Serum Hepatitis B Surface Antigen Research Articles

Hepatitis B surface antigen (HBsAg) glycan isomer is predictive of HBsAg seroclearance in patients with chronic hepatitis B.

Measurement of O-glycosylated middle hepatitis B surface antigen (HBsAg glycan isomer, HBsAgGi) has been developed to quantify hepatitis B virus (HBV) infectious virions and distinguish them from subviral particles. This study aimed to evaluate the association between serum HBsAg seroclearance and serum HBV virions measured by HBsAgGi in patients with chronic hepatitis B (CHB). Serum HBsAgGi levels were quantified in 232 treatment-naïve patients with CHB genotype C. Cox proportional hazards analysis was used to calculate hazard ratios (HRs) for factors associated with HBsAg seroclearance. Baseline HBsAgGi levels showed significant differences among HBV phenotypes. During a median follow-up period of 7.4years, 22 of the 232 patients achieved HBsAg seroclearance. Multivariate analysis demonstrated that quantitative HBsAg, nucleoside/nucleotide analog therapy during the follow-up period, and HBsAgGi levels were independent predictors of seroclearance. The adjusted HR indicated that the HBsAg seroclearance probability in patients with low HBsAgGi (≤3.5logng/mL) was over five times higher than that in patients with high HBsAgGi. Kaplan-Meier analysis indicated that the 10-year probabilities of HBsAg seroclearance were 21.0% and 3.0% in patients with low and high HBsAgGi levels, respectively (p<0.001), and that patients with high HBsAgGi levels showed low seroclearance probabilities irrespective of the other predictors. Serum HBV infectious virion levels, measured using HBsAgGi, may be a novel predictor of HBsAg seroclearance.

Clinical outcomes of treatment-naïve HBeAg-negative patients with chronic hepatitis B virus infection with low serum HBsAg and undetectable HBV DNA

ABSTRACT Serum hepatitis B surface antigen (HBsAg) level < 100 IU/ml and undetectable hepatitis B virus (HBV) DNA have been recently proposed as an alternate endpoint of “partial cure” in chronic hepatitis B (CHB). We investigated clinical outcomes of hepatitis B e antigen (HBeAg)-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA. Treatment-naïve HBeAg-negative CHB patients with undetectable HBV DNA and normal alanine aminotransferase were retrospectively included from three institutions. Patients were classified into the low HBsAg group (<100 IU/ml) and the high HBsAg group (≥100 IU/ml). Liver fibrosis was evaluated by noninvasive tests (NITs). A total of 1218 patients were included and the median age was 41.5 years. Patients with low HBsAg were older (45.0 vs. 40.0 years, P < 0.001) than those in the high HBsAg group, while the NIT parameters were comparable between groups. During a median follow-up of 25.7 months, patients with low HBsAg achieved a higher HBsAg clearance rate (13.0% vs. 0%, P < 0.001) and a lower rate of significant fibrosis development (2.2% vs. 7.0%, P = 0.049) compared to patients with high HBsAg. No patient developed HCC in either group. HBsAg level was negatively associated with HBsAg clearance (HR 0.213, P < 0.001) and patients with HBsAg < 100 IU/ml had a low risk of significant fibrosis development (HR 0.010, P = 0.002). The optimal cutoff value of HBsAg for predicting HBsAg clearance was 1.1 Log10 IU/ml. Treatment-naïve HBeAg-negative CHB patients with HBsAg <100 IU/ml and undetectable HBV DNA had favourable outcomes with a high rate of HBsAg clearance and a low risk of fibrosis progression.

Toward a Functional Cure for Hepatitis B.

Current treatment of chronic hepatitis B virus (HBV) infection, pegylated interferon-α (pegIFN-α) and nucleos(t)ide analogue (NA), can suppress HBV replication, reverse liver inflammation and fibrosis, and decrease risks of cirrhosis and hepatocellular carcinoma, but hepatitis B surface antigen (HBsAg) loss is rare. Functional HBV cure is defined as undetectable HBsAg and unquantifiable serum HBV DNA for at least 24 weeks after a finite course of therapy. This requires suppression of HBV replication and viral protein production as well as restoration of immune response to HBV. Direct-acting antivirals targeting virus entry, capsid assembly, viral protein production and secretion are in clinical trials. In parallel, immune modulatory therapies to stimulate HBV-specific immune response and to remove immune blockade are being tested. Clinical trials of direct-acting antivirals alone or immune modulatory therapies alone have not been successful in achieving HBV cure. Recent combinations of direct-acting antivirals and immune modulatory therapies have shown promising results particularly with combinations that included pegIFN-α. These results need to be confirmed in larger studies with longer follow-up, and further work is needed to develop simpler regimens with fewer drugs that can be administered orally and safely. While there is a strong desire to develop finite therapies that can achieve HBV cure, safety is paramount and new therapies must provide incremental value compared to standard of care, which is predominantly long-term NA therapy.

