The Potential Role of Autophagy in Progression of Liver Fibrosis in Chronic Hepatitis B Patients Receiving Antiviral Treatment: A Brief Report.

Despite antiviral treatment, some patients with chronic hepatitis B (CHB) progress to cirrhosis. Enhancement of autophagy was implicated in the proliferation of hepatitis B in hepatocytes. This study aimed to evaluate the potential role of autophagy in the progression of liver fibrosis in patients receiving antiviral treatments and having completely inhibited viral replication. This descriptive-analytical study was designed and conducted in 2020 at Mottahhari Hepatitis Clinic affiliated with Shiraz University of Medical Science (Shiraz, Iran). Patients who were on anti-hepatitis B nucleotide treatments for at least two years, and those who were not cirrhotic at baseline but later progressed to cirrhosis were identified to be included in the case group. Besides, for the control group, patients on the nucleotide regimens who did not have cirrhosis at baseline or during follow-up were randomly selected. Ultimately, 16 cases and 14 controls were included in the study. Data were analyzed using SPSS software, and P<0.05 was considered statistically significant. Serum Beclin-1 and LC3 levels were compared between the two groups using enzyme-linked immunosorbent assays. The t test was used to assess the statistical differences between the case and control groups. Beclin-1 level was significantly higher in cirrhosis patients than the control group (1283±244 vs. 1063±257, P=0.024). However, there was no statistical difference between the level of LC3 in the cirrhotic group (168±31) and the control group (150±16) (P=0.065). Autophagy may have a role in the progression of cirrhosis in patients with CHB. Future larger prospective studies are required to determine the effect of blocking on the progression of liver disease in this population A preprint of this study was published at https://www.researchsquare.com/article/rs-1435490/v1.pdf.

Patients with chronic hepatitis B who have persistently normal alanine aminotransferase or aged < 30 years may exhibit significant histologic damage.

BACKGROUND: The timing of antiviral therapy for chronic hepatitis B (CHB) patients with normal alanine transaminase (ALT) or aged < 30 years is still undetermined. We aimed to elucidate the correlation between liver histology, age, and ALT level in CHB patients and analyze the histological characteristics of the liver among patients with persistently normal ALT or aged < 30 years. METHODS: A retrospective analysis was conducted on 697 treatment-naive CHB patients. Liver biopsies were performed, and significant histological damage was defined as the grade of liver inflammation ≥ G2 and/or fibrosis ≥ S2 based on the Scheuer scoring system. RESULTS: The liver inflammation grades and fibrosis stages correlated positively with age, ALT, AST, GGT levels and negatively with the counts of PLT (all p < 0.050) in HBeAg-positive patients. Higher ALT levels and lower PLT counts were independently associated with significant liver inflammation and fibrosis in both HBeAg-positive and HBeAg-negative patients. Furthermore, among those with persistently normal ALT levels, the incidence of significant liver inflammation and fibrosis were 66.1% and 53.7% in HBeAg-positive groups, and 63.0% and 55.5% in HBeAg-negative groups. Moreover, there was no significant difference in the prevalence of significant liver damage between patients aged < 30 years and those aged ≥ 30 years, in both HBeAg-positive (≥ G2 or ≥ S2: 63.8% vs. 75.8%, p = 0.276) and HBeAg-negative (≥ G2 or ≥ S2: 65.9% vs. 72.5%, p = 0.504) groups, among patients with persistently normal ALT levels. CONCLUSIONS: A considerable proportion of CHB patients with persistently normal ALT, including those below the age of 30 years, exhibited significant histological damage. This highlights the importance of initiating early antiviral therapy for HBV-infected individuals, even in the absence of elevated ALT levels.

Effects of first-line nucleot(s)ide analogues on lipid profiles in patients with chronic hepatitis B: a network meta-analysis.

