BACKGROUND AND AIMS:Pradefovir mesylate is a novel liver-targeting prodrug of adefovir developed using HepDirect technology. We report that the phase 3 trial is to compare the efficacy and safety of pradefovir versus tenofovir disoproxil fumarate (TDF) in patients with chronic hepatitis B (CHB). APPROACH AND RESULTS:This ongoing randomized, double-blind, non-inferiority, phase 3 study was conducted at 58 sites in China. Patients with CHB were randomly assigned (2:1) to receive either 45 mg daily pradefovir or 300 mg daily TDF with a matching placebo. The primary efficacy endpoint was defined as the proportion of patients whose HBV DNA level was <29 IU/mL at week 48. All participants who received at least 1 dose of the study drug were included in efficacy and safety analyses with pre-specified renal and bone endpoints at week 96. A total of 1170 patients were screened during the study, and 908 patients received the study drug. At week 48, viral suppression (HBV DNA <29 IU/mL) rates of pradefovir were non-inferior to TDF in HBeAg-positive [-1.8% (95% CI: -9.7 to 6.1)] and HBeAg-negative [2.6% (95% CI: -5.1 to 10.3)] patients, using a non-inferiority margin of -12%. By week 96, HBeAg-positive patients showed significantly greater HBsAg decline (≥1 log 10  IU/mL) with pradefovir (39.3% vs. 29.9%). Pradefovir demonstrated a more favorable safety profile at week 96, including significantly fewer drug-related adverse events (58.6% vs. 71.9%), improved bone/renal safety, and a lower incidence of elevated creatine phosphokinase-MB. CONCLUSIONS:Pradefovir should be a highly recommended treatment option for adult patients with CHB.

Chronic liver diseases are a major global health burden, with cirrhosis and portal hypertension driving morbidity and mortality. Non-invasive assessment of portal hypertension is critical for risk stratification and clinical decision-making. Spleen stiffness measurement (SSM) has emerged as a novel elastography-based biomarker reflecting the hemodynamic consequences of portal hypertension. This review summarizes current evidence on SSM across major chronic liver disease etiologies, including viral hepatitis, metabolic-associated fatty liver disease, and autoimmune liver diseases. We outline the principles and technical evolution of SSM across elastography platforms, including transient elastography, shear-wave elastography, and magnetic resonance elastography. Emerging data indicate that SSM provides incremental value beyond established non-invasive markers such as liver stiffness measurement and platelet count, particularly in refining risk stratification for clinically significant portal hypertension and high-risk varices. SSM may reduce unnecessary endoscopic screening and improve patient selection for therapeutic interventions. This review is based on a structured literature search of PubMed and Web of Science. SSM is a promising non-invasive biomarker with increasing translational relevance in the management of chronic liver diseases. With further standardization and prospective validation, SSM has the potential to support precision risk stratification and guide individualized clinical decision-making.

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.

ABSTRACT Aims The tolerance of patients with compensated hepatitis B cirrhosis to interferon (IFN) therapy remains controversial. Therefore, this study aimed to evaluate the safety of pegylated interferon‐alpha in chronic hepatitis B (CHB) patients with compensatory cirrhosis. Methods Data from two prospective cohorts (the OASIS Project and CHESS 2306) from January 2018 to January 2024 were synthesized and analyzed. Patients with Child‐Pugh Class A hepatitis B cirrhosis who received IFN‐based therapy (n = 920) were included. The control groups included patients with compensated hepatitis B receiving nucleos(t)ide analog (Nuc) monotherapy (n = 714) and patients without cirrhosis receiving IFN‐based therapy (n = 4111), respectively. Propensity score matching was used to control for confounding factors; 566 versus 566 cases were analyzed among patients with cirrhosis treated with IFN‐based therapy or Nuc monotherapy, and 785 versus 785 cases were analyzed among patients with and without cirrhosis treated with IFN‐based therapy. Primary outcomes included decompensation events, and secondary outcomes included severe adverse events, overall adverse events, and treatment‐related hospitalizations or deaths. Results In patients with hepatitis B virus‐related cirrhosis, the incidence of decompensation events was similar between IFN‐based therapy and Nuc monotherapy (6/566 [1.1%] vs. 3/566 [0.5%], p = 0.506). No hospitalizations or deaths were associated with adverse events during the observation period (48 weeks). The incidences of severe adverse events were similar in patients with cirrhosis under IFN‐based therapy or Nuc monotherapy (severe neutropenia: 1/450 [0.2%] vs. 0/378 [0], p = 0.999; severe thrombocytopenia: 4/435 [0.9%] vs. 0/296 [0], p = 0.153; severe alanine aminotransferase level elevation: 1/523 [0.2%] vs. 1/458 [0.2%], p = 0.999; and severe total bilirubin [TBIL] level elevation: 5/419 [1.2%] vs. 3/385 [0.8%], p = 0.727). The incidences of severe adverse events were similar between patients with and without cirrhosis receiving IFN‐based therapy, except that severe TBIL level elevation was more frequent in patients with cirrhosis who already had mildly to moderately elevated TBIL levels at baseline than in those without (6/153 [3.9%] vs. 0/118 [0], p = 0.040). Conclusion IFN‐based therapy demonstrates favorable safety in Child‐Pugh A compensated cirrhosis. It did not increase decompensation events or severe adverse events compared to Nuc monotherapy, and adverse event profiles were largely similar between cirrhotic and non‐cirrhotic patients, except for a higher risk of severe hyperbilirubinemia in those with pre‐existing TBIL elevation. ClinicalTrials.gov identifier: NCT04896255. Chinese Clinical Trial Registry number: ChiCTR2500107592.

