Circulating metabolites are associated with persistent elevations of ALT in patients with chronic hepatitis B with complete viral suppression.

Hepatitis B virus (HBV) can be completely suppressed after antiviral treatment; however, some patients with chronic hepatitis B (CHB) exhibit elevated alanine aminotransferase (ALT) levels and sustained disease progression. This study provides novel insights into the mechanism and potential predictive biomarkers of persistently elevated ALT (PeALT) in patients with CHB after complete viral inhibition. Patients having CHB with undetectable HBV DNA at least 12 months after antiviral treatment were enrolled from a prospective, observational cohort. Patients with PeALT and persistently normal ALT (PnALT) were matched 1:1 using propensity score matching. Correlations between plasma metabolites and the risk of elevated ALT were examined using multivariate logistic regression. A mouse model of carbon tetrachloride-induced liver injury was established to validate the effect of key differential metabolites on liver injury. Of the 1238 patients with CHB who achieved complete viral suppression, 40 (3.23%) had PeALT levels during follow-up (median follow-up: 2.42 years). Additionally, 40 patients with PnALT levels were matched as controls. Ser-Phe-Ala, Lys-Ala-Leu-Glu, 3-methylhippuric acid, 3-methylxanthine, and 7-methylxanthine were identified as critical differential metabolites between the two groups and independently associated with PeALT risk. Ser-Phe-Ala and Lys-Ala-Leu-Glu levels could be used to discriminate patients with PeALT from those with PnALT. Furthermore, N-acetyl- l-methionine (NALM) demonstrated the strongest negative correlation with ALT levels. NALM supplementation alleviated liver injury and hepatic necrosis induced by carbon tetrachloride in mice. Changes in circulating metabolites may contribute to PeALT levels in patients with CHB who have achieved complete viral suppression after antiviral treatment.

Serum ß-klotho is a potential biomarker for the progression of hepatitis B virus-related liver diseases.

INTRODUCTION: Hepatitis B virus (HBV) infection is a global epidemic that can lead to several liver diseases, seriously affecting people's health. This study aimed to investigate the clinical potential of serum ß-klotho (KLB) as a promising biomarker in HBV-related liver diseases. METHODOLOGY: This study enrolled 30 patients with chronic hepatitis B (CHB), 35 with HBV-related cirrhosis, 66 with HBV-related hepatocellular carcinoma (HCC), and 48 healthy individuals. ELISA measured the levels of serum KLB in the four groups. We then compared the differences in serum KLB levels among the groups and analyzed the relationship between serum KLB and routine clinical parameters. RESULTS: The concentrations of serum KLB levels were increased sequentially among the healthy subjects, the HBV-related CHB group, the HBV-related cirrhosis group, and the HBV-related HCC group (p < 0.05). Expression of KLB was positively correlated with alpha-fetoprotein (AFP), total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl-transferase, alkaline phosphatase, total bile acid, serum markers for liver fibrosis, ascites, cirrhosis, splenomegaly, and model for end-stage liver disease sodium, while negatively correlated with platelet count, albumin, and prothrombin activity (p < 0.05). In addition, serum KLB has better sensitivity in diagnosing HCC than AFP, and serum KLB combined with AFP has higher sensitivity and specificity than AFP alone in diagnosing HCC. CONCLUSIONS: Serum KLB level is associated with the severity of HBV-related liver diseases and has important diagnostic value for HCC. Therefore, it could be a predictive biomarker for monitoring disease progression.

Investigation of SARS-CoV-2 antibody levels after COVID-19 vaccine in chronic hepatitis B patients.

