Hepatology International

, Volume 2, Supplement 1, pp 28–36 | Cite as

Natural history and clinical management of chronic hepatitis B virus infection in children



Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon α and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon α, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.


Hepatitis B virus Chronic hepatitis B Hepatitis B e antigen Children Adolescents 


  1. 1.
    Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med. 2004;350:1118–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Bortolotti F, Calzia R, Cadrobbi P, Giacchini R, Ciravegna B, Armigliato M, et al. Liver cirrhosis associated with chronic hepatitis B virus infection in childhood. J Pediatr. 1986;108:224–7.PubMedCrossRefGoogle Scholar
  3. 3.
    Hsu HC, Wu MZ, Chang MH, Su IJ, Chen DS. Childhood hepatocellular carcinoma develops exclusively in hepatitis B surface antigen carriers in three decades in Taiwan. Report of 51 cases strongly associated with rapid development of liver cirrhosis. J Hepatol. 1987;5:260–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Hsu HC, Lin YH, Chang MH, Su IJ, Chen DS. Pathology of chronic hepatitis B virus infection in children: with special reference to the intrahepatic expression of hepatitis B virus antigens. Hepatology. 1988;8:378–82.PubMedCrossRefGoogle Scholar
  5. 5.
    Leuschner I, Harms D, Schmidt D. The association of hepatocellular carcinoma in childhood with hepatitis B virus infection. Cancer. 1988;62:2363–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Stevens CE, Beasley RP, Tsui J, Lee WC. Vertical transmission of hepatitis B antigen in Taiwan. N Engl J Med. 1975;292:771–4.PubMedCrossRefGoogle Scholar
  7. 7.
    Beasley RP, Hwang LY, Lin CC, Leu ML, Stevens CE, Szmuness W, et al. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis. 1982;146:198–204.PubMedGoogle Scholar
  8. 8.
    Chang MH, Sung JL, Lee CY, Chen CJ, Chen JS, Hsu HY, et al. Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children. J Pediatr. 1989;115:385–90.PubMedCrossRefGoogle Scholar
  9. 9.
    Chu CM, Karayiannis P, Fowler MJ, Monjardino J, Liaw YF, Thomas HC. Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology. 1985;5:431–4.PubMedCrossRefGoogle Scholar
  10. 10.
    Beasley RP, Hwang LY, Lin CC, Ko YC, Twu SJ. Incidence of hepatitis among students at a university in Taiwan. Am J Epidemiol. 1983;117:213–22.PubMedGoogle Scholar
  11. 11.
    Tang JR, Hsu HY, Lin HH, Ni YH, Chang MH. Hepatitis B surface antigenemia at birth: a long-term follow-up study. J Pediatr. 1998;133:374–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Hsu HY, Chang MH, Hsieh KH, Lee CY, Lin HH, Hwang LH, et al. Cellular immune response to HBcAg in mother-to-infant transmission of hepatitis B virus. Hepatology. 1992;15:770–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Ni YH, Chang MH, Chen PJ, Tsai KS, Hsu HY, Chen HL, et al. Viremia profiles in children with chronic hepatitis B virus infection and spontaneous e antigen seroconversion. Gastroenterology. 2007;132:2340–5.PubMedCrossRefGoogle Scholar
  14. 14.
    Chang MH, Hsu HY, Hsu HC, Ni YH, Chen JS, Chen DS. The significance of spontaneous hepatitis B e antigen seroconversion in childhood: with special emphasis on the clearance of hepatitis B e antigen before 3 years of age. Hepatology. 1995;22:1387–92.PubMedGoogle Scholar
  15. 15.
    Bortolotti F, Cadrobbi P, Crivellaro C, Guido M, Rugge M, Noventa F, et al. Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood. Gastroenterology. 1990;99:805–10.PubMedGoogle Scholar
  16. 16.
    Bortolotti F, Guido M, Bartolacci S, Cadrobbi P, Crivellaro C, Noventa F, et al. Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study. Hepatology. 2006;43:556–62.PubMedCrossRefGoogle Scholar