As immunotherapy gains increasing attention and clinical application, the immune modulation therapy has been widely used in the treatment of infectious and critical diseases. Clinical evidence has been accumulated for application of thymosin alpha 1 (T alpha 1), a classical immune modulator, in related domains. The National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases and other institutions invited multidisciplinary experts to develop this expert consensus on clinical application of T alpha 1 in infectious diseases and critical care medicine. Based on the latest domestic and international research findings and considering relevant factors, including economics, patient preferences and values, tradeoffs, accessibility, fairness and acceptability, the consensus assesses the quality levels of current evidence and forms 10 recommendations on the application of T alpha 1 in treatment of liver diseases, viral infections, bacterial infections and critical illnesses. This consensus aims to enhance understanding of T alpha 1 and improving its standardized application for clinicians.

This report describes a case of Q fever with predominantly liver injury presentation. We used targeted next generation sequencing (tNGS) and immunologic methods to identify a case of acute stage infection of Q fever with liver injury; prompt diagnosis and treatment significantly improved the patient's prognosis and life quality. Further, to predict the homology and genetic diversity, the patient's sample was partially sequenced for insertion sequence (IS)1111 gene. Additionally, we reviewed similar cases in the past five years, aiming to provide evidence-based evidence for subsequent accurate diagnosis and treatment.

ObjectiveThis study investigated the hepatoprotective effect and underlying mechanisms of D-glucaro-1,4-lactone (1,4-GL), a natural compound found in fruits and vegetables, against acetaminophen (APAP)-induced acute liver injury (ALI) in mice, which had not been previously explored.MethodsA stable ALI model was established in male C57BL/6J mice using 300 mg/kg APAP after fasting. Mice were pretreated orally with glutathione (200 mg/kg), or 1,4-GL (100 mg/kg or 200 mg/kg) for five consecutive days before APAP challenge. Serum biochemical markers were measured. Liver histopathology was assessed via H&E staining. Gut microbiota composition was analyzed using 16S rRNA sequencing of fecal samples. Liver metabolites were profiled using 1HNMR metabolomics.Results1,4-GL pretreatment (especially 200 mg/kg) significantly ameliorated APAP-induced liver damage: it reduced serum ALT, AST, TBIL, and MDA levels (P < 0.05), increased GSH and SOD levels (P < 0.05), and attenuated hepatic necrosis and inflammation. 1,4-GL increased the abundance of the beneficial gut bacterium Lactobacillus (significantly reduced by APAP) and elevated hepatic levels of protective metabolites isoleucine, glutamine, and nicotinic acid. Correlation analyses between gut microbiota and liver metabolites revealed that glutamine and nicotinic acid were significantly positively correlated with Firmicutes and Lactobacillus, while showing a significant negative correlation with Lachnoclostridium. Lactobacillus was identified as a key beneficial bacterium, whereas Lachnoclostridium was associated with increased disease severity.Conclusion1,4-GL exerts a beneficial regulatory effect on APAP-induced ALI by the Lactobacillus-glutamine/nicotinic acid pathway, highlighting its potential as a therapeutic agent for drug-induced liver injury.

