Pediatric Drugs

, Volume 15, Issue 4, pp 311–317 | Cite as

Chronic Hepatitis B in Children and Adolescents: Epidemiology and Management

Review Article


Hepatitis B virus (HBV) infection is a worldwide health problem, which can cause acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer. It is most prevalent in Asia, Africa, Southern Europe, and Latin America. Approximately 2 billion people in the world have been infected by HBV, with more than 350 million as chronic carriers. Implementation of the HBV vaccine led to a significant reduction in viral transmission in many areas of the world; however, it remains highly endemic in many developing countries. The main source of infection in childhood is via perinatal transmission or horizontal transmission during preschool years. The majority of children with chronic hepatitis B (CHB) infection are asymptomatic; however, they may develop progressive disease and are at increased risk of advanced liver disease or liver cancer before their third decade. All children with chronic HBV infection should be regularly monitored for disease progression. The goal of therapy for children with CHB is to arrest disease progression and reduce the risk of developing cirrhosis and cancer. The available medications have a low success rate because of immunotolerance in the child and the development of viral resistance to standard therapy. Therefore, case selection and determination of the best time to commence treatment are essential to increase treatment efficacy and reduce the risk of viral resistance.



No sources of funding were used to assist in the preparation of this review. Professor Kelly has received research grants for hepatitis B studies from BMS, Roche, MSD, Janssen, Vertex, and Novartis, and consulting fees from Sanofi Pasteur MSD for advisory meetings. Dr Abdel-Hady has no conflicts of interest to declare.