AIM: The aim was to compare SARS-CoV-2 IgG antibody levels in chronic hepatitis B patients and healthcare personnel selected as the control group and to determine factors such as age, gender, vaccine type, and number of vaccines that may affect the antibody levels. MATERIALS AND METHODS: 87 chronic hepatitis B (CHB) patients followed in Ankara Training and Research Hospital Infectious Diseases Clinic and Mamak State Hospital Infectious Diseases outpatient clinic and 89 healthcare personnel selected as the control group were included in the study.SARS-CoV-2 IgG antibody levels in the serum samples of patients and healthcare personnel who received the COVID-19 vaccine were studied with the ELISA method in the Microbiology Laboratory of Ankara Training and Research Hospital, using a commercial ELISA kit (Abbott, USA) in line with the recommendations of the manufacturer. In the study, SARS-CoV-2 IgG levels were compared in CHB patients and healthcare personnel. In addition, the relationship between SARS-CoV-2 antibody level, gender, average age, natural history of the disease, number of vaccinations, vaccine type (Coronavac TM vaccine alone, BNT162b2 vaccine alone or Coronavac TM and BNT162b2 vaccine (heterologous vaccination)), treatment duration of CHB was investigated. Statistical analyses were made in the SPSS program. A value of p≤ 0.05 was considered statistically significant. FINDINGS: A total of 167 people, including 87 CKD patients and 80 healthcare personnel as the control group, were included in the study. SARS-CoV-2 IgG antibody levels were detected above the cut-off level in the entire study group, regardless of the vaccine type. No difference was detected in SARS-CoV-2 IgG titers after COVID-19 vaccination between CHB patients and healthcare personnel. There was a statistically significant difference in SARS-CoV-2 IgG antibody levels among individuals participating in the study according to vaccine types. Compared to those who received Coronavac TM vaccine alone, the average SARS-CoV-2 IgG level was found to be statistically significantly higher in those who received BNT162b2 vaccine alone or heterologous vaccination with Coronavac TM + BNT162b2 vaccine. There was no difference between the groups in terms of age, gender, number of vaccinations, natural transmission of the disease, and duration of antiviral therapy in the CHD patient group. CONCLUSION: As a result, SARS-CoV-2 IgG antibody levels above the cut-off value were achieved with Coronavac TM and BNT162b2 vaccines in both CHD patients and healthy control groups. however, both CHD patients and healthcare personnel had higher antibody levels than those who received BNT162b2 alone or those who received heterologous vaccination had higher antibody levels than those with Coronavac TM alone. Therefore, if there are no contraindications, BNT162b2 vaccine may be preferred in CHB and health personnel (Tab. 2, Ref. 14).

Serum ApoB/ApoA1 ratio in patients with CHB and the occurrence of HBV related cirrhosis and HBV related hepatocellular carcinoma.

Clinical research has suggested that chronic HBV infection exerts a certain effect on the occurrence of cardiovascular disease by regulating cholesterol metabolism in liver cells. High serum apolipoprotein B/apolipoprotein A1 (ApoB/ApoA1) ratio plays a certain role in the above regulation, and it serves as a risk factor for cardiovascular disease. However, whether the ApoB/ApoA1 ratio is correlated with chronic HBV infection and its disease progression remains unclear. In accordance with the inclusion and exclusion criteria, all 378 participants administrated at Renmin Hospital of Wuhan University from March 2021 to March 2022, fell into Healthy Control (HC) group (50 participants), Hepatocellular carcinoma (HCC) group (107 patients), liver cirrhosis (LC) group (64 patients), chronic hepatitis B (CHB) group (62 patients), chronic hepatitis C (CHC) group (46 patients) and Hepatitis E Virus (HEV) group (49 patients). Serum ApoA1 and ApoB concentrations were measured at admission, and the ApoB/ApoA1 ratio was determined. The levels of laboratory parameters in the respective group were compared and ApoB/ApoA1 ratios in HCC patients and LC patients with different severity were further analyzed. ROC curves were plotted to analyze the early diagnostic ability of ApoB/ApoA1 ratio for HBV-associated HCC. Logistic regression and restricted cubic spline analysis were used to explore the correlation between ApoB/ApoA1 ratio and LC and HCC risk. A comparison was drawn in terms of ApoB/ApoA1 ratio between the groups, and the result was expressed in descending sequence: HEV group > CHB group > LC group > HCC group > CHC group > HC group, early-stage HCC < middle-stage HCC < advanced-stage HCC, Class A LC < Class B LC < Class C LC. Serum ApoB/ApoA1 ratio combined diagnosis with AFP exhibited the capability of increasing the detection efficacy and specificity of AFP for HCC and AFP-negative HCC. The incidence of LC and HCC in the respective logistic regression model showed a negative correlation with the serum ApoB/ApoA1 ratio in CHB patients (P < 0.05). After all confounding factors covered in this study were regulated, the result of the restricted cubic spline analysis suggested that in a certain range, serum ApoB/ApoA1 ratio showed an inverse correlation with the prevalence of LC or HCC in CHB patients. Serum ApoB/ApoA1 ratio in CHB patients may be conducive to identifying high-risk patients for HCC or LC, such that LC and HCC can be early diagnosed and treated.

Predictive role of early treatment dynamics of HBV RNA and HBcrAg for HBeAg seroconversion in children with chronic hepatitis B.

