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Background: Evaluation of the impact of a hepatitis B virus (HBV) prevention program that incorporates maternal antiviral prophylaxis on mother-to-child transmission (MTCT) is limited using real-world data., Methods: We analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for hepatitis B surface antigen (HBsAg) among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 2008-2022. Through linkage with the National Health Insurance Database, information on maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies., Results: In total, 2 460 218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and hepatitis B e antigen (HBeAg) seropositivity rates among native pregnant women decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (P for both trends < .0001). Among the 22 859 at-risk infants who underwent PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; P < .001). MTCT risk increased with maternal HBeAg positivity (odds ratio [OR], 9.29; 95% confidence interval [CI], 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR, 0.28; 95% CI, .16-.49). For infants with maternal HBeAg positivity, MTCT risk was associated with mothers born in the immunization era (OR, 1.40; 95% CI, 1.17-1.67)., Conclusions: MTCT was related to maternal HBeAg positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk., Competing Interests: Potential conflicts of interest . The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background and Aims: Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination., Methods: A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated., Results: After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed., Conclusion: The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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 and Aims: The immunologic features involved in the immune-tolerant phase of chronic hepatitis B (CHB) virus (HBV) infection are unclear. The hepatitis B virus X (HBx) protein disrupts IFN-β induction by downregulating MAVS and may destroy subsequent HBV-specific adaptive immunity. We aimed to analyse the impacts of genetic variability of HBx in CHB patients on the immune-tolerant phase during long-term follow-up., Methods: Children with CHB in the immune-tolerant phase were recruited and followed longitudinally. HBx gene sequencing of infecting HBV strains was performed, and the effects of HBx mutations on the immune-tolerant phase were assessed. Restoration of the host immune response to end the immune-tolerant phase was investigated by immunoblotting, immunostaining, ELISA and reporter assays of MAVS/IFN-β signalling in liver cell lines, patient liver tissues and the HBV plasmid replication system., Results: A total of 173 children (median age, 6.92 years) were recruited. Patients carrying HBx R87G, I127V and R87G + I127V double mutations exhibited higher cumulative incidences of immune-tolerant phase breakthrough (p = .011, p = .006 and p = .017 respectively). Cells transfected with HBx R87G and I127V mutants and pHBV1.3-B6.3 replicons containing the HBx R87G and I127V mutations exhibited statistically increased levels of IFN-β, especially under poly(I:C) stimulation or Flag-MAVS cotransfection. HA-HBx wild-type interacted with Flag-MAVS and enhanced its ubiquitination, but this ability was diminished in the R87G and I127V mutants., Conclusions: HBx suppresses IFN-β induction. R87G and I127V mutation restored IFN-β production by preventing MAVS degradation, contributing to curtailing the HBV immune-tolerant phase in CHB patients., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Tenofovir disoproxil fumarate (TDF) is the preferred treatment to prevent mother-to-infant transmission in highly viremic HBV-infected women. Data on hepatitis B surface antigen (HBsAg) levels in pregnant women are lacking. We aimed to investigate prepartum and postpartum HBsAg kinetics and its correlation with HBV DNA in pregnant women. HBV-infected mothers with HBV DNA ≥7.5 log 10  IU/ml were tested for HBsAg and HBV DNA from baseline to 6 months postpartum. Of the 186 pregnant women with comparable baseline HBsAg and HBV DNA, 101 received TDF from the third trimester until 1 month postpartum. At delivery, TDF group had mildly lower HBsAg (4.32 ± 0.47 vs. 4.54 ± 0.35 log 10  IU/ml, p = .0004) and markedly lower HBV DNA (4.26 ± 0.97 vs. 8.11 ± 0.70 log 10  IU/ml, p < .0001) than the control group. In the TDF group, mean reduction of HBsAg and HBV DNA from baseline to delivery were 0.22 ± 0.38 and 3.96 ± 0.93 log 10  IU/ml. HBsAg reduction had a positive correlation (r = .309; p = .0017) with HBV DNA reduction, and was predictive of HBV DNA reduction ≥3 log 10  IU/ml (area under the receiver operating characteristic curve, 0.67; 95% confidence interval, 0.50-0.82). At 6 months postpartum, TDF and control group had comparable HBsAg and HBV DNA. In conclusion, HBsAg decreased slightly at delivery in pregnant women receiving TDF. For monitoring the effect of antiviral therapy during pregnancy, HBV DNA is a better marker than HBsAg. Our data provided valuable information regarding monitoring HBV-infected pregnant women using antiviral therapy., (© 2021 John Wiley & Sons Ltd.)

A universal hepatitis B virus (HBV) vaccination program has been implemented in Taiwan since 1984. A total of 1611 individuals in Taipei were enrolled to monitor long-term efficacy. The prevalences of hepatitis B surface antigen (HBsAg) and hepatitis B core antibody in the vaccinated birth cohort were lower than in those born before 1984 (0.4% vs 7.7%, and 2.2% vs 50.8%, respectively; P < .0001). Three vaccine-failure carriers all were born to HBsAg-carrier mothers, probably due to no antiviral intervention during pregnancy. Occult HBV infection was rare in the postvaccination era. High vaccination coverage, comprehensive HBV screening, and antiviral agents for pregnant mothers will be essential to eliminate HBV transmission., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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.)

Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population starting from birth dose, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective, the cancer preventive efficacy support it as the first successful example of cancer preventive vaccine in human. Addition of hepatitis B immunoglobulin immediately after birth and antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are existing or possible emerging strategies to enhance the prevention efficacy of HBV infection and its related liver cancer. Secondary prevention with current antiviral agents may reduce the risk or delay the onset of HCC development, but could not eradicate HBV infection and HCC. Better antiviral therapeutic agents are needed for better secondary prevention.

Objective: Mother-to-infant transmission (MIT) is the leading cause of hepatitis B virus (HBV) infections globally. The aim of this international study was to assess the impediments to prevention of (MIT) of HBV., Methods: A cross-sectional survey was developed by the Federation of the International Societies for Pediatric Gastroenterology, Hepatology and Nutrition. (FISPGHAN) The survey was sent to HBV experts of the 5-member societies of FISPGHAN, and 63 of 91 countries/regions responded. Main outcome measures include percentage of countries having vaccine programs, timing of the first dose of HBV vaccine, availability of HBV vaccine for outborn neonates, payment of HBV vaccine and hepatitis B immune globulin, screening HBV markers during pregnancy, and antivirals to highly infectious pregnant mothers., Results: Among the participating countries/regions, 11% did not implement infant HBV immunization programs. The first dose of vaccine was given >24 hours in 36% of the total countries and 100% of African countries. The recommended birth dose was unavailable for outborn neonates in 45% of the total countries, including 92% of African and 50% of Latin American countries/regions. During pregnancy, 44% countries do not screen maternal viral markers, and 46% do not provide third trimester antiviral therapy for highly viremic pregnant mothers., Conclusions: Our study demonstrated multiple obstacles to achieving the goal of preventing MIT of HBV. Comprehensive public health programs to enhance vaccine coverage rate, supply HBV vaccine for out-born neonates, screening maternal HBV markers, treating highly viremic pregnant mothers are proposed to overcome these obstacles and achieve the goal of preventing MIT of HBV.

