Overview of hepatitis B virus infection in children and adolescents
- Annemarie Broderick, MB, BCh, MMedSc, FRCPI
Annemarie Broderick, MB, BCh, MMedSc, FRCPI
- Senior Clinical Lecturer
- University College Dublin
- Maureen M Jonas, MD
Maureen M Jonas, MD
- Professor of Pediatrics
- Harvard Medical School
- Section Editors
- Sheldon L Kaplan, MD
Sheldon L Kaplan, MD
- Editor-in-Chief — Pediatrics
- Section Editor — Pediatric Infectious Diseases
- Professor and Vice Chairman for Clinical Affairs
- Baylor College of Medicine
- Elizabeth B Rand, MD
Elizabeth B Rand, MD
- Section Editor — Pediatric Hepatology
- Associate Professor of Pediatrics
- University of Pennsylvania School of Medicine
Hepatitis B virus (HBV) infection remains a global public health problem despite the availability of an effective vaccine.
An overview of HBV infection in children will be presented here. More detailed discussions of the microbiology, pathogenesis, clinical manifestations, and diagnosis are presented separately. (See "Characteristics of the hepatitis B virus and pathogenesis of infection" and "Clinical manifestations and natural history of hepatitis B virus infection" and "Diagnosis of hepatitis B virus infection".)
In the United States, the incidence of acute hepatitis B in children (<19 years) has decreased from approximately 13.8 cases per 100,000 population (10 to 19 years) in the 1980s  to 3.03 and 0.34 cases per 100,000 population in 1990 and 2002, respectively . Declines have been greatest among children who were born after 1991 when recommendations for universal hepatitis B vaccination of infants were implemented. By 2007, the incidence of acute hepatitis B in children <15 years had fallen to 0.02 cases per 100,000 population [3,4]. (See "Hepatitis B virus vaccination".)
In the United States and in several other non-endemic countries, most cases of acute hepatitis B infection develop in patients from high-risk groups such as intravenous drug users, homosexual men, in those living in communities with a large proportion of immigrants from regions where hepatitis B virus (HBV) is endemic, and in certain groups where HBV is endemic, such as Native Americans in Alaska . The majority of children with chronic HBV infections are immigrants, have immigrant parents, or became exposed through other household contacts [6,7].
In countries where HBV is endemic, perinatal transmission remains the most important cause of chronic infection because of high rates of disease in pregnant women. Perinatal transmission also occurs in non-endemic countries, including the United States, mostly in children of HBV-infected mothers who do not receive appropriate HBV immunoprophylaxis at birth [8,9]. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection" and "Clinical significance of hepatitis B virus genotypes".)
- Goldstein ST, Alter MJ, Williams IT, et al. Incidence and risk factors for acute hepatitis B in the United States, 1982-1998: implications for vaccination programs. J Infect Dis 2002; 185:713.
- Centers for Disease Control and Prevention (CDC). Acute hepatitis B among children and adolescents--United States, 1990-2002. MMWR Morb Mortal Wkly Rep 2004; 53:1015.
- Daniels D, Grytdal S, Wasley A, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis - United States, 2007. MMWR Surveill Summ 2009; 58:1.
- Wasley A, Kruszon-Moran D, Kuhnert W, et al. The prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis 2010; 202:192.
- 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.
- Ordög K, Szendrôi A, Szarka K, et al. Perinatal and intrafamily transmission of hepatitis B virus in three generations of a low-prevalence population. J Med Virol 2003; 70:194.
- Ladhani SN, Flood JS, Amirthalingam G, et al. Epidemiology and clinical features of childhood chronic hepatitis B infection diagnosed in England. Pediatr Infect Dis J 2014; 33:130.
- Centers for Disease Control and Prevention (CDC). Prevention of perinatal hepatitis B through enhanced case management--Connecticut, 1994-95, and the United States, 1994. MMWR Morb Mortal Wkly Rep 1996; 45:584.
- Jenkins CN, McPhee SJ, Wong C, et al. Hepatitis B immunization coverage among Vietnamese-American children 3 to 18 years old. Pediatrics 2000; 106:E78.
- Haber BA, Block JM, Jonas MM, et al. Recommendations for screening, monitoring, and referral of pediatric chronic hepatitis B. Pediatrics 2009; 124:e1007.
- Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1.
- American Academy of Pediatrics. Medical evaluation of internationally adopted children for infectious diseases. In: Red Book: 2012 Report of the Committee on Infectious Diseases, 29th ed, Pickering LK, Baker CJ, Kimberlin DW, Long SS, Eds (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2012. p.193.
- Kao JH, Hsu HM, Shau WY, et al. Universal hepatitis B vaccination and the decreased mortality from fulminant hepatitis in infants in Taiwan. J Pediatr 2001; 139:349.
- Chen HL, Chang CJ, Kong MS, et al. Pediatric fulminant hepatic failure in endemic areas of hepatitis B infection: 15 years after universal hepatitis B vaccination. Hepatology 2004; 39:58.
