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

Abstract

BACKGROUND

Chronic hepatitis B (CHB) is a significant public health problem. Most of the global burden of CHB is due to mother-to-child transmission, since perinatal infections lead to a high rate of chronicity. Spontaneous seroclearance of hepatitis B surface antigen (HBsAg) in CHB happens at a rate of 1% per year. Treatment options for CHB in children are available starting at 1 year of age. Current paediatric guidelines recommend treating children with hepatitis B envelope antigen (HBeAg) positive hepatitis with elevated serum transaminases levels for at least 6 months. Treatment is not indicated for children with HBeAg positive infection and normal transaminases. In 2024, the World Health Organization unified criteria for initiating antiviral treatment in children older than 12 years and in adults. Recent, preliminary evidence showed that antiviral therapy in infants and children younger than 2 years to 3 years of age with CHB infection led to higher rates of HBsAg loss than in adults and older children.

AIM

To evaluate the available evidence about treatment of CHB in young children and discuss the potential impact of early treatment.

METHODS

We searched the literature to identify studies reporting cases of HBsAg loss in children treated with antiviral drugs. We included only studies in which treatment-naïve patients started treatment before 2 years of age.

RESULTS

We identified 6 studies reporting results of CHB treatment, particularly HBsAg loss rates, hepatitis B virus DNA undetectability, and HBeAg loss.

CONCLUSION

Studies conducted on young children showed a higher HBsAg loss rate compared to those reached in older children and adults, offering new perspectives on the treatment of CHB. Further studies are needed to assess the effect of early treatment in larger populations and over a longer follow-up period.

Key Words: Chronic hepatitis B virus infection; Children; Functional cure; Hepatitis B surface antigen loss; Antiviral treatment

Core Tip: Chronic hepatitis B is a major global health issue, largely driven by mother-to-child transmission. Spontaneous hepatitis B surface antigen seroclearance occurs at about 1% per year. Emerging evidence suggests that starting antiviral therapy at a young age might lead to higher functional cure rates. This review examines evidence and implications of early treatment.

INTRODUCTION

Hepatitis B virus (HBV) infection represents a global significant health problem. HBV is responsible for either acute or chronic liver disease. Chronic hepatitis B (CHB) might cause severe liver complications, including hepatocarcinoma (HCC) and cirrhosis, and extra-hepatic manifestations. The World Health Organization (WHO) estimated that, in 2022, more than 254 million people worldwide were chronically infected by HBV, and 1.1 million deaths were caused by HBV infection[1]. In 2022, among children younger than five years, hepatitis B prevalence was less than 1% in all regions except the African region[2]. The African Region and the South-East Asia Region account for the majority of HBV infections in this age group. However, over the last years, the pattern of CHB prevalence worldwide has been influenced by migrations from HBV-endemic countries to low prevalence countries[3].

HBV is transmitted through percutaneous or mucosal exposure to infectious biological material, included blood, semen, and saliva. When HBV infection is acquired in adulthood, it most often leads to an acute and self-limiting disease, while in children it leads more frequently to chronic infection. The risk of developing a chronic infection is inversely proportional to the age at infection: 90% of infected neonates and infants younger than 6 months develop chronic infection, compared to 30% of children infected between 6 months and 5 years, and to less than 5% of immunocompetent individuals who acquire infection in adulthood[1,4,5]. Therefore, CHB is most commonly caused by mother-to-child-transmission, the predominant route of transmission in newborns and infants.

CHB natural history depends on the interaction of viral factors and immunological characteristics of the host, and it can be described as an evolution through five phases, not necessarily linear nor unidirectional[6,7]. The last phase, represented by spontaneous seroclearance of hepatitis B surface antigen (HBsAg), happens at a rate of 1% per year[8-10]. HBsAg seroconversion often follows the development of irreversible liver fibrosis, which is associated to high risk of liver dysfunction and HCC.

Current options for CHB treatment include immunomodulatory agents, such as interferon (IFN)-α or pegylated-IFN-α (pegIFN-α), and nucleotide or nucleoside analogues (NAs); NAs are classified based on their genetic barrier to resistance as either low (adefovir, lamivudine and telbivudine) or high (entecavir, tenofovir disoproxil fumarate and tenofovir alafenamide) (Table 1). Immunomodulatory agents stimulate immune-mediated control of HBV infection, whereas NAs impair and suppress HBV replication. The primary goal of treatment is to prevent progression to cirrhosis, liver failure, and HCC. Surrogate endpoints for improved outcomes in CHB include biochemical [alanine aminotransferase (ALT) normalization], virological (undetectable HBV DNA), serological [loss of hepatitis B envelope antigen (HBeAg), or HBsAg, with or without seroconversion], and histological outcomes (improvement in inflammation and/or fibrosis). Since a sterilizing cure-defined as the complete elimination of viral DNA from hepatocytes, including the covalently closed circular DNA (cccDNA) and integrated HBV DNA-is not achievable with current therapies, persistent HBsAg loss is accepted as the optimal endpoint and is defined as HBV functional cure[11,12].