Background and Aims:Epidemiological data on bacterial infections in cirrhosis in China remain limited. Therefore, we aimed to conduct a multicenter study to investigate the characteristics and outcomes of patients with cirrhosis and bacterial infections in China. Methods:We retrospectively enrolled 1,438 hospitalized adult patients with cirrhosis and bacterial or fungal infections from 24 hospitals across China between January 2018 and September 2024. Data on demographics, clinical features, microbiology, treatment, and outcomes were collected. Results:A total of 1,783 infection episodes were recorded, including 1,668 first infections and 115 second infections. Most infections were community-acquired (86.6%). Pneumonia was the most common infection type (26.7%), followed by spontaneous bacterial peritonitis (19.5%) and spontaneous bacteremia (14.1%). Among 754 pathogens isolated from 620 patients, Klebsiella pneumoniae (20.1%) was nearly as common as Escherichia coli (21.7%). Multidrug-resistant (MDR) organisms accounted for 41.0% of all isolates, with extended-spectrum β-lactamase-producing Escherichia coli being the most prevalent MDR strain (8.9% of patients). Adherence to empirical antibiotic treatment guidelines from the European Association for the Study of the Liver was significantly lower in this cohort compared to the global study (21.5% vs. 61.2%, P < 0.001), accompanied by a lower clinical resolution rate (63.5% vs. 79.8%, P < 0.001). Conclusions:The clinical and microbiological characteristics of bacterial infections in patients with cirrhosis in China differ substantially from those reported in other regions. These findings highlight the need for region-specific management and prevention strategies, particularly in light of the changing microbiological landscape, high MDR prevalence, and suboptimal antibiotic practices.

Host-virus interactions can significantly impact the viral life cycle and pathogenesis; however, our understanding of the specific host factors involved in highly pathogenic avian influenza A virus H7N9 (HPAI H7N9) infection is currently restricted. Herein, we designed and synthesized 65 small interfering RNAs targeting host genes potentially associated with various aspects of RNA virus life cycles. Afterward, HPAI H7N9 viruses were isolated and RNA interference was used to screen for host factors likely to be involved in the life cycle of HPAI H7N9. Moreover, the research entailed assessing the associations between host proteins and HPAI H7N9 proteins. Twelve key host proteins were identified: Annexin A (ANXA)2, ANXA5, adaptor related protein complex 2 subunit sigma 1 (AP2S1), adaptor related protein complex 3 subunit sigma 1 (AP3S1), ATP synthase F1 subunit alpha (ATP5A1), COPI coat complex subunit alpha (COP)A, COPG1, heat shock protein family A (Hsp70) member 1A (HSPA)1A, HSPA8, heat shock protein 90 alpha family class A member 1 (HSP90AA1), RAB11B, and RAB18. Co-immunoprecipitation revealed intricate interactions between viral proteins (hemagglutinin, matrix 1 protein, neuraminidase, nucleoprotein, polymerase basic 1, and polymerase basic 2) and these host proteins, presumably playing a crucial role in modulating the life cycle of HPAI H7N9. Notably, ANXA5, AP2S1, AP3S1, ATP5A1, HSP90A1, and RAB18, were identified as novel interactors with HPAI H7N9 proteins rather than other influenza A viruses (IAVs). These findings underscore the significance of host-viral protein interactions in shaping the dynamics of HPAI H7N9 infection, while highlighting subtle variations compared with other IAVs. Deeper understanding of these interactions holds promise to advance disease treatment and prevention strategies.

The contents of selenomethionine (SeMet) and selenomethylcysteine (SeMC) in Selenium-Enriched black garlic extract (Se-BGE), a popular functional food in Asian countries, were 2.9 ± 0.6 μg/g and 12.2 ± 2.3 μg/g by PITC pre-column derivatization UPLC-MS method. Improved histological injury, significant extension of the median survival time, and attenuated serum levels of alanine aminotransferase, total bilirubin and SOD activity were observed in the acute liver failure (ALF) rats treated with Se-BGE (1.0 g/mL). 1HNMR-based metabonomics revealed that serum levels of lactate, pyruvate, betaine, choline, taurine, and glycine were restored, and 16S rDNA sequencing analysis showed that the composition and number of the intestinal flora were regressed to healthy levels in ALF rats treated by Se-BGE. Serum choline and betaine showed significant correlations with g_Lactobacillus and g_Escherichia. Our findings demonstrated that Se-BGE protects against LPS/D-GalN-induced ALF in rats, possibly due to antioxidation, metabolism, and intestinal flora regulations of Se-BGE.

