HBcrAg Levels Research Articles

Characteristics of HBV Novel Serum Markers across Distinct Phases in Treatment-Naïve Chronic HBV-Infected Patients.

Methods A total of 111 patients in total from different disease phases were recruited, including 21 in immune-tolerant (IT) phase, 49 in immune-clearance (IC) phases, 29 in immune-control or low replicative (LR) phase, and 12 in reactivation phases. Serum HBV RNA, anti-HBc, HBcrAg, and intrahepatic covalently closed circular DNA (cccDNA) were quantified and each of these indicator's correlation with liver inflammation was analyzed. Results HBeAg-positive individuals had significant higher serum levels of HBV RNA and HBcrAg than those who were HBeAg negative, similar to that of serum HBV DNA. Comparatively, HBV RNA (r =0.79, P < 0.01) and HBcrAg (r =0.78, P < 0.01) had almost same higher overall correlation with the cccDNA, as that of HBV DNA (r =0.81, P < 0.01). Serum anti-HBc level (r = -0.52, P < 0.05) is negatively correlated with cccDNA level at IT phase rather than the other three phases. When set the cutoff value at 4.00 log10 IU/mL, serum anti-HBc showed potential to indicate liver inflammation, with AUC as 0.79 and the specificities as 78.85% for HBeAg positive, and with AUC as 0.72 and the specificities as 62.16% for HBeAg-negative patients, respectively. Conclusions In treatment-naïve patients, levels of serological markers HBV RNA and HBcrAg could mirror intrahepatic cccDNA level, but were not superior to HBV DNA level. Serum anti-HBc level had certain potential to be used as a predicting marker for liver inflammation.

THU374 - Early increase in HBcrAg levels after peginterferon withdrawal predicts subsequent ALT flares

THU374 - Early increase in HBcrAg levels after peginterferon withdrawal predicts subsequent ALT flares

Serum Pregenomic RNA Combined With Hepatitis B Core-Related Antigen Helps Predict the Risk of Virological Relapse After Discontinuation of Nucleos(t)ide Analogs in Patients With Chronic Hepatitis B.

Background and AimCessation of nucleos(t)ide analogs (NAs) therapy in patients with chronic hepatitis B (CHB) is uncommon. Although criteria for discontinuation appear in some guidelines, the indicators for assessing discontinuation of NAs are limited, whether NAs can be safely ceased remains a difficult clinical issue. Our study aimed to investigate the role of serum pregenomic RNA (pgRNA) and hepatitis B core-related antigen (HBcrAg) at the end of treatment (EOT) in guiding the safe discontinuation of NAs in CHB patients.MethodsThis is a retrospective study, clinical data of all CHB patients who discontinued NAs treatment at West China Hospital between June 2020 and January 2021 were collected, including EOT pgRNA, HBcrAg, hepatitis B surface antigen (HBsAg), etc. All patients should meet the Asian-Pacific guideline for discontinuation. Observing virological relapse (VR) rates during 1 year of NAs discontinuation and analyzing the relationship between EOT pgRNA, HBcrAg, and VR.ResultsA total of 64 patients were enrolled in this study and 33 (51.5%) patients experienced VR in 1 year. EOT pgRNA positivity (OR = 14.59, p = 0.026) and EOT higher HBcrAg levels (OR = 14.14, p = 0.001) were independent risk factors for VR. The area under the receiver-operating characteristic (AUROC) value of EOT HBcrAg for VR was 0.817 (p < 0.001), optimal cut-off value was 3.3 log10 U/mL. Patients with EOT pgRNA positivity and EOT HBcrAg >3.3 log10 U/mL were more likely to experience VR after discontinuation of NAs (88.9 vs. 45.5%, p = 0.027).ConclusionAccording to current guidelines, a higher VR rate occurs after cessation of NAs. EOT pgRNA positivity and higher HBcrAg level carries a higher risk of VR. Combining these novel markers can better help us assess whether patients can safely cease NAs treatment.