Predictive Value of Baseline Serum Marker Levels for the Effect of Interferon Therapy in Patients With Chronic Hepatitis B

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. 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. 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). 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.

The occurrence of immune-related adverse events is an independent risk factor both for serum HBsAg increase and HBV reactivation in HBsAg-positive cancer patients receiving PD-1 inhibitor combinational therapy.

Previous studies have suggested the potential of PD-1/PD-L1 inhibitors in the treatment of chronic HBV infection. However, since phase III clinical trials have not yet been announced, additional clinical insights may be obtained by observing changes in serum hepatitis B surface antigen (HBsAg) and HBV-DNA levels in cancer patients undergoing PD-1 inhibitor therapy. To explore the effects of PD-1 inhibitor combinational therapy on serum HBsAg and HBV-DNA levels, investigate the incidence of HBsAg loss, HBV reactivation (HBVr), and immune-related adverse events (irAEs), and identify the risk factors associated with significant HBsAg fluctuations and HBVr. A retrospective study including 1195 HBsAg-positive cancer patients who received PD-1 inhibitors between July 2019 and June 2023 was conducted, and 180 patients were enrolled in this study. Serum HBsAg levels before and after PD-1 inhibitor administration were compared across different subgroups. The Pearson χ2 or Fisher exact test was performed to investigate the relationships between categorical variables. Univariable and multivariable analysis were performed to identify the risk factors associated with significant HBsAg fluctuations and HBVr. With the concurrent use of antiviral agents, serum HBsAg levels decreased (Z=-3.966, P < 0.0001) in 129 patients and increased (t=-2.047, P=0.043) in 51 patients. Additionally, 7 patients (3.89%) achieved serum HBsAg loss. Virus replication was suppressed in most of the enrolled patients. When divided patients into different subgroups, significant HBsAg decreases after PD-1 inhibitor administration were discovered in lower baseline HBsAg group (Z=-2.277, P=0.023), HBeAg-seronegative group (Z=-2.200, P=0.028), non-irAEs occurrence group (Z=-2.007, P=0.045) and liver cancer group (Z=-1.987, P=0.047). Of note, 11 patients and 36 patients experienced HBVr (6.11%) and irAEs (20%), respectively, which could lead to discontinuation or delayed use of PD-1 inhibitors. After multivariable analysis, HBeAg-seropositive (OR, 7.236 [95% CI, 1.757-29.793], P=0.01) and the occurrence of irAEs (OR, 4.077 [95% CI, 1.252-13.273], P=0.02) were identified as the independent risk factors for significant HBsAg increase, the occurrence of irAEs (OR, 5.560 [95% CI, 1.252-13.273], P=0.01) was identified as the only independent risk factor for HBVr. PD-1 inhibitors combined with nucleos(t)ide analogues (NAs) may exert therapeutic potential for chronic HBV infection in cancer patients. However, attention also should be paid to the risk of significant elevation in HBsAg levels, HBVr, and irAEs associated with PD-1 inhibitor combinational therapy.

A Dual-domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration.

Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody-based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual-domain-engineered anti-hepatitis B virus (HBV) therapeutic antibody 73-DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV-tolerant mice, administration of a single dose of 73-DY at 2mgkg-1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL-1 and suppress HBsAg to < 100 IU mL-1 for two weeks, demonstrating a dose-lowering advantage of at least tenfold. Furthermore, 10mgkg-1 of 73-DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73-DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long-term immunotherapy with reverse chimeric 73-DY facilitated the restoration of anti-HBV immune responses. This study provides a foundation for the development of next-generation antibody-based CHB therapies.