This study aimed to assess the predictive capacity of emerging serological markers, serum HBV RNA and HBcrAg, for HBeAg seroconversion in children with HBeAg-positive chronic hepatitis B (CHB). Treatment-naïve HBeAg-positive CHB children who admitted to the Liver Disease Center of Hunan Children's Hospital between April 2021 and September 2022 and received treatment with the combined entecavir and interferon-alpha treatment were recruited. Serum HBV RNA and HBcrAg were measured at baseline and Weeks 12, 24, and 48 of treatment. Our study showed that serum HBV RNA (HR = 0.71, 95% CI: 0.56-0.91, p = 0.006), HBcrAg (HR = 0.60, 95% CI: 0.43-0.84, p = 0.003), and HBsAg (HR = 0.49, 95%CI: 0.36-0.69, p < 0.001) at Week 12 were independent predictors of HBeAg seroconversion. ROC curve analysis presented that serum HBV RNA decline value (ΔHBV RNA) at Week 36 and HBcrAg decline value (ΔHBcrAg) at Week 12 (AUC = 0.871, p = 0.003 and AUC = 0.810, p = 0.003, respectively) could effectively predict HBeAg seroconversion. Furthermore, the optimal critical values were determined and the children with ΔHBV RNA > 3.759 log10 copies/mL at Week 36 or ΔHBcrAg >0.350 log10 U/mL at Week 12 more likely to achieve HBeAg seroconversion. The serum HBV RNA and HBcrAg provide new insights into the treatment of CHB in children. Early assessment of serum HBV RNA and HBcrAg during treatment can assist clinical decision-making and optimize individualized therapeutic approaches.

Noninvasive models for the prediction of liver fibrosis in patients with chronic hepatitis B.

OBJECTIVE: To evaluate the diagnostic accuracy of aspartate aminotransferase(AST)/ alanine transaminase (ALT), AST to platelet ratio index (APRI), fibrosis-4 score (FIB-4) and gamma-glutamyl transpeptidase to platelet count ratio (GPR) for hepatic fibrosis in patients with chronic hepatitis B (CHB). METHODS: A total of 1210 CHB patients who underwent liver biopsy were divided into two groups: patients with no significant fibrosis (control group) and patients with significant fibrosis, and routine laboratory tests were retrospectively included. Logistic regression models were used for the prediction, and the area under the receiver operating characteristic (AUROC) was used to assess the diagnostic accuracy. RESULTS: A total of 631 (52.1%) and 275 (22.7%) patients had significant fibrosis (≥ S2) and advanced fibrosis (≥ S3), respectively. The GPR showed significantly higher diagnostic accuracy than that of APRI, FiB-4, and AST/ALT to predict ≥ S2(significant fibrosis) and ≥ S3 fibrosis(advanced fibrosis), with an AUROC was 0.69 (95%CI: 0.66-0.71) and 0.72 (0.69-0.75), respectively. After stratified by the status of HBeAg ( positive or negative), GPR, APRI, and FiB-4 showed improved predicting performance for significant fibrosis and advanced fibrosis in HBeAg positive patients, with the most significant improvement was shown for GPR in predicting significant fibrosis (AUROC = 0.74, 95%CI: 0.70-0.78). CONCLUSIONS: Among the four noninvasive models, GPR has the best performance in the diagnosis of hepatic fibrosis in CHB patients and is more valuable in HBeAg-positive patients.

Nursing observations of stage-based care in patients diagnosed with hepatitis B virus infection based on TBIL and ALT levels.

This study explored techniques and effects of stage-based care on patients with chronic hepatitis B virus (HBV) infection. The clinical data of 156 patients with chronic HBV infection treated in our hospital from September 2018 to December 2019 were retrospectively analyzed and classified as the experimental group (EG). Patients were categorized into early, intermediate, and late hepatitis stages and received targeted clinical care during the various phases of chronic HBV infection. In addition, 144 cases of patients with chronic HBV admitted to the hospital from January 2018 to August 2018 and treated without stage-based care were classified as the control group (COG). General care was implemented for all patients before the initiation of stage-based care. Patient satisfaction, mortality rates of patients at different stages, liver pain scores, depression scores, blood biochemical indices, and alanine transaminase and total bilirubin levels before and after nursing care were compared. The total satisfaction rate of the EG group (90.38%) was significantly higher than that of the COG group (83.33%) (P < .05). We found no significant differences in the mortality rates of early-, middle-, and late-stage patients in the EG group when compared with those of the COG group at corresponding stages (P < .05). The self-care agency scores (for all dimensions) and psychosocial adaptation scores in the EG group were significantly higher than those in the COG group (P < .05) after care. Moreover, the pain scores in the EG group were significantly lower than those in the COG group after care (P < .05). Furthermore, the observed psychological status of patients in the EG group significantly improved when compared with that in the COG group (P < .05). Stage-based care for patients with severe chronic type B hepatitis increased clinical satisfaction, relieved pain, reduced depression, and improved blood biochemical indices. Therefore, stage-based care for chronic HBV infection should be included in the clinical environment.