INTRODUCTION: Recent studies have found that lipid levels in patients with chronic hepatitis B (CHB) may change during antiviral therapy. OBJECTIVE: To assess the effects of first-line nucleot(s)ide analogues (NAs) on lipid profiles in patients with CHB using network meta-analysis. METHODS: Seven electronic databases (PubMed, Embase, Cochrane Library, and four Chinese databases) were searched for cohort studies on the effect of NA on lipids in patients with CHB up to August 1, 2023. The changes of serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were taken as outcomes. The mean difference (MD) of continuous variables and 95% confidence intervals (CI) were calculated using RevMan 5.4 and Stata 16.0 software, and network meta-analysis was based on a frequentist framework. RESULTS: A total of 4194 patients were included in the study, including patients with CHB treated with entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF), as well as patients not receiving antiviral therapy [patients with inactive CHB who were not receiving antiviral therapy (referred as inactive CHB patients) and non-HBV-infected patients]. TDF reduced TC levels compared to the non-antiviral group (TDF vs. inactive CHB patients: MD = - 17.27, 95% CI (- 30.03, - 4.47); TDF vs. non-HBV-infected individuals: MD = - 17.10, 95% CI (- 20.13, - 14.07)). TC changes in the TAF and ETV groups were not statistically different from the non-antiviral group (TAF vs. inactive CHB patients: MD = - 2.69, 95% CI (- 14.42, 9.04); TAF vs. non-HBV-infected individuals: MD = - 2.52, 95% CI (- 8.47, 3.43); ETV vs. inactive CHB patients: MD = - 4.24, 95% CI (- 17.12, 8.64); ETV vs. non-HBV-infected individuals: MD = - 4.07, 95% CI (- 9.90, 1.75)). The ranking of the effects for lowering TC is as follows: CHB patients treated with nucleotide analogues [with varying efficacy: TDF (SUCRA = 99.9) > ETV (SUCRA = 59.3) > TAF (SUCRA = 43.6)] > inactive CHB patients (SUCRA = 27.3) > non-HBV-infected individuals (SUCRA = 19.9). As for secondary outcomes, among the three antiviral drugs, TDF had the most significant effect on lowering TG, LDL-C, and HDL-C, but none of the three drugs was statistically different from the non-antiviral group. Subgroup analysis showed that the lipid-lowering effect of TDF was more pronounced in the elderly (≥ 50 years). CONCLUSION: TDF was effective in lipid reduction, particularly pronounced in the older population. TAF and ETV had a neutral effect to TC, TG, LDL-C, and HDL-C. Despite a relative increase in lipids observed in patients transitioning from TDF to TAF or ETV, these changes remained within acceptable limits.

Noninferiority Outcomes of Besifovir Compared to Tenofovir Alafenamide in Treatment-Naïve Patients with Chronic Hepatitis B.

Background/Aims: : Besifovir dipivoxil maleate (BSV) and tenofovir alafenamide fumarate (TAF) have been recently approved in Korea as the initial antiviral agents for chronic hepatitis B (CHB). However, the real-world outcome data for these drugs remain limited. Therefore, we conducted a noninferiority analysis using real-world data to compare the clinical outcomes of the two nucleotide analogs in treatment-naïve patients with CHB. Methods: : We retrospectively investigated a cohort of patients with CHB who received BSV or TAF as first-line antiviral agents. The endpoints were virological response (VR) and liver-related clinical outcomes. Results: : A total of 537 patients, consisting of 202 and 335 patients administered BSV and TAF, respectively, were followed up for 42 months. No significant difference was observed between the VRs of the patients from the two groups. The rates of biochemical response, virologic breakthrough, and incidence rates of hepatocellular carcinoma did not differ between the groups. However, the hepatitis B e antigen seroclearance rate was higher and the renal function declined less in the BSV group. Multivariable analysis indicated older age, alcohol abuse, cirrhosis and ascites, and lower serum HBV DNA level to be independently associated with increased hepatocellular carcinoma risk. The 1:1 propensity score-matched analysis with 400 patients showed VR rates of 85.0% and 88.7% in the BSV and TAF group patients, respectively, at 2 years. The absolute value of the 95% confidence interval for the difference (-0.04 to 0.12) satisfied the a priori limit of a noninferiority of 0.15. Conclusions: : BSV is noninferior to TAF in terms of VR, and their clinical outcomes are comparable to CHB.

Efficacy of ursodeoxycholic acid in the prevention and treatment of COVID-19 in patients with chronic hepatitis B / 临床肝胆病杂志

ObjectiveTo investigate the potential effect of ursodeoxycholic acid （UDCA） in the prevention and treatment of COVID-19 in patients with chronic hepatitis B. MethodsClinical data were collected from 324 patients with chronic hepatitis B who were treated in Beijing Ditan Hospital， Capital Medical University， from January to December 2022， and according to whether UDCA was administered， they were divided into UDCA group and control group. The propensity score matching （PSM） method was used to balance the confounding factors such as age， sex， and chronic complications， and the two groups were compared in terms of SARS-CoV-2 infection rate， symptoms， and recovery time after COVID-19. The two groups were also compared in terms of related laboratory markers （white blood cell count ［WBC］， hemoglobin ［Hb］， platelet count ［PLT］， alanine aminotransferase ［ALT］， aspartate aminotransferase ［AST］， albumin ［Alb］， alkaline phosphatase ［ALP］， total bilirubin ［TBil］， triglyceride ［TG］， and total cholesterol ［TC］）， vaccination， and the incidence rate of liver disease symptoms after COVID-19. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of data with skewed distribution between the two groups； the chi-square test and the continuously corrected chi-square test were used for comparison of categorical data between two groups. The binary Logistic regression model was used for univariate and multivariate analyses to investigate the influencing factors for COVID-19 after matching. ResultsThere were 87 patients in the UDCA group and 237 patients in the control group， and after PSM， there were 78 patients in the UDCA group and 137 patients in the control group， with good balance between the two groups. There was a significant difference in SARS-CoV-2 infection rate between the UDCA group and the control group ［82.1% （64/78） vs 95.6% （131/137）， χ2=10.847， P=0.001］. After COVID-19， compared with the control group， the UDCA group had a significantly lower proportion of the patients with chill （10.9% vs 38.9%， χ2=16.124， P<0.001） and cough （56.3% vs 74.8%， χ2=6.889， P=0.009）. There was a significant difference between the UDCA group and the control group in the proportion of the patients with a recovery time of ≤7 days after COVID-19 （79.7% vs 61.1%， χ2=6.760， P=0.009）. Both univariate and multivariate logistic regression analyses showed that UDCA was an independent influencing factor for COVID-19 （odds ratio=0.21 and 0.17， both P<0.05）. ConclusionUDCA is an protective factor against COVID-19 in patients with chronic hepatitis B and can alleviate related symptoms to some extent and shorten the recovery time， and therefore， it has an important value in the prevention and treatment of COVID-19.