Serum hepatitis B virus pregenomic RNA profiles in patients with chronic hepatitis B on long-term antiviral therapy

Objective: To explore the clinical changes in levels of the new clinical marker serum hepatitis B virus (HBV) pregenomic RNA (pgRNA) in patients with chronic hepatitis B (CHB) with long-term antiviral therapy. Methods: 100 CHB cases who were initially treated with nucleos(t)ide analogues (NAs) at Peking University First Hospital were included. The levels of alanine aminotransferase (ALT), HBV DNA, hepatitis B e-antigen (HBeAg), and hepatitis B surface antigen (HBsAg) during the follow-up period were measured. The TaqMan-based real-time quantitative PCR method was used to detect serum HBV pgRNA levels. The independent sample t-test and Mann-Whitney U test were used to compare continuous variables between groups, while Pearson's χ (2) test and Fisher's exact test were used to compare categorical variables. Results: HBV pgRNA levels decreased significantly in patients who developed virological responses at 48 weeks (n = 54) during subsequent treatment compared to those who did not (n = 46). The HBV pgRNA level was lower in HBeAg-positive patients than in HBeAg-negative patients (P < 0.05 or P < 0.01). Patients with higher HBV DNA and HBeAg-positivity levels at baseline had a higher HBV pgRNA level following antiviral therapy. There was no statistically significant difference in HBV pgRNA levels in patients with different HBV pgRNA levels at baseline after antiviral therapy. There was no correlation between serum HBV pgRNA and HBsAg at baseline, but there was a correlation after long-term antiviral therapy, while there was a weak correlation between HBV pgRNA and HBsAg at the fifth and ninth years of antiviral therapy (r = 0.262, P = 0.031; r = 0.288, P = 0.008). Conclusion: HBV pgRNA levels were higher with higher HBV activity in CHB patients with long-term antiviral therapy.

Accuracy of Saliva as a Diagnostic Medium for Hepatitis B Virus Infection: A Quantitative ELISA Analysis

Context: Diagnosis of hepatitis B virus infection (HBV) has been traditionally serum-based with its attendant risks and invasive procedure. Massive research interests are being directed to the use of saliva for screening, diagnosis, and monitoring of several infectious diseases, including HBV. Various reports suggest that saliva contains biomarkers that are comparable with that of sera. It can also be obtained with minimal risk to the clinician and patient as well. Aim: To determine the diagnostic accuracy of saliva in quantitative detection of hepatitis B surface antigen (HBsAg) using enzyme-linked immunosorbent assay (ELISA). Settings and Design: This cross-sectional analytical study was performed on HBV seropositive patients at the Gastroenterology clinic of the University of Benin Teaching Hospital, Benin City, Edo State. Materials and Methods: Under standardized conditions, equal amounts of blood and saliva samples of 43 HBsAg seropositive patients were analyzed using ELISA to quantitatively detect the concentration of HBsAg. Statistical Analysis Used: The analysis relied on Spearman’s correlation coefficient, linear regression analysis, and Bland–Altman plots to describe the correlational, predictive, and agreements between measurements of HBsAg in sera and saliva. The statistical significance was set at P &lt; 0.05, while a 95% confidence level was used to construct intervals. Results: All participants had detectable levels of HBsAg in both saliva and serum with mean titers of 1.70 ± 0.35 ng/ml and 2.80 ± 0.77 ng/ml, respectively. Correlational and linear regression showed poor fit and predictive relationships of the HBsAg levels. Bland–Altman analysis showed good agreement and no significant bias in their diagnostic agreements. Conclusion: Saliva can be reliably used in screening and diagnosis of HBV infection. There was agreement in their levels independently and within their averages. It may be premature to rely on saliva for quantitative assay of HBsAg in treatment monitoring.

The performance of hepatitis B surface antigen quantification as a noninvasive biomarker predicting liver injury and serum hepatitis B virus DNA level.