A machine learning-based model analysis for serum markers of liver fibrosis in chronic hepatitis B patients.

Early assessment and accurate staging of liver fibrosis may be of great help for clinical diagnosis and treatment in patients with chronic hepatitis B (CHB). We aimed to identify serum markers and construct a machine learning (ML) model to reliably predict the stage of fibrosis in CHB patients. The clinical data of 618 CHB patients between February 2017 and September 2021 from Zhejiang Provincial People's Hospital were retrospectively analyzed, and these data as a training cohort to build the model. Six ML models were constructed based on logistic regression, support vector machine, Bayes, K-nearest neighbor, decision tree (DT) and random forest by using the maximum relevance minimum redundancy (mRMR) and gradient boosting decision tree (GBDT) dimensionality reduction selected features on the training cohort. Then, the resampling method was used to select the optimal ML model. In addition, a total of 571 patients from another hospital were used as an external validation cohort to verify the performance of the model. The DT model constructed based on five serological biomarkers included HBV-DNA, platelet, thrombin time, international normalized ratio and albumin, with the area under curve (AUC) values of the DT model for assessment of liver fibrosis stages (F0-1, F2, F3 and F4) in the training cohort were 0.898, 0.891, 0.907 and 0.944, respectively. The AUC values of the DT model for assessment of liver fibrosis stages (F0-1, F2, F3 and F4) in the external validation cohort were 0.906, 0.876, 0.931 and 0.933, respectively. The simulated risk classification based on the cutoff value showed that the classification performance of the DT model in distinguishing hepatic fibrosis stages can be accurately matched with pathological diagnosis results. ML model of five serum markers allows for accurate diagnosis of hepatic fibrosis stages, and beneficial for the clinical monitoring and treatment of CHB patients.

Frequency of HBsAg variants in occult hepatitis B virus infected patients and detection by ARCHITECT HBsAg quantitative.

Objective: To analyze the amino acid substitution caused by mutations in the major hydrophilic region (MHR) of the S-region genes in the serum samples of occult hepatitis B virus infection (OBI), and to explore the reasons for the missed detection of HBsAg. Method: The full-length gene of the S-region in hepatitis B virus(HBV) in the chronic hepatitis B virus(CHB)(10 samples) and OBI groups(42 samples) was amplified using a lab-developed, two-round PCR amplification technology. The PCR amplification products were sequenced/clone sequenced, and the nucleotide sequences of the S-region gene in HBV were compared to the respective genotype consensus sequence. Results: Only 20 of the 42 samples in the OBI group had the S-region genes successfully amplified, with the lowest HBV DNA load of 20.1IU/ml. As S-region genes in HBV, 68 cloned strains were sequenced. In the OBI and CHB groups MHR region, with a mutation rate of 3.21% (155/4828) and 0.70% (5/710). The genetic mutation rate was significantly higher in the OBI group than in the CHB group (P<0.05). The common mutation types in the MHR region were: I126T, L162R, K122E, C124R, and C147Y.Mutations at s122, s126, and s162 were associated with subgenotypes, most of which being C genotypes. The high-frequency mutation sites L162R and K122E found in this study have not been reported in previous literature. Conclusion: The results of this study confirmed that MHR mutations can cause the missed detection of HBsAg, giving rise to OBI.

Predictors of Nucleos(t)ide Analogues Discontinuation Relapse: Hepatitis B Virus RNA versus Hepatitis B Surface Antigen.

