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.

Antiviral therapy response in patients with chronic hepatitis B and fatty liver: A systematic review and meta-analysis.

The impact of concurrent fatty liver (FL) on response to antiviral therapy in chronic hepatitis B (CHB) patients has not been well characterized. We aimed to systematically review and analyse antiviral treatment response in CHB patients with and without FL. We searched PubMed, Embase, Web of Science and the Cochrane Library databases from inception to 31 May 2023 for relevant studies. Biochemical response (BR), complete viral suppression (CVS) and hepatitis B e antigen (HBeAg) seroconversion in CHB patients with FL (CHB-FL) and without FL (non-FL CHB) were compared. In an initial pool of 2101 citations, a total of 10 studies involving 2108 patients were included. After 12 weeks of treatment, CHB-FL patients as compared with non-FL CHB patients had lower BR rate (48.37% [108/227] vs. 72.98% [126/174], p = .04) but similar trend for CVS (36.86% [80/227] vs. 68.81% [114/174], p = .05) and similar rates of HBeAg seroconversion (6.59% [7/103] vs. 7.40% [7/110], p = .89). However, at week 48, there were no statistically significant differences between CHB-FL and non-FL CHB patients in any of the outcomes, including BR (60.03% [213/471] vs. 69.37% [314/717], p = .67), CVS (65.63% [459/746] vs. 73.81% [743/1132], p = .27) and HBeAg seroconversion (10.01% [30/275] vs. 14.06% [65/453], p = .58) with similar findings for week 96. BR rate was lower in CHB-FL patients after 12 weeks of antiviral treatment. However, after a longer follow-up of either 48 or 96 weeks, no statistically significant differences were observed in BR, CVS or HBeAg seroconversion rates between CHB patients with and without FL.

CXCL10 and its receptor in patients with chronic hepatitis B and their ability to predict HBeAg seroconversion during antiviral treatment with TDF.

The serum chemokine C-X-C motif ligand-10 (CXCL10) and its unique receptor (CXCR3) may predict the prognosis of patients with chronic hepatitis B (CHB) treated with tenofovir disoproxil fumarate (TDF). Nevertheless, there are few reports on the profile of CXCL10 and CXCR3 and their clinical application in HBeAg (+) CHB patients during TDF antiviral therapy. CXCL10 and CXCR3 were determined in 118 CHB patients naively treated with TDF for at least 96 weeks at baseline and at treatment weeks 12 and 24. In addition, gene set enrichment analysis was used to examine the associated dataset from Gene Expression Omnibus and explore the gene sets associated with HBeAg seroconversion (SC). The change of CXCL10 (ΔCXCL10, baseline to 48-week TDF treatment) and CXCR3 (ΔCXCR3) is closely related to the possibility of HBeAg SC of CHB patients under TDF treatment. Immunohistochemical analysis of CXCL10/CXCR3 protein in liver tissue shows that there is a significant difference between paired liver biopsy samples taken before and after 96 weeks of successful TDF treatment of CHB patients (11 pairs) but no significance for unsuccessful TDF treatment (14 pairs). Multivariate Cox analysis suggests that the ΔCXCL10 is an independent predictive indicator of HBeAg SC, and the area under the receiver operating characteristic curve of the ΔCXCL10 in CHB patients is 0.8867 (p < 0.0001). Our results suggest that a lower descending CXCL10 level is associated with an increased probability of HBeAg SC of CHB patients during TDF therapy. Moreover, liver tissue CXCL10 might be involved in the immunological process of HBeAg SC.

Kinetics and Value of Hepatitis B Core-Related Antigen in Patients with Chronic Hepatitis B Virus Infection during Antiviral Treatment.

BACKGROUND: The hepatitis B core-related antigen (HBcrAg) correlates with HBV DNA in patients with chronic HBV infection without antiviral treatment. Its utility in monitoring patients during and after the cessation of nucleos(t)ide analog (NA) treatment is unknown. METHODS: The levels of HBcrAg were longitudinally determined in two cohorts of chronic HBV-infected patients with (A) newly started NA treatment or (B) after NA cessation during a median follow up (FU) of 60 months or 48 weeks, respectively. The correlation of HBcrAg and HBV DNA and the predictive value for HBeAg seroconversion and HBsAg loss were evaluated. RESULTS: Fifty-six patients with newly-started NA treatment and 22 patients with NA cessation were identified. HBcrAg and HBV DNA strongly correlated before NA treatment (r = 0.77, p < 0.0001) and at virological relapse (0.66, p = 0.0063). At the individual level, the discrepant kinetics of HBcrAg and HBV DNA became evident. During NA treatment, 33% (6/18) and 9% (5/56) of patients showed HBeAg seroconversion or HBsAg loss/HBsAg < 100 IU/mL, respectively. Low levels of HBcrAg were associated with these endpoints. CONCLUSION: HBcrAg levels before antiviral treatment help to identify patients with chances of HBsAg loss or HBeAg seroconversion. However, its utility in replacing quantitative HBV DNA to evaluate treatment efficacy or virological relapse off-treatment is limited.

Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B.

BACKGROUND AND AIMS: Functional cure is difficult to achieve using current antiviral therapies; moreover, limited data are available regarding treatment outcomes in children. This retrospective study aimed to assess the frequency of functional cure among children undergoing antiviral treatment for active chronic hepatitis B (CHB). METHODS: A total of 372 children aged 1-16 years, with active CHB were enrolled and underwent either nucleos(t)ide analog monotherapy or combination therapy with interferon-α (IFN-α) for 24-36 months. All children attended follow-up visits every 3 months. Functional cure was defined as evidence of hepatitis B virus (HBV) DNA loss, circulating hepatitis B e antigen (HBeAg) loss/seroconversion, and hepatitis B surface antigen (HBsAg) loss. RESULTS: After 36 months of antiviral treatment and/or follow-up visits, children with CHB aged 1- < 7 years exhibited higher rates of HBV DNA clearance, HBeAg seroconversion, and HBsAg loss than CHB children ≥ 7-16 years of age (93.75% versus [vs.] 86.21% [p < 0.0001]; 79.30% vs. 51.72% [p < 0.0001]; and 50.78% vs. 12.93% [p < 0.0001], respectively). Longitudinal investigation revealed more rapid dynamic reduction in HBV DNA, HBeAg, and HBsAg levels in children aged 1-7 years than in those aged ≥ 7-16 years with CHB. According to further age-stratified analysis, HBsAg loss rates were successively decreased in children with CHB who were 1- < 3, 3- < 7, 7- < 12, and 12-16 years of age (62.61% vs. 41.13% vs. 25.45% vs. 1.64%, respectively; p < 0.0001) at 36 months. In addition, baseline HBsAg level < 1,500 IU/mL was found to favor disease cure among these pediatric patients. No serious adverse events were observed throughout the study period. CONCLUSION: Results of the present study demonstrated that children aged 1- < 7 years, with active CHB can achieve a high functional cure rate by undergoing antiviral therapy compared to those aged ≥ 7 years, who undergo antiviral therapy. These data support the use of antiviral treatment at an early age in children with CHB. However, future prospectively randomized controlled trials are necessary to validate the findings of this study.

The 90-Day Survival Threshold: A Pivotal Determinant of Long-Term Prognosis in HBV-ACLF Patients - Insights from a Prospective Longitudinal Cohort Study.

This work aims to explore the long-term prognosis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). In this prospective study, eligible inpatients with HBV-ACLF are enrolled and followed up from December 2012 to February 2023, for clinical events, laboratory tests at least every 6 months. Overall, the survival rates at 28 days, 90 days, 1 year, 5 years, and 8 years are 64.7%, 48.8%, 46.1%, 43.8%, and 42.2%, respectively. Among the 8-year mortality and liver transplant cases, ACLF survivors (who survived over 90 days) accounted for 7.8% (9/115). Among 101 patients who survived for more than 90 days, 97.9% of patients achieve virologic response at 1 year. For HBeAg-positive patients, the HBeAg seroconversion are 25.5%, 63.6%, and 76.9% at 1, 5, and 8 years, respectively. Alanine aminotransferase, aspartate aminotransferase, total bilirubin, INR, white blood cell count, and albumin levels gradually improve within the first year. Fibrosis biomarkers APRI, FIB-4 and Chitinase-3-like protein 1 (CHI3L1) levels decreases within the first 5 years. The Cox proportional hazards regression reveal that high total bilirubin (HR = 1.008, p = 0.021) is the independent risk factor for 8-year survival of ALCF survivors. The 90-day period following of HBV-ACLF represented a critical juncture for long-term prognosis, revealing favorable outcomes beyond this timeframe.

HBV pregenome RNA as a predictor of spontanous HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients.

