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Background: Maternal tenofovir disoproxil fumarate (TDF) therapy during late pregnancy can reduce mother-to-infant transmission of hepatitis B virus (HBV). We investigated HBV mutations associated with maternal TDF therapy and their role in infant immunonophylaxis failure (IPF)., Methods: Serum samples from untreated (n = 89) and TDF-treated (n = 68), highly viremic, chronically infected mothers and their infants were analyzed for HBV DNA by nested polymerase chain reaction (PCR) and direct sequencing., Results: At delivery, compared with untreated mothers, TDF-treated mothers had a lower HBV DNA titer and a higher frequency of basal core promoter (BCP) gene mutations, but they had similar frequencies in pre-S/S and pre-core/core mutations. The 14 mothers harboring surface "a" determinant mutants did not transmit the mutants to their immunized infants. Such mutants were found in 3 of 13 IPF infants; the 13 mothers had wild-type hepatitis B surface antigen (HBsAg). In univariable analysis, maternal HBV DNA titer (odds ratio [OR]: 1.54; 95% confidence intervals [CI]: 1.02-2.33; P = .039), genotype C (OR: 4.18; 95% CI: 1.28-13.62; P = .018) and pre-S1 wild-type sequence (OR: 6.33; 95% CI: 1.85-21.68; P = .003) at delivery were associated with infant IPF. Multivariable analyses showed that maternal genotype C (OR: 3.71; 95% CI: 1.11-12.36; P = .033) and pre-S1 wild-type (OR: 6.34; 95% CI: 1.79-22.44; P = .004) were associated with infant IPF independently of maternal viremia., Conclusions: Along with high maternal HBV DNA titer at delivery, maternal genotype C and pre-S1 wild-type sequence were potential risk factors for infant IPF, although BCP mutations were not. The offspring of pregnant women harboring "a" determinant mutants as major strains seemed to be protected by immunoprophylaxis., Clinical Trials Registration: NCT01312012., Competing Interests: Potential conflicts of interest. The authors have no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: In the Taiwanese population born in the universal vaccination era, HBsAg carrier rates have fallen below 2%, while approximately 5% develop occult hepatitis B infection (OBI). However, the potential for transmission from mothers with OBI to their infants has not been well studied. We aimed to investigate whether mothers with OBI could transmit HBV to their babies., Methods: A total of 253 pregnant women who were born after July 1986 and had been fully vaccinated against HBV during infancy were recruited from a tertiary hospital in Northern Taiwan. HBV serology and DNA levels were determined. Babies born to mothers with OBI were followed-up until 1 year of age. The surface genes were sequenced., Results: HBV infection was documented in 18 vaccinated mothers, 2 of whom were HBsAg-reactive (0.79 %). Seventeen were positive for HBV DNA, among whom 16 (6.32%) presented with OBI with a median DNA level of 145 IU/ml (interquartile range: 37.8-657.3 IU/ml). Eleven babies born to 10 mothers with OBI were recruited. Three babies were HBsAg-reactive, and 2 were positive for HBV DNA (17.0 and 212.0 IU/ml). Seven mothers with OBI carried multiple surface gene variants. Two transiently infected babies harbored variants originating from their mother's HBV quasi-species. All infants received complete hepatitis B vaccines. At 12 months of age, none of the babies were positive for HBsAg or HBV DNA., Conclusions: It was possible for mothers with OBI to transmit HBV to their babies, who consequently harbored surface gene variants originating from their mothers' minor variants. Viremia was cleared 1 year after completing the hepatitis B vaccination series., Lay Summary: Since initiating the hepatitis B vaccination program in Taiwan, the rate of young individuals (i.e. born after 1986) carrying the HBV surface antigen has fallen below 2%, although around 5% of vaccinated individuals develop occult HBV infections. Herein, we show that pregnant mothers with occult HBV infections can transmit HBV to their offspring. However, no infant had sustained infection at 1 year of age having completed a full HBV vaccination series., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Tenofovir disoproxil fumurate (TDF) therapy during late pregnancy in highly viremic mothers can reduce residual overt hepatitis B virus (HBV) infections of their infants that occur despite immunoprophylaxis. 1 Occult HBV infection (OBI) has been defined as the presence of HBV DNA in liver or sera in subjects seronegative for hepatitis B surface antigen (HBsAg). , 2 Occult HBV infection (OBI) has been defined as the presence of HBV DNA in liver or sera in subjects seronegative for hepatitis B surface antigen (HBsAg). 3 OBI has been found in varying proportions of immunized infants born to HBsAg-positive mothers. 4-6 We aimed to investigate the impact of maternal TDF therapy during pregnancy on vertically acquired OBI., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Inevitable long-term therapy with nucleos(t)ide analogs in patients with chronic hepatitis B virus (HBV) infection has selected reverse-transcriptase (rt) mutants in a substantial proportion of patients. Some of these mutants introduce premature stop codons in the overlapping surface (s) gene, including rtA181T/sW172*, which has been shown to enhance oncogenicity. The oncogenicity of another drug-resistant mutant, rtM204I/sW196*, has not been studied. We constructed plasmids harboring rtM204I/sW196* and assessed the in vitro cell transformation, endoplasmic reticulum (ER) stress response, and xenograft tumorigenesis of the transformants. Cellular gene expression was analyzed by cDNA microarray and was validated. The rtM204I/sW196* transformants, compared with the control or wild type, showed enhanced transactivation activities for c-fos , increased cell proliferation, decreased apoptosis, more anchorage-independent growth, and enhanced tumor growth in mouse xenografts. X box-binding protein-1 ( XBP1 ) splicing analysis showed no ER stress response. Altered gene expressions, including up-regulated MGST2 and HIF1A , and downregulated transforming growth factor beta-induced ( TGFbi ), were unveiled by cDNA microarray and validated by RT-qPCR. The TGFbi alteration occurred in transformants with wild type or mutated HBV. The altered MGST2 and HIF1A were found only with mutated HBV. The rtM204I/sW196* preS/S truncation may endorse the cell transformation and tumorigenesis ability via altered host gene expressions, including MGST2, HIF1A, and TGFbi . Downregulated TGFbi may be a common mechanism for oncogenicity in HBV surface truncation mutants.

