Hepatitis B virus (HBV) DNA integration into the host cell genome is reportedly a major cause of liver cancer, and a source of hepatitis B surface antigen (HBsAg). High HBsAg levels can alter immune responses which therefore contributes to the progression of HBV-related disease. However, to what extent integration leads to the persistent circulating HBsAg is unclear. Here, we aimed to determine if the extent of HBV DNA integration is associated with the persistence of circulating HBsAg in people exposed to HBV. We established a digital droplet quantitative inverse PCR (dd-qinvPCR) method to quantify integrated HBV DNA in patients who had been exposed to HBV (anti-HBc positive and HBeAg-negative). Total DNA extracts from both liver resections (n = 32; 14 HBsAg-negative and 18 HBsAg-positive) and fine-needle aspirates (FNA, n = 10; 2 HBsAg-negative and 8 HBsAg-positive) were analysed. Using defined in vitro samples for assay establishment, we showed that dd-qinvPCR could detect integrations within an input of <80 cells. The frequency of integrated HBV DNA in those who had undergone HBsAg loss (n = 14, mean ± SD of 1.514 × 10-3 ± 1.839 × 10-3 integrations per cell) was on average 9-fold lower than those with active HBV infection (n = 18, 1.16 × 10-2 ± 1.76 × 10-2 integrations per cell; p = 0.0179). In conclusion, we have developed and validated a highly precise, sensitive and quantitative PCR-based method for the quantification of HBV integrations in clinical samples. Natural clearance of HBV is associated with fewer viral integrations. Future studies are needed to determine if dynamics of integrated HBV DNA can inform the development of curative therapies.

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.

Acute hepatitis E infection could induce severe outcomes among chronic hepatitis B (CHB) patients. Between 2016 and 2017, an open-label study was conducted to evaluate the immunogenicity and safety of hepatitis E vaccine (HepE) in CHB patients, using healthy adults as parallel controls in China. Eligible participants who were aged ≥30 y were enrolled in the study. The CHB group included participants who had ever developed symptoms of hepatitis because of CHB but was currently at a clinically stable stage, which was defined as ALT ≤ 1.5 times of upper limit of the normal range (ULN) in this study. The control group included healthy adults who had hepatitis B surface antigen (HBsAg) negative. HepE was administered for 0, 1, 6 months for all participants. At 1 month after the third-dose vaccination (month 7), the seroconversion rates of anti-HEV IgG were >97% in both groups. The geometric mean concentration (GMC) of anti-HEV IgG in the CHB group was non-inferior to the healthy adult group (0.69 WU/mL, 95% CI 0.55-0.85). The proportion of the participants with adverse events ≥ grade 3 was similar in both groups (p = .99), and no vaccine-associated severe adverse events were identified. Changes in the liver function indicators were not of clinical significance. The HepE was highly immunogenic and well tolerated among clinically stable CHB patients and healthy adults.

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.

Hepatitis B virus (HBV) is a 3.2 kb hepatotropic DNA that possesses a unique episomal DNA form known as covalently closed circular DNA (cccDNA). cccDNA is the major risk factor for persistent HBV infection and consequently causes chronic liver diseases such as hepatitis, cirrhosis, and hepatocellular carcinoma. To prevent the progression of liver disease, eradication of HBV, especially cccDNA, is essential. In this study, we established a drug screening system using artificial recombinant HBV cccDNA (rcccDNA), which is regulated by a loxP-HBV genome and CRE expression. To identify potential drugs targeting cccDNA, a total of 379 antiviral reagents were tested. Among them, several chemicals including danoprevir, L- and D-cycloserine, phenytoin sodium, amantadine, and germacrone showed a decrease in cccDNA levels. Especially, D-cycloserine diminished the secretion of HBV antigens and induced cccDNA degradation in the HBV infection system. This screening system helps to develop the therapeutic drug target to cccDNA This screening system may help develop therapeutic drugs targeting cccDNA.

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.

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.

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.