OBJECTIVE: To compare the predictive value of hepatitis B virus (HBV) RNA and HBsAg quantification upon discontinuation of nucleos(t)ide analogues (NAs) therapy for clinical and virological relapse in chronic hepatitis B (CHB). STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan, China, from July 2014 to December 2020. METHODOLOGY: CHB patients received single NAs and discontinued treatment following appropriate standards. HBsAg quantification was conducted using the i2000 Chemiluminescent Immunoassay (CLIA) Analyser, while serum HBV RNA quantification was performed using specific RNA target capture and simultaneous amplification and testing. The main observational endpoints included virological relapse and clinical relapse. RESULTS: Eighty-one patients were recruited, with 15 patients achieving HBsAg loss at cessation. Twenty-nine individuals encountered virological relapse, while 13 patients experienced clinical relapse. Thirty-one patients achieved HBsAg <100 IU/ml at NAs cessation, among whom 26 achieved undetectable HBV RNA, while four patients suffered virological relapse (15.4%). Serum HBV RNA emerged as an independent determinant of virological relapse (HR 1.850), clinical relapse (HR 2.020), and HBsAg loss after NAs cessation (HR 0.138). The presence of HBsAg <100 IU/ml at cessation did not serve as a predictor for virological relapse and clinical relapse. CONCLUSION: Lower HBV RNA levels predict a better off-treatment response. Discontinuation of prolonged NAs therapy appears as a viable and safe choice for patients with undetectable HBV RNA. In comparison to HBV RNA, HBsAg <100 IU/ml at cessation did not show sufficient predictive value for virological relapse and clinical relapse. KEY WORDS: HBV RNA, Hepatitis B surface antigen, Chronic hepatitis B, Relapse.

Predictive Value of Serum Albumin, Iron, Ferritin, and Hepcidin for Antiviral Efficacy of IFNα Treatment in Patients with Chronic Hepatitis B.

OBJECTIVE: Interferon-α (IFNα) therapy has been an integral part of the current treatment for hepatitis B virus (HBV) infection. However, the exact effect of IFNα antiviral therapy on liver function and iron metabolism in patients with chronic hepatitis B (CHB) remains unclear. Here, we investigated the characteristics of changes in liver function and iron metabolism indexes in patients with chronic hepatitis B before and after IFNα treatment. Additionally, we determined their predictive value for the therapeutic response of IFNα treatment. METHODS: In this study, 34 patients with CHB before and after IFNα treatment were enrolled. Serum levels of virological indicators, liver function, and iron metabolism markers were detected and analyzed in each patient. ROC curve analysis was performed to compare the predictive value of serum liver function and iron metabolism markers for the therapeutic response of IFN α treatment. RESULTS: A significant decrease in serum HBV DNA (P<0.001) and HBsAg (P<0.001) was observed before and after IFNα treatment. Compared to the patients before IFNα treatment, patients after IFNα treatment showed a significant increase in serum albumin (ALB) (P<0.05) and a significant decrease in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (P=0.003 and P=0.034). These findings suggested that the synthetic function of the liver was improved, and liver inflammation was alleviated. Serum HEPC and serum ferritin (SF) levels in patients after IFNα treatment were significantly higher (P<0.001, P<0.001); however, serum iron (SI) levels were significantly lower (P=0.005) than those in patients before IFNα treatment. These findings indicate that IFNα treatment regulated iron metabolism homeostasis in CHB patients. Combined liver function and iron metabolism markers, including ALB, SI, SF, and HEPC, had the highest predictive value for the therapeutic response of IFNα treatment for CHB. CONCLUSION: IFNα treatment improved liver function and iron metabolism homeostasis in patients with CHB. Regular monitoring of serum ALB, SI, SF, and HEPC can help predict the therapeutic response of IFNα treatment for CHB.

