HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults.

Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8(+) T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies.

Serious adverse events after cessation of nucleos(t)ide analogues in individuals with chronic hepatitis B: A systematic review and meta-analysis.

Background & Aims: The risk of serious clinical outcomes following cessation of nucleos(t)ide analogues (NUCs) in individuals with chronic hepatitis B remains poorly characterized. This systematic review and meta-analysis aimed to evaluate current literature on this issue. Methods: We searched PubMed, Embase, and Web of Science for NUC stop studies that noted clinical outcomes published between January 1, 2006 and August 18, 2022. We performed meta-research analyses to examine the relationships of reported outcomes with study designs and characteristics and also pooled studies with non-overlapping populations to provide risk estimates for the proportions of (1) severe hepatitis flares or hepatic decompensation or (2) hepatitis flare-related death or liver transplantation. Results: The meta-research analysis included 50 studies of highly heterogeneous designs and characteristics. We found that reporting of safety outcomes varied widely according to outcome definition, follow-up duration, and sample size. Only ten studies prespecified safety events as the study outcome, and only four had an outcome definition to include hepatic insufficiency, a follow-up duration >12 months, and a sample size >100 patients. We further pooled 15 studies with 4,525 individuals and estimated that severe hepatitis flares or decompensation would occur in 1.21% (95% CI 0.70-2.08%), with significant heterogeneity (I 2 = 54%, p <0.01), while hepatitis flare-related death or liver transplantation would occur in 0.37% (95% CI 0.20-0.67%), without significant heterogeneity (I 2 = 0.00%, p = 1.00). Conclusions: Current literature on the risk of serious clinical outcomes following NUC cessation is very limited and highly heterogeneous. Pooled analyses of available data found approximately 1% of patients who stopped NUCs developed severe flares or hepatic decompensation. Impact and implications: Current literature regarding the safety concerns surrounding NUC cessation for individuals with chronic hepatitis B is limited and heterogeneous in designs and characteristics, and thus should be interpreted with great caution. Based on currently available data, the proportion of patients that develop severe hepatitis flares or hepatic decompensation was estimated at 1.21% and that of flare-related death or liver transplantation at 0.37%. Our findings are important for individuals receiving nucleos(t)ide analogues for hepatitis B virus infection because we not only pooled currently available data to estimate the risk of serious clinical adverse events following treatment cessation but also uncovered critical limitations of existing literature regarding the safety of finite therapy.

Intrahepatic quantification of HBV antigens in chronic hepatitis B reveals heterogeneity and treatment-mediated reductions in HBV core-positive cells.

Background & Aims: Patterns of liver HBV antigen expression have been described but not quantified at single-cell resolution. We applied quantitative techniques to liver biopsies from individuals with chronic hepatitis B and evaluated sampling heterogeneity, effects of disease stage, and nucleos(t)ide (NUC) treatment, and correlations between liver and peripheral viral biomarkers. Methods: Hepatocytes positive for HBV core and HBsAg were quantified using a novel four-plex immunofluorescence assay and image analysis. Biopsies were analysed from HBeAg-positive (n = 39) and HBeAg-negative (n = 75) participants before and after NUC treatment. To evaluate sampling effects, duplicate biopsies collected at the same time point were compared. Serum or plasma samples were evaluated for levels of HBV DNA, HBsAg, hepatitis B core-related antigen (HBcrAg), and HBV RNA. Results: Diffusely distributed individual HBV core+ cells and foci of HBsAg+ cells were the most common staining patterns. Hepatocytes positive for both HBV core and HBsAg were rare. Paired biopsies revealed large local variation in HBV staining within participants, which was confirmed in a large liver resection. NUC treatment was associated with a >100-fold lower median frequency of HBV core+ cells in HBeAg-positive and HBeAg-negative participants, whereas reductions in HBsAg+ cells were not statistically significant. The frequency of HBV core+ hepatocytes was lower in HBeAg-negative participants than in HBeAg-positive participants at all time points evaluated. Total HBV+ hepatocyte burden correlated with HBcrAg, HBV DNA, and HBV RNA only in baseline HBeAg-positive samples. Conclusions: Reductions in HBV core+ hepatocytes were associated with HBeAg-negative status and NUC treatment. Variation in HBV positivity within individual livers was extensive. Correlations between the liver and the periphery were found only between biomarkers likely indicative of cccDNA (HBV core+ and HBcrAg, HBV DNA, and RNA). Impact and Implications: HBV infects liver hepatocyte cells, and its genome can exist in two forms that express different sets of viral proteins: a circular genome called cccDNA that can express all viral proteins, including the HBV core and HBsAg proteins, or a linear fragment that inserts into the host genome typically to express HBsAg, but not HBV core. We used new techniques to determine the percentage of hepatocytes expressing the HBV core and HBsAg proteins in a large set of liver biopsies. We find that abundance and patterns of expression differ across patient groups and even within a single liver and that NUC treatment greatly reduces the number of core-expressing hepatocytes.

