Advertisement

Chronic hepatitis B in children and adolescents

Open AccessPublished:May 24, 2012DOI:https://doi.org/10.1016/j.jhep.2012.03.036

      Abbreviations:

      HBV (hepatitis B virus), HCC (hepatocarcinoma), HBIG (hepatitis B immunoglobulins), CHB (chronic hepatitis B), ALT (alanine aminotransferases), cccDNA (covalently closed circular DNA), WHO (World Health Organization), ULN (upper limit of normal), IFN (interferon), FDA (Food and Drug Administration), VR (virologic response), PegIFN (pegylated interferon)

      Keywords

      Epidemiology

      HBV is transmitted by percutaneous and mucous membrane exposure to infectious blood, semen, vaginal secretions and saliva [
      • Kidd-Ljunggren K.
      • Holmberg A.
      • Bläckberg J.
      • Lindqvist B.
      High levels of hepatitis B virus DNA in body fluids from chronic carriers.
      ]. The extreme resilience of HBV, allowing its survival for more than a week on dry surfaces, explains the increased risk of horizontal intrafamilial transmission and the need of carriers counseling and household members vaccination [
      • Weinbaum C.M.
      • Williams I.
      • Mast E.E.
      • Wang S.A.
      • Finelli L.
      • Wasley A.
      • et al.
      Recommendations for identification and public health management of persons with chronic hepatitis B virus infection.
      ,
      • Mast E.E.
      • Margolis H.S.
      • Fiore A.E.
      • Brink E.W.
      • Goldstein S.T.
      • Wang S.A.
      • et al.
      A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States – recommendations of the advisory committee on immunization practices (ACIP) Part 1: Immunization of infants, children, and adolescents.
      ,
      • Sokal E.M.
      • Van Collie O.
      • Buts J.P.
      Horizontal transmission of hepatitis B from children to adoptive parents.
      ,
      • Martin A.
      • Moyes C.
      • Lucas C.
      • Milne A.
      Hepatitis B infection in households of HBsAg positive New Zealand children.
      ]. Nonetheless, after 20 years from the introduction of immunization programs, most infants and children are protected against HBV [

      Centers for Disease Control and Prevention CDC. Vaccination coverage among children in kindergarten--United States, 2009-10 school year. MMWR Morb Mortal Wkly Rep 2011;60:700-704. .

      ], and chronic carriers should not be isolated in schools or prevented from practicing sports. Transmission occurs rarely in childcare settings [
      • Mast E.E.
      • Margolis H.S.
      • Fiore A.E.
      • Brink E.W.
      • Goldstein S.T.
      • Wang S.A.
      • et al.
      A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States – recommendations of the advisory committee on immunization practices (ACIP) Part 1: Immunization of infants, children, and adolescents.
      ], but the risk is higher in detention centers, where adolescents are less likely to be immunized and have high-risk behaviors [
      • Bartlett L.
      • Kanellos-Sutton M.
      • van Wylick R.
      Immunization rates in a canadian juvenile corrections facility.
      ,
      • Sneller V.P.
      • Fishbein D.B.
      • Weinbaum C.M.
      • Lombard A.
      • Murray P.
      • McLaurin J.A.
      • et al.
      Vaccinating adolescents in high-risk settings: lessons learned from experiences with hepatitis b vaccine.
      ].
      In highly endemic areas, infection occurs mainly in infancy and early childhood, with mother-to-child transmission accounting for more than half of chronic infections. After exposure, the risk of developing CHB is indeed higher for newborns (90%) than for infants and children <5 years of age (25–30%) or adolescents and adults (<5%) [
      • McMahon B.J.
      • Alward W.L.
      • Hall D.B.
      • Heyward W.L.
      • Bender T.R.
      • Francis D.P.
      • et al.
      Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state.
      ,
      • Tassopoulos N.C.
      • Papaevangelou G.J.
      • Sjogren M.H.
      • Roumeliotou-Karayannis A.
      • Gerin J.L.
      • Purcell R.H.
      Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults.
      ]. To further reduce mother-to-child transmission, WHO recommends the administration of both the vaccine and hepatitis B immunoglobulins (HBIG) to newborns of HBsAg-positive mothers within 24 h from birth (90–98% protection rate) [
      • Mast E.E.
      • Margolis H.S.
      • Fiore A.E.
      • Brink E.W.
      • Goldstein S.T.
      • Wang S.A.
      • et al.
      A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States – recommendations of the advisory committee on immunization practices (ACIP) Part 1: Immunization of infants, children, and adolescents.
      ,

      World Health Organization. Hepatitis B vaccines - WHO position paper. Weekly epidemiological record 2009;89:405-420.

      ,
      • Chen H.-L.
      • Lin L.-H.
      • Hu F.-C.
      • Lee J.-T.
      • Lin W.-T.
      • Yang Y.-J.
      • et al.
      Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV.
      ,

      Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database Syst Rev 2006;Issue 2. Art. No.: CD004790. http://dx.doi.org/10.1002/14651858.CD004790.pub2.

      ]. HBIG administration to newborns of HBeAg-negative mothers does not change the overall protection rate but decreases the risk of fulminant hepatitis (higher in this group), proving to be cost-effective [
      • Chen H.-L.
      • Lin L.-H.
      • Hu F.-C.
      • Lee J.-T.
      • Lin W.-T.
      • Yang Y.-J.
      • et al.
      Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV.
      ,
      • Chang M.H.
      • Lee C.Y.
      • Chen D.S.
      • Hsu H.C.
      • Lai M.Y.
      Fulminant hepatitis in children in Taiwan: the important role of hepatitis B virus.
      ,
      • Chen H.-L.
      • Chang C.-J.
      • Kong M.-S.
      • Huang F.-C.
      • Lee H.-C.
      • Lin C.-C.
      • et al.
      Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination.
      ,
      • Vanclaire J.
      • Cornu C.
      • Sokal E.M.
      Fulminant hepatitis B in an infant born to a hepatitis Be antibody positive, DNA negative carrier.
      ].
      Newborns of highly viremic HBeAg-positive mothers are at increased risk of HBV infection despite proper immunization (breakthrough infection), compared to babies born to HBeAg-negative mothers (16.8% vs. 1.6%), and are at increased risk for chronicity [
      • Chen H.-L.
      • Lin L.-H.
      • Hu F.-C.
      • Lee J.-T.
      • Lin W.-T.
      • Yang Y.-J.
      • et al.
      Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV.
      ,
      • Wang Z.
      • Zhang J.
      • Yang H.
      • Li X.
      • Wen S.
      • Guo Y.
      • et al.
      Quantitative analysis of HBV DNA level and HBeAg titer in hepatitis B surface antigen positive mothers and their babies: HBeAg passage through the placenta and the rate of decay in babies.
      ]. Breakthrough infection is more likely to occur in newborns of mothers with genotype C, who have higher viral loads. Vaccination programs are therefore changing the HBV genotype distribution [
      • Wen W.-H.
      • Chen H.-L.
      • Ni Y.-H.
      • Hsu H.-Y.
      • Kao J.-H.
      • Hu F.-C.
      • et al.
      Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization.
      ]. Intrauterine infection, hyporesponsiveness to vaccine, and vaccine escape mutants could play a role as well [
      • Chen H.-L.
      • Lin L.-H.
      • Hu F.-C.
      • Lee J.-T.
      • Lin W.-T.
      • Yang Y.-J.
      • et al.
      Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV.
      ,
      • Wang Z.
      • Zhang J.
      • Yang H.
      • Li X.
      • Wen S.
      • Guo Y.
      • et al.
      Quantitative analysis of HBV DNA level and HBeAg titer in hepatitis B surface antigen positive mothers and their babies: HBeAg passage through the placenta and the rate of decay in babies.
      ,
      • McMahon B.J.
      • Bruden D.L.
      • Petersen K.M.
      • Bulkow L.R.
      • Parkinson A.J.
      • Nainan O.
      • et al.
      Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up.
      ,
      • Hsu H.-Y.
      • Chang M.-H.
      • Ni Y.-H.
      • Chiang C.-L.
      • Chen H.-L.
      • Wu J.-F.
      • et al.
      No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization.
      ]. The risk of mother-to-child transmission also depends on maternal serum HBsAg titer and mode of delivery (10.5% for elective cesarean section vs. 28% for vaginal delivery) [
      • Wang Z.
      • Zhang J.
      • Yang H.
      • Li X.
      • Wen S.
      • Guo Y.
      • et al.
      Quantitative analysis of HBV DNA level and HBeAg titer in hepatitis B surface antigen positive mothers and their babies: HBeAg passage through the placenta and the rate of decay in babies.
      ,
      • Xu D.-Z.
      • Yan Y.-P.
      • Choi B.C.K.
      • Xu J.-Q.
      • Men K.
      • Zhang J.-X.
      • et al.
      Risk factors and mechanism of transplacental transmission of hepatitis B virus: a case–control study.
      ,
      • Yang J.
      • Zeng X.-M.
      • Men Y.-L.
      • Zhao L.-S.
      Elective caesarean section versus vaginal delivery for preventing mother to child transmission of hepatitis B virus – a systematic review.
      ]. Vertical transmission can be further reduced by treating highly viremic mothers during the last trimester of pregnancy with either lamivudine, telbivudine, or tenofovir (1–2% risk reduction for lamivudine and 8% for telbivudine) [
      • Bzowej N.H.
      • Hepatitis B.
      Therapy in pregnancy.
      ,
      • Xu W.M.
      • Cui Y.T.
      • Wang L.
      • Yang H.
      • Liang Z.Q.
      • Li X.M.
      • et al.
      Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study.
      ,
      • Shi Z.
      • Yang Y.
      • Ma L.
      • Li X.
      • Schreiber A.
      Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis.
      ,
      • Han G.-R.
      • Cao M.-K.
      • Zhao W.
      • Jiang H.-X.
      • Wang C.-M.
      • Bai S.-F.
      • et al.
      A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.
      ].
      HBsAg and HBV DNA can be detected in breast milk of chronic carriers, but no increased risk of transmission to a breastfed infant has been shown and breastfeeding is currently recommended after proper infant immunization [

      World Health Organization. Hepatitis B and breastfeeding. World Health Organization. J Int Assoc Physicians AIDS Care 1998;4:20-21.

      ,
      • Shi Z.
      • Yang Y.
      • Wang H.
      • Ma L.
      • Schreiber A.
      • Li X.
      • et al.
      Breastfeeding of newborns by mothers carrying hepatitis B virus: a meta-analysis and systematic review.
      ,
      • Petrova M.
      Breastfeeding and chronic HBV infection: clinical and social implications.
      ].
      WHO has recommended universal HBV vaccination since 1991, with the first dose to be administered within 24 h from birth, followed by at least two doses at 1 and 6 months of life [

      World Health Organization. Hepatitis B vaccines - WHO position paper. Weekly epidemiological record 2009;89:405-420.