Significance of high-sensitivity polymerase chain reaction in detecting hepatitis B virus in chronic hepatitis B patients with a very low viral load / 临床肝胆病杂志

ObjectiveTo investigate the significance of high-sensitive polymerase chain reaction （PCR） in detecting hepatitis B virus （HBV） among the population with a very low viral load （HBV DNA 10‍ — ‍99 IU/mL）. MethodsThis study was conducted among the chronic hepatitis B （CHB） patients who were treated with nucleos（t）ide analogues for ≥48 weeks in The Fifth Affiliated Hospital of Guangzhou Medical University from September 2019 to February 2022 and had an HBV DNA load below the lower limit of ordinary-sensitivity detection （100 IU/mL）. Then high-sensitivity HBV DNA detection was performed for all patients， and according to these results， the patients were divided into very low viral load group （VLVL group with an HBV DNA load of 10‍ — ‍99 IU/mL） and complete virologic response group （CVR group with an HBV DNA load of <10 IU/mL or without HBV DNA detected）. The two groups were compared in terms of general characteristics， serum virological indicators， biochemical parameters， and noninvasive fibrosis markers； the value of related serum virological indicators in predicting the results of high-sensitivity HBV DNA above the lower limit of detection were assessed； the influencing factors for failure to achieve CVR were analyzed. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test or the Fisher’s exact test was used for comparison of categorical data between two groups. The receiver operating characteristic （ROC） curve was used to investigate the value of related serum virological indicators in predicting the results of high-sensitivity HBV DNA above the lower limit of detection， and a binary logistic regression analysis was used to investigate the influencing factors for failure to achieve CVR. ResultsA total of 106 CHB patients were enrolled， with 24 in the VLVL group and 82 in the CVR group. Compared with the CVR group， the VLVL group had a significantly younger age （P=0.004） and significantly higher quantitative hepatitis B surface antigen （qHBsAg） level （P=0.002）， HBeAg positive rate （P=0.002）， pgRNA positive rate （P=0.010）， and alanine aminotransferase level （P=0.017）. The qHBsAg level had an area under the ROC curve of 0.717 （P=0.002） in predicting the results of high-sensitivity HBV DNA above the lower limit of detection （>10 IU/mL）， with an optimal cut-off value of 1 214.5 IU/mL， a sensitivity of 95.5%， and a specificity of 53.9%. Positive HBeAg （odds ratio ［OR］=3.654， 95% confidence interval ［CI］： 1.162‍ —‍ ‍11.489， P=0.027） and qHBsAg （OR=2.985， 95%CI： 1.058‍ — ‍8.422， P=0.039） were independent influencing factors for failure to achieve CVR. ConclusionSome CHB patients have an HBV DNA load of <100 IU/mL by ordinary-sensitivity detection， but with the presence of VLVL determined by high-sensitivity PCR. The VLVL group had significantly higher level of inflammatory damage and positive rates of pgRNA and HBeAg. Positive HBeAg and high qHBsAg level are independent influencing factors for failure to achieve CVR. Clinicians should not ignore the presence of VLVL in CHB patients， and high-sensitivity HBV DNA detection should be performed in a timely manner.

Chronic hepatitis B virus infection and metabolic associated fatty liver disease： The known and unknown aspects / 临床肝胆病杂志

Chronic hepatitis B virus （HBV） infection is the main cause of the disease burden of viral hepatitis worldwide， and meanwhile， due to changes in lifestyle and dietary habits， the incidence rate of metabolic associated fatty liver disease （MAFLD） is constantly increasing， making MAFLD the leading chronic liver disease around the world. Chronic HBV infection comorbid with MAFLD is becoming more and more common in clinical practice. Metabolic factors， rather than viral factors， are the main cause of chronic HBV infection comorbid with MAFLD. During disease progression， steatohepatitis and fibrosis， rather than steatosis， are the main influencing factors for the progression to liver cirrhosis and hepatocellular carcinoma. For patients with chronic HBV infection and MAFLD， integrated management of virus and metabolic factors is of great importance. This article reviews the tissues regarding the interaction， prognosis， and clinical management of chronic HBV infection and MAFLD.

