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Management of chronic hepatitis B in childhood: ESPGHAN clinical practice guidelines

Consensus of an expert panel on behalf of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition
Open AccessPublished:May 28, 2013DOI:https://doi.org/10.1016/j.jhep.2013.05.016

      Abbreviations:

      ALT (alanine aminotransferases), CHB (chronic hepatitis B), HBIG (hepatitis B immunoglobulins), HBV (hepatitis B virus), HCC (hepatocellular carcinoma), cccDNA (covalently closed circular DNA), FDA (Food and Drug Administration), IFN (interferon), NA (nucleos(t)ide analogues), PegINF (pegylated interferon), SVR (sustained virological response), ULN (upper limit of normal), VR (virologic response), WHO (World Health Organization)

      Keywords

      Introduction

      More than 360 million persons worldwide (6% of the world population) are chronically infected by the hepatitis B virus (HBV). Although the incidence of HBV infection has dramatically declined since the implementation of universal immunization programs in several countries and blood-donor screening, a significant number of children are still infected each year, often developing chronic infection and requiring appropriate follow-up [
      • Paganelli M.
      • Stephenne X.
      • Sokal E.M.
      Chronic hepatitis B in children and adolescents.
      ]. Despite a rather benign course of chronic hepatitis B (CHB) during childhood and adolescence, 3–5% and 0.01–0.03% of chronic carriers develop cirrhosis or hepatocellular carcinoma (HCC), respectively, before adulthood [
      • 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.
      ,
      • Chang M.H.
      Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems.
      ]. Such a risk for HCC rises to 9–24% when considering the whole lifetime, with an incidence of cirrhosis of 2–3% per year [
      • 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.
      ,
      • 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.
      ]. Worldwide universal vaccination remains the goal for eliminating HBV infection and its complications. Treatment of CHB in childhood has been hampered by the chronic delay in licensing new drugs for pediatric use. Safe and effective antiviral therapies are available in adults, but few are labeled for the use in children, and an accurate selection of whom to treat and the identification of the right timing for treatment are needed to optimize response and reduce the risk of antiviral resistance. Although several guidelines on the management of adult patients with CHB have been published by major international societies, the clinical approach to infected children is still evolving, and is mostly based on consensus of expert opinion [
      • 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.
      ,
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
      ,
      • 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.
      ].

      Context

      Epidemiology and prevention

      Since the WHO recommended global immunization programs for HBV in 1991, the prevalence of HBV infection has declined worldwide [
      • 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.
      ,
      • 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.
      ]. Although among children born in Western Europe and North America HBsAg-positivity is rare, pediatricians are confronted with an increasing number of children adopted from higher prevalence countries, 2–5% of whom are still infected with HBV and often carry HBV genotypes which expose them to a higher risk of complications [
      • Paganelli M.
      • Stephenne X.
      • Sokal E.M.
      Chronic hepatitis B in children and adolescents.
      ,
      • 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.
      ].
      In countries where donor screening and blood testing have been implemented, the current risk of acquiring HBV infection after blood transfusion is estimated at 1 in 500,000 per unit exposure [
      • Zou S.
      • Stramer S.L.
      • Notari E.P.
      • Kuhns M.C.
      • Krysztof D.
      • Musavi F.
      • et al.
      Current incidence and residual risk of hepatitis B infection among blood donors in the United States.
      ,
      • Perkins H.A.
      • Busch M.P.
      Transfusion-associated infections: 50 years of relentless challenges and remarkable progress.
      ]. Nevertheless, as HBV nosocomial transmission is still a critical problem, vaccination status of children needs to be checked regularly and all preventive measures have to be strictly respected [
      • Dumpis U.
      • Kovalova A.
      • Jansons J.
      • Upane L.
      • Sominskaya I.
      • Michailova M.
      • et al.
      An outbreak of HBV and HCV infection in a paediatric oncology ward: epidemiological investigations and prevention of further spread.
      ].
      Mother-to-child transmission accounts for more than 50% of chronic infections in highly endemic areas. After exposure, the risk of chronicity is higher for newborns (90%), infants and children younger than 5 years (25–30%) than for adolescents or 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.
      ].
      Vaccination is the most effective measure to prevent hepatitis B transmission. In highly endemic areas, it is also the most cost-effective medical intervention, offering the higher benefit-cost ratio, whereas in low-endemicity countries, such cost-effectiveness is not as clear [
      • Beutels P.
      • Edmunds W.J.
      • Antoñanzas F.
      • De Wit G.A.
      • Evans D.
      • Feilden R.
      • et al.
      Economic evaluation of vaccination programmes: a consensus statement focusing on viral hepatitis.
      ,
      • Kim S.-Y.
      • Salomon J.A.
      • Goldie S.J.
      Economic evaluation of hepatitis B vaccination in low-income countries: using cost-effectiveness affordability curves.
      ,
      • Hung H.-F.
      • Chen T.H.-H.
      Probabilistic cost-effectiveness analysis of the long-term effect of universal hepatitis B vaccination: an experience from Taiwan with high hepatitis B virus infection and hepatitis B e antigen positive prevalence.
      ,
      • Siddiqui M.R.
      • Gay N.
      • Edmunds W.J.
      • Ramsay M.
      Economic evaluation of infant and adolescent hepatitis B vaccination in the UK.
      ]. Recombinant vaccine induces a seroprotective response (anti-HBs ⩾10 mIU/ml) in about 95% of subjects vaccinated with three doses [
      • 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.
      ,
      • World Health Organization
      Hepatitis B vaccines – WHO position paper.
      ]. The first dose of monovalent vaccine should be administered intramuscularly within 24 hours of birth, and should be followed by 2 or 3 doses (monovalent or combined) with a minimum interval of 4 weeks (A1) [
      • World Health Organization
      Hepatitis B vaccines – WHO position paper.
      ]. Preterm infants weighting <2000 g should receive 3 doses after the birth dose (B1) [
      • World Health Organization
      Hepatitis B vaccines – WHO position paper.
      ,
      • Losonsky G.A.
      • Wasserman S.S.
      • Stephens I.
      • Mahoney F.
      • Armstrong P.
      • Gumpper K.
      • et al.
      Hepatitis B vaccination of premature infants: a reassessment of current recommendations for delayed immunization.
      ]. Postvaccination testing for a protective concentration of anti-HBs is recommended only for high-risk populations (infants born to HBsAg-positive mothers and HIV-infected or other immunocompromised subjects), and should be performed 1–2 months after the end of the vaccination schedule (A1) [
      • World Health Organization
      Hepatitis B vaccines – WHO position paper.
      ]. Revaccination with further 3 doses induces protective anti-HBs response in the majority of non-responders [
      • Cheng K.F.
      • Chang M.H.
      • Lee C.Y.
      • Huang L.M.
      • Hsu H.Y.
      • Lee P.I.
      • et al.
      Response to supplementary vaccination with recombinant or plasma hepatitis B vaccine in healthy non-responding children.
      ,
      • Jafarzadeh A.
      • Zarei S.
      • Shokri F.
      Low dose revaccination induces robust protective anti-HBs antibody response in the majority of healthy non-responder neonates.
      ]. Immunocompromised subjects should be tested annually and revaccinated if anti-HBs <10 mIU/ml (C1) [
      • European Consensus Group on Hepatitis B Immunity
      Are booster immunisations needed for lifelong hepatitis B immunity?.
      ]. Although anti-HBs levels have been shown to decrease over time, long-lasting protection has been observed in vaccinated subjects with undetectable anti-HBs, and at present there is no clear evidence for recommending the administration of a booster dose in immunocompetent individuals [
      • Lu C.Y.
      • Ni Y.H.
      • Chiang B.L.
      • Chen P.J.
      • Chang M.H.
      • Chang L.Y.
      • et al.
      Humoral and cellular immune responses to a hepatitis B vaccine booster 15–18 years after neonatal immunization.
      ,
      • van der Sande M.A.
      • Waight P.
      • Mendy M.
      • Rayco-Solon P.
      • Hutt P.
      • Fulford T.
      • et al.
      Long-term protection against carriage of hepatitis B virus after infant vaccination.
      ]. Testing for coeliac disease, HIV or other causes of immune deficiency might be advisable for non-responders (C2) [
      • Leonardi S.
      • Spina M.
      • Spicuzza L.
      • Rotolo N.
      • La Rosa M.
      Hepatitis B vaccination failure in celiac disease: is there a need to reassess current immunization strategies?.
      ,
      • Vajro P.
      • Paolella G.
      • Nobili V.
      Children unresponsive to hepatitis B virus vaccination also need celiac disease testing.
      ,
      • Whitaker J.A.
      • Rouphael N.G.
      • Edupuganti S.
      • Lai L.
      • Mulligan M.J.
      Strategies to increase responsiveness to hepatitis B vaccination in adults with HIV-1.
      ].
      Vaccine failure and mother-to-child transmission of hepatitis B affect 17% of infants born to HBeAg-positive mothers [
      • 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.
      ]. The high viral load related to HBeAg-positivity seems to be the most important factor for breakthrough infection [
      • 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.
      ]. Moreover, when the mother is infected by genotype C HBV, intrauterine infection may occur before vaccination can be administred, in addition to hyporesponsivness to vaccination [
      • 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.
      ]. When the mother is a chronic carrier, vaccination at birth is not sufficient to avoid vertical transmission, and concurrent intramuscular administration of 0.5 ml of hepatitis B immunoglobulin (HBIG) is recommended to give immediate passive immunity to the newborn [
      • World Health Organization
      Hepatitis B vaccines – WHO position paper.
      ,
      • 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.
      ]. Administration of both the vaccine and HBIG to newborns of HBeAg-positive mothers within 12–24 h of birth allows the achievement of 90% protection rate (98% when mothers are HBeAg-negative), compared to vaccine alone [
      • 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.
      ,
      • World Health Organization
      Hepatitis B vaccines – WHO position paper.
      ,
      • Lee C.
      • Gong Y.
      • Brok J.
      • Boxall E.H.
      • Gluud C.
      Hepatitis B immunisation for newborn infants of hepatitis B surface antigen-positive mothers.
      ]. Administration of both vaccine and HBIG is recommended for newborns of HBeAg-positive mothers (A1). Although a clear benefit has not been shown for newborns of HBeAg-negative mothers, a reduction of the incidence of fulminant hepatitis justifies HBIG administration to all infants born of HBsAg-positive mothers [
      • 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.
      ], regardless of the maternal HBeAg status (C2). High breakthrough infection (17%) and chronicity (54%) rates have been reported in newborns of HBeAg-positive mothers despite concomitant active and passive immunization at birth [
      • 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.
      ]. As breakthrough infection rates are directly correlated to maternal viral load (as well as to HBV genotype C, high HBsAg titer, vaginal delivery, hyporesponsiveness to vaccine and vaccine escape mutants) [
      • 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.
      ,
      • 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.
      ], treatment with nucleos(t)ide analogues (NA) of highly viraemic women during the last trimester of pregnancy is currently recommended to prevent vertical transmission (B1, see below) [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
      ].
      Breastfeeding has been shown not to contribute significantly to HBV transmission from infected mothers to infants who have received active and passive immunoprophylaxis [
      • 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.
      ,
      • World Health Organization
      Hepatitis B and breastfeeding. World Health Organization.
      ]. In the absence of cracked or bleeding nipples, breastfeeding of properly immunized infants is encouraged (B2). Unlike interferon (IFN), which is not excreted in breast milk, lamivudine and tenofovir are excreted (although no data are available yet for tenofovir in humans), but the dose adsorbed by the infants is negligible compared to standard oral doses [
      • Moodley J.
      • Moodley D.
      • Pillay K.
      • Coovadia H.
      • Saba J.
      • van Leeuwen R.
      • et al.
      Pharmacokinetics and antiretroviral activity of lamivudine alone or when coadministered with zidovudine in human immunodeficiency virus type 1-infected pregnant women and their offspring.
      ,
      • Giles M.
      • Visvanathan K.
      • Sasadeusz J.
      Antiviral therapy for hepatitis B infection during pregnancy and breastfeeding.
      ]. Nevertheless, no systematic study has been conducted to evaluate the effects of nucleos(t)ide analogues (NA) absorbed from maternal milk on breastfed infants. Though there are data suggesting that breastfeeding while on lamivudine and tenofovir is safe [
      • Giles M.
      • Visvanathan K.
      • Sasadeusz J.
      Antiviral therapy for hepatitis B infection during pregnancy and breastfeeding.
      ] at present, breastfeeding cannot be recommended, and the risk of potential long-term effects on the infant should be weighed against the risk of stopping the antiviral therapy. Entecavir has not been studied in pregnant women as yet, but was shown to be excreted in breast milk in rats and to have carcinogenic potential both in mice and rats after placental transfer. No data are available yet for telbivudine.