BACKGROUND: Previous studies have indicated that HBV pregenome RNA (HBV pgRNA) could predict HBeAg seroconversion among the chronic hapatitis B (CHB) patients treated with pegylated interferon (Peg-IFN) or nucleos(t)ide analogues (NAs). However, the data about the prediction of HBV pgRNA for spontaneous HBeAg seroconversion is limited. METHODS: One hundred thirteen CHB patients with HBeAg-positive in the immune active phase were followed up for 76 weeks without antiviral treatment. Based on the laboratory test results of liver function, HBeAg, anti-HBe, and HBV DNA at week 76, patients were assigned to two groups: spontaneous HBeAg seroconversion (group A, n = 18) and non-spontaneous HBeAg seroconversion group. Among the latter group, 36 patients were selected as controls (group B, n = 36). RESULTS: At week 12, between group A and group B, there was a significant difference in the level of HBV pgRNA (group A 6.35 ± 1.24 log10 copies/ml and group B 7.52 ± 0.79 log10 copies/ml, P = 0.001), and the difference enlarged at week 28. The receiver operating characteristic curves (AUROCs) of the HBV pgRNA level and the ∆HBV pgRNA at week 28 were 0.912 (P = 0.001, 95% CI: 0.830-0.994), and 0.934 (P = 0.001, 95% CI: 0.872-0.996), respectively. The optimal cutoffs of HBV pgRNA and the reduction from baseline (∆HBV pgRNA) at week 28 for spontaneous HBeAg seroconversion prediction were 5.63 log10 copies/ml and 1.85 log10 copies/ml, respectively. The positive predictive value and negative predictive value of HBV pgRNA and ∆HBV pgRNA at week 28 were 86.7% and 87.2%, 87.5% and 89.5%, respectively. And the combination of the HBV pgRNA level and the HBV pgRNA decreased could provide better prediction. CONCLUSIONS: HBV pgRNA is a sound predictor for spontaneous HBeAg seroconversion among the CHB patients in immune active phase. Dynamic monitoring of HBV pgRNA is helpful for clinical treatment decision.

Impact of core protein naturally selected mutants associated with HBeAg-negative status in HBV biosynthesis.

Hepatitis B e antigen (HBeAg) loss represents a late stage of chronic hepatitis B virus (HBV) infection associated with a drastic decrease in HBV-DNA, a lower risk of disease progression, and the occurrence of several mutations in the preCore/core region. However, the underlying mechanisms supporting the downregulation of viral replication have yet to be elucidated. In the present study, the analysis of the frequency of subgenotype D1 core protein (HBc) mutations associated with HBeAg status revealed a higher mutation rate in HBeAg-negative sequences compared to HBeAg-positive ones. Particularly, 22 amino acids exhibited a higher frequency of mutation in HBeAg-negative sequences, while the remaining residues showed a high degree of conservation. Subsequently, the assessment of HBc mutants derived from HBeAg-negative patients in viral structure and replicative capacity revealed that HBc mutations have the ability to modulate the subcellular localization of the protein (either when the protein was expressed alone or in the context of viral replication), capsid assembly, and, depending on specific mutation patterns, alter covalently closed circular DNA (cccDNA) recycling and up- or downregulate viral replication. In conclusion, HBc mutations associated with HBeAg-negative status impact on various stages of the HBV life cycle modulating viral replication during the HBeAg-negative stage of infection.

A critique and systematic review of the clinical utility of hepatitis B core-related antigen.

BACKGROUND & AIMS: Hepatitis B core-related antigen (HBcrAg) is a new biomarker for chronic hepatitis B (CHB) whose performance has not been critically or systematically appraised. Herein, we performed a systematic review to determine its clinical utility. METHODS: We evaluated the biological pathway of HBcrAg and performed a systematic review of PubMed for clinical trials, cohort studies, and case-control studies that evaluated the clinical utility of HBcrAg. The effectiveness of HBcrAg in predicting HBV-specific clinical events (e.g. HBeAg seroconversion, phases of CHB, HBsAg loss, treatment response, and relapse after stopping therapy) was examined using receiver-operating characteristic curves. The correlation coefficients of HBcrAg with HBV DNA, quantitative HBsAg (qHBsAg), HBV RNA, and cccDNA were summarised from published studies. Median values were used as estimates. RESULTS: HBcrAg consists of three precore/core protein products: HBcAg, HBeAg, and a 22 kDa precore protein. HBcrAg assays have been associated with false-positive rates of 9.3% and false-negative rates of between 12-35% for CHB. The new iTACT-HBcrAg is more sensitive but does not reduce the false-positive rate. A PubMed search found 248 papers on HBcrAg, of which 59 were suitable for analysis. The clinical performance of HBcrAg was evaluated using AUROC analyses, with median AUROCs of 0.860 for HBeAg seroconversion, 0.867 for predicting HBeAg(-) hepatitis, 0.645 for HBsAg loss, 0.757 for treatment response, and 0.688 for relapse after stopping therapy. The median correlation coefficient (r) was 0.630 with HBV DNA, 0.414 with qHBsAg, 0.619 with HBV RNA and 0.550 with cccDNA. Correlation decreased during antiviral therapy, but combined biomarkers improved performance. CONCLUSIONS: HBcrAg has a mixed performance and has a poor correlation with HBsAg loss and antiviral therapy, hence HBcrAg results should be interpreted with caution. IMPACT AND IMPLICATIONS: Hepatitis B core-related antigen (HBcrAg) has been used to assess management of patients with chronic hepatitis B (CHB) without a systematic and critical Sreview of its performance. Our finding that HBcrAg had a false-positive rate of 9% and a false-negative rate of 12-35% raises concerns, although larger studies are needed for validation. A systematic review showed that the performance of HBcrAg was variable depending on the CHB endpoint; it was excellent at predicting HBeAg seroconversion and HBeAg-negative chronic hepatitis (vs. chronic infection), which should be its main use, but it was poor for relapse after stopping antiviral therapy and for HBsAg loss. HBcrAg results should be interpreted with considerable caution, particularly by physicians, researchers, guideline committees and agencies that approve diagnostic tests.

