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Hepatitis B (HB) infection is a major global health problem. There is limited knowledge about HB vaccination-induced immune memory responses. We compared the frequency of CD8 + memory T cell subsets between responders (RSs) and non-responders (NRs) to HB vaccination. Blood samples were collected from RSs and NRs. PBMCs were cultured in the presence of Hepatitis B surface antigens (HBsAg) and PHA for 48 h to restimulate CD8 + memory T cells and T cell memory subsets were detected by flow cytometry using memory cell markers. The frequency of T EM , T CM , and T CM hi was significantly higher in responders compared to non-responders (p = 0.024, 0.022, and 0.047, respectively). Additionally, we report a positive correlation between the frequency of T EM cells in RSs with age and anti-HBsAb level (p = 0.03 and r s  = 0.5; p = 0.01 and r s  = 0.06). Responders display a higher level of CD8 + T cell-mediated immunity. Therefore, we suggest a possible defect in the formation of immunological CD8 + memory T cells in NRs and it may reduce antibody production compared to the RSs, although more experiments are needed., (© 2024 The Scandinavian Foundation for Immunology.)

Pakistan harbours a large burden of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We utilised repeat sero-surveys to assess progress achieved towards hepatitis elimination in Pakistan. Multilevel logistic regression evaluated the change in HBV infection (HBV surface antigen (HBsAg)-positive) prevalence and HCV exposure (HCV antibody (HCV-Ab)-positive) prevalence between two sero-surveys from 2007 and 2019 for Sindh province and associated risk factors. Adjusted odds ratios (aORs) were estimated and population-attributable fractions (PAF) for modifiable risk factors for HCV exposure. The 2007 and 2019 surveys included 8855 and 6672 individuals. HBsAg prevalence decreased from 2.6% (95% confidence intervals (95% CI): 2.2-2.9) in 2007 to 1.1% (95% CI: 0.8-1.3) in 2019, while HCV-Ab prevalence increased from 5.1% (95% CI: 4.6%-5.5%) to 6.2% (95% CI: 5.6%-6.8%). The age and gender-adjusted HBsAg prevalence decreased by 80% (aOR = 0.2, 95% CI: 0.1-0.4) among children and 60% (aOR = 0.4, 95% CI: 0.3-0.6) among adults over 2007-2019, while HCV-Ab prevalence decreased by 60% (aOR = 0.4, 95%CI:0.2-0.7) in children and increased by 40% (aOR = 1.4, 95% CI: 1.2-1.7) in adults. HCV-Ab prevalence was lower in adults with secondary (aOR = 0.6, 95% CI: 0.5-0.8) and higher (aOR = 0.5, 95%CI:0.3-0.8) education compared to illiterates and higher among adults reporting blood transfusion (aOR = 1.7, 95% CI: 1.2-2.4), family history of hepatitis (aOR = 2.5, 95% CI: 1.9-3.3), past year medical injection (aOR = 2.1, 95% CI: 1.6-2.7), being tattooed (aOR = 1.4, 95% CI: 1.0-1.9) and shaved by traditional barber (aOR = 1.2, 95% CI: 1.0-1.5). Modifiable risk factors accounted for 45% of HCV exposure, with medical injection(s) accounting for 38% (95%CI,25.7-48.4%). Overall HCV has increased over 2007-2019 in Sindh province, while HBV prevalence has decreased. Medical injections should be an important focus of prevention activities., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Hepatitis B Virus (HBV) infectivity data were reviewed and the 50% infectious dose (ID 50 ) was reassessed in different HBsAg-positive infection stages enabling modelling of transfusion-transmitted (TT)-HBV infection risk if HBsAg donor screening was replaced by individual donation nucleic acid amplification technology (ID-NAT). Quantitative HBsAg and HBV-DNA assays were performed against international standards to compare the ratio between potential infectious HBV virions and subviral HBsAg particles in Egyptian HBsAg-positive blood donors as well as in Japanese chimpanzee samples of known infectivity. HBV-DNA load below the quantification limit of detection was estimated against a reference standard by replicate NAT testing (n = 25). Infectivity of chimpanzee samples collected during ramp-up and declining viremic phase were tested in a human liver chimeric mice (HLCM) model and compared with published infectivity data from different HBsAg-positive infection stages. Lowest estimates of ID 50 in HBsAg-positive plasma were 3-6 HBV virions in chimpanzee studies. Infectivity decreased approximately 10-100-fold in the declining viremic phase using HLCM. In acute phase samples, HBV to HBsAg particle ratios varied between 1:10 2 -10 4 but in HBsAg-positive blood donors this particle ratio reached 1:10 6 -10 12 when viral load was below 100 HBV-DNA copies/mL. Modelled TT-HBV risk of an HBsAg-positive/ID-NAT nonreactive blood transfusion was estimated at 5.5%-27% for components containing 20-200 mL of plasma when assuming an ID 50 of 316 (point estimate between 100 and 1000) virions. It cannot be ensured that discontinuation of HBsAg donor screening and reliance on ID-NAT alone is safe., (© 2024 John Wiley & Sons Ltd.)

Hepatitis D virus (HDV), which occurs as a co-infection with the hepatitis B virus (HBV), is a significant public health burden. Currently, there is a scarcity of data regarding this co-infection in the developing countries. This study aims to address the clinical prevalence of HDV among HBV-infected patients in Sulaymaniyah Governorate, Iraq. This prospective cross-sectional study, conducted from May to November 2022, screened HBV DNA-positive patients visiting Sulaimani Teaching Hospital in Sulaymaniyah governorate, Iraq, for anti-HDV antibodies and HDV RNA. The study included 150 confirmed HBV DNA-positive patients. Of these, 54.7% were male. The mean age of the patients was 49.1 ± 10.1 (18-68). Serological assessment found that 23 (15.3%) of the patients had anti-HDV IgG antibodies, suggesting past or chronic HDV infection, while 16 (10.7%) tested positive for anti-HDV IgM, indicating recent/acute infection. Further molecular analysis confirmed HDV RNA in 15 (10%) of HBV patients, indicating real HDV prevalence. The prevalence of anti-HDV and HDV RNA did not significantly differ by age, gender, marital status, residency, medical, family or medical history (p > 0.05). In conclusion, this study demonstrated a relatively high HDV prevalence among HBV patients in Sulaymaniyah Governorate, Iraq, at 10%, which stresses the need for better screening, health strategies and focused research to combat its impact., (© 2024 John Wiley & Sons Ltd.)

Chronic hepatitis B virus (HBV) infection is a global issue and can lead to cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B surface antigen (HBsAg) is an important marker of HBV infection and HBsAg quantification could be a useful tool in clinical practice. This systematic literature review aimed to explore the association between HBsAg titres and long-term disease outcomes and evaluate the relationship between HBsAg titres, or changes in HBsAg titres, and clinical and treatment characteristics in patients with chronic HBV infection. Structured searches were performed in MEDLINE and Embase (January 2000 to 31 March 2023). Eighty-two studies were included, comprising 51% retrospective cohort studies, mostly conducted in Asia (85%). HBsAg levels were shown to predict the long-term development of cirrhosis and HCC in patients who were untreated prior to and during follow-up; however, these data were inconclusive in mixed and treated populations. HBsAg titres were significantly associated with various virological markers including serum HBV DNA, HBcrAg, HBeAg, HBV RNA levels, intrahepatic covalently closed circular DNA (cccDNA) and intrahepatic HBsAg expression. HBsAg titres generally declined over time; this decline was more pronounced in early (HBeAg-positive) than later disease phases (HBeAg-negative). Higher decline in HBsAg levels was consistently associated with subsequent HBsAg seroclearance and a greater decline in total intrahepatic HBV DNA and cccDNA levels. In conclusion, this review showed that HBsAg levels and rates of decline could inform assessment, management and prediction of outcomes in chronic HBV infection. Further studies in broader, more diverse populations and treated patients are needed., (© 2024 GSK plc. Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Co-existing chronic hepatitis B virus (CHB) infection and metabolic dysfunction associated steatotic liver disease (MASLD) can exert complex effects on hepatic metabolism, requiring mechanistic study. CHB participants were assessed for MASLD and the impact of hepatic steatosis/metabolic syndrome (MetS) on novel viral and immunological markers. In this prospective, cohort study, untreated CHB subjects were assessed for liver disease by non-invasive tests (i.e. FibroScan, controlled attenuation parameter, CAP). Subjects were tested for cytokines and IFN-γ ELISPOT assay to HBV Surface (S) and Core (C) proteins. Standard HBV serological, exploratory biomarkers and deep sequencing of HBV S and C genes were performed. In 53 subjects (median age 45 years [SD = 10.6], 35% F, 56% Asian, 20% Black, 3% White), 94% (50) HBeAg negative, 63% genotype B/C, mean HBV DNA 3.2 log 10 IU/mL (SD = 1.8), quantitative HBsAg 2.9 log 10 IU/mL (SD = 1.2) and HBV pgRNA 2.1 log 10 copies/mL (SD = 1.3). In enrolled subjects, the mean ALT was 41.9 U/L (SD = 24.0), FibroScan was 5.7 kPa (SD = 1.9) and CAP was 306.4 dB/m (SD = 49.0). The mean BMI was 28.2 kg/m 2 (SD = 4.2), 20% (11/53) had diabetes, 35% (19/53) dyslipidaemia and 24% (13/53) hypertension. Subjects with MetS and steatosis showed lower HBV markers (p < .01), higher HBV S diversity (p = .02) and greater frequency of HBV variants associated with host-anti-viral immune escape. Pro-inflammatory cytokine levels and HBV-specific cellular responses were higher in participants with hepatic steatosis. In CHB, MASLD/hepatic steatosis was associated with HBV variants and systemic immune responses potentially impacting liver disease progression despite low-level viraemia., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