Background: The hepatitis B virus (HBV) status of pregnant women affects HBV vaccine failure in their offspring. This study is aimed to investigate the impact of the universal infant HBV vaccination program on the long-term hepatitis B surface antigen (HBsAg) rate in pregnant women., Methods: Using the National Immunization Information System, we examined a 32-year period of cross-sectional data on a maternal HBsAg and hepatitis B e antigen (HBeAg) screening program launched in July 1984. An age-period-cohort model analysis of 940 180 pregnant women screened for July 1996-June 1997 and the years 2001, 2006, 2011, and 2016 was applied., Results: The annual HBsAg- and HBeAg-seropositive rates decreased from 13.4% and 6.4%, respectively, for the period 1984-1985 to 5.9% and 1.0% in 2016 (P for both trends < .0001). Pregnant women with birth years after July 1986 (the HBV vaccination cohort) had the lowest relative risk (0.27 [95% confidence interval, .26-.28]) of HBsAg positivity compared with birth years before June 1984., Conclusions: The birth cohort effect in relation to the universal infant HBV immunization program has effectively reduced the HBV carrier rate in pregnant women and the burden of perinatal HBV infection on the next generation., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease and associated morbidity and mortality worldwide. Short-course, oral, curative, direct-acting antiviral regimens have transformed treatment for HCV infection. Since the 2016 launch of the first global strategy towards elimination of viral hepatitis as a public health threat by 2030, the predominant focus of the global response has been on the treatment of adults, who bear the greatest burden of morbidity and mortality of HCV-related chronic liver disease. Compared with adults, there has been little attention paid to addressing the response to HCV in children and adolescents, in part because of the scarcity of data to inform specific paediatric management practices and policy. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HCV infection in adolescents and children, and we highlight key differences from infection acquired in adulthood. The estimated global prevalence and burden of HCV infection in children aged 1-19 years is 0·15%, corresponding to 3·5 million people (95% CI 3·1-3·9 million). HCV infection is usually asymptomatic during childhood, and cirrhosis and hepatocellular carcinoma are rare. Sofosbuvir with ledipasvir and sofosbuvir with ribavirin have received regulatory approval and guidelines recommend their use in adolescents aged 12 years and older with HCV infection. In April, 2019, glecaprevir with pibrentasvir also received regulatory approval for adolescents aged 12-17 years. Key actions to address the current policy gaps and achieve treatment scale-up that is comparable to that in adults include: establishment of a campaign on access to testing and treatment that is targeted at children and adolescents; fast-track evaluation of pan-genotypic regimens; and accelerated approval of paediatric formulations. Research gaps that need to be addressed include: age-specific prevalence studies of HCV viraemia in priority countries; further validation of non-invasive tests for staging of liver disease in children; and establishment of paediatric treatment registries and international consortia to promote collaborative research agendas., (Copyright © 2019 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Despite the success of universal infant immunization initiated in Taiwan in 1984, occult hepatitis B virus infection (OBI) and circulating surface antigen mutants remain potential obstacles for eventual eradication of HBV infection., Methods: From 3299 apparently healthy, neonatally-vaccinated subjects (<30 years of age ) enrolled during 2014 serosurvey, we recruited all HBsAg-positive (n = 17), all HBsAg-negative but anti-HBc-positive (n = 132) and randomly selected HBsAg-negative and anti-HBc-negative subjects (n = 411). These recruited subjects and 81 HBsAg-negative children with various forms of hepatitis and multiple transfusions were analysed for serum HBV DNA., Results: In healthy, HBsAg-negative subjects, OBI frequency was higher in anti-HBc-positive than anti-HBc-negative individuals (8/90[8.9%] vs 8/301[2.7%], P = 0.0192) aged <18-years, but was not different between anti-HBc-positive and anti-HBc-negative individuals (0/11[0%] vs 3/110[2.7%], P > 0.05) aged 18 to 30 years. OBI occurred more frequently in children of HBsAg-positive mothers than in children of HBsAg-negative mothers (10/101 [9.9%] vs 1/75 [1.3%], P = 0.025). The prevalence of surface 'a' determinant (aa110-160) mutants was 13.3% (2/15) in OBI subjects compared to 36.4% (4/11) in HBsAg-positive subjects (P > 0.05). OBI was found in 30% (3/10) of serologic 'non-A to E' viral hepatitis, 14.3% (3/21) of chronic hepatitis C and 2.0% (1/50) of multitransfused, thalassemic children., Conclusions: In this highly immunized population, surface antigen mutant infection is uncommon and has low contribution to OBI development. HBsAg screening plus highly sensitive HBV DNA assays are needed for assurance of blood supply safety. Multiple transfusions from HBsAg-negative blood donors rarely result in persistent HBV infection. HBV might be related to some of serologic 'non-A to E' viral hepatitis., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver disease and associated morbidity and mortality worldwide. Vertical (mother-to-child) and horizontal early childhood transmission are the main routes of HBV transmission and are responsible for most chronic infections, including among adults who bear the greatest burden of morbidity and mortality. Universal hepatitis B immunisation at birth and in infancy is the key strategy for global elimination of HBV infection, and has been highly effective in reducing new vertical infections. However, global progress in scale-up of HBV testing and treatment has been slow in adults and children. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HBV infection in adolescents and children, and we highlight key differences from HBV infection in adults. The estimated global prevalence of HBV infection in children aged 5 years or younger is 1·3%. Most children are in the high-replication, low-inflammation phase of infection, with normal or only slightly raised aminotransferases; cirrhosis and hepatocellular carcinoma are rare. Although entecavir is approved and recommended for children aged 2-17 years, and tenofovir for those aged 12-18 years, a conservative approach to treatment initiation in children is recommended. Key actions to address current policy gaps include: validation of non-invasive tests for liver disease staging; additional immunopathogenesis studies in children with HBV infection; long-term follow-up of children on nucleoside or nucleotide analogue regimens to inform guidance on when to start treatment; evaluation of different treatment strategies for children with high rates of HBV replication; and establishment of paediatric treatment registries and international consortia to promote collaborative research., (Copyright © 2019 World Health Organization. Published by Elsevier Ltd. All rights reserved. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Taiwan began a universal hepatitis B virus (HBV) vaccination program for infants in July 1984. The seroprevalence of hepatitis B surface antigen (HBsAg) decreased from 9.8% before the vaccination program to less than 1% by 25 years afterward. We continued to monitor HBV infections in this population., Methods: We conducted a series of serologic and epidemiologic surveys in the Taipei metropolitan area every 5 years from 1984 through 2014. From January 1 through December 31 of 2014, we collected serum samples from 4605 apparently healthy individuals (ages: 287 were <3 y, 405 were 3-6 y, 675 were 7-12 y, 686 were 13-18 y, 468 were 18-22 y, and 2084 were 22-50 y). All subjects were tested for HBsAg, its antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). We performed genotype and viral load analyses for patients who tested positive for anti-HBc., Results: Of vaccinated participants (age, <30 y; n = 3299), 0.5% tested positive for HBsAg, 47.4% tested positive for anti-HBs, and 4.5% tested positive for anti-HBc. Of unvaccinated participants (age, 30-50 y, n = 1306), 6.7% tested positive for HBsAg (P < .0001), 69.4% tested positive for anti-HBs, and 44.1% tested positive for anti-HBc. One occult HBV infection was found in each age group. Among subjects positive for HBsAg younger than age 30, 77% were born to mothers positive for HBsAg., Conclusions: Based on a series of serologic and epidemiologic surveys performed in the Taipei metropolitan area, 6.7% of persons born before the universal HBV vaccination program were positive for HBsAg, compared with 0.5% of those born afterward. Most subjects positive for HBsAg younger than age 30 were born to mothers positive for HBsAg., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

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.