Correlation between serum HBV RNA and duration of treatment with nucleos（t）ide analogues in patients with chronic hepatitis B / 临床肝胆病杂志

‍ ObjectiveTo investigate the serum level of HBV RNA in untreated or treatment-experienced patients with chronic hepatitis B （CHB） and the correlation between serum HBV RNA level and the duration of antiviral therapy with nucleos（t）ide analogues （NAs）. MethodsA total of 300 patients with CHB who attended Department of Infectious Diseases in The First Affiliated Hospital of Shihezi University School of Medicine from February to July， 2022， were enrolled as subjects. Related clinical data were collected， and according to the duration of antiviral therapy， they were divided into untreated group with 73 patients， treatment duration ≤1 year group with 91 patients， and treatment duration >1 year group with 136 patients. Serum HBV RNA load， HBV DNA load， and HBsAg concentration were measured for all patients. The Mann-Whitney U test was used for comparison of continuous data between two groups， and the Kruskal-Wallis H test was used for comparison between multiple groups， further pairwise comparison using Bonferroni method； the chi-square test was used for comparison of categorical data； a Spearman correlation analysis was used to investigate the degree of correlation between various indicators. ResultsThe positive rate of HBeAg was 18.3%， and among the patients with negative HBV DNA， the patients with positive HBV RNA accounted for 44.1% （86/195）. There was a significant difference in the distribution of the serum levels of HBV RNA， HBV DNA， and HBsAg between the positive HBeAg group and the negative HBeAg group （Z=10.740， 6.300， and 7.280， all P<0.05）. There was a significant difference in the distribution of DNA level between the untreated group and the treatment duration ≤1 year group （P<0.05）； there was a significant difference in the distribution of HBV RNA and HBV DNA levels between the untreated group and the treatment duration >1 year group （P<0.05）； there was a significant difference in the distribution of HBV RNA， HBV DNA， and HBsAg levels between the treatment duration ≤1 year group and the treatment duration >1 year group （P<0.05）. The correlation analysis between the duration of antiviral therapy and the levels of HBV RNA， HBV DNA， and HBsAg showed that the duration of antiviral therapy had an extremely weak negative correlation with the levels of HBV RNA and HBsAg （r=-0.247 and -0.138， both P<0.05） and a strong negative correlation with the level of HBV DNA （r=-0.771， P<0.001）. There was a low degree of correlation between the serum level of HBV RNA and the serum levels of HBV DNA and HBsAg （r=0.360 and 0.442， both P<0.001）. Further stratified analysis showed that in the untreated group， there was a strong positive correlation between HBV RNA and HBV DNA （r=0.752， P<0.001） and a moderate positive correlation between HBV RNA and HBsAg （r=0.559， P<0.001）； in the treatment duration ≤1 year group， there was a low degree of positive correlation between HBV RNA and HBV DNA/HBsAg （r=0.396 and r=0.388， both P<0.001）； in the treatment duration >1 year group， there was a low degree of positive correlation between HBV RNA and HBsAg （r=0.352， P<0.001）. ConclusionSerum HBV RNA is negatively correlated with the duration of treatment with NAs， and the correlation of HBV RNA with HBV DNA and HBsAg gradually decreases with the increase in the duration of treatment. Therefore， it can be used as a supplementary indicator for monitoring the level of virologic response in CHB patients to a certain extent， with a relatively high accuracy in reflecting the level of viral replication in untreated patients.

Dynamic change and significance of Mindin protein in chronic hepatitis B treated with PEG-IFNα-2b / 临床肝胆病杂志

ObjectiveTo investigate the change and potential role of Mindin protein in the treatment of chronic hepatitis B （CHB） with PEG-IFNα-2b. MethodsA total of 29 CHB patients who received the treatment with PEG-IFNα-2b in The Second Affiliated Hospital of Xi’an Jiaotong University from January 2018 to December 2019 were enrolled， and according to their clinical outcome， they were divided into cured group with 17 patients and uncured group with 12 patients. Peripheral blood samples were collected from both groups at baseline， 12 weeks， and 24 weeks to measure blood routine indices， liver function parameters， hepatitis B markers， and Mindin protein. HBsAg， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， and Mindin protein at different time points were compared between the two groups. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； a Spearman correlation analysis was used to investigate correlation； a multiple linear regression analysis was used to investigate the influence of HBsAg and ALT on the content of Mindin protein. ResultsThe analysis of baseline data showed that there were significant differences in the levels of HBsAg， HBeAb， albumin， and albumin/globulin ratio between the cured group and the uncured group （all P<0.05）. The cured group tended to have a gradual increase in the level of Mindin， and the level of Mindin at 24 weeks was significantly higher than that at baseline （P<0.05）. The cured group had a significantly higher level of Mindin protein than the uncured group at 24 weeks （P=0.019）. The cured group had a significantly lower level of HBsAg than the uncured group （P<0.05）， with a significant change from baseline to each time point within the cured group （P<0.05）. In addition， the levels of ALT and AST in the cured group tended to first increase and then decrease， and the expression levels at 12 weeks were significantly higher than those at baseline （P<0.05）. At 12 weeks， there was a strong linear correlation between Mindin protein levels and ALT in the untreated group （r=0.760 8， P<0.05）， and further multiple linear regression analysis also demonstrated a linear relationship between the two （b=1.571， P=0.019）. ConclusionThere is a significant difference in the level of Mindin protein between the cured group and the non-cured group after 24 weeks of PEG-IFNα-2b antiviral treatment， and therefore， detecting the dynamic changes of Mindin protein can better predict the treatment outcome of CHB， which provides a reference for clinical practice.