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Objective: To study the changes in the serum markers in chronic hepatitis B patients who have had previous treatment with long-acting interferon therapy of nucleoside and those who have not and to assess the value of the serum markers for clinical prognosis evaluation. Methods: The clinical data of 411 cases of chronic hepatitis B were collected. All cases were given the additional treatment of long-acting interferon between October 2019 to April 2022. The cases were divided into two groups, a previously treated group consisting of patients who had been treated with nucleoside and nucleotide analogues (NAs) for more than 6 months after they became infected with hepatitis B virus (HBV) for over 6 months and an initial treatment group, or treatment naïve group, consisting of patients who had HBV infection for over 6 months and received no treatment or patients who have stopped NAs therapy for more than 6 months. The serum marker levels of the previously treated group and the initial treatment group, i.e., the previously treatment-naïve patients, were compared, and the receiver operating characteristics (ROC) curve was used to evaluate the value of the baseline levels of hepatitis B surface antigen (HBsAg) and HBV pregenomic RNA (pgRNA) for predicting the rate of cured cases in the two groups. Results: There was no significant difference in the rate of cured cases between the previously treated group and the initial treatment group. The baseline HBV DNA, HBsAg, and hepatitis B e antigen (HBeAg) levels of the cured cases in both groups were significantly lower than those in the uncured cases (P<0.0001). After 48 weeks of treatment, the serum HBsAb levels (mIU/mL) of the cured cases in both the previously treated and initial treatment groups were significantly higher than those of the uncured cases in the two groups (previously treated group: 78.97±22.57 vs. 0.99±0.38, P<0.0001; initial treatment group: 235.50±175.00 vs. 1.32±0.88, P<0.0001). The serum HBsAb levels (mIU/mL) of the cured cases in the initial treatment groups were significantly higher than that of cured cases in the previously treated group (235.50±175.00 vs. 78.97±22.57, P<0.0001). Within 0 to 60 weeks of treatment, HBV pgRNA levels of cured cases in both groups were significantly lower than those of the the uncured cases in both groups (P<0.0001). Multivariate logistic regression and ROC curve analysis showed that baseline serum HBsAg was the influencing factor and predictor of interferon efficacy in both the previously treated cases and the initial treatment cases, with the area under the curve (AUC) being 0.80 (95% confidence interval [CI]: 0.7423-0.8615, P<0.0001) and 0.74 (95% CI: 0.6283-0.8604, P=0.0079), respectively, and the optimal cut-off values being 244.60 IU/mL and 934.40 IU/mL, respectively. However, the baseline serum HBV pgRNA level of under 1340.00 copies/mL in the initial treatment cases led to better sensitivity and better specificity in efficacy prediction, with the AUC of the baseline HBV pgRNA being 0.9649 (95% CI: 0.9042-1.0000, P<0.0001). Conclusion: Among the previously treated cases and the initial treatment cases, patients who achieve clinical cure have lower levels of HBV DNA, HBsAg, and HBeAg at baseline, lower level of HBV pgRNA over the course of their treatment, and higher level of HBsAb at week 48. Baseline HBsAg levels can be used to effectively predict the clinical cure outcomes in previously treated cases and initial treatment cases. Baseline HBV pgRNA levels also exhibit a high predictive value for treatment outcomes in initial treatment cases.

Quantitative Measurement of Serum HBcrAg Can Be Used to Assess the Feasibility of Safe Discontinuation of Antiviral Therapy for Chronic Hepatitis B.

Hepatitis B virus (HBV) infection is a serious global health problem, and chronic HBV infection significantly increases the risk of liver fibrosis, cirrhosis, and even hepatocellular carcinoma in patients. Current first-line therapeutics such as nucleos(t)ide analogues and interferons are unable to completely clear cccDNA, so the vast majority of patients need to take long-term or even lifelong medication. However, long-term virological and biochemical responses can be achieved in some patients after drug withdrawal. Successfully screening these patients with drug withdrawal advantages is difficult. Hepatitis-B-core-related antigen (HBcrAg) is a new HBV serological marker that which can reflect the level and transcription activity of cccDNA in hepatocytes. Therefore, HBcrAg has potential value in guiding patients in drug withdrawal. This review summarizes previous reports on HBcrAg and evaluates the application value of HBcrAg in safe drug discontinuation.

Combination of an Autoantibody Panel and Alpha-Fetoprotein for Early Detection of Hepatitis B Virus-Associated Hepatocellular Carcinoma.

The purpose of this study was to identify biomarkers associated with hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and to develop a new combination with good diagnostic performance. This study was divided into four phases: discovery, verification, validation, and modeling. A total of four candidate tumor-associated autoantibodies (TAAb; anti-ZIC2, anti-PCNA, anti-CDC37L1, and anti-DUSP6) were identified by human proteome microarray (52 samples) and bioinformatics analysis. Subsequently, these candidate TAAbs were further confirmed by indirect ELISA with two testing cohorts (120 samples for verification and 663 samples for validation). The AUC for these four TAAbs to identify patients with HBV-HCC from chronic hepatitis B (CHB) patients ranged from 0.693 to 0.739. Finally, a diagnostic panel with three TAAbs (anti-ZIC2, anti-CDC37L1, and anti-DUSP6) was developed. This panel showed superior diagnostic efficiency in identifying early HBV-HCC compared with alpha-fetoprotein (AFP), with an AUC of 0.834 [95% confidence interval (CI), 0.772-0.897] for this panel and 0.727 (95% CI, 0.642-0.812) for AFP (P = 0.0359). In addition, the AUC for this panel to identify AFP-negative patients with HBV-HCC was 0.796 (95% CI, 0.734-0.858), with a sensitivity of 52.4% and a specificity of 89.0%. Importantly, the panel in combination with AFP significantly increased the positive rate for early HBV-HCC to 84.1% (P = 0.005) and for late HBV-HCC to 96.3% (P < 0.001). Our findings suggest that AFP and the autoantibody panel may be independent but complementary serologic biomarkers for HBV-HCC detection. PREVENTION RELEVANCE: We developed a robust diagnostic panel for identifying patients with HBV-HCC from patients with CHB. This autoantibody panel provided superior diagnostic performance for HBV-HCC at an early stage and/or with negative AFP results. Our findings suggest that AFP and the autoantibody panel may be independent but complementary biomarkers for HBV-HCC detection.

