Efficacy and Safety of Antiviral Therapy for Immune-tolerant Hepatitis B Viral Infection in Children: A Systematic Review and Meta-analysis

Abstract

Background: Chronic hepatitis B virus (HBV) infection burden in children remains a pressing public health concern. Whether antiviral therapy should be administered to children with HBV in the immune-tolerant phase remains controversial. We performed a meta-analysis to evaluate antiviral therapy efficacy and safety in children with immune-tolerant hepatitis B (ITHB). Methods: A search was conducted in multiple databases (PubMed, Embase, Cochrane, Web of Science, CBM, CNKI and Wanfang Data) to identify clinical trials examining antiviral therapy efficacy and safety in children (1–18 years) with ITHB viral infection from inception to February 2023. Outcomes were calculated separately for controlled and single-arm studies. Results: Nine trials (442 patients), including 2 randomized controlled trials (RCTs), 3 non-RCTs and 4 single-arm studies, were included in this meta-analysis. In the RCTs, antiviral therapy group exhibited greater rates of HBsAg loss [risk ratio (RR) = 6.11, 95% confidence interval (CI): 1.67–22.31, PZ-test = 0.006], HBsAg serologic response (RR = 5.29, 95% CI: 1.47–19.07, PZ-test = 0.011) and HBeAg loss (RR = 3.00, 95% CI: 1.35–6.66, PZ-test = 0.007) compared with the control group at the end of follow-up. In single-arm studies, the pooled incidences of HBsAg loss, HBeAg loss and HBsAg seroconversion were 24% (95% CI: −0.1% to 48%), 24% (95% CI: −0.1% to 48%) and 24% (95% CI: −5% to 52%), respectively. Conclusion: Current evidence suggests the effectiveness of antiviral therapy in children with HBV infection in the immune-tolerant stage, with few serious adverse events. Due to the limited quality and number of included studies, more high-quality studies are required to validate our findings.

Estimating the key outcomes and hepatocellular carcinoma risk in patients in immune‐tolerant phase of chronic hepatitis B virus infection: A systematic review and meta‐analysis

“…First, our results indicate significantly low rates of HBV DNA negative conversion (0%–2%) and HBsAg loss or seroconversion (0%) in both adult and paediatric untreated patients in the IT phase. This aligns with previous meta‐analyses, 12,13 suggesting that spontaneous achievement of HBV DNA undetectability and HBsAg clearance is rare in patients in the IT phase. However, our data revealed that approximately 4% of patients in the IT phase can spontaneously achieve HBeAg seroconversion within 48–96 weeks of follow‐up, potentially due to phase changes experienced by patients.…”

“…Conversely, Lee et al.’s meta‐analysis 9 comparing outcomes between the IT and IA phases found similar pooled HCC and mortality incidence. Four meta‐analyses 10–13 assessing antiviral therapy efficacy for patients in the IT phase yielded conflicting conclusions due to the lack of a strict IT phase definition, limited cases, and poor article quality. Updated data on patients in the IT phase are crucial for better disease understanding, enabling physicians to develop strategies, increase awareness, and implement interventions to reduce its burden.…”

Letter: Baseline age on antiviral treatment may significantly influence the clinical response of children with chronic hepatitis B ‐ authors' reply

“…For example, Wang et al found that the cumulative rate of HBsAg loss was 46% in paediatric patients with immune-active CHB after a median follow-up of 13 years, 3 which was significantly higher than the reported rate (22%-24%) among children with immune-tolerance CHB. 4,5 In addition, we divided the enrolled children into two groups according to their baseline condition, and demonstrated that paediatric patients with CHB in the IC phase had better treatment responses (HBsAg loss: 57.0% vs 27.3%, p < 0.05) than those in the IT phase. Our observations provide a more comprehensive understanding of the effects of treatment on different phases of CHB in children.…”

Expanding indications for chronic hepatitis B treatment: Is it really desirable to treat everyone?

“…It should not be ignored that studies with long observation periods of treated children compared to untreated children have not highlighted major differences in terms of complications and mortality over a period of 24-29 years[ 16 , 17 ]. The other pediatric studies that demonstrated an advantage of the treatment focused heavily on obtaining laboratory objectives rather than the risk of complications from cirrhosis and HCC and duration of survival[ 18 , 19 ]. Thus, as often happens, we run the risk of applying evidence carried out in adulthood to children and therefore medicalizing a group of subjects who may not have significant complications in the long term.…”