Chronic hepatitis B virus (HBV) infection is a significant global public health concern, and the clearance of HBV is closely linked to the activity of HBV-specific T cells, which is regulated by various co-suppressor molecules. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is among these co-suppressor molecules which induces T cell exhaustion by competitively inhibiting CD28 and dampening the function of HBV-specific T cells. CTLA-4 also plays a role in the regulation of T helper (Th) cell differentiation and influences cytokine release. In addition, CTLA-4 can impact glucose metabolism in hepatocellular carcinoma through its interaction with T regulatory (Treg) cells. This review aims to provide a comprehensive overview of the existing literature related to the role of CTLA-4 in HBV patients across different subsets of T cells. Additionally, we propose a discussion on the possible mechanisms through which CTLA-4 may contribute to HBV infection, as well as the development of HBV-induced cirrhosis and hepatocellular carcinoma., (© 2024 John Wiley & Sons Ltd.)

The WHO recommends hepatitis B birth-dose vaccination (HepB-BD), but it is not routinely given in most sub-Saharan African countries. We aimed to assess the immunogenicity of HepB-BD in addition to the existing hepatitis B vaccine (HepB3) schedule in Kinshasa, Democratic Republic of Congo among HBV-unexposed and HBV-exposed infants. Using an open-label, randomised, controlled design, HBV-unexposed infants were randomised (1:1) to receive the standard HepB3 vaccine series (group U3), or to receive HepB-BD in addition to HepB3 (group U4). A supplemental cohort of HBV-exposed infants (group E4) received HepB-BD and HepB3. We compared the proportion of infants with protective antibodies against HBV (HBV surface antibody ≥ 10 mIU/mL) between groups U3 and U4 and groups U4 and E4 at 12 months of age. Between August 20 and October 9, 2019, we enrolled 281 mother/infant dyads; 88 (31.3%) returned at 12 months. Most infants had protective antibodies against HBV at 12 months: 92.9% (75.7%-98.2%) in group U3, 85.7% (67.5%-94.5%) in group U4 and 96.9% (95% CI: 81.2%-99.6%) in group E4. Trends held in estimates adjusted for loss-to-follow-up (LTFU) and baseline imbalance across groups. In this first randomised trial assessing the addition of HepB-BD to the hepatitis B vaccine schedule in SSA, we found that HBV-unexposed infants who received the 3-dose and 4-dose vaccine series had similar immunogenicity against HBV at 12 months. A high proportion of infants, and notably HBV-exposed infants, had protective antibodies. Though extrapolation of findings may be limited by LTFU, this study adds real-world evidence regarding HepB-BD implementation in sub-Saharan Africa. Trial Registration: ClinicalTrials.gov identifier: NCT03897946., (© 2024 John Wiley & Sons Ltd.)

Cigarette smoking is associated with worse clinical outcomes in patients with chronic hepatitis B (CHB) infection, but the effects on hepatitis B surface antigen (HBsAg) seroclearance are unclear. This study aimed to investigate the effect of active smoking on HBsAg seroclearance (SC) and its impact on peripheral blood lymphocytes in patients with CHB infection. Longitudinal follow-up data was retrieved in 7833 antiviral-treated CHB subjects identified from a centralised electronic patient record database (Part 1). Phenotypic analysis of peripheral blood mononuclear cells (PBMCs) from 27 CHB-infected patients (6 active smokers; 13 with SC) was performed by flow cytometry to assess programmed death-1 (PD-1) expression and proportion of regulatory T cells (CD4 + CD25 + CD127 lo ). Effector function of HBV-specific T cells was examined by comparing granzyme B (GZMB) and transforming growth factor beta (TGFβ) production in undepleted PBMCs and Treg-depleted PBMCs after 7 days in vitro stimulation with HBV envelope protein overlapping peptides (Part 2). Over a median follow-up of 5 years, smoking was associated with lower probability of SC (aHR 0.70, 95% CI 0.57-0.87). PD-1 expression was increased in CD4 + T cells, CD8 + T cells and CD20 + B cells among smokers compared to non-smokers and positively correlated with pack years (all p < 0.05). Treg depletion led to partial functional recovery of HBV-specific T cells, with significantly bigger magnitude in smokers (p = 0.0451, mean difference = 4.68%) than non-smokers (p = 0.012, mean difference = 4.2%). Cigarette smoking is associated with lower chance of HBsAg seroclearance, higher PD-1 expression on lymphocytes, and impairment of effector functions of HBV-specific T cells in CHB., (© 2024 The Author(s). Journal of Viral Hepatitis published by John Wiley & Sons Ltd.)

There is still controversy about whether to continue antiviral therapy (AVT) after delivery, especially for pregnant women in the immune tolerance (IT) phase. In this study, a retrospective cohort study was conducted to explore the relationship between hepatitis B e antigen (HBeAg) decline rate (%) from mid-pregnancy to delivery and HBeAg seroconversion postpartum among patients using nucleos(t)ide analogs (NAs) to prevent mother-to-child transmission (MTCT), with the goal of identifying the ideal candidates for postpartum AVT continuation. This retrospective cohort study included 151 postpartum women. Univariate and multivariable logistic regression analyses were conducted to assess the association between the HBeAg decline rate (%) from mid-pregnancy to delivery and HBeAg seroconversion postpartum. Receiver operating characteristic (ROC) analysis was utilized to evaluate the predictive capacity of the HBeAg decline rate (%) and determine the optimal cut-off point. The univariate analysis revealed a significant association between the HBeAg decline rate (%) and HBeAg seroconversion postpartum (OR 1.068, 95% CI: 1.034-1.103, p < .001). In the multivariate regression analysis, adjusting for age, hepatitis B surface antigen (HBsAg) titre (log10 IU/mL) at mid-pregnancy, HBeAg titre (log10 S/CO) at mid-pregnancy, and hepatitis B virus (HBV) DNA load decline rate (%) from mid-pregnancy to delivery, the HBeAg decline rate(%) remained significantly associated with HBeAg seroconversion postpartum (OR 1.050, 95% CI: 1.015-1.093, p = .009). Then HBeAg decline rate (%) was treated as a categorical variable (tertiles) for sensitivity analysis. In the three distinct models, taking Tertile1 as a reference, women in Tertile3 still had a 4.201-fold (OR 4.201, 95% CI: 1.382-12.773, p = .011) higher risk of developing HBeAg seroconversion (p for trend <.05) after adjusting above covariates. The area under the curve (AUC) was 0.723 (95% CI: 0.627-0.819). The optimal cut-off value was 5.43%, with a sensitivity of 0.561, specificity of 0.791, and Youden's index of 0.352.A higher HBeAg decline rate (%) from mid-pregnancy to delivery independently correlated with an increased risk of HBeAg seroconversion postpartum. This decline rate can serve as a valuable clinical indicator for predicting HBeAg seroconversion., (© 2024 John Wiley & Sons Ltd.)

Limited data exist regarding the association between hepatitis B virus (HBV) DNA levels and liver histopathological changes in patients with chronic hepatitis B (CHB) during the immune tolerant (IT) phase. In this study, we retrospectively analysed liver biopsy results from 150 adult IT-CHB patients. The liver tissue necroinflammation and fibrosis were evaluated by the Scheuer scoring system. Multivariate logistic regression, smooth curve fitting, and segmented regression models were used to examine the association between HBV DNA levels and liver histopathological changes. A total of 26%, 30.67% and 42% of IT patients had significant necroinflammation (≥G2), significant fibrosis (≥S2) and significant histopathological changes (≥G2 and/or ≥S2), respectively. HBV DNA levels were independently and non-linear inversely associated with significant necroinflammation and histopathological changes in IT-CHB patients. Patients with HBV DNA levels <10 7  IU/mL had a higher risk of significant histopathological changes compared to those with levels >10 7  IU/mL. The findings were further confirmed by smooth curve fitting analyses, subgroup and sensitivity analyses. In segmented regression model analyses, the optimal DNA value for the lowest odds ratio of significant histopathological changes was 7.26 log10 IU/mL. A non-linear inverse association between HBV DNA levels and significant histopathological changes in IT-CHB patients. DNA 7.26 log10 IU/mL may serve as a potential cut-off point to define a 'true immune tolerant phase' with minimal liver histopathological changes., (© 2024 John Wiley & Sons Ltd.)