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.

Interferon-inducible transmembrane (IFITM) proteins have been widely reported as antiviral factors against various viral pathogens. However, the mechanisms of IFITM regulation on hepatitis B virus (HBV), which induces chronic infection resulting in cirrhosis as well as liver cancer, remain poorly characterized. In the present study, we identified that HBV infection significantly increased the expression of IFITM1. To dissect the role of IFITM1 in HBV infection, we overexpressed IFITM1 in HepG2.215 cells and revealed that the replication of HBV was restricted by IFITM1. Recently, we demonstrated that the anti-RNA virus activity of IFITM proteins depends on palmitoylation modification, and the depalmitoylase α/β-hydrolase domain-containing 16A (ABHD16A) negatively regulates IFITM1 against RNA virus infection in human and porcine cells. However, whether ABHD16A-IFITM1 regulates DNA virus infection has not been researched. Here, by using co-immunoprecipitation (Co-IP) and acyl-PEGyl exchange gel-shift assay, ABHD16A-catalyzed depalmitoylation of IFITM1 was verified in HepG2.215 cells. In addition, we respectively knocked out IFITM1 and ABHD16A via CRISPR/Cas9 and showed that the anti-HBV activity of IFITM1 was negatively regulated by ABHD16A through depalmitoylation. Collectively, our findings demonstrated for the first time that ABHD16A catalyzes the depalmitoylation of IFITM1 to regulate its antiviral activity against HBV, which expands the biological functions of ABHD16A in immune regulation and provides potential targets for HBV infection-related disease therapy.IMPORTANCENowadays, hepatitis B virus (HBV) infection remains a major global public health problem, with over 375 million people worldwide having been infected. Chronic HBV infection leads to serious liver diseases, such as liver cirrhosis and hepatocellular carcinoma. Therefore, it is urgent to reveal the mechanism of HBV infection and uncover novel drug targets. Interferon and interferon-stimulated genes are responsible for the inhibition of HBV infection. Interferon-inducible transmembrane (IFITM) is distributed on plasma membrane, restricting various virus invasions. Nevertheless, whether and how IFITM regulates HBV infection remains unclear. Here, we show that IFITM1 inhibited the replication of HBV, which depended on palmitoylation modification. In addition, the depalmitoylase α/β-hydrolase domain-containing 16A (ABHD16A) negatively regulates the anti-HBV activity of IFITM1. Overall, our findings provided ABHD16A as a potential target for interfering with HBV replication.

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.

This study aims to explore the effects of various hepatic steatosis conditions on histological outcomes in patients with significant inflammation and fibrosis in chronic hepatitis B (CHB) and analyze their impact on HBV virological suppression outcomes and biochemical improvement.

This retrospective study included 219 chronic hepatitis B (CHB) patients receiving nucleos(t)ide analogues therapy. Each of these patients underwent two liver biopsies. Patients were categorized into four groups based on hepatic steatosis status: sustained non-hepatic steatosis (n = 118), new-onset hepatic steatosis (n = 33), sustained hepatic steatosis (n = 37), and disappeared hepatic steatosis (n = 31). We compared the liver biochemical parameters and histological changes before and after treatment. Logistic regression analysis was performed to evaluate characteristics associated with the improvement of significant liver inflammation (G ≥ 2), significant fibrosis (S ≥ 2), and the persistence of hepatic steatosis.