  1. 1.
    Goldstein ST, Zhou F, Hadler SC, et al. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol. 2005;34:1329–39.PubMedCrossRefGoogle Scholar
  2. 2.
    McMahon BJ. The natural history of chronic hepatitis B virus infection. Hepatology. 2009;49:S45–55.PubMedCrossRefGoogle Scholar
  3. 3.
    Seeger C, Zoulim F, Mason WS. Hepadnavirses. In: Knipe DM, Howley P, Griffin DE, Lamb RA, Martin MA, et al., editors. Fields virology. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 2977–3029.Google Scholar
  4. 4.
    Liu CJ, Kao JH, Chen DS. Therapeutic implications of hepatitis B virus genotypes. Liver Int. 2005;25(6):1097–107.PubMedCrossRefGoogle Scholar
  5. 5.
    Palumbo E. Hepatitis B genotypes and response to antiviral therapy: a review. Am J Ther. 2007;14(3):306–9.PubMedCrossRefGoogle Scholar
  6. 6.
    McGlynn KA, Tsao L, Hsing AW, et al. International trends and patterns of primary liver cancer. Int J Cancer. 2001;94:290–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Stadler LP, Mezoff AG, Staat MA. Hepatitis B virus screening for internationally adopted children. Pediatrics. 2008;122:1223–8.PubMedCrossRefGoogle Scholar
  8. 8.
    Kidd-Ljunggren K, Holmberg A, Blackburg J, et al. High levels of hepatitis B virus DNA in body fluids from chronic carriers. J Hosp Infect. 2006;64(4):352–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Paganelli M, Stephenne X, Sokal K. Chronic Hepatitis B in children and adolescents. J Hepatol. 2012;57(4):885–96.PubMedCrossRefGoogle Scholar
  10. 10.
    Chang MH. Viral mutants and fulminant hepatitis. A dominant hepatitisB population defective in virus secretion because of several S-gene mutations from a patient with fulminant hepatitis. J Pediatr Gastroenterol Nutr. 2002;34(4):426.PubMedCrossRefGoogle Scholar
  11. 11.
    Xu DZ, Yan Y-P, Choi BCK, et al. Risk factors and mechanism of transplacental transmission of hepatitis B virus: a case–control study. J Med Virol. 2002;67:20–6.PubMedCrossRefGoogle Scholar
  12. 12.
    Harber B, Block J, Jonas MM, et al. Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B. Pediatrics. 2009;124(5):e1–7.Google Scholar
  13. 13.
    Petrova M, Kamburov V. Breastfeeding and chronic HBV infection: clinical and social implications. World J Gastroenterol. 2010;16(40):5042–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Zheng Y, Lu Y, Ye Q, et al. Should chronic hepatitis B mothers breastfeed? a meta analysis. BMC Public Health. 2011;11:502.PubMedCrossRefGoogle Scholar
  15. 15.
    Abdel-Hady M, Kelly DA. Viral hepatitis in children – hepatitis B and hepatitis C. Eur Paediatr. 2011;5:40–5.Google Scholar
  16. 16.
    Dumolard L, Gacic-Dobo M, Shapiro CN, et al. Immunization, vaccines, and biologicals, expanded programme on immunization, World Health Organization, Geneva, Switzerland. MMW 2008; 1249–52.Google Scholar
  17. 17.
    World Health Organisation. Global routine vaccination coverage, 2010. Wkly Epidemiol. 2011;86:509–13.Google Scholar
  18. 18.
    Petersen KM, Bulkow LR, McMahon MD, et al. Duration of hepatitis B immunity in low risk children receiving hepatitis B vaccinations from birth. Pediatr Infect Dis J. 2004;23(7):650–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Boxall EH, Sira J, El-Shukri N, et al. Long-term persistence of immunity to hepatitis B after vaccination during infancy in a country where endemicity is low. J Infect Dis. 2004;190:1264–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Iorio R, Giannattasio A, Cirillo FD, et al. Long-term outcome in children with chronic hepatitis B: a 24-year observation period. Clin Infect Dis. 2007;45:943–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Ni Y-H, Chang M-H, Chen P-J, et al. Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion. Gastroenterology. 2007;132:2340–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen M, Sällberg M, Hughes J, et al. Immune tolerance split between hepatitis B virus pre-core and core proteins. J Virol. 2005;79:3016–27.PubMedCrossRefGoogle Scholar
  23. 23.
    Shi YH, Shi CH. Molecular characteristics and stages of chronic hepatitis B virus infection. World J Gastroenterol. 2009;15(25):3099–105.PubMedCrossRefGoogle Scholar
  24. 24.
    Milich D. Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology. 2003;38:1075–86.PubMedCrossRefGoogle Scholar
  25. 25.
    Sokal RJ, Brumbaugh D. Treatment of chronic hepatitis B virus infection in children. Curr Hepat Rep. 2009;8:96–102.CrossRefGoogle Scholar
  26. 26.
    Marx G, Martin SR, Chicoine JF, et al. Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins. J Infect Dis. 2002;183(3):295–301.CrossRefGoogle Scholar
  27. 27.
    Chu CM, Liaw YF. Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion. J Viral Hepat. 2007;14:147–52.PubMedCrossRefGoogle Scholar
  28. 28.
    Bortolotti F, Guido M, Bartolacci S, et al. Chronic hepatitis B in children after e antigen seroclearance. Final report of a 29-year longitudinal study. Hepatology. 2006;43:556–62.PubMedCrossRefGoogle Scholar
  29. 29.
    Livingstone SE, Simonetti JP, Bulkow LR, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D and F. Gastroenterology. 2007;133(5):1425–57.Google Scholar
  30. 30.
    Chang Mei-Hwei. Natural history and clinical management of chronic hepatitis B virus infection in children. Hepatol Int. 2008;2(Suppl 1):28–36.PubMedCrossRefGoogle Scholar
  31. 31.
    McMohan BJ, Holck P, Bulkow L, et al. Serologic and clinical outcomes of 1536 Alaska natives chronically infected with chronic heaptitis B virus. Ann Intern Med. 2001;135(9):759–68.CrossRefGoogle Scholar
  32. 32.
    Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002;35(6):1522–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology. 2009;137(5):1593–1608.e2.PubMedCrossRefGoogle Scholar