The impact of concurrent fatty liver (FL) on response to antiviral therapy in chronic hepatitis B (CHB) patients has not been well characterized. We aimed to systematically review and analyse antiviral treatment response in CHB patients with and without FL. We searched PubMed, Embase, Web of Science and the Cochrane Library databases from inception to 31 May 2023 for relevant studies. Biochemical response (BR), complete viral suppression (CVS) and hepatitis B e antigen (HBeAg) seroconversion in CHB patients with FL (CHB-FL) and without FL (non-FL CHB) were compared. In an initial pool of 2101 citations, a total of 10 studies involving 2108 patients were included. After 12 weeks of treatment, CHB-FL patients as compared with non-FL CHB patients had lower BR rate (48.37% [108/227] vs. 72.98% [126/174], p = .04) but similar trend for CVS (36.86% [80/227] vs. 68.81% [114/174], p = .05) and similar rates of HBeAg seroconversion (6.59% [7/103] vs. 7.40% [7/110], p = .89). However, at week 48, there were no statistically significant differences between CHB-FL and non-FL CHB patients in any of the outcomes, including BR (60.03% [213/471] vs. 69.37% [314/717], p = .67), CVS (65.63% [459/746] vs. 73.81% [743/1132], p = .27) and HBeAg seroconversion (10.01% [30/275] vs. 14.06% [65/453], p = .58) with similar findings for week 96. BR rate was lower in CHB-FL patients after 12 weeks of antiviral treatment. However, after a longer follow-up of either 48 or 96 weeks, no statistically significant differences were observed in BR, CVS or HBeAg seroconversion rates between CHB patients with and without FL., (© 2024 John Wiley & Sons Ltd.)

Background and Aim: Hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) are novel markers that reflect intrahepatic cccDNA and could be useful in the prediction of relapse after nucleos(t)ide analogues (NA) discontinuation. The aim of the study is to perform a systematic review on this issue., Methods: Medline/Pubmed database was searched using text terms related to HBcrAg, RNA, NAs, discontinuation, and relapse. Included studies were those that enrolled adult patients who had been on NAs for more than 6 months with available information on end-of-treatment (EOT) HBcrAg and/or HBV RNA and relapse rates., Results: Sixteen studies were included. Virological and clinical relapse rates ranged from 11% to 100% and 11% to 73%, respectively. Low or undetectable EOT HBcrAg levels were associated with low off-treatment relapse rates in most studies with area under the receiver operating characteristic curve (AUROC) of 0.69-0.70 for predicting virological relapse (VR) and 0.61-0.77 for predicting clinical relapse (CR). Undetectable EOT HBV RNA was associated with a lower risk of off-treatment relapse with AUROC of 0.65-0.76 for predicting VR and 0.66-0.73 for predicting CR. Combined EOT HBcrAg and HBV RNA performed better in predicting off-treatment relapse than either test alone with AUROC of 0.816-0.846 for predicting CR. None of the patients with double-negative HBV RNA and HBcrAg developed CR., Conclusion: Combining HBcrAg with HBV RNA or HBsAg improved the discriminating abilities in the prediction of off-treatment relapse of each test. Patients with double-negative HBcrAg and HBV RNA at EOT had low risks of relapse and could be considered for NA discontinuation., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background and Aim: It has been reported that serum quantification of anti-HBc (qAnti-HBc) could predict antiviral response in chronic hepatitis B (CHB) patients, while its role in hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) remains unclear. Its implication in HBV-ACLF was evaluated in this study., Methods: Baseline serum qAnti-HBc levels were retrospectively detected in HBV-ACLF and CHB patients using recently developed double-sandwich immunoassay. The association of qAnti-HBc level with clinical outcomes was evaluated by multiple logistic regression. Nomogram was adopted to formulate an algorithm incorporating qAnti-HBc for the prediction of survival in HBV-ACLF. The post-hospitalization of HBV-ACLF patients were followed-up for 1 year., Results: Eighty-eight HBV-ACLF as training set, 80 HBV-ACLF as validation set and 216 CHB cases were included. Serum qAnti-HBc level was significantly higher in HBV-ACLF (4.95 ± 0.54 log 10  IU/mL) than CHB patients (4.47 ± 0.84 log 10  IU/mL) (P < 0.01). Among HBV-ACLF cases, both in training and validation set, patients with poor outcomes had lower qAnti-HBc level. Area under receiver operating characteristic curve of the novel qAnti-HBc inclusive model was 0.82, superior to 0.73 from model for end-stage liver disease scores (P = 0.018), which was confirmed in validation set. During follow-up, the qAnti-HBc level declined at month 3 and month 6, then plateaued at 3.84 log 10  IU/mL., Conclusions: Serum qAnti-HBc level was associated with disease severity and might be served as a novel biomarker in the prediction of HBV-ACLF clinical outcomes. The underlying immunological mechanism warrants further investigation., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

A significant proportion of patients infected with SARS-CoV-2 develop severe respiratory symptoms due to an excessive immune response. Treatment of this condition may include immunosuppressive therapies, such as IL-6 receptor antagonists and corticosteroids, which pose a risk for patients with active or past hepatitis B virus (HBV) infection. In this prospective cohort study, we analysed the risk of HBV reactivation in patients with severe COVID-19 and resolved HBV infection undergoing immunosuppressive therapy. From 15th March to 30th April 2020, 600 patients with severe COVID-19 were admitted to our hospital and treated with immune modulators. Data regarding HBV infection were available in 484, of whom 69 (14%) were HBsAg negative/anti-HBc positive. For these patients, HBV reactivation prophylaxis with entecavir was strongly recommended. Complete follow-up was available in 61 patients: 72% were male, median age was 67 years, and anti-HBs was >10 IU/mL in 72%. The immunosuppressive drug most used was tocilizumab (72%). Despite HBV prophylaxis recommendation, 38 (62%) patients received entecavir and 23 (38%) did not. Baseline features of both groups were similar. At follow-up, we found no cases of HBsAg seroreversion and only 2 (3%) patients (no prophylaxis group) had detectable serum HBV-DNA (<15 IU/mL). Both were anti-HBs negative and had normal aminotransferase levels. Our data show that the risk of HBV reactivation in patients with severe COVID-19 and resolved HBV infection undergoing immunosuppressive treatment is low. However, if a systematic follow-up after hospital discharge is unfeasible in patients without anti-HBs, a short course of antiviral prophylaxis may be a safe option., (© 2020 John Wiley & Sons Ltd.)

Background and Aim: Hepatitis B core-related antigen (HBcrAg) has been shown to correlate with various viral markers in chronic hepatitis B, but its role in defining natural history is not well studied. We aimed to investigate the use of HBcrAg to define different phases of chronic hepatitis B., Methods: Stored residual serum samples from longitudinal cohorts of chronic hepatitis B patients in Hong Kong and Japan were studied. Viral markers were measured in three serial serum samples for each patient. Patients were divided into six groups for analysis: hepatitis B e antigen (HBeAg)-positive chronic infection (EPI), HBeAg-positive chronic hepatitis (EPH), HBeAg seroconversion (ES), HBeAg-negative chronic hepatitis (ENH), HBeAg-negative chronic infection (ENI), and HBsAg seroclearance (SS)., Results: In total, 166 patients followed up for 100 (76-113) months were included. HBcrAg was correlated with hepatitis B virus DNA and HBsAg levels in both HBeAg-positive and HBeAg-negative patients. HBcrAg cut-off of ≥ 6.0 log U/mL could best differentiate HBeAg-positive from HBeAg-negative patients (area under receiver operating characteristic curve of 0.99, P < 0.001). HBcrAg could not differentiate patients in EPI and EPH phases, but HBcrAg declined dramatically at HBeAg seroconversion. In HBeAg-negative patients, HBcrAg ≥ 4.0 log U/mL could best differentiate ENH from ENI (area under receiver operating characteristic curve of 0.81; P < 0.001), with high specificity (81.6%) but only moderate sensitivity (65.7%) at baseline. Undetectable HBcrAg was found in 17%, 63%, and 89% patients in ENH, ENI, and SS groups at the last visit, respectively., Conclusions: HBcrAg provides useful information to stage the natural history of chronic hepatitis B, particularly identifying HBeAg-positive patients and HBeAg-negative patients with active disease., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

This observational study was designed to assess the prevalence, knowledge and attitude of pregnant females towards hepatitis B infection, in addition to their perspective of the healthcare practice about HBV in Jordan. A randomly selected group of pregnant females visiting public gynaecology clinics in Jordan were approached to participate in the study. Blood samples were collected from the participants, and HBV markers were detected in their serum using specialized ELISA Kits to assess for the prevalence of infection. Knowledge and attitude of participants was assessed via a developed and validated questionnaire. Statistical analysis was conducted using the Statistical Package for the Social Sciences (SPSS) version 24. Blood samples (n = 300) from 330 pregnant females were collected. The prevalence of hepatitis B surface antigen (HBsAg) among the pregnant females was found to be 5%. Anti-HBs and anti-HBc were found to be 33.3% and 7%, respectively. No significant correlation between age, socio-economic status and educational level was found with HBsAg positivity. Limited knowledge regarding HBV was revealed among the pregnant females (9.1%-41.3%, P < .05). The majority had a positive attitude regarding HBV vaccination and antiviral medications in case of infectivity. More than 90% agreed on the present lack of counselling and screening of HBV they obtained during their first perinatal visit to the gynaecology clinics. This study revealed a lack of knowledge on HBV, and low counselling and screening received were reported. Policymakers need to introduce new interventions to improve the current awareness of patients and gynaecologists regarding hepatitis B infection., (© 2020 John Wiley & Sons Ltd.)