Efficient stabilization of therapeutic hepatitis B vaccine components by amino-acid formulation maintains its potential to break immune tolerance.

Background & Aims: Induction of potent, HBV-specific immune responses is crucial to control and finally cure HBV. The therapeutic hepatitis B vaccine TherVacB combines protein priming with a Modified Vaccinia virus Ankara (MVA)-vector boost to break immune tolerance in chronic HBV infection. Particulate protein and vector vaccine components, however, require a constant cooling chain for storage and transport, posing logistic and financial challenges to vaccine applications. We aimed to identify an optimal formulation to maintain stability and immunogenicity of the protein and vector components of the vaccine using a systematic approach. Methods: We used stabilizing amino acid (SAA)-based formulations to stabilize HBsAg and HBV core particles (HBcAg), and the MVA-vector. We then investigated the effect of lyophilization and short- and long-term high-temperature storage on their integrity. Immunogenicity and safety of the formulated vaccine was validated in HBV-naïve and adeno-associated virus (AAV)-HBV-infected mice. Results: In vitro analysis proved the vaccine's stability against thermal stress during lyophilization and the long-term stability of SAA-formulated HBsAg, HBcAg and MVA during thermal stress at 40 °C for 3 months and at 25 °C for 12 months. Vaccination of HBV-naïve and AAV-HBV-infected mice demonstrated that the stabilized vaccine was well tolerated and able to brake immune tolerance established in AAV-HBV mice as efficiently as vaccine components constantly stored at 4 °C/-80 °C. Even after long-term exposure to elevated temperatures, stabilized TherVacB induced high titre HBV-specific antibodies and strong CD8+ T-cell responses, resulting in anti-HBs seroconversion and strong suppression of the virus in HBV-replicating mice. Conclusion: SAA-formulation resulted in highly functional and thermostable HBsAg, HBcAg and MVA vaccine components. This will facilitate global vaccine application without the need for cooling chains and is important for the development of prophylactic as well as therapeutic vaccines supporting vaccination campaigns worldwide. Impact and implications: Therapeutic vaccination is a promising therapeutic option for chronic hepatitis B that may enable its cure. However, its application requires functional cooling chains during transport and storage that can hardly be guaranteed in many countries with high demand. In this study, the authors developed thermostable vaccine components that are well tolerated and that induce immune responses and control the virus in preclinical mouse models, even after long-term exposure to high surrounding temperatures. This will lower costs and ease application of a therapeutic vaccine and thus be beneficial for the many people affected by hepatitis B around the world.

Hepatitis B virus infection combined with nonalcoholic fatty liver disease: Interaction and prognosis.

Hepatitis B virus (HBV) infection is still one kind of the infectious diseases that seriously threaten human health. Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. HBV infection complicated with NAFLD is increasingly common. This review mainly describes the interaction between HBV infection and NAFLD, the interaction between steatosis and antiviral drugs, and the prognosis of HBV infection complicated with NAFLD. Most studies suggest that HBV infection may reduce the incidence of NAFLD. NAFLD can promote the spontaneous clearance of hepatitis B surface antigen (HBsAg), but whether it affects antiviral efficacy has been reported inconsistently. HBV infection combined with NAFLD can promote the progression of liver fibrosis, especially in patients with severe steatosis. The outcome of HBV infection combined with NAFLD predisposing to the progression of HCC remains controversial.

