The infection of Hepatitis B virus (HBV) can result in severe consequences, including chronic hepatitis, liver fibrosis, cirrhosis, and even liver cancer. Effective antiviral treatment has the potential to slow down the progression of the disease. HBV serum biomarkers play a crucial role in the dynamic management of chronic hepatitis B (CHB) patients. However, the conventional hepatitis B virus markers, such as hepatitis B serologic testing and HBV DNA, are insufficient to meet the clinical requirements. This review provided a comprehensive overview of the current research on the quantification of HBsAg and anti-HBc, HBV RNA and HBV core-associated antigen, which summarized the crucial role these markers play in the administration of antiviral medications, predicting the efficacy of treatment and anticipating the likelihood of virologic rebound following drug cessation, as well as assessing disease progression in CHB patients.
Humans ; Hepatitis B virus/genetics* ; Clinical Relevance ; Hepatitis B, Chronic/drug therapy* ; Hepatitis B Core Antigens/therapeutic use* ; Biomarkers ; Liver Cirrhosis/drug therapy* ; Antiviral Agents/therapeutic use* ; Hepatitis B Surface Antigens/therapeutic use* ; DNA, Viral/therapeutic use* ; Hepatitis B e Antigens/therapeutic use* ; Hepatitis B/drug therapy*

BACKGROUND: Hepatitis B core-related antigen (HBcrAg) is a promising disease-monitoring marker for chronic hepatitis B (CHB). We investigated correlations between HBcrAg with antiviral efficacy and virological and histological variables. METHODS: One hundred and forty-five CHB patients from the mainland of China between August 2013 and September 2016 who underwent liver biopsy received entecavir therapy and had paired liver biopsy at 78 weeks. We analyzed correlations between HBcrAg and virological and histological variables in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients. We also explored the predictors of HBeAg loss after 78 weeks of antiviral therapy. Pearson correlation analysis and logistic forward stepwise regression were the main statistic methods. RESULTS: HBeAg-positive patients (n = 93) had higher baseline HBcrAg (median 7.4 vs. 5.3 log10 U/mL P < 0.001) and greater HBcrAg declines (median 1.6 vs. 0.9 log10 U/mL P = 0.007) than HBeAg-negative patients after 78 weeks of therapy. At baseline, HBcrAg correlated with hepatitis B virus (HBV) DNA in both HBeAg-positive (r = 0.641, P < 0.001) and -negative patients (r = 0.616, P < 0.001), with hepatitis B surface antigen (HBsAg) in HBeAg-positive patients (r = 0.495, P < 0.001), but not with anti-hepatitis B virus core antibody (anti-HBc). Weak correlations existed between HBcrAg, histology activity index (HAI; r = 0.232, P = 0.025), and Ishak fibrosis score (r = -0.292, P = 0.005) in HBeAg-positive patients. At 78 weeks, significant correlations existed only between HBcrAg and anti-HBc in HBeAg-positive (r = -0.263, P = 0.014) and HBeAg-negative patients (r = -0.291, P = 0.045). Decreased HBcrAg significantly correlated with reduced HBV DNA (r = 0.366, P = 0.001; r = 0.626, P < 0.001) and HBsAg (r = 0.526, P = 0.001; r = 0.289, P = 0.044) in HBeAg-positive and -negative patients, respectively, and with reduced HAI in HBeAg-positive patients (r = 0.329, P = 0.001). Patients with HBeAg loss (n = 29) showed a larger reduction in HBcrAg than those without (median 2.3 vs. 1.3 log10 U/mL, P = 0.001). In multivariate analysis, decreased HBcrAg was an independent predictor of HBeAg loss (P = 0.005). CONCLUSIONS: HBcrAg reflects viral replication and protein production. Decreased HBcrAg could predict HBeAg loss after antiviral therapy. TRIAL REGISTRATION Clinical Trials.gov: NCT01962155; https://www.clinicaltrials.gov/ct2/show/NCT01962155?term=NCT01962155&draw=2&rank=1.
Antiviral Agents/therapeutic use* ; Biomarkers ; China ; DNA, Viral ; Hepatitis B Core Antigens/therapeutic use* ; Hepatitis B Surface Antigens ; Hepatitis B e Antigens ; Hepatitis B virus/genetics* ; Hepatitis B, Chronic/drug therapy* ; Humans ; Virus Replication

