Existing nucleos（t）ide analogues and pegylated interferon exhibit limited efficacy in the functional cure of hepatitis B. Recently， small nucleic acid drugs， such as antisense oligonucleotides and small interfering RNAs， have brought unprecedented breakthroughs in the functional cure of hepatitis B with their brand-new mechanisms of action and remarkable efficacy in early clinical studies. Small nucleic acid drugs， such as antisense oligonucleotides and small interfering RNAs， can reduce the level of HBsAg and strive to achieve HBsAg seroclearance. The reduction in HBsAg may restore the hepatitis B-specific immune function of the body to some extent and may further transform the simple clearance of HBsAg into hard endpoints with clinical value， such as reducing hepatitis B-related liver events. By meticulously analyzing the dynamic trajectory of HBsAg alterations within the context of new drug applications and further optimizing combined treatment strategies and regimens， it is expected to transform the functional cure of hepatitis B into the ultimate goal of improving survival rates and quality of life.

Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.

Objective:To comprehensively evaluate the clinical value of Elecsys serum abnormal prothrombin (PIVKA-Ⅱ) test reagent for auxiliary diagnosis of hepatocellular carcinoma (HCC) in the Chinese population.Methods:A multicenter case-control design was used in the study. Samples from patients with first-time confirmed, diagnosed, and untreated HCC, benign liver disease and interfering controls were collected continuously. Elecsys PIVKA-II and alpha-fetoprotein (AFP) were tested for analysis. Various clinical details of the subjects were collected and analyzed. The efficacy of PIVKA-II (21.29 ng/ml) and AFP (400 ng/ml) for HCC diagnosis was calculated at specific positive cut-off values. Statistical analysis was performed using the Kruskal-Wallis test or receiver operating characteristic curve.Results:A total of 448 subjects were eventually enrolled from five centers, including 185 HCC cases. PIVKA-II had a higher diagnostic sensitivity and accuracy than AFP (84.86% vs. 30.81% and 89.01% vs. 63.66%) when the benign liver disease group was used as the control group, while the specificity was slightly lower. A sensitive analysis showed that PIVKA-II had a sensitivity of >80% at this specific positive cut-off value in the subgroup of AFP-negative subjects, patients with different etiologies, and HCC patients with multiple Barcelona Clinic liver cancer stages (including early-stage HCC). At the same time, the PIVKA-II subject had a slightly higher area under the receiver operating characteristic curve than the AFP (0.920 0 vs. 0.880 9).Conclusion:The clinical efficacy of Elecsys PIVKA-Ⅱ is good and stable in the Chinese population. Additionally, it has the clinical potential to improve the current missed diagnosis status of AFP-negative HCC and HCC monitoring at an early stage, as well as the effectiveness of accuracy promotion for HCC auxiliary diagnosis in China.

Chronic hepatitis B virus (HBV) infection remains a pivotal global public health concern. Attaining a functional cure for hepatitis B continues to be a hot and difficult issue that requires immediate attention in clinical practice. There are currently nucleos(t)ide analogues (NAs) that can persistently suppress HBV DNA; however, the functional cure rate of pegylated interferon alfa (PEG-IFN-α) alone or in combination with NAs has not yet met clinical needs. The research and development on novel mechanisms for HBV antiviral drugs, especially small nucleic acid drugs, has brought breakthroughs to the functional cure of hepatitis B. The functional cure trajectory mapping and its prediction model can guide the selection of clinical treatment strategies based on the longitudinal data for HBsAg at various time intervals. The personalized management of hepatitis B patients can be optimized by utilizing varying HBsAg levels as a key watershed to aid in the screening of subjects in clinical trials.

Background/Aims: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. Methods: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. Results: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1–2, and no linvencorvir-related serious adverse events were reported. Conclusions 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

Expanding antiviral therapy is currently the new trend for the diagnosis and treatment of chronic hepatitis B, and related research evidence should be studied and discussed. Reducing the threshold of alanine aminotransferase (ALT) for initiating antiviral therapy is one of the most important changes during the expansion of antiviral therapy. Chronic hepatitis B patients with a low-level increase in ALT or a high normal level of ALT still have a higher risk of liver cancer and thus require further intervention. At present, nucleos(t)ide analogues show a certain clinical effect in some patients in terms of virological inhibition and improvement in fibrosis, while reducing ALT threshold places higher requirements for biochemical response after treatment. In addition, although the mechanism and definition of low-level viremia (LLV) after treatment remain unclear, further intervention of LLV is an important strategy for optimizing patient management in clinical practice. Switch to another potent nucleos(t)ide analogue may improve the virologic response rate of patients with LLV, and nucleos(t)ide analogues combined with interferon or other new targeted drugs will be an important research direction for the treatment of LLV in the future.

Serum alanine aminotransferase (ALT) is a sensitive and important marker of liver injury, which is closely related to the disease progression. It is the key rather than the only parameter to initiate treatment decisions for patients with chronic hepatitis B virus infection. The normal reference range of ALT is derived from epidemiological investigation of healthy population, which varies among different countries, regions or laboratories. Hepatologists should conduct a large number of cohort clinical studies based on the natural history and the prognosis of the disease, and adjust the cut-off value of ALT levels to make clinical decisions in order to determine the degree of liver injury, the treatment initiation and response.

Noninvasive methods for the evaluation of liver fibrosis have been widely validated with liver biopsy as the gold standard. This article elaborates on the application of various imaging methods in the evaluation of liver fibrosis and their prospects in evaluating the reversal of liver fibrosis. Transient elastography is the main imaging method for evaluating the reversal of liver fibrosis and can show the improvement in liver fibrosis via liver stiffness measurement, but the association between the reduction in liver stiffness measurement and the improvement of liver fibrosis remains unclear.

Objective: To investigate the prevalence and risk factors of non-alcoholic fatty liver disease(NAFLD) in patients with chronic hepatitis B(CHB) receiving antiviral treatment. Methods: The cross-sectional study included 3 477 cases with CHB who received antiviral therapy. The prevalence of NAFLD was investigated, and then the risk factors were screened and analyzed by stepwise regression method in CHB patients with NAFLD as the dependent variable and the related influencing factors as independent variables. Results: The prevalence of NAFLD was 24.1% in CHB patients who received antiviral therapy. After adjusting for age and gender, central obesity (OR: 7.44, 95%CI: 6.06 ~ 9.14), hypertension (OR: 1.74, 95%CI: 1.51 ~ 2.20), and triglyceride (OR: 1.52, 95%CI: 1.18 ~ 1.96) were positively associated with NAFLD, and cirrhosis was negatively associated with NAFLD (OR: 0.42, 95%CI: 0.34 ~ 0.53). Patients with long-term antiviral therapy had increased risk of NAFLD. Conclusion A significant proportion of CHB patients receiving antiviral therapy have suffered from NAFLD. Therefore, CHB patients receiving long-term antiviral treatment should pay more attention to the prevalence of NAFLD.