Unlabelled: To determine whether universal infant immunization affects occult hepatitis B virus (HBV) infection (OBI), serum samples from hepatitis B surface antigen (HBsAg)-negative subjects <18 years enrolled during six sequential seroepidemiological surveys conducted between 1984 (just before universal infant immunization) and 2009 were analyzed. Study subjects were divided into unvaccinated cohorts (born before 1984) and vaccinated cohorts (born after 1984). HBV-DNA positivity was determined by positivity of nested polymerase chain reaction in at least two of three regions (pre-S, S, and pre-core/core genes). OBI frequency was lower in vaccinated than unvaccinated antibody to hepatitis B core antigen (anti-HBc)-negative subjects (0 of 392 [0%] vs. 4 of 218 [1.8%]; P = 0.007), tended to be higher in vaccinated than unvaccinated anti-HBc-positive subjects (16 of 334 [4.8%] vs. 3 of 181 [1.7%]; P = 0.072), and was higher in vaccinated than unvaccinated subjects seropositive for both antibody to hepatitis B surface antigen (anti-HBs) and anti-HBc (13 of 233 [5.6%] vs. 3 of 170 [1.8%]; P = 0.025). By using known anti-HBc seropositivity rate in children in our serosurveys, the estimated OBI frequency per 10(4) HBsAg-negative subjects declined from 160.7 in unvaccinated cohorts to 11.5 in vaccinated cohorts. In vaccinated cohorts, OBI frequency was higher in anti-HBc-positive subjects than in anti-HBc-negative subjects (16 of 334 [4.8%] vs. 0 of 392 [0%]; P < 0.001). Subjects with OBI had much lower viral load (P < 0.001) and a trend of higher mutation rates in "a" determinant of HBsAg than age-comparable, HBsAg-positive subjects., Conclusions: Reduction of OBI in immunized subjects complements the well-documented universal infant immunization-related benefit of markedly reduced overt HBV infection. Breakthrough infections in immunized subjects seem to associate with more occurrence of OBI than natural infections in unvaccinated subjects. In the postvaccination era, anti-HBc seropositivity is a useful marker for OBI screening in HBsAg-negative subjects, and a very-low-level viral replication and HBsAg expression is the major mechanism underlying OBI., (© 2014 by the American Association for the Study of Liver Diseases.)

Background: Infantile hepatitis B after neonatal immunoprophylaxis is a rare yet distinct disease. This study aimed to analyze the long-term outcomes and risk factors in immunized infants with hepatitis B., Methods: The clinical parameters and outcomes of 41 infants born after universal immunization, and admitted for HBV-positive hepatitis were studied. All patients were followed for at least 6 months (median  = 4.4 years, range 0.6-18.1 years). Patient survival, changes of HBsAg and HBeAg status, and complications were analyzed., Results: Among the 41 cases (32 males, 9 females), 21 presented with fulminant hepatitis (FH), and 20 with non-fulminant hepatitis (NFH). Ninety-five percent (36/38) of the mothers were positive for hepatitis B surface antigen (HBsAg). Multivariate analyses revealed younger age of onset (age <7 months) and negative maternal hepatitis B e antigen (HBeAg) were associated with FH (p = 0.03 and p = 0.01, respectively). An infantile fulminant hepatitis B risk score using maternal/infant HBeAg positivity and onset age was proposed. Among the FH cases, the rate of mortality, HBsAg clearance, and chronic HBV infection were 47.6%, 38.1%, and 14.3%, respectively. Among the NFH cases, 35% developed chronic infection. Of the 9 chronically infected children received long-term follow-up, 8 had HBeAg seroconversion before 4 years of age. One case of FH developed hepatocellular carcinoma 14 years later., Conclusions: Maternal HBsAg + /HBeAg- and early onset age were risk factors for FH in immunized infants. A significant portion of patients with FH or NFH evolve to chronic HBV infection, with HBeAg seroconversion in young childhood. Close surveillance for hepatocellular carcinoma is warranted in patients surviving infantile hepatitis B.

Background:  We aimed to elucidate the impact of hepatitis B virus (HBV) precore/core gene mutations on spontaneous hepatitis B e antigen (HBeAg) seroconversion, HBV biosynthesis, and the human immune responses in chronic HBV-infected patients., Methods:  We analyzed the HBV precore/core gene sequences by cloning method in 33 chronic HBV-infected patients during the inflammatory phase before spontaneous HBeAg seroconversion. The impact of the most prevalent mutant on HBeAg biosynthesis was assessed by Western blotting and native agarose gel analysis in Huh7 cells, and the human immune responses were assessed by in vitro stimulation of CD3+ CD8+ T lymphocytes of chronic HBV-infected subjects., Results:  The P135Q and G1896A were the most prevalent mutants before HBeAg seroconversion, acting as markers of HBeAg seroconversion (hazard ratios = 2.75 and 4.50; P = .01 and <.001, respectively). The P135Q mutants displayed decreased HBeAg secretion and HBV capsid molecular weight, while showing increased 22 kD HBeAg proprotein accumulation in Huh7 cells. The P135Q mutant peptide induced less interferon-γ expression in CD3+ CD8+ T lymphocytes in HBeAg-negative subjects compared to the wild-type peptide (P = .03)., Conclusions:  The HBV P135Q mutant emergence during the inflammatory phase was associated with HBeAg seroconversion. It was associated with altered HBV capsid assembly, HBeAg biosynthesis, and reduced human immune responses following HBeAg seroconversion.

Background: The current recommendation of giving the first dose of hepatitis B vaccine to very low birth weight (VLBW) infants at 30 days of chronologic age usually is not practical, because most VLBW infants are not medically stable at that age. We use an alternative body-weight-based protocol, and evaluate its efficacy in an endemic area under a universal immunization program., Methods: The immunogenicity of the current hepatitis B vaccination strategy in 155 VLBW preterm infants was evaluated at age 2 to 13 years, with parental consent. All of the infants were born between 1995 and 2006, and received their first dose of hepatitis B vaccine when they reached 2,000-2,200 g, irrespective of chronological age. Hepatitis B immunoglobulin (HBIG) was given at birth to infants born to HBsAg(+)/HBeAg(+) mothers., Results: All 155 of the recruited children were HBsAg and anti-HBc negative. The anti-HBs seropositivity rate (geometric mean titer) was 84.1% (146.5 mIU/mL) for children under 3 years, 73.5% (68.8 mIU/mL) for 4- to 7-year-olds, 27.7% (55.4 mIU/mL) for 8- to 11-year-olds and 20% (6.0 mIU/mL) for children ≥12 years of age. More than 90% of these children received the first vaccination after 30 days of age, half (51%) at 60 to 90 days, and 29 children (18.6%) after 90 days of age. Of the 26 infants born to HBsAg(+) mothers, 6/6 infants of HBeAg(+) mothers received HBIG at birth, and 12/20 infants of HBeAg(-) mothers received HBIG. None of the 26 infants became infected., Conclusions: Delaying hepatitis B vaccinations in VLBW preterm infants until they reach a weight of 2,000 g, with the administration of HBIG at birth for infants of HBsAg(+) mothers provided adequate immunogenicity and protection in a highly endemic area. Weight-based policy of hepatitis B vaccination is an effective and practical alternative strategy for VLBW infants.