Predicting hepatitis B e Antigen seroconversion after pregnancy-The SydPregScore.

BACKGROUND AND AIMS: Achieving Hepatitis B e antigen seroconversion (HBeAg SC) at an earlier age confers a better prognosis. We examined baseline and post-partum factors associated with HBeAg SC after pregnancy. We developed a tool, the SydPregScore, to estimate the likelihood of HBeAg SC in the years after pregnancy. METHODS: A retrospective analysis of an HBeAg-positive pregnant cohort was conducted. Variables including baseline age, parity, alanine aminotransferase level, HBV viral load, quantitative HBsAg, use of antiviral therapy and post-partum flare were collected. Univariate and multivariate Cox regression analyses to determine predictors of HBeAg SC and develop a predictor score were performed. RESULTS: We analysed HBeAg SC rates in 220 pregnancies to 149 HBeAg-positive women from 2006 to 2019. At baseline, their median age was 33 (IQR 29-37), ALT 23 U/L (IQR 17-33) and viral load 8 log10 IU/mL (IQR 6.3-8.2 log10 IU/mL). The majority (133/198, 67.2%) received short-course antiviral therapy to prevent mother-to-child transmission, and 109/192 (56.8%) had a post-partum flare. HBeAg SC occurred in 74/220 (33.6%) after pregnancy (median follow-up 814 days, IQR 405-1531). Multivariate analysis identified baseline viral load <8 log10 IU/mL (HR 2.426 [1.224-4.809], p = .011), baseline ALT ≥2 ULN (HR 2.726 [1.299-5.721], p = .008) and age <35 (HR 2.859 [1.255-6.513], p = .012) to be positive predictors of HBeAg SC. The 'SydPreg Score' estimated the probability of HBeAg SC at 2000 days as 10%, 30%, 70% and 80% for 0, 1, 2, and 3 predictors respectively. CONCLUSION: The SydPreg Score allows the prediction of HBeAg SC in the years after pregnancy. Even in those without elevated ALT, age <35 and viral load <8 log10 IU/mL can identify women with a good chance of subsequent HBeAg SC. Those without a chance may benefit from viral suppression.

[Study of the predictive role of serum HBV RNA on HBeAg serological conversion in children with chronic hepatitis B].

Objective: To investigate the role of serum hepatitis B virus RNA (HBV RNA) in predicting HBeAg serological conversion in children with chronic hepatitis B. Methods: 175 children aged 1~17 years with chronic hepatitis B who received interferon α (IFNα) for 48 weeks were selected. Patients were divided into HBeAg seroconversion and non-conversion based on whether HBeAg seroconversion occurred at 48 weeks of treatment.T-test and Mann-Whitney U test were used to compare between groups; chisquare test or Fisher exact probability method was used to compare the frequency between groups of classified variables; and Pearson correlation was used to analyze the correlation between indicators. Univariate and multivariate logistic regression analyses were used to identify influencing factors associated with HBeAg serological conversion. The predictive effect of HBV RNA, HBV DNA, and HBsAg on HBeAg serological conversion was compared and analyzed by the receiver operating characteristic curve (ROC). Results: The seroconversion rate of HBeAg at 48 weeks was 36.0% (63/175). The reduction in HBVRNA levels from baseline to the 12th, 24th, 36th, and 48th weeks of antiviral therapy was significantly greater in the HBeAg serological conversion group than that in the non-conversion group, and the difference was statistically significant between the two groups (P < 0.05). Univariate and multivariate regression analyses showed that age and a decline in HBV RNA levels at week 12 were independent predictors of HBeAg serological conversion. The area under the ROC curve (AUROC) of HBV RNA decline at week 12 was 0.677(95% CI∶0.549-0.806, P = 0.012), which was significantly better than the same period of AUROC of HBV DNA (0.657, 95% CI∶0.527-0.788, P = 0.025) and HBsAg (0.660, 95% CI∶0.526-0.795, P = 0.023) decline. HBV RNA levels decreased (>1.385 log10 copies/ml) at week 12, with a positive predictive value of 53.2%, a negative predictive value of 72.2%, a sensitivity of 77.4%, and a specificity of 57.9% for HBeAg seroconversion. Conclusion: HBV RNA level lowering during the 12th week of antiviral therapy can serve as an early predictor marker for HBeAg serological conversion in children with chronic hepatitis B.