      Natural history

      Chronic hepatitis B, defined as positivity for HBsAg for 6 months or longer, is a mild disease in childhood [
      • Paganelli M.
      • Stephenne X.
      • Sokal E.M.
      Chronic hepatitis B in children and adolescents.
      ]. Most infected children are asymptomatic, with a normal growth and a normal physical examination [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.
      • D Alessandro L.
      • Vegnente A.
      Long-term outcome in children with chronic hepatitis B: a 24-year observation period.
      ]. The great majority of perinatally infected subjects are HBeAg-positive, with high serum levels of HBV DNA and normal serum alanine aminotransferases (immunotolerant phase). Transplacental transfer of maternal HBeAg has been suggested to elicit HBe/HBcAg-specific Th cell tolerance in utero [
      • Wen W.H.
      • Chen H.L.
      • Ni Y.H.
      • Hsu H.Y.
      • Kao J.H.
      • Hu F.C.
      Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization.
      ,
      • 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 precore protein is to regulate the immune response to the core antigen.
      ,
      • Milich D.
      • Liang T.J.
      Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection.
      ]. Such mechanism could explain the different chronicity rates between neonatal and adult infection, as well as the higher chronicity rate in babies born to HBeAg-positive mothers, in whom high-level viral replication leading to large amount of HBeAg would maintain the tolerance to HBV [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • Kunz R.
      • Brozek J.
      • Alonso-Coello P.
      • et al.
      GRADE guidelines: 4. Rating the quality of evidence-study limitations (risk of bias).
      ]. This immunotolerant phase, which lasts 10–30 years, is usually marked by high viral replication and little liver damage. Nevertheless, 1.7–4.5% of children and adolescents infected at birth have cirrhosis at liver biopsy [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.
      • D 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.
      ].
      Over time, HBV DNA levels fluctuate and ALT levels rise, reflecting the histologic finding of necroinflammation of liver parenchyma. 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 increase before HBeAg clearance and may remain elevated (with flare-ups in 20% of subjects) for 6–12 months after seroconversion [
      • 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.
      ,
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.
      • D 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.
      ,
      • 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.
      ]. Most HBsAg-positive, HBeAg-negative, and anti-HBe-positive patients (i.e. those who undergo HBeAg seroconversion) are defined as inactive carriers, have absent or low viral replication (HBV DNA <2000 IU/ml) and usually inactive liver histology, with normal ALT levels. Over a long-term follow-up (24–29 years), inactive carriers with no signs of cirrhosis at seroconversion do not show disease progression, whereas 1–5% of HBeAg-positive children develop cirrhosis [
      • 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.
      ,
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.
      • D 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.
      ].
      Although the incidence of HCC in high HBV prevalence areas has been significantly reduced by global immunization programs, between 0.01% and 0.03% of children with CHB develop HCC during childhood (32 per 100,000 person-year) [
      • 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.
      ,
      • 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.
      ,
      • 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 to have undergone early seroconversion (suggesting that necroinflammation during seroconversion to anti-HBe may be severe enough to lead to cirrhosis and HCC) [
      • 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.
      ,
      • 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.
      ]. In adult patients, the long-term risk of both HCC and cirrhosis is directly correlated to serum HBV DNA levels and HBeAg positivity [
      • 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.
      ,
      • Yang H.-I.
      • Lu S.-N.
      • Liaw Y.-F.
      • You S.-L.
      • Sun C.-A.
      • Wang L.-Y.
      • et al.
      Hepatitis B e antigen and the risk of hepatocellular carcinoma.
      ]. No conclusion can be drawn from pediatric studies because of the rarity of HCC during childhood [
      • 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.
      ]. The role of viral genotype on the risk of developing HCC is still to be clarified in the pediatric population (80% of HCC are in cirrhotic genotype B children, whereas in adults, genotypes C and F are considered at increased risk) [
      • 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.
      ,
      • 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, the risk of HCC is higher in individuals with a family history of 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.
      ]. Seroconversion to anti-HBe reduces the risk of developing HCC, but 0.2% of HBeAg-negative adults and 1.6% of asymptomatic HBsAg carriers still develop HCC [
      • 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.
      ].
      A subgroup of anti-HBe-positive subjects has active viral replication with abnormal ALT levels and histologically active hepatitis (HBeAg-negative chronic hepatitis). HBeAg-negative hepatitis affects about 10% of pediatric patients, who show a more severe disease progression and have a higher incidence of HCC than HBeAg-negative patients in sustained remission [
      • 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.
      ].
      Between 7% and 25% of inactive carriers lose HBsAg and become anti-HBs-positive over a 20-year follow-up [
      • Chu C.-M.
      • Liaw Y.-F.
      HBsAg seroclearance in asymptomatic carriers of high endemic areas: appreciably high rates during a long-term follow-up.
      ]. Unfortunately, spontaneous seroconversion to anti-HBs is a rare event in childhood (0.6–1%/year) [
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.
      • D 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.
      ]. Such an event marks resolution of HBV infection, and leads to an improved liver histology. HBsAg seroclearance, if it occurs before the development of cirrhosis or HCC and in the absence of concomitant infections, has an excellent long-term prognosis [
      • 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, covalently closed circular DNA (cccDNA) persists indefinitely in hepatocytes, and low-level viral replication or reactivation upon immunosuppression is always possible. Moreover, the HBV genome may integrate in the host genome, increasing the risk of HCC development even after HBsAg seroclearance [
      • Chang M.-H.
      • Chen P.-J.
      • Chen J.-Y.
      • Lai M.-Y.
      • Hsu H.-C.
      • Lian D.-C.
      • et al.
      Hepatitis B virus integration in hepatitis B virus-related hepatocellular carcinoma in childhood.
      ,
      • Giacchino R.
      • Navone C.
      • Facco F.
      • Giambartolomei G.
      • Pontisso P.
      • Callea F.
      HBV-DNA-related hepatocellular carcinoma occurring in childhood. Report of three cases.
      ].
      As a reflection of the transcriptional activity of cccDNA, HBsAg levels decrease with age and disease progression, being higher during the immunotolerance phase, lower after seroconversion to anti-HBe, and reaching the lowest levels in inactive carriers [
      • Jang J.W.
      • Yoo S.H.
      • Kwon J.H.
      • You C.R.
      • Lee S.
      • Lee J.H.
      • et al.
      Serum hepatitis B surface antigen levels in the natural history of chronic hepatitis B infection.
      ].