Hepatocellular carcinoma (HCC) is one of the five leading causes of cancer death in human. Hepatitis B virus (HBV) is the most common etiologic agent of HCC in the world, particularly in areas prevalent for HBV infection such as Asia, Africa, southern part of Eastern and Central Europe, and the Middle East. Risk factors of HBV-related HCC include (1) viral factors-persistent high viral replication, HBV genotype C or D, pre-S2 or core promoter mutants; (2) host factors-older age (>40 years old) at HBeAg seroconversion, male gender; (3) mother-to-infant transmission; and (4) other carcinogenic factors-smoking, habitual use of alcohol, etc. Prevention is the best way to control cancer. There are three levels of liver cancer prevention, i.e., primary prevention by HBV vaccination targeting the general population, secondary prevention by antiviral agent for high-risk subjects with chronic HBV infection, and tertiary prevention by antiviral agent to prevent recurrence for patients who have been successfully treated for liver cancer. Primary prevention by hepatitis B vaccination is most cost effective. Its cancer preventive efficacy supports it as the first successful example of cancer preventive vaccine in human. This experience can be extended to the development of other cancer preventive vaccine. Careful basic and clinical research is needed to develop ideal vaccines to induce adequate protection. Understanding the main transmission route and age at primary infection may help to set the optimal target age to start a new cancer preventive vaccination program. Besides timely HBV vaccination, the earlier administration of hepatitis B immunoglobulin immediately after birth, and even antiviral agent during the third trimester of pregnancy to block mother-to-infant transmission of HBV are possible strategies to enhance the prevention efficacy of HBV infection and its related liver cancer.

Background & Aims: Hepatitis B virus (HBV) infection was hyperendemic in Taiwan before the implementation of the universal infant hepatitis B immunization program, which was launched in 1984. Five previous seroepidemiologic surveys were conducted at 0, 5, 10, 15, and 20 years after the launch of the vaccination program., Methods: We enrolled 3332 subjects younger than 30 years of age, with approximately 100 of them in each age cohort. Subjects were recruited voluntarily from schools and other institutions in Taipei, as in previous surveys. HBV seromarkers included hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and hepatitis B core antigen (anti-HBc). HBV DNA levels were measured in anti-HBc positive/HBsAg negative subjects (anti-HBc only)., Results: The HBsAg, anti-HBs, and anti-HBc seropositive rates were very different between subjects born after the program in 2009 and the baseline group in 1984 (0.9% vs. 10%, 55.9% vs. 24.5%, and 7.0% vs. 28%, respectively). In this 6th survey, we showed that HBsAg prevalence further decreased in the vaccinated cohorts. A positive maternal HBsAg status was found in 86% of vaccine failures. Serum HBV DNA was detected in 4.2% (6/142) of anti-HBc positive/HBsAg negative subjects, with a low level of HBV DNA. All of these six subjects' HBV were genotype C., Conclusions: The universal infant HBV immunization program in Taiwan has completed its 25-year follow-up and its efficacy in young adults is clear. The continued decrease in HBsAg prevalence suggests that the elimination of HBV infection is becoming a reality., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Raising concerns about the waning immunity of cohorts receiving hepatitis B virus (HBV) vaccination in infancy persuaded us to identify the changing incidence of acute hepatitis B (AHB) in children and young adults., Methods: Data on AHB surveillance through the National Notifiable Disease Surveillance System from July 2001 to June 2009 were collected and described. Cases were divided into 2 cohorts according to their birth year: before or after the universal newborn HBV vaccination program. Age-specific incidence was compared for the 2 birth cohorts with diagnosis at age 15-24 years., Results: In total, 2226 patients with AHB were identified. AHB rates varied by age; the highest rates occurred among unvaccinated individuals aged 25-39 years (2.33/100 000). Due to breakthrough HBV infection from mother-to-infant transmission, vaccinated infants (0.78/100 000) had higher rates than those aged 1-14 years (0.04/100 000), who had the lowest rates. The incidence in vaccinated birth cohorts was significantly lower than in unvaccinated birth cohorts among patients 15-24 years old, with an adjusted-relative risk of 0.42., Conclusions: Implementation of universal-at-birth HBV immunization programs has effectively reduced the occurrence of AHB among adolescents and young adults in Taiwan for >25 years, making infants and the 25-39-year-old cohort additional targets for preventing AHB.

Background: Here, we investigated the treatment response and evolution of HBV resistance during lamivudine (LAM) plus adefovir (ADV) and entecavir (ETV) monotherapy in patients with ADV-resistant mutants., Methods: Of the 53 patients with ADV-resistant mutants, 25 received combined LAM plus ADV therapy (LAM+ADV group) and 28 received ETV monotherapy (ETV group) for at least 12 months (median 24 months and range 12-67 months)., Results: During 24 months therapy, no significant difference was noted in HBV DNA reduction from baseline, HBV DNA<200 copies/ml, hepatitis B e antigen loss and ALT normalization between the two groups. In the LAM+ADV group, patients with single rtN236T resistant mutation had higher rates of undetectable HBV DNA than those with the double mutant rtA181T/V+rtN236T at months 3-18 of therapy. No virological breakthrough occurred except for one patient with rtN236T resistant mutation who experienced virological and biochemical breakthrough after the emergence of an additional rtA181T mutant under LAM+ADV therapy. Of the 28 patients receiving ETV monotherapy, ETV-resistant mutants developed in 8. The cumulative rates of ETV-resistant mutations and virological breakthrough at months 12, 24 and 36 were 3.6%, 25.7% and 46.8%, respectively. ADV-resistant mutations were rapidly replaced by LAM-resistant mutations (median 12 months) followed by ETV-resistant mutations., Conclusions: There was no significant difference in virological response between the LAM+ADV and ETV groups in patients with ADV-resistant mutants. LAM+ADV were less effective in patients with the double mutant rtA181T/V+rtN236T than the single rtN236T mutation. The incidence of ETV-resistant mutation was high in patients with LAM/ADV-resistant mutants treated with ETV monotherapy.