Chronic hepatitis B (CHB) is still a major public health problem worldwide. Recently, evidence indicating that serum hepatitis B surface antigen (HBsAg) quantification can be used for monitorization of hepatitis B virus (HBV) infection has been increased. In this study, we evaluated HBsAg levels during the natural course of CHB and identified correlations between HBsAg, HBV DNA levels and liver histopathology. From 6 August 2016 to 7 June 2017, naive patients, who are ≥18 years old, fulfilled the criteria for the diagnosis of CHB and had a liver biopsy within a year before or after admission, were included. HBsAg levels in serum samples were investigated by electrochemiluminescence immunoassay. Results were correlated with serum HBV DNA levels, histologic activity index (HAI) and fibrosis scores. In this study 66 patients were included. There was a moderate and significant correlation between HBsAg levels and fibrosis scores (r = 0.386, P = 0.001), but no correlation with HAI. Serum HBsAg levels showed a positive, strong and significant (r = 0.740, P < 0.001) correlation with HBV DNA levels. In hepatitis B e antigen-negative patients, serum HBsAg levels were perfectly correlated with HBV DNA levels (r = 0.992, P < 0.001) and moderately correlated with fibrosis scores (r = 0.360, P = 0.006). We found a positive correlation between serum HBsAg levels and the severity of fibrosis scores and serum HBV DNA levels. These findings suggest that serum HBsAg quantification might be a useful noninvasive diagnostic test for the prediction of fibrosis severity and HBV DNA level.

Chimeric antigen receptors of HBV envelope proteins inhibit hepatitis B surface antigen secretion

ObjectivesChronic hepatitis B (CHB) caused by HBV infection greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Hepatitis B surface antigen (HBsAg) plays critical roles in the pathogenesis of...

Unraveling the Complexity of Atypical Serological Profiles in Chronic Hepatitis B: Insights Into Disease Dynamics and Clinical Implications.

Introduction Chronic hepatitis B (CHB) continues to be a significant global public health problem. Conventional serological markers play a pivotal role in diagnosing and prognosticating CHB, but atypical serological profiles deviating from established norms pose challenges. Methods A cohort of 35 CHB patients who did not receive an antiviral treatment with atypical serological markers was followed for five years (2017-2022). Demographics, serological parameters, and changes were documented. Serological parameters and serum viral loads (hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) levels) were assayed at the central laboratory during their routine follow-ups. Three groups of atypical serological markers are defined: hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) positivity; hepatitis B e antigen(HBeAg) and anti-hepatitis B e-antigen (anti-HBe) positivity; and isolated core (anti-hepatitis B core (anti-HBc) immunoglobulin G (IgG)) positivity. Patients with concomitant HBsAg and anti-HBs were also stratified into seroreversion groups. Changes in serological markers and HBV-DNA levels across the study period were documented and evaluated at the end of the study period. Statistical analysis was conducted using the Kruskal-Wallis test and IBM SPSS Statistics software for Windows, Version 23.0 (IBM Corp., Armonk, NY, USA). Results In a cohort of 35 patients with atypical hepatitis B serology, demographic analysis revealed that 51.4% (n=18) were female and 48.6% (n=17) were male, with a mean age of 45.7 years. Educational distribution showed that 45.7% (n=16) completed primary education, 22.8% (n=8) had a high school education, and 31.5% (n=11) held university degrees. Among these patients, 10 displayed the concurrent presence of HBsAg and anti-HBs, with 60% (n=6) being female. Serum HBV-DNA was detectable in all cases. After five years, 60% (n=6) exhibited seroconversion from HBsAg to anti-HBs, particularly notable in females (66.7%). These patients showed lower HBsAg titers and serum HBV-DNA levels (p = 0.048, p = 0.036). A subset of 15 patients demonstrated simultaneous HBeAg and anti-HBe positivity. The HBeAg seropositivity waned over time, with 40% (n=6) and 26.7% (n=4) females and males, respectively, retaining positivity by the fifth year. During this period, serum HBV-DNA levels decreased. The remaining five patients sustained HBeAg and anti-HBe positivity. Among 10 patients solely positive for anti-HBc IgG, three had concurrent HBV-DNA positivity. Strikingly, three patients with negative HBV-DNA developed anti-HBs positivity after five years. Conclusion The complexity of CHB infection demands a comprehensive understanding. Atypical serological profiles suggest distinct disease stages, immune response variations, and viral mutations. This study enhances comprehension of viral replication, immune responses, and disease progression, potentially guiding tailored therapeutic strategies.

First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection

RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0mg/kg (n= 6) or placebo (n= 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0mg/kg (n= 4 in each cohort) or placebo (n= 6). RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. ClinicalTrials.gov NCT03772249. Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians.