      ,
      • National Center for Immunization and Respiratory Diseases
      General recommendations on immunization – recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,
      • World Health Organization
      Hepatitis B vaccines: WHO position paper—recommendations.
      ,
      • World Health Organization
      Expanded programme on immunization. Global Advisory Group–Part I.
      ]. By the end of 2010, 179 of the 193 WHO member states had implemented a nationwide childhood HBV immunization program and global HBV vaccine coverage was estimated at 75% [
      • World Health Organization
      Global routine vaccination coverage, 2010.
      ]. In countries where such programs have been implemented, prevalence of HBV infection decreased dramatically [
      • Luo Z.
      • Li L.
      • Ruan B.
      Impact of the implementation of a vaccination strategy on hepatitis B virus infections in China over a 20-year period.
      ,
      • Chien Y.C.
      Nationwide hepatitis B Vaccination program in Taiwan: effectiveness in the 20 years after it was launched.
      ,
      • Zanetti A.R.
      • van Damme P.
      • Shouval D.
      The global impact of vaccination against hepatitis B: a historical overview.
      ]. Many countries with high HBsAg seroprevalence (⩾8%) before vaccination programs (like China and Taiwan) are now considered at intermediate (2–7%) or low prevalence (<2%) [
      • Luo Z.
      • Li L.
      • Ruan B.
      Impact of the implementation of a vaccination strategy on hepatitis B virus infections in China over a 20-year period.
      ,
      • Liang X.
      • Bi S.
      • Yang W.
      • Wang L.
      • Cui G.
      • Cui F.
      • et al.
      Epidemiological serosurvey of Hepatitis B in China—declining HBV prevalence due to Hepatitis B vaccination.
      ,
      • Ni Y.-H.
      • Huang L.M.
      • Chang M.-H.
      • Yen C.J.
      • Lu C.Y.
      • You S.-L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ,
      • Chen S.-M.
      • Kung C.-M.
      • Yang W.-J.
      • Wang H.-L.
      Efficacy of the nationwide hepatitis B infant vaccination program in Taiwan.
      ]. In Taiwan, prevalence of HBsAg in children younger than 15 years of age decreased from 9.8% to 0.5% after 20 years of vaccination [
      • Ni Y.-H.
      • Huang L.M.
      • Chang M.-H.
      • Yen C.J.
      • Lu C.Y.
      • You S.-L.
      • et al.
      Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
      ]. In China, HBsAg prevalence in children aged 1–14 years decreased by 83% (from 8% in 1992 to 1.36% in 2006) [
      • Zhang L.
      • Xu A.
      • Yan B.
      • Song L.
      • Li M.
      • Xiao Z.
      • et al.
      A significant reduction in hepatitis B virus infection among the children of Shandong Province, China: the effect of 15 years of universal infant hepatitis B vaccination.
      ]. In a recent study, 4.6% of the total population of the Unites States has been exposed to HBV (past or chronic infection), with up to a 50-fold variation as age, ethnicity and country of birth vary. HBsAg seroprevalence in children and adolescents aged 6–12 years and 13–17 years is 0.03% and 0.02%, respectively. Prevalence of both exposure and chronic carrier state is higher among people coming from high or intermediate prevalence countries, and among those with lower family income or with high-risk behavior [
      • Ioannou G.N.
      • Hepatitis B.
      Virus in the United States: infection, exposure, and immunity rates in a nationally representative survey.
      ].
      Although, among children born in Western Europe and North America, prevalence of HBV infection is low, pediatricians and hepatologists are confronted with an increasing number of children adopted from higher prevalence countries (Table 1). Between 2% and 5% of all internationally adopted children, all coming from ⩾2% prevalence areas, are still infected with HBV [
      • Stadler L.P.
      • Mezoff A.G.
      • Staat M.A.
      Hepatitis B virus screening for internationally adopted children.
      ,
      • Cai W.
      • Poethko-Müller C.
      • Hamouda O.
      • Radun D.
      Hepatitis B virus infections among children and adolescents in Germany.
      ]. CDC and American Academy of Pediatrics recommend screening all children adopted from these countries for HBV (HBsAg, HBsAb, HBcAb), at arrival and after 6 months, in order to provide vaccination to those without protective antibody levels (anti-HBs ⩾10 mIU/ml) [

      World Health Organization. Hepatitis B vaccines - WHO position paper. Weekly epidemiological record 2009;89:405-420.

      ,
      • Jack A.D.
      • Hall A.J.
      • Maine N.
      • Mendy M.
      • Whittle H.C.
      What level of hepatitis B antibody is protective?.
      ] or diagnose a previously unknown infection and proceed to immunization of household contacts [
      • Weinbaum C.M.
      • Williams I.
      • Mast E.E.
      • Wang S.A.
      • Finelli L.
      • Wasley A.
      • et al.
      Recommendations for identification and public health management of persons with chronic hepatitis B virus infection.
      ,
      • National Center for Immunization and Respiratory Diseases
      General recommendations on immunization – recommendations of the Advisory Committee on Immunization Practices (ACIP).
      ,

      American Academy of Pediatrics. Medical evaluation of internationally adopted children for infectious diseases. In: Pickering L, Baker C, Long S, MacMillan J, editors. Red book: 2009 report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2009. p. 177–184.

      ].
      Table 1Estimated HBsAg seroprevalence and HBV genotype in countries of origin of internationally adopted children. (
      • Custer B.
      • Sullivan S.D.
      • Hazlet T.K.
      • Iloeje U.
      • Veenstra D.L.
      • Kowdley K.V.
      Global epidemiology of hepatitis B virus.
      ,
      • Tessema B.
      • Yismaw G.
      • Kassu A.
      • Amsalu A.
      • Mulu A.
      • Emmrich F.
      • et al.
      Seroprevalence of HIV, HBV, HCV and syphilis infections among blood donors at Gondar University Teaching Hospital, Northwest Ethiopia: declining trends over a period of five years.
      ,
      • Andernach I.E.
      • Nolte C.
      • Pape J.W.
      • Muller C.P.
      Slave Trade and Hepatitis B Virus Genotypes and Subgenotypes in Haiti and Africa.
      ,
      • Mitchell T.
      • Armstrong G.L.
      • Hu D.J.
      • Wasley A.
      • Painter J.A.
      The increasing burden of imported chronic hepatitis B — United States, 1974–2008.
      ,
      • Juon H.-S.
      • Choi K.
      • Park E.-C.
      • Kwak M.-S.
      • Lee S.
      Hepatitis B vaccinations among Koreans: results from 2005 Korea National Cancer Screening Survey.
      ,
      • Chang M.-H.
      Impact of hepatitis B vaccination on hepatitis B disease and nucleic acid testing in high-prevalence populations.
      ,
      • Alvarado-Mora M.V.
      • Gutierrez Fernandez M.F.
      • Gomes-Gouvêa M.S.
      • de Azevedo Neto R.S.
      • Carrilho F.J.
      • Pinho J.R.R.
      Hepatitis B (HBV), hepatitis C (HCV) and hepatitis delta (HDV) viruses in the Colombian population—how is the epidemiological situation?.
      ,
      • Nguyen V.T.T.
      • Law M.G.
      • Dore G.J.
      An enormous hepatitis B virus-related liver disease burden projected in Vietnam by 2025.
      ,
      • Magdzik W.W.
      • Hepatitis B.
      Epidemiology in Poland, Central and Eastern Europe and the newly independent states.
      ,
      • Pereira L.M.M.B.
      • Martelli C.M.T.
      • Merchán-Hamann E.
      • Montarroyos U.R.
      • Braga M.C.
      • de Lima M.L.C.
      • et al.
      Population-based multicentric survey of hepatitis B infection and risk factor differences among three regions in Brazil.
      ,
      • Livramento A.D.
      • de Cordova C.M.M.
      • Spada C.
      • Treitinger A.
      Seroprevalence of hepatitis B and C infection markers among children and adolescents in the southern Brazilian region.
      ,
      • Datta S.
      An overview of molecular epidemiology of hepatitis B virus (HBV) in India.
      ,
      • Ugwuja E.
      • Ugwu N.
      Seroprevalence of hepatitis B surface antigen and liver function tests among adolescents in Abakaliki, South Eastern Nigeria.
      ,
      • Eke A.C.
      • Eke U.A.
      • Okafor C.I.
      • Ezebialu I.U.
      • Ogbuagu C.
      Prevalence, correlates and pattern of hepatitis B surface antigen in a low resource setting.
      ,
      • Alikor E.
      • Erhabor O.
      Seroprevalence of hepatitis B surface antigenaemia in children in a tertiary health institution in the Niger Delta of Nigeria.
      ,
      • Nurgalieva Z.Z.
      • Hollinger F.B.
      • Graham D.Y.
      • Zhangabylova S.
      • Zhangabylov A.
      Epidemiology and transmission of hepatitis B and C viruses in Kazakhstan.
      ,
      • Allain J.P.
      The risk of hepatitis B virus infection by transfusion in Kumasi.
      ,
      • Olinger C.M.
      • Lazouskaya N.V.
      • Eremin V.F.
      • Muller C.P.
      Multiple genotypes and subtypes of hepatitis B and C viruses in Belarus: similarities with Russia and western European influences.
      ,
      • Thüring E.
      • Joller-Jemelka H.
      • Sereth H.
      • Reth C.
      • Grob P.
      Prevalence of markers of hepatitis viruses A, B, C and of HIV in healthy individuals and patients of a Cambodian province.
      ,
      • Wong D.
      • Cheung A.
      • O’Rourke K.
      • Naylor C.
      • Detsky A.
      • Heathcote J.
      Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.
      ,
      • Dienstag J.L.
      • Schiff E.R.
      • Wright T.L.
      • Perrillo R.P.
      • Hann H.W.
      • Goodman Z.
      • et al.
      Lamivudine as initial treatment for chronic hepatitis B in the United States.
      ,
      • Marcellin P.
      • Chang T.-T.
      • Lim S.-G.
      • Tong M.J.
      • Sievert W.
      • Shiffman M.L.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Lau G.K.K.
      • Piratvisuth T.
      • Luo K.X.
      • Marcellin P.
      • Thongsawat S.
      • Cooksley G.
      • et al.
      Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
      .)
      Prevalence obtained from a study on 18-year old freshmen.
      aData refer to year 2010 (Bureau of Consular Affairs, US Department of State. US Intercountry Adoption [Internet]. adoption.state.gov 2011; [cited 10.01.12] Available from: http://adoption.state.gov/about_us/statistics.php). HBsAg seroprevalence in the United States is 0.27% (0.03% in 6–12 years old)
      • Ioannou G.N.
      • Hepatitis B.
      Virus in the United States: infection, exposure, and immunity rates in a nationally representative survey.
      .
      bData refer to year 2010 (Commission for intercountry adoptions. Data and perspectives in intercountry adoptions in Italy. Report on files from January 1 to December 31, 2010. Commission for intercountry adoptions; 2011. Available from: http://commissioneadozioni.it/it/per-una-famiglia-adottiva/rapporto-statistico.aspx). HBsAg seroprevalence in Italy is 0.9%
      • Bonanni P.
      • Pesavento G.
      • Bechini A.
      • Tiscione E.
      • Mannelli F.
      • Benucci C.
      • et al.
      Impact of universal vaccination programmes on the epidemiology of hepatitis B: 10 years of experience in Italy.
      .
      cData refer to year 2010 (Agence française de l’adoption. Statistiques de l’adoption international 2010. [Internet]. France Diplomatie 2011; [cited 10.01.12] Available from: http://www.diplomatie.gouv.fr). HBsAg seroprevalence in France is 0.65%
      • Meffre C.
      • Le Strat Y.
      • Delarocque-Astagneau E.
      • Dubois F.
      • Antona D.
      • Lemasson J.-M.
      • et al.
      Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: Social factors are important predictors after adjusting for known risk factors.
      .
      dData refer to year 2008 (HCCH Hague Conference Statistics. Canada: annual adoption statistics 2005–2009. [Internet]. HCCH 2012; [cited 10.01.12] Available from: http://www.hcch.net). HBsAg seroprevalence in Canada is 0.3–0.6% (0.4% for preadolescents)
      • Zhang J.
      • Zou S.
      • Giulivi A.
      Epidemiology of hepatitis B in Canada.
      .
      Ten genotypes (A–J) and several subtypes have been described for HBV, with a distinctive geographic distribution. Although in most of Europe and North America, genotype A is predominant, many of the children coming from high or intermediate endemicity countries are infected with genotype B, C, D, or F (Table 1), are at increased risk of complications and may have a worse response to therapy [
      • Liu H.F.
      • Sokal E.
      • Goubau P.
      Wide variety of genotypes and geographic origins of hepatitis B virus in Belgian children.
      ,
      • Ni Y.-H.
      • Chang M.-H.
      • Wang K.-J.
      • Hsu H.-Y.
      • Chen H.-L.
      • Kao J.-H.
      • et al.
      Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma.
      ,
      • Lin C.-L.
      • Kao J.-H.
      The clinical implications of hepatitis B virus genotype: recent advances.
      ].