Objective: To compare the incidence of hepatitis B virus (HBV)-associated membranous nephropathy (HBVMN) before and after universal HBV vaccination and to identify factors underlying the change., Methods: This study included 471 hospitalized children with nephrotic syndrome (NS) and 488 long-term follow-up hepatitis B surface antigen (HBsAg)-carrier children. Horizontal transmission (negative maternal HBsAg status) of HBVMN and HBV was assessed, and the incidence of HBVMN was compared before and after initiation of the universal HBV vaccination program started in 1984., Results: The frequency of HBVMN in children with NS was 11.6% between 1974 and 1984, 4.5% between 1984 and 1994, 2.1% between 1994 and 2004, and 0% between 2004 and 2009. Similarly, the number of HBsAg-seropositive children with NS (mainly via horizontal infection) decreased after universal vaccination. The prevaccination frequency of HBV horizontal transmission in chronic HBsAg carriers from the general population was 36.5% compared with 5% in the postvaccination period. The incidence of HBVMN in these carriers revealed a parallel decline., Conclusions: Our results revealed a significant decrease in the frequency of HBVMN in children with NS and in long-term follow-up HBsAg carriers. Children with HBVMN are primarily infected with HBV via horizontal transmission; thus, the significant reduction in horizontal transmission in HBsAg-carrier children in the general population after universal HBV vaccination may explain the reduction of HBVMN in the vaccinated population. These findings confirm the effectiveness of HBV vaccination on reducing the incidence of HBVMN, possibly through a significant decline in horizontal HBV infection.

Unlabelled: Genotypes B and C are the major hepatitis B virus (HBV) genotypes in Taiwan, and genotype C is associated with more severe liver disease than genotype B. Whether the implementation of the hepatitis B immunization program has affected the secular trend of the HBV genotype distribution remains unknown. We thus investigated the HBV genotypes in hepatitis B surface antigen (HBsAg)-carrier children born before the implementation of the universal infant immunization program and in those born afterward. One hundred seven children who were infected with HBV despite appropriate immunization were enrolled as immunized cases with HBV breakthrough infection. Each case was matched with two unimmunized HBsAg carriers according to the age at enrollment. HBV genotypes were determined with molecular methods. Compared with unimmunized HBsAg carriers, more immunized children had HBsAg-positive mothers (65.9% versus 100%, P < 0.001) and were infected with genotype C (16.4% versus 42.1%, P < 0.001). Among the children born to HBsAg-positive mothers, the mothers' and children's HBV genotypes were highly concordant in both unimmunized [κ = 0.97, 95% confidence interval (CI) = 0.90-1.00] and immunized children (κ = 0.97, 95% CI = 0.92-1.00). After adjustments for gender, maternal age, and delivery mode, immunized HBsAg-carrier children born to HBsAg-positive mothers had a higher likelihood of genotype C infection than unimmunized children (odds ratio = 3.03, 95% CI = 1.62-5.65, P = 0.001). However, the increased genotype C to genotype B ratio was not seen in the HBsAg-carrier mother pool in the postimmunization era., Conclusion: In the postimmunization era, most HBV breakthrough infections are due to maternal transmission, and immunized children born to genotype C mothers may have a higher rate of breakthrough infection than those born to genotype B mothers., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Background: This study aimed to investigate the roles of tumour necrosis factor-α (TNF-α) gene polymorphisms in the spontaneous clearance of HBsAg after a hepatitis B virus (HBV) infection., Methods: Polymorphisms in the TNF-α (-1031 T to C, -863 C to A, -857 C to T, -308 G to A and -238 G to A transition) gene were evaluated in 274 chronic HBV-infected patients and 194 patients with resolved HBV infection. The peripheral blood mononuclear cells (PBMC) isolated from 77 (28%) of the 274 chronic HBV-infected patients with negative HBeAg and positive antibody to HBeAg were stimulated with HBcAg. Data on TNF-α genotypes and phenotypes in subjects with/without the A allele at the TNF-α-863 promoter single nucleotide polymorphism (rs1800630) were compared., Results: The A allele in the -863 promoter region of the TNF-α gene was present in 154 (56.2%) chronic HBV-infected patients and 87 (44.8%) patients who recovered from HBV infection (odds ratio 1.58; P<0.01). The TNF-α-863 A allele genotype predicted lower TNF-α production by PBMC after in vitro HBcAg stimulation (P<0.02)., Conclusions: The A allele at the -863 locus of the promoter region of the TNF-α gene predicts lower HBcAg-inducible TNF-α secretion. It is also associated with chronicity of HBV infection., (© 2010 John Wiley & Sons A/S.)

Background: This study is aimed to investigate if there was increased risk of HBV acquisition among first graders in Taiwan during a 3-year follow-up period., Methods: A total of 1545 healthy first graders, who were vaccinated against HBV in infancy, were recruited in 2005. All subjects were checked for hepatitis B surface antigens (HBsAg), antibodies to HBsAg (anti-HBs), and to the hepatitis B core antigen (anti-HBc). Nucleotide sequence of the "a" determinant of HBsAg was determined by polymerase chain reaction and direct sequencing in the HBsAg carriers., Results: Among 1545 subjects, 0.78% were HBsAg seropositive, 54.30% were anti-HBs seropositive, and 1.68% anti-HBc seropositive. Three of the 10 HBV carriers (30%), whose HBV DNA were sequenced for the S gene, had surface antigen mutants at the "a" determinant., Conclusion: There were no new chronic HBV infections in this cohort of children for two consecutive years. HBV S gene vaccine escape mutants did exist in the vaccine-failure population, but they may not have made a major health impact., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Prevention is most cost effective toward successful control of hepatitis B virus (HBV) infection and its complications. It is particularly urgent where HBV infection and hepatocellular carcinoma (HCC) are prevalent. To achieve better results of primary HCC prevention globally, higher world coverage rates of HBV vaccine, better strategies against breakthrough infection/nonresponder, and good long-term protection are needed. With the universal hepatitis B vaccination program starting from neonates in most countries, HBV infection and its complications will be further reduced in this century. An effective decline in the incidence of HCC in adults is expected in the near future. The concept of a cancer preventive vaccine, using HBV as an example, can be applied further to other infectious agents and their related cancers., (2010 Elsevier Inc. All rights reserved.)

The characteristics of hepatitis B virus (HBV) in vaccinated children who acquire de novo HBV infections after orthotopic liver transplantation (OLT) remain largely unknown. The aim of this study was to explore HBV mutants in pediatric OLT recipients with de novo HBV infections. In all, 50 recipients underwent OLT between December 1997 and October 2005, and they were regularly checked for HBV serum markers from November 2005 to April 2009. Before OLT, all were hepatitis B surface antigen (HBsAg)-negative and under the coverage of the universal infant HBV vaccination program. Those who became HBsAg-positive after OLT were diagnosed with de novo HBV infection. HBV viral loads and full-length genome sequencing were determined when the diagnosis of de novo HBV infection was established. Nine patients (9/50, 18%) acquired de novo HBV infections after OLT. None had graft loss or fulminant hepatitis. Five cleared HBsAg, and 4 of the 5 even recovered with antibody to hepatitis B surface antigen (anti-HBs) formation. The other 4 were persistently HBsAg-positive. Mutations in the major S gene (681 base pairs) were discovered in 8 (88.9%) of the de novo HBV-infected children. Six of them harbored mutations within the "a" determinant region (codons 124-147), whereas the other 2 had mutations outside this region. These 2 cleared HBsAg and recovered with anti-HBs formation. HBV DNA levels were not different between those who cleared HBsAg and those who did not. In conclusion, surface mutants are frequent among pediatric liver transplant recipients with de novo HBV infections, but their clinical relevance requires further study.

