乙肝病毒(Hepatitis B virus，HBV)感染仍然是全球公共卫生的主要威胁。 全世界约有8%–10%的新生儿通过乙肝表面抗原(HBV surface antigen，HBsAg)阳性的母亲感染慢性乙肝(chronic hepatitis B，CHB)，中国约有600万儿童感染该病毒。 无论是免疫清除型CHB(immune clearance CHB，IC-CHB)还是免疫耐受型CHB(immune tolerant CHBIT-CHB)，乙肝e抗原(hepatitis B e antigen，HBeAg)阳性的CHB儿童很少会在未接受抗病毒治疗的情况下自发清除HBsAg。
Current antiviral drugs, including interferon-α α (IFN-α) and nucleos(t)ide analogs (NAs), are effective in inhibiting HBV replication and significantly reducing the risk of disease progression to cirrhosis and HCC. However, current antiviral therapies are difficult to achieve a functional cure, and data on treatment outcomes in children are limited. A retrospective study evaluating the functional cure rate in children with active CHB receiving antiviral therapy was excerpted by Yimaitongte for clinicians' reference.
1. Research Methodology
A total of 372 children aged 1 to 16 years with active CHB were enrolled and treated with NAs monotherapy or in combination with IFN-α for 24 to 36 months. All children were followed up every 3 months. Functional cure is defined as HBV DNA clearance, HBeAg seroconversion, HBsAg clearance. (Figure 1)
Figure 1 Research flow chart
2. Findings
1. Baseline characteristics and factors related to functional cure
The study cohort included 372 HBeAg-positive children admitted between June 2014 and September 2021, including 239 boys and 133 girls, with a median age of 4.60 years. Table 1 summarizes the baseline characteristics of the children and their response to treatment at the end of the 36-month study period.
The cumulative rates of serum HBV DNA disappearance, HBeAg seroconversion, and HBsAg disappearance after 36 months were 91.4% (340/372), 70.7% (263/372), and 39.0% (145/372), respectively, in 372 children with IC-CHB (Table 1). At the end of the study, there was no difference in the accumulation rates of serum HBV DNA clearance (P =0.418), HBeAg seroconversion (P =0.591) and HBsAg clearance (P =0.343) among the three antiviral regimens (Table 1). However, multivariate Cox regression analysis showed that baseline age was an important independent factor affecting HBsAg clearance (Table 1), while both gender and baseline quantitative HBsAg clearance were affected.
Table 1 Baseline characteristics and clinical outcomes of the three antiviral regimen groups
2. Children with IC-CHB receiving antiviral therapy may have a faster and more cumulative effect of viral suppression
The analysis showed that serum HBV DNA levels in groups A and B decreased sharply within 6 months after treatment (Fig. 2a) and by the end of 12 months, they had dropped to near normal levels (Fig. 2a). By 24 months, serum HBV DNA levels in group A were lower than those in group B, although this difference slightly exceeded the significance threshold (P=0.078). A total of 372 children were classified as cured or uncured, and further analysis showed that the HBV DNA levels of cured children after 6 months were lower than those of uncured children (Fig. 2b). HBV replication inhibition is faster and deeper in cured children than in uncured children, especially in the first 12 months. Notably, while children in the non-cure group did not achieve functional cure at the end of the study, the majority of HBV DNA-positive children had HBV DNA levels between 40 and 200 IU/mL at 36 months (Figure 2b).
A two-age stratified analysis of 372 children with CHB showed that at 6, 12, 24, and 36 months after initiation of antiviral therapy, HBV DNA clearance was significantly higher in group A than in group B: 28.9% vs. 19.0%, respectively. 61.7%vs.38.8%； 87.9% vs. 77.6% and 93.8% vs. 86.2% (Figure 2c). A similar situation was observed in the PSM group (Figure 2d). As shown in Figure 2e, at 36 months, HBV DNA clearance was higher in the two younger groups (i.e., 1–<3 years and 3–<7 years) than in the two older groups (80.0% and 91.8%). Notably, lower HBV DNA clearance in the 7–<12 year age group may be related to a smaller sample size (n=55) compared to the other three groups; A higher proportion of children receiving IFN-α monotherapy (6/55 [10.9%]) were treated with IFN-α therapy, and IFN- therapy had limited antiviral efficacy in controlling viral replication compared with NAs.
