Background: Achieving functional cure, with the prerequisite of hepatitis B surface antigen (HBsAg) seroclearance, or partial cure with sustained low-level HBsAg, is a key goal in chronic hepatitis B (CHB) management. With currently available antiviral agents, detailed data are lacking to define the likelihood of achieving and maintaining these treatment endpoints across the full spectrum of baseline HBsAg levels in real-world practice. Methods: In this nationwide, retrospective-prospective, multicenter cohort study, adults with CHB receiving nucleos(t)ide analogue (NA) or pegylated interferon (PegIFN)-based therapy between September 2020 and December 2023, were enrolled from 98 centers in China. Patients with hepatocellular carcinoma (HCC) or liver failure before baseline, or concurrent participation in other clinical trials, were excluded. All enrolled individuals were followed by prospective data collection. Cumulative HBsAg seroclearance and the dynamics of HBsAg levels were analyzed across finely stratified baseline HBsAg categories. For PegIFN-treated patients, post-treatment HBsAg trajectories after cessation of PegIFN were also evaluated. Results: Among 7271 participants included, 3623 received IFN-based therapy and 3648 received NA only. Baseline HBsAg distribution was consistent with the real-world situation in China, and refined stratification retained sufficient sample size within each HBsAg interval. Overall, the cumulative incidence of HBsAg loss was 1·25% in NA cohort and 23·36% in IFN cohort by week 168. With NA monotherapy, clinically meaningful HBsAg seroclearance was largely confined to patients with baseline HBsAg <20 IU/mL (20·97% for those <10 IU/mL and 6·76% for those with 10-20 IU/mL by week 144). For patients with higher baseline HBsAg levels in this cohort, HBsAg seroclearance occurred only as sporadic events. In contrast, HBsAg seroclearance under IFN-based therapy was observed across the full baseline HBsAg spectrum, with incidence significantly dependent on both baseline HBsAg and follow-up duration. At week 48, the cumulative HBsAg seroclearance rate exceeded 30% for patients with baseline HBsAg <50 IU/mL, 20% for those <100 IU/mL, and 10% for those <500 IU/mL. By week 144, the rate surpassed 50% for patients with baseline HBsAg <10 IU/mL, 30% for those <100 IU/mL, 15% for those <1000 IU/mL, and 10% for those <3000 IU/mL. Most patients who achieved HBsAg reduction to a low level maintained stable after IFN discontinuation (60·29% in population with baseline HBsAg <10 IU/mL and 63·58% in population with baseline 10≤ HBsAg <100 IU/mL), and a proportion of patients achieved seroclearance during subsequent follow-up after stopping IFN (30·88% among those with baseline HBsAg <10 IU/mL and 16·56% among those with baseline 10≤ HBsAg <100 IU/mL). A total of 12·53% of patients in NA cohort and 31·75% in IFN cohort attained low-level HBsAg state (with positive HBsAg but lower than 100 IU/mL) until last measurement. In IFN cohort, among patients with baseline HBsAg <100 IU/mL, median HBsAg concentrations declined rapidly to a low plateau by week 12-24, whereas among those with baseline HBsAg >3000 IU/mL, it stabilized beyond 60 weeks, and extending IFN duration beyond 48 weeks was associated with higher long-term seroclearance. Interpretation: This study presented a continuous landscape of cure likelihood across all baseline HBsAg strata for current available antiviral regimens, defined antigen-specific thresholds for therapeutic goals towards cure and provided insights for individualizing finite treatment courses. It also demonstrated that nearly half of patients with IFN-based therapy and over 85% of those on NA monotherapy did not achieve the prerequisite of either functional or partial cure, highlighting the unmet need for novel agents. Our findings provide critical real-world evidence for individualizing on-treatment goals and inform strategies for therapy optimization and future drug development aimed at achieving functional cure or partial cure of hepatitis B.