Application value of liver/spleen CT value， controlled attenuation parameter， and magnetic resonance imaging-proton density fat fraction in chronic hepatitis B patients with hepatic steatosis / 临床肝胆病杂志

ObjectiveTo investigate the application value of liver/spleen CT value （CTL/S）， controlled attenuation parameter （CAP）， and magnetic resonance imaging-proton density fat fraction （MRI-PDFF） in chronic hepatitis B （CHB） patients with hepatic steatosis. MethodsA retrospective analysis was performed for the clinical data of 213 CHB patients who underwent liver CT， CAP， and MRI-PDFF examinations in Affiliated Hospital of Yan’an University from October 2018 to December 2022. According to MRI-PDFF， the 213 patients were divided into CHB group with 111 patients （MRI-PDFF<5%） and CHB+hepatic steatosis group with 102 patients （MRI-PDFF≥5%）， among whom there were 69 patients with mild hepatic steatosis and 33 patients with moderate to severe hepatic steatosis. The independent-samples t test was used for comparison of normally distributed continuous data between groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups. The Bland-Altman plot was used to evaluate the consistency in MRI-PDFF measurement between two physicians. The Spearman’s correlation coefficient was used to analyze the correlation between CTL/S and MRI-PDFF and between CAP and MRI-PDFF. The receiver operating characteristic （ROC） curve was plotted and the area under the ROC curve （AUC） was calculated to investigate the value of CTL/S and CAP in the diagnosis of different degrees of hepatic steatosis， and the DeLong test was used to compare the AUCs of the two radiological examinations. ResultsMRI-PDFF had relatively high repeatability and stability in CHB patients. There is a significant negative correlation between CTL/S and MRI-PDFF （r=-0.800， P<0.001） and a significant positive correlation between CAP and MRI-PDFF （r=0.692， P<0.001）. Both CTL/S and CAP had a relatively high accuracy in the diagnosis of hepatic steatosis in CHB patients， with an AUC of 0.951 and 0.902， respectively， and CTL/S had a better accuracy than CAP （P<0.05）. In the diagnosis of mild and moderate-to-severe hepatic steatosis， CTL/S had an AUC of 0.921 and 0.895， respectively， and CAP had an AUC of 0.859 and 0.825， respectively， suggesting that CTL/S had a slightly higher diagnostic efficiency than CAP. ConclusionMRI-PDFF has high repeatability and stability in CHB patients， and CTL/S and CAP have a high diagnostic value for different degrees of hepatic steatosis in CHB patients.

Hepatocellular carcinoma prediction model performance decreases with long-term antiviral therapy in chronic hepatitis B patients.

BACKGROUND/AIMS: Existing hepatocellular carcinoma (HCC) prediction models are derived mainly from pretreatment or early on-treatment parameters. We reassessed the dynamic changes in the performance of 17 HCC models in patients with chronic hepatitis B (CHB) during long-term antiviral therapy (AVT). METHODS: Among 987 CHB patients administered long-term entecavir therapy, 660 patients had 8 years of follow-up data. Model scores were calculated using on-treatment values at 2.5, 3, 3.5, 4, 4.5, and 5 years of AVT to predict threeyear HCC occurrence. Model performance was assessed with the area under the receiver operating curve (AUROC). The original model cutoffs to distinguish different levels of HCC risk were evaluated by the log-rank test. RESULTS: The AUROCs of the 17 HCC models varied from 0.51 to 0.78 when using on-treatment scores from years 2.5 to 5. Models with a cirrhosis variable showed numerically higher AUROCs (pooled at 0.65-0.73 for treated, untreated, or mixed treatment models) than models without (treated or mixed models: 0.61-0.68; untreated models: 0.51-0.59). Stratification into low, intermediate, and high-risk levels using the original cutoff values could no longer reflect the true HCC incidence using scores after 3.5 years of AVT for models without cirrhosis and after 4 years of AVT for models with cirrhosis. CONCLUSION: The performance of existing HCC prediction models, especially models without the cirrhosis variable, decreased in CHB patients on long-term AVT. The optimization of existing models or the development of novel models for better HCC prediction during long-term AVT is warranted.