      Methods

      These guidelines were developed by a panel of experts chosen by the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). Recommendations were based on evidence from existing papers published before June 2012 and, when evidence was not available, on experts’ personal experience. Evidence has been evaluated by the authors and classified as high (A), moderate (B), or low (C) quality according to the Grading of Recommendations Assessment Development and Evaluation (GRADE) system [
      • Balshem H.
      • Helfand M.
      • Schünemann H.J.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • et al.
      GRADE guidelines: 3. Rating the quality of evidence.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Kunz R.
      • Falck-Ytter Y.
      • Vist G.E.
      • Liberati A.
      • et al.
      Going from evidence to recommendations.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.
      • Kunz R.
      • Brozek J.
      • Alonso-Coello P.
      • et al.
      GRADE guidelines: 4. Rating the quality of evidence-study limitations (risk of bias).
      ]. The strength of recommendations (1: strong; 2: weak) reflects the extent to which we can be confident that the desirable effects of the intervention outweigh the undesirable effects, and is based on the balance between desirable and undesirable effects, the quality of underlying evidence, variability in values and preferences and the costs of the intervention (Table 1).
      Table 1Grading of evidence and recommendations according to the GRADE system
      • Balshem H.
      • Helfand M.
      • Schünemann H.J.
      • Oxman A.D.
      • Kunz R.
      • Brozek J.
      • et al.
      GRADE guidelines: 3. Rating the quality of evidence.
      .

      End points of treatment and definitions of response

      The goal of anti-HBV therapy, in children as in adults, is to improve long-term survival and quality of life by reducing the risk of progressive liver disease, cirrhosis, and HCC.
      For all patients, the ideal end point of treatment is sustained HBsAg clearance, as it stops disease progression and reduces the risk of HCC, although it occurs in a minority of treated subjects (A1) [
      • 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.
      ,
      • 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.
      ].
      When HBsAg seroclearance is not achieved, sustained off-therapy suppression of viral replication (undetectable HBV DNA levels with a sensitive real time polymerase chain reaction assay), associated with durable anti-HBe seroconversion in originally HBeAg-positive patients, is a good end point, being associated with improved prognosis, including decreased risk of HCC (A1) [
      • Yang H.-I.
      • Lu S.-N.
      • Liaw Y.-F.
      • You S.-L.
      • Sun C.-A.
      • Wang L.-Y.
      • et al.
      Hepatitis B e antigen and the risk of hepatocellular carcinoma.
      ]. In the absence of off-therapy viral suppression, undetectable HBV DNA under long-term antiviral therapy (maintained virological response) is the next desirable end point (A1). Reduction of viremia levels leads to decreased liver inflammation and subsequent normalization of ALT levels, reducing the risk of disease progression [
      • 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.
      ,
      • Iorio R.
      • Giannattasio A.
      • Cirillo F.
      • D 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.
      ,
      • 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.
      ].
      Response to treatment can be evaluated at biochemical, serological, virological and histological levels. In the few available pediatric trials, several end points have been used to evaluate response. A consensus on the definition of response would be required to compare the different clinical trials. Current AASLD and EASL definitions can be adapted to pediatric clinical trials [
      • 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 virus infection.
      ]:
      • Biochemical response: normalization of ALT levels, which reflects reduction of histological activity index. ALT level is, however, a difficult parameter to assess because it can fluctuate widely over time and can remain elevated up to 6–12 months after HBeAg seroconversion. ALT levels, therefore, should be monitored every 3 months during the first year post-treatment (C1) and every 6 months during the second year post-treatment (C2).
      • Serological response for HBeAg is defined as HBeAg loss and seroconversion to anti-HBe (only for HBeAg-positive patients); serological response for HBsAg is defined as loss of HBsAg and development of anti-HBs antibodies (valid for all chronic hepatitis B patients).
      • Virological response (VR): undetectable levels of HBV DNA (as determined by a sensible PCR assay) after 3–6 months of treatment for NA-treated patients or HBV DNA <2000 IU/ml after 6 months and at the end of treatment for IFN-treated patients.
      • Complete response: off-treatment virological response associated with HBsAg loss sustained on long-term follow-up.
      • Sustained off-treatment virological response (SVR): VR persisting at least 12 months after cessation of treatment.
      • Maintained virological response: undetectable HBV DNA under long-term antiviral therapy.
      • Partial virological response: decrease in HBV DNA of more than 1 log10 IU/ml but detectable HBV DNA after at least 6 months of treatment with NA.
      • Primary non-response: less than 1 log10 IU/ml decrease in HBV DNA levels from baseline after 3 months of therapy.
      • Virologic breakthrough: HBV DNA level increase of more than 1 log10 IU/ml during therapy, usually caused by poor adherence to treatment or emergence of a drug-resistant HBV mutant.
      • Histologic assessment of necroinflammatory activity has not been used as a criterion to evaluate response to treatment in pediatric studies.