Serum O-glycosylated hepatitis B surface antigen levels in patients with chronic hepatitis B during nucleos(t)ide analog therapy

BackgroundSerum hepatitis B surface antigen (HBsAg) is a component of both hepatitis B virus (HBV) virions and non-infectious subviral particles (SVPs). Recently, O-glycosylation of the PreS2 domain of middle HBsAg protein has been identified as a distinct characteristic of genotype C HBV virions versus SVPs. This study aimed to evaluate serum O-glycosylated HBsAg levels in patients with chronic hepatitis B (CHB) treated with nucleos(t)ide analogs (NAs).MethodsForty-seven treatment-naïve patients with genotype C CHB were retrospectively enrolled. Serum O-glycosylated HBsAg levels at baseline and after 48 weeks of NA therapy were quantified by immunoassay using a monoclonal antibody against the O-glycosylated PreS2 domain of middle HBsAg, and their correlations with conventional HBV marker levels were analyzed.ResultsAt baseline, the serum O-glycosylated HBsAg levels were significantly correlated with the HBV DNA (P = 0.004), HBsAg (P = 0.005), and hepatitis B-core related antigen (HBcrAg, P = 0.001) levels. Both HBV DNA and O-glycosylated HBsAg levels were decreased after 48 weeks of NA therapy. The significant correlation of the O-glycosylated HBsAg level with the HBsAg or HBcrAg level was lost in patients who achieved undetectable HBV DNA (HBsAg, P = 0.429; HBcrAg, P = 0.065). Immunoprecipitation assays demonstrated that HBV DNA and RNA were detected in the O-glycosylated HBsAg-binding serum fraction, and the proportion of HBV RNA increased during NA therapy (P = 0.048).ConclusionSerum O-glycosylated HBsAg levels change during NA therapy and may reflect combined levels of serum HBV DNA and RNA virions. An O-glycosylated HBsAg-based immunoassay may provide a novel means to monitor viral kinetics during NA therapy.

Clinical usefulness of a novel high-sensitivity hepatitis B core-related antigen assay to determine the initiation of treatment for HBV reactivation.

A fully automated, novel, high-sensitivity hepatitis B core-related antigen assay (iTACT-HBcrAg) has been developing. The purpose of this study is to evaluate the efficacy of measuring HBcrAg, using that assay, to diagnose HBV reactivation in a multi-center setting, compared with ultra-high-sensitivity HBsAg (iTACT-HBsAg) and HBV DNA assays. Forty-four patients with HBV reactivation from 2008 to 2020 were enrolled in four hospitals. Serial serum specimens from the patients were assessed retrospectively for their HBcrAg levels by iTACT-HBcrAg (lower limit of detection; 2.0 log U/mL) and HBsAg levels by iTACT-HBsAg (lower limit of detection; 0.0005IU/mL); these were compared to the HBV DNA levels. HBV reactivation was defined as detection of serum HBV DNA, including unquantifiable detection. At HBV reactivation and/or thereafter, HBV DNA levels were quantified (≥ 1.3 log IU/mL) in the sera of 27 patients, and were below the level of quantification (< 1.3 log IU/mL) in the sera of 17 patients. Of the 27 patients with HBV reactivation and whose serum HBV DNA was quantified, the sera of 26 and 24 patients (96.3% and 88.9%) were positive by iTACT-HBcrAg and iTACT-HBsAg, respectively. HBcrAg was detectable by iTACT-HBcrAg before HBV DNA was quantifiable in 15 of the 27 patients. Of the 11 patients with HBV reactivation and undetectable HBcrAg by iTACT-HBcrAg at HBV reactivation and/or thereafter, 10 had unquantifiable HBV DNA and none developed HBV reactivation-related hepatitis. The iTACT-HBcrAg assay is useful for monitoring HBV reactivation to determine the initiation of treatment with nucleos(t)ide analogues.

From the Editor’s Desk...

From the Editor’s Desk...