      Natural history

      Chronic HBV infection is defined as a positive HBsAg for 6 months or longer. Chronic hepatitis B (CHB) in childhood is a mild disease, and infected children are mostly asymptomatic, have normal growth and a normal physical examination [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ]. Most perinatally infected subjects present a positive HBeAg and high serum levels of HBV DNA, with normal or minimally elevated serum alanine aminotransferases (ALT). A transplacental transfer of maternal HBeAg has been proved both in mice and in humans, and could elicit HBe/HBcAg-specific Th cell tolerance in utero [
      • Zanetti A.R.
      • van Damme P.
      • Shouval D.
      The global impact of vaccination against hepatitis B: a historical overview.
      ,
      • Milich D.R.
      • Jones J.E.
      • Hughes J.L.
      • Price J.
      • Raney A.K.
      • McLachlan A.
      Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?.
      ,
      • Chen M.T.
      • Billaud J.-N.
      • Sällberg M.
      • Guidotti L.G.
      • Chisari F.V.
      • Jones J.
      • et al.
      A function of the hepatitis B virus pre-core protein is to regulate the immune response to the core antigen.
      ,
      • Milich D.
      Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection.
      ]. Such an induced tolerance could explain the higher chronicity rate in babies born to HBeAg-positive mothers and the different rate of chronicity between neonatal and adult infection. The synthesis of large amounts of HBeAg by the wild type virus could be necessary to maintain the tolerance [
      • Chen M.
      • Sällberg M.
      • Hughes J.
      • Jones J.
      • Guidotti L.G.
      • Chisari F.V.
      • et al.
      Immune tolerance split between hepatitis B virus pre-core and core proteins.
      ]. This immunotolerant phase is characterized by high viral replication and little liver damage, although in Italian children, after 7 years of disease, 7–10% of subjects showed severe hepatitis at liver biopsy and 1.7–4.5% had cirrhosis [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ]. It lasts 10–30 years when infection is acquired perinatally, whereas it is of minimal duration in subjects infected later in life.
      Viral mutants not capable of secreting HBeAg are then slowly selected (pre-core mutants are detected in 89% of HBeAg-positive patients) [
      • Chu C.-M.
      • Yeh C.-T.
      • Lee C.-S.
      • Sheen I.-S.
      • Liaw Y.-F.
      Pre-core stop mutant in HBeAg-positive patients with chronic hepatitis B: clinical characteristics and correlation with the course of HBeAg-to-anti-HBe seroconversion.
      ]. Selection seems to be secondary to an advantage of such mutants over wild type HBV, as hepatocytes infected by the latter are more susceptible to cytotoxic T lymphocyte-mediated clearance [
      • Frelin L.
      • Wahlstrom T.
      • Tucker A.E.
      • Jones J.
      • Hughes J.
      • Lee B.O.
      • et al.
      A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection.
      ]. Pre-core mutants selection leads to a lower secretion of HBeAg. When the decreased amount of secreted tolerogen is no more sufficient to maintain immunotolerance, the immune system starts attacking infected hepatocytes [
      • Milich D.
      Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection.
      ,
      • Chen M.
      • Sällberg M.
      • Hughes J.
      • Jones J.
      • Guidotti L.G.
      • Chisari F.V.
      • et al.
      Immune tolerance split between hepatitis B virus pre-core and core proteins.
      ]. ALT levels rise, reflecting the bioptic finding of necroinflammation of liver parenchyma, and HBV DNA levels fluctuate. This phase of active hepatitis leads to seroconversion to anti-HBe antibodies in 60–95% of patients on long-term follow-up [
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ,
      • Tseng Y.-R.
      • Wu J.-F.
      • Ni Y.-H.
      • Chen H.-L.
      • Chen C.-C.
      • Wen W.-H.
      • et al.
      Long-term effect of maternal HBeAg on delayed HBeAg seroconversion in offspring with chronic hepatitis B infection.
      ]. ALT levels significantly increase before HBeAg clearance and may remain elevated for 6 months after seroconversion [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ,
      • Ni Y.-H.
      • Chang M.-H.
      • Chen P.-J.
      • Tsai K.-S.
      • Hsu H.-Y.
      • Chen H.-L.
      • et al.
      Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion.
      ,
      • Wu J.-F.
      • Su Y.-R.
      • Chen C.-H.
      • Chen H.-L.
      • Ni Y.-H.
      • Hsu H.-Y.
      • et al.
      Predictive effect of serial serum alanine aminotransferase levels on spontaneous HBeAg seroconversion in chronic genotype B and C HBV–infected children.
      ]. Up to 20% of spontaneous seroconverters may have ALT flare-ups in the years following seroconversion, which seems to be more likely in subjects carrying a pre-core mutant [
      • Ni Y.-H.
      • Chang M.-H.
      • Chen P.-J.
      • Tsai K.-S.
      • Hsu H.-Y.
      • Chen H.-L.
      • et al.
      Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion.
      ]. Spontaneous seroconversion occurs earlier and more frequently in subjects who have acquired HBV horizontally than in those infected perinatally (14–16% vs. 4–5% per year) [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ,
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ,
      • Chu C.M.
      • Liaw Y.F.
      Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion.
      ]. It usually occurs after puberty, with about 90% of children <15 years of age still HBeAg positive [
      • Chu C.M.
      • Liaw Y.F.
      Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion.
      ]. It was shown that boys with earlier-onset puberty seroconverted at younger age (13 vs. 22 years), suggesting that androgens play a role in this process [
      • Wu J.-F.
      • Su Y.-R.
      • Chen C.-H.
      • Chen H.-L.
      • Ni Y.-H.
      • Hsu H.-Y.
      • et al.
      Predictive effect of serial serum alanine aminotransferase levels on spontaneous HBeAg seroconversion in chronic genotype B and C HBV–infected children.
      ]. Environmental factors, such as nutritional status, have been suggested to influence immune response to HBV, accelerating seroconversion in children after adoption from developing countries [
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ]. Genotype C and maternal HBeAg-positive status were also associated with delayed spontaneous seroconversion [
      • Hsu H.-Y.
      • Chang M.-H.
      • Ni Y.-H.
      • Chiang C.-L.
      • Chen H.-L.
      • Wu J.-F.
      • et al.
      No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization.
      ,
      • Tseng Y.-R.
      • Wu J.-F.
      • Ni Y.-H.
      • Chen H.-L.
      • Chen C.-C.
      • Wen W.-H.
      • et al.
      Long-term effect of maternal HBeAg on delayed HBeAg seroconversion in offspring with chronic hepatitis B infection.
      ,
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ,
      • Kao J.H.
      • Chen P.J.
      • Lai M.Y.
      • Chen D.S.
      Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.
      ,
      • Chu C.-J.
      • Hussain M.
      • Lok A.S.
      Hepatitis B virus genotype B is associated with earlier hbeag seroconversion compared with hepatitis B virus genotype C.
      ,
      • Livingston S.E.
      • Simonetti J.P.
      • Bulkow L.R.
      • Homan C.E.
      • Snowball M.M.
      • Cagle H.H.
      • et al.
      Clearance of hepatitis B e Antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F.
      ].
      HBsAg-positive, HBeAg-negative, and anti-HBe-positive patients are considered inactive carriers, express absent or low viral replication, with low or undetectable HBV DNA, and have inactive liver histology, with normal ALT levels. Inactive carriers with no signs of cirrhosis at seroconversion did not show progression to cirrhosis over 24–29 year follow-up [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ].
      On the contrary, 1–5% of HBeAg-positive children developed cirrhosis [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ,
      • Chang M.
      • Hsu H.
      • Hsu H.
      • Ni Y.
      • Chen J.
      • Chen D.
      The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age.
      ]. Between 2% and 5% of children with CHB developed HCC during childhood [
      • Hsu H.-Y.
      • Chang M.-H.
      • Ni Y.-H.
      • Chiang C.-L.
      • Chen H.-L.
      • Wu J.-F.
      • et al.
      No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ,
      • Wen W.-H.
      • Chang M.-H.
      • Hsu H.-Y.
      • Ni Y.-H.
      • Chen H.-L.
      The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection.
      ]. Incidence of HCC in high prevalence areas was significantly reduced after the implementation of immunization programs [
      • Chang M.H.
      • You S.L.
      • Chen C.J.
      • Liu C.J.
      • Lee C.M.
      • Lin S.M.
      • et al.
      Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: A 20-year follow-up study.
      ]. Children developing HCC are more likely to be males (70%), with cirrhosis (80%) and undergoing early seroconversion, suggesting that necroinflammation during seroconversion to anti-HBe may be severe and lead to cirrhosis and HCC [
      • Hsu H.-Y.
      • Chang M.-H.
      • Ni Y.-H.
      • Chiang C.-L.
      • Chen H.-L.
      • Wu J.-F.
      • et al.
      No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ,
      • Wen W.-H.
      • Chang M.-H.
      • Hsu H.-Y.
      • Ni Y.-H.
      • Chen H.-L.
      The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection.
      ]. Long-term risk of both HCC and cirrhosis is directly correlated to viral replication and serum HBV DNA levels [
      • Iloeje U.H.
      • Yang H.-I.
      • Su J.
      • Jen C.-L.
      • You S.-L.
      • Chen C.-J.
      Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
      ,
      • Chen C.-J.
      • Yang H.-I.
      • Su J.
      • Jen C.-L.
      • You S.-L.
      • Lu S.-N.
      • et al.
      Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
      ]. The role of viral genotype on the risk of developing HCC is still to be defined: in children, 80% of HCCs are present in cirrhotic genotype B patients, whereas young adults with HCC are mostly non-cirrhotic [
      • Hsu H.-Y.
      • Chang M.-H.
      • Ni Y.-H.
      • Chiang C.-L.
      • Chen H.-L.
      • Wu J.-F.
      • et al.
      No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization.
      ,
      • Kao J.H.
      • Chen P.J.
      • Lai M.Y.
      • Chen D.S.
      Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.
      ]. In adults, genotypes C and F increase the risk for HCC [
      • Kao J.H.
      • Chen P.J.
      • Lai M.Y.
      • Chen D.S.
      Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.
      ,
      • Sánchez-Tapias J.M.
      • Costa J.
      • Mas A.
      • Bruguera M.
      • Rodés J.
      Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients.
      ,
      • Yu M.W.
      • Yeh S.H.
      • Chen P.J.
      • Liaw Y.F.
      • Lin C.L.
      • Liu C.J.
      • et al.
      Hepatitis B Virus Genotype and DNA Level and Hepatocellular Carcinoma: A Prospective Study in Men.
      ,
      • Livingston S.E.
      • Simonetti J.P.
      • McMahon B.J.
      • Bulkow L.R.
      • Hurlburt K.J.
      • Homan C.E.
      • et al.
      Hepatitis B virus genotypes in Alaska native people with hepatocellular carcinoma: preponderance of genotype F.
      ]. Furthermore, such a risk is higher in persons with a family history of HCC, and a new susceptibility locus has been recently described in 1p36.22 [
      • Yu M.W.
      • Chang H.C.
      • Liaw Y.F.
      • Lin S.M.
      • Lee S.D.
      • Liu C.J.
      • et al.
      Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives.
      ,
      • Zhang H.
      • Zhai Y.
      • Hu Z.
      • Wu C.
      • Qian J.
      • Jia W.
      • et al.
      Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers.
      ]. Seroconversion to anti-HBe reduces the overall risk of developing HCC later in life, but an annual incidence of 0.2% has been described in HBeAg-negative adults (1.6% of asymptomatic HBsAg carriers) [
      • Hsu Y.-S.
      • Chien R.-N.
      • Yeh C.-T.
      • Sheen I.-S.
      • Chiou H.-Y.
      • Chu C.-M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ].
      In 5% of anti-HBe-positive children, a pre-core mutant is selected, with persistent viral replication, abnormal ALT levels and histologically active hepatitis (HBeAg-negative chronic hepatitis). The latter progresses slowly in children, whereas adult patients are at increased risk of cirrhosis and HCC [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ,
      • Hsu Y.-S.
      • Chien R.-N.
      • Yeh C.-T.
      • Sheen I.-S.
      • Chiou H.-Y.
      • Chu C.-M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      ]. A stronger immune response with a faster turnover of infected cells could account for such an increased severity, and could be secondary to the reduced secretion of the tolerogen HBeAg [
      • Chen M.T.
      • Billaud J.-N.
      • Sällberg M.
      • Guidotti L.G.
      • Chisari F.V.
      • Jones J.
      • et al.
      A function of the hepatitis B virus pre-core protein is to regulate the immune response to the core antigen.
      ,
      • Ribeiro R.M.
      • Germanidis G.
      • Powers K.A.
      • Pellegrin B.
      • Nikolaidis P.
      • Perelson A.S.
      • et al.
      Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections.
      ].
      In long-term longitudinal studies, it was shown that 7–14% of inactive carriers lost HBsAg and became anti-HBs-positive. Spontaneous seroconversion to anti-HBs is a rare event in childhood (1%/year and 0.6%/year in horizontally and perinatally infected children, respectively) [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Bortolotti F.
      • Guido M.
      • Bartolacci S.
      • Cadrobbi P.
      • Crivellaro C.
      • Noventa F.
      • et al.
      Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
      ,
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ,
      • Fattovich G.
      • Bortolotti F.
      • Donato F.
      Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
      ]. HBsAg clearance and anti-HBs seroconversion mark the resolution of HBV infection, and are accompanied by improved liver histology. Long-term prognosis after HBsAg seroclearance is excellent if it occurs before the development of cirrhosis or HCC and in the absence of concomitant infections [
      • Arase Y.
      • Ikeda K.
      • Suzuki F.
      • Suzuki Y.
      • Saitoh S.
      • Kobayashi M.
      • et al.
      Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B.
      ]. Nevertheless, cccDNA persists indefinitely in hepatocytes, and low-level viral replication or reactivation upon immunosuppression are still possible.