      Who and when to treat

      Decision to treat must take into account the mild evolution of the disease during childhood, the risk of disease progression later in life, the development of severe complications in few, not yet well identified children, the efficacy of current antivirals, their side effects, and the limited number of drugs labeled for use in this age group. A treatment algorithm is proposed in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Treatment algorithm for pediatric patients with CHB (modified from
      [
      • Paganelli M.
      • Stephenne X.
      • Sokal E.M.
      Chronic hepatitis B in children and adolescents.
      ]
      ). Recommendation valid until results of ongoing trials on the treatment of immunotolerant children are available. ∗∗It is likely that PegIFN will replace IFN-α as the first-line treatment for CHB once the results of ongoing clinical trials are available.
      The need for treatment should be evaluated at each follow-up visit, in order to initiate antiviral drugs at the earliest signs of liver damage (C2). Children with CHB should undergo physical examination and measurement of serum ALT and HBeAg/anti-HBe levels every 6 months (C1). In HBeAg-positive patients with persistently elevated ALT, their levels should be monitored every 3 months for at least one year (B1). In HBeAg-negative patients, ALT and HBV DNA levels should be measured 4-monthly within the first year to rule out HBeAg-negative hepatitis. After confirmation of the inactive carrier status (normal ALT and HBV DNA <2000 IU/ml), patients should be monitored every 6 months (B1). Full blood count and liver function tests should be performed yearly (C1). HCC surveillance with liver ultrasound should be done every 6–12 months, depending on the stage of fibrosis [
      • Bruix J.
      • Sherman M.
      American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update.
      ]. Alpha-fetoprotein (AFP), although widely used, was recently shown to provide insufficient sensitivity and specificity for effective surveillance [
      • Singal A.
      • Volk M.L.
      • Waljee A.
      • Salgia R.
      • Higgins P.
      • Rogers M.A.
      • et al.
      Meta-analysis: surveillance with ultrasound for early-stage hepatocellular carcinoma in patients with cirrhosis.
      ,
      • Lok A.S.
      • Sterling R.K.
      • Everhart J.E.
      • Wright E.C.
      • Hoefs J.C.
      • Di Bisceglie A.M.
      • et al.
      HALT-C Trial Group. Des-gamma-carboxy prothrombin and alpha-fetoprotein as biomarkers for the early detection of hepatocellular carcinoma.
      ]. Lifetime follow-up is warranted even for inactive carriers, because of the risk of cirrhosis, HCC and reactivation of HBV infection, with seroreversion to HBeAg-positive status or progression to HBeAg-negative hepatitis (C1) [
      • 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.
      ].
      Currently, decision to start treatment is based on ALT levels (which reflect ongoing liver damage), HBeAg positivity, HBV DNA levels, liver histology, family history of HCC, co-existing liver diseases and patient’s treatment history.
      As the upper limit of normal (ULN) for ALT levels in pediatric age has not been established yet, it is advised that a patient should be considered for antiviral treatment if ALT levels are more than 1.5 times the laboratory ULN or more than 60 IU/L (value used as inclusion criterion in the three largest trials in children [
      • 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.
      ]), whichever is lower (C2) [
      • 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.
      ]. Patients with lower transaminases have fewer chances to achieve serological response [
      • 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.
      ]. A lower threshold based on larger pediatric cohorts may be used in future studies to avoid underestimation of liver damage, but this approach may reduce the overall rate of serological response and increase the need of prolonged treatment of patients with maintained VR under antiviral drugs [
      • Schwimmer J.B.
      • Dunn W.
      • Norman G.J.
      • Pardee P.E.
      • Middleton M.S.
      • Kerkar N.
      • et al.
      SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease.
      ].
      Antivirals should be considered for children with elevated serum ALT levels for at least 6 months (12 months if HBeAg-negative), in order to avoid treating patients who are undergoing spontaneous HBeAg seroconversion (C1).
      In the presence of high ALT levels, assessment of serum HBV DNA levels is important, as high HBV DNA values warrant antiviral treatment, whereas low levels should instigate investigations to exclude other causes of liver disease. The cut-off value for HBV DNA, however, has not been defined for children. As young patients have a higher HBV replication rate than adults, 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 for adult patients identified 2000 IU/ml to be a more reliable cut-off [
      • 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 virus infection.
      ]. Such a cut-off appears to be appropriate for children as well (C1).
      In patients older than 40 years of age, antiviral treatment is advocated in the presence of a high viral load in isolation, as this is an independent risk factor for 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 antivirals in children is partial and limited to specific subgroups, histologic assessment of the degree of inflammation and of the stage of fibrosis is recommended before considering treatment (A1). Response to both interferon(IFN)-α and NA is more likely when at least moderate necroinflammation or moderate fibrosis is found at liver histology (A1) [
      • 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 (B2) [
      • 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.
      ].
      Although still not fully validated, non-invasive methods to assess the degree of hepatic fibrosis, such as FibroScan, could prove useful to avoid liver biopsy, especially during follow-up [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
      ,
      • Marcellin P.
      • Ziol M.
      • Bedossa P.
      • Douvin C.
      • Poupon R.
      • de Lédinghen V.
      • et al.
      Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B.
      ,
      • Castera L.
      Transient elastography and other noninvasive tests to assess hepatic fibrosis in patients with viral hepatitis.
      ,
      • Cardoso A.C.
      • Carvalho-Filho R.J.
      • Stern C.
      • Dipumpo A.
      • Giuily N.
      • Ripault M.P.
      • et al.
      Direct comparison of diagnostic performance of transient elastography in patients with chronic hepatitis B and chronic hepatitis C.
      ,
      • Poynard T.
      • Munteanu M.
      • Deckmyn O.
      • Ngo Y.
      • Drane F.
      • Castille J.M.
      Validation of liver fibrosis biomarker (FibroTest) for assessing liver fibrosis progression: proof of concept and first application in a large population.
      ]. However, no sufficient data are available in children and, at present, these non-invasive methods cannot substitute for liver biopsy in the decision to treat a child or an adolescent with chronic hepatitis B, as these methods evaluate more fibrosis than necroinflammatory activity (C2).
      Antiviral treatment with NA should be instituted in HBV infected children undergoing liver transplantation or in recipients of grafts from anti-HBc-positive donors to prevent (or treat) recurrent HBV infection (C1). Prophylactic anti-HBV therapy should also be administered to HBsAg-positive patients who are going to receive immunosuppressive or cytotoxic treatment, as it decreases the risk of mortality and morbidity related to HBV reactivation (B1) [
      • 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.
      ]. Children with cirrhosis, HBV-related glomerulonephritis, or co-infection with HDV, HCV or HIV are at increased risk for a rapid progression of liver disease. These patients might benefit from treatment even if ALT, HBV DNA levels, and liver histology do not match the criteria listed above (C2).
      If antiviral treatments were able to achieve complete viral control (i.e., anti-HBs seroconversion), the ideal children to treat would be those tolerant to HBV, in order to obtain the production of neutralizing antibodies before the onset of complications. These children, who have normal or mildly elevated ALT levels and a high viral load, have been shown not to respond to isolated interferon treatment [
      • 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.
      ,
      • Lai C.L.
      • Lok A.S.
      • Lin H.J.
      • Wu P.C.
      • Yeoh E.K.
      • Yeung C.Y.
      Placebo-controlled trial of recombinant alpha 2-interferon in Chinese HBsAg-carrier children.
      ,
      • Lai C.L.
      • Lin H.J.
      • Lau J.N.
      • Flok A.S.
      • Wu P.C.
      • Chung H.T.
      • et al.
      Effect of recombinant alpha 2 interferon with or without prednisone in Chinese HBsAg carrier children.
      ,
      • Jara P.
      • Bortolotti F.
      Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children.
      ] and are not good candidates for current NA therapy because of the risk of developing antiviral resistance [
      • Zoulim F.
      • Locarnini S.
      Hepatitis B virus resistance to nucleos(t)ide analogues.
      ]. A pilot open study in small cohort of tolerant children has shown promising results with a combined protocol, in which 8 weeks of lamivudine treatment to decrease the viral load were followed by 44 weeks of combined lamivudine and IFN-α treatment [
      • 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.
      ]. On the basis of this study, two controlled trials in tolerant children are currently being conducted in the UK (lamivudine/pegylated IFN-α) and in the USA (entecavir/pegylated IFN-α) [
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Entecavir/pegylated interferon in immune tolerant children with chronic hepatitis B virus (HBV) infection.
      ,

      Roche. Lamivudine/pegylated interferon in immune tolerant children with chronic hepatitis B virus infection. Single center clinical trial at the Paediatric Liver Centre, King’s College Hospital, London, United Kingdom. Study identifier: NV2536.

      ]. Until the results of these studies become available, children in the immunotolerant phase should not be treated, but should be monitored, and treated only if an increase of ALT levels reveals immune activation (A1).

      Efficacy of currently available therapies

      The U.S. Food and Drug Administration (FDA) approved five medications for treatment of children with CHB: IFN-α, lamivudine, adefovir, entecavir and, recently, tenofovir. IFN-α can be used in children older than 12 months of age, lamivudine starting at 3 years of age, adefovir and tenofovir in children aged 12 years and older, and entecavir starting from 16 years of age. Each of these treatments has advantages and disadvantages (Table 2). Response rates and side effects are summarized in Fig. 2 and Table 3. So far, none of these medications have been approved by the European Medical Agency for the treatment of children.
      Table 2Available treatments for chronic hepatitis B in pediatric age.
      Figure thumbnail gr2
      Fig. 2Response to antiviral treatments currently licensed for children: rates of virological (white bars), serological (HBeAg loss: light blue bars; HBeAg seroconversion: blue bars; HBsAg loss: dark blue bars) and biochemical (black bars) response in pediatric clinical trials. Entecavir has not been included as no pediatric trials have been conducted so far.
      Table 3Efficacy and safety of treatments for chronic hepatitis B
      • 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.
      ,
      • 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.
      ,
      • Murray K.F.
      • Szenborn L.
      • Wysocki J.
      • Rossi S.
      • Corsa A.C.
      • Dinh P.
      • et al.
      Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B.
      ,
      • Dienstag J.L.
      • Schiff E.R.
      • Wright T.L.
      • Perrillo R.P.
      • Hann H.L.
      • Goodman Z.
      • et al.
      Lamivudine as initial treatment for chronic hepatitis B in the United States.
      . (
      • 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.
      ,
      • 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.
      ,
      • Liaw Y.F.
      • Jia J.D.
      • Chan H.L.
      • Han K.H.
      • Tanwandee T.
      • Chuang W.L.
      • et al.
      Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C.
      Table 3 reports studies on HBeAg-positive chronic hepatitis as, in children and adolescents, it is much more common than HBeAg-negative hepatitis.
      P, pediatric study; A, adults study; VR, virological response; SC, seroconversion; DB, double-blind; PDB, partially double-blind; OL, open-label; RCT, randomized controlled trial; HR, histologic response [reduction of 2 or more points in the Knodell necroinflammatory score (K), with no worsening in the fibrosis score, or in the Ishak fibrosis score (I) at the end of the study protocol, as compared to baseline], n.s., not significant.
      aOn-treatment analysis.
      bIntention-to-treat analysis.