After treatment, the sustained non-steatosis group exhibited the highest rate of improvement in baseline significant inflammation (75.31%), while the sustained steatosis group had the lowest (42.31%, p = 0.008). The sustained steatosis group also had the highest rate of inflammation progression (15.38%, p = 0.020) and was identified as a risk factor for inadequate baseline inflammation improvement (p = 0.006, OR = 0.244, 95% CI 0.090-0.665). In terms of baseline significant liver fibrosis improvement, the sustained non-hepatic steatosis group showed the highest improvement rate (67.14%), while the sustained hepatic steatosis group had the lowest (28.00%, p = 0.006). The new-onset steatosis group had the highest rate of liver fibrosis progression (15.00%, p = 0.027), and sustained hepatic steatosis was a risk factor for poor baseline fibrosis improvement (p = 0.001, OR = 0.180, 95% CI 0.064-0.507). Furthermore, the sustained hepatic steatosis group showed the smallest decrease in liver enzyme markers ALT, GGT, and ALP post-treatment, with reductions of 22.11% (p = 0.023), 13.86% (p = 0.003), and 1.98% (p = 0.025), respectively. Logistic regression analysis revealed that high baseline BMI and LDL-C levels were significantly associated with persistent fatty liver, with high BMI (p = 0.042, OR = 1.109, 95% CI 1.004-1.226) and high LDL-C (p < 0.001, OR = 2.570, 95% CI 1.524-4.332).

In CHB patients with significant inflammation and fibrosis, the persistence of hepatic steatosis during antiviral treatment may impede the improvement of inflammation and fibrosis, leading to disease progression and biochemical abnormalities.

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.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of pathologically expanded immature myeloid cells originating from bone marrow precursors, characterized by their potent immunosuppressive activity through mechanisms such as T cell inhibition, cytokine dysregulation, and metabolic interference. These cells are critically implicated in diverse pathological contexts, including cancer progression, chronic infections, and inflammatory disorders. In chronic liver diseases, MDSCs contribute to the pathogenesis of multiple conditions, such as chronic viral hepatitis, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and autoimmune liver diseases (AILD). Emerging evidence highlights their dual roles in both exacerbating tissue injury and modulating immune responses, positioning MDSCs as pivotal regulators of disease progression and potential therapeutic targets. In this review, we summarize the biological roles of MDSCs in a variety of chronic inflammatory liver diseases and explore the therapeutic potential of targeting these diseases to provide new insight for the treatment of chronic liver diseases.

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.

The limitations of pathogen-directed therapies include growing antimicrobial resistance or the complete lack of any effective antimicrobial agents. This review highlights the potential for host-directed immunotherapies.

This review provides a current status of host-directed immunotherapies to fight infectious diseases (HIFI), defining the concept and existing modalities. Drawing on large-scale viral studies - most of which are historical with limited recent research - the review highlights key lessons for its future clinical application.

HIFI represents a paradigm shift in infectious disease management, moving beyond pathogen-targeting to harnessing and modulating host immunity. This approach requires better mechanistic and pharmacologic understanding of existing modalities, development of newer agents based on tractable immunobiology, and robust clinical studies.

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.

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).

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.

Hepatitis B core related antigen (HBcrAg) measurement predicts treatment outcomes and reflects intrahepatic HBV replication. The commercially available automated assay for HBcrAg has a linear range of 3.0 - 7.0 logU/mL, with higher levels requiring dilution. However, using different diluents across studies may impact comparability and cross-reactivity, which has not been thoroughly investigated. This study aims to validate a dilution method for specimens above the upper limit of quantification (7.0 logU/mL) to improve comparability.

The dilution procedure was two-site tested with three matrices for practicability, accuracy and repeatability using samples from HBV-infected patients with high HBcrAg levels. Samples were tested undiluted or diluted when overrange using Fujirebio's specific dilution reagent (SD1) with reflex testing of pre-treated samples, or manually diluted with fetal calf serum (FCS) or human serum (HS) of samples before restarting pre-treatment. Overrange dilution was further validated in three patient cohorts: untreated HBV-infected patients (n = 157) and patients treated with nucleos(t)ide analogues (NA, n = 19), or pegylated interferon-2alpha (PEG-IFN, n = 80) RESULTS: On-board dilution with SD1 showed higher background signals compared to HS or FCS. The dilution process was reproducible across sites, but SD1 underestimated HBcrAg levels. Dilution with FCS showed an early decrease in HBcrAg levels in patients with HBeAg SC during NA treatment (after 3 months, p = 0.022) and PEG-IFN treatment, whereas no change in HBcrAg levels was found without overrange dilution.