      Who and when to treat

      Even though several guidelines have been published by major international societies on the management of adult patients with CHB, treatment strategies for children are still evolving and are mostly based on consensus of expert panels (Fig. 1) [
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B: update 2009.
      ,
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B.
      ,
      • Shah U.
      • Kelly D.
      • Chang M.-H.
      • Fujisawa T.
      • Heller S.
      • González-Peralta R.P.
      • et al.
      Management of chronic hepatitis B in children.
      ,
      • Jonas M.M.
      • Block J.M.
      • Haber B.A.
      • Karpen S.J.
      • London W.T.
      • Murray K.F.
      • et al.
      Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options.
      ]. Decision to start a therapy must take into account the mild evolution of the disease during childhood for most of the patients and the potentially severe complications in few, not yet well identified cases, and it is complicated by the limited number of drugs labeled for use in children.
      Figure thumbnail gr1
      Fig. 1Who and when to treat: algorithm for treatment of children and adolescents with chronic hepatitis B.
      The goal of the anti-HBV therapy, in children as in adults, is to reduce the risk of progressive liver disease, cirrhosis, and HCC. It can be achieved by suppressing viral replication through durable HBeAg seroconversion and undetectable serum HBV DNA levels. Reduction of viremia levels leads to decreased liver inflammation and subsequent normalization of ALT levels. The final goal is anti-HBs seroconversion, as it stops disease progression and reduces the risk of HCC, although it occurs in a minority of treated subjects [
      • Simonetti J.
      • Bulkow L.
      • McMahon B.J.
      • Homan C.
      • Snowball M.
      • Negus S.
      • et al.
      Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus.
      ].
      Need for treatment should be evaluated at each follow-up visit, in order to treat as soon as early signs of liver damage are detected. Children with CHB should undergo physical examination and measurement of serum ALT, HBeAg/anti-HBe, and alpha-fetoprotein levels every 6 months. ALT should be monitored every 3 months at diagnosis (for 1 year) and if persistently elevated, and every 12 months in HBeAg-negative patients with low viral load (<2000 IU/ml). HBV DNA levels should be assessed every 12 months, along with a complete blood count, a full liver panel and a liver ultrasound [
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B: update 2009.
      ,
      • Shah U.
      • Kelly D.
      • Chang M.-H.
      • Fujisawa T.
      • Heller S.
      • González-Peralta R.P.
      • et al.
      Management of chronic hepatitis B in children.
      ,
      • Haber B.A.
      • Block J.M.
      • Jonas M.M.
      • Karpen S.J.
      • London W.T.
      • McMahon B.J.
      • et al.
      Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B.
      ]. Lifetime follow-up is warranted even for inactive carriers, because of the risk of cirrhosis (7.8% of patients at 25 years), HCC (2.2%) and reactivation of HBV infection, with seroreversion to HBeAg positivity (1–4% of patients) or progression to HBeAg-negative hepatitis (15–24%) [
      • Hsu Y.-S.
      • Chien R.-N.
      • Yeh C.-T.
      • Sheen I.-S.
      • Chiou H.-Y.
      • Chu C.-M.
      • et al.
      Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
      ,
      • Fattovich G.
      • Olivari N.
      • Pasino M.
      • D’Onofrio M.
      • Martone E.
      • Donato F.
      Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.
      ].
      Decision to treat should be based on the following parameters: ALT levels, HBeAg positivity, HBV DNA levels, liver histology, family history of cirrhosis, and/or HCC, co-existing liver diseases, and patient’s treatment history. Serum ALT level is the most useful marker of liver damage and should be used to identify patients who could be considered for possible antiviral therapy. Published evidence suggests that patients with normal or mildly elevated ALT respond poorly to available treatments [
      • Sokal E.M.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • Goyens P.
      • et al.
      Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
      ,
      • Jonas M.M.
      • Kelly D.A.
      • Mizerski J.
      • Badia I.B.
      • Areias J.A.
      • Schwarz K.B.
      • et al.
      Clinical trial of lamivudine in children with chronic hepatitis B.
      ]. Benefit of treating children with normal ALT has not been established, and the risk of developing antiviral resistance could turn it deleterious when considering the future of these patients [
      • Zoulim F.
      • Locarnini S.
      Hepatitis B virus resistance to nucleos(t)ide analogues.
      ]. Therefore, children in the immunotolerant phase should not be treated outside of clinical trials, and should be monitored and treated when the increase of ALT levels reveals immune activation. The three largest clinical trials of antiviral drugs in children used ALT levels higher than 1.5 times the laboratory ULN or more than 60 IU/L, whichever was lower, as inclusion criteria [
      • Sokal E.M.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • Goyens P.
      • et al.
      Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
      ,
      • Jonas M.M.
      • Kelly D.A.
      • Mizerski J.
      • Badia I.B.
      • Areias J.A.
      • Schwarz K.B.
      • et al.
      Clinical trial of lamivudine in children with chronic hepatitis B.
      ,
      • Jonas M.M.
      • Kelly D.
      • Pollack H.
      • Mizerski J.
      • Sorbel J.
      • Frederick D.
      • et al.
      Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B.
      ]. Unfortunately, the upper limit of normal (ULN) for ALT levels has not yet been established for children [
      • Schwimmer J.B.
      • Dunn W.
      • Norman G.J.
      • Pardee P.E.
      • Middleton M.S.
      • Kerkar N.
      • et al.
      SAFETY study: alanine aminotransferase cut-off values are set too high for reliable detection of pediatric chronic liver disease.
      ].
      Serum ALT level has to be elevated for at least 6 months (12 months if HBeAg-negative), in order to avoid treating patients who are undergoing spontaneous HBeAg seroconversion. Persistent ALT elevation mandates assessment of serum HBV DNA levels. High HBV DNA values warrant treatment, whereas low HBV DNA levels should lead to the exclusion of other causes of liver disease. The cut-off value for HBV DNA has not been defined, and arbitrary values are used in clinical trials and guidelines. As children have a higher HBV replication rate, a value of 20,000 IU/ml has been chosen by different authors [
      • Shah U.
      • Kelly D.
      • Chang M.-H.
      • Fujisawa T.
      • Heller S.
      • González-Peralta R.P.
      • et al.
      Management of chronic hepatitis B in children.
      ,
      • Hsu E.K.
      • Murray K.F.
      Hepatitis B and C in children.
      ]. However, lower values have been associated with progressive liver disease in adults and latest management guidelines identified 2.000 IU/ml to be a good cut-off [
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B: update 2009.
      ].
      In adult patients older than 40 years of age, treatment can be started solely upon detection of a high viral load, as it is an independent risk factor of cirrhosis and HCC [
      • Iloeje U.H.
      • Yang H.-I.
      • Su J.
      • Jen C.-L.
      • You S.-L.
      • Chen C.-J.
      Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
      ,
      • Chen C.-J.
      • Yang H.-I.
      • Su J.
      • Jen C.-L.
      • You S.-L.
      • Lu S.-N.
      • et al.
      Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
      ]. No data exist in children to support such an approach. Therefore, as response to currently available treatments for children is partial and limited to specific subgroups, histologic assessment of the grade of inflammation and the stage of fibrosis remains recommended before treating a child. Response to both interferon(IFN)-alfa and nucleos(t)ide analogues is more likely when at least moderate necroinflammation or moderate fibrosis are found at liver histology [
      • Sokal E.M.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • Goyens P.
      • et al.
      Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
      ,
      • Hom X.
      • Little N.R.
      • Gardner S.D.
      • Jonas M.M.
      Predictors of virologic response to lamivudine treatment in children with chronic hepatitis B infection.
      ]. Although the benefit of treatment has not been established for children with mild inflammation or fibrosis, a family history of HCC may warrant treatment even in children with mild histological changes, as they are at increased risk of developing HCC [
      • Yu M.W.
      • Chang H.C.
      • Liaw Y.F.
      • Lin S.M.
      • Lee S.D.
      • Liu C.J.
      • et al.
      Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives.
      ].
      There are other special populations of children at increased risk of rapid disease progression (cirrhosis, HBV-related glomerulonephritis, co-infection with HDV, HCV, or HIV). These patients could benefit from treatment even if ALT, HBV DNA levels, and liver histology do not match the above listed cut-offs. An antiviral treatment should be always considered in recipients of a liver graft from an anti-HBc-positive donor and to prevent (or treat) a recurrent HBV infection in children undergoing liver transplantation [
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B: update 2009.
      ,
      • Shapira R.
      • Mor E.
      • Bar-Nathan N.
      • Sokal E.M.
      • Tur-Kaspa R.
      • Dinari G.
      • et al.
      Efficacy of lamivudine for the treatment of hepatitis B virus infection after liver transplantation in children.
      ,
      • Cholongitas E.
      • Papatheodoridis G.V.
      • Burroughs A.K.
      Liver grafts from anti-hepatitis B core positive donors: a systematic review.
      ,
      • Perrillo R.
      • Hepatitis B.
      Virus prevention strategies for antibody to hepatitis B core antigen-positive liver donation: a survey of North American, European, and Asian-Pacific transplant programs.
      ]. Furthermore, prophylactic treatment should be administered to HBsAg-positive patients who have to receive immunosuppressive or cytotoxic therapy, as it decreases the risk of mortality and morbidity related to HBV reactivation [
      • Katz L.H.
      • Fraser A.
      • Gafter-Gvili A.
      • Leibovici L.
      • Tur-Kaspa R.
      Lamivudine prevents reactivation of hepatitis B and reduces mortality in immunosuppressed patients: systematic review and meta-analysis.
      ].
      Several studies conducted in adults showed a better response to interferon for viral genotypes A and B, compared to D and C, respectively [
      • Xu D.-Z.
      • Yan Y.-P.
      • Choi B.C.K.
      • Xu J.-Q.
      • Men K.
      • Zhang J.-X.
      • et al.
      Risk factors and mechanism of transplacental transmission of hepatitis B virus: a case–control study.
      ,
      • Wai C.T.
      • Chu C.-J.
      • Hussain M.
      • Lok A.S.F.
      HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.
      ,
      • Erhardt A.
      Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D.
      ,
      • Flink H.J.
      • van Zonneveld M.
      • Hansen B.E.
      • de Man R.A.
      • Schalm S.W.
      • Janssen H.L.A.
      • et al.
      Treatment with peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype.
      ]. On the contrary, no significant difference was found when nucleoside analogues were used [
      • Raimondi S.
      • Maisonneuve P.
      • Bruno S.
      • Mondelli M.U.
      Is response to antiviral treatment influenced by hepatitis B virus genotype?.
      ]. No studies have investigated the role of genotype on treatment response in pediatric patients, and genotype determination before treatment is not currently recommended [
      • Jonas M.M.
      • Block J.M.
      • Haber B.A.
      • Karpen S.J.
      • London W.T.
      • Murray K.F.
      • et al.
      Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options.
      ].

      Treatment options

      The US Food and Drug Administration (FDA) approved four medications for treatment of children with CHB: IFNα, lamivudine, adefovir, and entecavir. IFNα can be used in children older than 12 months of age, lamivudine starting at 3 years of age, adefovir in children aged 12 years and older and entecavir starting from 16 years of age. Each of these treatments, together with others currently studied or used off-label in reference centers, has advantages and disadvantages (Table 2), and different response and resistance rates (Fig. 2).
      Table 2Available treatments for chronic hepatitis B in pediatric age.
      pts, Patients.
      Figure thumbnail gr2
      Fig. 2Comparison between available treatments in term of HBeAg seroconversion (light blue bars), undetectable HBV DNA (blue bars) and resistant mutations emergence (dark blue bars). Pediatric clinical trials (P) are compared to studies on adult patients (A). (
      • Sokal E.M.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • Goyens P.
      • et al.
      Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
      ,
      • Jonas M.M.
      • Kelly D.A.
      • Mizerski J.
      • Badia I.B.
      • Areias J.A.
      • Schwarz K.B.
      • et al.
      Clinical trial of lamivudine in children with chronic hepatitis B.
      ,
      • Jonas M.M.
      • Kelly D.
      • Pollack H.
      • Mizerski J.
      • Sorbel J.
      • Frederick D.
      • et al.
      Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B.
      ,
      • Chang T.-T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.-C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      ,
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ,
      • Wong D.
      • Cheung A.
      • O’Rourke K.
      • Naylor C.
      • Detsky A.
      • Heathcote J.
      Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis.
      ,
      • Dienstag J.L.
      • Schiff E.R.
      • Wright T.L.
      • Perrillo R.P.
      • Hann H.W.
      • Goodman Z.
      • et al.
      Lamivudine as initial treatment for chronic hepatitis B in the United States.
      ,
      • Marcellin P.
      • Chang T.-T.
      • Lim S.-G.
      • Tong M.J.
      • Sievert W.
      • Shiffman M.L.
      • et al.
      Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Lau G.K.K.
      • Piratvisuth T.
      • Luo K.X.
      • Marcellin P.
      • Thongsawat S.
      • Cooksley G.
      • et al.
      Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.
      .)

