Editor’s Note : With the widespread implementation of standard immunization programs and mother-to-child transmission prevention measures, the incidence of new HBV infections among children in China has significantly declined. However, due to the large base of hepatitis B patients and regional developmental disparities, the number of new and existing cases of HBV infections among children remains high.
To further address the challenges of preventing and treating hepatitis B in children, clarify standard diagnostic and treatment protocols, and provide references for disease prevention and treatment, the inaugural National Clinical Conference on Viral Hepatitis in Children and the Expert Consensus Meeting on the Prevention and Treatment of Chronic Hepatitis B in Children was held in Beijing. The conference was organized by the National Clinical Research Center for Infectious Diseases, the Infectious Diseases Branch of the Chinese Medical Association, the Hepatology Branch of the Chinese Medical Association, the China Foundation for Hepatitis Prevention and Control, the Infectious Diseases Group of the Pediatric Branch of the Chinese Medical Association, and the Fifth Medical Center of the Chinese PLA General Hospital. At this event, the “Expert Consensus on Prevention and Treatment of Chronic Hepatitis B in Children” (hereinafter referred to as “Consensus”) was officially released. The consensus was led by Professor Fusheng Wang, director of the National Clinical Research Center for Infectious Diseases and the Fifth Medical Center of the Chinese PLA General Hospital, and formulated by multidisciplinary experts in infectious diseases, hepatology, pediatrics, statistics, pharmacology, ethics, and law. Experts highlighted the key points of the consensus during the conference. This article is organized for the benefit of our readers.
I. Prevention and Health Education
1. Prenatal Prevention
Recommendation 1: For pregnant women with HBV DNA ≥2×105 IU/mL or positive HBeAg (when HBV DNA quantification is not available), antiviral treatment is recommended to start between weeks 24 to 28 of pregnancy, using TDF; TAF is considered if TDF is not suitable.
2. Postnatal Prevention
Recommendation 2: Newborns of HBsAg-positive mothers should receive their first dose of the hepatitis B vaccine and 100 IU of HBIG within 12 hours of birth, followed by additional doses of the vaccine at 1 and 6 months of age.
Interpretation: If the first step of mother-to-child transmission prevention is unsuccessful, reliance on postnatal prevention measures is necessary. Administering the hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) to newborns further reduces the risk of HBV mother-to-child transmission. Regardless of the mother’s HBsAg status, including in cases of premature or low-weight infants, the type, dosage, timing, and response monitoring of the vaccination should be carefully managed. Attention should be paid to special cases such as critically ill newborns, children undergoing chemotherapy or immunosuppressive therapy, post-hematopoietic stem cell transplant, post-solid organ transplant, and newborns of HIV-infected mothers, as well as the occasional need to delay vaccination.
For infants born to HBsAg(+) mothers, those with a family history of hepatitis B or who are at high risk of exposure to hepatitis B, it is encouraged to test for HBsAg and/or HBeAg around 3 months of age (1-2 months after the second dose of the vaccine). If any test is positive, further HBV DNA testing should be conducted. This enables early detection, diagnosis, and treatment of HBV infections in children, with the hope that more evidence-based medical evidence will be gathered in the future to refine these recommendations.
II. Clinical Manifestations and Diagnosis
Recommendation 3: Positive HBsAg and/or HBV DNA indicates an HBV infection. For children with chronic HBV infection who have normal ALT (≤ULN), a liver histopathological assessment should be considered, especially if older than 7 years.
Interpretation: Positive HBsAg and/or hepatitis B virus DNA are definite markers of HBV infection in children. Assessing liver damage in CHB involves not only virological markers but also biochemical indicators, with ALT being highly sensitive. A normal ALT in children with chronic HBV infection does not imply the absence of liver damage. Studies have shown that a significant number of children with normal ALT actually have active liver damage.
Recent studies both domestically and internationally have delved into ALT levels, generally agreeing that for children under 16, ALT levels should be kept below 30 U/L. The National Health Commission of the People’s Republic of China’s 2021 “Reference Intervals for Commonly Used Clinical Biochemistry Tests in Children” specifically states that the reference range for ALT in children aged 2-13 years should be 7-30 U/L. Many medical institutions have adopted this new standard as a reference for clinical practice. Although this consensus does not form a specific recommendation, it is generally advised that the ALT levels in children aged 2-13 should be controlled below 30 U/L.
III. Antiviral Treatment
1. Indications for Treatment
Recommendation 4: For CHB children, both HBeAg positive and HBeAg negative, antiviral treatment should be considered regardless of age.