Using machine learning models to predict HBeAg seroconversion in CHB patients receiving pegylated interferon-α monotherapy.

BACKGROUND AND OBJECTIVE: Though there are many advantages of pegylated interferon-α (PegIFN-α) treatment to chronic hepatitis B (CHB) patients, the response rate of PegIFN-α is only 30 ~ 40%. Therefore, it is important to explore predictors at baseline and establish models to improve the response rate of PegIFN-α. METHODS: We randomly divided 260 HBeAg-positive CHB patients who were not previously treated and received PegIFN-α monotherapy (180 µg/week) into a training dataset (70%) and testing dataset (30%). The intersect features were extracted from 50 routine laboratory variables using the recursive feature elimination method algorithm, Boruta algorithm, and Least Absolute Shrinkage and Selection Operator Regression algorithm in the training dataset. After that, based on the intersect features, eight machine learning models including Logistic Regression, k-Nearest Neighbors, Support Vector Machine, Decision Tree, Random Forest, Gradient Boosting, Extreme Gradient Boosting (XGBoost), and Naïve Bayes were applied to evaluate HBeAg seroconversion in HBeAg-positive CHB patients receiving PegIFN-α monotherapy in the training dataset and testing dataset. RESULTS: XGBoost model showed the best performance, which had largest AUROC (0.900, 95% CI: 0.85-0.95 and 0.910, 95% CI: 0.84-0.98, in training dataset and testing dataset, respectively), and the best calibration curve performance to predict HBeAg seroconversion. The importance of XGBoost model indicated that treatment time contributed greatest to HBeAg seroconversion, followed by HBV DNA(log), HBeAg, HBeAb, HBcAb, ALT, triglyceride, and ALP. CONCLUSIONS: XGBoost model based on common laboratory variables had good performance in predicting HBeAg seroconversion in HBeAg-positive CHB patients receiving PegIFN-α monotherapy.

The decline of HBV RNA associated with HBeAg seroconversion and double-negative HBV DNA and RNA in chronic hepatitis B patients who received entecavir therapy: a 10-year retrospective cohort study.

Background: Whether the decline of hepatitis B virus (HBV) RNA was associated with antiviral efficacy in chronic hepatitis B (CHB) patients receiving long-term nucleos(t)ide analogues (NAs) therapy remains unclear. We observed the levels of serum HBV RNA in CHB patients treated with entecavir (ETV) for 10 years and explored the clinical significance of HBV RNA during long-term antiviral treatment. Methods: A total of 33 hepatitis B surface antigen (HBsAg)-positive CHB patients treated with ETV for up to 10 years were recruited for this study. Liver function, HBsAg, hepatitis B envelope antigen (HBeAg), HBV DNA, and HBV RNA were measured at the baseline and each follow-up points. Antiviral efficacy was defined as negative HBV DNA (<20 IU/mL) and HBV RNA (<300 Copies/mL). Results: (I) Serum HBV DNA and HBV RNA declined with the duration of antiviral treatment over 10 years (P<0.001). (II) There were positive correlations between serum HBV DNA and HBV RNA at each follow-up point (r=0.62 and P<0.001 at baseline, r=0.77 and P<0.001 at week 24, r=0.71 and P<0.001 at week 48, r=0.81 and P<0.001 at week 96, r=0.60 and P<0.01 at year 5 and r=0.77 and P<0.001 at year 10). (III) HBeAg and HBsAg levels at baseline and 10th year after ETV treatment have significant difference (P<0.05 and P<0.01). (IV) The decline of HBV RNA after ETV treatment was associated with HBeAg seroconversion, the area under the ROC curves (AUROCs) of the declines of HBV RNA were 0.25 at the baseline, 0.62 at week 24, 0.78 at week 48 and 0.86 at week 96, respectively. (V) The decline of HBV RNA after ETV treatment was associated with antiviral efficacy, the AUROCs of the declines of HBV RNA were 0.33 at the baseline, 0.74 at week 24, 0.83 at week 48 and 0.86 at week 96, respectively. Conclusions: Serum HBV DNA and HBV RNA declined with the duration of antiviral treatment over 10 years. The decline of HBV RNA was associated with HBeAg seroconversion and antiviral efficacy in CHB patients receiving long-term ETV therapy, and the earliest prediction point was week 24.

