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Purpose: This study was designed to analyze the liver tissue changes among the CHB patients who received treatment for at least 6 months and follow-up for at least 1 year, together with the correlation between the different disease condition and serum markers., Methods: One-hundred and eighty-five CHB patients underwent antiviral therapy for at least 6 months were enrolled. In the 12-month follow-up, ultrasonography-guided biopsy was performed. The patients were grouped based on the serum markers and pathological changes in liver tissues. Then we determined the serum markers, virological tests and Tim-3 expression among these groups., Results: Antiviral therapy significantly reduced liver inflammation indicators and serum Tim-3 level. However, the fibrosis process of liver tissue was not changed, and there are still disputes on the serum marker and hepatic lesion outcomes. Under normal liver function or negative hepatitis B e antigen (HBeAg) of CHB patients, there might be consensus between Tim-3 change and liver pathological outcome. According to the liver tissue inflammation and fibrosis conditions, Tim-3 was positively correlated with liver function indices. Besides, it was also related to fibrosis stage and inflammation grade., Conclusion: There were inconsistent changes between serum markers and liver tissue conditions after anti-viral therapy. Tim-3 expression was more suitable to indicate the changes of liver inflammatory and fibrosis response to some extent than ALT and AST. It may serve as a certain indicator to predict the CHB prognosis, which could be used as one of the monitoring indicators in liver pathological changes of chronic HBV infection, especially in monitoring liver tissue inflammation., (© 2022. The Author(s).)

Early diagnosis of hepatic cancer is a major public health challenge. While changes in serum N-glycans have been observed as patients progress from liver fibrosis/cirrhosis to hepatocellular carcinoma (HCC), the predictive performance of N-glycans is yet to be determined for HCC early diagnosis as well as differential diagnosis from liver fibrosis/cirrhosis. In a total sample of 247 patients with hepatitis B virus-related liver disease, we characterized and compared the serum N-glycans in very early/early and intermediate/advanced stages of HCC and those with liver fibrosis/cirrhosis. Additionally, we performed a retrospective timeline analysis of the serum N-glycans 6 and 12 months before a diagnosis of the very early/early stage of HCC (EHCC). A predictive model was built, named hereafter as Glycomics-EHCC, incorporating the glycan peaks (GPs) 1, 2, and 4. The model showed a larger area under the receiver operating characteristic curve compared with a traditional model with the α-fetoprotein (0.936 vs. 0.731, respectively). The Glycomics-EHCC model had a sensitivity of 84.6% and specificity of 85.0% at a cutoff value of -0.39 to distinguish EHCC from liver fibrosis/cirrhosis. Moreover, the Glycomics-EHCC model was able to forecast a future EHCC diagnosis with a sensitivity and specificity over 90% and 85%, respectively, using the serum N-glycan biosignatures 6 or 12 months earlier when the patients were suffering from liver fibrosis/cirrhosis before being diagnosed with EHCC. This serum glycomic biosignature model warrants further clinical studies in independent population samples and offers promise to forecast EHCC and its differential diagnosis from liver fibrosis/cirrhosis.

Dendritic cells (DCs) play a predominant role in initiating cell immune responses. Here we generated a DC-targeting lentiviral vector (LVDC-UbHBcAg-LIGHT) and evaluated its capacity to elicit HBV-specific cytotoxic T lymphocyte (CTL) responses. DC-SIGN-mediated specific transduction using this construct was confirmed in DC-SIGN-expressing 293T cells and ex vivo-cultured bone marrow cells. LVDC-UbHBcAg-LIGHT-loaded DCs were highly effective in inducing HBV-specific CTLs. Mechanistic studies demonstrated autophagy blocking led to a significant increase in apoptosis and obvious inhibition of CD8 + T cells entry into S-phase, correspondingly attenuated LVDC-UbHBcAg-LIGHT-loaded DC-induced T cell responses. This observation was supported by accumulation of pro-apoptotic proteins and the main negative cell cycle regulator-CDKN1B that otherwise would be degraded in activated T cells where autophagy preferentially occured. Our findings revealed an important role of autophagy in the activation of T cells and suggested LVDC-UbHBcAg-LIGHT may potentially be used as a therapeutic strategy to combat persistent HBV infection with higher security.