BACKGROUND & AIMS:Acute-on-chronic liver failure (ACLF) is characterised by multiorgan failure and high short-term mortality in hospitalised patients with acute decompensation of cirrhosis. Although the EASL-CLIF criteria are widely used for diagnosis and prognostication, evolving definitions of organ dysfunction and emerging therapies require updated, tailored criteria to improve diagnostic accuracy, treatment assessment, and applicability in clinical trials. We aimed to develop and validate the A-TANGO organ failure (OF) score to refine ACLF diagnosis and enhance its utility for treatment response evaluation and risk stratification. METHODS:We performed a retrospective analysis of prospective observational cohorts. The derivation cohort comprised three EF-CLIF consortium studies conducted in Europe and Latin America (CANONIC, PREDICT, ACLARA; n = 3,896). Validation cohorts included one study from India (Ambi-spective study n = 2,055) and one from China (CATCH-LIFE; n = 2,568). Patients were enrolled between 2011 and 2023, with follow-up completed in 2023. The primary objective was to redefine thresholds for organ dysfunction and failure using three subscores per organ, with subscore 3 corresponding to ≥15% 28-day mortality and defining organ failure. RESULTS:Compared with the CLIF-C OF score, the A-TANGO OF score introduced revised thresholds for organ failure and added an ACLF grade 4 to address the wide mortality variation within CLIF-C OF grade 3. A-TANGO identified more organ failures, increasing ACLF diagnosis from 24% to 36% and improving the net reclassification index by 16%, while maintaining similar predictive accuracy for 28- and 90-day mortality. Two additional prognostic models (A-TANGO ACLF-WBC and A-TANGO ACLF-CRP) demonstrated strong associations with 28- and 90-day mortality and improved prognostic performance. Findings were confirmed in external validation cohorts. CONCLUSIONS:The A-TANGO OF score is a reproducible and comprehensive tool for ACLF diagnosis with preserved prognostic performance, validated across large international cohorts. It provides a robust framework for clinical trials by enabling more accurate diagnosis, reducing required sample sizes, and offering clinically meaningful endpoints such as ACLF resolution for treatment response assessment. IMPACT AND IMPLICATIONS:The A-TANGO organ failure (OF) score provides a scientifically justified advancement in ACLF research by refining organ-specific dysfunction thresholds and introducing a new grade 4, thereby addressing limitations in current EASL-CLIF criteria and improving identification of high-risk patients. These findings are important for clinicians, researchers, and healthcare systems globally, as they increase detection of organ failure, enhance risk stratification, and enable more accurate prediction of short-term mortality in hospitalized patients with cirrhosis. The A-TANGO OF score and its associated prognostic scores (ACLF-WBC and ACLF-CRP) can be applied in clinical practice to guide treatment decisions, and serve as reliable, measurable endpoints in clinical trials evaluating emerging therapies. Although limitations such as missing data, cohort-specific recruitment differences, and historical classification criteria exist, the consistent and robust performance of the A-TANGO scores across large, multinational cohorts highlights their potential applicability and utility on a global scale.

Objectives: GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that inhibits HBV replication by interfering with assembly and disassembly of the virus nucleocapsid, this prospective, open-label, comparative, phase 2b trial evaluated the antiviral activity and safety of GLS4/ritonavir (RTV) combined with entecavir in hepatitis B e antigen-positive patients. Methods: 250 CHB patients were enrolled, including treatment-na & iuml;ve patients and those interrupted anti-HBV drugs for >= 6 months (Part A, n=125), and patients who had taken ETV for >= 1 year and had achieved viral suppression (Part B, n=125). Patients were randomly allocated to receive 120 mg GLS4/100 mg RTV plus 0.5 mg ETV or 0.5 mg ETV monotherapy for 96 weeks. Results: In the mid-term, in Part A (n=122), greater least-squares mean (LSM) changes from baseline were observed in the GLS4/RTV plus ETV cohort than in ETV monotherapy cohort in HBV DNA (-6.28 vs -5.72 log10 IU/ml, p=0.0005), HBsAg (-0.87 vs -0.65 log10 IU/ml, p=0.0653), HBV pgRNA (-3.83 vs -1.91 log10 copies/ml, p<0.0001); The proportions of both HBV DNA and pgRNA negative patients were 17.3% (13/75, GLS4/RTV plus ETV) and 0% (0/30, ETV monotherapy). In Part B (n=123), greater mean LSM reductions in HBsAg (-0.17 vs -0.06 log10 IU/ml, p=0.0013), HBV pgRNA (-1.61 vs -0.28 log10 copies/ml, p<0.0001) were also observed in the GLS4/RTV+ETV cohort. the proportions of both HBV DNA and pgRNA-negative patients were 71.6% (48/67, GLS4/RTV plus ETV) and 18.9% (7/37, ETV monotherapy), respectively. No patients achieved HBsAg loss at week 48. GLS4/RTV + ETV were well tolerated, the most common adverse events were elevated alanine aminotransferase levels and hypertriglyceridemia, which were reversed by temporary GLS4/RTV discontinuation. Conclusions: The primary analysis at week 48 showed that the antiviral efficacy of GLS4/RTV with ETV was clearly superior to that of ETV monotherapy. GLS4/RTV with ETV was well tolerated; further studies evaluating its safety and efficacy are ongoing. (clinical trial identifier: NCT04147208). (c) 2025 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND AND AIMS:Metabolic dysfunction-associated steatotic liver disease (MASLD) can progress to severe forms such as metabolic dysfunction-associated steatohepatitis (MASH). Effective treatments for MASH are urgently needed. This study aimed to evaluate the efficacy and safety of chiglitazar, a PPAR pan-agonist, in MASLD with hypertriglyceridemia and insulin resistance. APPROACH AND RESULTS:In this phase II multicenter, randomized, double-blind and placebo-controlled study, 104 patients with MASLD with hypertriglyceridemia and insulin resistance were randomized 2:2:1 to receive 48 mg, 64 mg of chiglitazar, or placebo once daily for 18 weeks. The primary endpoint was the percentage change in liver fat content measured by magnetic resonance imaging proton density fat fraction (MRI-PDFF) at week 18. Chiglitazar significantly reduced liver fat content, with percentage change from baseline at week 18 of -28.1% (95% CI -37.5 to -18.7) in the 48 mg group and -39.5% (95% CI -49.0 to -30.0) in the 64 mg group, compared with -3.2% (95% CI -16.8 to 10.4) in placebo group. The differences compared with placebo were -24.9% ( p <0.05) for the 48 mg group and -36.3% ( p <0.001) for the 64 mg group. Chiglitazar also significantly improved liver injury-related biomarkers such as ALT, AST, and γ-GT. Liver fibrosis indicators, lipid parameters, insulin resistance, and metabolic syndrome showed an improved trend. Both doses of chiglitazar were well tolerated, with most adverse events being mild to moderate. CONCLUSIONS:Chiglitazar significantly reduced liver fat content in MASLD with hypertriglyceridemia and insulin resistance, with a dose-dependent effect and a favorable safety profile.

Background Despite inadequate supply and potential contamination risk, human plasma has remained the only source for human serum albumin (pHSA) intravenous administration since the 1940s. Objective We sought to establish the safety and efficacy of OsrHSA, a recombinant HSA from bioengineered Oryza sativa (rice). Design In this multicentre, randomised, double-blind and positive-controlled study, patients with decompensated liver cirrhosis and serum albumin ≤30 g/L were recruited from 22 centres in China. The patients were randomly assigned to OsrHSA or pHSA (4:1) to once-daily intravenous injection (10 g or 20 g) until their serum albumin level reached 35 g/L, for a maximum of 2 weeks, with 2 weeks of follow-up. The primary outcome was the proportion of patients to reach a serum albumin level of 35 g/L (non-inferiority margin <−0.20). Outcomes were evaluated in patients who received the study drug and had at least one post-baseline serum albumin value (full analysis set, FAS). Safety was evaluated in all patients who received the study drug. Results Between 22 March 2021 and 2 June 2022, 220 patients received OsrHSA (n=175) or pHSA (n=45). 216 patients were included in the FAS (OsrHSA, n=171; pHSA, n=45). Primary outcome of OsrHSA (130/171, 76%) was non-inferior to pHSA (34/45, 75.6%) (difference=0.5%; lower limit of 97.5% CI=−0.119). There was no significant difference between all secondary outcomes of OsrHSA and pHSA. There were no drug-related serious adverse events. Conclusions Rice-derived HSA is non-inferior to plasma-derived HSA in efficacy and safety. This finding should be confirmed in phase 3 trial. Trial registration number NCT04835480 .