Advances in the treatment of malignant and inflammatory diseases have developed over time, with increasing use of chemotherapeutic and immunosuppressive agents of a range of drug classes with varying mechanism and potency in their effects on the immune system. These advances have been met with the challenge of increased risk of hepatitis B virus (HBV) reactivation in susceptible individuals. The magnitude of risk of HBV reactivation is associated with the individual's HBV serological status and the potency and duration of immunosuppression. Individuals with chronic hepatitis B (CHB) and previously infected but serologically cleared HBV infection are both susceptible to HBV reactivation. HBV reactivation in the setting of immunosuppression is a potentially life threatening condition leading to liver failure and death in extreme cases. It is important to recognize that HBV reactivation in the setting of immunosuppression is potentially preventable. Therefore, identification of patients at risk of HBV reactivation and institution of prophylactic antiviral therapy prior to initiation of immunosuppression is essential.
Antiviral Agents/therapeutic use ; Autoimmune Diseases/complications/pathology ; Hematopoietic Stem Cell Transplantation ; Hepatitis B/complications/drug therapy ; Hepatitis B Core Antigens/blood ; Hepatitis B Surface Antigens/blood ; Hepatitis B virus/*physiology ; Humans ; Immunosuppressive Agents/therapeutic use ; Organ Transplantation ; Virus Activation/*physiology

Advances in the treatment of malignant and inflammatory diseases have developed over time, with increasing use of chemotherapeutic and immunosuppressive agents of a range of drug classes with varying mechanism and potency in their effects on the immune system. These advances have been met with the challenge of increased risk of hepatitis B virus (HBV) reactivation in susceptible individuals. The magnitude of risk of HBV reactivation is associated with the individual's HBV serological status and the potency and duration of immunosuppression. Individuals with chronic hepatitis B (CHB) and previously infected but serologically cleared HBV infection are both susceptible to HBV reactivation. HBV reactivation in the setting of immunosuppression is a potentially life threatening condition leading to liver failure and death in extreme cases. It is important to recognize that HBV reactivation in the setting of immunosuppression is potentially preventable. Therefore, identification of patients at risk of HBV reactivation and institution of prophylactic antiviral therapy prior to initiation of immunosuppression is essential.
Antiviral Agents/therapeutic use ; Autoimmune Diseases/complications/pathology ; Hematopoietic Stem Cell Transplantation ; Hepatitis B/complications/drug therapy ; Hepatitis B Core Antigens/blood ; Hepatitis B Surface Antigens/blood ; Hepatitis B virus/*physiology ; Humans ; Immunosuppressive Agents/therapeutic use ; Organ Transplantation ; Virus Activation/*physiology