Predictors of HBsAg seroclearance in patients with chronic HBV infection treated with pegylated interferon-α: a systematic review and meta-analysis.

BACKGROUND AND AIMS: The identification of reliable predictors for hepatitis B surface antigen (HBsAg) seroclearance remains controversial. We aimed to summarize potential predictors for HBsAg seroclearance by pegylated interferon-α (PegIFNα) in patients with chronic HBV infection. METHODS: A systematic search of the Cochrane Library, Embase, PubMed, and Web of Science databases was conducted from their inception to 28 September 2022. Meta-analyses were performed following the PRISMA statement. Predictors of HBsAg seroclearance were evaluated based on baseline characteristics and on-treatment indicators. RESULTS: This meta-analysis encompasses 27 studies, including a total of 7913 patients. The findings reveal several factors independently associated with HBsAg seroclearance induced by PegIFNα-based regimens. These factors include age (OR = 0.961), gender (male vs. female, OR = 0.537), genotype (A vs. B/D; OR = 7.472, OR = 10.738), treatment strategy (combination vs. monotherapy, OR = 2.126), baseline HBV DNA (OR = 0.414), baseline HBsAg (OR = 0.373), HBsAg levels at week 12 and 24 (OR = 0.384, OR = 0.294), HBsAg decline from baseline to week 12 and 24 (OR = 6.689, OR = 6.513), HBsAg decline from baseline ≥ 1 log10 IU/ml and ≥ 0.5 log10 IU/ml at week 12 (OR = 18.277; OR = 4.530), and ALT elevation at week 12 (OR = 3.622). Notably, subgroup analysis suggests no statistical association between HBsAg levels at week 12 and HBsAg seroclearance for treatment duration exceeding 48 weeks. The remaining results were consistent with the overall analysis. CONCLUSIONS: This is the first meta-analysis to identify predictors of HBsAg seroclearance with PegIFNα-based regimens, including baseline and on-treatment factors, which is valuable in developing a better integrated predictive model for HBsAg seroclearance to guide individualized treatment and achieve the highest cost-effectiveness of PegIFNα.

Assessment of compensated advanced chronic liver disease based on serum bile acids in chronic hepatitis B patients.

Patients with chronic liver disease progressed to compensated advanced chronic liver disease (cACLD), the risk of liver-related decompensation increased significantly. This study aimed to develop prediction model based on individual bile acid (BA) profiles to identify cACLD. This study prospectively recruited 159 patients with hepatitis B virus (HBV) infection and 60 healthy volunteers undergoing liver stiffness measurement (LSM). With the value of LSM, patients were categorized as three groups: F1 [LSM ≤ 7.0 kilopascals (kPa)], F2 (7.1 < LSM ≤ 8.0 kPa), and cACLD group (LSM ≥ 8.1 kPa). Random forest (RF) and support vector machine (SVM) were applied to develop two classification models to distinguish patients with different degrees of fibrosis. The content of individual BA in the serum increased significantly with the degree of fibrosis, especially glycine-conjugated BA and taurine-conjugated BA. The Marco-Precise, Marco-Recall, and Marco-F1 score of the optimized RF model were all 0.82. For the optimized SVM model, corresponding score were 0.86, 0.84, and 0.85, respectively. RF and SVM models were applied to identify individual BA features that successfully distinguish patients with cACLD caused by HBV. This study provides a new tool for identifying cACLD that can enable clinicians to better manage patients with chronic liver disease.

A noninvasive model discriminating significant histological changes in treatment-naive chronic hepatitis B patients with normal ALT.