Seroprevalence of Hepatitis B Virus Among Pregnant Women in India: A Systematic Review and Meta-Analysis.

Objectives: Hepatitis B virus (HBV) infection during pregnancy is associated with perinatal transmission contributing to the pool of HBV infection in the population. There is a wide variation in the reported data on the seroprevalence of HBV in pregnant patients from various parts of India. Hence, a systematic review and meta-analysis was conducted to determine the pooled seroprevalence of HBV and its associated demographic factors. Methods: A comprehensive literature search of Medline, Scopus, and Google Scholar was conducted from January 2000 to April 2022 for studies evaluating the prevalence of HBV in pregnant patients from India. Results: A total of 44 studies with data on 272,595 patients were included in the meta-analysis. The pooled prevalence of hepatitis B surface antigen (HBsAg) in pregnant women was 1.6% [95% confidence interval (CI), 1.4-1.8]. Among patients with HBsAg positivity, the pooled prevalence of hepatitis B e antigen was 26.0% (95%CI 17.4-34.7). There was no significant difference in the odds of HBV seroprevalence based on the age (<25 years vs. > 25 years) [odds ratio (OR) 1.07, 95%CI 0.74-1.55], parity (primipara vs. multipara) (OR 1.09, 95%CI 0.70-1.70) or area of residence (urban vs. rural) (OR 0.88, 95%CI 0.56-1.39). However, the odds of HBV seroprevalence in those with no or primary education was higher than in those with secondary level education or higher (OR 2.29, 95%CI 1.24-4.23). Prior history of risk factors was present in 13.5-22.7% of patients indicating a vertical mode of acquisition. Conclusion: There is a low endemicity of HBV among pregnant women in India. Risk factors are seen in less than 25% of the cases, indicating vertical transmission as the predominant mode of acquisition, which can be reduced by improving vaccination coverage.

A Prospective Five-Year Follow-up After peg-Interferon Plus Nucleotide Analogue Treatment or no Treatment in HBeAg Negative Chronic Hepatitis B Patients.

Background: Currently available treatment options for chronic hepatitis B (CHB) are not recommended for HBeAg-negative patients with a low viral load. These patients may however benefit from treatment by achieving a functional cure, defined by HBsAg-loss and undetectable HBV DNA. This study evaluated the long-term effect of combination treatment with peg-interferon-alpha-2a (peg-IFN) and adefovir or tenofovir compared to no treatment in these patients. Methods: HBeAg-negative CHB patients with HBV-DNA levels < 20,000 IU/mL (n = 151) were previously randomised 1:1:1 for peg-IFN 180 µg/week plus either adefovir 10 mg/day or tenofovir 245 mg/day, or no treatment and treated for 48 weeks in an open-label study. In this prospective long-term follow-up study, patients were monitored yearly up to five years after end of treatment (week 308). The primary outcome was sustained HBsAg-loss and secondary outcome the dynamics of HBsAg and HBV-DNA levels over time. Results: Of the 131 followed patients, the HBsAg-status was known for 118 patients after five-year follow-up. HBsAg-loss occurred similarly (P = 0.703) in all arms: 8/43 (18.6%) peg-IFN + adefovir, 4/34 (11.7%) peg-IFN + tenofovir, and 6/41 (14.6%) among the untreated patients. The time to HBsAg-loss did not differ between groups (P = 0.641). Low baseline HBsAg levels and genotype A were independently associated with HBsAg-loss irrespective of allocation. HBsAg and HBV-DNA levels declined similarly during follow-up in all patient groups. Conclusions: This prospective randomised controlled study showed that HBsAg-loss overtime was not influenced by treatment with a combination of nucleotide analogue and Peg-IFN. Low baseline HBsAg levels can predict HBsAg-loss irrespective of treatment allocation.