Impact of HCV viremia on HBV biomarkers in patients coinfected with HBV and HCV

Backgrounds:Hepatitis B virus (HBV) biomarkers reflect the status of HBV infection; however, their role in patients with chronic hepatitis B and C (HBV/HCV) coinfection remains unknown. This study evaluated the characteristics of HBV biomarkers in patients with chronic HBV/HCV coinfection.MethodsOne hundred untreated HBV/HCV coinfected patients were enrolled. Active viral infection was defined as viral load above 2000 U/L and 15 U/L for HBV and HCV, respectively. Blood samples were analyzed for HBV biomarkers, including hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), HBV DNA, and HBV pregenomic RNA (HBV pgRNA). The impact of HCV viremia was also studied.ResultsA total of 15 patients were HBV-inactive/HCV-inactive, 63 patients were HBV-inactive/HCV-active, 14 patients were HBV-active/HCV-inactive and 8 patients were HBV-active/HCV-active. A total of 71 (71%) patients were active HCV and 22 (22%) were active HBV. HBsAg, HBcrAg, and HBV DNA correlated with each other (P < 0.001). HBV pgRNA displayed no correlations with HBV DNA, HBsAg, or HBcrAg. Patients with HCV viremia had significantly lower HBV DNA, HBsAg, and HBcrAg levels as well as higher HBV pgRNA levels and lower HBV DNA:pgRNA ratio than those without viremia (HBV DNA, P < 0.001; HBsAg, P = 0.015; HBcrAg, P = 0.006; HBV pgRNA, P = 0.073; and HBV DNA:pgRNA ratio, P < 0.001).ConclusionsIn patients coinfected with HBV and HCV, HBsAg, HBcrAg, and HBV DNA significantly correlated with each other. HBV and HCV coinfected patients with HCV viremia have lower HBV DNA, HBsAg, HBcrAg, and HBV DNA:pgRNA ratio as well as higher HBV pgRNA levels.

Hepatitis B Core-Related Antigen Is Useful for Predicting Phase and Prognosis of Hepatitis B e Antigen-Positive Patients.

The role of hepatitis B core-related antigen (HBcrAg) level in defining clinical phase and predicting prognosis of chronic hepatitis B (CHB) has not been fully studied. CHB patients who had undergone liver biopsy in Korea University Medical Center were included. Patients with liver cirrhosis were excluded. The associations of HBcrAg level with CHB phase, and nucleos(t)ide analogue (NA)-induced hepatitis B e antigen (HBeAg) seroconversion were analyzed. In total, 387 patients (median follow-up of 82.4 months) were included. The CHB phases of patients were defined histologically as immune-tolerant (IT, n = 32, 8.3%), HBeAg-positive and immune-active (PIA, n = 211, 54.5%), HBeAg-negative and immune-active (n = 125, 32.3%), and inactive (n = 19, 4.9%), respectively. In HBeAg-positive patients, the mean HBV DNA levels were comparable between the two groups (p = 0.990). However, the mean HBsAg (7.4 log IU/mL and 6.9 log IU/mL, p = 0.002) and HBcrAg levels (8.2 log U/mL vs. 7.6 log U/mL, p < 0.001) of IT patients were significantly higher than that of PIA patients. In multivariate analysis, younger age (odds ratio [OR] 0.949, p = 0.025), lower alanine aminotransferase (OR 0.988, p = 0.002) and higher HBcrAg level (OR = 2.745 p = 0.022) were independent predictors of the IT phase. Of the patients in the PIA phase, 194 received NA after liver biopsy, and 61 (31.4%) had achieved HBeAg seroconversion after antiviral therapy. In Cox regression analysis, the higher HBcrAg level was the only independent predictor of the NA-induced HBeAg seroconversion (hazard ratio 1.285, p = 0.028). The HBcrAg level is useful for predicting clinical phase of CHB and NA-induced HBeAg seroconversion in HBeAg-positive patients.

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 log10copies/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 log10copies/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.

Divergent patterns of hbv-rna and hbcrag levels in untreated chronic hepatitis delta: a large european cross-sectional study

Methods: Consecutive patients with untreated CHD were enrolled in this investigator driven cross-sectional study in two EU centers. All the standard clinical and virological characteristics were collected. HDV RNA was quantified by sensitive and specific assays (Robogene or a local validated in-house assay). Serum HBV RNA was quantified by an automated real-time PCR based investigational assay (cobas® 6800, Roche Diagnostics, Pleasanton, Ca, USA, LLOQ 10 cp/mL) while serum HBcrAg levels were measured using LUMIPULSE® G HBcrAg assay (Fujirebio Europe, LLOQ 3 log10 U/mL).

Superiority of tenofovir alafenamide fumarate over entecavir for serum HBsAg level reduction in patients with chronic HBV infection: A 144-week outcome study after switching of the nucleos(t)ide analog.