Effects of Zhenggan Huayu decoction combined with entecavir on gut microbiota in patients with chronic hepatitis B fibrosis.

OBJECTIVE: To evaluate the effects of Zhenggan Huayu decoction (, ZGHY) combined with entecavir (ETV) on the gut microbiota in patients with chronic hepatitis B (CHB) fibrosis. METHODS: A total of 59 CHB-related fibrosis patients were enrolled and treated with ZGHY combined with ETV (ZGHY + ETV) and ETV alone. Fecal samples were collected from patients at weeks 0, 12, and 24 after treatment and gut microbiota were analyzed by 16S rRNA gene sequencing. RESULTS: Compared to the ETV group, microbiota diversity in the ZGHY + ETV group was increased after 24 weeks. Some potentially pathogenic bacteria, including spp., spp., and spp. were reduced in the ZGHY + ETV group, while spp., spp., and several other beneficial bacteria were increased. CONCLUSION: Decreases in pathogenic bacteria and increases in probiotics were not always observed in the Traditional Chinese Medicine (TCM) group (e.g., was abundant). As an adjuvant TCM formulation for ETV, ZGHY had a positive role in the treatment of CHB patients.

Predictive factors for functional cure after sequential therapy with nucleos(t)ide analogues and pegylated interferon alfa-2b in treatment of chronic hepatitis B / 临床肝胆病杂志

Objective To investigate the independent predictive factors for functional cure after long-term nucleos(t)ide analogue (NUC) antiviral therapy followed by pegylated interferon α-2b therapy in chronic hepatitis B (CHB) patients. Methods A total of 162 CHB patients who were admitted to several hospitals in Qingdao, China, from 2018 to 2021 were enrolled as subjects, and all patients received pegylated interferon α-2b for at least 48 weeks after NUC therapy for one year or longer. According to whether HBsAg clearance was achieved at week 48 of pegylated interferon α-2b treatment, the patients were divided into functional cure group with 79 patients and non-cure group with 83 patients, and related clinical indices were compared between the two groups. The two-independent-samples t test and the Mann-Whitney U rank sum test were used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The Spearman correlation analysis was performed, and the univariate and multivariate logistic regression analyses were used to investigate the independent predictive factors for functional cure. The receiver operating characteristic (ROC) curve was plotted for related variables, and the area under the ROC curve (AUC) was used to evaluate the prediction accuracy of the variables. Results Compared with the non-cure group, the functional cure group had a significantly lower HBsAg level at baseline [21.63 (3.33-157.60) IU/mL vs 794.70 (336.10-1 185.34) IU/mL, Z =-8.869, P 1000 IU/mL (0 vs 8.4%, χ 2 =5.073, P =0.024), a significantly lower level of total bilirubin at baseline [12.60 (10.12-15.93) μmol/L vs 15.50 (11.80-24.10) μmol/L, Z =-3.611, P 2×upper limit of normal (16.5% vs 4.8%, χ 2 =5.835, P =0.016). The multivariate logistic regression analysis showed that baseline HBsAg (odds ratio [ OR ]=0.996, 95% confidence interval [ CI ]: 0.995-0.997, P < 0.001), HBsAg at week 12 of pegylated interferon α-2b treatment ( OR =0.990, 95% CI : 0.986-0.994, P < 0.001), HBsAg at week 24 of pegylated interferon α-2b treatment ( OR =0.983, 95% CI : 0.975-0.991, P < 0.001), and baseline total bilirubin ( OR =0.885, 95% CI : 0.826-0.949, P =0.001) were independent predictive factors for functional cure. The ROC curve of baseline HBsAg showed an AUC of 0.904 and the optimal cut-off value of 118.24 IU/mL; the ROC curve of HBsAg at week 12 of pegylated interferon α-2b treatment showed an AUC of 0.948 and the optimal cut-off value of 73.74 IU/mL; the ROC curve of HBsAg at week 24 of pegylated interferon α-2b treatment showed an AUC of 0.975 and the optimal cut-off value of 11.01 IU/mL; the ROC curve of baseline total bilirubin showed an AUC of 0.664 and the optimal cut-off value of 19.9 μmol/L. Conclusion Baseline HBsAg, HBsAg at week 12 of pegylated interferon α-2b treatment, HBsAg at week 24 of pegylated interferon α-2b, and baseline total bilirubin are independent predictive factors for functional cure at week 48 of pegylated interferon α-2b treatment in CHB patients receiving sequential therapy with NUC and pegylated interferon α-2b.