Background/aims: Developing engineered dendritic cell (DC)-targeting lentivectors (LVs) have been the target of intense research for their potential to create antigen-directed immunotherapeutics which can be safely administered to patients. In this study, we constructed a DC-directed LV (LVDC-UbHBcAg-LIGHT) as a potential vaccine to induce anti-HBV immune responses., Methods: Specificity of LVDC-UbHBcAg-LIGHT for DCs in vivo was confirmed through live animal imaging studies. The levels of cytokine production in T cells were assessed by flow cytometry. The HBcAg-specific cytotoxic T lymphocyte (CTL) responses and antibody responses induced by direct administration of the LVs were detected by LDH release assay and ELISA respectively. The levels of serum HBsAg and HBV DNA were evaluated by Abbott kits and quantitative PCR respectively. The expression levels of HBsAg and HBcAg in liver tissues of HBV transgenic mice were examined by immunohistochemistry. In addition, molecular mechanism underlying the activation of CD8+ T cells was explored., Results: Live animal imaging studies showed that following subcutaneous administration of LVDC-UbHBcAg-LIGHT, no obvious luminescence signal was detected at the injection site. Immunization with LVDC-UbHBcAg-LIGHT elicited potent T cell responses in HBV transgenic mice evidenced by increased percentages of IFN-γ, TNF-α and GzmB producing CD8+ T cells as well as IFN-γ producing CD4+ T cells, improved HBcAg-specific CTL activities and antibody responses. Additionally, vaccination with LVDC-UbHBcAg-LIGHT efficiently reduced serum HBsAg, HBV DNA levels and the expression of HBsAg and HBcAg in liver tissues of HBV transgenic mice. More importantly, autophagy was induced in the activated CD8+ T cells, and the induced autophagy noticeably promoted the proliferation of T cells and decreased the frequencies of apoptotic CD8+ T cells by selectively degrading ubiquitinated apoptosis and cell cycle-associated protein aggregates. Futhermore, we confirmed the interaction between autophagosomes and ubiquitinated aggregates by confocal microscopy and immunoprecipitation analysis., Conclusions: These results demonstrated that LVDC-UbHBcAg-LIGHT provided a simple method of eliciting effective antiviral immune responses in HBV transgenic mice and might potentially be used as a therapeutic strategy to eradicate HBV with more safety and efficiency. Moreover, our results revealed a direct role of autophagy in promoting the survival and proliferation of activated CD8+ T cells., (© 2018 The Author(s). Published by S. Karger AG, Basel.)

Background/aims: About 400 million individuals are chronically infected with hepatitis B virus, at high risk of developing liver cirrhosis and hepatocellular carcinoma. Recent studies have demonstrated an interaction between hepatitis B virus replication and autophagy activity of hepatocytes. In the present study, we aimed to investigate the role of miR-141 in regulating autophagy and hepatitis B virus replication., Methods: The expression of HBV-DNA, miR-141 and Sirt1 mRNA was determined by quantitative real-time PCR analysis. The expression of HBsAg and HBeAg was determined by ELISA. Western blotting was performed to detect protein expression. The LC3 puncta was determined by immunofluorescence. To test whether miR-141 directly regulate the expression level of Sirt1 mRNA, dual-luciferase reporter gene assay was performed., Results: In vitro studies showed that miR-141 mimic inhibited the autophagic response, hepatitis B virus and the expression of Sirt1 in hepatocytes. And transfection with miR-141 inhibitor enhanced autophagic response and Sirt1 expression. The autophagy induced by overexpression of Sirt1 was inhibited by miR-141 mimic. In addition, miR-141 mimic also decreased the expression of Sirt1 mRNA. Sirt1 was predicted as a potential miR-141 target by bioinformatic analysis of its 3'-UTR, and confirmed by luciferase reporter assays which analyzing the interaction of miR-141 with the wild- type or the mutated Sirt1 3'-UTR., Conclusion: We have therefore demonstrated a role of miR-141 in regulating autophagy-mediated hepatitis B virus inhibition by targeting Sirt1, and may provide potential targets for drug development., (© 2017 The Author(s) Published by S. Karger AG, Basel.)

Disease progression could be altered or even reversed in decompensated patients with HBV-related cirrhosis once they initiate antiviral therapy. However, little is known about the stable re-compensation in these patients. In this retrospective study, HBV-related liver cirrhosis patients were consecutively enrolled at the first decompensated event of ascites or variceal hemorrhage (VH), and divided into immediate-treatment, on-treatment and delayed/no treatment groups. Patients were followed up to at least presence of second decompensation event or to June 2021. Re-compensation was defined as patients who did not occur second (further) decompensation during follow-up. A total of 130 HBV-related decompensated cirrhotic patients were included with a median follow-up of 61.0 (41.6, 72.0) months. The cumulative incidence of re-compensation at year 6 was 39.0, 9.8 and 6.6 in immediate-treatment, on-treatment and delayed/no treatment group (p = 0.001). Among 87 patients in immediate-treatment group, thirty-seven (37/87, 42.5%) were recognized as stable re-compensation. Seventy percent (35/50) of second decompensated events occurred in the first 2 years. In patients free of 2-year decompensated complications, about 71.2% (37/52) maintained stable re-compensation. The cumulative incidence of death (and/or transplantation) and HCC in patients free of 2-year decompensated complications or not was 2.9 vs. 27.3% (HR 9.4, 95% CI 2.2–40.0, p = 0.002) and 12.6 vs. 37.7% (HR 4.5, 95% CI 1.5–13.3, p = 0.006), respectively. In decompensated patients with HBV-related cirrhosis, about 40% in immediate-treatment group maintained stable re-compensation during 6 years of antiviral therapy. Two-year free of complications could predict stable re-compensation. [ABSTRACT FROM AUTHOR]