      Predictors of response

      Several baseline and on-treatment predictors of response have been identified for children treated with IFN-α and lamivudine, whereas no data from pediatric studies exists for other NA.
      In HBeAg-positive patients, likelihood of response to IFN-α is associated with low HBV DNA levels and elevated ALT levels (more than twice the ULN) before treatment, younger age and female sex (A1) [
      • 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.
      ,
      • 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.
      ,
      • Perrillo R.P.
      • Schiff E.R.
      • Davis G.L.
      • Bodenheimer H.C.
      • Lindsay K.
      • Payne J.
      • et al.
      A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group.
      ,
      • 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.
      ]. Elevated ALT levels at baseline are associated with higher long-term seroconversion rate after treatment (B2) [
      • 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.
      ]. Early response to IFN-α is more likely to lead to HBsAg loss than late or no-response (C2) [
      • 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.
      ]. A better response to IFN-α has been shown in adults for viral genotypes A and B, compared to D and C [
      • Lin C.-L.
      • Kao J.-H.
      The clinical implications of hepatitis B virus genotype: recent advances.
      ,
      • 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.
      ]. No pediatric studies have yet investigated the role of genotype on response to antiviral therapy, and genotype determination before treatment is not currently recommended (C2), until the role of the viral genotype in assigning children to treatment and in predicting response has been clarified. A decrease of the HBsAg serum levels after the first 3 months of treatment predicts SVR and HBsAg loss in adults treated with pegylated IFN (PegIFN), but no data are available in children treated with IFN-α [
      • Brunetto M.R.
      • Moriconi F.
      • Bonino F.
      • Lau G.K.K.
      • Farci P.
      • Yurdaydin C.
      • et al.
      Hepatitis B virus surface antigen levels: a guide to sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B.
      ,
      • Moucari R.
      • Mackiewicz V.
      • Lada O.
      • Ripault M.-P.
      • Castelnau C.
      • Martinot-Peignoux M.
      • et al.
      Early serum HBsAg drop: a strong predictor of sustained virological response to pegylated interferon alfa-2a in HBeAg-negative patients.
      ,
      • Moucari R.
      • Martinot-Peignoux M.
      • Mackiewicz V.
      • Boyer N.
      • Ripault M.P.
      • Castelnau C.
      • et al.
      Influence of genotype on hepatitis B surface antigen kinetics in hepatitis B e antigen-negative patients treated with pegylated interferon-alpha2a.
      ].
      The likelihood to respond to lamivudine is greater in children with higher ALT levels (at least twice the ULN), and high histologic activity index at baseline (A1) [
      • 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.
      ,
      • 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.
      ]. In adult patients, the same parameters, as well as low HBV DNA levels (HBV DNA <2 × 108 IU/ml), were predictive of response to all NA (A1) [
      • 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.
      ,
      • 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.
      ,
      • Perrillo R.
      Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.
      ,
      • 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.
      ]. No significant difference in response to NA was found among different genotypes (A1) [
      • Wiegand J.
      • Hasenclever D.
      • Tillmann H.L.
      Should treatment of hepatitis B depend on hepatitis B virus genotypes? A hypothesis generated from an explorative analysis of published evidence.
      ,
      • Raimondi S.
      • Maisonneuve P.
      • Bruno S.
      • Mondelli M.U.
      Is response to antiviral treatment influenced by hepatitis B virus genotype?.
      ]. In adults, VR at 24 weeks during treatment with lamivudine or telbivudine (and 48 weeks during treatment with adefovir) is associated with a higher chance of HBeAg seroconversion, maintained virological response, and lower incidence of resistance (B1) [
      • 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.
      ,
      • Yuen M.
      Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy.
      ,
      • Zeuzem S.
      • Gane E.
      • Liaw Y.F.
      • Lim S.G.
      • DiBisceglie A.
      • Buti M.
      • et al.
      Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B.
      ,
      • Hadziyannis S.J.
      • Tassopoulos N.C.
      • Heathcote E.J.
      • Chang T.-T.
      • Kitis G.
      • Rizzetto M.
      • et al.
      Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years.
      ]. The decline of HBsAg serum levels during NA treatment predicts HBeAg seroconversion or HBsAg loss (C2) [
      • Wursthorn K.
      • Jung M.
      • Riva A.
      • Goodman Z.D.
      • Lopez P.
      • Bao W.
      • et al.
      Kinetics of hepatitis B surface antigen decline during 3 years of telbivudine treatment in hepatitis B e antigen-positive patients.
      ,
      • Lee J.M.
      • Ahn S.H.
      • Kim H.S.
      • Park H.
      • Chang H.Y.
      • Kim D.Y.
      • et al.
      Quantitative hepatitis B surface antigen and hepatitis B e antigen titers in prediction of treatment response to entecavir.
      ,
      • Chan H.L.-Y.
      • Thompson A.
      • Martinot-Peignoux M.
      • Piratvisuth T.
      • Cornberg M.
      • Brunetto M.R.
      • et al.
      Hepatitis B surface antigen quantification: why and how to use it in 2011 – a core group report.
      ].