      Interferon-alfa

      IFNα-2b has been the first drug to be approved and it has been used to treat CHB in children for about 15 years. Efficacy in children is similar to that in adults. In the largest multinational randomized controlled trial of IFNα therapy in children, 26% of patients achieved virologic response (VR: undetectable HBV DNA and loss of HBeAg) after 24 weeks of treatment, compared to 11% of untreated controls, and an additional 7% responded during the 24 weeks after treatment cessation. Response rate rose to 35% when only patients with ALT at least twice the ULN were considered. ALT levels decreased in all responders, and they were normal in 44% of cases at the end of treatment. Histological activity index improved in responders and loss of HBsAg occurred in 10% of treated children, as compared to 1.2% in the control group. Likeliness of a response was associated with low HBV DNA levels before treatment, younger age and female sex [
      • Sokal E.M.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • Goyens P.
      • et al.
      Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
      ]. A better response in young patients was subsequently confirmed in children younger than 5 years of age [
      • Kobak G.E.
      • MacKenzie T.
      • Sokol R.J.
      • Narkewicz M.R.
      Interferon treatment for chronic hepatitis B: enhanced response in children 5 years old or younger.
      ].
      IFNα is thought to simply accelerate seroconversion, as many patients who do not respond to treatment may still seroconvert to anti-HBe later in life. In three different series of 108, 107, and 174 children with CHB, IFNα treatment was shown to accelerate HBeAg seroconversion, but treated and untreated patients had a similar rate of HBeAg clearance at long-term follow-up (Fig. 3) [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ,
      • Bortolotti F.
      • Jara P.
      • Barbera C.
      • Gregorio G.V.
      • Vegnente A.
      • Zancan L.
      • et al.
      Long-term effect of alpha interferon in children with chronic hepatitis B.
      ]. These data were confirmed in a recent study on Asian children [
      • Hsu H.-Y.
      • Tsai H.-Y.
      • Wu T.-C.
      • Chiang C.-L.
      • Ni Y.-H.
      • Chen P.-J.
      • et al.
      Interferon-α treatment in children and young adults with chronic hepatitis B: a long-term follow-up study in Taiwan.
      ]. Furthermore, children of Asian origin seroconverted slower than those of other ethnic origin, but they reached the same proportion of seroconversion in the long-term [
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ]. In a series of 74 children followed-up for 7 years, treated patients with elevated baseline ALT levels showed a higher long-term seroconversion rate, whereas elevated ALT at baseline did not significantly influence the long-term natural seroconversion rate in untreated children [
      • Vo Thi Diem H.
      • Bourgois A.
      • Bontems P.
      • Goyens P.
      • Buts J.-P.
      • Nackers F.
      • et al.
      Chronic hepatitis B infection: long-term comparison of children receiving interferon alpha and untreated controls.
      ].
      Figure thumbnail gr3
      Fig. 3HBeAg seroconversion rates in children treated with INF-alfa (light blue bars) as compared to untreated subjects (dark blue bars). Differences between the two groups in each study are not statistically significant.
      HBsAg clearance was observed in 4–15% of children treated with IFN (15–25% of responders), compared to 0–10% of controls [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.D.
      • Cirillo F.
      • Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ,
      • Marx G.
      • Martin S.R.
      • Chicoine J.-F.
      • Alvarez F.
      Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
      ,
      • Sokal E.M.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • Goyens P.
      • et al.
      Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
      ,
      • Bortolotti F.
      • Jara P.
      • Barbera C.
      • Gregorio G.V.
      • Vegnente A.
      • Zancan L.
      • et al.
      Long-term effect of alpha interferon in children with chronic hepatitis B.
      ,
      • Hsu H.-Y.
      • Tsai H.-Y.
      • Wu T.-C.
      • Chiang C.-L.
      • Ni Y.-H.
      • Chen P.-J.
      • et al.
      Interferon-α treatment in children and young adults with chronic hepatitis B: a long-term follow-up study in Taiwan.
      ,
      • Vo Thi Diem H.
      • Bourgois A.
      • Bontems P.
      • Goyens P.
      • Buts J.-P.
      • Nackers F.
      • et al.
      Chronic hepatitis B infection: long-term comparison of children receiving interferon alpha and untreated controls.
      ]. The difference in HBsAg seroconversion rate between treated and untreated patients was shown to be significant in the randomized controlled trial, whereas none of long-term studies was able to find such a difference to be statistically significant. Nevertheless, children who responded promptly to IFN were more likely to lose HBsAg than late or no-responders [
      • Bortolotti F.
      • Jara P.
      • Barbera C.
      • Gregorio G.V.
      • Vegnente A.
      • Zancan L.
      • et al.
      Long-term effect of alpha interferon in children with chronic hepatitis B.
      ].
      Overall, although pediatric studies failed to show an impact of treatment over time, large case–control studies and meta-analyses in adults showed that IFNα reduced the risk of cirrhosis (RR 0.65) and HCC (RR 0.59–0.66) in the long-term [
      • Lin S.M.
      • Yu M.L.
      • Lee C.M.
      • Chien R.N.
      • Sheen I.S.
      • Chu C.M.
      • et al.
      Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma.
      ,
      • Yang Y.F.
      • Zhao W.
      • Zhong Y.D.
      • Xia H.M.
      • Shen L.
      • Zhang N.
      Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis.
      ,
      • Sung J.J.Y.
      • Tsoi K.K.F.
      • Wong V.W.S.
      • Li K.C.T.
      • Chan H.L.Y.
      Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma.
      ].
      European consensus recommendations for IFNα treatment suggest to treat HBeAg-positive children aged 2 years or older, with abnormal ALT and low-intermediate HBV DNA levels. The recommended regimen is 5–10 million units per square meter, three times weekly for 6 months [
      • Jonas M.M.
      • Block J.M.
      • Haber B.A.
      • Karpen S.J.
      • London W.T.
      • Murray K.F.
      • et al.
      Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options.
      ,
      • Jara P.
      • Bortolotti F.
      Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children.
      ]. The benefit of priming with corticosteroids has not been proven [
      • Boxall E.H.
      • Sira J.
      • Ballard A.L.
      • Davies P.
      • Kelly D.A.
      Long-term follow-up of hepatitis B carrier children treated with interferon and prednisolone.
      ,
      • Gregorio G.V.
      • Jara P.
      • Hierro L.
      • Diaz C.
      • La Vega de A.
      • et al.
      Lymphoblastoid interferon alfa with or without steroid pretreatment in children with chronic hepatitis B: a multicenter controlled trial.
      ]. IFNα is contraindicated in children with decompensated cirrhosis, cytopenia, autoimmune disorders, cardiac or renal failure, and in transplanted patients [
      • Jara P.
      • Bortolotti F.
      Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children.
      ]. As VR may be achieved in the 6 months following the end of treatment, at least 6–12 months should pass by before another therapy is started.
      Side effects of IFNα treatment included fever and flu-like symptoms, behavioral disorders, gastrointestinal disorders and neutropenia [
      • Sokal E.M.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • Goyens P.
      • et al.
      Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
      ]. Furthermore, IFNα was shown to temporarily affect growth [
      • Comanor L.
      • Minor J.
      • Conjeevaram H.S.
      • Roberts E.A.
      • Alvarez F.
      • Bern E.M.
      • et al.
      Impact of chronic hepatitis B and interferon-alpha therapy on growth of children.
      ]. All side effects resolve after treatment is stopped.
      Pegylated interferon-alfa (PegIFN) has not yet been approved for the treatment of CHB in children. Polyethylene glycol addition to IFNα enhances its half-life, allowing a once-weekly administration. Such a formulation is licensed for the use in children with chronic hepatitis C. In adults with CHB, PegIFN proved to have superior efficacy than conventional IFNα, with the same safety profile [
      • Cooksley W.G.
      • Piratvisuth T.
      • Lee S.D.
      • Mahachai V.
      • Chao Y.C.
      • Tanwandee T.
      • et al.
      Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.
      ]. Clinical trials of PegIFN in children with CHB are ongoing. Preliminary reports in children with HCV infection showed that it was well tolerated, while leading to better response rates than IFNα [
      • Wirth S.
      • Pieper-Boustani H.
      • Lang T.
      • Ballauff A.
      • Kullmer U.
      • Gerner P.
      • et al.
      Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C.
      ,
      • Sokal E.M.
      • Bourgois A.
      • Stephenne X.
      • Silveira T.
      • Porta G.
      • Gardovska D.
      • et al.
      Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in children and adolescents.
      ].

      Lamivudine

      Lamivudine is a pyrimidine nucleoside analogue approved for children aged 3 years and older. In the largest pediatric randomized, controlled trial, VR was achieved by 23% of patients receiving lamivudine after 1-year treatment (compared to 13% in the control group). Response increased to 35% when considering only children with ALT levels of at least twice the ULN [
      • Jonas M.M.
      • Kelly D.A.
      • Mizerski J.
      • Badia I.B.
      • Areias J.A.
      • Schwarz K.B.
      • et al.
      Clinical trial of lamivudine in children with chronic hepatitis B.
      ]. An open label extension study was then carried out on the same cohort, reaching a total of 2 or 3 years of treatment. At the end of the extension period, response rate was 56% for children receiving lamivudine in the absence of resistant mutations (being 5% in patients with a YMDD mutant HBV). Resistance rate increased over time (24% after 1 year of treatment, 49% at 2 years, and 64% at 3 years) [
      • Sokal E.M.
      • Kelly D.A.
      • Mizerski J.
      • Badia I.B.
      • Areias J.A.
      • Schwarz K.B.
      • et al.
      Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B.
      ]. Likeliness of response was greater in patients with higher ALT levels and histologic activity index at baseline. In children, no data is yet available on the long-term impact of treatment with lamivudine (or any other nucleoside analogue) on the natural history of the disease.
      Lamivudine is well tolerated with no significant side effects. The recommended treatment dose is 3 mg/kg/day (maximum 100 mg/day), administered orally once daily. Such a dose provides levels of exposure and trough concentrations similar to the 100 mg dose in adults [
      • Sokal E.M.
      • Roberts E.A.
      • Mieli-Vergani G.
      • McPhillips P.
      • Johnson M.
      • Barber J.
      • et al.
      A dose ranging study of the pharmacokinetics, safety, and preliminary efficacy of lamivudine in children and adolescents with chronic hepatitis B.
      ]. Optimal treatment duration is more difficult to determine. Published data suggest continuing treatment until VR is achieved, and possibly for 6 months following seroconversion [
      • Sokal E.M.
      • Kelly D.A.
      • Mizerski J.
      • Badia I.B.
      • Areias J.A.
      • Schwarz K.B.
      • et al.
      Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B.
      ]. As a longer treatment duration leads to higher resistance rates, it is recommended to discontinue lamivudine after 6 months if a complete suppression of viral replication is not achieved or if YMDD mutations emerge. As post-treatment ALT flares are possible, children should be carefully followed and an alternative therapy should be started in the rare cases of severe and protracted ALT elevation [
      • Jonas M.M.
      • Little N.R.
      • Gardner S.D.
      International Pediatric Lamivudine Investigator Group. Long-term lamivudine treatment of children with chronic hepatitis B: durability of therapeutic responses and safety.
      ].
      Combination of lamivudine with IFNα (either concurrent or sequential) proved to be more effective that the single drugs alone in adult patients with elevated ALT levels [
      • Schalm S.W.
      • Heathcote J.
      • Cianciara J.
      • Farrell G.
      • Sherman M.
      • Willems B.
      • et al.
      Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.
      ,
      • Sarin S.K.
      • Kumar M.
      • Kumar R.
      • Kazim S.N.
      • Guptan R.C.
      • Sakhuja P.
      • et al.
      Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients.
      ]. The two drugs were shown to have a synergistic effect on cells in vitro [
      • Korba B.
      • Cote P.
      • Hornbuckle W.
      • Schinazi R.
      • Gangemi J.
      • Tennant B.
      • et al.
      Enhanced antiviral benefit of combination therapy with lamivudine and alpha interferon against WHV replication in chronic carrier woodchucks.
      ]. In children, fewer data are available. Three studies investigated combined therapy in 32, 33, and 45 treatment-naïve children with elevated ALT levels. Although no difference was found between different combination strategies, the children reached 30–60% seroconversion to anti-HBe and 9–17% to anti-HBs [
      • Dikici B.
      • Bosnak M.
      • Bosnak V.
      • Dagli A.
      • Ece A.
      • Yagci R.V.
      • et al.
      Combination therapy for children with chronic hepatitis B virus infection.
      ,
      • Yilmaz A.
      • Akcam M.
      • Gelen T.
      • Artan R.
      Lamivudine and high-dose interferon alpha 2a combination treatment in naïve HBeAg-positive immunoactive chronic hepatitis B in children: an East Mediterranean center’s experience.
      ,
      • Akman S.A.
      • Okcu S.C.
      • Halicioglu O.
      • Sutcuoglu S.
      • Anil M.
      • Kizilgunesler A.
      • et al.
      Therapeutic efficacy of sequential and simultaneous treatments with interferon-alpha and lamivudine in children with chronic hepatitis B.
      ]. An 8-week treatment with lamivudine followed by 10-month combination therapy with lamivudine and IFN has been tested on 23 immunotolerant children: complete suppression of viral replication was achieved in 78% of subjects and 22% of children seroconverted to anti-HBe. The concurrent administration of IFNα appeared to be protective against mutations emergence [
      • D’Antiga L.
      • Aw M.
      • Atkins M.
      • Moorat A.
      • Vergani D.
      • Mieli-Vergani G.
      Combined lamivudine/interferon-alpha treatment in “immunotolerant” children perinatally infected with hepatitis B: a pilot study.
      ]. No difference was seen on histological response between monotherapy and combined therapy [
      • Kuloglu Z.
      • Krsaçloglu C.T.
      • Kansu A.
      • Erden E.
      • Girgin N.
      Liver histology of children with chronic hepatitis treated with interferon-alpha alone or in combination with lamivudine.
      ]. As no large clinical trials have been conducted so far, advantages of combination therapy over monotherapy in children are still to be confirmed.