Genetic variants of NTCP gene and hepatitis B vaccine failure in Taiwanese children of hepatitis B e antigen positive mothers.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) vaccine failure remains a hurdle to the global elimination of HBV infections in the vaccination era. We aimed to elucidate the relationships between HBV entry receptor sodium taurocholate co-transporting polypeptide (NTCP) and vaccine failure in children born to highly infectious mothers. METHODS: The genetic variants rs7154439, rs4646285, rs4646287, and rs2296651 were genotyped in 170 children with chronic HBV infections and 138 control children of mothers positive for hepatitis B e antigen (HBeAg). All children received hepatitis B immunoglobulin and complete HBV vaccination. Total RNAs from 82 adult non-tumor liver tissues were quantified for NTCP, type I interferons and interferon-induced transmembrane protein 3 (IFITM3) levels. RESULTS: A higher rate of the GA/AA genotype (28.3% vs. 15.3%, p = 0.006) of the genetic variant rs4646287 in intron 1 of the NTCP gene was detected in control children compared to the carrier children. The rs4646287 G > A genotype was associated with younger ages at which spontaneous HBeAg seroconversion occurred (10.8 ± 8.4 vs. 14.6 ± 8.7 years, p = 0.003) in chronic HBV-infected children. Unique correlation patterns of NTCP and innate immunity-related genes (type I interferons and IFITM3) were found in HBV-infected liver tissues with the rs4646287 G > A genotype. CONCLUSION: The rs4646287 G > A genotype of the NTCP gene may be associated with lower risk for HBV vaccine failure in children born to highly infectious mothers. The protective effect of rs4646287 G > A was also present in carrier children, evidenced by earlier spontaneous HBeAg seroconversion.

STAT4 genetic polymorphism significantly affected HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients receiving Peginterferon-α therapy: A prospective cohort study in China.

A variant in signal transducer and activator of transcription 4 (STAT4) was reported to correlate with the response of interferon-α (IFN-α) in a retrospective study in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B virus (CHB) patients. Here, we conducted a prospective study to analyze the effect of STAT4 genetic polymorphism on the response of pegylated interferon-α-2a (PegIFN-α-2a) in HBeAg-positive patients. A prospective, multicenter, open-label, parallel cohort study was performed. One hundred and fifty treatment-naïve and 156 nucleos(t)ide analog (NA)-experienced HBeAg-positive CHB patients were enrolled, respectively. All patients received PegIFN-α-2a treatment for 48 weeks and 24-week follow-up post PegIFN-α-2a treatment. Before treatment, STAT4 genetic polymorphism was determined by PCR and DNA sequencing. Serological markers, serum HBV DNA levels, and adverse events were collected at each visit. We observed a larger reduction of HBV DNA load and a significantly higher HBeAg seroconversion rate in the GT/TT group than in the GG group at week 72 (p = 0.002 and p = 0.023) in treatment-naïve patients. In NA-experienced patients, the HBeAg seroconversion rate in the GT/TT group was higher than that in the GG group at week 72 (p = 0.005). STAT4 rs7574865 gene polymorphism was the strongest independent predictor of HBeAg seroconversion in both paralleled cohorts. Also, patients in the GT/TT group had a higher hepatitis B surface antigen loss rate than in the GG group in the study. There was no significant difference in adverse events between GG and GT/TT groups. This prospective cohort study confirmed that STAT4 rs7574865 gene polymorphism is associated with HBeAg seroconversion and HBsAg loss irrespective of naïve and NA-experienced HBeAg-positive CHB patients treated with PegIFN-α-2a.

Significance of T-Cell Subsets for Clinical Response to Peginterferon Alfa-2a Therapy in HBeAg-Positive Chronic Hepatitis B Patients.