  17. 17.
    Chang MH, Chen DS, Hsu HC, Hsu HY, Lee CY. Maternal transmission of hepatitis B virus in childhood hepatocellular carcinoma. Cancer. 1989;64:2377–80.PubMedCrossRefGoogle Scholar
  18. 18.
    Marx G, Martin SR, Chicoine JF, Alvarez F. Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins. J Infect Dis. 2002;186:295–301.PubMedCrossRefGoogle Scholar
  19. 19.
    Wen WH, Chang MH, Hsu HY, Ni YH, Chen HL. The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection. J Pediatr. 2004;144:397–99.PubMedCrossRefGoogle Scholar
  20. 20.
    Ferns RB, Naoumov NV, Gilson RJ, Tedder RS. Presence of hepatitis B virus core promoter mutations pre-seroconversion predict persistent viral replication after HBeAg loss. J Clin Virol. 2007;39:199–204.PubMedCrossRefGoogle Scholar
  21. 21.
    Smith PR, Zampino R, Gutteridge C, Karayiannis P, Aitken C. Reactivation of precore variant hepatitis B virus in a child with severe aplastic anaemia. J Med Virol. 2001;65:470–2.PubMedCrossRefGoogle Scholar
  22. 22.
    Hsu HY, Chang MH, Lee CY, Chen JS, Hsu HC, Chen DS. Spontaneous loss of HBsAg in children with chronic hepatitis B virus infection. Hepatology. 1992;15:382–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology. 1988;8:1130–3.PubMedCrossRefGoogle Scholar
  24. 24.
    Boxall EH, Sira J, Standish RA, et al. Natural history of hepatitis B in perinatally infected carriers. Arch Dis Child Fetal Neonatal Ed. 2004;89:F456–60.PubMedCrossRefGoogle Scholar
  25. 25.
    Chang MH, Hwang LY, Hsu HC, Lee CY, Beasley RP. Prospective study of asymptomatic HBsAg carrier children infected in the perinatal period: clinical and liver histologic studies. Hepatology. 1988;8:374–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Chang MH. Hepatitis B infections in infancy and childhood. Int Semin Pediatric Gastroenteorl Nutr. 1996;5:3–9.Google Scholar
  27. 27.
    Chang MH, Chen TH, Hsu HM, Wu TC, Kong MS, Liang DC, et al. Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems. Clin Cancer Res. 2005;11:7953–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Oommen PT, Wirth S, Wintermeyer P, Gerner P. Relationship between viral load and genotypes of hepatitis B virus in children with chronic hepatitis B. J Pediatr Gastroenterol Nutr. 2006;43(3):342–7.PubMedCrossRefGoogle Scholar
  29. 29.
    Dusheiko GM, Brink BA, Conradie JD, Narimuthu T, Sher R. Regional prevalence of hepatitis B, delta, and human immunodeficiency virus infection in southern Aftrica: a large population survey. Am J Epidemol. 1989;129:138–45.Google Scholar
  30. 30.
    Kramvis A, Kew MC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res. 2007;37:S9–19.PubMedCrossRefGoogle Scholar
  31. 31.
    McMahon BJ, Alward WL, Hall DB, et al. Acute hepatitis B virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. J Infect Dis. 1985;151:599–603.PubMedGoogle Scholar
  32. 32.
    Livingston SE, Simounetti JP, Bulkow LR, et al. Clearance of hepatitis B e antigen in patients with chronic hepaitis B and genotypes A, B, C, D, and F. Gastroenterology. 2007;133:1452–7.PubMedCrossRefGoogle Scholar
  33. 33.
    Livingston SE, Simonetti JP, McMahon BJ, et al. Hepatitis B virus genotypes in Alaska native people with hepatocellular carcinoma; preponderance of genotype F. J Infect Dis. 2007;195:5–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Chang MH, Hsu HY, Ni YH, Tsai KS, Lee PI, Chen PJ, et al. Precore stop codon mutant in chronic hepatitis B virus infection in children: its relation to hepatitis B e seroconversion and maternal hepatitis B surface antigen. J Hepatol. 1998;28:915–22.PubMedCrossRefGoogle Scholar