BackgroundTo evaluate the long-term efficacy of switching of the nucleos(t)ide analog used for treatment from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in patients with chronic HBV infection.MethodsA total of 103 patients with serum HBsAg levels of ≥100 IU/mL who had received ETV were enrolled. The nucleos(t)ide analog used for the treatment was switched from ETV to TAF, and the changes in serum HBsAg levels during the 144-week period before and after the drug switching were compared in 74 patients who had received ETV at least for 192 weeks.ResultsSignificant decreases of serum HBsAg levels were observed during both the ETV and the TAF administration period, although the degree of reduction was greater during the latter period than during the former period (P<0.001). Significant decreases of serum HBsAg levels were seen in both patients with genotype B HBV infection and genotype C HBV infection, irrespective of the serum HBsAg and HBcrAg levels at the time of the drug switching.ConclusionSwitching of the nucleos(t)ide analog used for treatment from ETV to TAF merits consideration in patients with chronic HBV infection, since the extent of reduction of the serum HBsAg level was greater during the TAF treatment period than during the ETV treatment period.

Hepatitis B Core-Related Antigen Stratifies the Risk of Liver Cancer in HBeAg-Negative Patients With Indeterminate Phase.

Many patients with chronic hepatitis B (CHB) are classified as indeterminate patients because they fall outside the defined CHB phases. We aimed to explore hepatocellular carcinoma (HCC) risk in hepatitis B e antigen (HBeAg)-negative patients with indeterminate phase and investigated whether the risk could be stratified by serum levels of hepatitis B core-related antigen (HBcrAg). Two retrospective cohorts enrolling HBeAg-negative, treatment-naïve CHB patients without cirrhosis were constructed (N = 2,150 in Taiwanese discovery cohort and N = 1,312 in Japanese validation cohort with a mean follow-up period of 15.88 and 12.07 years, respectively). The primary end point was HCC development. According to the American Association for the Study of Liver Disease guidelines, 990 (46%) HBeAg-negative patients had indeterminate CHB phase at baseline in the Taiwanese cohort. Compared with the patients with inactive CHB and those with immune-active CHB, the indeterminate patients exhibited intermediate but diverse risk of HCC. When HCC risk was stratified by a HBcrAg level of 10,000 U/mL, 10-year HCC cumulative incidence was 0.51% and 5.33% for low HBcrAg and high HBcrAg groups, respectively, with a hazard ratio of 4.47 (95% confidence interval: 2.62-7.63). This cutoff was validated to stratify HCC risk not only in different subgroup analyses but also in an independent Japanese cohort. Finally, the overall HBeAg-negative CHB patients could be simply reclassified into high-risk and low-risk groups by combining ALT, hepatitis B virus DNA, and HBcrAg levels in both cohorts. Serum HBcrAg level of 10,000 U/mL stratifies HCC risk in HBeAg-negative patients with indeterminate phase, which is useful for optimizing their clinical management.

End-of-treatment HBcrAg and HBsAb levels identify durable functional cure after Peg-IFN-based therapy in patients with CHB

Functional cure can be sustained in a proportion of patients with chronic hepatitis B (CHB) who lose hepatitis B surface antigen (HBsAg) after pegylated interferon alpha (Peg-IFN-ɑ)-based treatment. In this study, we aimed to identify biomarkers associated with a durable functional cure and to dissect potential immunological mechanisms. Of 257 nucleos(t)ide analogue-suppressed patients with CHB in the ANCHOR study, 80 patients randomly assigned to 96-week Peg-IFN-α-based therapy with 24-week off-treatment follow-up were included in this parallel study. Virologic and immunological biomarkers were examined dynamically. A response was defined as HBsAg loss or hepatitis B surface antibody (HBsAb) appearance at the end of treatment (EOT). Sustained response (SR) or durable functional cure was defined as sustained HBsAg loss with or without the appearance of HBsAb at the end of follow-up (EOF). Thirty-six (45.0%) out of 80 patients achieved a response at EOT; 58.3% (21/36) of responders maintained SR at EOF. Quantitative hepatitis B core-related antigen (qHBcrAg) and HBsAb at EOT were associated with SR, with AUROCs of 0.697 (0.512-0.882, p= 0.047) and 0.744 (0.573-0.915, p= 0.013), respectively. A combination of HBcrAg <4 log10U/ml and HBsAb >2 log10IU/L at EOT had a positive predictive value of 100% for SR with an AUROC of 0.822 (0.684-0.961, p= 0.001). These patients showed maintained proportions of HBV envelope-specific CD8+T and B cells, a markedly increased proportion of T follicular helper cells after Peg-IFN-ɑ discontinuation, and significantly higher proportions of HBV polymerase-specific CD8+T and CD86+CD19+B cells at EOF. Lower HBcrAg and higher HBsAb levels at EOT were associated with sustained cellular and humoral immune responses. They can be used to identify patients likely to achieve durable functional cure post Peg-IFN-based therapy. NCT02327416 LAY SUMMARY: Functional cure can be sustained in a proportion of patients with chronic hepatitis B after pegylated interferon alpha-based treatment. However, predicting who will achieve durable functional cure remains challenging. Herein, we show that low levels of hepatitis B core-related antigen and higher levels of hepatitis B surface antibodies at the end of treatment are linked to immunological responses and are associated with durable functional cure.

