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

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Abstract

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.

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References

  1. Ganem D, Prince AM. Hepatitis B virus infection-natural history and clinical consequences. N Engl J Med. 2004;350:1118–29.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  5. Leuschner I, Harms D, Schmidt D. The association of hepatocellular carcinoma in childhood with hepatitis B virus infection. Cancer. 1988;62:2363–9.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  23. Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology. 1988;8:1130–3.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  26. Chang MH. Hepatitis B infections in infancy and childhood. Int Semin Pediatric Gastroenteorl Nutr. 1996;5:3–9.

    Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  38. Liaw Y-F, the ACT-HBV Asia Pacific Steering Committee Members. Chronic hepatitis B: treatment alert. Liver Int. 2006;26:47–58.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  49. Torre D, Tambini R. Interferon-alpha therapy for chronic hepatitis B in children: a meta-analysis. Clin Infect Dis. 1996;23:131–7.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

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Chang, MH. Natural history and clinical management of chronic hepatitis B virus infection in children. Hepatol Int 2 (Suppl 1), 28–36 (2008). https://doi.org/10.1007/s12072-008-9050-9

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