      Adefovir

      Adefovir dipivoxil is a purine analogue approved to treat children with CHB aged 12 years and older. In a large pediatric randomized controlled trial, 23% of patients aged 12–17 years achieved VR after 48-week treatment with adefovir (compared to 0% of placebo-treated subjects). The efficacy on HBV DNA suppression and ALT normalization was less evident in younger children (15% vs. 3%), with differences between groups not being statistically significant [
      • Jonas M.M.
      • Kelly D.
      • Pollack H.
      • Mizerski J.
      • Sorbel J.
      • Frederick D.
      • et al.
      Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B.
      ]. Adefovir was well tolerated by children of all age groups, with no resistance-associated mutation registered. However, adefovir resistant mutations are reported in more than 20% of HBeAg-positive adults after a 5-year treatment [
      • Marcellin P.
      • Chang T.-T.
      • Lim S.G.L.
      • Sievert W.
      • Tong M.
      • Arterburn S.
      • et al.
      Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.
      ]. A dose-dependent proximal renal tubular toxicity, with occasional Fanconi-like renal tubular acidosis, is a known side effect of adefovir, which has been rarely reported in adults, but never in children. The nephrotoxicity is usually reversible if the therapy is rapidly stopped [
      • Fontana R.J.
      Side effects of long-term oral antiviral therapy for hepatitis B.
      ,
      • Viganò M.
      • Lampertico P.
      • Colombo M.
      Drug safety evaluation of adefovir in HBV infection.
      ]. The recommended dose in patients 12–18 years of age is 10 mg orally once daily [
      • Sokal E.M.
      • Kelly D.
      • Wirth S.
      • Mizerski J.
      • Dhawan A.
      • Frederick D.
      The pharmacokinetics and safety of adefovir dipivoxil in children and adolescents with chronic hepatitis B virus infection.
      ]. Treatment duration has not been established, but experts agree to continue for at least 6 months after HBeAg seroconversion. Adefovir should be discontinued if a complete VR is not achieved after 24 weeks or if a resistant mutation emerges. As with other nucleos(t)ide analogues, patients should be monitored after discontinuation because post-treatment flares are not uncommon.

      Entecavir

      Entecavir is a carbocyclic analogue of 2′-deoxyguanosine that proved to be more potent than both lamivudine and adefovir in adult patients [
      • Chang T.-T.
      • Gish R.G.
      • de Man R.
      • Gadano A.
      • Sollano J.
      • Chao Y.-C.
      • et al.
      A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B.
      ,
      • Leung N.
      • Peng C.-Y.
      • Hann H.-W.
      • Sollano J.
      • Lao-Tan J.
      • Hsu C.-W.
      • et al.
      Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: a randomized international study of entecavir versus adefovir.
      ]. Furthermore, entecavir resistance is rare, even after 5 years of treatment, and entecavir is active (although less effective) on lamivudine-resistant strains [
      • Colonno R.J.
      • Rose R.
      • Baldick C.J.
      • Levine S.
      • Pokornowski K.
      • Yu C.F.
      • et al.
      Entecavir resistance is rare in nucleoside naïve patients with hepatitis B.
      ,
      • Tenney D.J.
      • Rose R.E.
      • Baldick C.J.
      • Pokornowski K.A.
      • Eggers B.J.
      • Fang J.
      • et al.
      Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy.
      ,
      • Sherman M.
      • Yurdaydin C.
      • Simsek H.
      • Silva M.
      • Liaw Y.-F.
      • Rustgi V.K.
      • et al.
      Entecavir therapy for lamivudine-refractory chronic hepatitis B: improved virologic, biochemical, and serology outcomes through 96 weeks.
      ]. The safety profile of entecavir is similar to that of lamivudine. Based on adult studies, entecavir has been approved by the FDA for treatment of adolescents aged 16 years or older. The recommended dose is 0.5 mg once daily for nucleoside-naïve patients and 1 mg/day for lamivudine-resistant patients. A phase III clinical trial in children as young as 2 years old is underway [

      Bristol-Myers Squibb. A Phase III Study of the Safety and Efficacy of Entecavir in Pediatric Patients With Chronic HBV-Infection. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 – [cited 18.09.11]. Available from: http://clinicaltrials.gov/show/NCT01079806 NLM Identifier: NCT01079806.

      ].

      New drugs

      Telbivudine is an L-nucleoside analogue with a potent antiviral activity and a safety profile similar to lamivudine (although myopathy and peripheral neuropathy were reported in adults) [
      • Liaw Y.F.
      • Gane E.
      • Leung N.
      • Zeuzem S.
      • Wang Y.
      • Lai C.L.
      • et al.
      2-year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B.
      ]. Resistance rate is lower than lamivudine but higher than adefovir. For such a reason, telbivudine is only used in combination with other antiviral drugs. A phase I clinical trial is ongoing on children 2–18 years of age [

      Novartis Pharmaceuticals. Pharmacokinetics and Safety of Single-Dose Telbivudine in Children and Adolescents With Chronic Hepatitis B. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 – [cited 18.09.11]. Available from: http://clinicaltrials.gov/show/NCT00907894 NLM Identifier: NCT00907894.

      ].
      Tenofovir disoproxil fumarate is a nucleos(t)ide analogue originally licensed for treatment of HIV infection, which is structurally similar to adefovir and of equal antiviral activity. Nevertheless, as it proved to be less nephrotoxic than adefovir, the approved dose for adults is higher than that of adefovir (300 mg/day). For such a reason, tenofovir was shown to have a greater antiviral activity than adefovir in clinical trials (undetectable HBV DNA in 76% of patients vs. 13% of adefovir-receiving subjects after 48 weeks of treatment) [
      • Marcellin P.
      • Heathcote E.J.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
      ]. After three years of treatment, 72% of HBeAg-positive and 87% of HBeAg-negative patients have HBV DNA levels <400 copies/ml [
      • Heathcote E.J.
      • Marcellin P.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.
      ]. The safety profile of tenofovir is similar to that of adefovir, although associated with decreased bone mineral density in children with HIV [
      • Purdy J.B.
      • Gafni R.I.
      • Reynolds J.C.
      • Zeichner S.
      • Hazra R.
      Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus.
      ]. No genotypic resistance to tenofovir has yet been confirmed [
      • Heathcote E.J.
      • Marcellin P.
      • Buti M.
      • Gane E.
      • de Man R.A.
      • Krastev Z.
      • et al.
      Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B.
      ,
      • Snow-Lampart A.
      • Chappell B.
      • Curtis M.
      • Zhu Y.
      • Myrick F.
      • Schawalder J.
      • et al.
      No resistance to tenofovir disoproxil fumarate detected after up to 144 weeks of therapy in patients monoinfected with chronic hepatitis B virus.
      ]. Tenofovir is currently used to treat HIV infection in children, and it proved to be well tolerated in phase I studies conducted in patients 4–18 years of age [
      • Hazra R.
      • Balis F.M.
      • Tullio A.N.
      • DeCarlo E.
      • Worrell C.J.
      • Steinberg S.M.
      • et al.
      Single-dose and steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virus-infected children.
      ,
      • Bouazza N.
      • Urien S.
      • Hirt D.
      • Frange P.
      • Rey E.
      • Benaboud S.
      • et al.
      Population pharmacokinetics of tenofovir in HIV-1 infected pediatric patients.
      ]. As there is no preparation suitable for young children, a phase III trial is ongoing on 12–17 year old CHB patients [

      Gilead Sciences. Evaluation of Tenofovir Disoproxil Fumarate in Adolescents With Chronic Hepatitis B Infection. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000 – [cited 18.09.11]. Available from: http://clinicaltrials.gov/show/NCT00734162 NLM Identifier: NCT00734162.

      ].

      Proposition of a treatment scheme

      Outside clinical trials, until new drugs are licensed for pediatric patients, IFNα is still the drug of choice, unless decompensated cirrhosis is present. The impossibility of developing a genotypic resistance against such a drug is a big advantage, even though adverse effects are more pronounced and a clear benefit on the long-term period remains to be confirmed. Furthermore, IFNα is the only treatment licensed for treating children younger than 3 years of age, although patients in this age group requiring treatment, are extremely rare. Currently available nucleos(t)ide analogues are second-line therapies, as the risk of emergence of resistant mutant strains is high. In adolescents older than 16 years of age, entecavir is the best choice, as resistance is less likely. Such a risk is higher with both lamivudine and adefovir, the latter being preferable in children aged 12–15 years. The use of lamivudine is currently limited to young children unresponsive to IFNα, in special populations (co-infection with HIV, transplant recipients or patients with HBV-related glomerulonephritis) or to prevent reactivation in children receiving immunosuppressive therapies. Combination therapy is promising, but further data are needed in children.
      Newer drugs such as PegIFN and tenofovir are extremely promising and their licensing for children could change management of pediatric CHB. As the emergence of resistant mutant strains is becoming a major public health problem, pediatric practitioners should refrain from treating children who are not likely to benefit from a licensed therapy and consider waiting for safer and more effective drugs made available through clinical trials or future market approval.

      Conclusions

      A dramatic reduction of pediatric HBV infection prevalence has been observed in countries where global immunization programs have been implemented. Nevertheless, an important number of children are still infected every year. Prevention and management of breakthrough infection, along with a better identification of children at higher risk for disease progression and complications, are the current challenges.
      Overall, management of pediatric patients with CHB is satisfactory, but hampered by a chronic delay in licensing new drugs as compared to adults. As the approval by regulatory agencies is based on the completion of appropriate clinical trials, studies on treatments that, in adults, have already been proved safe and more effective than available drugs should be conducted without undue delays. The current (2007) European regulation on medicines for children offers the appropriate regulatory framework to speed up this process.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      References

      1. World Health Organization. Hepatitis B [Internet]. WHO Website. 2008 [cited 25.10.11]; Available from: http://www.who.int/mediacentre/factsheets/fs204/en/index.html.

        • Lavanchy D.
        • Hepatitis B.
        Virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures.
        J Viral Hepat. 2004; 11: 97-107
        • Goldstein S.T.
        • Zhou F.
        • Hadler S.C.
        • Bell B.P.
        • Mast E.E.
        • Margolis H.S.
        A mathematical model to estimate global hepatitis B disease burden and vaccination impact.
        Int J Epidemiol. 2005; 34: 1329-1339
        • McMahon B.J.
        The natural history of chronic hepatitis B virus infection.
        Hepatology. 2009; 49: S45-S55
        • Kidd-Ljunggren K.
        • Holmberg A.
        • Bläckberg J.
        • Lindqvist B.
        High levels of hepatitis B virus DNA in body fluids from chronic carriers.
        J Hosp Infect. 2006; 64: 352-357
        • Weinbaum C.M.
        • Williams I.
        • Mast E.E.
        • Wang S.A.
        • Finelli L.
        • Wasley A.
        • et al.
        Recommendations for identification and public health management of persons with chronic hepatitis B virus infection.
        MMWR Recomm Rep. 2008; 57: 1-20
        • Mast E.E.
        • Margolis H.S.
        • Fiore A.E.
        • Brink E.W.
        • Goldstein S.T.
        • Wang S.A.
        • et al.
        A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States – recommendations of the advisory committee on immunization practices (ACIP) Part 1: Immunization of infants, children, and adolescents.
        MMWR Recomm Rep. 2005; 54: 1-23
        • Sokal E.M.
        • Van Collie O.
        • Buts J.P.
        Horizontal transmission of hepatitis B from children to adoptive parents.
        Arch Dis Child. 1995; 72: 191
        • Martin A.
        • Moyes C.
        • Lucas C.
        • Milne A.
        Hepatitis B infection in households of HBsAg positive New Zealand children.
        N Z Med J. 1996; 109: 463-465
      2. Centers for Disease Control and Prevention CDC. Vaccination coverage among children in kindergarten--United States, 2009-10 school year. MMWR Morb Mortal Wkly Rep 2011;60:700-704. .