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.

Indications for treatment in both adults and children are provided by scientific societies, including American Association for the Study of Liver Disease, European Association for the Study of the Liver, European Society of Paediatric Gastroenterology, Hepatology and Nutrition, Asian-Pacific Association for the Study of the Liver. Furthermore, in 2024, WHO released updated guidelines for the prevention and treatment of CHB in both adults and children (Table 2)[1,13-17]. Treatment is generally indicated in patients with elevated transaminases and not indicated in children younger than 2 years of age.

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.

Results of previous studies on adult populations suggest that, in highly selected patients, combination or sequential therapy (IFN-α and NAs) can increase the rate of HBsAg clearance[18,19]. These studies showed an increase in HBsAg loss from 2%-3% at the end of a course of pegIFN-α treatment, to 8%-14% 3-5 years post-treatment. However, in these studies, HBsAg loss was observed mainly in genotype A HBV infection. Regarding the role of NAs, it was found that 0%-5% of patients achieve HBsAg loss after 10 years of treatment. Some studies found that this percentage increases in patients who interrupt NAs therapy after at least 2-3 years of treatment, and who present with persistently undetectable viral DNA. Concurrently, emerging preliminary evidence shows that antiviral therapy in children with CHB infection led to higher rates of functional cure than in adults. In our study, we evaluated recent studies showing that treatment response is correlated to young age, with higher HBsAg loss in infants and young children compared to older children and adolescents.

MATERIALS AND METHODS

The review was conducted following the PRISMA statement and the protocol followed the PRISMA guidelines[20].

We searched the literature using PubMed and EMBASE to identify studies reporting cases of HBsAg loss (either associated or not associated with HBsAg seroconversion) in children treated with antiviral drugs, published until September 20, 2025. We found 143 articles using the following terms for research: (“hepatitis B” AND “children” AND “treatment” AND “HbsAg loss”). Only studies including the following data were considered: Patients age, treatment regimens, serological status regarding HBsAg and HBeAg prior to and after treatment; HBV DNA levels prior to and after treatment. We also searched reference lists of articles identified through this strategy and included additional relevant studies. We included only studies in which treatment-naïve patients started treatment before 2 years of age. Studies in languages different from English were excluded. Among the 143 studies, 135 did not match inclusion criteria, while 2 were not in English, so they were excluded from our analysis (Figure 1). Title, abstract, and full-text screening were performed independently by two reviewers (Indolfi G and Carrera S).

Figure 1  PRISMA flow diagram.

RESULTS

We identified 6 studies reporting results of CHB treatment in children under 2 years of age (Table 3). In all studies, patients with hepatitis A virus, hepatitis C virus, hepatitis D virus, human immunodeficiency virus infection, or with other liver comorbidities were excluded.

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.

In a 2022 study by Yao et al[21], the authors conducted a retrospective analysis of 83 treatment-naïve patients, aged 0-16 years, with CHB acquired through vertical transmission. Thirty-six patients with ALT flares initiated antiviral therapy, receiving either PegIFN for 48 weeks, IFN-α for 48 weeks, or NAs (entecavir or tenofovir). The primary endpoints included assessment of spontaneous ALT flares and therapy-induced HBsAg loss. The median follow-up duration was 2.5 years (range: 0.1-14.8 years). During the observation period, 36 children initiated antiviral therapy, among whom 9 (25%) achieved HBsAg loss. Specifically, 4 of 11 (36.4%) patients treated with IFN-based regimens and 5 of 25 (20%) treated with entecavir achieved HBsAg clearance. Among the 36 treated patients, 30 were HBeAg-positive at baseline; of these, 15/30 (50.0%) achieved HBeAg clearance, and 11/30 (36.7%) achieved HBeAg seroconversion. Antiviral therapy also produced favourable effects on serum HBV DNA, which became undetectable in 24/36 (66.7%) treated patients. Children who achieved HBsAg loss following antiviral therapy were significantly younger at baseline. A multivariable Cox model identified younger age at therapy initiation as the only independent predictor of HBsAg loss [hazard ratio = 0.544, 95% confidence interval (CI): 0.353-0.838, P = 0.006]. Further statistical analysis identified 6.2 years of age as the optimal threshold for antiviral therapy initiation to discriminate children with a higher probability of achieving HBsAg loss. Kaplan-Meier survival analysis further confirmed that children initiating antiviral therapy before 6.2 years of age exhibited a significantly higher cumulative probability of achieving HBsAg loss compared with those initiating therapy after 6.2 years.