Probability of HBsAg loss after nucleo(s)tide analogue withdrawal depends on HBV genotype and viral antigen levels

Nucleo(s)tide analogue (NUC) withdrawal may result in HBsAg clearance in a subset of patients. However, predictors of HBsAg loss after NUC withdrawal remain ill-defined. We studied predictors of HBsAg loss in a global cohort of HBeAg-negative patients with undetectable HBV DNA who discontinued long-term NUC therapy. Patients requiring retreatment after treatment cessation were considered non-responders. We enrolled 1,216 patients (991 with genotype data); 98 (8.1%) achieved HBsAg loss. The probability of HBsAg loss was higher in non-Asian patients (adjusted hazard ratio [aHR] 8.26, p <0.001), and in patients with lower HBsAg (aHR 0.243, p <0.001) and HBV core-related antigen (HBcrAg) (aHR 0.718, p= 0.001) levels. Combining HBsAg (<10, 10-100 or >100 IU/ml) and HBcrAg (<2log vs. ≥2 log) levels improved prediction of HBsAg loss, with extremely low rates observed in patients with HBsAg >100 IU/ml with detectable HBcrAg. HBsAg loss rates also varied with HBV genotype; the highest rates were observed for genotypes A and D, and none of the patients with HBV genotype E experienced HBsAg loss (p <0.001 for the overall comparison across genotypes; p <0.001 for genotypes A/D vs. genotypes B/C). HBV genotype C was independently associated with a higher probability of HBsAg loss when compared to genotype B among Asian patients (aHR 2.494; 95% CI 1.490-4.174, p= 0.001). The probability of HBsAg loss after NUC cessation varies according to patient ethnicity, HBV genotype and end-of-treatment viral antigen levels. Patients with low HBsAg (<100 IU/ml) and/or undetectable HBcrAg levels, particularly if non-Asian or infected with HBV genotype C, appear to be the best candidates for treatment withdrawal. A subset of patients may achieve clearance of hepatitis B surface antigen (HBsAg) - so-called functional cure - after withdrawal of nucleo(s)tide analogue therapy. In this multicentre study of 1,216 patients who discontinued antiviral therapy, we identified non-Asian ethnicity, HBV genotype C, and low hepatitis B surface antigen and hepatitis B core-related antigen levels as factors associated with an increased chance of HBsAg loss.

Combining the HBcrAg decline and HBV mutations predicts spontaneous HBeAg seroconversion in chronic hepatitis B patients during the immune clearance phase.

To assess predictive ability of hepatitis B virus (HBV) markers and genome mutations for spontaneous hepatitis B e antigen (HBeAg) seroconversion. A total of 113 chronic hepatitis B (CHB) patients were followed up for 76 weeks without antiviral treatment. Baseline basal core promoter (BCP) and precore mutations were detected and serum hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen (HBcrAg), and HBV DNA levels were serially quantified. Eighteen patients experienced spontaneous HBeAg seroconversion (Group A), and the remaining 95 patients did not experience spontaneous HBeAg seroconversion (Group B). At Week 28, HBsAg (p = 0.03) and HBcrAg (p = 0.01) levels were significantly different between Groups A and B. Reduced HBsAg (p = 0.02) and HBcrAg (p < 0.01) levels from baseline to Week 28 were significantly different between two groups. Multivariate logistic regression showed that lower HBcrAg (odds ratio [OR] = 1.02, p = 0.03) levels at Week 28, and HBcrAg levels with sharp decrease at Week 28 (OR = 0.19, p = 0.02) were related with spontaneous HBeAg seroconversion. The areas under the receiver operating characteristic curve (AUROC) showed that reduction in HBcrAg levels from baseline to Week 28 (0.93, p = 0.001, 95% CI: 0.74-1.08) have excellent prediction value. The mutation frequencies of A1574T (51.11% vs. 18.18%, p = 0.001), G1862A (30.00% vs. 13.03%, p = 0.001), G1896A (27.22% vs. 5.45%, p = 0.001), and C1913G (32.78% vs. 12.73%, p = 0.001) in Group A were significantly higher than Group B. Baseline A1574T, G1862A, G1896A, and C1913G mutations and HBcrAg levels with a sharp decrease at Week 28 were associated with spontaneous HBeAg seroconversion.

