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Objective: The aims of this study were to investigate the kinetic changes of serum, virological, and immunological markers during entecavir (ETV) antiviral therapy and to explore whether these indicators can predict the antiviral efficacy of ETV in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients., Methods: HBeAg-positive CHB patients were enrolled and treated with ETV 0.5 mg/day. Clinical biochemical, virological, and serological tests were performed at baseline and every 12 weeks during the 48-week treatment. Plasma levels of cytokines (Flt-3L, IFN-α2, IFN-γ, IL-10, IL-17A, IL-6, TGF-β1, TGF-β2, TGF-β3, and TNF-α) were measured at baseline and at 12 and 24 weeks after treatment. Analysis of the trends of these clinical indicators in ETV antiviral therapy was performed., Results: A total of 105 HBeAg-positive CHB patients were enrolled, and 100 of them completed 48 weeks of ETV treatment and follow-up. After 48 weeks of treatment, hepatitis B s antigen (HBsAg) decline ≥ 1 log10 was found in seven patients, but no patient achieved HBsAg disappearance. serological HBeAg disappeared in 13 patients, and serological HBeAg transformed in 3 patients. The baseline HBsAg and HBeAg levels, HBV DNA load, IL-10, and TGF-β1 levels in the complete virological response group were lower than those in the incomplete virological response group, while the ALT level in the complete virological response group was higher than that in the incomplete virological response group. Both univariate analysis and multivariate analysis showed that baseline biochemical indexes, virological indexes, and cytokine levels had no correlation with the complete virological response at 48 weeks. In multivariate analysis, low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment (HBeAg OR = 1.003, 95% CI 1.001-1.006, p = 0.007; HBV DNA OR = 0.184, 95% CI 0.046-0.739, p = 0.017; IL-10 OR = 0.040, 95% CI 0.972-0.999, p = 0.040)., Conclusion: Cytokine levels changed dynamically during ETV antiviral therapy. Low baseline HBV DNA load, and HBeAg and IL-10 levels were significantly associated with ALT normalization after 48 weeks of ETV treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The editor declared a shared parent affiliation with the authors at the time of review., (Copyright © 2022 Li, Gao, Yang, Lin, Deng, Jiang, Bi, Lu, Zhang, Shen, Liu, Wu, Chang, Xu, Hu, Song, Jiang, Yi and Xie.)

Background: Acute-on-chronic liver failure (ACLF) is a clinical syndrome characterized by acute deterioration of liver function and high short-term mortality. Clusterin, with biological functions similar to small heat shock proteins, can protect cells from apoptosis induced by various stressors. The aim of this study was to detect the level of serum clusterin in hepatitis B virus- (HBV-) related ACLF and to assess the predictive value of clusterin for the short-term prognosis of HBV-ACLF., Methods: We detected serum clusterin by ELISA in 108 HBV-ACLF patients, 63 HBV-non-ACLF patients, and 44 normal controls., Results: Serum clusterin was markedly lower in HBV-ACLF patients (median, 51.09  μ g/mL) than in HBV-non-ACLF patients (median, 188.56  μ g/mL) and normal controls (median, 213.45  μ g/mL; all P < 0.05). Nonsurviving HBV-ACLF patients who died within 90 days had much lower clusterin levels than did surviving patients, especially those who died within 28 days (nonsurvival group vs. survival group: 39.82 ± 19.34 vs. 72.26 ± 43.52, P < 0.001; survival time ≤ 28 vs. survival time > 28: median 28.39 vs. 43.22, P = 0.013). The results showed that for identifying HBV-ACLF, the sensitivity of clusterin (93.7%) was similar to the sensitivities of the international normalized ratio (INR; 94.4%) and total bilirubin (TBIL; 94.8%), but its specificity (90.7%) was higher than that of prothrombin activity (PTA; 65.8%) and TBIL (69.8%) and was similar to INR (88.9%). As the concentration of clusterin increased, the mortality of HBV-ACLF patients decreased significantly from 59.3% to 7.0%. Clusterin had better ability for predicting the prognosis of HBV-ACLF patients than did the model for end-stage liver disease (MELD) score and the chronic liver failure consortium (CLIF-C) ACLF score (MELD vs. clusterin: P = 0.012; CLIF-C ACLF vs. clusterin: P = 0.031)., Conclusion: Serum clusterin is a potential biomarker for HBV-ACLF which can be used to assess clinical severity and the short-term prognosis of patients with this disease and may help clinicians identify HBV-ACLF with greater specificity and improved prognostic accuracy than existing prognostic markers., Competing Interests: All authors have declared that they do not have any conflicts of interest in this manuscript., (Copyright © 2020 Huimin Liu et al.)