The universal HBV vaccination programme in Taiwan has effectively led to the reduction of acute and chronic hepatitis B, and of hepatocellular carcinoma among vaccinated children. Seropositivity rates for hepatitis B surface antigen (HBsAg) decreased from 10-17% in those born before the start of the vaccination programme to the current 0.5-1.7%. Nonetheless, breakthrough infection continues to be observed. The main causes include high maternal viral load, intrauterine infection, emergence of S gene mutants and immunosuppression. Among vaccinated individuals with breakthrough HBV infection, sG145R & sT126A/S mutations (which account for 48% of the mutants detected) have become prominent. However, owing to the marked reduction in the HBsAg carrier rate, the prevalence rate of S gene mutants in the total vaccinated population has not increased. With limited evidence of spread, S gene mutants do not need to be incorporated into the HBV vaccine. Further studies are required to design better strategies to prevent breakthrough HBV infection of both wild-type and S gene mutants.

Objective: De novo hepatitis B virus (HBV) infection is defined as infection occurring in HBV surface antigen (HBsAg)-negative patients who become HbsAg positive after organ transplantation. We assessed the incidence and risk factors of de novo HBV infection in pediatric liver transplant recipients., Patients and Methods: From 1996 to 2006, 71 Taiwanese children with non-HBV-related liver diseases underwent orthotopic liver transplantation (OLT) at the National Taiwan University Hospital. All of the surviving recipients were tested regularly for liver function, serum levels of immunosuppressant, HBsAg, titers of antibodies to hepatitis B surface antigen (anti-HBs), antibodies to hepatitis B core antigen (anti-HBc), and antibodies to hepatitis C virus (anti-HCV). HBV vaccination histories and the anti-HBs titers before OLT were recorded. No regular prophylaxis was given., Results: Fifty-nine patients (33 girls and 26 boys) were followed up for a median of 4.4 years (range 1.0-10.0). Of those, 36 (61.0%) received allografts from anti-HBc-positive and HBsAg-negative donors. De novo HBV infection was found in 9 (15.3%) patients after OLT, 8 of whom received allografts from HBsAg-negative and anti-HBc-positive donors. Forty-eight (81.4%) patients received 3 or more doses of HBV vaccine before OLT. Pre-OLT anti-HBs titers were available for 49 recipients. Of the 9 de novo HBV-infected recipients, 8 had anti-HBs titers <200 mIU/mL. No graft loss or fulminant hepatitis was noted., Conclusions: In the absence of adequate prophylaxis, the incidence of de novo HBV infection in pediatric OLT recipients is 15.3%. An anti-HBs titer of >200 mIU/mL before OLT may be sufficient to prevent de novo HBV infection in HBsAg-negative recipients.

Chronic inflammation caused by persistent infection is closely related to a number of cancers; these include hepatitis B (HBV) or C and hepatoma, human papilloma virus and cervical cancer, and Helicobacter pylori and gastric cancer. The first evidence of cancer prevention by vaccination in humans was provided by HBV vaccination in infants. Chronic HBV is related to approximately 60%-90% of hepatocellular carcinomas (HCC) in adults and nearly 100% of childhood HCC in areas endemic for HBV infection. The first universal HBV vaccination program was launched in Taiwan and has continued for more than 20 years. Three or four doses of HBV vaccine were given to all infants starting from the first week of life. In addition, infants of high-risk mothers (with positive hepatitis B e antigen or high HBsAg titers) were given hepatitis B immunoglobulin within 24 h after birth. At 20 years after the launch of the HBV vaccination program in Taiwan, chronic HBV infection (HBsAg seropositive) rates in the general population below 20 years of age have revealed a remarkable reduction from 10%-17% before the vaccination program to 0.7%-1.7% after the program. HCC incidence rate in children 6-14 years old also fell from 0.52-0.54 to 0.13-0.20 per 100,000 (R.R. = 0.25-0.36). HCC prevention failure is mainly related to vaccine failure to prevent chronic HBV infection. The causes of vaccine failure have included intrauterine infection, vaccine escape mutants, genetic hyporesponsiveness, and poor compliance. Future efforts to reduce vaccine failure will improve the efficacy of liver cancer prevention by HBV vaccination. The experience of HCC prevention by HBV immunization may be applied to the prevention of other infection-related cancers.

Background: A hepatitis B virus (HBV) universal vaccination program for infants was implemented for 24 years in Taiwan. Most of the children who received organ transplantation were primarily vaccinated before transplantation. This study investigated the efficacy of HBV vaccination and booster responses in children after liver transplantation (LT)., Methods: Totally 31 children were enrolled. They were clinically stable for more than 1 year after LT. Twenty of them kept a titer of antibody to hepatitis B surface antigen (anti-HBs) more than 10 mIU/mL and received no booster, while 11 received one booster because their anti-HBs titers were less than 10 mIU/mL. Cellular immunity was checked by enzyme-linked immunospot assay with interferon-gamma surrogated for T-helper 1 cells and interleukin-5 for T-helper 2 before and after booster vaccine., Results: One of the non-boosters had de novo HBV infection after LT and recovered to be anti-HBs positive. The first booster restored an adequate titer in 64% (7/11) of those with anti-HBs titer less than 10 mIU/mL after LT. The four patients who failed the first booster responded well to the second dose. After the booster, the mononuclear cells of all 11 had more than one spot-forming cell for interferon-gamma or interleukin-5. Transplanted girls maintained a higher antibody titer than boys., Conclusion: Primary HBV vaccination or the booster dose(s) of HBV vaccine could provide adequate humoral and cellular immunity in children with LT.

Hepatitis B virus (HBV) infection is a worldwide health problem and may cause acute, fulminant, chronic hepatitis, liver cirrhosis, or hepatocelullar carcinoma (HCC). Infection with HBV in infancy or early childhood may lead to a high rate of persistent infection (25-90%), while the rates are lower if infection occurs during adulthood (5-10%). In most endemic areas, infection occurs mainly during early childhood and mother-to-infant transmission accounts for approximately 50% of the chronic infection cases. Hepatitis B during pregnancy does not increase maternal mortality or morbidity or the risk of fetal complications. Approximately 90% of the infants of HBsAg carrier mothers with positive hepatitis B e-antigen (HBeAg) will become carriers if no immunoprophylaxis is given. Transplacental HBeAg may induce a specific non-responsiveness of helper T cells and HBcAg. Spontaneous HBeAg seroconversion to anti-HBe may develop with time but liver damage may occur during the process of the immune clearance of HBV and HBeAg. Mother-to-infant transmission of HBV from HBeAg negative but HBsAg positive mothers is the most important cause of acute or fulminant hepatitis B in infancy. Although antiviral agents are available to treat and avoid the complications of chronic hepatitis B, prevention of HBV infection is the best way for control. Screening for maternal HBsAg with/without HBeAg, followed by three to four doses of HBV vaccine in infancy and hepatitis B immunoglobulin (HBIG) within 24h of birth is the most effective way to prevent HBV infection. In areas with a low prevalence of HBV infection or with limited resources, omitting maternal screening but giving three doses of HBV vaccine universally in infancy can also produce good protective efficacy. The first universal HBV immunisation programme in the world was launched in Taiwan 22 years ago. HBV infection rates, chronicity rates, incidence of HCC and incidence of fulminant hepatitis in children have been effectively reduced.