Validation showed high background and underestimating levels of HBcrAg with SD1, while FCS-based overrange dilution resulted in significant early HBcrAg decreases and better correlation with treatment response.

The significance of occult hepatitis B virus (HBV) infection (OBI) has been increasingly recognized while the underlying mechanisms remain incompletely understood. This study aimed to identify high-frequency OBI-related mutations in HBV surface antigen (HBsAg)-negative samples tested by the ultrasensitive Lumipulse G HBsAg-Quant assay. OBI samples were collected from 32 blood establishments across 14 provinces in China. Lumipulse G HBsAg-Quant assay was performed for the re-testing and reclassification of OBI. Mutations in genotypes B (GTB) and C (GTC) were analyzed to identify high-frequency single and combined mutations. Additionally, the efficacy of commercial reagents commonly employed in clinical diagnostics for detecting mutant HBsAg was evaluated. Western Blot was used for the confirmation of extracellular HBsAg as well as the detection of intracellular HBsAg. Hydrophilicity analysis and transmembrane distribution prediction of HBsAg were utilized for further validation. Single mutations at 17 sites and 9 combined mutations in GTB indicated a significantly elevated mutation frequency. In GTC, there were single mutations at 16 sites and 9 combined mutations. Several commercial reagents commonly demonstrated limited capacity toward mutant HBsAg with T123A/P, K141C, and P142R/I/K/L (GTB) and S114A/P (GTC). The findings indicated that mutations including T123A/C/K/S, S132G/Y, P142L/R/S/T, T143M, D144G, G145A, K160R+V168A, I4T+V168A, M103I+K122R, and M103I+Q181R (GTB), along with Q101H, M103I, R160K+C221Y (GTC), were associated with reduced levels of HBsAg both extracellularly and intracellularly. Additionally, K160R (GTB) and E2G (GTC) were associated with intracellular aggregation. This study elucidates the mutations associated with decreased extracellular HBsAg with ultrasensitive HBsAg assay, providing insight for further investigation into the mechanisms of OBI.

The sensitivity of HBsAg detection reagents directly impacts the identification of occult hepatitis B virus (HBV) infection (OBI). This study aims to identify high-frequency OBI-related mutations in HBV surface antigen (HBsAg)-negative samples evaluated using a Fujirebio-Lumipulse ultrasensitive HBsAg assay and to investigate the implications of these mutations on the antigenicity of HBsAg, the detection capacities of various HBsAg assays, and the effects on intracellular and extracellular levels of HBsAg. Generally, our study offers a new perspective on OBI-related mutations by ultrasensitive HBsAg assay and lays the groundwork for further research on the OBI mechanism and the enhancement of HBsAg detection reagents.

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 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.

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology which may affect any patient irrespective of age, sex, and ethnicity. At baseline, the clinical spectrum of the disease varies largely from asymptomatic cases to acute liver failure with massive hepatocyte necrosis. The aim of these EASL guidelines is to provide updated guidance on the diagnosis and management of AIH both in adults and children. Updated guidance on the management of patients with variants and specific forms of AIH is also provided, as is detailed guidance on the management of AIH-associated cirrhosis, including surveillance for portal hypertension and hepatocellular carcinoma, as well as liver transplantation in decompensated cirrhosis.

The impact of hepatitis B virus (HBV) diversity and evolution on disease progression is not well-understood. This study aims to compare intra-individual viral evolution in two groups of chronic hepatitis B (CHB) patients, using antiviral treatment initiation as a measure of lack of immunological control. From the Danish Database for Hepatitis B and C (DANHEP), 25 CHB patients were included; 14 with antiviral treatment initiation (TI group), and 11 without (NTI group). For each patient, three serial plasma samples taken before potential treatment initiation were selected. HBV DNA was amplified by PCR and analyzed by next-generation sequencing. HBV DNA and alanine transaminase were elevated in the TI group throughout the study period. Significantly higher substitution rates in the NTI group versus the TI group were found both within the viral population and at consensus level. Putative predicted CD8+ T cell epitopes contained significantly more substitutions in the NTI group. Genome-wide association analysis revealed several amino acid residues in the HBV genome associated with treatment initiation. This study shows that HBV has a higher rate of substitutions in CHB patients not requiring treatment. This could be linked to host immune pressure leading to disease control.