  34. 34.
    Shah U, Kelly DA, Chang M-H, et al. Management of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr. 2009;48(4):399–404.PubMedCrossRefGoogle Scholar
  35. 35.
    Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa2a, lamivudine, and the combination for HBeAG-positive chronic hepatitis B. N Engl J Med. 2005;352(26):2682–90.PubMedCrossRefGoogle Scholar
  36. 36.
    Sokal EM, Conjeevaram HS, Roberts EA, et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology. 1998;114:988–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Jonas MM, Kelly DA, Mizerski J, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med. 2002;346:1706–13.PubMedCrossRefGoogle Scholar
  38. 38.
    Viganò M, Lampertico P, Colombo M. Drug safety evaluation of adefovir in HBV infection. Expert Opin Drug Safety. 2011;10:809–18.CrossRefGoogle Scholar
  39. 39.
    Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naive patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–14.PubMedCrossRefGoogle Scholar
  40. 40.
    Cooksley WG, Piratvisuth T, Lee SD, et al. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat. 2003;10:298–305.PubMedCrossRefGoogle Scholar
  41. 41.
    Jara P, Bortolotti F. Interferon-α treatment of chronic hepatitis B in childhood: a consensus advice based on experience in European children. J Paediatr Gastroenterol Nutr. 1999;29(2):163–70.CrossRefGoogle Scholar
  42. 42.
    Bortolotti F, Jara P, Barbera C, et al. Long term effect of alpha interferon in children with chronic hepatitis B. Gut. 2000;46(5):715–8.PubMedCrossRefGoogle Scholar
  43. 43.
    Boxall E, Sira J, Ballard A, et al. Long-term follow-up of hepatitis B carrier children treated with interferon and prednisolone. J Med Virol. 2006;78(7):888–95.PubMedCrossRefGoogle Scholar
  44. 44.
    Sokal EM, Conjeevaram HS, Roberts EA, et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomised control trial. Gastroenterology. 1999;114(5):988–95.CrossRefGoogle Scholar
  45. 45.
    Nafa S, Ahmed S, Tavan D, et al. Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B. Hepatology. 2000;32:1078–88.PubMedCrossRefGoogle Scholar
  46. 46.
    Sokal AM, Kelly DA, Mizerski J, et al. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology. 2006;43:225–32.PubMedCrossRefGoogle Scholar
  47. 47.
    Lai CL, Dienstag J, Schiff E, et al. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B. Clin Infect Dis. 2003;36:687–96.PubMedCrossRefGoogle Scholar
  48. 48.
    Liaw YF, Sung JJ, Chow WC, et al. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:1521–31.PubMedCrossRefGoogle Scholar
  49. 49.
    Perrillo RP, Lai CL, Liaw YF, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36:186–94.PubMedCrossRefGoogle Scholar
  50. 50.
    Hom X, Little NR, Gardner SD, Jonas MM. Predictors of virologic response to lamivudine treatment in children with chronic hepatitis B. Pediatr Infect Dis J. 2004;23:441–5.PubMedCrossRefGoogle Scholar
  51. 51.
    Jonas MM, Kelly D, Pollack H, et al. Efficacy and safety of long-term adefovir dipivoxil therapy in children with chronic hepatitis B infection. Pediatr Infect Dis J. 2012;31(6):578–82.PubMedCrossRefGoogle Scholar
  52. 52.
    Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology. 2009;49:S185–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Hadziyannis S, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. 2005;352(26):2672–81.CrossRefGoogle Scholar
  54. 54.
    Chang T–T, Gish RG, de Man R, Gadano A, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–10.PubMedCrossRefGoogle Scholar
  55. 55.
    Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–20.PubMedCrossRefGoogle Scholar
  56. 56.
    Bristol-Myers Squibb. A phase III study of the safety and efficacy of entecavir in pediatric patients with chronic HBV-infection (NLM Identifier: NCT01079806). In: National Library of Medicine (US), Bethesda (MD). Accessed 18 Sep 2011.
  57. 57.
    Novartis Pharmaceuticals. Pharmacokinetics and safety of single-dose telbivudine in children and adolescents with chronic hepatitis B (NLM Identifier: NCT00907894). In: National Library of Medicine (US), Bethesda (MD). Accessed 18 Sep 2011.
  58. 58.
    Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442–55.PubMedCrossRefGoogle Scholar
  59. 59.
    Heathcote EJ, Gane E, deMan R, et al. Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg-positive patients with chronic hepatitis B (study 103), preliminary analysis. Hepatology. 2008;48(Suppl 1):376A.Google Scholar
  60. 60.
    Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology. 2012;142(4):773–81.Google Scholar
  61. 61.
    D’Antiga L, Aw M, Atkins M, et al. Combined lamivudine/interferon alfa treatment in immune tolerant children perinatally infected with hepatitis B: a pilot study. J Pediatr. 2006;148(2):228–33.PubMedCrossRefGoogle Scholar
  62. 62.
    Kansu A, Doganci T, Akman SA, et al. Comparison of two different regimens of combined interferon-alpha2a and lamivudine therapy in children with chronic hepatitis B infection. Antivir Ther. 2006;11:255–61.PubMedGoogle Scholar
  63. 63.
    Chu M, Cho SM, Choe BH, et al. Virologic responses to add-on adefovir dipivoxil treatment versus entecavir monotherapy in children with lamivudine resistant chronic hepatitis B. J Pediatr Gastroenterol Nutr. 2012;55(6):648–52.PubMedCrossRefGoogle Scholar
  64. 64.
    Terrault NA. Treatment of recurrent hepatitis B infection in liver transplant recipients. Liver Transpl. 2002;10:S74–81.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Liver Unit, Birmingham Children’s HospitalBirminghamUK

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