  35. 35.
    Ni YH, Chang MH, Hsu HY, Tsuei DJ. Longitudinal study on mutation profiles of core promoter and precore regions of the hepatitis B virus genome in children. Pediatr Res. 2004;56:396–9.PubMedCrossRefGoogle Scholar
  36. 36.
    Ni YH, Chang MH, Hsu HY, Tsuei DJ. Different hepatitis B virus core gene mutations in children with chronic infection and hepatocellular carcinoma. Gut. 2003;52:122–5.PubMedCrossRefGoogle Scholar
  37. 37.
    Ni YH, Chang MH, Hsu HY, Chen HL. Long-term follow-up study of core gene deletion mutants in children with chronic hepatitis B virus infection. Hepatology. 2000;32:124–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Liaw Y-F, the ACT-HBV Asia Pacific Steering Committee Members. Chronic hepatitis B: treatment alert. Liver Int. 2006;26:47–58.CrossRefGoogle Scholar
  39. 39.
    Liaw YF, Leung N, Guan R, Lau GK, Merican I, McCaughan G, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2005 update. Liver Int. 2005;25:472–89.PubMedCrossRefGoogle Scholar
  40. 40.
    Sokal EM, Conjeevaram HS, Roberts EA, Alvarez F, Bern EM, Goyens P, et al. Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial. Gastroenterology. 1998;114:988–95.PubMedCrossRefGoogle Scholar
  41. 41.
    Lai CL, Lok AS, Lin HJ, Wu PC, Yeoh EK, Yeung CY. Placebo-controlled trial of recombinant alpha 2-interferon in Chinese HBsAg-carrier children. Lancet. 1987;2:877–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Lai CL, Lin HJ, Lau JN, Flok AS, Wu PC, Chung HT, et al. Effect of recombinant alpha 2 interferon with or without prednisone in Chinese HBsAg carrier children. Q J Med. 1991;78:155–63.PubMedGoogle Scholar
  43. 43.
    Barbera C, Bortolotti F, Crivellaro C, Coscia A, Zancan L, Cadrobbi P, et al. Recombinant interferon-alpha 2a hastens the rate of HBeAg clearance in children with chronic hepatitis B. Hepatology. 1994;20:287–90.PubMedGoogle Scholar
  44. 44.
    Narkewicz MR, Smith D, Silverman A, Vierling J, Sokol RJ. Clearance of chronic hepatitis B virus infection in young children after alpha interferon treatment. J Pediatr. 1995;127:815–18.PubMedCrossRefGoogle Scholar
  45. 45.
    Ruiz-Moreno M, Camps T, Jimenez J, Lopez R, Castillo I, Bartolome J, et al. Factors predictive of response to interferon therapy in children with chronic hepatitis B. J Hepatol. 1995;22:540–4.PubMedCrossRefGoogle Scholar
  46. 46.
    Gregorio GV, Jara P, Hierro L, Diaz C, de la Vega A, Vegnente A, et al. Lymphoblastoid interferon alfa with or without steroid pretreatment in children with chronic hepatitis B: a multicenter controlled trial. Hepatology. 1996;23:700–7.PubMedCrossRefGoogle Scholar
  47. 47.
    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. Pediatr Infect Dis J. 1996;15:223–31.PubMedCrossRefGoogle Scholar
  48. 48.
    Bortolotti F, Jara P, Barbera C, Gregorio GV, Vegnente A, Zancan L, et al. Long term effect of alpha interferon in children with chronic hepatitis B. Gut. 2000;46:715–8.PubMedCrossRefGoogle Scholar
  49. 49.
    Torre D, Tambini R. Interferon-alpha therapy for chronic hepatitis B in children: a meta-analysis. Clin Infect Dis. 1996;23:131–7.PubMedGoogle Scholar
  50. 50.
    Perry CM, Faulds D. Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection. Drugs. 1997;53:657–80.PubMedGoogle Scholar
  51. 51.
    Jonas MM, Mizerski J, Badia IB, Areias JA, Schwarz KB, Little NR, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med. 2002;346:1706–13.PubMedCrossRefGoogle Scholar
  52. 52.
    Sokal EM, Kelly DA, Mizerski J, Badia IB, Areias JA, Schwarz KB, et al. Long-term lamivudine therapy for children with HBeAg-positive chronic hepatitis B. Hepatology. 2006;43:225–32.PubMedCrossRefGoogle Scholar
  53. 53.