We examined the characteristic changes of hepatitis B virus (HBV) in antiviral drug treatment-naive patients referred for pretreatment evaluation in Taiwan during 2008-2012. Over time, we observed substantial decreases in the prevalence of HBV e antigen (HBeAg) and increasing prevalence of the precore G1899A mutation and HBV-DNA levels in HBeAg-positive patients.

The presence of anti-hepatitis B virus (HBV) core antibody (anti-HBc) is considered a sensitive lifetime marker of HBV infection. Here, we examined this dogma by investigating the prevalence of hepatitis B viremia in anti-HBc negative complete vaccines in Taiwan.A total of 795 participants (1.7-20.0 years old) had completed HBV vaccination in infancy and were anti-HBc negative. Serum samples were available for 460 individuals with isolated anti-HBV surface antibodies (anti-HBs) (HBsAg-negative and anti-HBc negative) and for 245 individuals who tested negative for all 3 markers (triple seronegative). All samples were submitted for polymerase chain reaction (PCR) targeting both the preS/S and X/pre-C gene regions.Of the 460 participants with isolated anti-HBs, 26 (5.65%) were positive for HBV by 2-target PCR. Of the 245 triple seronegative samples, 12 (4.90%) were positive for HBV DNA. In the former group, the prevalence of viremia was significantly higher in individuals aged 6 to 10 years than in all other ages combined (11.82% vs 3.7%, P = 0.001). The anti-HBs titers were significantly lower in participants 6 to 10 years old than in all other ages combined (72.06 vs 99.64 mIU/mL, P = 0.038). In total, 7 (0.99%) subjects had quantifiable HBV DNA levels (280-18,820 IU/mL). Sequence analysis of the S gene revealed vaccine escape like mutations.Hepatitis B viremia can occur in completely vaccinated individuals who are negative for anti-HBc., Competing Interests: The authors declare no conflicts of interest.