Novel machine learning models outperform risk scores in predicting hepatocellular carcinoma in patients with chronic viral hepatitis.

BACKGROUND & AIMS: Accurate hepatocellular carcinoma (HCC) risk prediction facilitates appropriate surveillance strategy and reduces cancer mortality. We aimed to derive and validate novel machine learning models to predict HCC in a territory-wide cohort of patients with chronic viral hepatitis (CVH) using data from the Hospital Authority Data Collaboration Lab (HADCL). METHODS: This was a territory-wide, retrospective, observational, cohort study of patients with CVH in Hong Kong in 2000-2018 identified from HADCL based on viral markers, diagnosis codes, and antiviral treatment for chronic hepatitis B and/or C. The cohort was randomly split into training and validation cohorts in a 7:3 ratio. Five popular machine learning methods, namely, logistic regression, ridge regression, AdaBoost, decision tree, and random forest, were performed and compared to find the best prediction model. RESULTS: A total of 124,006 patients with CVH with complete data were included to build the models. In the training cohort (n = 86,804; 6,821 HCC), ridge regression (area under the receiver operating characteristic curve [AUROC] 0.842), decision tree (0.952), and random forest (0.992) performed the best. In the validation cohort (n = 37,202; 2,875 HCC), ridge regression (AUROC 0.844) and random forest (0.837) maintained their accuracy, which was significantly higher than those of HCC risk scores: CU-HCC (0.672), GAG-HCC (0.745), REACH-B (0.671), PAGE-B (0.748), and REAL-B (0.712) scores. The low cut-off (0.07) of HCC ridge score (HCC-RS) achieved 90.0% sensitivity and 98.6% negative predictive value (NPV) in the validation cohort. The high cut-off (0.15) of HCC-RS achieved high specificity (90.0%) and NPV (95.6%); 31.1% of patients remained indeterminate. CONCLUSIONS: HCC-RS from the ridge regression machine learning model accurately predicted HCC in patients with CVH. These machine learning models may be developed as built-in functional keys or calculators in electronic health systems to reduce cancer mortality. LAY SUMMARY: Novel machine learning models generated accurate risk scores for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. HCC ridge score was consistently more accurate than existing HCC risk scores. These models may be incorporated into electronic medical health systems to develop appropriate cancer surveillance strategies and reduce cancer death.

Clinical and virological features of chronic hepatitis B in the French national surveillance program, 2008-2012: A cross-sectional study.

Background & Aims: Among people living with HBV, only a subset of individuals with chronic hepatitis is in need of treatment, and this proportion varies according to the population, region, and setting. No estimates of the proportion of people who are infected with HBV and meet the treatment eligibility criteria in France are available. Methods: 552 treatment-naïve individuals with chronic HBV infection referred for the first time to a hepatology reference centre between 2008 and 2012 were prospectively included. Demographic, clinical, and laboratory data were analysed. Results: In total, 61.1% of patients were males, with a median age of 37.5 years. Moreover, 64% were born in an intermediate- or high-HBV endemicity country, and 90% were HBeAg-negative. At referral, median HBV DNA and HBsAg levels were 3.3 and 3.6 log IU/ml, respectively; 37.8% of patients had alanine aminotransferase >40 U/L, and 29.0% had moderate or severe fibrosis (≥F2), including 9.4% with cirrhosis. The most prevalent genotypes were D (34.7%), E (27.4%), and A (25.7%). Coinfections were rare: 2.4% were HIV-positive, 4.0% were HCV-positive, and 6.0% were HDV-positive. According to the 2017 EASL Clinical Practice Guidelines, using a single time point analysis, 2.7% of patients were classified as HBeAg-positive chronic infection, 6.1% as HBeAg-positive chronic hepatitis B, 26.5% as HBeAg-negative chronic hepatitis B, and 61.1% as HBeAg-negative chronic infection, whereas 3.6% patients could not be classified. The performance of HBsAg level quantification to identify individuals with HBeAg-negative chronic hepatitis B was poor. A total of 29.1% met the criteria for initiation of antiviral treatment, whereas 66.5% remained under routine clinical surveillance. Most eligible patients initiated recommended first-line therapies, including tenofovir (45.3%), entecavir (36.8%), or pegylated interferon alpha (11.6%). Conclusions: Of all cases, 9.4% had cirrhosis at presentation and 29.1% met the 2017 EASL Clinical Practice Guidelines treatment criteria. HBsAg levels failed to accurately identify individuals with HBeAg-negative chronic infection. Lay summary: Among French adults chronically infected with HBV referred for the first time to hepatology reference centres, about one-third had a significant liver disease. Approximately one-third of individuals met criteria for initiation of antiviral treatment based on entecavir or tenofovir or, occasionally, pegylated interferon alpha.