Blocking and reversing liver fibrosis with traditional Chinese medicine compound prescriptions: Beyond the known frontiers / 临床肝胆病杂志

Liver fibrosis is the inevitable course for the progression of chronic hepatitis B to liver cirrhosis and is also the most important risk factor for hepatocarcinogenesis, and therefore, blocking and reversing liver fibrosis is an important strategy to effectively reduce the development of chronic hepatitis B cirrhosis and liver cancer. There are currently no effective drugs and measures for the treatment of liver fibrosis in Western medicine, and traditional Chinese medicine (TCM) has unique advantages in the treatment of liver fibrosis; however, due to a lack of strict and standardized clinical research, there is still no high-quality evidence for support from the aspect of evidence-based medicine (EBM). With subsidies from National Science and Technology Major Project in the 12th and 13th five-year plans, the authors conducted a multicenter, randomized, double-blind, placebo-controlled clinical trial on compound Biejia Ruangan tablets combined with entecavir in blocking and reversing chronic hepatitis B liver fibrosis. With liver biopsy as the gold standard, 1000 patients were enrolled to confirm the efficacy of compound Biejia Ruangan tablets combined with entecavir in blocking and reversing liver fibrosis and cirrhosis, and this study has become the first clinical trial investigating the anti-liver fibrosis effect of TCM supported by high-quality EBM evidence, bringing great hope to patients with chronic liver diseases and helping TCM move towards the world. This article introduces these research findings and reviews the current status and challenges of TCM in blocking and reversing liver fibrosis.

Advances and thoughts in traditional Chinese medicine diagnosis and treatment of chronic hepatitis B-related liver fibrosis / 临床肝胆病杂志

Liver fibrosis is a necessary intermediate process from the progression of chronic hepatitis B to liver cirrhosis and liver cancer. In recent years, breakthroughs have been made in the research on traditional Chinese medicine (TCM) for the prevention and treatment of chronic hepatitis B liver fibrosis. For the purpose of improving clinical outcome, multidisciplinary industry-university-research studies are conducted to explain the biological basis of TCM syndromes of chronic hepatitis B liver fibrosis, and establishment and development of a non-invasive diagnostic model with TCM characteristics, optimization of TCM/integrated traditional Chinese and Western medicine treatment regimens, and elaboration on the scientific connotation of TCM treatment can help TCM for the prevention and treatment of liver fibrosis to enter the global world.

Expression and significance of immune cells in patients with hepatitis B virus-related acute-on-chronic pre-liver failure / 临床肝胆病杂志

Objective To investigate the expression of myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), IL-17-producing CD4 + T cells (Th17), and CD8 + T cells (Tc17) in hepatitis B virus-related acute-on-chronic pre-liver failure (pre-ACHBLF), and to provide ideas for the early treatment of acute-on-chronic hepatitis B liver failure (ACHBLF). Methods A total of patients with pre-ACHBLF and 15 patients with ACHBLF who were hospitalized in Shijiazhuang Fifth Hospital, from August 2018 to May 2019 were enrolled as subjects, and 15 patients with chronic hepatitis B (CHB) and 15 healthy controls (HC) who underwent physical examination were enrolled as controls. Flow cytometry was used to measure the expression levels of MDSC and Th17, Treg, and Tc17 cells in peripheral blood; a blood analyzer was used to measure routine blood parameters and calculate neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index(SIRS) to evaluate the degree of inflammation, and the correlation between the expression of immune cells and the degree of inflammation was analyzed. An analysis of variance for independent samples was used for comparison of normally distributed continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups, and the Nemenyi test was used for further comparison between two groups. A Pearson linear correlation analysis or Spearman's rank correlation analysis was used to investigate the correlation between variables. Results Compared with the CHB group, the ACHBLF and pre-ACHBLF groups had significant increases in the expression levels of Th17, Treg, and Tc17 cells, and the pre-ACHBLF group also had a significant increase in the expression level of MDSC (all P < 0.05). The correlation analysis showed that in pre-ACHBLF patients, MDSC were positively correlated with leukocyte count, neutrophil count, NLR, MLR, and SII ( r =0.775, 0.727, 0.571, 0.786, and 0.846, all P < 0.05), and Treg cells were only positively correlated with leukocyte count ( r =0.618, P =0.043); Th17/Treg ratio and Tc17 cells were negatively correlated with the number of lymphocytes ( r =-0.790 and -0.795, both P < 0.05). Conclusion Cellular immune dysfunction is observed in patients with pre-ACHBLF, and the expression of MDSC is closely associated with the degree of inflammation and should be taken seriously in the early stage.

Clinical features and related risk factors of chronic hepatitis B patients with concomitant minimal hepatic steatosis / 临床肝胆病杂志