Hepatitis B virus (HBV) infection causes long-term, life-threatening liver diseases worldwide. HBV is transmitted through either the horizontal or mother-to-infant route, which is the major route of transmission in endemic areas. Administration of hepatitis B immunoglobulin and hepatitis B vaccine to newborns of infected mothers prevents mother-to-infant transmission. Implementation of a universal hepatitis B vaccination program has proven successful in eliminating the infection and related complications. Nevertheless, efforts are still needed to improve global coverage of the hepatitis B vaccine. Infants born to highly viremic mothers are still at risk of infection despite current immunoprophylaxis. An increasing number of reports have shown promising efficacy and safety profiles with the use of nucleoside/nucleotide analogues in highly viremic pregnant women to prevent mother-to-infant transmission.

Background & Aims: The correlation between chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC) has been well-established. But the roles of viral factor remain uncertain. Only HBV X gene and nonsense mutations of S gene (C-terminal truncation of HBV surface protein) have been demonstrated to have transforming activity. Whether they play a significant role in hepatocarcinogenesis is still uncertain., Methods: Twenty-five HBV-related HCC patients were positive for hepatitis B core antigen (HBcAg) in the cancerous parts of their HCC liver tissues by immunohistochemistry studies, and had available tissue for whole HBV genome sequence analysis. The results were compared with 25 gender and age-matched HBcAg negative HCCs. Plasmids encoding HBV S gene nonsense mutations identified from HBcAg (+) HCC tissue were constructed to investigate their cell proliferation, transformation activity and the oncogenic potentials by xenograft study and in vivo migration assay., Results: HBcAg (+) HCC patients were significantly associated with cirrhosis and small tumor size (≦2 cm) when compared with HBcAg (-) HCC patients. Southern blot analyses revealed freely replicative forms of HBV in the cancerous parts of HBcAg(+) HCC. Three nonsense mutations of S gene (sL95*, sW182*, and sL216*) were identified in the HBcAg(+) HCC tumor tissues. sW182* and sL216* were recurrently found in the 25 HBcAg (-) HCC tumor tissue, too. Functional studies of the above 3 non-sense mutations all demonstrated higher cell proliferation activities and transformation abilities than wild type S, especially sW182*. Tumorigenicity analysis by xenograft experiments and in vitro migration assay showed potent oncogenic activity of sW182* mutant., Conclusions: This study has demonstrated potent oncogenic activity of nonsense mutations of HBV S gene, suggesting they may play an important role in hepatocarcinogenesis.

