Treatment of hepatitis B virus infection in children and adolescents

Table 1 Patients’ categories and phases in natural history of chronic hepatitis B virus infection defined by European Association for the Study of the Liver guidelines 2017[11]

	HBeAg positive	HBeAg negative	HBsAg negative
HBV infection (normal ALT)	High HBsAg	Low HBsAg	HBcAb-positive with/without positive HBsAb
	HBV DNA > 107 IU/mL	HBV DNA < 2000 IU/mL	HBV DNA usually undetectable
	None/minimal liver disease	No liver disease	No liver disease
	Old terminology: Immune-tolerant	Old terminology: Inactive carrier/immune control	Old terminology: Occult HBV infection
Hepatitis B (abnormal ALT)	High or intermediate HBsAg	Intermediate HBsAg
	HBV DNA 104-107 IU/mL	HBV DNA > 2000 IU/mL
	Moderate to severe liver disease	Moderate to severe liver disease
	Old terminology: immune-active	Old terminology: immune escape

HBV: Hepatitis B virus; ALT: Alanine aminotransferase levels; HBeAg: Hepatitis B e antigen; HBsAg: Hepatitis B s antigen; DNA: Deoxyribonucleic acid; HBcAb: Hepatitis B c antibodies.

Table 2 Antiviral drugs approved for children and adolescents with chronic hepatitis B virus infection[14]

	Ages approved for drug administration	Drug dosage	Drug formulations
Interferon alfa-2b	≥ 1 yr	6 million UI/m2 three times a week	Subcutaneous injection
Peginterferon alfa-2a	≥ 3 yr	180 µg/1.73 m2 once a week	Subcutaneous injection
Lamivudine	≥ 3 yr	3 mg/kg daily (maximum 100 mg)	Oral solution (5 mg/mL) or tablets (100 mg)
Entecavir	≥ 2 yr	10-30 kg: 0.015 mg/kg daily (maximum 0.5 mg)	Oral solution (0.05 mg/mL) or tablets (0.5 mg and 1 mg)
		> 30 kg: 0.5 mg daily
Adefovir	≥ 12 yr	10 mg daily	Tablets (10 mg)
Tenofovir disoproxil fumarate	≥ 2 yr1	8 mg/kg daily (maximum 300 mg)	Oral powder (40 mg per 1 g) or tablets (150 mg, 200 mg, 250 mg and 300 mg)
	≥ 12 yr1	300 mg daily
Tenofovir alafenamide	≥ 12 yr2	25 mg daily	Tablet (25 mg)

¹Approved for ≥ 2 yr by the European Medicines Agency and ≥ 12 yr by the United States Food and Drug Administration.

²Approved independent of age for weight > 35 kg.

Table 3 Differences among recommendations and indications for treatment of chronic hepatitis B virus infection in adults, adolescents, and children from five professional societies or international organizations

Organization
ESPGHAN[16]	HBeAg-positive adolescents and children with persistent alanine aminotransferase elevation for at least 6 mo
	HBeAg-negative adolescents and children with persistent alanine aminotransferase elevation for at least 6 mo for at least 12 mo
	HBV DNA > 2000 IU/mL and either
	Moderate necroinflammation or fibrosis
	Mild inflammation or fibrosis with a family history of hepatocellular carcinoma
AASLD[17]	HBeAg-positive adolescents and children with both elevated alanine aminotransferase and measurable HBV DNA concentrations
	Therapy should be deferred when HBV DNA is < 10000 IU/mL, until spontaneous HBeAg seroconversion is excluded
APASL[18]	Non-cirrhotic HBeAg-positive adolescents and children when HBV DNA level is higher than 20000 IU/mL and alanine aminotransferase is more than twice the upper limit of normal for more than 12 mo
	Non-cirrhotic HBeAg-positive adolescents and children either HBV DNA > 20000 IU/mL and ALT more than two times ULN for more than 12 mo, or a family history of hepatocellular carcinoma or cirrhosis and moderate-to-severe inflammation or pronounced fibrosis
	Non-cirrhotic, HBeAg-positive chronic HBV infection, HBV DNA < 20000 IU/mL and moderate to severe inflammation or pronounced fibrosis
	Non-cirrhotic, HBeAg-negative chronic HBV infection, HBV DNA > 2000 IU/mL, and ALT more than two times ULNNon-cirrhotic, HBeAg-negative chronic HBV infection and moderate to severe inflammation or pronounced fibrosis, regardless of HBV DNA concentration
EASL[11]	A conservative approach is warranted

ESPGHAN: European Society for Paediatric Gastroenterology Hepatology and Nutrition; HBeAg: Hepatitis B e antigen; HBV: Hepatitis B virus; DNA: Deoxyribonucleic acid; AASLD: American Association for the Study of Liver Diseases; APASL: Asian Pacific Association for the Study of the Liver; ALT: Alanine aminotransferase levels; ULN: Upper limit of normal; EASL: European Association for the Study of the Liver.