Background: Nucleos(t)ide analogues (NAs) are the first-line option against chronic hepatitis B (CHB). NAs produce potent suppression of viral replication with a small chance of HBsAg seroclearance and a high risk of virological relapse after discontinuation. The combined therapy of NAs plus traditional Chinese medicine (TCM) is widely accepted and has been recognized as a prospective alternative approach in China. Based on preliminary works, this study was designed to observe the therapeutic effect of TCM plus entecavir (ETV) against HBeAg-positive chronic hepatitis B with respect to reducing the recurrence risk after NA withdrawal., Methods/design: The study is a nationwide, multicenter, double-blind, randomized, placebo-controlled trial with a duration of 120 weeks. A total of 18 hospitals and 490 eligible Chinese HBeAg-positive CHB patients will be enrolled and randomly allocated into the experimental group and control group in a 1:1 ratio. Patients in the experimental group will be prescribed TCM formulae (Tiaogan-BuXu-Jiedu granules) plus ETV 0.5 mg per day for consolidation therapy for 96 weeks. Patients in the control group will be prescribed TCM granule placebo plus ETV 0.5 mg per day for the same course. After consolidation therapy, all patients will discontinue their trial drugs and be closely monitored over the next 24 weeks. Once clinical recurrence (CR) occurs, ETV treatment will be restarted. The primary outcome is the cumulative rate of CR at the end of this trial., Conclusion: This study is the first of its kind to observe therapeutic effects with respect to reducing recurrence after NA withdrawals after unified integrative consolidation therapy in the CHB population., Trial Registration: Chinese Clinical Trial Registry No. ChiCTR1900021232 . Registered on February 2, 2019.

Background/aims: Studies have shown that nucleos(t)ide analogue (NA) treatment can reduce the risk of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients, but it is unclear which NA is most effective. We performed a meta-analysis and systematic review comparing the efficacies of NAs in CHB patients., Methods: We searched literature databases for randomized controlled trials (RCTs) and observational studies that analyzed the hepatic biochemical response, virological response, seroconversion rate, drug resistance rate, and HCC incidence rate in CHB patients treated with NAs. Meta-analyses were performed with RevMan and Stata/SE software., Results: Twelve cohort studies and one RCT were selected, in which entecavir (ETV), lamivudine (LAM), telbivudine (LdT), and/or tenofovir disoproxil fumarate (TDF) were evaluated in CHB patients. The meta-analysis showed that ETV was superior to LAM with regard to the HCC incidence (p<0.001), biochemical response (p=0.001), virological response (p=0.02), and drug resistance (p<0.001), and ETV was superior to LdT with regard to the virological response (p<0.001) and drug resistance (p<0.001). We found no significant difference between ETV and TDF with regard to the HCC incidence (p=0.08), biochemical response (p=0.39), virological response (p=0.31), serological conversion (p=0.38), or drug resistance (p=0.95). NA-treated patients with pre-existing cirrhosis had a 5.49 times greater incidence of HCC than those without cirrhosis (p<0.001)., Conclusions: ETV or TDF should be used for long-term first-line monotherapy in CHB patients according to the current guidelines. Standardized protocols are needed for future studies of ETV and TDF to facilitate conclusive comparisons. Patients with cirrhosis are at significantly elevated risk for HCC, despite the benefits of NA treatment.

Aim: The CANONIC study proposed the Chronic Liver Failure Consortium acute-on-chronic liver failure (CLIF-C ACLF) prognostic model at the European Association for the Study of the Liver-CLIF diagnosis. This study aimed to develop and validate a prognostic model for predicting the short-term mortality of hepatitis B virus (HBV) ACLF as defined by the Asia-Pacific Association for the Study of the Liver., Patients and Methods: A retrospective cohort of 381 HBV ACLF patients and a prospective cohort of 192 patients were included in this study. Independent predictors of disease progression were determined using univariate and multivariate Cox proportional hazard regression analysis, and a regression model for predicting prognosis was established. Patient survival was estimated by Kaplan-Meier analysis and subsequently compared by log-rank tests. The area under the receiver operating characteristic curve was used to compare the performance of various current prognostic models., Results: Our model was constructed with five independent risk factors: hepatic encephalopathy, international normalized ratio, neutrophil-lymphocyte ratio, age, and total bilirubin, termed as the HINAT ACLF model, which showed the strongest predictive values compared with CLIF-C ACLF, CLIF-C Organ Failure, Sequential Organ Failure Assessment, CLIF-Sequential Organ Failure Assessment, Model for End-stage Liver Disease, Model for End-stage Liver Disease-sodium, and Child-Turcotte-Pugh scores; this model reduced the corresponding prediction error rates at 28 and 90 days by 16.4-54.5% after ACLF diagnosis in both the derivation cohort and the validation cohorts., Conclusion: The HINAT ACLF model can accurately predict the short-term mortality of patients with HBV ACLF as defined by Asia-Pacific Association for the Study of the Liver.