The latest epidemiological data in Spain were obtained a decade ago and revealed a prevalence of hepatitis B surface antigen (HBsAg) of 0.7%; hence, updated epidemiological data are necessary. Our aim was to determine the prevalence of hepatitis B virus (HBV) infection, and to analyse associated factors and characterize chronic infection. A population-based, cross-sectional study was performed in Spain between July 2015 and April 2017. Participants from three regions were selected using two-stage conglomerate sampling and stratified by age. Anthropometric and demographic data were collected, and blood samples were taken to detect serological markers of HBV infection and to quantify HBV-DNA. The characterization of chronic HBV infection was based on ALT (alanine aminotransferase) values, HBV-DNA levels, and results of transient elastography. The overall prevalence rates of HBsAg and antibody to hepatitis B core antigen (anti-HBc) among 12 246 participants aged 20-74 years (58.4% females) were 0.6% (95% CI [0.4-0.7]) and 8.2% (7.7-8.7), respectively. The risk factors for HBV infection identified in the multivariate analysis were age, nosocomial risk, and non-Spanish nationality. Moreover, most patients HBsAg positive (76.6%) presented as hepatitis B e antigen (HBeAg)-negative chronic infection (formerly 'inactive carriers') and only 6 (9.4%) HBsAg carriers fulfilled current criteria for treatment. The current HBV burden in Spain remains low but virtually unchanged over the past 15 years. Increased efforts are still needed to reach the goal set forth by the World Health Organization (WHO) for HBV elimination by 2030., (© 2020 John Wiley & Sons Ltd.)

Nowadays, intensive immunosuppressive therapy including rituximab is commonly used prior to kidney transplantation (KT), raising concerns over hepatitis B virus (HBV) reactivation among hepatitis B surface antigen (HBsAg)-negative and anti-hepatitis B core (HBc)-positive KT recipients. Recent practice guidelines suggested watchful monitoring or antiviral prophylaxis for the first 6-12 months, the period of maximal immunosuppression. However, the actual risk for HBV reactivation, and whether short-term antiviral therapy in the early period is necessary, remains unclear. A total of 449 HBsAg-negative and anti-HBc-positive KT recipients were analysed for HBV reactivation. During a median follow-up of 6.7 (interquartile range: 4.2-9.4) years, HBV reactivation was observed in 9 patients (2.0%). The median time of HBV reactivation from KT was 2.8 years (range: 1.4-11.5 years), with cumulative incidence rates of 0%, 1% and 2% for 1, 3 and 5 years, respectively. There were no severe adverse outcomes, including liver transplantation or mortality related to HBV reactivation. The risk of HBV reactivation was not high, even in anti-HBs-negative patients (n = 60, 4% at 5 years), ABO mismatch (n = 92, 4% at 5 years), use of rituximab (n = 66, 3% at 5 years) or plasmapheresis (n = 17, 7% at 5 years), and acute rejection (n = 169, 3% at 5 years). In conclusion, the HBV reactivation risk was not high and the time of detection was not clustered in the early post-KT period. Our findings favour continued watchful monitoring over antiviral prophylaxis in the early period., (© 2020 John Wiley & Sons Ltd.)

Background and Aim: We aim to investigate the risk factors of de novo hepatitis B virus (HBV) infection in pediatric liver transplantation recipients receiving hepatitis B core antibody positive grafts and to evaluate the efficacy of our prophylactic strategies., Methods: One hundred thirty-nine pediatric recipients receiving hepatitis B core antibody positive grafts operated from September 2016 to September 2018 were retrospectively enrolled, and all the patients received prophylactic treatment to prevent de novo HBV infection. Donor and recipient features, operative information along with graft, and recipient outcomes were compared between recipients with or without de novo HBV infection. Univariate and multivariate analyses were applied to identify the risk factors of de novo HBV infection., Results: The mean follow-up time was 23.5 ± 15.7 months, and the overall incidence of de novo HBV infection was 3.6%. Recipients with de novo HBV infection showed equal graft and recipient outcome compared with the recipients without de novo HBV infection during the follow-up time. Recipient preoperative hepatitis B surface antibody titer of < 1000 IU/L (odds ratio [OR] = 9.652, P = 0.024), graft HBV DNA of > 1000 copies (OR = 9.050, P = 0.032), and intraoperative fresh-frozen plasma transfusion of > 400 mL (OR = 10.462, P = 0.023) were identified as independent risk factors for de novo HBV infection., Conclusion: Hepatitis B core antibody positive grafts can safely be used in pediatric liver transplantation under rational prophylactic therapy., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Hepatitis B virus (HBV) infection causes a self-limiting disease in most individuals. However, < 10% of infected subjects develop a chronic disease. Genetic host variability of polymorphic genes at the interface of innate and acquired immunity, such as killer immunoglobulin-like receptors (KIR), their human leucocyte antigen (HLA) and IgG allotypes (GM), could explain this different clinical picture. We previously showed a protective role of the KIR2DL3 gene for the development of chronic hepatitis B (CHB), and a detrimental role of the KIR ligand groups, HLA-A-Bw4 and HLA-C2. We have expanded the previous analysis genotyping patients for GM23 and GM3/17 allotypes. The comparison of the patients with CHB with those who resolved HBV infection showed that the presence of GM17 allele virtually eliminated the risk of developing CHB (OR, 0·03; 95% CI, 0·004-0·16; P < 0·0001). In addition, the combination of GM17, KIR2DL3, HLA-A-Bw4 and HLA-C2 was highly sensitive to predict the outcome of HBV infection., (© 2019 John Wiley & Sons Ltd.)

High rates (~25%) of developing chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen (HBsAg)-positive for > 6 months following infection) have been observed in people who use drugs (PWUD) and men who have sex with men (MSM). We aimed to estimate the frequency of delayed HBsAg seroclearance, along with its determinants, and time to delayed HBsAg seroclearance. Data were used from MSM and PWUD enrolled in the Amsterdam Cohort Studies (1985-2002) who had anti-hepatitis B core antibody seroconversion. Potential determinants for standard HBsAg seroclearance, delayed HBsAg seroclearance and chronic HBV were examined using multinominal logistic regression. Time to HBsAg seroclearance was estimated using Kaplan-Meier curves. A total of 147 incident HBV infections occurred during follow-up. On initial HBsAg testing after infection (6-12 months), 42 (29%) were HBsAg-positive and 105 (71%) were HBsAg-negative ('standard HBsAg seroclearance'). Of the 42 initially HBsAg-positive individuals, 22 subsequently tested HBsAg-negative (of whom 7 (31.8%) were HBV DNA positive at last visit, suggesting occult HBV). Overall, 15 became HBsAg-negative and HBV DNA-negative ('delayed HBsAg seroclearance'), while 27 remained HBsAg and/or HBV DNA-positive ('chronic HBV'). The 5-year cumulative probability of delayed HBsAg seroclearance was 41.6% for initially HBsAg-positive individuals. Delayed HBsAg seroclearance and remaining chronically infected were associated with younger age and HIV/hepatitis C virus (HCV)-co-infection. In conclusion, delayed HBsAg seroclearance is common in these key adult populations at-risk for HBV, while proportion developing HBV chronicity (18%) is still higher compared to the general population (~5%). Given the proportion of individuals with occult HBV infection and that HCV direct-acting antivirals can lead to HBV reactivation, HBV DNA testing in HCV co-infected MSM/PWUD are warranted prior to treatment initiation., (© 2019 John Wiley & Sons Ltd.)

Hepatitis B core-related antigen (HBcrAg) is a novel serological marker for hepatitis B virus infection. Its clinical significance after HBeAg seroconversion has not been defined. We aimed to determine the relationship between HBcrAg levels after spontaneous HBeAg seroconversion and hepatocellular carcinoma (HCC). A total of 207 chronic hepatitis B patients with documented time of HBeAg seroconversion were enrolled. HBcrAg and HBsAg were checked within 3 years (as baseline), at 5 and 10 years after HBeAg seroconversion. HBV DNA was measured at the baseline. Multivariate Cox regression model was used to investigate the predictors for HCC development. The median follow-up time was 13.1 (11.8-15.5) years. Fourteen patients developed HCC (15-year cumulative incidence: 7%). The median level of HBcrAg at baseline was significantly higher in patients who developed HCC when compared with patients without HCC (5.68 vs 4.78 log U/ml, respectively; P = .003). Cox proportional hazards model indicated that age of HBeAg seroconversion older than 40 years (hazard ratio (HR): 4.60; P = .049), presence of baseline cirrhosis (HR: 6.23; P = .003) and a higher baseline HBcrAg (HR: 1.75; P = .032) were independently associated with HCC development. A cut-off value of baseline HBcrAg level ≥5.21 log U/mL yielded an AUROC of 0.74 with a negative predictive value of 97.7%. High HBcrAg levels within 3 years after HBeAg seroconversion were independently associated with the development of HCC in chronic hepatitis B patients., (© 2019 John Wiley & Sons Ltd.)