      Treatment strategy

      Currently, a finite-duration IFN-α therapy remains the treatment strategy of choice for HBeAg-positive children with elevated ALT levels (A1), as in this patient population seroconversion to anti-HBs is the main aim. IFN-α is the only available treatment offering a chance of sustained off-treatment VR. It is likely that, as soon as results of trials using PegIFN in children [
      • Hoffmann-La Roche
      A study of pegasys (peginterferon Alfa-2a) versus untreated control in children with HBeAg positive chronic hepatitis B.
      ] are available, this medication will become the recommended drug. Although adverse effects may be serious and a clear benefit on the long-term remains to be confirmed, the use of IFN-α is not associated with the emergence of genotypic resistance. The recommended regimen is 5–10 million units per square meter, three times weekly for 6 months (A1). For PegIFN, studies in adults show the highest HBeAg seroconversion rate with 48-week treatment schedules [
      • Liaw Y.F.
      • Jia J.D.
      • Chan H.L.
      • Han K.H.
      • Tanwandee T.
      • Chuang W.L.
      • et al.
      Shorter durations and lower doses of peginterferon alfa-2a are associated with inferior hepatitis B e antigen seroconversion rates in hepatitis B virus genotypes B or C.
      ] (A1). IFN-α is contraindicated in children with decompensated cirrhosis, cytopenia, autoimmune disorders, cardiac or renal failure, and in transplanted patients (B1) [
      • Jara P.
      • Bortolotti F.
      Interferon-alpha treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children.
      ]. The possible benefit of priming with corticosteroids has not been proven (C2) [
      • 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.
      • Vega La.
      • et al.
      Lymphoblastoid interferon alfa with or without steroid pretreatment in children with chronic hepatitis B: a multicenter controlled trial.
      ,
      • Vajro P.
      • Tedesco M.
      • Fontanella A.
      • De Vincenzo A.
      • Vecchione R.
      • Ammendola R.
      • et al.
      Prolonged and high dose recombinant interferon alpha-2b alone or after prednisone priming accelerates termination of active viral replication in children with chronic hepatitis B infection.
      ]. On-treatment response was higher with the combination of IFN-α and lamivudine than with IFN-α alone, both in adults and in children, but no benefit was seen for off-treatment response rate [
      • 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.
      ,
      • 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.
      ,
      • 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.
      ,
      • Janssen H.L.
      • van Zonneveld M.
      • Senturk H.
      • Zeuzem S.
      • Akarca U.S.
      • Cakaloglu Y.
      • et al.
      Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.
      ,
      • Marcellin P.
      • Lau G.K.
      • Bonino F.
      • Farci P.
      • Hadziyannis S.
      • Jin R.
      • et al.
      Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.
      ]. Thus, the combination is currently not recommended (C2). Furthermore, in adults combined IFN-α and telbivudine treatment has been reported to be associated with polyneuropathy (A1) [
      • Fleischer R.D.
      • Lok A.S.
      Myopathy and neuropathy associated with nucleos(t)ide analog therapy for hepatitis B.
      ]. IFN-α is the only treatment licensed for treating children younger than 3 years of age, who however rarely require therapy (A1). In this age group, the risk of IFN-related neurotoxicity (although mostly minor and transient) has to be taken into account [
      • 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.
      ,
      • Dubois J.
      • Hershon L.
      • Carmant L.
      • Bélanger S.
      • Leclerc J.M.
      • David M.
      Toxicity profile of interferon alfa-2b in children: a prospective evaluation.
      ]. In case of no response, at least 6–12 months should elapse before considering other therapies, as VR may be achieved during the 6 months following the end of IFN-α treatment (B1).
      NA used to be second-line therapies because of the high risk of emergence of resistant mutant strains. Nevertheless, the recent FDA approval of NA with higher genotypic barrier to resistance has opened the way for the use of such drugs as first-line treatment for adolescents. In patients older than 12 years of age, tenofovir (or entecavir for patients ⩾16 years old) is the best choice, as response rate is high and resistance is less likely (A1). The recommended dose for tenofovir is 300 mg once daily, and for entecavir is 0.5 mg once daily (for nucleoside-naïve patients) (A1). Although not yet approved for the treatment of CHB in patients <12 years of age, the use of tenofovir might be safe in younger children, as it is already widely used (and FDA-licensed) for patients older than 2 years of age with HIV infection. A phase 3 clinical trial in 2–11-year-old CHB patients is currently underway [
      • Gilead Sciences
      Evaluating the efficacy, safety and tolerability of tenofovir DF in pediatric patients with chronic hepatitis B infection.
      ]. Since the approval of tenofovir for adolescents, adefovir is no more recommended because of the higher risk of resistance and the lower response rate (B1) [
      • 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.
      ,
      • Jonas M.M.
      • Kelly D.
      • Pollack H.
      • Mizerski J.
      • Sorbel J.
      • Frederick D.
      • et al.
      Efficacy and safety of long-term adefovir dipivoxil therapy in children with chronic hepatitis B infection.
      ].
      A finite-duration treatment with tenofovir or entecavir is possible if seroconversion to anti-HBe is achieved on treatment (C2). Duration of treatments with NA has not been established, but they should be continued for at least 12 months after reaching undetectable HBV DNA levels and HBeAg seroconversion (B1) [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
      ,
      • Lee H.W.
      • Lee H.J.
      • Hwang J.S.
      • Sohn J.H.
      • Jang J.Y.
      • Han K.J.
      • et al.
      Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B.
      ]. As an important proportion of adult patients was shown not to maintain their serological and virological response, treatment up to HBsAg clearance could be a safer choice for patients with histological evidence of severe fibrosis (C2) [
      • Reijnders J.G.
      • Perquin M.J.
      • Zhang N.
      • Hansen B.E.
      • Janssen H.L.
      Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B.
      ]. Patients should be monitored after discontinuation because of the possibility of post-treatment flares (B1).
      Patients who do not undergo HBeAg seroconversion on treatment, the rare children with HBeAg-negative chronic hepatitis and cirrhotic patients need long-term treatment with NA (B1). Tenofovir or entecavir, if allowed by the age, are the first choice (A1). Long-term efficacy and safety data in adults support such a strategy, but no data are available for adolescents as yet [
      • Gordon S.C.
      • Krastev Z.
      • Horban A.
      • Petersen J.
      • Sperl J.
      • Dinh P.
      • et al.
      Efficacy of tenofovir disoproxil fumarate at 240 weeks in patients with chronic hepatitis b with high baseline viral load (⩾9 log10 copies/mL).
      ,
      • Marcellin P.
      • Gane E.
      • Buti M.
      • Afdhal N.
      • Sievert W.
      • Jacobson I.M.
      • et al.
      Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
      ,
      • Chang T.T.
      • Lai C.L.
      • Kew Yoon S.
      • Lee S.S.
      • Coelho H.S.
      • Carrilho F.J.
      • et al.
      Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B.
      ,
      • Chang T.T.
      • Liaw Y.F.
      • Wu S.S.
      • Schiff E.
      • Han K.H.
      • Lai C.L.
      • et al.
      Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B.
      ]. During long-term treatment with NA, HBV DNA levels should be monitored every 3 months, as HBV DNA reduction to undetectable level is of paramount importance to avoid resistance (B1).
      Although guidelines in adults do not recommend the use of lamivudine monotherapy [
      • 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 virus infection.
      ], the risk of the emergence of resistant strains has to be balanced against the fact that lamivudine is the only NA currently approved for younger children. Its use should be limited to the rare young children unresponsive to IFN-α and requiring immediate treatment and to special populations (see below) (C1). The recommended treatment dose for lamivudine is 3 mg/kg/day (maximum 100 mg/day), administered orally once daily (A1) [
      • 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. Treatment should be continued until VR is achieved, and possibly for 12 months after seroconversion (B1) [
      • 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.
      ,
      • Lee H.W.
      • Lee H.J.
      • Hwang J.S.
      • Sohn J.H.
      • Jang J.Y.
      • Han K.J.
      • et al.
      Lamivudine maintenance beyond one year after HBeAg seroconversion is a major factor for sustained virologic response in HBeAg-positive chronic hepatitis B.
      ]. As 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 resistant mutations emerge (B1). As post-treatment ALT flares are possible, children should be carefully monitored and a reinstitution of lamivudine treatment (in patients who have not developed resistance) or an alternative therapy (tenofovir if possible for the age) should be started in the rare cases with severe and protracted ALT elevation (A1) [
      • 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.
      ]. For children with cirrhosis, who need antiviral treatment to be continued, switch to tenofovir (if ⩾12 years of age), alone or in combination with entecavir (if ⩾16 years of age) or maintenance of lamivudine (if <12 years of age) despite an incomplete VR is recommended (C2) [
      • Petersen J.
      • Ratziu V.
      • Buti M.
      • Janssen H.L.
      • Brown A.
      • Lampertico P.
      • et al.
      Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: an international multicenter cohort study.
      ,
      • Liaw Y.F.
      • Sheen I.S.
      • Lee C.M.
      • Akarca U.S.
      • Papatheodoridis G.V.
      • Suet-Hing Wong F.
      • et al.
      Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease.
      ]. Combination therapy with IFN-α and lamivudine is promising, but further data are needed in children (C2). Combination therapy with adefovir and lamivudine has been tried only in children not responding to adefovir monotherapy, and its efficacy has not been compared to monotherapy [
      • Jonas M.M.
      • Kelly D.
      • Pollack H.
      • Mizerski J.
      • Sorbel J.
      • Frederick D.
      • et al.
      Efficacy and safety of long-term adefovir dipivoxil therapy in children with chronic hepatitis B infection.
      ].
      Although no data are available from pediatric studies, current guidelines in adults suggest that, for HBeAg-negative patients who have persistently elevated ALT values (at least 3 measurements in 12 months) and high HBV DNA levels, the same treatment algorithm applied to HBeAg-positive children should be considered (C1) [
      • 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 virus infection.
      ]. Nevertheless, attention should be paid to the higher relapse rate and the longer duration of treatment needed [
      • Papatheodoridis G.V.
      • Manesis E.K.
      • Hadziyannis S.J.
      The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.
      ,
      • Santantonio T.
      • Mazzola M.
      • Iacovazzi T.
      • Miglietta A.
      • Guastadisegni A.
      • Pastore G.
      Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine.
      ,
      • Hadziyannis S.J.
      • Sevastianos V.
      • Rapti I.
      • Vassilopoulos D.
      • Hadziyannis E.
      Sustained responses and loss of HBsAg in HBeAg-negative patients with chronic hepatitis B who stop long-term treatment with adefovir.
      ].