Interpretation: The goal in treating CHB in children is not just to suppress viral replication or achieve serological conversion of HBeAg but more importantly, to pursue a clinical cure, i.e., clearance of HBsAg. According to multiple large-scale domestic clinical studies, the HBsAg clearance rate for HBeAg-positive CHB children is close to 50%, and even higher in specific age groups, such as children aged 1-3 years. For HBeAg-negative children, the clearance rate also tends to increase with decreasing age. These data indicate that treating CHB in childhood has a high potential for cure. Thus, it is recommended that CHB children, both HBeAg positive and HBeAg negative, be actively treated with antivirals if they are over one year old to control the disease early and increase the likelihood of a cure.
Recommendation 5: For HBeAg-positive chronic HBV-infected children aged 1-7 years, antiviral treatment should be considered after thorough communication with guardians and obtaining informed consent. For children over 7 years, a liver biopsy is recommended after guardian consent; if the liver shows inflammation necrosis grade G≥1 or fibrosis stage S≥1, antiviral treatment should be pursued.
Interpretation: The 2022 version of China’s “Guidelines for the Prevention and Treatment of Chronic Hepatitis B” defines the immune-tolerant phase of CHB as having HBsAg levels >1×104 IU/mL, positive HBeAg, HBV DNA >2×107 IU/mL, persistently normal ALT levels, and no significant inflammation necrosis or fibrosis on liver pathology, recommending antiviral treatment for all seropositive HBV DNA individuals over the age of 30.
However, the immune-tolerant phase in children is different, typically characterized by HBsAg >2.5×104 IU/mL, HBV DNA >2×107 IU/mL, high HBeAg (+++), and persistently normal ALT. Current evidence is insufficient to establish cutoff values for HBsAg and HBV DNA levels for antiviral treatment during the immune-tolerant phase in children. Past studies have shown that about 20% of children in the immune-tolerant phase can achieve HBsAg clearance after treatment. Age is a significant factor influencing HBsAg clearance. However, considering the treatment duration and efficacy, it is crucial to fully assess the adverse reactions of the drugs and the patient’s compliance. Therefore, thorough communication with guardians and obtaining their consent is essential before deciding on treatment.
2. Antiviral Treatment Regimens and Follow-up Management
Recommendation 6: For antiviral treatment drug selection, children aged 1 and above can consider standard IFN-α treatment, children aged 2 and above can choose ETV or TDF, children aged 3 and above can opt for Peg-IFN-α, and children aged 12 and above can be treated with TAF (treatment options for infants under 1 year old see Recommendation 11).
Recommendation 7: For CHB children aged 1-7 years, either HBeAg positive or HBeAg negative, IFN-α/Peg-IFN-α or NAs monotherapy can be used based on informed consent from guardians, and combination therapy may be considered depending on the child’s response to treatment; for children over 7 years, both HBeAg positive and HBeAg negative, after weighing the pros and cons, IFN-α/Peg-IFN-α combined with NAs treatment can be initiated.
Interpretation: In the treatment of CHB in children, the choice of antiviral drugs is crucial. The main antiviral drugs are divided into IFN-α/Peg-IFN-α and NAs, each with their unique advantages and limitations. Although there is clinical evidence for the use of TAF in children aged 6-12 years, due to considerations of safety and effectiveness, a clear recommendation has yet to be formed.
Additionally, while monotherapy has achieved certain efficacy in CHB children, combination therapy as an optimized treatment strategy may be more advantageous. Particularly, the combination of IFN-α/Peg-IFN-α and NAs could help accelerate the rebuilding of the body’s immune response, thus enhancing the treatment effect.
When devising combination therapy plans, it is necessary to consider host factors, hepatitis B virus factors, and drug factors, and choose the appropriate combination method. Standardized treatment is fundamental, but personalized treatment is more crucial. Past clinical studies have proven that combination therapy has advantages over monotherapy in terms of HBeAg serological conversion. Although clearance of HBsAg has not yet received more robust support due to limitations in age and case numbers in previous clinical data, with the accumulation of subsequent clinical evidence, combination therapy is expected to show superior effects compared to monotherapy.
Recommendation 8: The treatment duration for children receiving IFN-α/Peg-IFN-α is generally recommended to be 48 weeks; extending the treatment can further improve the efficacy, but the benefits and risks of extending the treatment should be fully assessed, and the total duration of continuous treatment should not exceed 96 weeks. During the IFN-α/Peg-IFN-α treatment period, close monitoring of its impact on child growth is necessary.
Interpretation: Extending treatment is another aspect of optimizing therapy; past research has shown that extended treatment helps improve the rate of HBeAg serological conversion and HBsAg clearance.
Although extending the treatment duration can further enhance the therapeutic effect, when making decisions, it is necessary to comprehensively weigh the potential benefits and risks of extending the treatment to ensure the best overall health of the child.