Background & Aims: Despite the success of a universal vaccination program against hepatitis B virus (HBV) in Taiwan, a small but substantial proportion of individuals remain infected by mutant viruses that escape the vaccine. We investigated the seroepidemiology and genotypic characteristic of HBV for long periods after neonatal vaccination., Methods: We measured hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), and antibody to hepatitis B surface antigen (anti-HBs) in 1214 serum samples collected throughout Taiwan from individuals 0.6-87.8 years old in 2007. HBV DNA was detected using polymerase chain reaction and sequence analysis in vaccine recipients who tested positive for anti-HBc and/or HBsAg., Results: The overall seroprevalence of HBsAg and anti-HBc was significantly lower among individuals born after the initiation of the nationwide vaccination program (P < .001). However, we observed increasing seroprevalence of anti-HBc and isolated anti-HBs when subjects were grouped by age: at 10-14, 14-18, to 18-21 years of age, values were 0.4%, 1.9%, and 8.1% (P = .0135) and 43.7%, 55.4%, and 59.6% (P = .0093), respectively (χ(2) test for trend). A large increase was observed in the percentage of patients who tested positive for HBV DNA at 18-21 years of age (3.0% vs 0.2% [P = .002] for all eligible subjects and 5.7% vs 0.3% [P < .001] for subjects vaccinated with ≥3 doses). Five of 8 completely vaccinated individuals who were seropositive for HBV DNA carried variants with mutations in the S gene., Conclusions: Universal vaccination effectively controls HBV infection in children and adolescents. However, after adolescence, there is a significant increase in the seroprevalence of anti-HBs, anti-HBc, and HBV DNA, indicating that new preventative strategies are needed for adults., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: The replication defect of hepatitis B virus (HBV) lamivudine-resistant mutants can be restored by the development of compensatory mutations. Such mutations have long been recognized for the rtM204V mutant, while little is known about any compensatory mutation specific to the rtM204I mutant. The aim of this study was to search for previously unrecognized compensatory mutations following development of lamivudine-resistant mutants., Methods: Of 83 lamivudine-resistant patients, 49 and 34 patients harboured the rtM204I and rtM204V mutations, respectively. Serial serum samples obtained during the therapeutic course were submitted to sequence analysis. Site-directed mutagenesis experiments were performed to examine the functions of the identified associated mutations., Results: Of the 49 patients carrying the rtM204I mutation, 5 subsequently developed an rtS117F substitution during the follow-up, whereas 4 harboured an rtN124D substitution prior to the development of the rtM204I mutation. Emergence of the rtS117F mutation was associated with an increase in hepatitis activity, whereas prior existence of the rtN124D mutation was associated with decompensated liver function upon development of the rtM204I mutation. Site-directed mutagenesis experiments showed that the rtS117F mutation by itself did not confer lamivudine resistance but it compensated for replication deficiency of the rtM204I mutant in HepG2 and Mahlavu cells. Additionally, virion and hepatitis B surface antigen secretion of the rtS117F mutant was significantly impaired., Conclusions: The rtS117F substitution served as a compensatory mutation for rtM204I. Emergence of the rtS117F mutation in lamivudine-resistant patients carrying rtM204I was associated with increased hepatitis activities. Prior existence of the rtN124D substitution was associated with liver decompensation upon development of the rtM204I mutation.

Background: CD133 was detected in several types of cancers including hepatocellular carcinoma (HCC), which raised the possibility of stem cell origin in a subset of cancers. However, reappearance of embryonic markers in de-differentiated malignant cells was commonly observed. It remained to be elucidated whether CD133-positive HCCs were indeed of stem cell origin or they were just a group of poorly differentiated cells acquiring an embryonic marker. The aim of this study was to investigate the significance of CD133 expression in HCC in an area endemic for hepatitis B virus (HBV) infection to gain insights on this issue., Methods: 154 HCC patients receiving total removal of HCCs were included. 104 of them (67.5%) were positive for HBV infection. The cancerous and adjacent non-cancerous liver tissues were subjected for Western blot and immunohistochemistry analysis for CD133 expression. The data were correlated with clinical parameters, patient survivals, and p53 expression., Results: Of 154 patients, 24 (15.6%) had CD133 expression in HCC. Univariate and multivariate logistic regression analysis revealed that CD133 expression was negatively correlated with the presence of hepatitis B surface antigen (HBsAg). The unadjusted and adjusted odds ratios were 0.337 (95%CI 0.126 - 0.890) and 0.084 (95%CI 0.010 - 0.707), respectively. On the other hand, p53 expression was positively associated with the presence of HBsAg in univariate analysis. The unadjusted odds ratio was 4.203 (95%CI 1.110 - 18.673). Survival analysis indicated that both CD133 and p53 expression in HCC predicted poor disease-free survival (P = 0.009 and 0.001, respectively), whereas only CD133 expression predicted poor overall survival (P = 0.001). Cox proportional hazard model showed that p53 and CD133 expression were two independent predictors for disease-free survival. The hazard ratios were 1.697 (95% CI 1.318 - 2.185) and 2.559 (95% CI 1.519 - 4.313), respectively (P < 0.001 for both)., Conclusion: In area where HBV infection accounts for the major attributive risk of HCC, CD133 expression in HCC was negatively associated with the presence of HBsAg, implicating a non-viral origin of CD133-positive HCC. Additionally, CD133 expression predicted poor disease-free survival independently of p53 expression, arguing for two distinguishable hepatocarcinogenesis pathways.