BACKGROUND/AIMS: The widespread use of cytotoxic chemotherapy and immunosuppressants has resulted in reactivation of hepatitis B virus (HBV) recently becoming an issue. Although rituximab (an anti-CD20 monoclonal antibody) has revolutionized the treatment of lymphoma, recent reports have suggested that rituximab therapy increases the risk of viral-mediated complications, and particularly HBV reactivation. This study analyzed real clinical practice data for rituximab-related HBV reactivation. METHODS: Between January 2005 and December 2011, 169 patients received treatment with rituximab. Screening status of the HBV infection and frequency of preemptive therapy were determined in these patients, and the clinical features of HBV reactivation were analyzed. RESULTS: Seventy-nine of the 169 patients with chronic or past HBV infection were selected for evaluation of HBV reactivation. Of the 90 patients who were excluded, 22 (13.0%) were not assessed for HBsAg and anti-HBc, and 14 (8.3%) were not assessed for anti-HBc due to seronegativity for HBsAg. The selected patients were divided into those with chronic HBV infection (n=12) and those with past HBV infection (n=67); six patients (7.6%) experienced HBV reactivation. Eight patients received preemptive therapy, but three patients (37.5%) underwent HBV reactivation. Although HBsAg seropositivity was an independent risk factor for HBV reactivation (P=0.038), of the six patients with HBV reactivation, two (33.3%) had past HBV infection and three (50%) died of liver failure. CONCLUSIONS: The findings of this study demonstrate that adherence to guidelines for screening and preemptive therapy for HBV reactivation was negligent among the included cohort. Attention should be paid to HBV reactivation in patients with past as well as chronic HBV infection during and after rituximab therapy.
Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies/blood ; Antibodies, Monoclonal, Murine-Derived/*adverse effects/therapeutic use ; Antineoplastic Agents/adverse effects/*therapeutic use ; Child ; Child, Preschool ; Hepatitis B/etiology/mortality/virology ; Hepatitis B Core Antigens/immunology ; Hepatitis B Surface Antigens/blood ; Hepatitis B virus/*physiology ; Humans ; Lymphoma/*drug therapy ; Middle Aged ; Odds Ratio ; Retrospective Studies ; Risk Factors ; *Virus Activation ; Young Adult

<b>OBJECTIVEb>To analyze the liver function in patients with diffuse large B-cell lymphoma(DLBCL), who are hepatitis B surface antigen negative/antibody to hepatitis B core antigen positive (HBsAg-/HBcAb+), treated with CHOP and R-CHOP regimens.

<b>METHODSb>In this retrospective study, 86 DLBCL patients, who were HBsAg-/HBcAb+, were collected from Cancer Hospital of Chinese Academy of Medical Sciences between January 2005 and December 2008. The patients were given at least two cycles of chemotherapy using CHOP-like or R-CHOP-like regimen without anti-HBV treatment, and followed-up for at least 12 months after completion of therapy.

<b>RESULTSb>Forty-seven patients received CHOP-like regimen while 39 patients received R-CHOP-like regimen. There were no significant differences in the degree of liver dysfunction between CHOP group and R-CHOP group after the 1st, 2nd, 3rd, 4th and 6th cycles (22.7% - 46.7% with CHOP and 17.6% - 34.2% with R-CHOP, respectively, (all P > 0.05), except for the 5th cycles (28.6% vs. 6.2%, P = 0.026). Liver function in most patients in CHOP group and R-CHOP group was normal after every cycle (53.3% - 77.3% and 65.8%-93.8%, respectively). Meanwhile, there were no significant differences in the degree of liver dysfunction between CHOP group and R-CHOP group in the 1st-3rd month, 4th-6th month, 7th-9th month and 10th-12th month after completion of therapy (7.7% - 40.0% with CHOP and 7.4% - 32.0% with R-CHOP, respectively, all P > 0.05).

<b>CONCLUSIONSb>The present study reveals a low incidence of liver dysfunction in HBsAg-/HBcAb+ DLBCL patients, both in CHOP group and in R-CHOP group. It may indicate a potential low incidence of HBV reactivation in these groups, and Rituximab do not increase the rate of liver dysfunction. Therefore, these data may not support regularly prophylactic antiviral therapy during chemotherapy, but close monitoring of liver function, HBV serum markers and HBV DNA level are demanded.

Alanine Transaminase ; blood ; Antibodies, Monoclonal, Murine-Derived ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Aspartate Aminotransferases ; blood ; Bilirubin ; blood ; Cyclophosphamide ; therapeutic use ; Doxorubicin ; therapeutic use ; Female ; Follow-Up Studies ; Hepatitis B Antibodies ; metabolism ; Hepatitis B Core Antigens ; immunology ; Hepatitis B Surface Antigens ; metabolism ; Humans ; Liver Function Tests ; Lymphoma, Large B-Cell, Diffuse ; blood ; drug therapy ; immunology ; virology ; Male ; Prednisolone ; therapeutic use ; Prednisone ; therapeutic use ; Retrospective Studies ; Vincristine ; therapeutic use