BACKGROUND:Artificial liver support systems (ALSSs) are important approaches for treating acute-on-chronic liver failure (ACLF) patients. Few studies have investigated potential serum therapeutic markers of ACLF patients treated by ALSSs.METHODS:Serum samples were obtained from 57 early to middle stage ACLF patients before and after ALSSs treatment and analyzed by metabonomics. The diagnostic values were evaluated by the area under receiver-operating characteristic curve (AUROC). A retrospective cohort analysis was further employed.RESULTS:Metabonomic study showed that serum ratios of lactate: creatinine in ACLF patients is significantly altered and then restored to normal levels after ALSSs treatment. A retrospective cohort analysis (n = 47) validated that the lactate: creatinine ratio of ACLF patients in the one-month death group remained unchanged after ALSSs treatment, but fell markedly in the survival group with AUROC of 0.682 for diagnosis of survival group from death group, which is a more sensitive measure than measures of prothrombin time activity (PTA) to evaluate the therapeutic effect of ALSSs treatment.CONCLUSIONS:Our results demonstrated the greater the decline in the serum lactate: creatinine ratio with better effective treatments of ALSSs in the ACLF patients with early to middle stage, which presents a potential therapeutic biomarker of ALSSs treatment.

The effects of interleukin-7 (IL-7) on the carbon tetrachloride (CCL4) induced hepatic fibrosis were investigated in this study. Thirty-six female BALB/C mice were randomized into group A (control group) injected with saline, group B (fibrotic model group) and group C (IL-7 intervention group). Histopathological changes were observed by HE, Masson as well as reticular fiber staining. The apoptosis cells and hepatic stellate cell (HSC) were detected from the tissues, and the expressions of Bax and Bcl-2 gene were also detected. The results of histological HE, Masson and reticular fiber staining showed that compared with group B, the degree of inflammation and fibrosis of the tissue were statistically reduced in group C. Compared with sub-group B and C, the degree of reduce inflammation of the liver and inhibit hepatic fibrosis were more obviously with the extension of treatment time. The inflammatory activity and liver fibrosis score were statistical significant between groups (P<0.05), the highest score was group B, followed by group C. The apoptosis cells were similar between fibrotic model group and IL-7 intervention group, while the HSC count was obviously higher in group B compared to the other two groups. The Bax gene was up-regulated when intervened with IL-7 for hepatic fibrosis and Bcl-2 showed to the contrary. IL-7 could inhibit hepatic fibrosis in mice induced by CCL4 and reduce liver inflammation process. The anti-fibrosis mechanismmight be involved in inducing apoptosis through P53 pathway regulated Bcl-2 and Bax genes.

乙型肝炎病毒相关慢加急性肝衰竭(HBV-ACLF)病死率高，目前发病机制不明确，大量肝细胞坏死是其发病的关键因素之一，除肝移植外，尚无特效治疗。细胞信号共抑制分子疱疹病毒侵入介导因子(HVEM)-B和T淋巴细胞衰减因子(BTLA)参与多种免疫细胞的免疫应答过程并通过调控Janus激酶3-信号转导及转录激活蛋白3通路影响炎症细胞因子表达，可能在HBV-ACLF的发病中发挥重要的调节作用。本综述阐述了HVEM-BTLA通路在乙型肝炎病毒相关免疫中的作用机制和研究现状，以及其在HBV-ACLF免疫触发和疾病发生、发展中可能发挥的作用与机制，并讨论了HVEM-BTLA通路作为HBV-ACLF潜在治疗靶点、短期或长期临床预后生物标志物的可能性和应用前景。