A retrospective cohort study included 306 treatment-naïve children (age < 18 years) treated for CHB with entecavir, IFN/pegIFN, or both in combination. Criteria for starting treatment were not specified. Children were grouped by age [1-3 years (253, 82.7%); 4-6 years (28, 9.2%); 7-17 years (25, 8.2%)] and were followed up for a median duration of 26 months. Significant differences in baseline characteristics were identified for HBV DNA levels, highest in the 1-3 year-old group (6.86 ± 0.11 Log₁₀IU/mL vs 6.15 ± 0.21 Log₁₀IU/mL and 6.20 ± 0.30 Log₁₀IU/mL in the 4-6 and 7-17 year-old groups respectively), and for the fibrosis grade, expressed as fibrosis-4 index, as the youngest group presented more often (98.6%) with a value lower than 1.45, compared with 93.7% and 89.8% in the two older groups. Primary outcome was HBsAg loss, secondary outcomes were HBeAg clearance and HBV DNA undetectability. The incidence of the primary outcome, HBsAg clearance, was significantly higher in the younger group: 87/139, 62.6% (1-3 years), 33/79, 41.7% (4-6 years), 15/88, 17.0% (7-17 years). HBeAg clearance and HBV undetectability were observed, respectively, in 68.4% and 85.5% of the 1-3 years group, 56.1% and 82.4% of the 4-6 years group, and 47.0% and 71.8% in the oldest group (7-17 years). The cumulative incidence rate of HBsAg loss was the highest in the 1-3 years group, compared to the older groups (90.1% vs 61.5% vs 38.8%, P < 0.01). Adjusted Cox regression model showed that children in the 1-3 years group, compared to the 4-6 years group, had a higher probability to clear HBsAg [odds ratio (OR) = 5.07, 95%CI: 2.91-8.82 vs 2.42, 95%CI: 1.31-4.46] and HBeAg (1.73, 95%CI: 1.18-2.53 vs 1.14, 95%CI: 0.73-1.77). Therefore, starting treatment before the age of 3 was associated with better outcomes[22].

Another retrospective study enrolled 372 children aged 1-16 years (median age 4.6 years) with HBeAg-positive CHB, with an HBV DNA load > 20000 IU/mL, ALT values > 60 IU/L for 2 consecutive tests in a period of 3-6 months. These patients were treated with three possible antiviral regimens based on IFN-α and NAs (lamivudine or entecavir) and were followed up for 36 months. The three regimens were: IFN-α in combination with NAs; IFN-α monotherapy, possibly implemented with NAs after 6 months in accordance with HBV DNA response; NAs monotherapy, implemented with IFN if a poor viral response was observed. Regimens including IFN were administered for 24 months, while NAs in monotherapy for 36 months. The study also divided the 372 cases by age group: 1-7 years, and 7-16 years; eventually, population was further stratified by age into four groups (1-3 years; 3-7 years; 7-12 years; 12-16 years). HBV DNA loss, HBeAg seroconversion, and HBsAg loss were analysed by age groups. The cumulative rates of HBV DNA undetectability, HBeAg seroconversion and HBsAg loss after 36 months were respectively 91.4%, 70.7%, and 39.0%. HBV DNA loss occurred earlier and in higher rates at the end of the follow up period in the younger groups: At 36 months HBV DNA loss rate was 93.9% (100/115) and 93.6% (132/141) in the groups 1-3 years and 3-7 years, vs 80.0% (44/55) and 91.8% (56/68) in the older groups. Similar results were found for HBeAg seroconversion: At 36 months the cumulative HBeAg seroconversion rate decreased as baseline age increased, with 87.0% (100/115) in the 1-3, 73.1% (103/141) in the 3-7, 65.5% (36/55) in the 7-12, and 39.3% (24/61) in the 12-16 years age groups. HBsAg loss cumulative rates at 36 months were higher in the youngest, respectively 62.6% (72/115) in the 1 to < 3, 41.1% (58/141) in the 3-7, 25.5% (14/55) in the 7-12, and 1.6% (1/61) in the 12-16 years age groups. Cox regression analysis found that another factor associated with functional cure was baseline HBsAg level, with higher rates of HBsAg loss for lower baseline HBsAg values. Moreover, this study showed that baseline levels of CD4-positive and CD8-positive T lymphocytes, natural killer cells, B cells, and neutrophils were significantly associated with functional cure. Besides, in the study population, baseline values of this cell types decreased with age[23].