Introduction: The adaptive immune response may reflect the immunomodulatory efficacy during peginterferon alfa-2a (PEG-IFN α-2a) treatment in chronic hepatitis B (CHB) patients. We evaluated the predictive efficiency of T-cell subsets on patient's response to PEG-IFN α-2a treatment. Methods: The proportions of CD8+PD-1+, CD8+Tim-3+ and CD4+CD25high T-cells were measured at baseline and week 52 in CHB patients who underwent PEG-IFN α-2a treatment. The proportions of T-cell subsets were compared among different responders and non-responders (determined by biochemical, serological, and virological responses). Results: The baseline proportions of the three T-cell subsets were significantly higher in CHB patients (65 cases) than in healthy controls (28 cases), while the proportions declined significantly after 52 weeks of PEG-IFN treatment. Responders (ALT < 40 IU/L, 89.2% [58/65]; HBV DNA < 2.7 log10 IU/ml, 66.2% [43/65]; and HBeAg seroconversion [SR], 53.9% [35/65]) experienced more pronounced declines in the proportion of T-cell subsets compared to non-responders. In particular, the baseline proportions of CD4+CD25high T-cells displayed significant difference between SR and non-SR groups. The stepwise logistic regression analysis identified that CD4+CD25high T-cells combined with baseline HBV DNA and ALT can predict SR and CR (ALT < 40 IU/L, HBV DNA < 2.7 log10 IU/mL and HBeAg seroconversion) after 52 weeks of PEG-IFN treatment with high accuracy. Conclusion: PEG-IFN therapy induces significant declines in the proportion of some key T-cell subsets in HBeAg-positive patients. The model constructed with CD4+CD25high T-cells combined with ATL and HBV DNA may help to predict the efficacy of PEG-IFN α-2a therapy.

Serum HBV RNA predicts HBeAg clearance and seroconversion in patients with chronic hepatitis B treated with nucleos(t)ide analogues.

This study evaluated the predictive value of serum HBV DNA, HBV RNA, HBcrAg, HBsAg, intrahepatic HBV DNA and cccDNA for HBeAg clearance and seroconversion during long-term treatment with nucleos(t)ide analogues (NAs) in patients with chronic hepatitis B (CHB). A single centre, prospective cohort of CHB patients was used for this study. Serum HBV RNA levels were retrospectively measured at baseline, 6, 12, 24, 36, 48, 60, 72 and 84 months post-NAs treatment. Serum HBsAg and HBcrAg levels were quantified at baseline, month 6, 60 and 72. Histological samples from liver biopsy at baseline and month 60 were analysed for intrahepatic HBV DNA and cccDNA. Eighty-three HBeAg-positive patients were enrolled with a median follow-up time of 108 months (range 18-138 months). Of them, 53 (63.86%) patients achieved HBeAg clearance, and 37 (44.58%) achieved HBeAg seroconversion. Cox multivariate analysis showed that only baseline HBV RNA was independently associated with HBeAg clearance and seroconversion (<5.45 log10 copies/mL, HR = 5.06, 95% CI: 1.87-13.71, p = .001; HR = 3.38, 95% CI: 1.28-8.91, p = .01). The independent association with HBeAg clearance and seroconversion remained for HBV RNA levels at month 6 (<4.72 log10 copies/mL, HR = 4.16, 95% CI: 1.61-10.72, p = .003; HR = 6.52, 95% CI: 1.85-22.94, p = .003) and month 12 (<4.08 log10 copies/mL, HR = 3.68, 95% CI: 1.96-6.90, p < .001; HR = 2.79, 95% CI: 1.31-5.94, p = .008). The AUCs of baseline HBV RNA for predicting the HBeAg clearance (0.83, 95% CI: 0.70-0.96, 0.83, 95% CI: 0.70-0.96 and 0.82, 95% CI: 0.69-0.95 respectively) and seroconversion (0.89, 95% CI: 0.77-1.00; 0.81, 95% CI: 0.66-0.95 and 0.84, 95% CI: 0.71-0.98 respectively) at month 36, 60 and 84 were higher than those of HBV DNA, HBsAg and HBcrAg. In conclusion, lower serum HBV RNA at baseline, month 6 and 12 post-NAs treatment could predict HBeAg clearance and seroconversion during long-term NAs treatment.

Dynamic metabolic profiles for HBeAg seroconversion in chronic hepatitis B (CHB) patients by gas chromatography-mass spectrometry (GC-MS).