BACKGROUND AND AIMS:Acute-on-chronic liver failure (ACLF) is a highly dynamic syndrome. The objective of this study was to delineate the clinical course of patients with HBV-ACLF and to develop a model to estimate the temporal evolution of disease severity. METHODS:We enrolled eligible patients from 2 large, multicenter prospective cohorts. The ACLF grade, organ failures, and outcomes were assessed at multiple time points (days 1/4/7/14/21/28). Probabilities for ACLF transitions between these disease states and to death within 28 days were calculated using a multi-state model that used baseline information and updated ACLF status. The model was validated in independent patients. RESULTS:Among all the 445 patients with HBV-ACLF, 76 represented disease progression, 195 had a stable or fluctuating course, 8 with improvement, and the remaining 166 with resolution within 28-day follow-up. New coagulation (63.64%) or renal failure (45.45%) was frequently observed during early progression. Patients with disease progression had a higher incidence of new episodes of ascites [10 (13.16%) vs. 22 (5.96%), p = 0.027] and HE [13(17.11%) vs. 21 (5.69%), p = 0.001], and a significant increase in white blood cell count. The multi-state model represented dynamic areas under the receiver operating characteristic curves ranging from 0.71 to 0.84 for predicting all ACLF states and death at 4, 7, 14, 21, and 28 days post-enrollment and from 0.73 to 0.94 for predicting death alone, performing better than traditional prognostic scores. CONCLUSIONS:HBV-ACLF is a highly dynamic syndrome with reversibility. The multi-state model is a tool to estimate the temporal evolution of disease severity, which may inform clinical decisions on treatment.

Background and aimA high aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio is associated with liver injury in liver disease; however, no data exist regarding its relationship with 90-day prognosis in patients with acute exacerbation of chronic liver disease.MethodsIn this study, 3,758 participants (955 with advanced fibrosis and 2,803 with cirrhosis) from the CATCH-LIFE cohort in China were included. The relationships between different AST/ALT ratios and the risk of adverse 90-day outcomes (death or liver transplantation) were determined in patients with cirrhosis or hepatitis B virus (HBV)-associated advanced fibrosis, respectively.ResultsIn the patients with HBV-associated advanced fibrosis, the risk of 90-day adverse outcomes increased with AST/ALT ratio; after adjusting for all confounding factors, the risk of adverse 90-day outcomes was the highest when AST/ALT ratio was more than 1.08 (OR = 6.91 [95% CI = 1.789–26.721], p = 0.005), and the AST/ALT ratio of >1.9 accelerated the development of adverse outcomes. In patients with cirrhosis, an AST/ALT ratio > 1.38 increased the risk of adverse 90-day outcomes in all univariables (OR = 1.551 [95% CI = 1.216–1.983], p < 0.001) and multivariable-adjusted analyses (OR = 1.847 [95% CI = 1.361–2.514], p < 0.001), and an elevated AST/ALT ratio (<2.65) accelerated the incidence of 90-day adverse outcomes. An AST/ALT ratio of >1.38 corresponded with a more than 20% incidence of adverse outcomes in patients with cirrhosis.ConclusionThe AST/ALT ratio is an independent risk factor for adverse 90-day outcomes in patients with cirrhosis and HBV-associated advanced fibrosis. The cutoff values of the AST/ALT ratio could help clinicians monitor the condition of patients when making clinical decisions.

BACKGROUND:Acute decompensation (AD) of cirrhosis is associated with high short-term mortality, mainly due to the development of acute-on-chronic liver failure (ACLF). Thus, there is a need for biomarkers for early and accurate identification of AD patients with high risk of development of ACLF and mortality. Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is released from activated innate immune cells and correlated with various inflammatory processes.AIM:To explore the prognostic value of sTREM-1 in patients with AD of cirrhosis.METHODS:A multicenter prospective cohort of 442 patients with cirrhosis hospitalized for AD was divided into a study cohort (n = 309) and validation cohort (n = 133). Demographic and clinical data were collected, and serum sTREM-1 was measured at admission. All enrolled patients were followed-up for at least 1 year.RESULTS:In patients with AD and cirrhosis, serum sTREM-1 was an independent prognosis predictor for 1-year survival and correlated with liver, coagulation, cerebral and kidney failure. A new prognostic model of AD (P-AD) incorporating sTREM-1, blood urea nitrogen (BUN), total bilirubin (TBil), international normalized ratio (INR) and hepatic encephalopathy grades was established and performed better than the model for end-stage liver disease (MELD), MELD-sodium (MELD-Na), chronic liver failure-consortium (CLIF-C) ACLF and CLIF-C AD scores. Additionally, sTREM-1 was increased in ACLF and predicted the development of ACLF during first 28-d follow-up. The ACLF risk score incorporating serum sTREM-1, BUN, INR, TBil and aspartate aminotransferase levels was established and significantly superior to MELD, MELD-Na, CLIF-C ACLF, CLIF-C AD and P-AD in predicting risk of ACLF development.CONCLUSION:Serum sTREM-1 is a promising prognostic biomarker for ACLF development and mortality in patients with AD of cirrhosis.