A phylogenetic perspective of antiviral species of the genus Artemisia (Asteraceae-Anthemideae): A proposal of anti SARS-CoV-2 (COVID-19) candidate taxa.

Introduction: Different classes of disease-causing viruses are widely distributed universally. Plant-based medicines are anticipated to be effective cures for viral diseases including the COVID-19, instigated by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). This study displays the phylogenetic perspective of Artemisia and proposes some candidate taxa against different viral diseases, including SARS-CoV-2. Methods: Data of Artemisia with antiviral activity were obtained from different published sources and electronic searches. A phylogenetic analysis of the nrDNA ITS sequences of reported antiviral Artemisia species, along with the reference species retrieved from the NCBI GenBank database, was performed using the maximum likelihood (ML) approach. Results: In total, 23 Artemisia species have been documented so far with antiviral activity for 17 different types of viral diseases. 17 out of 23 antiviral Artemisia species were included in the ITS phylogeny, which presented the distribution of these antiviral Artemisia species in clades corresponding to different subgenera of the genus Artemisia. In the resultant ML tree, 10 antiviral Artemisia species appeared within the subgenus Artemisia clade, 2 species appeared within the subgenus Absinthium clade, 3 species appeared within the subgenus Dracunculus clade, and 2 species appeared within the subgenus Seriphidium clade. Discussion: Artemisia species from different subgenera with antiviral activity are prevalent in the genus, with most antiviral species belonging to the subgenus Artemisia. A detailed analysis of taxa from all subgenera, particularly the subgenus Artemisia, is therefore proposed in order to discover compounds with potential anti-SARS-CoV-2 activity.

Tenofovir is Superior to Entecavir in Patients with Treatment-naïve Hepatitis B e-Antigen-Positive Chronic Hepatitis B.

BACKGROUND AND AIM: Chronic Hepatitis B (CHB) is a global health problem affecting around 400 million of people worldwide. Two available first-line antiviral drugs are tenofovir disoproxil fumarate (TDF) and Entecavir (ETV). Till date,there are few published reports from India comparing efficacy of TDF and ETV in CHB cases. Therefore, this present study was carried out with an aim to compare the efficacy of ETV and TDF in patients with nucleos(t)ide naïve CHB. MATERIALS AND METHODS: This retrospective cohort study was carried out in 192 treatment naïve CHB cases, who completed 24 months of treatment with either TDF or ETV between March 2015 and August 2017. The primary end point of the study was undetectable hepatitis B virus DNA after 24 months of therapy. RESULTS: Of total 192 patients with CHB, 38 hepatitis B e-antigen (HBeAg)-positive and 53 HBeAg-negative patients were treated with tenofovir, whereas 40 HBeAg-positive and 61 HBeAg-negative patients were treated with ETV. Pretreatment characteristics at baseline were not statistically different between the TDF and ETV groups. Patients treated with TDF achieved significantly higher complete viral suppression as compared with ETV-treated patients (Log rank: 7.04, P = 0.008) in HBeAg-positive CHB during the 24 months follow-up time; whereas no significant difference in viral suppression rate could be noticed in HBeAg-negative patients (Log rank: 0.98, P = 0.38). Both univariate and multivariate analysis by cox proportional hazard model confirmed that tenofovir had significant rate of complete viral suppression in comparison with ETV in HBeAg-positive patients (P < 0.05); whereas complete viral suppression rates were similar in HBeAg-negative patients. CONCLUSION: In our study, tenofovir had more effective antiviral suppressive effect compared with ETV in HBeAg-positive, nucleos(t)ide-naïve CHB cases.