Evaluation of RNAi therapeutics VIR-2218 and ALN-HBV for chronic hepatitis B: Results from randomized clinical trials

Current therapy for chronic hepatitis B virus (cHBV) infection involves lifelong treatment. New treatments that enable HBV functional cure would represent a clinically meaningful advance. ALN-HBV and VIR-2218 are investigational RNA interference therapeutics that targetall major HBV transcripts. We report on: i) the safety of single doses of VIR-2218 (modified from ALN-HBV by enhanced stabilization chemistry plus technology to reduce off-target, seed-mediated binding while maintaining on-target antiviral activity) and ALN-HBV in humanized mice; ii) a cross-study comparison of the safety of single doses of VIR-2218 and ALN-HBV in healthy human volunteers (n= 24 and n= 49, respectively); and iii) the antiviral activity of two doses of 20, 50, 100, 200mg of VIR-2218 (total n= 24) vs. placebo (n= 8), given 4 weeks apart, in participants with cHBV infection. In humanized mice, alanine aminotransferase (ALT) levels were markedly lower following administration of VIR-2218 compared with ALN-HBV. In healthy volunteers, post-treatment ALT elevations occurred in 28% of participants receiving ALN-HBV compared with none in those receiving VIR-2218. In participants with cHBV infection, VIR-2218 was associated with dose-dependent reductions in hepatitis B surface antigen (HBsAg). The greatest mean reduction of HBsAg at Week 20 in participants receiving 200mg was 1.65 log IU/ml. The HBsAg reduction was maintained at 0.87 log IU/ml at Week 48. No participants had serum HBsAg loss or hepatitis B surface antibody seroconversion. VIR-2218 demonstrated an encouraging hepatic safety profile in preclinical and clinical studies as well as dose-dependent HBsAg reductions in patients with cHBV infection. These data support future studies with VIR-2218 as part of combination regimens with a goal of HBV functional cure. ClinicalTrials.gov identifiers: NCT02826018 and NCT03672188. A significant unmet need exists for therapies for chronic HBV (cHBV) infection that achieve functional cure. We report clinical and non-clinical data on two investigational small-interfering RNAs that target HBx, ALN-HBV and VIR-2218, demonstrating that incorporation of enhanced stabilization chemistry plus technology in VIR-2218 reduces its propensity to cause ALT elevations relative to its parent compound, ALN-HBV. We also show that VIR-2218 reduces hepatitis B surface antigen levels in a dose-dependent manner in participants with cHBV infection. These studies support the continued development of VIR-2218 as part of therapeutic regimens for cHBV infection, with the goal of a functional cure, and are important for HBV researchers and physicians.

Does hepatic steatosis impact chronic hepatitis B?

Does hepatic steatosis impact chronic hepatitis B?

Functional Cure of Chronic Hepatitis B with Antiviral Treatment in Children having High-level Viremia and Normal or Mildly Elevated Serum Aminotransferase.

There is a lack of data supporting the notion that antiviral treatments can benefit children with chronic hepatitis B (CHB) having high viremia and normal or mildly elevated serum alanine aminotransferase (ALT) levels. We aimed to analyze the efficacy of antiviral treatments in children with CHB and explore the factors associated with functional cure. Forty-eight children with CHB having high viremia and normal or mildly elevated serum ALT levels were screened in this real-world study. Thirty-two children received either interferon-alpha (IFN-α) monotherapy, IFN-α therapy with a nucleoside analog (NA) add-on, or IFN-α and NA combination therapy. The 16 children in the control group did not receive antiviral treatment. All 48 children were available for follow-up assessments for the entire 36-month study period. We identified a functional cure with respect to hepatitis B virus (HBV) DNA loss, loss /seroconversion of circulating hepatitis B e antigen (HBeAg), and loss of hepatitis B surface antigen (HBsAg) with or without seroconversion. Cox regression analysis was employed to evaluate the factors that may have influenced the functional cure. After 36 months, the cumulative functional cure rate was 56.25% (18/32) in the treated group and 0% (0/16) in the control group (p<0.001). In the treated group, the serum HBV DNA levels declined rapidly at the end of a 6-month visit and the cured children achieved a loss rate of 100% (18/18) within 16 months of beginning treatment, compared with 64.29% (9/14) of the uncured children (p<0.001). The rates of HBeAg seroconversion were significantly higher among the cured children than among the uncured children (p<0.001). All 16 children in the control group maintained high levels of serum HBV DNA and were positive for both serum HBeAg and HBsAg during the entire 36 months of the study period. Functional cure was associated with younger ages (1-6 vs. 7-14 years, p=0.013), CD8+ T lymphocyte counts (p=0.013), and B lymphocyte counts (p=0.003). No serious adverse events were observed. Antiviral treatment achieved a functional cure of CHB in a high proportion of children having high-level viremia and normal or mildly elevated ALT levels. Younger age and high peripheral lymphocyte counts were associated with this functional cure.