Study of hepatitis B core-related antigen as a predictor marker of hepatocellular carcinoma in patients with chronic hepatitis B

Background Cirrhosis and hepatocellular cancer are the most common complications of chronic hepatitis B and therefore it is necessary to avoid these complications in high-risk patients with high replicative capability. Conventional serum indicators are insufficient for detecting hepatocellular carcinoma in these patients early. Aim The goal of this study was to see if hepatitis B core-related antigen (HBcrAg) could be used as a marker for hepatocellular cancer in people who had hepatitis B. Patients and methods This research was conducted on 90 people who attended the Hepatitis Outpatient Clinics at the Department of Tropical Medicine and Tanta University Educational Hospital between January 2019 and August 2020. Results In comparison to the control group, hepatocellular carcinoma (HCC), and chronic hepatitis B (CHB) patients had a marked decline in hemoglobin, serum albumin, white blood cells count, and platelet count. Aspartate transaminase (AST), Alanine aminotansferase (ALT), bilirubin, and international normalization ratio (INR) levels all increased considerably. Hepatocellular carcinoma and CHB patients had relatively high levels of alkaline phosphatase (ALP) and Alpha-feto protien (AFP) than the control group. In both patient groups, there was a strong whereas ALT. Levels was within normal values. In the HCC group, HBcrAg levels were closely linked with ALP, AFP, and DNA levels. In both patient groups, the AST to Platelet Ratio Index (APRI) score indicated a strong association. Conclusion As an excellent biomarker of intrahepatic cccDNA, HBcrAg demonstrated encouraging results as a potential biomarker of HCC incidence in CHB patients.

Development of hepatocellular carcinoma from various phases of chronic hepatitis B virus infection.

Background & aimsThere is insufficient data on the clinical course of chronic hepatitis B (CHB) patients in the immune-tolerant (IT) and immune-clearance, inactive (IC) phases over a long follow-up period.DesignWe enrolled 466 CHB patients from our historical cohort, including 56 IT+MA (mildly active), 134 IC, 230 with chronic active hepatitis (CH) and 46 with liver cirrhosis (LC), who were categorized to each phase by at least one year of follow-up period from the first visit to our hospital. We investigated long-term risks, and their factors, of developing hepatocellular carcinoma (HCC), and the transition between the clinical phases, especially in the IT+MA and IC groups.ResultsOf the 56 patients in the IT+MA group, 27 remained the IT+MA phase, but 29 transitioned to the CH phase and started nucleot(s)ide analogue (NA) treatment during the follow-up period. Meanwhile, of the 134 patients in the IC group, only 5 started NA treatment after progressing to the CH phase. The development of HCC from the IT+MA, IC, CH, and LC groups was observed in 2, 2, 9, and 20 cases, respectively. The cumulative incidence rates of developing HCC in the IT+MA, IC, CH, and LC groups were 9.9, 1.8, 3.0, and 53.1% at 10 years. In the CH and LC group, patients who developed HCC were older, had higher levels of FIB-4 index, M2BPGi, HBcrAg and AFP, and had lower levels of albumin and platelet counts. In CH patients, FIB-4 index levels were elevated at the diagnosis of HCC compared to baseline, whereas these decreased during the follow-up period in non-HCC patients.ConclusionsHCC occurred at a certain rate among patients in the IT+MA and IC groups. Careful follow-up is required for CH patients with higher levels of FIB-4 index and/or M2BPGi because of the high incidence of HCC development. (299 words)

Construction of an anti-hepatitis B virus preS1 antibody and usefulness of preS1 measurement for chronic hepatitis B patients: Anti-HBV PreS1 antibody