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.

Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study.

BACKGROUND & AIMS: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. METHOD: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 µg BRII-179 (Part 1, n = 25) and 40 µg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. RESULTS: Both 20 µg and 40 µg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. CONCLUSION: In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. CLINICAL TRIAL NUMBER: ACTRN12619001210167. LAY SUMMARY: BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.

Rebound of HBV DNA after cessation of nucleos/tide analogues in chronic hepatitis B patients with undetectable covalently closed.

BACKGROUND & AIMS: Nucleos(t)ide analogues (NUCs) effectively suppress serum HBV DNA. Previously, we have identified 21 patients with undetectable covalently closed circular DNA (cccDNA) upon long-term NUC therapy. This study investigated the effect of NUC withdrawal in patients with undetectable cccDNA. METHODS: Nineteen patients on long term NUCs (median 13.4 years) were recruited: 13 were randomized to discontinue NUCs; 6 to continue taking NUCs. All had undetectable cccDNA at the time of last liver biopsy (median time 2.9 years prior to randomization). Serum HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg), liver biochemistry, and serum HBV RNA were monitored. RESULTS: At the time of randomization, all patients had undetectable serum HBV DNA and HBV RNA. Twelve of the 13 patients had HBV DNA rebound to 100 IU/ml within 20 weeks of NUC discontinuation. The thirteenth patient had HBV DNA rebound at week 70. Three patients experienced biochemical flares after re-treatment which subsequently resolved. There was no significant association between the time of HBV DNA rebound and baseline HBsAg, HBcrAg and alanine aminotransferase, duration of treatment, and age at which treatment was stopped (all p >0.05). At the time of HBV DNA rebound, HBV DNA levels correlated with HBcrAg levels (p = 0.003), but not with HBsAg levels (p = 0.262). CONCLUSIONS: In patients with undetectable intrahepatic cccDNA, virologic rebound still occurred after NUC cessation. At the rebound of HBV DNA, the kinetics of HBsAg production were independent of those of viral DNA replication. Additional studies are required to determine the factors that may predict virologic rebound and when NUCs can be discontinued in HBsAg-positive patients with chronic hepatitis B. LAY SUMMARY: It has been shown that following long-term nucleos(t)ide analogue treatment for chronic hepatitis B, some patients have undetectable levels of viral DNA in their livers. We tested the results of withdrawing nucleos(t)ide analogue treatment in these patients and found that viral relapse could occur in patients with undetectable viral DNA. Further research is required to determine whether nucleos(t)ide analogue treatment can be discontinued in specific patients with chronic hepatitis B.

EGF receptor inhibitors comprehensively suppress hepatitis B virus by downregulation of STAT3 phosphorylation.

Current antiviral therapy can not cure chronic hepatitis B virus (HBV) infection or eliminate the risk of hepatocellular carcinoma. The licensed epidermal growth factor receptor (EGFR) inhibitors have found to inhibit hepatitis C virus replication via downregulation of signal transducers and activators of transcription 3 (STAT3) phosphorylation. Since STAT3 is also involved in HBV replication, we further studied the anti-HBV efficacy of the EGFR inhibitors in this study. HBV-transfected HepG2.2.15 cells and HBV-infected HepG2-NTCP cells were used as cell models, and HBV replication, the syntheses of viral antigens and the magnitude of the covalently closed circular DNA (cccDNA) reservoir were used as indictors to test the anti-HBV effects of EGFR inhibitors erlotinib and gefitinib. Erlotinib inhibited HBV replication with a half-maximal inhibitory concentration of 1.05 µM. It also reduced the syntheses of viral antigens at concentrations of 2.5 µM or higher. The underlying mechanism was possibly correlated with its inhibition on STAT3 phosphorylation via up-regulation of suppressor of cytokine signaling 3. Gefitinib also inhibited HBV replication and antigen syntheses. Compared with the commonest antiviral drug entecavir, these EGFR inhibitors additionally reduced hepatitis B e antigen and erlotinib also marginally affected the cccDNA reservoir in HBV-infected HepG2-NTCP cells. Interestingly, these promising anti-HBV effects were significantly enhanced by extension of treatment duration. In conclusion, EGFR inhibitors demonstrated a comprehensive anti-HBV potential, highlighting a new strategy to cure HBV infection and suggesting animal model-related studies or clinical try in the future.