Rapid Decline Rather Than Absolute Level of HBsAg Predicts Its Seroclearance in Untreated Chronic Hepatitis B Patients From Taiwanese Communities.

Hepatitis B surface antigen (HBsAg) clearance leads to favorable outcomes in patients with chronic hepatitis B. HBsAg levels <200 IU/mL with HBsAg decline >0.5 log 10 IU/mL in 1 year have been reportedly predictive of HBsAg loss. This study aimed to use the REVEAL-hepatitis B virus cohort to validate and simplify this prediction rule and verify whether the simplified algorithm can be used among various clinical subgroups. We analyzed 707 patients with untreated chronic hepatitis B who had 3 or more HBsAg measurements within 5 years before HBsAg seroclearance or last visit, greater than 1 year apart from one another. Rapid HBsAg decline was defined as HBsAg decline >0.5 log 10 IU/mL in 1 year or >1 log 10 IU/mL in 2 years. Sensitivity, specificity, positive predictive values, and negative predictive values were compared to assess the predictability of HBsAg seroclearance. During a median follow-up of 10.7 years, 41 of the 707 patients cleared serum HBsAg. HBsAg levels at all measurements were lower ( P < 0.0001) and HBsAg decline was greater ( P < 0.0001) in patients with seroclearance compared with non-seroclearance patients. The predictive accuracy of predicting 1-year HBsAg loss using only the rapid decline algorithm (sensitivity = 0.4412, specificity = 0.9792, positive predictive value = 0.5172, negative predictive value = 0.972) was the same as the model combining rapid HBsAg decline and HBsAg levels <200 IU/mL. The simplified algorithm including only the rapid decline performed similarly among various levels of HBsAg, hepatitis B virus DNA, and alanine aminotransferase and was independent of inactive carrier state. HBsAg decline >0.5 log 10 IU/mL/yr was a practical predictor of HBsAg seroclearance within 1 year in our community-based untreated cohort.

Values of Serum HBsAg and HBeAg Levels for Virological Response of Patients with HBV-Related Liver Cirrhosis Treated by Entecavir.

The aim is to explore the clinical values of quantitative detection of serum hepatitis B surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg) levels for the virological response [hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) level] of patients with HBV-related liver cirrhosis (HBV-LC) treated by entecavir. A total of 147 patients with HBV-LC treated from January 2016 to January 2019 were assigned to virol-ogical response (VR) group (n = 87) and no virological response (NVR) group (n = 60) according to whether virological response occurred after treatment. The values of serum HBsAg and HBeAg levels for predicting virological response were determined by receiver operating characteristic (ROC) curve, Kaplan-Meier survival analysis, and 36-Item Short Form Survey (SF-36). Serum HBsAg and HBeAg levels before treatment were positively correlated with HBV-DNA level in patients with HBV-LC, and there were significant differences in serum HBsAg and HBeAg levels in the 8th, 12th, 24th, 36th, and 48th weeks of treatment (p < 0.01). In the 48th week of treatment, the area under the ROC curve (AUC) of serum HBsAg log value for predicting virological response was the largest [0.818, 95% confidence interval (CI): 0.709 - 0.965], and the optimal cutoff value, sensitivity, and specificity was 2.53 ± 0.53 IU/mL, 91.34%, and 71.93%, respectively. AUC of serum HBeAg level for predicting virological response was the largest (0.801, 95% CI: 0.673 - 0.979), and the optimal cutoff value, sensitivity, and specificity was 27.38 ± 2.14 PEIU/mL, 88.52%, and 83.42%, respectively. Serum HBsAg and HBeAg levels are correlated with the virological response of patients with HBV-LC treated by entecavir.

Maximize Donor Cornea Use in a Hepatitis B Endemic Area via Serology Matching.