Chronic HBV infection results in various clinical manifestations due to different levels of immune response. In recent years, hepatitis B treatment has improved by long-term administration of nucleos(t)ide analogues (NUCs) and peg-interferon. Nucleic acid polymers (NAPs; REP 2139-Ca and REP 2139-Mg) are new antiviral drugs that block the assembly of subviral particles, thus preventing the release of HBsAg and allowing its clearance and restoration of functional control of infection when combined with various immunotherapies. In the REP 102 study (NCT02646189), 9 of 12 patients showed substantial reduction of HBsAg and seroconversion to anti-HBs in response to REP 2139-Ca, whereas 3 of 12 patients did not show responses (>1 log reduction of HBsAg and HBV DNA from baseline). We characterized the dynamic changes of HBV quasispecies (QS) within the major hydrophilic region (MHR) of the 'pre-S/S' open reading frame including the 'a' determinant in responders and nonresponders of the REP 102 study and four untreated matched controls. HBV QS complexity at baseline varied slightly between responders and nonresponders (P = .28). However, these responders showed significant decline in viral complexity (P = .001) as REP 2139-Ca therapy progressed but no significant change in complexity was observed among the nonresponders (P = .99). The MHR mutations were more frequently observed in responders than in nonresponders and matched controls. No mutations were observed in 'a' determinant of major QS population which may interfere with the detection of HBsAg by diagnostic assays. No specific mutations were found within the MHR which could explain patients' poor HBsAg response during REP 2139-Ca therapy., (© 2019 John Wiley & Sons Ltd.)

Recently, HLA class II loci, including HLA-DPB1, have been reported to be associated with interindividual variance in the hepatitis B (HB) vaccine response. In this study, we investigated significant single nucleotide polymorphisms (SNPs) for anti-HBs antibody levels in 6867 healthy Koreans using a genome-wide association study (GWAS). In GWAS, the top 20 SNPs that showed significant association with anti-HBs levels (P < 1.0 × 10 -29 ) all resided in HLA-DPB1. Utilizing PCR sequencing, we verified the relationship of the top 3 most significant SNPs (rs1042169, rs9277355 and rs9277356) from the GWAS and genotypes of HLA-DPB1 with the HB vaccine response in Korean infants who received a scheduled vaccination. The DPB1*04:02 allele has G, C and A nucleotides for the 3SNP sites, and was significantly more frequent in responders than in nonresponders (10.9% vs 1.0%, P c  = 0.018). DPB1*05:01 was significantly more frequent in nonresponders than in responders (49.0% vs 31.1%, P c  = 0.018). In multivariate logistic regression, DPB1*04:02 showed a significant association with both vaccine response (P = 0.037, OR = 8.465) and high-titre response (P = 0.027, OR = 9.860). The haplotypes rs1042169 G - rs9277355 C - rs9277356 A showed a significant association with a high-titre response only (P = 0.002, OR = 2.941). In conclusion, DPB1*04:02 possessing rs1042169 G - rs9277355 C - rs9277356 A is an independent predictor of the HB vaccine response in Koreans., (© 2019 John Wiley & Sons Ltd.)

Cessation of nucleos(t)ide analogue (Nuc) therapy in HBeAg-negative patients may increase HBsAg loss rate in patients with sustained remission (SR) and non-retreated clinical relapsers (CR). To investigate and compare the HBsAg kinetics from end of treatment (EOT) to HBsAg loss in these patients, serial serum samples after EOT from 36 SR and 12 CR with HBsAg loss (study group) and an 1:1 matched control who remained HBsAg-seropositive (control group) were assayed retrospectively for quantitative HBsAg (qHBsAg). The results showed that study group SR and CR had comparable EOT features except SR had lower EOT qHBsAg (67.5 vs 350.5 IU/mL; P = 0.02; < 100 IU/mL: 58.3% vs 25%; P = 0.09). All showed gradual qHBsAg decrease then "precipitous HBsAg decline" (>0.5 log 10 IU/mL in 1 year) prior to HBsAg loss. Patients with EOT qHBsAg <100 showed earlier (<12 months) "precipitous HBsAg decline" (91.7% vs 58.3%; P = 0.017) and sooner HBsAg loss (5.5 vs 21.9 months; P = 0.026). The control group also showed gradual qHBsAg decrease but less frequent "precipitous HBsAg decline" (39.6% vs 100%; P < 0.001) which occurred later (15.1 vs 5.7 months; P = 0.003) and was less steep (slope -0.6 vs -1.65 log 10 IU/mL/year; P < 0.001). HBsAg loss was achieved in 92.9% of the patients with "precipitous HBsAg decline" >0.76 log 10 IU/mL in 1 year. In conclusion, both the SR and CR groups showed gradual HBsAg decrease followed by a "precipitous HBsAg decline", which is a prerequisite for HBsAg loss. Lower EOT HBsAg in the SR group and qHBsAg <100 IU/mL may reflect better immune control hence followed by sooner HBsAg loss., (© 2019 John Wiley & Sons Ltd.)

Hepatitis C virus (HCV) and hepatitis B virus (HBV) coinfection reciprocally influences viral replication and host defence responses. This study aimed to investigate the impact of HBV coinfection on circulating T follicular helper cell (cTfh) distribution and the HCV neutralizing antibody (nAb) response. HCV neutralizing antibody responses were measured in individuals with HCV monoinfection (n = 83) and HBV/HCV coinfection (n = 78) using the HCV pseudoparticle neutralization assay. The frequencies of cTfh cells and their subsets in HCV monoinfection (n = 34) and HBV/HCV coinfection (n = 30) were analysed by flow cytometry. The correlations of clinical parameters, cTfh cells and neutralizing antibody responses were analysed. Compared with HCV monoinfection, the HBV coinfection group showed significantly lower HCV neutralizing antibody responses (P < 0.001) and a decreased frequency of circulating Th1-like Tfh cells (Tfh1) (P = 0.004). In HCV monoinfection, the frequency of the Tfh1 subset was positively correlated with HCV neutralizing antibody responses (R = 0.378, P = 0.03), but this correlation was lost under HBV/HCV coinfection (R = 0.115, P = 0.551). In contrast, the frequency of circulating Th2-like Tfh cells (Tfh2) was negatively correlated with the HCV neutralizing antibody responses (R = 0.404, P = 0.003). Further analysis showed that HBV coinfection enhanced the Tfh2 subset composition within cTfh cells (P < 0.001), which was associated with serum HBsAg in HBV/HCV coinfection (R = 0.521, P = 0.003). As expected, HBsAg also exhibited an inverse association with HCV neutralizing antibody responses in HBV/HCV coinfection (R = 0.59, P < 0.001). In contrast to HCV monoinfection, HBV/HCV coinfection leads to altered cTfh cell distribution and impaired HCV neutralizing antibody responses, which are associated with HBsAg. These findings will be helpful for better understanding the immunopathogenesis of HBV/HCV coinfection., (© 2019 John Wiley & Sons Ltd.)

Invariant NKT (iNKT) cells express markers of both T and NK cells and may produce various cytokines to regulate liver immunity. However, the role of iNKT cells in the progression of HBV-relative liver cirrhosis (HBV-LC) is incompletely understood. Here, we investigated the impact of peripheral iNKT cells on a cohort of patients with HBV-LC. The frequency, number, activation status, apoptosis and proliferation ability of peripheral iNKT cells were detected with flow cytometry. The impact of peripheral iNKT cells on the proliferation of hepatocyte cell line (MIHA) and activation of hepatic stellate cell line (LX-2) was detected with flow cytometry and PCR. In HBV-LC patients, the frequency and absolute number of peripheral iNKT cells significantly reduced, but the expression levels of CD25, interleukin (IL)-4, IL-13 and interferon (IFN)-γ increased. No difference was observed in the proliferation and apoptosis of circulating iNKT cells between patients and healthy controls (HCs). CXCR6 (CD186), known to be closely associated with iNKT cells migration from the periphery to the liver, was highly expressed on peripheral iNKT cells in HBV-LC patients. Furthermore, peripheral iNKT cells had a profound impact on MIHA cell proliferation and LX-2 cell activation through IL-4 or IL-13. Our data suggest that in HBV-LC patients, highly activated peripheral iNKT cells may migrate to the liver and affect hepatocyte cell line (MIHA) proliferation and hepatic stellate cell line (LX-2) activation through the expression of type 2 cytokines, which may result in excessive healing and contributing to the progression of fibrosis toward cirrhosis in liver., (© 2019 The Foundation for the Scandinavian Journal of Immunology.)

Most of the current guidelines and the existing data suggest that long-term therapy with nucleos(t)ide analogue(s) [NA(s)] may be stopped in carefully selected chronic hepatitis B patients who remain HBsAg positive. In particular, NA(s) may be discontinued in such patients without pre-existing cirrhosis who achieved long-term on-therapy virological remission (>12 months of HBeAg seroconversion and HBV DNA undetectability for initially HBeAg-positive cases; ≥3 years of HBV DNA undetectability for HBeAg-negative cases) and are expected to remain under close follow-up after NA(s) discontinuation. The majority of patients will develop post-NA(s) virological relapses and a proportion of them will have biochemical relapses and occasionally flares, but prompt retreatment can reintroduce remission. No reliable predictor(s) of post-NA(s) relapses have been identified so far. HBsAg loss develops in a progressively increasing proportion of chronic hepatitis B patients who discontinue NA(s) with HBsAg loss rates being higher in Caucasian patients with HBeAg-negative chronic hepatitis B. Follow-up at least every 3 months for the first year seems to be appropriate for all chronic hepatitis B patients who discontinue NA(s), while HBeAg-negative patients need to be followed more closely (monthly) during the first 3 months. Predefined criteria for retreatment are quite important, and the best candidates for retreatment are probably the patients with persistent (≥3 months) liver disease activity and those with severe flares., (© 2019 John Wiley & Sons Ltd.)