BACKGROUNDS/AIMS: Negative hepatitis B core antigen (HBcAg) staining in hepatocytes is indicative of viral replication by an active immune response. HBcAg is expressed mainly in the cytoplasm in patients with active hepatitis and hepatocyte regeneration, and mainly in the nuclei of hepatocytes in patients with minimal liver injury in the absence of hepatocyte regeneration. The aim of this study was to elucidate whether the existence and expression pattern of HBcAg predicts the response to antiviral treatment. METHODS: The study involved 58 patients with biopsy-proven chronic hepatitis B who were treated with lamivudine. Hepatitis B e antigen (HBeAg), antibody to HBeAg, hepatitis B virus DNA, and alanine aminotransferase in serum were recorded every 3 months. The inflammation grade and the fibrosis stage of chronic hepatitis were scored from 0 to 4 according to lobular inflammation, portal inflammation, periportal inflammation, and fibrosis. RESULTS: The 58 patients included 49(84%) HBcAg-positive patients, with HBcAg staining confined to the cytoplasm in 15(31%) and in both cytoplasm and nuclei in 34(69%). The grade of lobular inflammation and the total histology score were significantly higher in patients with cytoplasmic expression of HBcAg than in HBcAg-negative patients (lobular inflammation: 2.9 vs 2.1, P=0.02; total histology score: 12.2 vs 10.3, P=0.04). The virologic responses at 3, 6, 9, and 12 months differed significantly between the cytoplasmic and mixed expression groups (P<0.01). CONCLUSIONS: The expression pattern of HBcAg (including its possible absence) before initial therapy appears to predict the response to antiviral treatment.
Adult ; Antiviral Agents/*therapeutic use ; DNA, Viral/blood ; Female ; Hepatitis B Core Antigens/*analysis/metabolism ; Hepatitis B e Antigens/metabolism ; Hepatitis B virus/isolation & purification ; Hepatitis B, Chronic/*drug therapy/virology ; Humans ; Lamivudine/*therapeutic use ; Male ; Middle Aged ; Predictive Value of Tests ; Retrospective Studies

<b>OBJECTIVEb>To measure the neutralization activity in vitro of the antibodies induced by recombinant TGFbeta1 vaccine and to evaluate the vaccine's anti-liver fibrosis activity.

<b>METHODSb>Balb/c mice were immunized with a fusion protein of the human TGFbeta1 epitope-inserted into a hepatitis B core antigen using a prokaryotic expression system. The antibody produced by the recombinant vaccine was determined using ELISA. The biological activity of the anti-TGFbeta1 antibody induced by the vaccine was measured by MTT using mink lung epithelial cell Mv-1-Lu as inhibiting cells. The fusion protein was used as a vaccine in a mice hepatic-fibrosis model.

<b>RESULTSb>A high titer of anti-TGFbeta1 antibody and a low of anti-HBc antibody were detected in the mice after the immunization. The serum antibodies induced combined with the fusion and antigenic peptide prevented the TGFbeta1 inhibiting activity in the Mv-1-Lu cell.

<b>CONCLUSIONb>Recombinant fusion protein can be used as a cytokine vaccine to induce high titers of anti-TGFbeta1 antibodies. Our results show the potentiality of the fusion protein to be used as a vaccine for preventing liver fibrosis.

Animals ; Antibodies ; blood ; Carbon Tetrachloride ; Carbon Tetrachloride Poisoning ; Female ; Hepatitis B Core Antigens ; biosynthesis ; immunology ; Liver Cirrhosis, Experimental ; chemically induced ; prevention & control ; Mice ; Mice, Inbred BALB C ; Prokaryotic Cells ; metabolism ; Random Allocation ; Recombinant Fusion Proteins ; biosynthesis ; immunology ; Transforming Growth Factor beta1 ; biosynthesis ; immunology ; Vaccines, Synthetic ; therapeutic use

<b>BACKGROUNDb>To investigate the frequency of circulating HBV specific T helper cell and evaluate its association with serum levels of HBV DNA before and during lamivudine treatment in patients with chronic hepatitis B.