Zhu et al[24] conducted a prospective cohort study, enrolling 29 children under 1 year of age, with CHB, serum HBV DNA ≥ 100000 IU/mL, ALT values ≥ 2 × upper normal limit, without comorbidities. Eighteen children were treated with lamivudine before 1 year of age, with the eventual addition after 1 year of age of IFN if HBsAg loss was not obtained. Eleven children were started on IFN after 1 year of age, and lamivudine was added if the decline in serum HBV DNA was < 2 Log₁₀ after three months of treatment. Nine children treated with lamivudine reached HBsAg loss before 1 year of age. No child reached spontaneous HBsAg loss if untreated before 1 year. In the group treated earlier, the cumulative rates of HBsAg loss at month 3, 6, 9 and 12 of treatment were respectively 39% (7/18), 67% (12/18), 78% (14/18) and 83% (15/18). At 12 months after treatment, all 15 infants also developed anti-HBs. In the IFN group, the cumulative rates of HBsAg loss at month 3, 6, 9 and 12 of treatment were respectively 18% (2/11), 27% (3/11), 27% (3/11) and 36% (4/11). In this group, at 12 months after treatment, 3 infants developed anti-HBs. In the follow-up period after treatment, 2 more infants in the group treated earlier lost HBsAg, while no infant lost HBsAg in the group treated later. A significant difference in the rate of HBsAg loss was found between the two groups at month 12 of treatment (P = 0.0169). Overall, 28 children reached HbsAg or HbeAg seroconversion during the observation period: In the group treated with lamivudine, 17 infants achieved both HBsAg and HBeAg seroconversion, 1 achieved only HBeAg seroconversion; in the group treated later with IFN, 4 infants achieved both HBsAg and HBeAg seroconversion, 6 achieved only HBeAg seroconversion. The group treated earlier had higher rates of HBsAg loss, with a more rapid decrease in HBsAg. After discontinuation of therapy, patients were followed up for a median of 102 months, and no reactivation or seroconversion was observed.

Another prospective study enrolled 48 children (1-14 years) with HBeAg-positive CHB, with serum HBV DNA > 10000000 IU/mL, and normal or mildly elevated ALT (< 60 IU/L) for two consecutive times in a period of 3 months. Thirty-two patients started treatment with IFN-α or IFN-α combined with NA (entecavir or lamivudine). Specifically, 13 patients were initially treated with IFN-α monotherapy, and NA was added after 6 months if the patient exhibited a decrease in the Log₁₀ serum HBV DNA level of < 2. Nineteen patients began with combination therapy of IFN-α and either lamivudine or entecavir. Sixteen patients were enrolled as the control group and did not receive any treatment. At 36 months after starting treatment, HBsAg seroconversion occurred in 56.25% (18/32), DNA loss in 84.38% (27/32), and HBeAg seroconversion in 50% (16/32) of treated patients, while HBsAg seroconversion, DNA loss, and HBeAg seroconversion did not occur in any untreated patient. Significant age differences were found between the treated group that obtained HBsAg loss (cured) and the treated group that did not obtain HBsAg loss (uncured). More specifically, among the 18 cured patients, 9 were < 3 years of age, 8 were 3-6 years of age, and 1 was > 6 years of age. Furthermore, Cox regression analysis indicated that the baseline age at treatment initiation was closely correlated with HBsAg loss (P = 0.013). Therefore, a significant correlation was found between baseline age at treatment and functional cure. Besides, CD4-positive and CD8-positive T lymphocytes and B lymphocytes were significantly higher in the cured group than in the uncured group[25].

An open-label randomized study investigated the rates of HBeAg seroconversion, HBV DNA loss, and HBsAg loss in 69 children, 1 years old to 16 years old, with CHB and “immune-tolerant” characteristics. Patients started treatment with IFN monotherapy. Lamivudine was added after 12 weeks of treatment in patients who had serum HBV DNA decline to < 2 Log₁₀. Patients were followed up until week 96 after starting treatment. Forty-six patients were randomized in the treatment group, 23 patients in the control group. Rates of serum HBsAg loss, HBV DNA undetectability and HBeAg loss were respectively 21.74% (10/46), 73.91% (34/46), and 32.61% (15/46) in the treated group. In this study, a multivariate analysis identified elevated ALT at baseline levels as the independent predictor of HBeAg loss. Analysis to identify factors as possible predictors for HBsAg loss were not conducted[26].

