Treatment of chronic hepatitis B infection in infants and young children: A systematic review

Table 1 Antiviral drugs approved by European Medicine Agency and Food and Drug Administration for adults, adolescents and children with chronic hepatitis B virus infection

	EMA age of approval	EMA recommended dose	FDA age of approval	FDA recommended dose	Formulations
IFNα-2b	Authorisation withdrawn	-	1 year	6 million IU/m2 3 times a week	Subcutaneous injection
pegIFNα-2a	3 years	180 μg/1.73 m2 once a week	3 years	180 μg/1.73 m2 once a week	Subcutaneous injection
pegIFNα-2b	Authorisation withdrawn	-	Not approved	-	-
Lamivudine	18 years	100 mg/daily	2 years	3 mg/kg daily	Oral solution (5 mg/mL) or tablets (100 mg)
Adefovir	Authorisation withdrawn	-	12 years	10 mg daily	Tablets (10 mg)
Telbivudine	Authorisation withdrawn	-	16 years	600 mg daily	Oral solution (100 mg/5 mL) or tablets (600 mg)
Entecavir	2 years	10-32.6 kg: 0.015 mg/kg daily (maximum 0.5 mg); 32.6 kg: 0.5 mg/daily	2 years	10-30 kg: 0.015 mg/kg daily (maximum 0.5 mg); > 30 kg: 0.5 mg daily	Oral solution (0.05 mg/mL) or tablets (0.5 mg and 1 mg)
Tenofovir disoproxil fumarate	2 years	10-35 kg: 6.5 mg/kg/daily1; 35 kg ( 12 years): 245 mg/daily1	2 years	10-35 kg: 8 mg/kg/daily2; 35 kg: 300 mg daily2	Oral powder (40 mg per 1 g) or tablets (150 mg, 200 mg, 250 mg, and 300 mg)
Tenofovir alafenamide	6 years	25 mg daily	6 years	25 mg daily	Tablets (25 mg)

¹Ddose expressed as tenofovir disoproxil.

²Dose expressed as tenofovir disoproxil fumarate.

EMA: European Medicine Agency; FDA: Food and Drug Administration; IFN: Interferon; pegIFN: Pegylated interferon.

Table 2 Indications to treat according to different scientific societies

	Adults	Children
ESPGHAN[15]	N/A	CHB patients presenting with elevated serum ALT levels for at least 6 months if HBeAg-positive, or for at least 12 months if HBeAg-negative, and either moderate necroinflammation or fibrosis, or mild inflammation or fibrosis with a family history of HCC
WHO[1]	In the presence of significant fibrosis or cirrhosis regardless of HBV DNA and ALT levels, or HBV DNA > 2000 IU/mL and an ALT level above the upper limit of normal (for adolescents in at least two measurements 6-12 months apart), or in the presence of other factors, such as co-infections, family history of HCC or cirrhosis, immune-suppression, comorbidities or extra-hepatic manifestations	For adolescents (12 years and older) the indications for adults are applicable. For children < 12 years, WHO states that current evidence is insufficient to give recommendations on when to start treatment
AASLD[16,17]	ALT elevation > 2 × ULN (30 U/L for men and 19 U/L for women) or evidence of significant histological disease, plus HBV DNA > 2000 IU/mL (HBeAg-negative) or > 20000 IU/mL (HBeAg-positive); adults > 40 years old with immune-tolerant CHB and normal ALT, elevated HBV DNA (> 1000000 IU/mL), and liver biopsy showing substantial necroinflammation or fibrosis; adults with compensated cirrhosis and low viraemia (< 2000 IU/mL); HBsAg-positive adults with decompensated cirrhosis regardless of HBV DNA concentration, HBeAg status, or ALT concentration (these patients should be treated with antiviral therapy indefinitely); HBsAg-positive pregnant women with HBV DNA > 200000 IU/mL	HBeAg-positive children (aged 2-17 years) with elevated ALT and measurable HBV DNA concentrations
EASL[18]	CHB (HBeAg-positive or -negative), with HBV DNA > 2000 IU/mL, ALT > ULN and/or at least moderate liver necroinflammation or fibrosis; adults with compensated or decompensated cirrhosis and detectable HBV DNA, regardless of ALT levels. Patients with HBV DNA > 20000 IU/mL and ALT > 2 × ULN, regardless of the degree of fibrosis. HBeAg-positive chronic HBV infection, (persistently normal ALT and high HBV DNA levels) if older than 30 years, regardless of the severity of liver histological lesions. Patients with HBeAg-positive or HBeAg-negative chronic HBV infection and family history of HCC or cirrhosis and extrahepatic manifestations, even if typical treatment indications are not fulfilled	Refer to the joint EASL-ESPGHAN guidelines
APASL[19]	Decompensated cirrhosis, and detectable HBV DNA or severe reactivation of chronic infection; compensated cirrhosis and HBV DNA > 2000 IU/mL; persistently elevated (≥ 1 month between observations) ALT concentration more than two times ULN and HBV DNA > 20000 IU/mL if HBeAg-positive or > 2000 IU/mL if HBeAg-negative (liver biopsy or a non-invasive method to estimate the extent of fibrosis might provide further useful information); pronounced fibrosis, and normal or slightly elevated ALT concentration or HBV DNA < 20 000 IU/mL if HBeAg-positive or < 2000 IU/mL if HBeAg-negative	In the presence of cirrhosis (compensated or decompensated); children with severe reactivation of chronic HBV (detectable HBV DNA and elevated ALT); non-cirrhotic, HBeAg-positive chronic HBV infection, HBV DNA > 20000 IU/mL, and ALT more than two times ULN for > 12 months; non-cirrhotic, HBeAg-positive chronic HBV infection and either HBV DNA > 20000 IU/mL and ALT less than two times ULN for more than 12 months, 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 ULN; non-cirrhotic, HBeAg-negative chronic HBV infection and moderate to severe inflammation or pronounced fibrosis, regardless of HBV DNA concentration