- Bhimma R, Coovadia HM, Adhikari M, Connolly CA. The impact of the hepatitis B virus vaccine on the incidence of hepatitis B virus-associated membranous nephropathy. Arch Pediatr Adolesc Med 2003; 157:1025.
- Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology 1988; 8:1130.
- Lok AS, Lai CL, Wu PC, et al. Treatment of chronic hepatitis B with interferon: experience in Asian patients. Semin Liver Dis 1989; 9:249.
- Ni YH, Huang LM, Chang MH, et al. Two decades of universal hepatitis B vaccination in taiwan: impact and implication for future strategies. Gastroenterology 2007; 132:1287.
- Chang MH, Sung JL, Lee CY, et al. Factors affecting clearance of hepatitis B e antigen in hepatitis B surface antigen carrier children. J Pediatr 1989; 115:385.
- Liaw YF, Chu CM, Lin DY, et al. Age-specific prevalence and significance of hepatitis B e antigen and antibody in chronic hepatitis B virus infection in Taiwan: a comparison among asymptomatic carriers, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. J Med Virol 1984; 13:385.
- Wu JF, Tsai WY, Hsu HY, et al. Effect of puberty onset on spontaneous hepatitis B virus e antigen seroconversion in men. Gastroenterology 2010; 138:942.
- Bortolotti F, Cadrobbi P, Crivellaro C, et al. Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood. Gastroenterology 1990; 99:805.
- 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.
- Livingston 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; 133:1452.
- Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology 2002; 35:1522.
- Bortolotti F, Calzia R, Cadrobbi P, et al. Liver cirrhosis associated with chronic hepatitis B virus infection in childhood. J Pediatr 1986; 108:224.
- Godra A, Perez-Atayde AR, Jonas MM. Histologic features of chronic hepatitis B in children (abstract). Hepatology 2005; 42(Suppl 1):478A.
- Wang SH, Yeh SH, Lin WH, et al. Estrogen receptor α represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4α. Gastroenterology 2012; 142:989.
- Tong S. Hepatitis B virus, a sex hormone-responsive virus. Gastroenterology 2012; 142:696.
- Tanaka T, Miyamoto H, Hino O, et al. Primary hepatocellular carcinoma with hepatitis B virus-DNA integration in a 4-year-old boy. Hum Pathol 1986; 17:202.
- Cheah PL, Looi LM, Lin HP, Yap SF. Childhood primary hepatocellular carcinoma and hepatitis B virus infection. Cancer 1990; 65:174.
- Giacchino R, Navone C, Facco F, et al. HBV-DNA-related hepatocellular carcinoma occurring in childhood. Report of three cases. Dig Dis Sci 1991; 36:1143.
- Pontisso P, Basso G, Perilongo G, et al. Does hepatitis B virus play a role in primary liver cancer in children of Western countries? Cancer Detect Prev 1991; 15:363.
- Hsu HC, Wu MZ, Chang MH, et al. 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.
- NIH Consensus Development Conference: Management of Hepatitis B, October 20-22, 2008. Draft statement available at: http://consensus.nih.gov/2008/2008HepatitisBCDC120main.htm.
- Wen WH, Chang MH, Hsu HY, et al. The development of hepatocellular carcinoma among prospectively followed children with chronic hepatitis B virus infection. J Pediatr 2004; 144:397.
- Ni YH, Chang MH, Wang KJ, et al. Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology 2004; 127:1733.
- Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 1997; 336:1855.
- Chang MH, You SL, Chen CJ, et al. Decreased incidence of hepatocellular carcinoma in hepatitis B vaccinees: a 20-year follow-up study. J Natl Cancer Inst 2009; 101:1348.
- Jonas MM, Block JM, Haber BA, et al. Treatment of children with chronic hepatitis B virus infection in the United States: patient selection and therapeutic options. Hepatology 2010; 52:2192.
- Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology 2009; 50:661.
- Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1: immunization of infants, children, and adolescents. MMWR Recomm Rep 2005; 54:1.
- American Academy of Pediatrics. Hepatitis B. In: Red Book: 2015 Report of the Committee on Infectious Diseases, 30th ed, Kimberlin DW, Brady MT, Jackson MA, Long SS (Eds), American Academy of Pediatrics, Elk Grove Village, IL 2015. p.400.
- Murray KF, Shah U, Mohan N, et al. Chronic hepatitis. J Pediatr Gastroenterol Nutr 2008; 47:225.
- Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45:507.
- Whittle H, Jaffar S, Wansbrough M, et al. Observational study of vaccine efficacy 14 years after trial of hepatitis B vaccination in Gambian children. BMJ 2002; 325:569.
- Torre D, Tambini R. Interferon-alpha therapy for chronic hepatitis B in children: a meta-analysis. Clin Infect Dis 1996; 23:131.
- Jonas MM, Mizerski J, Badia IB, et al. Clinical trial of lamivudine in children with chronic hepatitis B. N Engl J Med 2002; 346:1706.
- Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med 2009; 150:104.
- Shah U, Kelly D, Chang MH, et al. Management of chronic hepatitis B in children. J Pediatr Gastroenterol Nutr 2009; 48:399.