      Treatment failure and antiviral resistance

      Partial response to NA or primary non-response is often due to the emergence of genotypic resistant strains or to patient non-adherence to treatment. In non-responders, HBV genotypic analysis is warranted in order to differentiate between resistance and patient non-compliance (C1). Non-compliance may be a major issue in adolescents, especially if long-term treatment is required to maintain response.
      In responders, virologic breakthrough (which may be followed by biochemical breakthrough) is usually secondary to genotypic resistance. Likelihood of virologic breakthrough depends on the intrinsic barrier to resistance of the specific NA (lamivudine >telbivudine >adefovir >entecavir >tenofovir). All children receiving NA should be monitored for virologic breakthrough by measuring HBV DNA levels every 3 months (C1). Ideally, identification of virologic breakthrough and consequent adaptation of treatment should be performed as early as possible, before ALT levels rise [
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B: update 2009.
      ,
      • Zoulim F.
      • Locarnini S.
      Hepatitis B virus resistance to nucleos(t)ide analogues.
      ]. Because of the low number of effective drugs approved, when resistance to an NA develops in children, the decision on therapy adjustment is based on liver biopsy and the patient’s age. If mild hepatitis is present, he/she should be switched to either entecavir (for adefovir-resistant, ⩾16 years old and lamivudine-naïve patients) or tenofovir (for ⩾12 years old, lamivudine-resistant patients or adefovir-resistant patients previously treated with lamivudine) (C2). For younger children, for whom no other NA other than lamivudine is approved at the moment, switching to IFN-α (PegIFN when approved) can be a possibility (C2). Treatment with lamivudine should be stopped and the child should be followed up in the eventuality of post-treatment flares (C2). In case of moderate hepatitis/fibrosis, the patient should be switched to tenofovir if ⩾12 years old, or, if younger, to IFN-α (C2). If severe hepatitis is found at liver biopsy, switching to tenofovir is the only available choice (as monotherapy or associated to entecavir if the child is ⩾16 years old and has high viral load) (C2) [
      • Petersen J.
      • Ratziu V.
      • Buti M.
      • Janssen H.L.
      • Brown A.
      • Lampertico P.
      • et al.
      Entecavir plus tenofovir combination as rescue therapy in pre-treated chronic hepatitis B patients: an international multicenter cohort study.
      ,
      • Liaw Y.F.
      • Sheen I.S.
      • Lee C.M.
      • Akarca U.S.
      • Papatheodoridis G.V.
      • Suet-Hing Wong F.
      • et al.
      Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease.
      ]. Both tenofovir and entecavir are effective in lamivudine-resistant patients [
      • Zoulim F.
      • Locarnini S.
      Hepatitis B virus resistance to nucleos(t)ide analogues.
      ], but an increased resistance rate has been observed for entecavir (8% after 2-year treatment) and higher dose (1 mg daily) is required (B1) [
      • 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.
      ,
      • Chang T.-T.
      • Gish R.G.
      • Hadziyannis S.J.
      • Cianciara J.
      • Rizzetto M.
      • Schiff E.R.
      • et al.
      A dose-ranging study of the efficacy and tolerability of entecavir in lamivudine-refractory chronic hepatitis B patients.
      ]. Lamivudine should therefore be discontinued when switching to entecavir to decrease the risk of emergence of resistant mutants (C2) [
      • Lok A.S.F.
      • McMahon B.J.
      Chronic hepatitis B: update 2009.
      ]. Tenofovir can be used in lamivudine-resistant mutant strains, as their activity is not hampered by such mutations (B1) [
      • Zoulim F.
      • Locarnini S.
      Hepatitis B virus resistance to nucleos(t)ide analogues.
      ,
      • Jonas M.M.
      • Kelly D.
      • Pollack H.
      • Mizerski J.
      • Sorbel J.
      • Frederick D.
      • et al.
      Efficacy and safety of long-term adefovir dipivoxil therapy in children with chronic hepatitis B infection.
      ].
      In patients with partial virological response at week 24 (for those receiving lamivudine) or 48 (for those receiving adefovir), switch to tenofovir or entecavir (if allowed by the age) is recommended (B1). The strategy for children younger than 12 years of age is difficult to define. Patients could be switched to IFN-α (or PegIFN) if not tried yet (C1), or lamivudine could be either continued up to the 12th birthday (the only choice in those with severe fibrosis or cirrhosis) or stopped (with proper post-treatment follow-up) (C2).
      As the emergence of resistant mutant strains is becoming a major public health problem, pediatric practitioners should not treat children who are not likely to benefit from a licensed therapy and consider waiting for market approval of more effective drugs (C1).

      Special populations

      Treatment strategies for special populations of HBV infected children are rarely based on strong evidence. Indications and type of treatment are decided on the basis of few available case reports and are often extrapolated from evidence obtained in adult patients. Such children should be referred to specialized tertiary centers where individualized treatments (even with off-label newer antivirals) can be administered.

      Immunocompromised children

      All children candidate for chemotherapy or immunosuppressive therapy should be screened for HBsAg, anti-HBs, and anti-HBc, and seronegative patients should be vaccinated (A1). Prophylactic treatment with NA should be considered for inactive carriers requiring immunosuppressive therapy (transplanted patients, patients undergoing cytotoxic chemotherapy, corticosteroids treatment, rituximab, anti-TNF-α or other monoclonal antibody therapies), in order to prevent reactivation (A1) [
      • 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.
      ]. NA treatment should be continued for 12 months after cessation of the immunosuppressive therapy (C1). NA with high genetic barriers to resistance should be used for patients with CHB and for inactive carriers requiring long or repeated cycles of immunosuppressive therapy (C1). Lamivudine could be sufficient for children with low viral load or requiring a short duration of immunosuppression (C2). HBsAg-negative, anti-HBc-positive children (prior infection) should be treated as HBsAg-positive subjects if they have detectable HBV DNA (C2). If they have undetectable HBV DNA levels, they should be followed and treated upon reactivation of HBV infection (C2). Prophylaxis with lamivudine should be administered to HBsAg-negative, anti-HBc-positive children receiving rituximab or combined regimens for hematological malignancies or undergoing bone marrow or stem cell transplantation (C1) [
      • Marzano A.
      • Angelucci E.
      • Andreone P.
      • Brunetto M.
      • Bruno R.
      • Burra P.
      • et al.
      Prophylaxis and treatment of hepatitis B in immunocompromised patients.
      ,
      • Loomba R.
      • Rowley A.
      • Wesley R.
      • Liang T.J.
      • Hoofnagle J.H.
      • Pucino F.
      • et al.
      Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy.
      ,
      • Hsu C.
      • Hsiung C.A.
      • Su I.J.
      • Hwang W.S.
      • Wang M.C.
      • Lin S.F.
      • et al.
      A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial.
      ,
      • Evens A.M.
      • Jovanovic B.D.
      • Su Y.C.
      • Raisch D.W.
      • Ganger D.
      • Belknap S.M.
      • et al.
      Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports.
      ,
      • Viganò M.
      • Vener C.
      • Lampertico P.
      • Annaloro C.
      • Pichoud C.
      • Zoulim F.
      • et al.
      Risk of hepatitis B surface antigen seroreversion after allogeneic hematopoietic SCT.
      ].

      Organ transplantation

      If the recipient has been successfully immunized before surgery, the risk of HBV infection after transplantation of non-hepatic solid organs from HBsAg-negative, anti-HBc-positive donors (i.e., with past HBV infection) is low, despite immunosuppression [
      • Natov S.N.
      • Pereira B.J.G.
      Transmission of viral hepatitis by kidney transplantation: donor evaluation and transplant policies (Part 1: hepatitis B virus).
      ]. The risk of infection is higher after liver transplantation from anti-HBc-positive donors, with a 10% rate of de novo hepatitis in successfully vaccinated recipients and 69% recurrence rate in HBsAg-positive recipients [
      • Dickson R.C.
      • Everhart J.E.
      • Lake J.R.
      • Wei Y.
      • Seaberg E.C.
      • Wiesner R.H.
      • et al.
      Transmission of hepatitis B by transplantation of livers from donors positive for antibody to hepatitis B core antigen. The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database.
      ,
      • Wachs M.E.
      • Amend W.J.
      • Ascher N.L.
      • Bretan P.N.
      • Emond J.
      • Lake J.R.
      • et al.
      The risk of transmission of hepatitis B from HBsAg(−), HBcAb(+), HBIgM(−) organ donors.
      ,
      • Cholongitas E.
      • Papatheodoridis G.V.
      • Burroughs A.K.
      Liver grafts from anti-hepatitis B core positive donors: a systematic review.
      ]. Presence of anti-HBs antibodies per se does not guarantee protection against de novo HBV infection, whereas the achievement of a high anti-HBs titer (>200 mIU/ml) is protective [
      • Su W.-J.
      • Ho M.-C.
      • Ni Y.-H.
      • Chen H.-L.
      • Hu R.-H.
      • Wu Y.-M.
      • et al.
      High-titer antibody to hepatitis B surface antigen before liver transplantation can prevent de novo hepatitis B infection.
      ]. Therefore, immunization (with the achievement of an adequate anti-HBs titer) and prophylaxis with lamivudine, tenofovir or entecavir (according to patient’s age) for an indefinite period of time, and HBIG are recommended when transplanting an anti-HBc-positive liver to an HBV naïve recipient (C1) [
      • 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.
      ]. Anyway, because of the long post-transplant life expectancy, HBc-positive liver grafts should be discarded when transplanting pediatric patients (C2).

      Co-infection with HIV, HCV or HDV

      HIV infection should be ruled out in children from high-prevalence countries, as well as in adolescents who are injection drugs users. HBV/HIV-co-infected patients are at increased risk of disease progression [
      • Thio C.L.
      • Seaberg E.C.
      • Skolasky R.J.
      • Phair J.
      • Visscher B.
      • Munoz A.
      • et al.
      HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS).
      ]. Furthermore, they are at increased risk of developing resistance against lamivudine if used as monotherapy [
      • Benhamou Y.
      • Bochet M.
      • Thibault V.
      • Di Martino V.
      • Caumes E.
      • Bricaire F.
      • et al.
      Long-term incidence of hepatitis B virus resistance to lamivudine in human immunodeficiency virus-infected patients.
      ]. Because of the risk of inducing HIV resistance, entecavir should only be used in patients receiving effective antiretroviral therapy [
      • McMahon M.A.
      • Jilek B.L.
      • Brennan T.P.
      • Shen L.
      • Zhou Y.
      • Wind-Rotolo M.
      • et al.
      The HBV drug entecavir – effects on HIV-1 replication and resistance.
      ] (A1). In HBV/HIV-co-infected adult patients, the combination of tenofovir (approved for HIV-infected children ⩾2 years old) and emtricitabine or lamivudine is the recommended treatment (A1). Tenofovir monotherapy should not be administered to co-infected patients because of the risk of HIV resistance (A1). Until stronger pediatric evidence is available, such recommendations may be extrapolated to co-infected children (C2) [
      • Soriano V.
      • Puoti M.
      • Bonacini M.
      • Brook G.
      • Cargnel A.
      • Rockstroh J.
      • et al.
      Care of patients with chronic hepatitis B and HIV co-infection: recommendations from an HIV-HBV International Panel.
      ,
      • Mofenson L.M.
      • Brady M.T.
      • Danner S.P.
      • Dominguez K.L.
      • Hazra R.
      • Handelsman E.
      • et al.
      Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics.
      ]. The indications for therapy are the same as in HIV-negative patients. According to HHS pediatric guidelines, no HIV treatment is required if the CD4 count is ⩾500 cells/mm3 in children ⩾5 years of age (⩾750 if aged 3 to <5 years and ⩾1000 if aged 1 to <3 years) [

      HHS Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines, section accessed February 21st 2013.