AASLD: American Association for the Study of Liver Diseases; APASL: Asian-Pacific Association for the Study of the Liver; CHB: Chronic hepatitis B; EASL: European Association for the Study of the Liver; ESPGHAN: European Society for Paediatric Gastroenterology Hepatology and Nutrition; HBeAg: Hepatitis B envelope antigen; HCC: Hepatocarcinoma; N/A: Not applicable; WHO: World Health Organization; ULN: Upper limit of normal; HBV: Hepatitis B virus; ALT: Alanine aminotransferase.

Table 3 Summary of the analysed studies

	Study design	Sample size (n)	Treatment regimens	Follow-up duration	Age groups, n (%)	HBsAg loss rates (%, age group)	HBeAg loss rates (%, age group)	HBV DNA loss rates (%, age group)
Yao et al[21]	Retrospective	83 (36 started antiviral treatment)	PegIFN, IFN-α, ETV or tenofovir	Median 2.5 years (IQR 0.1-14.8 years)	N/A	Treated group 25.0%, N/A	Treated group 50%, N/A	Treated group 66.7%, N/A
Wu et al[22]	Retrospective	306	IFN/pegIFN ETV combination therapy	Median 26 months (IQR 17-42)	1-3 years (253, 82.7), 4-6 years (28, 9.2), 7-17 years (25, 8.2)	62.6%, 1-3 years, 41.7%, 4-6 years, 17.0%, 7-17 years	68.4%, 1-3 years, 56.1%, 4-6 years, 47.0%, 7-17 years	85.5%, 1-3 years, 82.4%, 4-6 years, 71.8%, 7-17 years
Zhang et al[23]	Retrospective	372	IFN-α in combination with NA (ETV or LAM); IFN-α for 6 months, and subsequent addition of NA if inadequate HBV DNA response. NA monotherapy with possible subsequent addition of IFN-α if inadequate HBV DNA response	36 months	1- < 3 years (115, 30.9); 3- < 7 years (141, 37.9); 7- < 12 years (55, 14.8); 12-16 years (61, 16.4)	62.6%, 1- < 3 years, 41.1%, 3- < 7 years, 25.5%, 7- < 12 years, 1.6%, 12-16 years	87.0%, 1- < 3 years, 73.1%, 3- < 7 years, 65.5%, 7- < 12 years, 39.3%, 12-16 years	93.9%, 1- < 3 years, 93.6%, 3- < 7 years, 80.0%, 7- < 12 years, 91.8%, 12-16 years
Zhu et al[24]	Prospective	29 (all < 1 year-old at enrolment)	LAM (started before 1 year of age); IFN-α (started after 1 year of age)	12 months after treatment; median of 102 months in case of HBsAg or HBeAg seroconversion	< 1 year at starting treatment (18, 62); > 1 year at starting treatment (11, 38)	94.4%, < 1 year; 36.4%, > 1 year	100%, < 1 year; 90.9%, > 1 year	100%, < 1 year; 100%, > 1 year
Li et al[25]	Prospective	48 (32 in the treated group; 16 in the control group)	IFN-α monotherapy; IFN-α with NA (LAM or ETV) add-on; IFN-α and NA (LAM or ETV) combination therapy	36 months	Treated group ≥ 1 and < 3 (9, 28); ≥ 3 and < 7 (19, 59); 7-14 (4, 13)	Treated group 100%, ≥ 1 and < 3 year; 47%, ≥ 3 and < 7 years; 0%, ≥ 7 years	Treated group 59.38%, N/A	Treated group 84.38%, N/A
Zhu et al[26]	RCT	69, 1-16 years old (46 in the treatment group, 23 in the control group)	IFN-α monotherapy; IFN-α with NA (LAM) add-on if inadequate viral response	96 weeks after treatment initiation	N/A	Treated group 21.74%, N/A	Treated group 32.61%, N/A	Treated group 73.91%, N/A

HBsAg: Hepatitis B surface antigen; HBeAg: Hepatitis B envelope antigen; HBV: Hepatitis B virus; ETV: Entecavir; IFN: Interferon; IQR: Interquartile range; LAM: Lamivudine; NA: Nucleos(t)ide analogues; N/A: Not applicable; pegIFN: Pegylated interferon; RCT: Randomized clinical trial.