Potential Implications of Detecting HBsAg in Asymptomatic People in an Endemic Community Through Medical Camps.

BACKGROUND: In a developing country like India with intermediate level of prevalence of hepatitis B, most of the patients remain undiagnosed as they are asymptomatic. The purpose of the study was to diagnose asymptomatic HBsAg positive patients from the general population and evaluate further the potential clinical implications of IDAHS. METHODS: Asymptomatic subjects with unknown HBV status were screened free of cost for hepatitis-B surface antigen. Those who tested positive for HBsAg were further tested to identify those who were potential candidates for anti-viral therapy. To explore the relevance of our screening we assessed potential implications of HBsAg detection. RESULTS: A total of 30,836 patients were screened in medical camps over the period of 7 years. Out of these 704 (2.3%) subjects were found to be positive for HBsAg. Distress of being diagnosed with HBV was expressed by 649 (92%) of the positive subjects. High cost of further testing and antiviral therapy, leading to inability to pursue further management was elicited in 510 (72%) of the positive subjects. HBV DNA was detected in 349 (59%) out of 592 subjects, out of which 236 (67%) had high viral load. CONCLUSION: Incidental detection of asymptomatic HBsAg positive subjects was seen in 2.3% of subjects. One third of these patients had an actively replicating virus and required antiviral therapy. Financial support was required in 72% of the subjects for further HBV management. Detecting HBsAg in asymptomatic person in an endemic community has considerable health and psycho-economic impact on the individual.

Prevalence and Characteristics of Hepatitis Delta Virus Infection in a Tertiary Hospital Setting in Cameroon.

BACKGROUND/AIMS: Hepatitis B virus (HBV) and hepatitis D virus (HDV) coinfection is associated with more severe liver disease than HBV alone. More knowledge on the epidemiology and clinical impact of HDV-infected individuals is needed in Cameroon.We aimed at determining the frequency of anti-HDV antibody testing in hepatitis B surface antigen (HBsAg) positive patients, the proportion of anti-HDV positivity, and the characteristics of anti-HDV positive compared to anti-HDV negative patients in a tertiary hospital setting in Cameroon. METHODS: A cross-sectional study was conducted. Clinical records of chronic HBV-infected patients attending the gastroenterology unit at the Douala General Hospital from 2010 to 2014 were reviewed. RESULTS: Of 365 files of HBsAg-positive patients defined as chronic HBV infection, 80.5% (294) were tested for anti-HDV antibodies, among whom 10.5% (31/294) were positive. Median aspartate aminotransferase (P < 0.0001), alanine aminotransferase (P < 0.0001), and gamma glutaryl transpeptidase (P < 0.0001) were significantly higher while platelets count (P < 0.002) and prothrombin time (P < 0.0001) were significantly lower in anti-HDV positive compared to anti-HDV negative patients. Liver necroinflammation (P < 0.0001), fibrosis score (P < 0.0001), and decompensated cirrhosis (P < 0.0001) were also significantly associated with anti-HDV positivity. CONCLUSION: The proportion of anti-HDV antibody positivity remains high in this setting and was significantly associated with more severe liver disease compared to those who were anti-HDV negative. More studies are needed to evaluate rates of HDV testing in other centers in Cameroon and the subregion. Preventive strategies for HBV prevention, which also apply to HDV, must still be reinforced by healthcare providers and policy makers.