Introduction: Universal infant hepatitis B virus (HBV) vaccination program has reduced HBV infection dramatically in vaccinated young generations. Management of chronically infected children is still challenging concerning high viral load with mostly mild diseases, yet with a nonnegligible proportion of advanced diseases, and long-term effect of antivirals. However, with more potent antivirals approved for pediatric patients, to start antivirals earlier in eligible patients may benefit their outcomes. This review aimed to update the current management of chronic hepatitis B in children. Areas covered: This review covered the natural history of chronic HBV infection, management of chronic hepatitis B in children from the past to the present, current consensus on the treatment of chronic hepatitis B in children, controversies in cessation of oral antivirals, and management of special populations such as pregnancy and co-infections. Expert opinions: Without contraindication, peginterferon is recommended for immune-active children ≥ 3 years old. For those intolerant, decompensating or preferring oral therapy, first-line Nucleos(t)ide analogs (NUC), Entecavir or Tenofovir, may be applied. For immune-tolerant or inactive carriers, close monitoring is crucial. When to stop NUCs and novel therapies for HBV cure await further research. [ABSTRACT FROM AUTHOR]

Background: Although men carry a higher risk of hepatocellular carcinoma (HCC) than women, it is still controversial whether men also have a poorer postoperative prognosis. A retrospective study was conducted to evaluate the postoperative prognostic predictors of HCC focusing on sex differences.Methods: We enrolled 516 consecutive adult patients with HCC (118 women, 398 men), who received surgical resection between January 2000 and December 2007, and were followed-up for >10 years. Clinical and laboratory data together with postoperative outcomes were reviewed.Results: At baseline, female patients had a higher anti-hepatitis C virus antibody prevalence (P = 0.002); lower hepatitis B virus surface antigen prevalence (P = 0.006); less microvascular invasion (P = 0.019); and lower alpha-fetoprotein (P = 0.023), bilirubin (P = 0.002), and alanine transaminase (P = 0.001) levels. Overall, there were no significant sex differences in terms of intrahepatic recurrence-free survival (RFS), distant metastasis-free survival (MFS), and overall survival (OS). However, subgroup analysis showed that women had favorable RFS (P = 0.019) and MFS (P = 0.034) in patients with alpha-fetoprotein ≤ 35 ng/mL, independent of other clinical variables (adjusted P = 0.008 and 0.043, respectively). Additionally, men had favorable OS in patients with prothrombin time (international normalized ratio [INR]) <1.1 (P = 0.033), independent of other clinical variables (adjusted P = 0.042).Conclusions: Female sex is independently associated with favorable postoperative RFS and MFS in patients with alpha-fetoprotein ≤35 ng/mL, while male sex is independently associated with favorable OS in patients with prothrombin time INR <1.1. [ABSTRACT FROM AUTHOR]

Introduction: After the initiation of a mass hepatitis B vaccination program in Taiwan, the prevalence of hepatitis B virus infection has declined progressively. However, about 1 percent of the young generation, who received hepatitis B vaccination at birth, remain carriers. Infection with vaccine-escape hepatitis B virus mutants always occurs shortly after birth. Here, we report two female siblings in whom the infection occurred in their adolescence. This report raises the question of whether a booster for hepatitis B vaccination is needed.Case Presentation: Two 19 and 14-year-old Taiwanese female siblings were born to a mother infected with hepatitis B virus and received a complete course of hepatitis B vaccination at birth. They remained negative for serum hepatitis B surface antigen and positive for serum anti-hepatitis B surface antibody throughout their childhood. However, both were infected with the hepatitis B virus in their adolescence. Hepatitis B virus DNA was extracted from serum samples from the mother and two siblings. Hepatitis B virus pre-S/S sequence was amplified by polymerase chain reaction followed by nucleotide sequencing. When compared with the sequence obtained from the mother, multiple amino acid substitutions located near or in the major hydrophilic region of the surface antigen were identified in the elder sister. Four of these mutations (sL97S, sL98S, sG102R, and sA159P) were novel. A novel in-frame deletion (14 amino acids deleted, pre-S 127-140) was found in the hepatitis B virus pre-S2 region in the younger sister.Conclusions: Despite having received hepatitis B vaccination at birth, hepatitis B virus infection can still occur in adolescence with the emergence of novel mutations in the pre-S/S gene. This is a rare event and, to the best of our knowledge, has not been previously reported. [ABSTRACT FROM AUTHOR]