        • Bartlett L.
        • Kanellos-Sutton M.
        • van Wylick R.
        Immunization rates in a canadian juvenile corrections facility.
        J Adolesc Health. 2008; 43: 609-611
        • Sneller V.P.
        • Fishbein D.B.
        • Weinbaum C.M.
        • Lombard A.
        • Murray P.
        • McLaurin J.A.
        • et al.
        Vaccinating adolescents in high-risk settings: lessons learned from experiences with hepatitis b vaccine.
        Pediatrics. 2008; 121: S55-S62
        • McMahon B.J.
        • Alward W.L.
        • Hall D.B.
        • Heyward W.L.
        • Bender T.R.
        • Francis D.P.
        • et al.
        Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state.
        J Infect Dis. 1985; 151: 599-603
        • Tassopoulos N.C.
        • Papaevangelou G.J.
        • Sjogren M.H.
        • Roumeliotou-Karayannis A.
        • Gerin J.L.
        • Purcell R.H.
        Natural history of acute hepatitis B surface antigen-positive hepatitis in Greek adults.
        Gastroenterology. 1987; 92: 1844-1850
      3. World Health Organization. Hepatitis B vaccines - WHO position paper. Weekly epidemiological record 2009;89:405-420.

        • Chen H.-L.
        • Lin L.-H.
        • Hu F.-C.
        • Lee J.-T.
        • Lin W.-T.
        • Yang Y.-J.
        • et al.
        Effects of maternal screening and universal immunization to prevent mother-to-infant transmission of HBV.
        Gastroenterology. 2011; https://doi.org/10.1053/j.gastro.2011.12.035
      4. Lee C, Gong Y, Brok J, Boxall EH, Gluud C. Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers. Cochrane Database Syst Rev 2006;Issue 2. Art. No.: CD004790. http://dx.doi.org/10.1002/14651858.CD004790.pub2.

        • Chang M.H.
        • Lee C.Y.
        • Chen D.S.
        • Hsu H.C.
        • Lai M.Y.
        Fulminant hepatitis in children in Taiwan: the important role of hepatitis B virus.
        J Pediatr. 1987; 111: 34-39
        • Chen H.-L.
        • Chang C.-J.
        • Kong M.-S.
        • Huang F.-C.
        • Lee H.-C.
        • Lin C.-C.
        • et al.
        Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination.
        Hepatology. 2004; 39: 58-63
        • Vanclaire J.
        • Cornu C.
        • Sokal E.M.
        Fulminant hepatitis B in an infant born to a hepatitis Be antibody positive, DNA negative carrier.
        Arch Dis Child. 1991; 66: 983-985
        • Wang Z.
        • Zhang J.
        • Yang H.
        • Li X.
        • Wen S.
        • Guo Y.
        • et al.
        Quantitative analysis of HBV DNA level and HBeAg titer in hepatitis B surface antigen positive mothers and their babies: HBeAg passage through the placenta and the rate of decay in babies.
        J Med Virol. 2003; 71: 360-366
        • Wen W.-H.
        • Chen H.-L.
        • Ni Y.-H.
        • Hsu H.-Y.
        • Kao J.-H.
        • Hu F.-C.
        • et al.
        Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization.
        Hepatology. 2011; 53: 429-436
        • McMahon B.J.
        • Bruden D.L.
        • Petersen K.M.
        • Bulkow L.R.
        • Parkinson A.J.
        • Nainan O.
        • et al.
        Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up.
        Ann Intern Med. 2005; 142: 333-341
        • Hsu H.-Y.
        • Chang M.-H.
        • Ni Y.-H.
        • Chiang C.-L.
        • Chen H.-L.
        • Wu J.-F.
        • et al.
        No increase in prevalence of hepatitis B surface antigen mutant in a population of children and adolescents who were fully covered by universal infant immunization.
        J Infect Dis. 2010; 201: 1192-1200
        • Xu D.-Z.
        • Yan Y.-P.
        • Choi B.C.K.
        • Xu J.-Q.
        • Men K.
        • Zhang J.-X.
        • et al.
        Risk factors and mechanism of transplacental transmission of hepatitis B virus: a case–control study.
        J Med Virol. 2002; 67: 20-26
        • Yang J.
        • Zeng X.-M.
        • Men Y.-L.
        • Zhao L.-S.
        Elective caesarean section versus vaginal delivery for preventing mother to child transmission of hepatitis B virus – a systematic review.
        Virol J. 2008; 5: 100
        • Bzowej N.H.
        • Hepatitis B.
        Therapy in pregnancy.
        Curr Hepatitis Rep. 2010; 9: 197-204
        • Xu W.M.
        • Cui Y.T.
        • Wang L.
        • Yang H.
        • Liang Z.Q.
        • Li X.M.
        • et al.
        Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study.
        J Viral Hepat. 2009; 16: 94-103
        • Shi Z.
        • Yang Y.
        • Ma L.
        • Li X.
        • Schreiber A.
        Lamivudine in late pregnancy to interrupt in utero transmission of hepatitis B virus: a systematic review and meta-analysis.
        Obstet Gynecol. 2010; 116: 147-159
        • Han G.-R.
        • Cao M.-K.
        • Zhao W.
        • Jiang H.-X.
        • Wang C.-M.
        • Bai S.-F.
        • et al.
        A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.
        J Hepatol. 2011; 55: 1215-1221
      5. World Health Organization. Hepatitis B and breastfeeding. World Health Organization. J Int Assoc Physicians AIDS Care 1998;4:20-21.

        • Shi Z.
        • Yang Y.
        • Wang H.
        • Ma L.
        • Schreiber A.
        • Li X.
        • et al.
        Breastfeeding of newborns by mothers carrying hepatitis B virus: a meta-analysis and systematic review.
        Arch Pediatr Adolesc Med. 2011; 165: 837-846
        • Petrova M.
        Breastfeeding and chronic HBV infection: clinical and social implications.
        World J Gastroenterol. 2010; 16: 5042-5046
        • National Center for Immunization and Respiratory Diseases
        General recommendations on immunization – recommendations of the Advisory Committee on Immunization Practices (ACIP).
        MMWR Recomm Rep. 2011; 60: 1-64
        • World Health Organization
        Hepatitis B vaccines: WHO position paper—recommendations.
        Vaccine. 2010; 28: 589-590
        • World Health Organization
        Expanded programme on immunization. Global Advisory Group–Part I.
        Wkly Epidemiol Rec. 1992; 67: 11-15
        • World Health Organization
        Global routine vaccination coverage, 2010.
        Wkly Epidemiol Rec. 2011; 86: 509-513
        • Luo Z.
        • Li L.
        • Ruan B.
        Impact of the implementation of a vaccination strategy on hepatitis B virus infections in China over a 20-year period.
        Int J Infect Dis. 2012; 16: e82-8
        • Chien Y.C.
        Nationwide hepatitis B Vaccination program in Taiwan: effectiveness in the 20 years after it was launched.
        Epidemiol Rev. 2006; 28: 126-135
        • Zanetti A.R.
        • van Damme P.
        • Shouval D.
        The global impact of vaccination against hepatitis B: a historical overview.
        Vaccine. 2008; 26: 6266-6273
        • Liang X.
        • Bi S.
        • Yang W.
        • Wang L.
        • Cui G.
        • Cui F.
        • et al.
        Epidemiological serosurvey of Hepatitis B in China—declining HBV prevalence due to Hepatitis B vaccination.
        Vaccine. 2009; 27: 6550-6557
        • Ni Y.-H.
        • Huang L.M.
        • Chang M.-H.
        • Yen C.J.
        • Lu C.Y.
        • You S.-L.
        • et al.
        Two decades of universal hepatitis B vaccination in Taiwan: impact and implication for future strategies.
        Gastroenterology. 2007; 132: 1287-1293
        • Chen S.-M.
        • Kung C.-M.
        • Yang W.-J.
        • Wang H.-L.
        Efficacy of the nationwide hepatitis B infant vaccination program in Taiwan.
        J Clin Virol. 2011; 52: 11-16
        • Zhang L.
        • Xu A.
        • Yan B.
        • Song L.
        • Li M.
        • Xiao Z.
        • et al.
        A significant reduction in hepatitis B virus infection among the children of Shandong Province, China: the effect of 15 years of universal infant hepatitis B vaccination.
        Int J Infect Dis. 2010; 14: e483-e488
        • Ioannou G.N.
        • Hepatitis B.
        Virus in the United States: infection, exposure, and immunity rates in a nationally representative survey.
        Ann Intern Med. 2011; 154: 319-328
        • Stadler L.P.
        • Mezoff A.G.
        • Staat M.A.
        Hepatitis B virus screening for internationally adopted children.
        Pediatrics. 2008; 122: 1223-1228
        • Cai W.
        • Poethko-Müller C.
        • Hamouda O.
        • Radun D.
        Hepatitis B virus infections among children and adolescents in Germany.
        Pediatr Infect Dis J. 2011; 30: 19-24
        • Jack A.D.
        • Hall A.J.
        • Maine N.
        • Mendy M.
        • Whittle H.C.
        What level of hepatitis B antibody is protective?.
        J Infect Dis. 1999; 179: 489-492
      6. American Academy of Pediatrics. Medical evaluation of internationally adopted children for infectious diseases. In: Pickering L, Baker C, Long S, MacMillan J, editors. Red book: 2009 report of the Committee on Infectious Diseases. Elk Grove Village, IL: American Academy of Pediatrics; 2009. p. 177–184.