It is not clear whether chronic hepatitis B virus (HBV) infection during pregnancy can increase the risk of adverse pregnancy outcomes for both mothers and neonates. We conducted a hospital-based prospective cohort study on pregnant women (PW) and used an analysis strategy that was guided by directed acyclic graphs (DAGs). Maternal characteristics and major adverse pregnancy outcomes were collected both from questionnaires and hospital-based electronic medical records. Serum hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) status were determined. In total, 3329 of the 3416 pregnant women who received routine antenatal care in a hospital setting at baseline, including 346 HBsAg carriers, were available for analysis. Maternal HBsAg carrier status was associated with an increased risk of intrahepatic cholestasis pregnancy [aOR (adjusting odds ratio) = 1.70; 95% CI (confidence interval) = 1.16-2.49], premature rupture of the membranes (aOR = 1.38; 95% CI = 1.00-1.89) and large for gestational age birth aOR = 1.67; 95% CI = 1.17-2.39). The risk of intrahepatic cholestasis remained in pregnant women with either HBeAg-positive (aOR = 2.96; 95% CI = 1.33-6.62) or HBeAg-negative (aOR = 1.52; 95% CI =1.00-2.32)] status; notably, only maternal HBeAg-negative status was associated with a higher risk of large for gestational age birth (aOR = 1.91; 95% CI = 1.33-2.76). Our results implied that chronic HBV infection during pregnancy may increase the risk of intrahepatic cholestasis of pregnancy, premature rupture of membranes and large for gestational age pregnancies., (© 2019 John Wiley & Sons Ltd.)

Liver necroinflammation is the indicator for treating patients with chronic hepatitis B (CHB) infection. However, there is no suitable non-invasive index for diagnosing liver necroinflammation. This study aimed to create a non-invasive index to predict liver necroinflammation in patients who lack clear-cut clinical inflammation parameters. Patients who were hepatitis B e antigen (HBeAg)-negative and underwent liver histological diagnosis, had a normal or minimally increased alanine aminotransferase (ALT) level were enrolled. Liver necroinflammation was defined as histological active index ≥4. A logistic regression model (LRM) was established based on the parameters independently associated with liver necroinflammation. Of all 550 patients, 36.73% had necroinflammation. In patients with an abnormal ALT level, the rate of necroinflammation was 52.49%. The area under the curve (AUC) of the ALT level for predicting necroinflammation was 0.655 (95% confidence interval [CI], 0.609-0.702), and that of the HBV DNA level ≥2000 IU/mL combined with an abnormal ALT level was 0.618. By using the LRM, the AUC improved to 0.769 (95% CI, 0.723-0.815) with a Youden index of 0.519 and diagnostic accuracy of 75.3%. The cutoff value ≥0.7 in the LRM had a specificity of 97.4% and positive predictive value of 85.0% for predicting necroinflammation. By using the cutoff value <0.15 in the LRM, the presence of necroinflammation could be excluded with a negative predictive value of 90.8%. This study indicated that the LRM can be used to effectively diagnose liver necroinflammation in HBeAg-negative patients with CHB who have normal or minimally elevated ALT levels., (© 2019 John Wiley & Sons Ltd.)

Therapeutic vaccines may be promising treatments for chronic hepatitis B (CHB), but their clinical efficacy and safety are unclear. We conducted a systematic review of the evidence for the efficacy and safety of therapeutic vaccines in CHB patients. We searched PubMed, EMBASE and Google Scholar from 1990 until present and abstracts from EASL, APASL and AASLD from 2012 to 2017 and selected randomized controlled trials of CHB patients, comparing therapeutic vaccines with no treatment or standard of care. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by hepatitis B e antigen (HBeAg) status and the comparator (therapeutic vaccines vs no treatment, or therapeutic vaccines + standard of care vs standard of care). Efficacy outcomes were HBeAg seroconversion, hepatitis B virus DNA reduction and hepatitis B virus surface antigen (HBsAg) loss, measured at the end of treatment or end of follow-up. Effects were reported as risk differences with 95% confidence intervals using a random effects model. Fifteen studies were included. A wide variety of therapeutic vaccines were tested. For HBeAg clearance at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = 0.01, 95% CI -0.05 to 0.07, and when comparing therapeutic vaccines + standard of care vs standard of care, RD = 0.03, 95% CI -0.03 to 0.09. For HBVDNA reduction at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = -0.03, 95% CI -0.08 to 0.02, and when comparing therapeutic vaccines + standard of care, RD = 0.15, 95% CI 0.02-0.28. There were only a few studies on HBsAg loss, and hence, the findings were inconclusive. The only efficacy finding was HBVDNA reduction at the end of follow-up for therapeutic vaccines + standard of care vs standard of care; otherwise, therapeutic vaccines do not appear to be efficacious for the treatment of CHB, but were limited by few RCTs, suboptimal therapeutic vaccines and patient selection., (© 2019 John Wiley & Sons Ltd.)

Hepatitis B e antigen (HBeAg) seroconversion experienced during nucleo(s)tide analogue (NUC) therapy is often not sustained. We aimed to study whether hepatitis B core-related antigen (HBcrAg) levels predict sustained HBeAg seroconversion in patients treated with NUCs. We studied HBeAg-positive patients treated with NUCs for at least 6 months. We quantified HBcrAg at baseline and at the time of HBeAg seroconversion and studied the relationship with HBeAg seroconversion and subsequent relapse. HBcrAg was quantified at baseline in 196 patients; levels varied significantly by HBV genotype and correlated with HBsAg, HBV DNA and HBeAg. Baseline HBcrAg levels were lower in patients who achieved HBeAg seroconversion than in those who did not; the unadjusted hazard ratio (HR) was 0.802 (95% CI: 0.656-0.980, P = 0.031); and this association was not sustained in multivariate analysis. HBcrAg remained detectable in all patients at the time of HBeAg seroconversion. Higher HBcrAg at the time of seroconversion was an independent predictor of relapse (adjusted HR: 1.855 (95% CI: 1.099-3.133, P = 0.021), and none of the patients with HBcrAg < 4.90 log U/mL experienced relapse. Baseline HBcrAg is not an independent predictor of HBeAg seroconversion during NUC therapy. HBcrAg remains detectable in patients after HBeAg seroconversion. Patients with lower levels at the time of seroconversion have a higher probability of sustained HBeAg seroconversion., (© 2019 John Wiley & Sons Ltd.)

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)-negative CHB patients. In this prospective study, 176 HBeAg-negative CHB patients with functional cure were enrolled for 12 weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3 months; liver imaging examinations were performed every 3-6 months during the 48-week follow-up. The sustained functional cure was evaluated. After the 48-week follow-up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment ≥ 12 weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment < 12 weeks (76.19% vs 90.00%, P = 0.022 and 23.81% vs 9.23%, P = 0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P = 0.012). Consolidation treatment ≥ 12 weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135-127.151; P = 0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824-37.881; P = 0.006) were independent predictors of sustained functional cure. Results suggested that 12 weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure., (© 2019 John Wiley & Sons Ltd.)

Hepatitis B e antigen (HBeAg) is an important serological marker of hepatitis B virus (HBV) infection and is associated with higher levels of viraemia, increased risk of infectivity to others and increased risk of hepatocellular carcinoma. We analysed HBeAg status in a large cohort of adults and children enrolled in Cohort Studies of the Hepatitis B Research Network, long-term natural history studies of chronic HBV infection. A cross-sectional analysis examined factors associated with HBeAg positivity, including demographic and virologic data, across the age spectrum. Among 2241 enrolled participants who met criteria for this analysis, 825 (37%) were seropositive for HBeAg. The prevalence of HBeAg was lower in those with older age, ranging from 85% among those up to 10 years of age to only 12% among those older than 50 years. In addition to age, both race and HBV genotype were independently associated with HBeAg positivity. There was a significant interaction between age and race; the prevalence of HBeAg was significantly higher among Asians > 10-30 years old vs Whites or Blacks who were >10 to 30 years old and those infected with HBV genotype C. Conversely, the presence of the basal core promoter and precore variants was associated with significantly lower prevalence of HBeAg, even when adjusted for age, race and genotype. These data will provide a better understanding of factors associated with seropositivity for HBeAg and may lead to better strategies for preventing HBV infection and broader indications for antiviral therapy., (© 2019 John Wiley & Sons Ltd.)

The optimal duration of treatment with nucleos(t)ide analogues (NAs) for patients with HBeAg-negative chronic hepatitis B (CHB) is unknown. The aim of this study was to identify an immune signature associated with off-treatment remission to NA therapy. We performed microarray analysis of peripheral blood mononuclear cell (PBMCs) from six patients with chronic hepatitis B who stopped NA therapy (three with off-treatment remission, three with relapse) and five patients with chronic HBV infection (previously termed 'inactive carriers') served as controls. Results were validated using qRT-PCR on a second group of 21 individuals (17 patients who stopped treatment and four controls). PBMCs from 38 patients on long-term NA treatment were analysed for potential to stop treatment. Microarray analysis indicated that patients with off-treatment remission segregated as a distinct out-group. Twenty-one genes were selected for subsequent validation. Ten of these were expressed at significantly lower levels in the patients with off-treatment remission compared to the patients with relapse and predicted remission with AUC of 0.78-0.92. IFNγ, IL-8, FASLG and CCL4 were the most significant by logistic regression. Twelve (31.6%) of 38 patients on long-term NA therapy had expression levels of all these four genes below cut-off values and hence were candidates for stopping treatment. Our data suggest that patients with HBeAg-negative CHB who remain in off-treatment remission 3 years after NA cessation have a distinct immune signature and that PBMC RNA levels of IFNγ, IL-8, FASLG and CCL4 may serve as potential biomarkers for stopping NA therapy., (© 2019 John Wiley & Sons Ltd.)