- Nikolaidis N, Vassiliadis T, Giouleme O, et al. Effect of lamivudine treatment in patients with decompensated cirrhosis due to anti-HBe positive/HBeAg-negative chronic hepatitis B. Clin Transplant 2005; 19:321.
- Prescribing information for Baraclude (entecavir), 2014. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021797s018,021798s019lbl.pdf (Accessed on April 16, 2014).
- Jonas MM, Kelly D, Pollack H, et al. Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B. Hepatology 2008; 47:1863.
- Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebo-controlled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology 2012; 56:2018.
- Ruiz-Moreno M, Rua MJ, Molina J, et al. Prospective, randomized controlled trial of interferon-alpha in children with chronic hepatitis B. Hepatology 1991; 13:1035.
- Barbera C, Bortolotti F, Crivellaro C, et al. Recombinant interferon-alpha 2a hastens the rate of HBeAg clearance in children with chronic hepatitis B. Hepatology 1994; 20:287.
- Narkewicz MR, Smith D, Silverman A, et al. Clearance of chronic hepatitis B virus infection in young children after alpha interferon treatment. J Pediatr 1995; 127:815.
- Vajro P, Tedesco M, Fontanella A, 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.
- 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.
- Giacchino R, Main J, Timitilli A, et al. Dual-centre, double-blind, randomised trial of lymphoblastoid interferon alpha with or without steroid pretreatment in children with chronic hepatitis B. Liver 1995; 15:143.
- Gürakan F, Koçak N, Ozen H, Yüce A. Comparison of standard and high dosage recombinant interferon alpha 2b for treatment of children with chronic hepatitis B infection. Pediatr Infect Dis J 2000; 19:52.
- Lai CL, Lok AS, Lin HJ, et al. Placebo-controlled trial of recombinant alpha 2-interferon in Chinese HBsAg-carrier children. Lancet 1987; 2:877.
- Lai CL, Lin HJ, Lau JN, et al. Effect of recombinant alpha 2 interferon with or without prednisone in Chinese HBsAg carrier children. Q J Med 1991; 78:155.
- Iorio R, Pensati P, Botta S, et al. Side effects of alpha-interferon therapy and impact on health-related quality of life in children with chronic viral hepatitis. Pediatr Infect Dis J 1997; 16:984.
- Liberek A, Łuczak G, Korzon M, et al. Tolerance of interferon-alpha therapy in children with chronic hepatitis B. J Paediatr Child Health 2004; 40:265.
- Gottrand F, Michaud L, Guimber D, et al. Influence of recombinant interferon alpha on nutritional status and growth pattern in children with chronic viral hepatitis. Eur J Pediatr 1996; 155:1031.
- Comanor L, Minor J, Conjeevaram HS, et al. Impact of chronic hepatitis B and interferon-alpha therapy on growth of children. J Viral Hepat 2001; 8:139.
- Koçak N, Gürakan F, Saltik IN, et al. Long-term prognosis of interferon nonresponder children with hepatitis B. Am J Gastroenterol 2000; 95:1841.
- Ballauff A, Schneider T, Gerner P, et al. Safety and efficacy of interferon retreatment in children with chronic hepatitis B. Eur J Pediatr 1998; 157:382.
- Abstract "A comparative study of the antiviral efficacy and safety of entecavir versus placebo in HBeAg-positive pediatric subjects with chronic hepatitis B". [As of 5/7/14, these data are being analyzed for further publication]. Abstract available at: http://www.abstractsmanager.com/conf/apasl/public/documents-view.php?id=268&cat=7.
- Lok AS, Lai CL, Leung N, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 2003; 125:1714.
- Dikici B, Ozgenc F, Kalayci AG, et al. Current therapeutic approaches in childhood chronic hepatitis B infection: a multicenter study. J Gastroenterol Hepatol 2004; 19:127.
- Chevaliez S, Hézode C, Bahrami S, et al. Long-term hepatitis B surface antigen (HBsAg) kinetics during nucleoside/nucleotide analogue therapy: finite treatment duration unlikely. J Hepatol 2013; 58:676.
- WHO SHOULD BE SCREENED
- CLINICAL MANIFESTATIONS AND DIAGNOSIS
- Acute HBV infection
- Chronic HBV infection
- NATURAL HISTORY
- Phases of chronic HBV infection
- - Immune tolerant
- - Immune active (clearance)
- - Inactive carrier
- - Resolution of infection
- - Reactivation
- Progression to cirrhosis
- Hepatocellular carcinoma
- MANAGEMENT OF CHRONIC HBV
- Initial evaluation
- Counseling and prevention
- Monitoring of patients
- - Disease activity
- - HCC surveillance
- Selection of patients for treatment
- CHOICE OF TREATMENT
- Interferon alfa
- - Pegylated interferon
- - Efficacy
- - Side effects
- - Non-responders
- Tenofovir disoproxil fumarate
- Adefovir dipivoxil
- MANAGEMENT OF ACUTE HBV
- SUMMARY AND RECOMMENDATIONS