BACKGROUND: Traditionally part of chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) are recommended to antiviral therapy referring to liver biopsy. However, liver biopsy is an invasive method with various potential complications. A noninvasive model was established in the study to evaluate liver histology and to identify the need of antiviral therapy. METHODS: A total of 614 liver biopsied CHB patients with ALT less than upper limit of normal from 2 centers were retrospectively analyzed. They were divided into a training cohort and a validation cohort. A noninvasive model to predict the significant liver histological changes was established and validated. RESULTS: The results of analysis showed that ALT, Age, platelet (PLT) and liver stiffness (LS) were independent risk factors for significant liver injury. The model was established based on the 4 indexes, with the area under the curve of 0.85 and 0.87 in training cohort and validation cohort. Meanwhile, 2 cut-off scores were selected. By applying the low cut-off score (- 0.207), patients without significant liver injury could be identified with high accuracy, with negative predictive value of 72.7% and 73.7% in training and validation cohorts. By applying the high cut-off score (0.537), the presence of significant liver injury could be diagnosed with high accuracy, with positive predictive value of 90.3% and 88.8% in the training and validation cohorts. By applying the model, liver biopsy would have been avoided in 87.6% (538/614) patients, with correct prediction in 87.9% (473/538). CONCLUSION: The novel noninvasive model composed of ALT, Age, PLT, LS can correctly assess liver histology in CHB patient with normal ALT, which helps to determine the need of antiviral therapy without liver biopsy.

Long-term Hepatitis B Surface Antigen Profile and Seroclearance after Severe Acute Flares of Chronic Hepatitis B.

Background/Aims: Hepatitis B surface antigen (HBsAg) seroclearance remains uncommon in chronic hepatitis B (CHB) infection. During acute flares of CHB (AFOCHB), alanine aminotransferase elevation reflects a mounting immune response toward viral clearance. We hypothesized that severe AFOCHB is associated with a greater quantitative HBsAg (qHBsAg) decline and HBsAg seroclearance rate. Methods: A total of 75 patients with severe AFOCHB with alanine aminotransferase 10× the upper limit of normal were matched to a control group by age and sex in a 1:2 ratio. qHBsAg levels were measured at the time of flare and annually (for both cases and controls) until the last follow-up. Results: The median follow-up times for patients with severe AFOCHB and controls were 8.8 and 10.5 years, respectively. The cumulative rate of HBsAg seroclearance was higher in the severe AFOCHB group than in the control group (11.8% vs 5.0%, p=0.04) despite the former group having a trend of a higher baseline median qHBsAg (3,127 IU/mL vs 1,178 IU/mL, p=0.076). Compared with the control group, the severe AFOCHB group had a greater annual qHBsAg reduction (-242.4 IU/mL/yr vs -47.3 IU/mL/yr, p=0.002). Increasing age (p=0.049), lower baseline qHBsAg (p=0.002), and severe AFOCHB (p=0.014) were independently associated with HBsAg seroclearance. However, the cumulative rate of hepatocellular carcinoma was significantly higher in the severe AFOCHB group than in the control group (15.8% vs 1.9%, p<0.001). Conclusions: Severe AFOCHB was associated with a greater incidence of HBsAg seroclearance and qHBsAg decline. However, it was associated with a higher incidence of hepatocellular carcinoma.

Baseline Hepatitis B Virus Surface Antigen Titers in Childhood Predict the Risk of Advanced Liver Fibrosis in Adulthood.

BACKGROUND & AIMS: Hepatitis B virus (HBV) surface antigen (HBsAg) is a marker of both HBV covalently closed circular DNA and integrated HBV genome, whereas the HBV core-related antigen (HBcrAg) indicates the transcriptional activity of covalently closed circular DNA. This study examined the relationship between HBsAg and HBcrAg titers in childhood and advanced fibrosis in adulthood. METHODS: We recruited 214 initially hepatitis B e antigen-positive chronic HBV-infected patients who were followed for a total of 6371 person-years. None of the patients were co-infected with hepatitis C or D virus. Serum HBsAg and HBcrAg titers were assessed at 10 and 15 years of age. Transient elastography was performed at a mean final age of 38.21 years to identify advanced fibrosis. RESULTS: Patients with advanced fibrosis in adulthood had a higher rate of genotype C HBV infection and a higher HBsAg titer at 10 and 15 years of age (P = .003, P = .03, and P = .005, respectively). The HBcrAg titer was not correlated with advanced fibrosis (P > .05). Receiver operating characteristic curve analysis showed that HBsAg cutoffs of >4.23 and >4.44 log10 IU/mL at 10 and 15 years of age, respectively, best predicted advanced fibrosis in the fourth decade of life (P = .001 and P < .001, respectively). In a multivariate analysis, both an HBsAg titer >4.44 log10 IU/mL at 15 years of age and HBV genotype C were predictors of advanced fibrosis (odds ratios, 15.43 and 4.77; P = .01 and P = .02, respectively). CONCLUSIONS: HBsAg titers in childhood predict the progression to liver fibrosis in adulthood.