Objective To investigate the changes of clinical indices in chronic hepatitis B (CHB) patients with concomitant minimal hepatic steatosis and related factors for minimal hepatic steatosis. Methods A total of 179 CHB patients who underwent liver biopsy in Department of Infectious Diseases, Affiliated Drum Tower Hospital of Nanjing University Medical School, from July 2018 to March 2022 were enrolled, and according to the degree of steatosis, they were divided into non-steatosis group with 98 patients and minimal hepatic steatosis group with 81 patients. Demographic information, clinical data, and liver histopathology data were collected, and related observation indices were compared between the two groups. The independent samples t -test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test was used for comparison of categorical data between groups. A Spearman correlation analysis was performed, and a Logistic regression analysis was used to investigate the risk factors for minimal hepatic steatosis. Results Compared with the non-steatosis group, the minimal hepatic steatosis group had a significantly higher proportion of male patients (69.1% vs 52.0%, χ 2 =5.390, P < 0.05) and a significantly higher proportion of patients with significant liver fibrosis (43.2% vs 25.5%, χ 2 =6.234, P < 0.05). Compared with the non-steatosis group, the minimal hepatic steatosis group had significantly higher levels of body mass index (BMI) (23.61±2.95 kg/m 2 vs 22.13±2.67 kg/m 2 , t =-4.150, P < 0.05), uric acid (UA) [333.0(291.0-375.5) μmol/L vs 287.5(244.8-345.3) μmol/L, Z =-3.620, P < 0.05], triglyceride [0.92 (0.66-1.14) μmol/L vs 0.77 (0.62-1.02) μmol/L, Z =-2.224, P < 0.05], and controlled attenuation parameter (CAP) [234 (214-258) dB/m vs 218 (201-237) dB/m, Z =-2.867, P < 0.05]. In the group with normal body weight, the patients with minimal hepatic steatosis had significantly higher levels of UA (333.0±63.9 μmol/L vs 291.0±72.8 μmol/L, t =-2.395, P < 0.05) a nd HBV DNA [4.44 (3.51-6.79) log 10 IU/mL vs 3.42 (3.00-5.03) log 10 IU/mL, Z =-2.474, P < 0.05]. BMI (odds ratio [ OR ]=1.223, 95% confidence interval [ CI ] : 1.086-1.378, P =0.001) and UA ( OR =1.006, 95% CI : 1.002-1.010, P =0.008) were risk factors for minimal hepatic steatosis in CHB patients, and UA ( OR =1.007, 95% CI : 1.001-1.013, P =0.022) was a risk factors for minimal hepatic steatosis in CHB patients with normal body weight. Conclusion Compared with the non-steatosis CHB patients, the CHB patients with minimal hepatic steatosis have a significantly higher proportion of patients with significant liver fibrosis and a significantly higher level of CAP. BMI and UA are independent risk factors for minimal hepatic steatosis in CHB patients, and for the CHB patients with normal body weight, elevated UA is closely associated with the onset of minimal hepatic steatosis.

Expression levels of HBV pregenomic RNA and hepatitis B core-related antigen in circulating serum and their association with recurrence in chronic hepatitis B patients after withdrawal from nucleos(t)ide analogues / 临床肝胆病杂志

Objective To investigate the expression levels of HBV pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) in circulating serum of chronic hepatitis B (CHB) patients after withdrawal from nucleos(t)ide analogues (NUC), as well as the correlation of HBV pgRNA and HBcrAg levels in circulating blood in different periods of time with recurrence in CHB patients after drug withdrawal. Methods Among the patients who attended the outpatient service of Affiliated Hospital of North Sichuan Medical College from December 2019 to July 2022, a total of 108 CHB patients who received anti-HBV therapy for at least 5 years and met the criteria for drug withdrawal in 2017 EASL Guidelines were enrolled. According to the time of drug withdrawal, the patients were divided into 4-, 12-, and 24-week groups after drug withdrawal, and according to the presence or absence of recurrence, they were divided into recurrence group and non-recurrence group. Quantitative real-time PCR was used to measure the level of HBV pgRNA in circulating serum of CHB patients; ELISA was used to measure the expression level of HBcrAg in peripheral venous blood; quantitative real-time PCR was used to measure HBV DNA load with high accuracy. The t -test was used for comparison of continuous data between two groups. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t -test was used for further comparison between two groups. The Pearson correlation test was used to investigate the correlation between the indices in circulating blood. Results For the CHB patients after drug withdrawal, the recurrence rate was 17.1% at 4-12 weeks, cumulative recurrence rate reached 29.3% after 24 weeks of follow-up, the patients with positive HBV DNA alone accounted for 64.3% and 60.0%, respectively, those with positive HBeAg alone accounted for 28.5% and 20.0%, respectively, and those with positive HBV DNA and HBeAg accounted for 7.1% and 20.0%, respectively. The expression levels of HBV pgRNA, HBcrAg, and HBV DNA in circulating serum of CHB patients at 24 weeks after drug withdrawal were significantly higher than those at the time of drug withdrawal and at 4 weeks after drug withdrawal, and there was a significant difference between groups at different time points (all P 0.05). Conclusion The recurrence group had significantly higher expression levels of HBV pgRNA and HBcrAg than the non-recurrence group at the time of drug withdrawal, suggesting that the levels of HBV pgRNA and HBcrAg in the CHB patients of the non-recurrence group at the time of drug withdrawal may be used as the reference thresholds for safe drug withdrawal in CHB patients, and measurement of HBV pgRNA and HBcrAg may be one of the potential reference indicators for the selection of anti-HBV treatment endpoints in the future.