DISCUSSION

HBV cure represents a clinical challenge, as drugs available are insufficient to achieve the ideal goal of sterilizing cure. The nearest attainable goal is functional cure, which represents the best achievable target with existing therapies. The main obstacles to HBV eradication include both viral factors, such as the presence of cccDNA in hepatocytes nuclei and the integration of viral DNA into the host DNA, and host immunological factors[27].

Studies conducted on young children showed an interestingly higher HBsAg loss rate compared to those reached in older children and adults[21-26,28-32]. This finding was confirmed in 5 out of 6 studies analysed in this paper; only Zhu et al[26] conducted a statistical analysis to reveal factors correlated with HBeAg clearance, but not with HBsAg loss. When study populations were divided in age groups, the best results for HBsAg, HBeAg and HBV DNA loss were obtained in the youngest age group, which in most studies included patients < 3 years. Moreover, when treatment was administered in a small cohort of patients younger than 1, HBsAg loss was observed in 83% of cases[24]. HBsAg clearance rates was shown to decrease with age, with rates in adolescence comparable to those observed in adults. According to Yao et al[21], treatment initiation before 6.2 years of age was associated with higher functional cure rates. Other studies proposed slightly different cut-off ages: Xu et al[33] identified 5 years as the optimal cut-off for patients in the immune-tolerant phase, while Li et al[34] reported a value of 7 years. In addition to young age, other factors have been identified as predictors of HBsAg loss in children, such as low HBsAg level at baseline, the trajectory of HBsAg and HBeAg decline after initiation of treatment, elevated ALT at treatment initiation[31,35,36]. However, young age at treatment initiation was the only factor consistently associated with higher rates of HBsAg loss in almost all the aforementioned studies. In the included studies, side effects were almost exclusively reported with IFN-α therapy (fatigue, fever, neutropenia, nausea, myalgia, growth retardation), but they were reversible in all cases after stopping treatment.

The reason for the different effectiveness of treatment in children and in adults has not been completely understood; in this regard, HBV characteristics, host characteristics, and type of antiviral therapy might have a role. First, it has been proposed that the amount of infected hepatocyte is low in younger children, and it progressively increases with age and liver growth; therefore, an early start of the treatment would promptly suppress HBV replication, reducing both the circulating viral pool and the amount of infected hepatocytes, also for the dilution effect of the replicating hepatocytes[37,38]. Then, genetic diversity of HBV is less represented in younger children. Also, immunological response, particularly T cell exhaustion, might be more easily “reversed” in younger children[39-41].

The analysed studies show higher HBsAg loss rates in younger children, a result that might open new therapeutic perspectives. However, several limitations must be highlighted. First, since all analysed studies were conducted in China, the most represented HBV genotypes were B and C. Second, different treatment regimens were used, with different criteria for starting treatment and for different durations. Both these features limit the possibility to generalize the results to all HBV genotypes and to different treatment regimens. Furthermore, a significant limit of the studies included in our review is the retrospective nature of most of them. The retrospective design introduces risks of selection bias and of incomplete data; besides, as the inclusion criteria for the studies were very strict, we did not perform a quality assessment for the studies included. Also, the retrospective design might have caused an incomplete reporting of side effects during treatment. Last, some studies have been conducted in the same centres, determining possible overlap of included patients.

CONCLUSION

Our review offers new perspectives on the treatment of CHB. The possibility to obtain functional cure in a high proportion of patients might redefine the indications to treatment in young patients and positively impact the natural history of HBV infection. Early control of the viral load might reduce the risk of long-term consequences, particularly cirrhosis and HCC. Early treatment may also offer advantages in terms of public health and psychosocial well-being; in fact, it might reduce the risk of horizontal transmission, and the social stigma associated with chronic hepatitis. Although the results of the analysed studies are promising, the obstacles for long-term therapy in the paediatric clinical practice should also be considered. Since IFN-based treatment would require frequent subcutaneous injections and paediatric formulations of NAs are not commonly available, caregivers might be reluctant to start a possibly chronic treatment in a young child, with negative consequences on compliance[42]. Further perspective studies are needed to assess the effect of early treatment in larger populations and over a longer follow-up period. Besides, future studies are necessary to investigate other factors possibly implied in determining functional cure, such as host characteristics, treatment regimens, and their effectiveness on different HBV genotypes, with the goal of offering the best possibility of treatment to every patient.