    Zoulim F, Trepo C. Drug therapy for chronic hepatitis B: antiviral efficacy and influence of hepatitis B virus polymerase mutations on the outcome of therapy. J Hepatol. 1998;29:151–68.PubMedCrossRefGoogle Scholar
  54. 54.
    Melegari M, Scaglioni PP, Wands JR. Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective. Hepatology. 1998;27:628–33.PubMedCrossRefGoogle Scholar
  55. 55.
    Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology. 1999;30:567–72.PubMedCrossRefGoogle Scholar
  56. 56.
    Kansu A, Doganci T, Akman SA, Artan R, Kuyucu N, Kalayci AG, 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
  57. 57.
    van Bommel F, Zollner B, Sarrazin C, Spengler U, Huppe D, Moller B, et al. Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy. Hepatology. 2006;44:318–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Yilmaz A, Akcam M, Gelen T, Artan R. Lamivudine and high-dose interferon alpha 2a combination treatment in naive HBeAg-positive immunoactive chronic hepatitis B in children: an East Mediterranean center’s experience. Eur J Pediatr. 2007;166:195–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Sokucu S, Gokce S, Suoglu OD, Emiroglu H, Cevikbas U. Comparison of interferon monotherapy with interferon-lamivudine combination treatment in children with chronic hepatitis B. Indian J Gastroenterol. 2006;25:136–9.PubMedGoogle Scholar
  60. 60.
    Dikici B, Bosnak M, Bosnak V, Dagli A, Davutoglu M, Yagci RV, et al. Comparison of treatments of chronic hepatitis B in children with lamivudine and alpha-interferon combination and alpha-interferon alone. Pediatr Int. 2002;44:517–21.PubMedCrossRefGoogle Scholar
  61. 61.
    Selimoglu MA, Aydogdu S, Unal F, Zeytinoglu A, Yuce G, Yagci RV. Alpha interferon and lamivudine combination therapy for chronic hepatitis B in children. Pediatr Int. 2002;44:404–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Dikici B, Bosnak M, Bosnak V, Dagli A, Ece A, Yagci RV, et al. Combination therapy for children with chronic hepatitis B virus infection. J Gastroenterol Hepatol. 2002;17:1087–91.PubMedCrossRefGoogle Scholar
  63. 63.
    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. J Pediatr. 2006;148:228–33.PubMedCrossRefGoogle Scholar
  64. 64.
    Hartman C, Berkowitz D, Eshach-Adiv O, Hino B, Rimon N, Satinger I, et al. Long-term lamivudine therapy for chronic hepatitis B infection in children unresponsive to interferon. J Pediatr Gastroenterol Nutr. 2006;43:494–8.PubMedCrossRefGoogle Scholar
  65. 65.
    Papaleo A, Warszawski J, Salomon R, et al. Increased beta-2 microglobulinuria in human immunodeficiency virus-1-infected children and adolescents treated with tenofovir. Pediatric Infect Dis J. 2007;26:949–51.CrossRefGoogle Scholar
  66. 66.
    Schwarz KB, Mohan P, Narkewicz MR, Molleston JP, Nash SR, Hu S, et al. Safety, efficacy and pharmacokinetics of peginterferon alpha2a (40 kd) in children with chronic hepatitis C. J Pediatr Gastroenterol Nutr. 2006;43:499–505.PubMedCrossRefGoogle Scholar
  67. 67.
    Kowala-Piaskowska A, Sluzewski W, Figlerowicz M, Mozer-Lisewska I. Early virological response in children with chronic hepatitis C treated with pegylated interferon and ribavirin. Infection. 2007;35:175–9.PubMedCrossRefGoogle Scholar
  68. 68.
    Baker RD, Dee D, Baker SS. Response to pegylated interferon alpha-2b and ribavirin in children with chronic hepatitis C. J Clin Gastroenterol. 2007;41:111–4.PubMedCrossRefGoogle Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2008

Authors and Affiliations

  1. 1.Division of Gastroenterology and Hepatology, Department of PediatricsNational Taiwan University HospitalTaipeiTaiwan

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