The massive implementation of the vaccine and antiviral agents against hepatitis B virus (HBV), targeting the envelope and viral polymerase genes, induces a selection pressure that might lead to the emergence of variants that impair the effectiveness of the vaccine, diagnostic methods and antiviral therapy. The aim of this study was to evaluate the prevalence of HBV vaccine escape mutants (VEMs), diagnostic failure mutants (DFMs) and treatment resistance mutants (ARMs) among individuals from Buenos Aires, Argentina. HBV surface antigen and polymerase sequences obtained from serum samples of 530 HBV-infected individuals were analysed. Samples belonged to genotypes A (28.1%), D (13.6%) and F (58.3%). VEMs, DMFs and ARMs were present in 40 (7.5%), 57 (10.7%) and 27 (5.1%) samples within the studied population. Additionally, eight nonpreviously reported VEMs and nine DFMs were identified. VEMs and DFMs were biased by genotype, being higher in genotype D (33.3% and 33.3%) compared to genotype A (6% and 17.4%) and genotype F (2.3% and 2.3%) (P > 0.001). On the contrary, there was no association between the presence of ARMs and HBV genotype (P = 0.324). VEMs, DFMs and ARMs create public health concerns. The current study provided valuable information about mutants in surface antigen and polymerase in HBV-infected patients from Argentina where HBV-F is the most prevalent genotype. Consequently, it constitutes an important reference for Latin American clinicians in order to optimize the management of HBV-infected patients., (© 2018 John Wiley & Sons Ltd.)

The treatment of patients suffering from HBeAg-positive chronic hepatitis B with REP 2139-Ca resulted in potent reductions in HBsAg and HBV DNA, seroconversion to anti-HBs and the establishment of functional control of infection. In this cohort of 12 patients, we investigated whether differences between HBsAg sequences might explain the lack of response to REP 2139-Ca observed in 3 of 12 patients. We also assessed if the reduction or complete loss of HBsAg in serum observed during therapy were caused by mutations in the "a" determinant preventing the detection of HBsAg by standard diagnostic assays. The complete pre-S/S open reading frame (ORF) was sequenced and pre-S1, pre-S2 and S amino acid sequences were analysed. We found no major differences between pre-S1, pre-S2 and S sequences in responders and nonresponders correlated with low reduction in HBsAg. In addition, we found no mutations in the "a" determinant that would significantly affect the reactivity of HBsAg in diagnostic assays. These results demonstrate that the amino acid sequence of complete pre-S/S ORF has no direct influence on response to REP 2139-Ca therapy., (© 2018 John Wiley & Sons Ltd.)

Background and Aim: Hepatitis delta virus (HDV) infection is the most rapidly progressive chronic viral hepatitis. Little is understood about the immune responses to HDV. This study aims to characterize the systemic immune environments of hepatitis B virus (HBV) and HDV patients at various disease stages., Methods: A total of 129 subjects were evaluated: 53 HBV, 43 HDV, and 33 healthy controls. HBV and HDV subjects were categorized by aspartate aminotransferase to platelet ratio index (APRI) into mild (APRI < 0.5), moderate, and severe (APRI > 1.0). Serum cytokines and immune markers were assessed at a single treatment-naïve time-point., Results: Type 1 cytokines are elevated in both HBV and HDV. Both groups show higher tumor necrosis factor-α (TNF-α), interleukin (IL)-12p40, and C-X-C motif chemokine ligand 9 when compared with controls (all P < 0.05). However, only HBV group displayed elevated γ-interferon compared with controls. Type 2 cytokines are elevated in HBV. HBV group shows higher IL-4, IL-13, and C-C motif chemokine ligand (CCL) 26 compared with healthy controls and HDV. Chemokines CCL2 and CCL13 are lower in HDV. When assessing ratios, HDV displays higher γ-interferon/IL-4, TNF-α/IL-4, and TNF-α/IL-13 ratios than HBV and controls., Conclusion: Hepatitis B virus and HDV subjects show similarly elevated type 1 cytokines. HDV subjects display relatively lower type 2 cytokines. These differences in the systemic immune environments, particularly the predominance of type 1 responses, may contribute to the comparatively rapid progression of HDV disease. Characterization of the imbalance in type 1 and type 2 immunity unique HDV has the potential to provide immunological insights for designing therapeutic targets in HDV-associated disease progression., (© 2019 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Seroclearance of hepatitis B surface antigen (HBsAg) has been widely studied; however, seroconversion of HBsAg and characteristics of viral load among hepatitis B e antigen (HBeAg)-negative chronic infection patients after HBsAg lost is not clear. We performed a large-scale study in a HBeAg-negative chronic infection cohort to evaluate spontaneous HBsAg seroclearance incidence from October 2012 to April 2017 in Jiangsu province, China. We also elucidated the characteristics of HBsAg seroconversion and hepatitis B virus (HBV) DNA detectability among patients who cleared HBsAg. A total of 2997 HBeAg-negative chronic infection patients (mean age 52.3 ± 12.9 years at baseline) were included. With 10 519 person-years of follow-up, 348 patients successfully spontaneously cleared HBsAg, with an incidence rate of 3.31 per 100 person-years. Patients with HBV DNA detectable ~1999 IU/mL at baseline had a lower probability of HBsAg seroclearance relative to those with undetectable HBV DNA, with a hazard ratio of 0.31 (95% CI = 0.23, 0.41). HBsAg seroconversion occurred in 37.3% of those patients who cleared HBsAg. The geometric mean of anti-HBs among those with HBsAg conversion was 79.4 mIU/mL. Female had a higher HBsAg seroconversion rate (P = 0.011). Among those with HBsAg seroclearance, 11.2% still had HBV DNA levels of higher than 100 IU/mL. Patients with higher HBV DNA at baseline had a higher risk of detectable HBV DNA levels even after HBsAg seroclearance (P < 0.001). This study reveals HBsAg seroconversion rates and HBV DNA undetectability epidemiological characteristics of patients with HBsAg seroclearance and suggests that monitoring HBV DNA is needed when managing HBeAg-negative chronic patients, even after clearing HBsAg., (© 2018 John Wiley & Sons Ltd.)

The activation of hepatitis B virus (HBV)-related hepatitis is associated with both natural killer (NK) cells and cytotoxic T lymphocytes (CTLs). We analyzed the association between the immune response and changes in the proportion of Pre-S deletion variants. We quantified Pre-S deleted HBV (HBV-del) and wild-type HBV (HBV-wt) DNA levels in sera obtained from HBV-infected mice and chronic hepatitis B patients. In chronic hepatitis B patients, the HBV-del proportion usually increased during or after ALT elevation but did not occur during all ALT elevations. To clarify this difference in the immunological responses, we performed in vivo analyses using HBV-infected human hepatocyte chimeric mice. Although HBV-del proportions did not change in mice with NK cell-associated hepatitis or in mice treated with entecavir, the proportions sharply increased in mice with CTL-associated hepatitis. Furthermore, the number of patients in which HBV-del proportions were greater than 5% was significantly higher in chronic hepatitis B patients than in asymptomatic carriers (P = 0.023). We identified associations between virological response in chronic hepatitis B patients and two different immune responses. The proportion of HBV-del variants could be a useful biomarker for distinguishing between chronic hepatitis and asymptomatic carriers., (© 2018 John Wiley & Sons Ltd.)

HBV surface antigen (HBsAg) reduction is well observed in chronic hepatitis B (CHB) patients treated with pegylated interferon alpha-2a (PegIFNα). However, the mechanism of HBsAg suppression has not been fully elucidated. Twenty-seven of 55 entecavir-treated CHB e antigen positive patients were switched to PegIFNα treatment (Group A) whereas 28 patients continued entecavir treatment (Group B). The percentage or absolute number of CD56 bright /CD56 dim NK cells, expression of receptors and cytokines were evaluated by flow cytometry for 48 weeks and correlated with treatment efficacy. In vitro, purified NK cells were co-cultured with HepAD38 cells for measurement of HBsAg, apoptosis and covalently closed circular DNA (cccDNA). In association with a reduction of HBsAg, the percentage and absolute number of CD56 bright NK cells was significantly elevated in patients in group A, especially in Virologic Responders (VRs, HBsAg decreased). Furthermore, the percentage of NKp30 + , NKp46 + , TRAIL + , TNF-α + and IFNγ + CD56 bright NK cells were significantly expanded in Group A, which were positively correlated with the decline of HBsAg at week 48. In vitro, peripheral NK cells from Group A induced a decline of HBsAg in comparison with NK cells from Group B which was significantly inhibited by anti-TRAIL, anti-TNF-α and anti-IFNγ antibodies. Furthermore, apoptosis of HepAD38 cells and levels of cccDNA, were significantly reduced by TRAIL + and TNF-α + /IFNγ + NK cells from Group A, respectively. A functional restoration of CD56 bright NK cells in entecavir-treated patients who were switched to PegIFNα contributes to HBsAg and cccDNA clearance through TRAIL-induced cytolysis and TNF-α/IFNγ-mediated noncytolytic pathways., (© 2018 John Wiley & Sons Ltd.)

