Functional cure is associated with younger age in children undergoing antiviral treatment for active chronic hepatitis B

Abstract

Background and aims: Functional cure is difficult to achieve using current antiviral therapies; moreover, limited data are available regarding treatment outcomes in children. This retrospective study aimed to assess the frequency of functional cure among children undergoing antiviral treatment for active chronic hepatitis B (CHB).

Methods: A total of 372 children aged 1-16 years, with active CHB were enrolled and underwent either nucleos(t)ide analog monotherapy or combination therapy with interferon-α (IFN-α) for 24-36 months. All children attended follow-up visits every 3 months. Functional cure was defined as evidence of hepatitis B virus (HBV) DNA loss, circulating hepatitis B e antigen (HBeAg) loss/seroconversion, and hepatitis B surface antigen (HBsAg) loss.

Results: After 36 months of antiviral treatment and/or follow-up visits, children with CHB aged 1- < 7 years exhibited higher rates of HBV DNA clearance, HBeAg seroconversion, and HBsAg loss than CHB children ≥ 7-16 years of age (93.75% versus [vs.] 86.21% [p < 0.0001]; 79.30% vs. 51.72% [p < 0.0001]; and 50.78% vs. 12.93% [p < 0.0001], respectively). Longitudinal investigation revealed more rapid dynamic reduction in HBV DNA, HBeAg, and HBsAg levels in children aged 1-7 years than in those aged ≥ 7-16 years with CHB. According to further age-stratified analysis, HBsAg loss rates were successively decreased in children with CHB who were 1- < 3, 3- < 7, 7- < 12, and 12-16 years of age (62.61% vs. 41.13% vs. 25.45% vs. 1.64%, respectively; p < 0.0001) at 36 months. In addition, baseline HBsAg level < 1,500 IU/mL was found to favor disease cure among these pediatric patients. No serious adverse events were observed throughout the study period.

Conclusion: Results of the present study demonstrated that children aged 1- < 7 years, with active CHB can achieve a high functional cure rate by undergoing antiviral therapy compared to those aged ≥ 7 years, who undergo antiviral therapy. These data support the use of antiviral treatment at an early age in children with CHB. However, future prospectively randomized controlled trials are necessary to validate the findings of this study.

Keywords: Antiviral therapy; Child; Chronic hepatitis B; Functional cure; HBV; HBV DNA loss; HBeAg seroconversion; HBsAg loss; Interferons; Nucleoside Analogs.

Fig. 1

Flow diagram of the retrospective study. Of 537 children with CHB aged 1–16 years, a total of 372 were deemed eligible according to the inclusion and exclusion criteria and enrolled for antiviral treatment under the following regimens: Regimen-a comprised IFN-α treatment plus NAs over the course of 24 months; Regimen-b consisted of initial treatment with IFN-α monotherapy for six months and an additional treatment of 18 months with IFN-α monotherapy in cases of a ≥ 2 log₁₀ decrease in serum HBV DNA; otherwise, the extensional treatment used IFN-α add-on lamivudine (3 mg/kg/day) or entecavir (0.015 mg/kg/day); Regimen-c, for those initially reluctant to undergo IFN-α treatment, involved NAs monotherapy over 36 months. Nevertheless, some individuals exhibited a poor viral response to NAs monotherapy after six months and shifted to an NAs add-on IFN-α treatment plan after obtaining their guardians’ consent. All patients received antiviral treatment and follow-up visits during the 36-month research period. The study also divided the 372 cases by age group for further analysis of their cumulative rates of HBV DNA loss, HBeAg seroconversion, and HBsAg loss. Abbreviations: HBV hepatitis B virus, CHB chronic hepatitis B, IFN-α interferon-α, NAs nucleos(t)ide analogs

Fig. 2

Dynamic changes of serum HBV DNA levels and the cumulative rate of HBV DNA loss in children with IC-CHB during the 36-month study period. a Serum HBV DNA changes in the children with CHB in group-A (1– < 7-year-olds) and group-B (≥ 7–16-.\year-olds); b Serum HBV DNA changes in the cured and non-cured children; c–d the cumulative rates of serum HBV DNA loss in different age groups; c the total number of cases; d PSM cases; and e comparisons of serum HBV DNA loss in the different age groups at the end of the 36-month follow-up period. Seventy-six patients lacked HBV DNA data, as they had received a follow-up by telephone call rather than visiting our hospital in this retrospective study. There were 11 children with serum positive HBV DNA in the 7– < 12 age-group, but nine of 11 cases had low loads of HBV DNA on antiviral treatment. For example, seven of 11 children were with HBV DNA loads ranging within 50–100 IU/mL and two of 11 children were with positive HBV DNA loads ranging within 100–200 IU/mL. Abbreviations: *: p < 0.05; **: p < 0.01; HBV hepatitis B virus, CHB chronic hepatitis B, IC immune clearance, PSM propensity score matching

Fig. 3

Dynamic changes of serum HBeAg and anti-HBe levels and cumulative rates of HBeAg seroconversion in children with IC-CHB during the 36-month study period. a Serum HBeAg changes in the children with CHB in group-A (1– < 7-year-olds) and group-B (≥ 7–16-year-olds); b–c Serum HBeAg changes in the cured and non-cured children in the two groups; d Serum anti-HBe changes in the children with CHB in the two groups; e–f Serum anti-HBe changes in the cured and non-cured children in the two groups; and g–h the cumulative rates of HBeAg seroconversion in the different age groups. g The total number of cases; h total number of PSM cases; and i a comparison of the HBeAg seroconversion rates in the different age groups at the end of the 36-month follow-up period. Eighty-two patients lacked HBeAg and anti-HBe data, as they had received a follow-up by telephone rather than visiting our hospital in this retrospective study. Abbreviations: PSM propensity score matching, *: p < 0.05; **: p < 0.01; ***: p < 0.001; IC-CHB immune clearance chronic hepatitis B, HBeAg hepatitis B e antigen

Fig. 4

Dynamic changes of serum HBsAg and anti-HBs levels and cumulative rates of HBsAg loss in children with IC-CHB during the 36-month study period. a Serum HBsAg changes in the children with CHB in group-A (1– < 7-year-olds) and group-B (≥ 7–16-year-olds); b–c Serum HBsAg changes in the cured and non-cured children in the two groups; d Serum anti-HBs changes of the children in the two groups during the antiviral treatment period; e–f Serum anti-HBs changes in the cured and non-cured children in the two groups; g–h cumulative rates of serum HBsAg loss in the different age groups; g the total number of cases; h PSM cases; and i a comparison of HBsAg loss in the different age groups at the end of the 36-month follow-up period. A total of 159 patients lacked HBsAg and anti-HBs data, as they had received a follow-up by telephone rather than visiting our hospital in this retrospective study. Abbreviations: PSM propensity score matching. ***: p < 0.001; IC-CHB immune clearance chronic hepatitis B, HBeAg hepatitis B e antigen