HBeAg seroconversion occurred and was maintained in 13 of the 14 HBeAg-positive patients (92.9%, 13/14) at an average of 12 weeks during treatment, and 1 patient (patient 6) exhibited persistent HBeAg positivity. The other 4 HBeAg-negative children (patients 3, 9, 16, and 18) remained HBeAg negative (Table 2 and Fig. 2).
HBsAg loss or seroconversion occurred in 4 patients (22.2%, 4/18) (patients 5, 10, 11, and 13) at an average of 21 weeks during treatment (Table 2). Two (patients 5 and 11) of these patients experienced HBsAg seroconversion at 12 weeks during treatment and maintained HBsAg seroconversion. One child (patient 10) became HBsAg negative at 36 weeks during treatment but exhibited recurrence with a low level of HBsAg positivity at 48 weeks after withdrawal. One child (patient 13) became HBsAg seroconverted at 24 weeks during treatment and exhibited HBsAg-positive recurrence at 8 weeks after IFN-α withdrawal, with the HBsAg level showing a rising trend.
3.6 Adverse events
Only mild flu-like symptoms, such as pyrexia (low grade), and rhinorrhea, and transient neutropenia appeared in some children at the early stage of treatment. No treatment reduction or withdrawal was performed for the children with flu-like symptoms, and the transient neutropenia disappeared rapidly. No patients reported adverse events of hypothyroidism or hyperthyroidism or required dose modification for thyroid function abnormalities. No severe abnormal results were observed in other laboratory assessments.
This observational and open cohort study was conducted in children and adolescents aged 1 to <18 years old with CHB in the immune-active stage. IFN α-2b monotherapy administered per the BSA category-based dosing regimen provided comparable exposure across BSA categories, showed an acceptable safety profile and was efficacious in pediatric patients without advanced fibrosis. The primary efficacy assessments included ALT normalization, HBV-DNA suppression, and HBeAg loss or seroconversion in HBeAg-positive patients; HBsAg loss or seroconversion was the ultimate goal.
In this study, 18 children with naïve CHB were treated with IFN α-2b for a median of 48 weeks, and the results of this study confirmed the significantly high HBeAg seroconversion rate in patients treated with IFN α-2b (92.9%) observed in previous reports. The rate of HBsAg loss or seroconversion (22.2%) was higher than that reported in adults (2.3%–3.3%) and previous pediatric studies.[6,8–13]
Sustained HBsAg clearance is considered the ideal endpoint in CHB because it is associated with complete remission, lack of disease progression, and reduced risk of HCC.[14,15] However, HBsAg clearance is difficult to achieve in practice,[16,17] and spontaneous HBsAg clearance is considered a rare event in childhood (0%–1%/year).[15,18,19] In this study, 4 patients (22.2%) achieved HBsAg loss or seroconversion at an average of 21 weeks during treatment. Two of these patients achieved HBsAg seroconversion at 12 weeks during treatment and maintained the HBsAg seroconversion. One became HBsAg negative at 36 weeks during treatment and recurred low-level HBsAg positivity at 48 weeks after withdrawal. One became HBsAg seroconverted at 24 weeks during treatment but exhibited recurrent HBsAg positivity at 8 weeks after withdrawal, and the HBsAg level showed a rising trend.
Although it is reported that HBV genotype C is a difficult-to-treat genotype, the HBeAg seroconversion rate in our children with this genotype was 100% (6/6), and this rate was significantly higher than that in previous adult (27.6%-39.0%) and pediatric (4.3%–38.2%) studies.[6,8–13,20] This finding may be associated with the young age of the children in this study. The interpretation of results from the genotype A and D subgroups was limited by low patient numbers.