The preS1 region plays an essential role in hepatitis B virus (HBV) infection. We construct an antibody that binds to preS1 and a measurement system for serum preS1 in chronic HBV-infected patients. Hybridoma clones that produce anti-preS1 antibodies were obtained by the iliac lymph node method. Epitope mapping was conducted, and an enzyme-linked immunosorbent assay (ELISA)-based method was developed. Using this ELISA system, serum preS1 levels were measured in 200 chronic HBV-infected patients. Eight types of hybridomas were obtained, of which antibody 3-55 using amino acids 38-47 as the epitope showed high binding affinity to preS1. Serum preS1 levels measured by ELISA using 3-55 antibody were correlated with HBsAg, HBcrAg and HBV DNA levels. Among HBeAg-negative patients without antiviral therapeutic objective (HBV DNA <3.3logIU/mL or alanine aminotransferase ≤30U/L), preS1 was significantly higher in subjects who had progressed to the point of requiring antiviral therapy compared to subjects who had maintained their status for the preceding three years (p<0.01). We constructed an antibody against preS1 and an ELISA system capable of measuring serum preS1 levels. PreS1 may serve as a novel tool to predict the need for antiviral therapy in HBeAg-negative HBV-infected patients.

Earlier and Higher Rate of Hepatitis B Virus Relapse After Discontinuing Tenofovir Versus Entecavir in Hepatitis B e Antigen–Positive Patients

This study investigated the incidence and predictors of hepatitis B virus (HBV) relapse in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who discontinued entecavir (ETV) or tenofovir disoproxil fumarate (TDF). A total of 205 and 111 HBeAg-positive patients without cirrhosis who had stopped ETV or TDF treatment, respectively, for at least 6 months were recruited. In the entire cohort, patients with HBeAg seroconversion during treatment, and propensity score-matched patients, those who discontinued TDF had significantly higher rates of virological and clinical relapse than patients who discontinued ETV therapy. Multivariate analysis identified that TDF was independently associated with virological and clinical relapse in the entire cohort and subgroup analysis. Patients with HBeAg loss without anti-HBe antibody formation during treatment had significantly higher rates of off-therapy HBV relapse and HBeAg seroreversion than patients with HBeAg seroconversion during treatment. The hepatitis B core-related antigen (HBcrAg) level at end of treatment (EOT) was independently associated with HBV relapse and HBeAg seroreversion in all patients and patients with HBeAg seroconversion during treatment. TDF therapy, HBeAg loss without seroconversion during treatment, and higher HBcrAg levels at EOT are significant predictors of HBV relapse in HBeAg-positive patients who discontinued ETV or TDF.

Insufficient immunity led to virologic breakthrough in NAs-treated chronic hepatitis B patients switching to Peg–IFN–ɑ

BackgroundVirologic breakthrough (VBT) may occur in chronic hepatitis B (CHB) patients after switching from nucleos(t)ide analogues (NAs) to pegylated interferon alpha (Peg–IFN–ɑ). This study aimed to characterize the clinical and immunological features of VBT. MethodsIn NAs-treated patients switching to Peg–IFN–ɑ, innate and adaptive immune cell proportions were examined in peripheral blood and liver biopsy specimens. In vitro effect of IFN-ɑ on the expressions of toll-like receptors 2 (TLR2) and programmed cell death ligand 1 (PDL1) on monocytes, programmed cell death 1 (PD1) on CD8+T cells was examined. Peripheral blood mononuclear cells (PBMCs) were treated with TLR2 agonist and/or PDL1 blockade to evaluate their effect on HBV replication. Results33 of 166 patients switching to Peg–IFN–ɑ experienced VBT after NA cessation, with majority being hepatitis B e antigen (HBeAg) positive or having higher hepatitis B core-related antigen (HBcrAg) levels. Patients with VBT exhibited lower proportions of TLR2+monocyte and increased PD1+HBV-specific CD8+T cell during the early phase of Peg–IFN–ɑ therapy after NA cessation in peripheral blood, as well as fewer TLR2+CD68+macrophages but more PDL1+CD68+macrophages and PD1+CD8+T cells in liver tissues. Simultaneous use of TLR2 agonist and PDL1 blockage ex vivo suppressed HBV replication by promoting cytokines production and CD8+T cells cytotoxicity. Upon in vitro IFN-ɑ stimulation, PDL1+monocytes and PD1+CD8+T cells were upregulated, whereas TLR2+monocytes were not increased in PBMC isolated from HBeAg-positive patients, or those with high HBcrAg titers. ConclusionsIn NAs-treated patients, lower TLR2+monocyte and increased PD1+HBV-specific CD8+T cell proportions potentially contribute to VBT after switching to Peg–IFN–ɑ therapy. This insufficient immunity may be associated with the HBeAg status and HBcrAg levels.