Fig.2 Dynamic changes in serum HBV DNA levels and cumulative HBV DNA clearance during the follow-up period
3. The cumulative HBeAg seroconversion rate was higher in young children receiving IC-CHB antiviral therapy
The baseline HBeAg level in group A was significantly higher than that in group B (P = 0.004) (Fig. 3a). However, by 24 months, group A had decreased significantly (P = 0.003). Similarly, as shown in Figures 3b and c, HBeAg levels in the cured subgroup in group A were significantly higher at the start of treatment, but had decreased to significantly lower levels than in the non-cured subgroup by 12 months (P=0.013, Fig. 3b). In addition, there was no significant difference in HBeAg levels between the cured and uncured subgroups in group B until 24 months, when the HBeAg levels in the cured subgroup were significantly lower than those in the uncured subgroup (P <0.001, Fig. 3c).
A decrease in the anti-HBe cut-off index (COI) value to <1 indicates that the anti-HBe has turned positive. In the first 12 months, the decline in anti-HBe was significantly greater in group A than in group B (Fig. 3d), and by 24 months, the median anti-HBe COI in both groups A and B decreased to <1, and there was no difference between cured and uncured groups (Fig. 3e, f). These results suggest that 24 months of antiviral therapy in children with IC-CHB can lead to HBeAg seroconversion.
The cumulative HBeAg seroconversion rate at 36 months was very high in all 372 children with CHB [263/372 (70.7%)] (Table 1). The analysis based on two-age stratification showed that the accumulation rate of HBeAg seroconversion in group A was 1.81 times higher than that in group B at 6 months (25.0% vs. 13.8%; P=0.014）。 This significant difference between the two groups persisted at 12, 24, and 36 months: 49.2% vs. 22.4%, 71.9% vs. 41.4%, and 79.3% vs. 51.7%, respectively (Figure 3g). In addition, an age effect was observed in the PSM-treated data, P <0.001 (Fig. 3h).
Fig.3 Dynamic changes in serum HBeAg and anti-HBe levels and cumulative HBeAg seroconversion rate during follow-up
4. Young children receiving IC-CHB antiviral therapy had a higher rate of functional cure
As shown in Fig. 4a, the serum HBsAg levels in groups A and B continued to decrease after treatment, but the serum HBsAg levels in group A decreased more rapidly than those in group B (Fig. 4a). Regardless of groups A and B, the serum HBsAg decreased faster in the cured group than in the uncured group (Fig. 4b, c). Therefore, the serum level of anti-HBs in group A continued to increase rapidly after the start of treatment, which was higher than that in group B (Fig. 4d), and far exceeded that level in group B at 6 months (P = 0.002). Compared with group A, the levels of anti-HBs in the cured subgroup were significantly higher than those in the uncured subgroup at all time points (Fig. 4e), while there was no significant difference in the levels of anti-HBs between the cured and uncured groups in group B up to 12 months (Fig. 4f).
By the end of the study, the cumulative HBsAg clearance rate of 372 children with IC-CHB was 39.0% (145/372). Of the 256 children in group A, 130 (50.8%) achieved functional cure, while only 15 (12.9%) of the 116 children in group B achieved HBsAg disappearance (P <0.001) (Fig. 4g, Table 2). During the period of antiviral therapy, the disappearance rate of HBsAg in the PSMA group was higher than that in the PSMB group (p<0.001), as shown in Figure 4h.
Fig.4 Dynamic changes in serum HBsAg and anti-HBs levels and cumulative HBsAg clearance during follow-up
5. Security Assessment
Among the 372 children with CHB who received antiviral therapy, no serious adverse events were observed during the 36-month follow-up period. However, mild to moderate adverse events occurred in 351 children treated with IFN-α. The two most common adverse events observed during IFN-α treatment were fever (219/351) and neutropenia (203/351) (Table 2), followed by fatigue (114/351), nausea (112/351), and alopecia (81/351). Other adverse events included thyroid dysfunction (27/351), arthralgia (17/351), rash (15/351), thrombocytopenia (13/351), and growth retardation (5/351). Once IFN-α treatment is discontinued, all of these adverse events or symptoms resolve or reverse on their own. Essentially, antiviral therapy in children with CHB has demonstrated acceptable safety and tolerability.
Table 2 Cumulative adverse events occurred during antiviral therapy and follow-up
3. Conclusions of the study
Studies have found that children with IC-CHB who receive antiviral therapy have a higher functional cure rate, and the younger the age, the higher the functional cure rate. These findings provide preliminary evidence for antiviral therapy decisions in children with IC-CHB. However, prospective, multicenter, and large-sample clinical trials are needed to confirm the safety and efficacy of antiviral therapy in children with this disease. In addition, the associated viruses and immune mechanisms with high functional cure rates also need to be explored in future studies.
Bibliography:
Xie JZ, Lin X, Fan XY, et al. Global Burden and Trends of Primary Liver Cancer Attributable to Comorbid Type 2 Diabetes Mellitus Among People Living with Hepatitis B: An Observational Trend Study from 1990 to 2019 [J]. J Epidemiol Glob Health, 2024, 14(2): 398-410.
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