A Chinese study of 49 HBeAg-negative cases of 1 to 7-year-old children with CHB treated with IFN-α found that, the liver of most of the children exhibited active inflammation and relatively severe fibrosis, and the authors suggested that children patients can obtain a higher HBsAg clearance rate if they receive antiviral treatment before 3 years of age. In our study, the histological scores of the 4 HBeAg-negative patients were G2S3, G2S2, G2S3 and G3S4 before antiviral treatment, which indicated relatively serious disease. Their ages at the beginning of antiviral treatment were 1 year old, 2 years and 1 month old, 5 years and 2 months old, 2 years, and 3 months old, respectively. The antiviral treatment durations were 48 weeks, 40 weeks, 48 weeks, and 48 weeks, respectively. The time at which the elevated ALT level fell into the normal was week 20, week 16, week 48, and week 36 during treatment, respectively. HBV-DNA became undetectable by 36 weeks, 24 weeks, 24 weeks, and 36 weeks, respectively. HBeAg remained negative, and no cases of HBsAg loss or seroconversion occurred.
The main adverse events to IFN-α antiviral therapy include influenza-like syndrome, granulocytopenia, mental abnormalities (anxiety, depression, illusion, and so on), autoimmune diseases, and so on. In this study, only mild flu-like symptoms such as pyrexia (low grade), and rhinorrhea, and transient neutropenia appeared in some children at the early stage of treatment. No severe abnormal results were observed in other laboratory assessments. No treatment reduction or withdrawal was performed with the children with flu-like symptoms, and transient neutropenia disappeared rapidly. Due to the incomplete data for height and weight, the evidence of treatment effects on growth in this study is insufficient, and this lack of data was 1 of the limitations of our study.
Currently, mother-to-child transmission is the dominant transmission method in China due to the use of disposable medical consumables and strict management of disinfection. Therefore, children with CHB are currently the main source of the CHB population in China. Antiviral treatment is not usually considered due to the particularities of children's growth and development, and infants and young children are often in the phase of immune tolerance when they are infected with HBV. According to some recent studies, scientists from China, which has a high prevalence of CHB, have suggested that children with CHB should be given antiviral treatment as soon as they enter the immune clearance phase and have antiviral indications. Of course, further long-term clinical research is needed, and more samples are needed to confirm the concrete antiviral therapy and antiviral treatment duration, efficacy, adverse reactions, resistance, etc. for children with CHB and to provide more evidence for guidelines for the antiviral treatment of children.
No 1 drug currently achieves reliable complete eradication of HBV. The treatment of chronic HBV infection in children should be individualized. The purpose of treatment is to reduce viral replication, which is defined as undetectable HBV-DNA levels in the serum and the development of anti-HBe antibodies. Seroconversion changes the disease to an inactive form. Currently, treatment is indicated for only patients who are in the immune-active phase. The use of IFN-α is limited due to the subcutaneous administration method, the duration of treatment for 24 weeks, and possible side effects. IFN-α treatment cannot be used for decompensated cirrhosis.
The sample size of our study was small, which was 1 of the limitations of this study, and the sample size needs to be expanded in the future studies. Moreover, in adverse events monitoring, the growth parameters were not measured or recorded completely to monitor the impact of the antiviral treatment on children's growth and development.
In conclusion, the antiviral monotherapy of 48 weeks of IFN-α was well tolerated and good responded, which was associated with higher rates of HBeAg seroconversion and HBsAg clearance in the children in this study than in previously reported adults and pediatric patients.
We appreciate all the staff that helped with and supported this study. We are grateful for all the participating children and their parents.
Conceptualization: Yao Hu, Hui Yu.
Data curation: Yao Hu.
Formal analysis: Yao Hu.
Methodology: Yao Hu, Yingzi Ye, Lijing Ye, Xiaohong Wang.
Software: Yao Hu.
Supervision: Hui Yu.
Validation: Hui Yu.
Writing – original draft: Yao Hu.
Writing – review & editing: Yingzi Ye, Lijing Ye, Xiaohong Wang, Hui Yu.
Yao Hu orcid: 0000-0001-5175-6164.
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Keywords:Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
antiviral therapy; children; chronic hepatitis B; interferon-alpha