Sorafenib is a first-line treatment for patients with advanced hepatocellular carcinoma (HCC). These patients may simultaneously receive anti-hepatitis B treatment if they are viremic. The N-Acetylgalactosaminyltransferase 14 (GALNT14) gene can serve as a biomarker to guide HCC treatments. However, the enzyme substrates of its gene product, GalNAc-T14 (a glycosyltransferase), remained uncharacterized. Here, we conducted a glycoproteome-wide search for GalNAc-T14 substrates using lectin affinity chromatography followed by tandem mass spectrometry. Seventeen novel GalNAc-T14 substrates were identified. A connective map analysis showed that an antiviral drug, tenofovir, was the leading medicinal compound to down-regulate the expression of these substrates. In vitro assays showed that HCC cells were resistant to sorafenib if pretreated by tenofovir but not entecavir. Clinical analysis showed that the concomitant use of tenofovir and sorafenib was a previously unrecognized predictive factor for unfavorable overall survival (hazard ratio = 2.060, 95% confidence interval = [1.256, 3.381], p = 0.004) in a cohort of 181 hepatitis-B-related, sorafenib-treated HCC patients (concomitant tenofovir versus entecavir treatment; p = 0.003). In conclusion, by conducting a glycoproteome-wide search for GalNAc-T14 substrates, we unexpectedly found that tenofovir was a major negative regulator of GalNAc-T14 substrates and an unfavorable anti-hepatitis B drug in HCC patients receiving sorafenib. [ABSTRACT FROM AUTHOR]

Simple Summary: The quantitative assessment of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) is essential to the development of next generation antiviral therapies against hepatitis B. Here, we developed a peptide nucleic acid (PNA)-clamping qPCR method to quantify cccDNA, which was comparable to the recently proposed exonuclease-based cccDNA assays. Using this method, we showed that cccDNA levels in the para-neoplastic liver tissues were independently correlated with overall survival, as well as extrahepatic metastasis in patients with or without virological suppression. These results suggest that in HBV-related hepatocellular carcinoma, patients under antiviral suppression might further benefit from new antivirals, which are designed to reduce cccDNA. New antiviral therapies against hepatitis B virus (HBV) focus on the elimination of covalently closed circular DNA (cccDNA). However, traditional cccDNA-specific quantitative PCR (qPCR) has a narrow effective range, hindering a reliable comparison between the levels of biopsy-derived cccDNAs. Collaterally, the prognostic role of cccDNA in HBV-related hepatocellular carcinoma (HCC) cannot be clearly defined. Here, we developed a peptide nucleic acid (PNA)-clamping qPCR method to provide a wider range of specific cccDNA quantification (up to 5 logs of effective range). Extrachromosomal DNA was extracted from para-neoplastic tissues for cccDNA quantification. In total, 350 HBV-related HCC patients were included for an outcome analysis. Without differential pre-dilution, cccDNA levels in para-neoplastic liver tissues were determined, ranging from < 2 × 103 to 123.0 × 106 copies/gram. The multivariate linear regression analysis showed that cccDNA was independently correlated with the HBV e antigen (p < 0.001) and serum HBV-DNA levels (p = 0.012). The Cox proportional hazard model analysis showed that cccDNA independently predicted overall survival (p = 0.003) and extrahepatic metastasis-free survival (p = 0.001). In virologically suppressed HCC patients, cccDNA still effectively predicted intrahepatic recurrence-free (p = 0.003) and extrahepatic metastasis-free (p = 0.009) survivals. In conclusion, cccDNA independently predicted postoperative extrahepatic metastasis-free survival. [ABSTRACT FROM AUTHOR]