<b>METHODSb>The frequency of circulating HBV specific T helper cells in response to HBcAg in 25 chronic HBV-infected patients was determined by Elispot assay; serum HBV DNA was quantitated by real-time PCR.

<b>RESULTSb>The frequency of HBV specific T helper cell before antiviral treatment (47.30 +/- 25.50 SFCs /1 x 10(6) PBMC) was significantly higher than that at the third month of therapy (23.10 +/- 18.45 SFCs /1 x 10(6) PBMC, P < 0.05). All 8 patients observed dynamically had decreased frequency of HBV specific T helper cell at the third month of therapy; six patients with serum HBV DNA level reduced had higher frequency of HBV specific T helper cell before treatment than 2 patients without serum HBV DNA level decrease.

<b>CONCLUSIONb>HBV specific T helper cell response at the time of hepatitis flare in chronic hepatitis B patients was significantly augmented compared to that at the time of catabasis.

Adult ; Antiviral Agents ; therapeutic use ; DNA, Viral ; blood ; genetics ; Enzyme-Linked Immunosorbent Assay ; methods ; Female ; Hepatitis B Core Antigens ; immunology ; Hepatitis B virus ; drug effects ; genetics ; immunology ; Hepatitis B, Chronic ; blood ; drug therapy ; virology ; Humans ; Lamivudine ; therapeutic use ; Male ; T-Lymphocytes, Helper-Inducer ; cytology ; drug effects ; immunology

<b>BACKGROUNDb>RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. Our previous study has demonstrated that small interfering RNAs (siRNAs) have sufficiently inhibited hepatitis B virus (HBV) replication and expression in vitro. In this study we observed the RNAi-mediated inhibitory effects on HBV replication in mice models and accessed the specificity of these effects.

<b>METHODSb>A mutant RNAi vector (pSI-C mut) with two base pairs different from the original target gene sequence at the RNAi vector (pSI-C) was constructed according to the method described in this study. A mouse model of acute hepatitis B virus infection was established by injecting naked plasmid pHBV1.3 via the tail vein with acute circulatory overload. pSI-C, pSI-C mut and the irrelevant RNAi control plasmid for green fluorescent protein (GFP) gene, pSIGFP were respectively delivered with pHBV1.3 by tail vein injection method. Six days post injection, enzyme-linked immunosorbent assay (ELISA) assay was used to measure the concentration of HBV surface antigen (HBsAg) in mouse serum, immunohistochemical straining method was used to visualize the expression of HBV core protein (HBcAg) in liver tissues, and the transcriptional level of HBV C mRNA in liver tissues was detected by reverse transcriptase PCR (RT-PCR) analysis.

<b>RESULTSb>Injection of pSI-C exerted magnificent and specific inhibitory effects on the replication and expression of HBV in the murine model. After 6-day post-injection (p.i.), the OD values were shown to be 5.07 +/- 1.07 in infecting group and 0.62 +/- 0.59 in pSI-C group. The concentration of HBsAg in pSI-C group was significantly lower than that in infecting group (P < 0.01). Liver intracellular synthesis of viral core protein was sharply reduced to 0.9% +/- 0.1%, compared with 5.4% +/- 1.2% of positive hepatocytes in infecting group (P < 0.01), and the transcriptional level of HBV C mRNA was greatly reduced by 84.7%. However, the irrelevant RNAi control plasmid (pSIGFP), and the pSI-C mut did not show the same robust inhibitory effects as pSI-C.

<b>CONCLUSIONb>pSI-C exert efficient and specific inhibitory effects on HBV replication and expression in mice models.

Animals ; Hepatitis B ; therapy ; virology ; Hepatitis B Core Antigens ; biosynthesis ; Hepatitis B Surface Antigens ; blood ; Hepatitis B virus ; genetics ; physiology ; Male ; Mice ; Mice, Inbred BALB C ; RNA Interference ; RNA, Messenger ; analysis ; RNA, Small Interfering ; therapeutic use ; RNA, Viral ; analysis ; Virus Replication