        • Liu H.F.
        • Sokal E.
        • Goubau P.
        Wide variety of genotypes and geographic origins of hepatitis B virus in Belgian children.
        J Pediatr Gastroenterol Nutr. 2001; 32: 274-277
        • Ni Y.-H.
        • Chang M.-H.
        • Wang K.-J.
        • Hsu H.-Y.
        • Chen H.-L.
        • Kao J.-H.
        • et al.
        Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma.
        Gastroenterology. 2004; 127: 1733-1738
        • Lin C.-L.
        • Kao J.-H.
        The clinical implications of hepatitis B virus genotype: recent advances.
        J Gastroenterol Hepatol. 2011; 26: 123-130
        • Iorio R.
        • Giannattasio A.
        • Cirillo F.D.
        • Cirillo F.
        • Alessandro L.
        • Vegnente A.
        Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
        Clin Infect Dis. 2007; 45: 943-949
        • Milich D.R.
        • Jones J.E.
        • Hughes J.L.
        • Price J.
        • Raney A.K.
        • McLachlan A.
        Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?.
        Proc Natl Acad Sci U S A. 1990; 87: 6599-6603
        • Chen M.T.
        • Billaud J.-N.
        • Sällberg M.
        • Guidotti L.G.
        • Chisari F.V.
        • Jones J.
        • et al.
        A function of the hepatitis B virus pre-core protein is to regulate the immune response to the core antigen.
        Proc Natl Acad Sci U S A. 2004; 101: 14913-14918
        • Milich D.
        Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection.
        Hepatology. 2003; 38: 1075-1086
        • Chen M.
        • Sällberg M.
        • Hughes J.
        • Jones J.
        • Guidotti L.G.
        • Chisari F.V.
        • et al.
        Immune tolerance split between hepatitis B virus pre-core and core proteins.
        J Virol. 2005; 79: 3016-3027
        • Bortolotti F.
        • Guido M.
        • Bartolacci S.
        • Cadrobbi P.
        • Crivellaro C.
        • Noventa F.
        • et al.
        Chronic hepatitis B in children after e antigen seroclearance. final report of a 29-year longitudinal study.
        Hepatology. 2006; 43: 556-562
        • Chu C.-M.
        • Yeh C.-T.
        • Lee C.-S.
        • Sheen I.-S.
        • Liaw Y.-F.
        Pre-core stop mutant in HBeAg-positive patients with chronic hepatitis B: clinical characteristics and correlation with the course of HBeAg-to-anti-HBe seroconversion.
        J Clin Microbiol. 2002; 40: 16-21
        • Frelin L.
        • Wahlstrom T.
        • Tucker A.E.
        • Jones J.
        • Hughes J.
        • Lee B.O.
        • et al.
        A mechanism to explain the selection of the hepatitis e antigen-negative mutant during chronic hepatitis B virus infection.
        J Virol. 2009; 83: 1379-1392
        • Tseng Y.-R.
        • Wu J.-F.
        • Ni Y.-H.
        • Chen H.-L.
        • Chen C.-C.
        • Wen W.-H.
        • et al.
        Long-term effect of maternal HBeAg on delayed HBeAg seroconversion in offspring with chronic hepatitis B infection.
        Liver Int. 2011; 31: 1373-1380
        • Marx G.
        • Martin S.R.
        • Chicoine J.-F.
        • Alvarez F.
        Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.
        J Infect Dis. 2002; 186: 295-301
        • Ni Y.-H.
        • Chang M.-H.
        • Chen P.-J.
        • Tsai K.-S.
        • Hsu H.-Y.
        • Chen H.-L.
        • et al.
        Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion.
        Gastroenterology. 2007; 132: 2340-2345
        • Wu J.-F.
        • Su Y.-R.
        • Chen C.-H.
        • Chen H.-L.
        • Ni Y.-H.
        • Hsu H.-Y.
        • et al.
        Predictive effect of serial serum alanine aminotransferase levels on spontaneous HBeAg seroconversion in chronic genotype B and C HBV–infected children.
        J Pediatr Gastroenterol Nutr. 2012; 54: 97-100
        • Chu C.M.
        • Liaw Y.F.
        Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion.
        J Viral Hepat. 2007; 14: 147-152
        • Kao J.H.
        • Chen P.J.
        • Lai M.Y.
        • Chen D.S.
        Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.
        Gastroenterology. 2000; 118: 554-559
        • Chu C.-J.
        • Hussain M.
        • Lok A.S.
        Hepatitis B virus genotype B is associated with earlier hbeag seroconversion compared with hepatitis B virus genotype C.
        Gastroenterology. 2002; 122: 1756-1762
        • Livingston S.E.
        • Simonetti J.P.
        • Bulkow L.R.
        • Homan C.E.
        • Snowball M.M.
        • Cagle H.H.
        • et al.
        Clearance of hepatitis B e Antigen in patients with chronic hepatitis B and genotypes A, B, C, D, and F.
        Gastroenterology. 2007; 133: 1452-1457
        • Chang M.
        • Hsu H.
        • Hsu H.
        • Ni Y.
        • Chen J.
        • Chen D.
        The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age.
        Hepatology. 1995; 22: 1387-1392
        • Wen W.-H.
        • Chang M.-H.
        • Hsu H.-Y.
        • Ni Y.-H.
        • Chen H.-L.
        The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection.
        J Pediatr. 2004; 144: 397-399
        • Chang M.H.
        • You S.L.
        • Chen C.J.
        • Liu C.J.
        • Lee C.M.
        • Lin S.M.
        • et al.
        Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: A 20-year follow-up study.
        JNCI J Natl Cancer Inst. 2009; 101: 1348-1355
        • Iloeje U.H.
        • Yang H.-I.
        • Su J.
        • Jen C.-L.
        • You S.-L.
        • Chen C.-J.
        Predicting cirrhosis risk based on the level of circulating hepatitis B viral load.
        Gastroenterology. 2006; 130: 678-686
        • Chen C.-J.
        • Yang H.-I.
        • Su J.
        • Jen C.-L.
        • You S.-L.
        • Lu S.-N.
        • et al.
        Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level.
        JAMA. 2006; 295: 65-73
        • Sánchez-Tapias J.M.
        • Costa J.
        • Mas A.
        • Bruguera M.
        • Rodés J.
        Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients.
        Gastroenterology. 2002; 123: 1848-1856
        • Yu M.W.
        • Yeh S.H.
        • Chen P.J.
        • Liaw Y.F.
        • Lin C.L.
        • Liu C.J.
        • et al.
        Hepatitis B Virus Genotype and DNA Level and Hepatocellular Carcinoma: A Prospective Study in Men.
        JNCI J Natl Cancer Inst. 2005; 97: 265-272
        • Livingston S.E.
        • Simonetti J.P.
        • McMahon B.J.
        • Bulkow L.R.
        • Hurlburt K.J.
        • Homan C.E.
        • et al.
        Hepatitis B virus genotypes in Alaska native people with hepatocellular carcinoma: preponderance of genotype F.
        J Infect Dis. 2007; 195: 5-11
        • Yu M.W.
        • Chang H.C.
        • Liaw Y.F.
        • Lin S.M.
        • Lee S.D.
        • Liu C.J.
        • et al.
        Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives.
        J Natl Cancer Inst. 2000; 92: 1159-1164
        • Zhang H.
        • Zhai Y.
        • Hu Z.
        • Wu C.
        • Qian J.
        • Jia W.
        • et al.
        Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers.
        Nat Genet. 2010; 42: 767-770
        • Hsu Y.-S.
        • Chien R.-N.
        • Yeh C.-T.
        • Sheen I.-S.
        • Chiou H.-Y.
        • Chu C.-M.
        • et al.
        Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.
        Hepatology. 2002; 35: 1522-1527
        • Fattovich G.
        • Bortolotti F.
        • Donato F.
        Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors.
        J Hepatol. 2008; 48: 335-352
        • Ribeiro R.M.
        • Germanidis G.
        • Powers K.A.
        • Pellegrin B.
        • Nikolaidis P.
        • Perelson A.S.
        • et al.
        Hepatitis B virus kinetics under antiviral therapy sheds light on differences in hepatitis B e antigen positive and negative infections.
        J Infect Dis. 2010; 202: 1309-1318
        • Arase Y.
        • Ikeda K.
        • Suzuki F.
        • Suzuki Y.
        • Saitoh S.
        • Kobayashi M.
        • et al.
        Long-term outcome after hepatitis B surface antigen seroclearance in patients with chronic hepatitis B.
        Am J Med. 2006; 119: 71e9-71e16
        • Lok A.S.F.
        • McMahon B.J.
        Chronic hepatitis B: update 2009.
        Hepatology. 2009; 50: 661-662
        • European Association for the Study of the Liver
        EASL clinical practice guidelines: management of chronic hepatitis B.
        J Hepatol. 2009; 50: 227-242
        • Shah U.
        • Kelly D.
        • Chang M.-H.
        • Fujisawa T.
        • Heller S.
        • González-Peralta R.P.
        • et al.
        Management of chronic hepatitis B in children.
        J Pediatr Gastroenterol Nutr. 2009; 48: 399-404
        • Jonas M.M.
        • Block J.M.
        • Haber B.A.
        • Karpen S.J.
        • London W.T.
        • Murray K.F.
        • et al.
        Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options.
        Hepatology. 2010; 52: 2192-2205
        • Simonetti J.
        • Bulkow L.
        • McMahon B.J.
        • Homan C.
        • Snowball M.
        • Negus S.
        • et al.
        Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus.
        Hepatology. 2010; 51: 1531-1537
        • Haber B.A.
        • Block J.M.
        • Jonas M.M.
        • Karpen S.J.
        • London W.T.
        • McMahon B.J.
        • et al.
        Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B.
        Pediatrics. 2009; 124: e1007-e1013
        • Fattovich G.
        • Olivari N.
        • Pasino M.
        • D’Onofrio M.
        • Martone E.
        • Donato F.
        Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years.
        Gut. 2008; 57: 84-90
        • Sokal E.M.
        • Conjeevaram H.S.
        • Roberts E.A.
        • Alvarez F.
        • Bern E.M.
        • Goyens P.
        • et al.
        Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.
        Gastroenterology. 1998; 114: 988-995
        • Jonas M.M.
        • Kelly D.A.
        • Mizerski J.
        • Badia I.B.
        • Areias J.A.
        • Schwarz K.B.
        • et al.
        Clinical trial of lamivudine in children with chronic hepatitis B.
        N Engl J Med. 2002; 346: 1706-1713
        • Zoulim F.
        • Locarnini S.
        Hepatitis B virus resistance to nucleos(t)ide analogues.
        Gastroenterology. 2009; 137: 1593-1608
        • Jonas M.M.
        • Kelly D.
        • Pollack H.
        • Mizerski J.
        • Sorbel J.
        • Frederick D.
        • et al.
        Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B.
        Hepatology. 2008; 47: 1863-1871
        • Schwimmer J.B.
        • Dunn W.
        • Norman G.J.
        • Pardee P.E.
        • Middleton M.S.
        • Kerkar N.
        • et al.
        SAFETY study: alanine aminotransferase cut-off values are set too high for reliable detection of pediatric chronic liver disease.
        Gastroenterology. 2010; 138: 1357-1364
        • Hsu E.K.
        • Murray K.F.
        Hepatitis B and C in children.
        Nature Clin Prac Gastroenterol Hepatol. 2008; 5: 311-320
        • Hom X.
        • Little N.R.
        • Gardner S.D.
        • Jonas M.M.
        Predictors of virologic response to lamivudine treatment in children with chronic hepatitis B infection.
        Pediatr Infect Dis J. 2004; 23: 441-445
        • Shapira R.
        • Mor E.
        • Bar-Nathan N.
        • Sokal E.M.
        • Tur-Kaspa R.
        • Dinari G.
        • et al.
        Efficacy of lamivudine for the treatment of hepatitis B virus infection after liver transplantation in children.
        Transplantation. 2001; 72: 333-336
        • Cholongitas E.
        • Papatheodoridis G.V.
        • Burroughs A.K.
        Liver grafts from anti-hepatitis B core positive donors: a systematic review.
        J Hepatol. 2010; 52: 272-279
        • Perrillo R.
        • Hepatitis B.
        Virus prevention strategies for antibody to hepatitis B core antigen-positive liver donation: a survey of North American, European, and Asian-Pacific transplant programs.
        Liver Transpl. 2009; 15: 223-232
        • Katz L.H.
        • Fraser A.
        • Gafter-Gvili A.
        • Leibovici L.
        • Tur-Kaspa R.
        Lamivudine prevents reactivation of hepatitis B and reduces mortality in immunosuppressed patients: systematic review and meta-analysis.
        J Viral Hepat. 2008; 15: 89-102
        • Wai C.T.
        • Chu C.-J.
        • Hussain M.
        • Lok A.S.F.
        HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.
        Hepatology. 2002; 36: 1425-1430
        • Erhardt A.
        Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D.
        Gut. 2005; 54: 1009-1013
        • Flink H.J.
        • van Zonneveld M.
        • Hansen B.E.
        • de Man R.A.
        • Schalm S.W.
        • Janssen H.L.A.
        • et al.
        Treatment with peg-interferon alpha-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype.
        Am J Gastroenterol. 2006; 101: 297-303
        • Raimondi S.
        • Maisonneuve P.
        • Bruno S.
        • Mondelli M.U.
        Is response to antiviral treatment influenced by hepatitis B virus genotype?.
        J Hepatol. 2010; 52: 441-449
        • Kobak G.E.
        • MacKenzie T.
        • Sokol R.J.
        • Narkewicz M.R.
        Interferon treatment for chronic hepatitis B: enhanced response in children 5 years old or younger.
        J Pediatr. 2004; 145: 340-345
        • Bortolotti F.
        • Jara P.
        • Barbera C.
        • Gregorio G.V.
        • Vegnente A.
        • Zancan L.
        • et al.
        Long-term effect of alpha interferon in children with chronic hepatitis B.
        Gut. 2000; 46: 715-718
        • Hsu H.-Y.
        • Tsai H.-Y.
        • Wu T.-C.
        • Chiang C.-L.
        • Ni Y.-H.
        • Chen P.-J.
        • et al.
        Interferon-α treatment in children and young adults with chronic hepatitis B: a long-term follow-up study in Taiwan.
        Liver Int. 2008; 28: 1288-1297
        • Vo Thi Diem H.
        • Bourgois A.
        • Bontems P.
        • Goyens P.
        • Buts J.-P.
        • Nackers F.
        • et al.
        Chronic hepatitis B infection: long-term comparison of children receiving interferon alpha and untreated controls.
        J Pediatr Gastroenterol Nutr. 2005; 40: 141-145
        • Lin S.M.
        • Yu M.L.
        • Lee C.M.
        • Chien R.N.
        • Sheen I.S.
        • Chu C.M.
        • et al.
        Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma.
        J Hepatol. 2007; 46: 45-52
        • Yang Y.F.
        • Zhao W.
        • Zhong Y.D.
        • Xia H.M.
        • Shen L.
        • Zhang N.
        Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis.
        J Viral Hepat. 2009; 16: 265-271
        • Sung J.J.Y.
        • Tsoi K.K.F.
        • Wong V.W.S.
        • Li K.C.T.
        • Chan H.L.Y.
        Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma.
        Aliment Pharmacol Ther. 2008; 28: 1067-1077