Background: The neutrophil-lymphocyte ratio (NLR) is a new prognostic predictor for patients with liver cancer. The association of NLR and T lymphocytes with the pathogenesis and progression of liver cancer is poorly understood., Methods: Seventy-three patients with hepatitis B virus (HBV)-associated primary liver cancer (HBV-PLC), 50 patients with HBV-associated liver cirrhosis (HBV-LC) and 37 patients with chronic HBV infection (CHB) were prospectively enrolled from July 1, 2013 to February 28, 2014 in Beijing Ditan Hospital, Capital Medical University (Beijing, China). The NLR, proportions and concentrations of neutrophils and lymphocytes, concentration of subpopulations of lymphocytes, and the expression of CD31 (index for recent thymic output) and HLA-DR (index for activation of T lymphocytes) of T cells in the peripheral blood samples of the patients were assessed and statistically compared between different groups., Results: The NLR was significantly increased from patients with CHB, those with HBV-LC to those with HBV-PLC (P<0.05), along with significant increase of neutrophils and decrease of lymphocytes in the same way (P<0.05). The concentrations of T lymphocytes, natural killer cells, B cells, CD4+ T cells and CD8+ T cells were decreased from patients with CHB, those with HBV-LC to those with HBV-PLC, and were significantly reduced in patients with HBV-PLC compared with those in patients with CHB (P<0.05). The CD31 and HLA-DR expression of naive CD4+ and CD8+ T cells was significantly decreased and increased, respectively in patients with HBV-PLC compared with that in patients with CHB., Conclusions: Elevated NLR, resulted from the increase of neutrophils and decrease of lymphocytes, is positively associated with the pathogenesis and progression of HBV-PLC. The reduced thymic output and hyperactivation of T lymphocytes may contribute to the decrease of T lymphocytes, which could be also related to the pathogenesis of HBV-PLC.

Aim . To determine whether nucleot(s)ide analogs therapy has survival benefit for patients with HBV-related HCC after unresectable treatment. Method . A systematic search was conducted through seven electronic databases including PubMed, OVID, EMBASE, Cochrane Databases, Elsevier, Wiley Online Library, and BMJ Best Practice. All studies comparing NA combined with unresectable treatment versus unresectable treatment alone were considered for inclusion. The primary outcome was the overall survival (OS) after unresectable treatment for patients with HBV-related HCC. The secondary outcome was the progression-free survival (PFS). Results were expressed as hazard ratio (HR) for survival with 95% confidence intervals. Results . We included six studies with 994 patients: 409 patients in nucleot(s)ide analogs therapy group and 585 patients without antiviral therapy in control group. There were significant improvements for the overall survival (HR = 0.57; 95% CI = 0.47-0.70; p < 0.001) and progression-free survival (HR = 0.84; 95% CI = 0.71-0.99; p = 0.034) in the NA-treated group compared with the control group. Funnel plot showed that there was no significant publication bias in these studies. When it comes to antiviral drugs and operation method, it also showed benefit in NA-treated group. At the same time, overall mortality as well as mortality secondary to liver failure in NA-treated group was obviously lesser. Sensitivity analyses confirmed the robustness of the results. Conclusions . Nucleot(s)ide analogs therapy after unresectable treatment has potential beneficial effects in terms of overall survival and progression-free survival. NA therapy should be considered in clinical practice., Competing Interests: The authors deny any conflict of interests.

Aim: Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) has significant morbidity and mortality. There is no standard approach for the management of HBV-related ACLF with nucleos(t)ide analogs. Our objective was to compare the short-term mortality between entecavir (ETV) and lamivudine (LAM) in patients with HBV-related ACLF., Methods: We recruited 311 inpatients with HBV-related ACLF from December 2002 to January 2015. The patients were treated with ETV (n=143) or LAM (n=168). The primary endpoint was mortality rate at week 8. Virological and biochemical responses were also studied., Results: By week 8, 53 (37.06%) patients in the ETV group and 57 (33.93%) patients in the LAM group died, and the two groups had similar mortality (P=0.414). Multivariate analysis showed that age, total bilirubin, international normalized ratio, and model for end-stage liver disease (MELD) score were independent factors for mortality at week 8. The best cut-off value of the MELD score was 24.5 for 8-week mortality. Twenty-nine of the 170 (17.06%) patients with MELD score less than 24.5 died at week 8, and the ETV and LAM groups had similar mortality (P=0.743). Eighty-one of the 141 (57.45%) patients with MELD score of at least 24.5 died at week 8 and the LAM group had lower mortality than the ETV group (P=0.018 at week 4; P=0.039 at week 8). Both groups showed similar virological and biochemical responses at 4 weeks., Conclusion: LAM reduces the 8-week mortality rate significantly in patients with HBV-related ACLF who had MELD score of at least 24.5.