Background & Aims: Non‐invasive assessment criteria to rule out high‐risk varices (HRV) in compensated hepatitis B virus (HBV) cirrhosis on antiviral therapy remains unclear. Methods: HBV‐related compensated cirrhotic patients who underwent screening endoscopy during antiviral therapy were enrolled and randomly divided into the derivation and validation sets. HRV were defined as medium to large varices or small varices with red signs. Univariate and multivariate logistic analysis were used to determine the parameters associated with HRV. Results: A total of 436 HBV‐related compensated cirrhotic patients screened for varices were enrolled, the median duration of antiviral therapy was 4 years (IQR: 2.5‐5.5 years). In the derivation set (N = 290, 17.2% with HRV), only platelet (PLT) count (OR = 0.972, 95% CI 0.961‐0.984, P <.05) was independently associated with HRV, whereas liver stiffness measurement was not associated with the presence of HRV. With a PLT count cut‐off value of 105 × 109/L, unnecessary endoscopies could be spared in 56.9% patients, with a 3.6%. risk of missing HRV. In the validation cohort (N = 146, 16.4% with HRV), the proportion of patients that could safely spare endoscopies (61.0%) identified by this PLT count cut‐off value was higher than that obtained by using Baveno VI criteria (34.9%), with an acceptable risk of missing HRV (3.4%). Conclusion: Compared with the 'Baveno VI criteria or beyond' criteria, PLT count higher than 105 × 109/L could safely spare more screening endoscopies without increasing the risk of missing HRV in patients with HBV‐related compensated cirrhosis on antiviral therapy. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) causes hepatitis, which progresses to fatal liver diseases and remains a global health problem. Current treatments for chronic hepatitis B are unable to cure hepatitis. Thus, new antiviral drugs must be developed. In this study, the viral inhibition effects of dandelion and taraxasterol were assessed in HepG2.2.15 cell line. Taraxacum officinale F.H.Wigg. (compositae) with English name dandelion is used as a traditional herb for liver disorders and as a common antiviral agent. Taraxasterol is one of the active compounds of dandelion. The secretion of HBV DNA and HBV surface antigen (HBsAg) and HBeAg was detected using fluorescence quantitative PCR (qPCR) and ELISA, respectively. Intracellular HBsAg was detected by immunofluorescence. In order to demonstrate the potential mechanism of anti-viral activity, the expression levels of host factors polypyrimidine tract binding protein 1 (PTBP1) and sirtuin 1 (SIRT1) were detected with Western blotting and qPCR. Dandelion and taraxasterol effectively reduced the secretion of HBsAg, HBeAg and the HBV DNA in cell supernatants, and significantly reduced the intracellular HBsAg as indicated by immunofluorescence results. Taraxasterol may be one of the main effective components of dandelion. It significantly decreased the protein expression levels of PTBP1 and SIRT1. The present study revealed that dandelion and its component taraxasterol could inhibit HBV and may be a potential anti-HBV drug, whose potential targets were the host factors PTBP1 and SIRT1. [ABSTRACT FROM AUTHOR]

Microvascular invasion (MVI) is an important predictor of metastatic tumour recurrence and is associated with adverse outcomes and poor prognosis in Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. The association between varying regimens of anti-viral drugs with the incidence of MVI in HBV-related HCC has been demonstrated, however, no meta-analysis of the available data has been conducted. Therefore, the current study sought to evaluate the association of preoperative antiviral therapy with incidence of microvascular invasion in HCC hepatitis virus patients. A systematic search of the literature was performed in MEDLINE/PubMed, Web of Science (WoS), and Scopus, up to January 2020. A random-effects model was used to estimate pooled odds ratios (ORs). Overall, six studies, with 4988 patients, met our inclusion criteria. The pooled OR of MVI in the patients who had preoperative antiviral therapy versus the patients who did not have antiviral therapy was; OR: 0.60, 95% Confidence Interval (CI): 0.49–0.73; I2 = 25%. In this study, a significant reduction in the OR of MVI was evident in patients who had anti-viral therapy. • Antiviral therapy reduces the risk of microvascular invasion. • HCC patients who had antiviral regimes had a 40% lower risk of microvascular invasion. • Antiviral therapy helps to improve the prognosis of HCC patients. [ABSTRACT FROM AUTHOR]