Chronic hepatitis B (CHB) remains a major public health problem globally. HBeAg seroconversion is a vital hallmark for the improvement of CHB. The plasma metabolic profile has not been clear in CHB patients and searching metabolic candidates to represent HBeAg seroconversion is also difficult currently. In this study, CHB patients were recruited, followed and divided into the HBeAg-positive (HBeAg-pos.) group (n = 29) and the HBeAg-negative (HBeAg-neg.) group (n = 29) based on HBeAg seroconversion or not. The plasma metabolic profiles were measured by gas chromatography-mass spectrometry (GC-MS) at 0 week (0w), 24 weeks (24w) and 48 weeks (48w) after administration. The acquired data was analyzed using orthogonal partial least squares discriminate analysis (OPLS-DA) and the differential metabolites were further assessed by self and group comparison. No differences of age, gender and serological characteristics were observed between two groups at 0w and 48w separately. The OPLS-DA score plots depending on administration time displayed robust metabolic differences no matter HBeAg turned to be negative or not. According to VIP> 1.0, a total of 15 differential metabolites were same in the two groups, 7 differential metabolites (glycolic acid, D-talose, L-proline, L-(-)-arabitol, ethyl-alpha-D-glucopyranoside, L-leucine and dihydroxybutanoic acid) were derived from one group alone and considered as metabolic candidates. At 0w versus (vs.) 24w, only 3 of 7 candidates (L-proline, L-(-)-arabitol, dihydroxybutanoic acid) showed nonuniform in the two groups, while at 0w vs. 48w, all of them varied inconsistently. Conclusively the dynamic metabolic profiles assayed by GC-MS were different between CHB patients with and without HBeAg seroconversion. The 7 metabolic candidates probably had the ability to reflect the CHB progression for HBeAg seroconversion and 3 of them showed strong relationship with HbeAg seroconversion early.

On-treatment HBV RNA dynamic predicts entecavir-induced HBeAg seroconversion in children with chronic hepatitis B.

BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion is an important intermediate outcome in HBeAg-positive chronic hepatitis B patients. This study aimed to explore whether hepatitis B virus (HBV) RNA serum levels can predict HBeAg seroconversion treated with entecavir. METHODS: Serum samples from HBeAg-positive children previously treated with entecavir were retrospectively analyzed. HBV RNA levels were measured at baseline, weeks 12, 24, 48, 72 of therapy. Ability of individual biomarkers to predict HBeAg seroconversion was evaluated using receiver operating characteristics (ROC) analyzes. RESULTS: Serum HBV RNA was detectable in 51 children with a median of 6.05 (4.04-8.29) log10 IU/mL at baseline. Patients with subsequent HBeAg seroconversion showed a significantly larger decline in median HBV RNA levels during treatment from baseline to week 12 of 1.96 (0.30-3.38) and to week 24 of 2.27 (1.20-3.38) log10 IU/mL, respectively, in comparison to HBeAg-positive patients without HBeAg seroconversion (P < 0.001). Levels of HBV RNA at treatment weeks 12 and 24 showed good ability to predict HBeAg seroconversion (area under ROC scores > 0.85, P < 0.001). CONCLUSION: On-treatment HBV RNA dynamic predicts entecavir-induced HBeAg seroconversion in children with chronic hepatitis B living in China.

Baseline serum hepatitis B core antibody level predicts HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B after antiviral treatment.

Antibody to hepatitis B core antigen (anti-HBc) is one of the most classical serological markers of HBV infection. This study aimed to investigate the association of serum anti-HBc and HBeAg seroconversion in patients with HBeAg-positive chronic hepatitis B (CHB) after antiviral treatment. Two hundred and seventeen HBeAg-positive CHB patients treated with entecavir (ETV) or tenofovir disoproxil fumarate (TDF) for 48 weeks were retrospectively enrolled. Serological response (SR) is defined as HBeAg seroconversion at 48 weeks of antiviral treatment. Serum anti-HBc level was measured using the Abbott ARCHITECT assay. After 48 weeks of antiviral treatment, twenty-two (10.1 %) patients achieved SR. Baseline level of serum anti-HBc in the SR patients (11.8 S/CO) was significantly higher than patients with non-SR (9.6 S/CO, P < 0.001). The median anti-HBc level was significantly declined after 48 weeks of antiviral therapy (9.9 vs. 8.9 S/CO, P < 0.001). Multivariate logistic regression analysis showed baseline of serum anti-HBc was an independent predictor of SR (odds ratio [OR]: 1.462, 95 % confidence interval [CI] 1.170-1.825, P = 0.001). The area under receiver operating characteristic curve (AUROC) of baseline anti-HBc level for predicting SR was 0.781 with the cut-off of 11.1 S/CO, with a sensitivity of 77.27 % and a specificity of 72.82 %. Our findings highlighted that baseline serum anti-HBc level is a promising indictor for predicting HBeAg seroconversion in HBeAg-positive CHB patients after antiviral treatment.