Abstract Background Ursodeoxycholic acid (UDCA) was reported to reduce susceptibility to SARS-CoV-2 infection by downregulating farnesoid X receptor (FXR) -ACE2 signaling. However, we found a different story in real-world clinical studies. Objectives We attempted to verify whether UDCA can effectively prevent SARS-CoV-2 transmission or have positive therapeutic effects in a real-world clinical study. Methods We performed a retrospective study, collected and assessed clinical presentation and laboratory data on patients with liver diseases infected with SARS-CoV-2 Omicron sub-variant BA.5.2 who had been treated with or without UDCA. Results Treatment with UDCA did not prevent infection with the Omicron sub-variant BA.5.2, failed in reducing the duration of infection and hardly mitigated the severity of COVID-19. Meanwhile, the severity of liver diseases, especially TBil, ALP, γ-GT, liver cirrhosis and Child-Pugh classification, should be considered as risk factors for severe COVID-19 in chronic hepatic patients. Conclusion UDCA failed to show inhibitory effects against SARS-CoV-2 infection in complex clinical settings. The regulatory mechanism of the novel UDCA-FXR-ACE2 pathway needs to be further investigated in real-world clinical studies.

Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a rare and severe form of end-stage liver disease with high mortality; gut microbes are strongly associated with the development of this severe liver disease but the exact association is unclear. Artificial liver support systems (ALSS) are clinically important in prolonging the waiting time for liver transplantation and in aiding drug therapy to achieve remission. The aim of this study was to investigate the effect of ALSS on the abundance and diversity of microorganisms in the gut of HBV-ACLF patients. In this study, 109 stool samples were collected from patients with hepatitis B virus-associated acute chronic liver failure (HBV-ACLF) for 16S rRNA sequencing. Among them, 44 samples were from patients treated with ALSS therapy as an adjunct to standard medical treatment (SMT) and 65 were from patients receiving SMT only. Analysis of the sequencing results suggested that there were significant differences in the abundance and diversity of gut microbiota between the with-ALSS and without-ALSS groups (p < 0.05). The operational taxonomic units and Shannon indexes indicated that the diversity and abundance of the gut microbiome, while decreasing after the first ALSS treatment, gradually increased after an increase in the number of ALSS therapies. The overall proportion of HBV-ACLF patients with coinfection was 27.59%; the coinfection can reduce the abundance of the Bacteroidetes phylum in the microbiome significantly whereas Proteobacteria were highly enriched. After ALSS therapy, HBV-ACLF patients had a decrease in potentially harmful bacteria, an increase in potentially beneficial bacteria, an increase in the diversity of the intestinal microbiota, and the intestinal microecological disorders were corrected to a certain extent. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) levels, as well as the international normalized ratio (INR), showed a decreasing trend whereas plasminogen activity (PTA) increased and the condition of patients with HBV-ACLF progressed in a favorable direction. In addition, the abundance of Blautia and Coprococcus was negatively correlated with TBIL and INR, positively correlated with PTA, and positively correlated with disease recovery. Our study shows that ALSS can alter the composition of the gut microbiota and have an ameliorating effect on the gut microecological imbalance in HBV-ACLF patients. It is worth mentioning that Blautia and Coprococcus may have great potential as biomarkers.

Abstract Background Human brucellosis has become one of the major public health problems in China, and increases atypical manifestations, such as fever of unknown origin (FUO), and misdiagnosis rates has complicated the diagnosis of brucellosis. To date, no relevant study on the relationship between brucellosis and FUO has been conducted. Methods We retrospectively reviewed the medical charts of 35 patients with confirmed human brucellosis and prospectively recorded their outcomes by telephone interview. The patients were admitted to the Second Affiliated Hospital of Nanchang University between January 01, 2013 and October 31, 2019. Patient data were collected from hospital medical records. Results The percentage of males was significantly higher than that of female in FUO (78.95% vs. 21.05%, P < 0.05), and 80% of the patients had a clear history of exposure to cattle and sheep. Moreover, 19 (54%) cases were hospitalized with FUO, among which the patients with epidemiological histories were significantly more than those without (P < 0.05). The incidence of toxic hepatitis in FUO patients was higher than that in non-FUO patients (89% vs. 50%, P < 0.05). Meanwhile, the misdiagnosis rate was considerably higher in the FUO group than in the non-FUO group (100% vs. 63%; P < 0.05). Conclusion Brucellosis is predominantly FUO admission in a non-endemic area of China, accompanied by irregular fever and toxic hepatitis. Careful examination of the epidemiological history and timely improvement of blood and bone marrow cultures can facilitate early diagnosis and prevent misdiagnosis.