Chronic hepatitis B virus (HBV) infection is a prevalent public health issue worldwide. Its impact on important pregnancy outcomes, such as gestational diabetes mellitus (GDM), has not been clearly established. The findings from published studies are inconsistent. In this systematic review and meta-analysis, we aimed to clarify whether HBV infection manifested during pregnancy is associated with an increased risk of GDM. We searched MEDLINE and EMBASE for cohort studies and case-control studies that investigated the association between maternal hepatitis B surface antigen (HBsAg) positivity and GDM. We pooled adjusted odds ratio (aOR) and unadjusted OR, respectively, using the random-effect generic inverse variance method. We assessed risk of bias using the Quality in Prognosis Studies tool and conducted five pre-specified subgroup analyses. In total, 23 cohort studies involving 3 529 223 participants were included. The risk of GDM was 6.48% (1868/28 829) among HBsAg-positive pregnant women and 3.41% (119 283/3 500 394) among HBsAg-negative pregnant women. Meta-analyses of both unadjusted and adjusted effect estimates showed that HBsAg positivity during pregnancy was associated with higher risk of developing GDM (unadjusted OR 1.35, 95% CI: 1.17 to 1.56, I 2  = 82.6%; adjusted OR 1.47, 1.22 to 1.76, I 2  = 62%). Among pre-specified subgroup analysis, significant differences were found among studies with high vs low or moderate risk of bias. The results were robust to sensitivity analyses. In conclusion, HBsAg positivity during pregnancy has a moderate effect on an increased risk of GDM. Given the size of the population with HBV infection worldwide, however, this effect could have substantial impact on pregnancy. Further studies are warranted to investigate whether active infection with HBeAg positivity would further elevate the risk of adverse events during pregnancy., (© 2018 John Wiley & Sons Ltd.)

Chronic hepatitis D is caused by coinfection of hepatitis B and hepatitis D virus. While HDV is the dominant virus over HBV in the majority of cases, mechanisms and consequences of viral dominance are largely unknown. We aimed to investigate associations between viral dominance patterns and patients' characteristics and inflammatory features; 109 HDV-infected patients treated with PEG-IFNa-2α within the international multicentre, prospective HIDIT-2 trial were studied. Patients were classified as D- or B-dominant if the viral load of one virus exceeded that of the other virus by more than 1log 10 . Otherwise, no viral dominance (ND) was described. We used Luminex-based multiplex technology to study 50 soluble immune mediators (SIM) in pretreatment samples of 105 HDV RNA-positive patients. Dominance of HDV was evident in the majority (75%) of cases. While only 7% displayed B-dominance, 17% showed nondominance. D-dominance was associated with downregulation of 4 interleukins (IL-2ra, IL-13, IL-16 and IL-18) and 5 chemokines/cytokines (CTACK (CCL27), MCP-1 (CCL2), M-CSF, TRAIL and ICAM-1) while no analyte was increased. In addition, D-dominance could be linked to a delayed HDV RNA response to pegylated interferon as patients with B-dominance or nondominance showed higher early HDV RNA responses (61% at week 12) than D-dominant patients (11%; P < .001). In conclusion, this study revealed unexpected effects of viral dominance on clinical and immunological features in chronic hepatitis delta patients. Individualizing PEG-IFNa-2α treatment duration should consider viral dominance. Overall, our findings suggest an activated but exhausted IFN system in D-dominant patients., (© 2018 John Wiley & Sons Ltd.)

Transmission of Hepatitis B Virus (HBV) usually occurs due to the transfusion of blood or blood products from chronic HBV (CHB) or occult HBV-infected (OBI) patients. Besides serological tests, e.g. HBsAg and anti- HBc (total), detection of HBVDNA is necessary for the diagnosis of OBI patients. Different nucleic acid tests (NATs) including real- time-Polymerase Chain Reaction (qPCR) are used to detect HBV- DNA. The NATs are expensive and require technical expertise which are barriers to introduce them in resource-limited settings. This study was undertaken to evaluate the use of Loop-Mediated Isothermal Amplification (LAMP) assay as an alternative to qPCR for the detection of HBV-DNA in CHB and potential OBI patients in resource-limited settings. Following the published protocols with some modifications, a LAMP assay was developed for detection of HBV-DNA by either using a heat block followed by detection in an agarose gel or using a qPCR thermocycler. The LAMP assay was applied to supernatant prepared from heat-treated serum collected from CHB and potential OBI patients. HBV viral load in serum was measured by qPCR using a single-step HBV-DNA quantification kit. Among 200 samples tested, qPCR was capable to detect HBV-DNA in 25.5% of cases, whereas LAMP assay detected HBV-DNA in 43.5% cases. The qPCR was able to detect 11 (9.16%) potential OBI cases, whereas LAMP assay identified HBV-DNA in 43 (35.83%) cases. In addition to tests for HBsAg and/or anti-HBc (total), detection of HBV-DNA by LAMP assay may aid in preventing post-transfusion HBV infection in resource-limited settings., (© 2018 John Wiley & Sons Ltd.)

Entecavir 0.5 mg (ETV) is widely used among treatment-naïve chronic hepatitis B (CHB) patients. However, 10%-30% of patients show partial virologic response (PVR) to the drug. If the hepatitis B virus (HBV) continues to replicate, the underlying liver disease may progress. Herein, we compared the efficacy of switching to tenofovir disoproxil fumarate (TDF) with that of continuing ETV in CHB patients with PVR to ETV. This was an open-label randomized controlled trial including CHB patients who had been receiving 0.5 mg of ETV for >12 months, but who still had detectable HBV DNA levels of >60 IU/mL without known resistance to ETV. Sixty patients were enrolled and 45 qualified for the study: Twenty-two patients were randomly assigned into the TDF group and 23 into the ETV group. After 12 months of treatment, the virologic response rate (HBV DNA <20 IU/mL) was significantly higher in the TDF group than in the ETV group, as measured using per-protocol analysis (55% vs 20%; P = .022) and intention-to-treat analysis (50% vs 17.4%; P = .020). The reduction in HBV DNA was greater (-1.13 vs -0.67 log 10 IU/mL; P = .024), and the mean HBV DNA level was lower (1.54 vs 2.01 log 10 IU/mL; P = .011) in the TDF group than in the ETV group. In conclusion, to achieve optimal response in CHB patients with PVR to ETV, switching to TDF would be a better strategy than continuing ETV. Appropriate modification of therapy would further improve the outcome of chronic HBV infection., (© 2018 John Wiley & Sons Ltd.)

Vesatolimod is an oral agonist of toll-like receptor 7 designed to minimize systemic exposure and side effects. We assessed the safety and efficacy of vesatolimod in viremic chronic hepatitis B (CHB) patients not currently on oral antiviral treatment (OAV) in a phase 2, multicentre, double-blind, randomized, placebo-controlled study. A total of 192 patients stratified by HBeAg status and alanine aminotransferase level were randomized 2:2:2:1 to receive oral vesatolimod (1-, 2- or 4-mg) or placebo once weekly for 12 weeks; tenofovir disoproxil fumarate (300-mg daily) was administered daily for 48 weeks. Efficacy was assessed by quantitative serum HBsAg decline at Week 24 from baseline. In addition to safety assessments, changes in whole-blood interferon-stimulated gene (ISG) transcripts and serum cytokines were explored. Most patients were male (64.1%) and HBeAg-negative (60.9%) at baseline. Among vesatolimod-treated patients, most (60.4%-69.1%) experienced ≥1 treatment-emergent adverse event; the majority were mild or moderate in severity. No clinically meaningful differences in HBsAg changes from baseline were observed between treatment groups. No patients experienced HBsAg loss, while 3 patients experienced HBeAg loss and hepatitis B e-antibody seroconversion at week 48. HBV DNA suppression rates were similar across all treatment arms at Week 24. ISG15 induction was dose-dependent and did not correlate with HBsAg changes. A small proportion of patients exhibited dose-dependent interferon-α induction that correlated with grade of influenza-like adverse events. Overall, vesatolimod is safe and well tolerated in CHB patients. Although consistent dose-dependent pharmacodynamic induction of ISGs was demonstrated, it did not result in clinically significant HBsAg decline., (© 2018 John Wiley & Sons Ltd.)

The management of chronic hepatitis B virus (HBV) infection is challenged by its varying natural course and its stealthy nature. Not all HBV-infected patients will develop complications of infection; however, it is of utmost importance to identify patients who are at risk and require antiviral treatment and/or close surveillance. Hepatic inflammation and quantification of HBV DNA have guided treatment decisions in the last decade, and these guided interventions have been shown to reduce liver-related complications and death. Data on the quantification of additional HBV markers such as hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) and hepatitis B virus RNA (HBV RNA) have accumulated in recent years. Here, we review the current evidence of how to use these markers and discuss open issues that require additional research., (© 2018 John Wiley & Sons Ltd.)