Background & Aims: Following the world's first successful implementation of a universal hepatitis B virus (HBV) vaccination program for infants in Taiwan 20 years ago, we performed this study to evaluate the long-term protection afforded by HBV vaccination and to rationalize further prevention strategies., Methods: HBV seromarkers, including hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti-HBs) and core antigen (anti-HBc), were studied in 18,779 subjects from neonates to adults below 30 years of age in 2004. The birth cohort effect was evaluated by comparing the results of the same birth cohorts at different ages among this survey and the previous 1984, 1989, 1994, and 1999 surveys., Results: The seropositive rates for HBsAg, anti-HBs, and anti-HBc were 1.2%, 50.5%, and 3.7%, respectively, in those born after the vaccination program (<20 years of age) in 2004. A positive maternal HBsAg status was found in 89% of the HBsAg seropositive subjects born after the vaccination program. The absence of an increase in HBsAg seropositive subjects at different ages in the same birth cohorts born after the vaccination program implied no increased risk of persistent HBV infection with aging., Conclusions: Universal HBV vaccination provides long-term protection up to 20 years, and a universal booster is not indicated for the primary HBV vaccinees before adulthood. Maternal transmission is the primary reason for vaccine failure and is the challenge that needs to be addressed in future vaccination programs. This may include an appropriate hepatitis B immunoglobulin administration strategy for high-risk infants and involve efforts to minimize noncompliance.

Hepatitis B virus (HBV) infection is highly prevalent in Asia, Africa, southern Europe and Latin America, HBV vaccination has effectively reduced the acute and chronic infection rates as well as related complications in the vaccinated children. The incidence of hepatocellular carcinoma in children has been reduced to approximately 25% of the incidence before the vaccination program, and fulminant hepatitis in children has also been reduced after universal hepatitis B vaccination. HBV DNA sero-positive rate was 98-100% in HBsAg positive vaccinated children, while the positive rate was only 11-20% in those vaccinees with a negative HBsAg but positive anti-HBc reaction. Hepatitis B surface gene mutants in HBV DNA positive children increased gradually from 7.8% before the vaccination program, to 19.6%, 28.1% and 23.1% at 5, 10 and 15 years after the vaccination program. Long-term follow-up of vaccinated children has confirmed that universal HBV vaccination in infancy has produced adequate protection up to 14 years of age. The annual decay rate of hepatitis B surface antibody (anti-HBs) was 10.2% in children who did not receive a booster dose. The new HBV infection rate was not different between those who did and those who did not receive a booster dose of HBV vaccine. During a follow-up period of seven years for 1200 vaccinated 7-year-old children in Taiwan, the mean annual hepatitis B core antibody sero-conversion rate was 0.2%. All were negative for HBV DNA. No new chronic HBV infections developed. A booster dose of HBV vaccine is not recommended in children under 15 years of age. Systematic HBV DNA screening of a large population such as blood donors may be instrumental in following the long-term effect of the universal vaccination program on the incidence of silent HBV infection and vaccine escape mutants.

The aims of the present study were to determine (i) the long-term immunogenicity and the decay rate of hepatitis B virus (HBV) surface antibody (anti-HBs) from universal hepatitis B vaccination at infancy for a healthy population in an area of hyperendemicity and (ii) whether the anti-HBs levels measured by enzyme immunoassay (EIA) were closely correlated with those assayed by radioimmunoassay (RIA) methods during long-term monitoring. A total of 1,337 apparently healthy children (696 boys and 641 girls) who were vaccinated against HBV at infancy and monitored for anti-HBs annually from 7 to 16 years of age entered the study. Serum samples were analyzed for anti-HBs by RIA at 7 to 15 years of age and were also analyzed by EIA at 13 to 16 years of age. Antibody titers were quantified in mIU/ml by EIA as well as by the ratio of the count in the sample to the count for a negative control (S/N) by RIA. In non-boosted children, the average decay of anti-HBs from 7 to 16 years of ages indicated that approximately 20% of the geometric mean titer decays per year. There was a good correlation between serum anti-HBs levels measured by the RIA and the EIA methods (r=0.91; P<0.0001). An equation for RIA to EIA level conversion was established: log EIA titer=-0.12+ (1.31 . log RIA S/N). The anti-HBs titers measured by EIA correlate well with the S/N assayed by RIA. The annual decay rate of the log anti-HBs level may help in planning booster immunizations for hypo-responders or individuals at risk in adolescence.

Aim: To investigate the factors affecting the outcome of fulminant hepatic failure (FHF) in children in relation to hepatitis B virus (HBV) infection., Methods: Retrospective review of a total of 94 cases (61 males and 33 females, aged from 1 month to 15 years) recruited from nine tertiary referral centers in Taiwan from 1985 to 1999., Results: The overall mortality rate was 75%. Patients in the mortality group were of an older age, had higher peak total bilirubin levels, a longer prothrombin time, and a lower percentage of HBV positivity (P < 0.001, P = 0.003, P = 0.0027 and P = 0.042, respectively). Mortality was 65% in the HBV positive (n = 42) and 83% in the HBV negative (n = 52) group (P = 0.05). In the HBV positive group, the prothrombin time was noted to be the single factor affecting outcome (P = 0.036). In the HBV negative group, older age and higher peak value of total serum bilirubin were suggestive of poor survival rate (P < 0.001 and P = 0.006, respectively). Multivariate analysis revealed that total bilirubin was the single factor affecting outcome in the HBV-negative group. The mortality rate of HBV positive children in three consecutive time periods without liver transplantation (1985-1989, 1990-1994, 1995-1999) decreased gradually (91, 67 and 38%, respectively, with P = 0.027). This change was not observed in HBV-negative cases., Conclusions: Hepatitis B virus positive FHF had a lower mortality rate than HBV negative FHF, with each group having different factors affecting mortality.

Neonatal immunization with hepatitis B (HB) vaccine is highly effective; however, more needs to be learned about the duration of protection and indications for boosters. We measured antibody to HB core antigen (anti-HBc), HB surface antigen (HBsAg), and pre- and postbooster titers of HBsAg antibody (anti-HBs) 15 years after primary neonatal immunization with plasma-derived HB vaccines in 2 cohorts of 15-year-old children. Group A consisted of 78 children who were born to HB e antigen-positive HBsAg carrier mothers and had developed protective levels of anti-HBs antibodies (> or =10 mIU/mL) following HB immunization. Group B consisted of 113 apparently healthy children whose anti-HBs titers after vaccination were unknown. Anti-HBs was undetectable (antibody titer <10 mIU/mL) in 29.9% in group A and 62.4% in group B (P < .001). Anti-HBc was detected in 33.3 % in group A and 4.4 % in group B (P < .001). After a single booster dose of HB vaccine, 2.7% in group A and 3.3% in group B remained anti-HBs-negative. A blunted serological response was noted in approximately 20% in both groups. One HBsAg carrier was detected in group A (1.3%) and 4 in group B (3.5%). Fifteen years after neonatal immunization with plasma-derived HB vaccine, a large proportion of children exhibited waning immunity. This poses the risk of breakthrough infection. A single booster augmented the serological response to the vaccine in most but not all subjects. In conclusion, our findings suggest that one or more booster immunizations are needed in seronegative subjects by at least 15 years following neonatal immunization with plasma-derived HB vaccine.

