appearance of anti-HBs presented a robustly reduced HBsAg recurrence risk at both therapy cessation and followed-up. No HBV DNA positivity or occurrence of end-stage liver disease was observed during treatment or followed-up.

The cumulative HBsAg recurrence rate was 15.84% after discontinuation of medications in chronic HBV-infected patients who achieved functional cure with PEG-IFN-α-2b-based therapy. The presence of anti-HBs reduced the HBsAg recurrence risk.

This trial is a part of ZhuFeng Project (ClinicalTrials.gov, identifier NCT04035837) and a part of E-Cure Study (ClinicalTrials.gov, identifier NCT05182463).

Hepatitis D is estimated to affect 12 million people worldwide and is caused by the hepatitis D virus (HDV), a defective virus that requires the presence of the hepatitis B virus (HBV) for infection. Here, we report a new recombinant antigen (DTH10.1) to detect anti-HDV IgG antibodies, designed to include a consensus sequence of the HDV antigen, based on bioinformatic analysis of the eight HDV genotypes. Using serum samples from patients living in the endemic area of the Brazilian Amazon basin, the enzyme-linked immunosorbent assay (ELISA) based on this protein displayed a sensitivity of 90.6% (95% CI: 84.2%-94.5%) and a specificity of 100% (95% CI: 94.2%-100.0%), while a rapid immunochromatographic test (ICT) showed a sensitivity of 91.3% (95% CI: 85.0%-95.1%) and specificity of 99.0% (95% CI: 94.5%-99.95%). Commercial monoclonal antibodies for HBV surface antigen (HBsAg) detection were then added to the test, resulting in a multiplex ICT with a sensitivity of 87.1% (95% CI: 81.3%-91.4%) for HBsAg and 95.2% (95% CI: 90.0%-97.8%) for anti-HDV IgG and specificity of 100% (95% CI: 91.0%-100.0%) and 98.0% (95% CI: 92.9%-99.6%), respectively. Finally, the three tests were evaluated against a panel of 79 patient samples infected, covering the eight HDV genotypes. The results indicated that all the DTH10.1-based tests were able to detect anti-IgG HDV antibodies with high sensitivity and specificity, regardless of the infecting HDV genotype. In conclusion, the prototypes developed for serodiagnosis of HDV using the DTH10.1 recombinant protein are promising tools for the universal diagnosis of HDV infection.IMPORTANCEThe manuscript outlines the complete strategy for developing tools for the diagnosis of hepatitis D, including an enzyme-linked immunosorbent assay (ELISA), an immunochromatographic test (ICT), and a multiplex ICT for the simultaneous detection of hepatitis B virus surface antigen and anti-hepatitis D virus (HDV) IgG antibodies. All the tests described are capable of detecting all eight HDV genotypes with high accuracy.

Chronic hepatitis B (CHB) patients who do not meet any immunostaging criteria are categorized as the "grey zone" (GZ). However, there are discrepancies in the definition of the GZ in different areas.

To investigate the prevalence and clinical characteristics of Chinese GZ patients and to validate the application value of three international guidelines.

Data from 807 naïve CHB patients with liver biopsies from seven Chinese centres were retrospectively collected. GZ patients were defined and compared across four guidelines: the Chinese guidelines, the American Association for the Study of Liver Diseases (AASLD) guidelines, the European Association for the Study of the Liver (EASL) guidelines, and the Asian Pacific Association for the Study of the Liver (APASL) guidelines.

When the Chinese guidelines were used, 38.79% of patients were categorized into the GZ, 78.91% of whom were indicated for antiviral therapy. The EASL guidelines yielded a greater proportion of GZ patients (50.56%) than did the APSAL (36.68%) and AASLD guidelines (33.21%). The APASL guidelines yielded a lower proportion of GZ patients who were indicated for antiviral therapy (42.57%) than did the AASLD (47.76%) and EASL guidelines (60.54%). According to the AASLD, EASL, APASL and Chinese guidelines, if liver biopsy was not performed, 13.06%, 31.86%, 0% and 64.54% of GZ patients were indicated for antiviral therapy, respectively.

GZ patients account for a significant proportion of CHB patients, with approximately half of them requiring antiviral therapy.

NCT06041022.

Little is known about the short-term and long-term outcomes of non-cirrhotic chronic hepatitis B (CHB) patients who experience hepatic decompensation. Therefore, this study aimed to investigate the clinical outcomes of decompensated non-cirrhotic CHB patients.

We conducted a retrospective study and enrolled a total of 304 decompensated non-cirrhotic CHB patients. Cox regression model was used to analyze factors associated with all-cause mortality. Additionally, the incidence of HBsAg seroclearance and its associated factors were estimated by the competing risk analysis.

The median follow-up time was 4.36 years (IQR 1.04-7.16). Out of the total enrolled patients, 63 (20.72 %) patients either died or underwent liver transplantation, and 14 patients achieved HBsAg seroclearance. Risk factors associated with 1-month, 3-month, and long-term all-cause mortality were the presence of ascites and hepatic encephalopathy, baseline HBV DNA levels, and MELD scores. The cumulative incidence of HBsAg seroclearance was 1.78 %, 3.72 %, 4.25 %, 5.68 %, 5.68 %, 8.28 %, and 8.28 % at the 1-year, 2-year, 3-year, 4-year, 5-year, 6-year, and 7-year follow-up, respectively. Independent predictors for HBsAg seroclearance were baseline alanine aminotransferase (ALT)≧ 25 times upper limit of normal (subdistribution hazard ratio [sHR] = 5.97; 95 %CI, 1.82-19.63; p = 0.0032) and HBV DNA <5 log10 IU/ml (sHR = 4.43; 95 %CI, 1.55-12.63; p = 0.0054).

The presence of ascites and hepatic encephalopathy, baseline HBV DNA levels, and MELD scores were associated with short-term and long-term all-cause mortality. Additionally, lower HBV DNA levels and higher ALT levels at baseline were independently predictive of sequential HBsAg seroclearance.

The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.