This study aims to investigate the rationality of the allocation guidelines in a hepatitis B endemic area that uses corneas from hepatitis B donors. Under Taiwan's current guidelines, corneas donated from hepatitis B surface antigen (HBsAg)(+) donors can be allocated to HBsAg(+) or hepatitis B surface antibody recipients. From January 1, 2015, to December 31, 2019, corneas donated to National Taiwan University Hospital were divided into HBsAg(+), HBsAg(-)/hepatitis B core antibody (anti-HBc)(+), and HBsAg(-)/anti-HBc(-) groups. Hepatitis B virus (HBV) DNA extracted from corneoscleral rims was quantified by polymerase chain reaction and correlated with donor serum HBsAg, anti-HBc, and HBV DNA. Recipients of HBV DNA(+) grafts were called back for serology and serum HBV DNA tests. The corneoscleral HBV DNA of 170 corneas (113 donors) was quantified, of which 45 corneas were from 28 HBsAg(+) donors, 87 were from 57 HBsAg(-)/anti-HBc(+) donors, and 38 were from 28 HBsAg(-)/anti-HBc(-) donors, and HBV DNA was detected in 80.0%, 9.2%, and 0% of the corneoscleral rims in each group. Donor anti-HBc(+) provided the highest sensitivity (1.00) and negative predictive value (1.00) for corneoscleral HBV DNA. Twenty-eight of 40 recipients (70%) using HBV DNA(+) grafts were called back, and none developed hepatitis in follow-up periods ranging from 6 to 55.5 mo. Donor anti-HBc should be tested routinely with HBsAg. Allocating corneas from HBsAg(+) or anti-HBc(+) donors to HBsAg(+) or hepatitis B surface antibody recipients maximizes cornea usage from hepatitis B donors without compromising transplant safety in a hepatitis B endemic setting.

Some HBeAg-negative chronic hepatitis B patients treated with nucleos(t)ide analogue can achieve HBsAg loss after drug withdrawal: stop-to-cure may be coming

Nucleoside/Nucleotide analogues (NAs) are widely used for the antiviral treatment of chronic hepatitis B (CHB), however, it is difficult to achieve serum hepatitis B surface antigen (HBsAg) loss with NAs therapy. In recent years, several prospective trails have reported that HBsAg loss (functional cure or clinical cure) also occurs in a small number of hepatitis B e antigen (HBeAg) negative CHB patients who discontinued long-term treatment with NAs. Accordingly, the "stop-to-cure" strategy is proposed. Although the mechanism has not been fully elucidated, the known factors related to serum HBsAg loss with NAs withdrawal include HBV genotype, duration of NAs treatment, serum HBsAg and HBV RNA levels at end-of-treatment, and ethnic differences. In the review, we discuss the best time to stop NAs therapy, the potential markers for predicting relapse after cessation of NAs and the possible mechanism of "stop-to-cure" in HBeAg-negative CHB patients, and propose some suggestions on the time of retreatment.

Follow-Up of Newborns with Hepatitis B Antigenemia.

There is a need for data to evaluate hepatitis B antigenemia in newborns of mothers with hepatitis B virus (HBV) infection. This study aims to investigate this. Newborns with positive serum hepatitis B surface antigen (HBsAg) and/or e antigen (HBeAg) were enrolled in the study. One hundredand one newborns from 98 HBV-infected mothers were included. Median maternal serum HBV DNA level was 23,200IU/mL at delivery. Among the newborns, 48 were boys and 53 were girls. Mean birth weight was 3190.5g. Twenty-one newborns had concurrent seropositive HBsAg and HBeAg, nine had seropositive HBsAg and seronegative HBeAg, and 71 had seronegative HBsAg and seropositive HBeAg. Eight newborns had detectable serum HBV DNA. In the follow-up, serum HBsAg and HBeAg in the newborns with undetectable HBV DNA became negative before 6months of age. Two infants with detectable HBV DNA were diagnosed with immunoprophylaxis failure, one of whom developed active hepatitis at 3months of age. Liver biopsy in this case showed significant interface hepatitis, fibrous septa formation, and expansion of portal areas with occasional bridging fibrosis. Concurrent HBV viremia and antigenemia in newborns of HBV-infected mothers requires attention, while antigenemia without viremia is often transient.