The role of hepatitis B virus (HBV) RNA in the management of patients with chronic hepatitis B (CHB) experienced with low-level viremia (LLV) remains poorly defined. This study was designed to evaluate the prognostic utility of serum HBV RNA as a biomarker for predicting treatment outcomes in this population.

A retrospective cohort analysis was conducted on 117 pediatric patients with LLV (mean age: 13.14 years; 34% female) treated with continuous entecavir (ConT) or modified regimens (switching to or combining with tenofovir disoproxil fumarate) for ≥ 120 weeks. Virological response was defined as HBV DNA < 10 IU/mL at week 120.

No significant baseline differences existed between ConT and modified regimen groups. Compared to ConT, modified regimens achieved greater reductions in serum HBV DNA, HBV RNA, and quantitative HBsAg, with higher cumulative undetectable rates at week 120 (HBV DNA: ≥ 80.0%; HBV RNA: ≥ 54.8%; P < 0.05). Notably, qHBsAg levels remained elevated in most patients, with only 3 individuals achieving undetectable levels (< 0.05 IU/mL). Multivariate analysis identified higher HBV RNA levels at week 48 as an independent risk factor for non-virological response (adjusted odds ratio: 5.86; 95% confidence interval: 1.40-24.62; P = 0.016). Although HBV RNA alone was less predictive than HBV DNA (area under the receiver operating characteristic curve [AUC]: 0.76 vs. 0.80; P = 0.459), combining both markers improved prediction accuracy (AUC: 0.82; P < 0.05 vs. single markers).

In children with LLV, serum HBV RNA level is an independent risk factor for non-virological response and may serve as a complementary biomarker to HBV DNA for guiding antiviral therapy adjustments.

Hepatitis B, hepatitis C, cytomegalovirus (CMV), and tuberculosis (TB) pose significant risks to patients with inflammatory bowel disease (IBD) receiving biological therapy. However, data on the prevalence of these infections in Syria are scarce.

We conducted a retrospective chart review of IBD patients receiving biologic therapy at Damascus Hospital and Ibn Al-Nafees Hospital, two major public institutions in Syria, between January 2021 and November 2024. A minimum sample size of 130 was estimated; however, all available records were reviewed.

Among 185 IBD patients (104 from Damascus and 81 from Ibn Al-Nafees), 51.4% had ulcerative colitis and 47.6% had Crohn's disease. The smoking prevalence was 9.2%, which was higher in Crohn's disease (5.9%) than in ulcerative colitis (3.2%). TST performed in 61.1% of patients, with 4.3% positivity, and interferon-gamma release assay (IGRA) in 8.7% (1.1% positive). Hepatitis B surface antigen (HBsAg) and anti-HBc antibodies were found in 2.7% and 5.4% of the patients, respectively, while hepatitis C seroprevalence was low (0.5%). CMV seropositivity was high in Damascus (50.8%), with two cases (1.1%) of CMV colitis. Biologic therapies included infliximab (42.7%), ustekinumab (24.3%), golimumab (10.8%), and adalimumab (6.5%). Data gaps, particularly in viral serology and TB screening, are notable.

This study identifies deficiencies in TB/hepatitis B screening (notably anti-HBs Ab) and elevated CMV seroprevalence among Syrian IBD patients receiving biologics, extending to immunosuppressed cohorts (rheumatology, dermatology, oncology). Insufficient screening heightens occult infection/reactivation risks, necessitating standardized pretreatment protocols to reduce morbidity in high-risk populations.

Not applicable.