T cell--associated immunoregulation and antiviral effect of oxymatrine in hydrodynamic injection HBV mouse model.

Although oxymatrine (OMT) has been shown to directly inhibit the replication of hepatitis B virus (HBV) in vitro, limited research has been done with this drug in vivo. In the present study, the antiviral effect of OMT was investigated in an immunocompetent mouse model of chronic HBV infection. The infection was achieved by tail vein injection of a large volume of DNA solution. OMT (2.2, 6.7 and 20 mg/kg) was administered by daily intraperitoneal injection for 6 weeks. The efficacy of OMT was evaluated by the levels of HBV DNA, hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg) and hepatitis B core antigen (HBcAg). The immunoregulatory activity of OMT was evaluated by serum ELISA and flow cytometry. Results shows that OMT at 20 mg/kg inhibited HBV replication, and it was more efficient than entecavir (ETV) in the elimination of serum HBsAg and intrahepatic HBcAg. In addition, OMT accelerated the production of interferon-γ (IFN-γ) in a dose-dependent manner in CD4+ T cells. Our findings demonstrate the beneficial effects of OMT on the enhancement of immunological function and in the control of HBV antigens. The findings suggest this drug to be a good antiviral therapeutic candidate for the treatment of HBV infection.

Immunization of babies born to HBsAg positive mothers: An audit on the delivery and completeness of follow up in Norfolk and Suffolk, United Kingdom.

Perinatal transmission of hepatitis B infection has increased in the UK over the last decade. Routine antenatal screening of pregnant mothers (based on HBsAg) provides an effective means to identify 'at risk' babies. Follow up of babies born to infected mothers involves 4 doses of vaccination and/or a single dose of HBIG at birth. In this study we report the outcome of follow up of babies born to infected mothers over a 5 y period. One hundred sixty-three babies born to HBsAg positive mothers were followed up to ascertain the completeness for immunization and serological testing. Vaccination completion was 99.4% (162 of babies) at birth (1st dose), 95.6% (152 babies) for the second dose (at 1st month), 94.3 % (148 babies) for the 3rd dose (at 2nd month) and 83.4% (106 babies) for the 4th dose (at 12 months). Additionally, at 12 months 29.9% (38) of babies had their blood tested serologically to ascertain infection status; all babies receiving antigen testing were HBsAg negative. The overall vaccination coverage was good, although there is scope to improve the coverage of 4th dose. However, the proportion of children who were serologically tested for surface antigen at 12 months was considerably lower and there is a greater need to test babies concurrently at the time of giving the 4(th) dose. The proposed dried blood spot testing which will be rolled out from September 2014 should address this issue.

Designing immune therapy for chronic hepatitis B.

Presently-available antiviral drugs may not be a satisfactory option for treatment of patients with chronic hepatitis B (CHB). In spite of presence of several antiviral drugs, sustained off-treatment clinical responses are not common in CHB patients treated with antiviral drugs. In addition, antiviral drug treatment may have limited effects on blocking the progression of HBV-related complications. However, substantial long-term risk of viral resistance and drug toxicity are related with maintenance antiviral therapy in CHB patients with presently-available antiviral agents. The infinite treatments with antiviral drugs for CHB patients are also costly and may be unbearable by most patients of developing and resource-constrained countries. In this situation, there is pressing need to develop new and innovative therapeutic approaches for patients with chronic hepatitis B virus (HBV) infection. Immune therapy has emerged as an alternate therapeutic approach for CHB patients because studies have shown that host immunity is either impaired or derailed or distorted or diminished in CHB patients compared to patients with acute resolved hepatitis B who contain the HBV replication and control liver damages. Both non antigen-specific immune modulators and HBV antigen-specific agents have been used in CHB patients during last three decades. However, similar to antiviral therapy, the ongoing regimens of immune therapeutic approaches have also been unable to show real promises for treating CHB patients. The concept of immune therapy for treating CHB patients seems to be rationale and scientific, however, concerns remain about suitable designs of immune therapy for CHB patients.