      ]. In these cases, HBV may be treated before the institution of an anti-HIV therapy with drugs inactive against HIV (such as IFN-α or PegIFN) (C2).
      HBV/HCV co-infection is rare, and few data are available. IFN-α (at doses recommended for HBV treatment) and ribavirin may be a good option (C2). HBV/HDV co-infected children have more severe liver disease than those with HBV alone. IFN-α is also the drug of choice for these patients, although the only pediatric study available has shown a transient effect with no therapeutic benefit in the long-term (24 months) compared to medium-term (12 months) treatment (C2) [
      • Di Marco V.
      • Giacchino R.
      • Timitilli A.
      • Bortolotti F.
      • Crivellaro C.
      • Calzia R.
      • et al.
      Long-term interferon-alpha treatment of children with chronic hepatitis delta: a multicentre study.
      ,
      • Rizzetto M.
      Hepatitis D: thirty years after.
      ].

      Acute hepatitis B

      Acute symptomatic infection is rare in pediatric age, and it can vary from a mild to a fulminant hepatitis. Classic symptoms are present in 30–50% of older children and adolescents with acute hepatitis B and include fever, jaundice, nausea and vomiting, abdominal pain, liver tenderness, and fatigue, which last approximately 2–3 months. Less than 10% of infants born to HBeAg-positive mothers develop acute hepatitis, and jaundice may be the only sign [
      • Shiraki K.
      • Yoshihara N.
      • Sakurai M.
      • Eto T.
      • Kawana T.
      Acute hepatitis B in infants born to carrier mother with the antibody to hepatitis B e antigen.
      ,
      • Bortolotti F.
      • Cadrobbi P.
      • Bertaggia A.
      • Rude L.
      • Alberti A.
      • Realdi G.
      A 7 year survey of acute hepatitis type B.
      ]. Fulminant hepatitis is uncommon in infants and children but it is associated with a more than 40% mortality rate without liver transplantation [
      • Squires Jr., R.H.
      • Shneider B.L.
      • Bucuvalas J.
      • Alonso E.
      • Sokol R.J.
      • Narkewicz M.R.
      • et al.
      Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group.
      ,
      • Sundaram S.S.
      • Alonso E.M.
      • Narkewicz M.R.
      • Zhang S.
      • Squires R.H.
      Pediatric Acute Liver Failure Study Group. Characterization and outcomes of young infants with acute liver failure.
      ]. Therefore, patients with fulminant hepatitis must be evaluated for liver transplantation (A1). Such patients may benefit from treatment with entecavir, tenofovir (according to the age of the patient) or lamivudine (C2) [
      • Tillmann H.L.
      • Hadem J.
      • Leifeld L.
      • Zachou K.
      • Canbay A.
      • Eisenbach C.
      • et al.
      Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience.
      ]. Although the duration of treatment is not defined, continuation of antiviral therapy for at least 3 months after anti-HBs seroconversion or 1 year after anti-HBe seroconversion may be recommended (C2) [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
      ].

      Pregnant women

      No antiviral agent has been approved by the FDA for use in pregnancy. Lamivudine and entecavir are classified pregnancy class C by the FDA, while both tenofovir and telbivudine are class B. Although interference with organogenesis secondary to the activity of the drug on replication of mitochondrial DNA cannot be excluded, data from the Antiretroviral Pregnancy Registry has shown no increased incidence of birth defects with the use of lamivudine (3.1% when used during the first trimester and 2.7% during the second or third trimester) or tenofovir (2.4% and 2%, respectively) compared to the CDC’s population-based birth defects surveillance system (2.72% of total prevalence) [
      • Brown Jr., R.S.
      • Verna E.C.
      • Pereira M.R.
      • Tilson H.H.
      • Aguilar C.
      • Leu C.-S.
      • et al.
      Hepatitis B virus and human immunodeficiency virus drugs in pregnancy: findings from the Antiretroviral Pregnancy Registry.
      ]. PegIFN is contraindicated during pregnancy (A1). Children of lamivudine-treated mothers have 13–23% lower incidence of intrauterine infection and 1–2% lower mother-to-child transmission rate [
      • 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.
      ]. Treatment with telbivudine during the third trimester of pregnancy has proven effective in reducing maternal viral load and preventing perinatal transmission (0% vs. 8% in controls) [
      • 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.
      ]. No studies are yet available for tenofovir. Nevertheless, in order to reduce the risk of mother-to-child transmission, treatment of highly viraemic (serum HBV DNA >106 IU/ml) HBsAg-positive women during the last trimester of pregnancy with tenofovir is currently recommended because of its high genetic barrier to resistance and the possibility to continue therapy post-partum if needed (B1) [
      • European Association for the Study of the Liver
      EASL clinical practice guidelines: management of chronic hepatitis B virus infection.
      ]. Although no studies have been conducted in pregnant teens, the same recommendations for treatment in the third trimester of pregnancy may apply (C1).

      Household contacts

      The extreme resilience of HBV, which allows its survival for more than a week on dry surfaces, is the cause of the significant risk of horizontal intrafamilial transmission. Counseling of HBV carriers and vaccination of uninfected household members are therefore essential [
      • 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.
      ,
      • 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.
      ]. Surprisingly, although between 8% and 24% of household contacts of HBV infected subjects (children and adults) have been reported to be HBsAg-positive [
      • 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.
      ,
      • Staff M.
      • Angel P.
      Vaccination among household contacts of chronic hepatitis B carriers by general practitioners.
      ,
      • Chakravarty R.
      • Chowdhury A.
      • Chaudhuri S.
      • Santra A.
      • Neogi M.
      • Rajendran K.
      • et al.
      Hepatitis B infection in Eastern Indian families: need for screening of adult siblings and mothers of adult index cases.
      ,
      • Kumar G.T.
      • Kazim S.N.
      • Kumar M.
      • Hissar S.
      • Chauhan R.
      • Basir S.F.
      • et al.
      Hepatitis B virus genotypes and hepatitis B surface antigen mutations in family contacts of hepatitis B virus infected patients with occult hepatitis B virus infection.
      ], vaccination coverage in this high-risk group is still low (15–25%) even in developed countries [
      • Staff M.
      • Angel P.
      Vaccination among household contacts of chronic hepatitis B carriers by general practitioners.
      ,
      • Richardson G.
      • Evans M.R.
      • Westmoreland D.
      Hepatitis B immunisation of household contacts: retrospective study of vaccine coverage.
      ,
      • Weinberg M.S.
      • Gunn R.A.
      • Mast E.E.
      • Gresham L.
      • Ginsberg M.
      Preventing transmission of hepatitis B virus from people with chronic infection.
      ,
      • Scognamiglio P.
      • Girardi E.
      • Fusco M.
      • Piselli P.
      • Russo Spena S.
      • Maione C.
      • et al.
      Lack of implementation of hepatitis B virus (HBV) vaccination policy in household contacts of HBV carriers in Italy.
      ]. All household contacts of an HBV infected child should be screened for HBsAg, HBsAb, and HBcAb in order to offer vaccination to those without protective antibody levels and diagnose those with a previously unknown infection (C1).

      Conclusions

      CHB is a mild disease in most children and adolescents. Nevertheless, a minority of patients is at risk of rapid disease progression and early development of complications, and a quarter of infected individuals develop serious complications in adult life. Treatment of patients with elevated ALT levels is overall satisfactory, but several unsolved issues need to be addressed (Table 4). IFN-α is still the treatment of choice for most children. Although in specialized centres PegIFN is currently used, this drug cannot be recommended until the results of ongoing trials become available. Licensing of highly-effective NA for older children and adolescents has opened new possibilities of treatment. Nevertheless, the risk of emergence of drug resistant strains is a public health problem and a major long-term issue for young patients. Before starting a child on NAs, therefore, the risks of treatment should be carefully weighed against the possible benefits, and treatment should be offered only to those patients who need to be treated and are likely to respond. While waiting for the results of ongoing trials, immunotolerant patients should not be treated, but monitored routinely to identify early signs of liver damage. As the management of special patient populations is problematic and not evidence-based, their referral to highly specialized centers is highly recommended.
      Table 4Unsolved issues in the management of pediatric CHB.

      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.

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