Background: It is not known whether hepatitis B virus (HBV) with mutations in the a determinant (amino acids (aa) 121-149) of the hepatitis B surface antigen (HBsAg) affect vaccination efficacy., Aim: To investigate the prevalence and clinical significance of these mutants in children, 15 years after universal vaccination in Taiwan., Methods: Nucleotide sequences encoding the a determinant region (aa 110-160) of HBsAg were analysed in all HBV-DNA positive sera from 1357 children and 219 adolescents serosurveyed in 1999. We then compared the prevalence and changes in the mutants in these children with our previous surveys in the same area conducted in 1984 (just before vaccination), 1989, and 1994., Results: The prevalence of a determinant mutants in HBV-DNA positive children was 7.8% (8/103) in 1984, which significantly increased to 19.6% (10/51) in 1989, peaked at 28.1% (9/32) in 1994, and remained at 23.1% ((3/13) (T131I, G145R, G145R)) in 1999; it was higher in those fully vaccinated compared with those not vaccinated (15/46 v 15/153; p<0.001). However, the number of mutant infected children in each survey was stable in the first 5-10 year period but decreased 10-15 years post vaccination. Increased amino acid variation in the a determinant region occurred in carrier children in the post vaccination survey. Mutated residues tended to occur more frequently in the region with greater local hydrophilicity (residues 140-149) in those vaccinated than in unvaccinated children with variant infection (12/15 v 6/15; p = 0.062). More HBsAg positive a determinant mutants emerged in children fully vaccinated with plasma derived vaccine than those given recombinant vaccine (10/2399 (0.46%) v 0/503; p = 0.122)., Conclusion: We found that a determinant variants have an advantage in infecting immunised children but do not threaten current HBV vaccination strategies in Taiwan.

Background: The efficacy of hepatitis B immunoglobulin (HBIG) in infants of hepatitis B e antigen (HBeAg)-negative hepatitis B surface antigen (HBsAg) carrier mothers in Taiwan is not clear., Objective: To describe the responses of infants born to HBeAg-negative carrier mothers receiving HBIG combined with hepatitis B vaccine., Methods: Term babies born to HBeAg-negative carrier mothers were assigned based on chart number to 1 of the 2 treatment groups. Group A infants (n = 94) received 0.5 ml (145 IU) of HBIG within 24 h of birth and 3 subsequent doses of recombinant hepatitis B virus (HBV) vaccine at 3 to 5 days, 1 month and 6 months of age. Group B infants (n = 122) received 3 doses of vaccines only. Infants (n = 19) born to HBeAg-positive carrier mothers were treated like those in Group A and are referred to as Group C. Sera obtained from infants at 2 and 7 months of age were tested for hepatitis B virus (HBV) markers., Results: There were 2 (1%; one in Group A and one in Group B) subclinical breakthrough hepatitis B infections among studied infants. One (5%) child of Group C had asymptomatic HBV infection at the age of 7 months and became a chronic carrier. The rate of protective anti-hepatitis B surface antibody (anti-HBs) titers achieved (>10 mIU/ml) by 2 months of age was significantly higher in Group A than that in Group B (98% vs. 57%, P < 0.001). However, it was not different by 7 months of age. Infants (Group A) immunized with HBIG and vaccine had a significantly higher geometric mean titer (GMT, milli-International Units/ml) of anti-HBs than those (Group B) with vaccines only at 2 months of age (P < 0.001). Conversely at 7 months of age, the GMT of anti-HBs was significantly higher in infants who received vaccine only (P = 0.001)., Conclusions: A protective level of antibodies was achieved earlier in those infants receiving both passive and active immunizations. However, infants receiving active immunizations alone achieved a higher GMT at 7 months of age. There was no clear benefit of passive-active vs.active immunization alone for chronic HBV infection in infants of HBsAg-positive, HBeAg-negative mothers.

Background: Hepatitis B virus (HBV) infection is hyperendemic in Taiwan. Before universal HBV immunization was started in Taiwan in 1984, the carrier rate for hepatitis B surface antigen (HBsAg) was 15% to 20% in the general population., Objective: To quantify the population impact of a mass vaccination program for HBV 15 years after its implementation., Design: Descriptive analysis of serologic markers of HBV in healthy children and adolescents., Setting: Chung-Cheng District, Taipei City, Taiwan, in 1999., Participants: 1357 persons younger than 15 years of age, who were born after the implementation of universal HBV vaccination, and 559 persons 15 to 20 years of age, who were born before the program began., Measurements: Repeated serologic surveys similar to those done before and 5 and 10 years after the national vaccination program was implemented. All participants were tested for serum HBsAg, its antibody (anti-HBs), and hepatitis B core antibody (anti-HBc)., Results: During the 15 years since the vaccination program was implemented, the prevalence of HBsAg among persons younger than 15 years of age decreased from 9.8% in 1984 to 0.7% in 1999; among persons 15 to 20 years of age, the 1999 prevalence of HBsAg was 7% (P < 0.001). Hepatitis B core antibody seropositivity, which represents HBV infection, was found in 2.9% of persons younger than 15 years of age and in 20.6% of persons 15 to 20 years of age (P < 0.001); in the same age groups, the rate of anti-HBs seropositivity was 75.8% and 70.7%, respectively (P = 0.02)., Conclusions: Universal vaccination significantly decreased the HBV carrier rate and infection rate among children and adolescents born since the program began. By decreasing the carrier pool, continuation of the national HBV immunization program should prevent HBV infection in the children of Taiwan, and, subsequently, adults as well.

Hepatitis B virus (HBV) infection during childhood can cause acute, fulminant or chronic hepatitis, liver cirrhosis, and liver cancer. Approximately 90% of the infants of hepatitis B e antigen (HBeAg) seropositive mothers become hepatitis B surface antigen (HBsAg) carriers. Children chronically infected are mostly asymptomatic. Although liver damage is usually mild during childhood, severe liver disease, including cirrhosis and hepatocellular carcinoma, may develop insidiously for 2-7 years. Spontaneous HBeAg seroconversion occurs gradually as the age of the child increases. Viral replication is reduced during this process, which is usually preceded by an elevation of aminotransferases. In a long-term follow-up study, the annual HBeAg seroconversion rate was 4-5% in children older than 3 years of age and less than 2% in children under 3 years. The annual seroconversion rate of HBsAg was very low (0.56%). Age at infection, maternal HBsAg and HBeAg status, host immune status, and possibly the HBV strain are the main factors determining the course of HBV infection in children.