It is particularly important to closely monitor changes in children’s growth and development during interferon therapy, especially during the growth spurt stage of 8-12 years, to ensure that the treatment does not affect the normal growth of the child.
Recommendation 9: NAs discontinuation criteria, for HBeAg-positive CHB children, if HBV DNA becomes negative and HBeAg serological conversion occurs, stopping the medication when HBsAg <100 IU/mL can reduce the risk of relapse after discontinuation; for HBeAg-negative CHB children, NAs treatment should continue until HBsAg becomes negative, with or without the appearance of anti-HBs, followed by at least 6 months of consolidation treatment before considering discontinuation.
Interpretation: In pediatric patients, the NAs discontinuation criteria are still lacking sufficient evidence, so the current practice mainly refers to the standards for adults. This discontinuation strategy helps reduce the risk of relapse after stopping the medication. For HBeAg-negative children, it is recommended to continue consolidation treatment until HBsAg conversion is achieved, with or without the appearance of surface antibodies. In this case, treatment should be consolidated for an additional 6 months before discontinuation.
Recommendation 10: IFN-α/Peg-IFN-α discontinuation criteria, for HBeAg-positive CHB children, treatment should continue until HBsAg conversion occurs, with or without the appearance of anti-HBs, followed by 12-24 weeks of consolidation treatment before stopping; for those who do not achieve HBsAg conversion, treatment should continue until HBeAg serological conversion, followed by 12-24 weeks of consolidation treatment before considering discontinuation, with the total treatment course generally not exceeding 96 weeks.
IV. Special Circumstances
1. Infant HBV Infection
Recommendation 11: For HBV-infected infants under 1 year of age diagnosed with persistently elevated ALT (>ULN) and after excluding other causes, antiviral treatment is recommended; if ALT is normal, antiviral treatment may be considered after obtaining informed consent from guardians. LAM (4 mg/kg/d) is the drug of choice, and if clinical cure is not achieved by the age of 1, IFN-α can be added.
2. Poor Response and Low Viral Load in Children
Recommendation 12: For children who have had a poor response to NAs monotherapy for 48 weeks or more or who develop low viral load, sequential combination therapy with IFN-α/Peg-IFN-α or switching to/adding other age-appropriate NAs may be considered.
3. Children with Cirrhosis
Recommendation 13: Children with cirrhosis, rapidly deteriorating liver function, and liver failure require prompt antiviral treatment. For children with compensated hepatitis B-related cirrhosis, oral antiviral medications appropriate for their age, such as ETV or TDF, can be chosen, and IFN-α and Peg-IFN-α can be added under close monitoring; for decompensated cirrhosis, oral ETV or TDF appropriate for the child’s age is preferred, and IFN-α and Peg-IFN-α are contraindicated. For children with cirrhosis and rapidly deteriorating or decompensated liver function, antiviral treatment should be initiated promptly to control disease progression.
Interpretation: Studies show that for children with compensated cirrhosis, combined interferon therapy can be cautiously chosen after assessment, not only to suppress viral replication but also potentially to achieve HBsAg clearance and reverse cirrhosis.
4. Children with HBV and Other Viral Infections
Recommendation 14: Depending on the type of co-infection, it is recommended to refer to the guidelines for chronic hepatitis C and AIDS for antiviral treatment.
5. Children with Acute Hepatitis B
Recommendation 15: For children diagnosed with acute hepatitis B, antiviral treatment appropriate for their age can be used during the course of the illness to promote clinical cure and reduce the risk of chronicity; antiviral treatment can be considered for discontinuation 1 month after HBV DNA conversion, HBeAg serological conversion, and HBsAg serological conversion.
6. Children with Organ Transplants (Liver Transplants)
7. Children Undergoing Chemotherapy or Immunosuppressive Therapy
Recommendation 16: For children with HBV infection undergoing immunosuppressive therapy or cytotoxic chemotherapy due to organ transplantation or other reasons, prophylactic NAs oral antiviral treatment should be provided to prevent HBV reactivation.
8. HBV-Associated Glomerulonephritis
Recommendation 17: For children with HBV-associated glomerulonephritis, NAs treatment suitable for their age and with good renal safety should be preferred, and IFN-α/Peg-IFN-α antiviral treatment may also be considered.
9. Children with HBV-Related HCC
Recommendation 18: For children with HBV-related HCC, if HBsAg is positive, antiviral treatment with NAs should be considered based on the child’s age and tolerance, and IFN-α treatment may also be considered as appropriate.
V. Issues to be Researched and Addressed
Firstly, further refinement and optimization of HBV infection screening, early diagnosis, and standardized treatment management strategies are needed for infants and young children at high risk of exposure, to reduce the risk of disease progression. Secondly, multicenter cohort studies are urgently needed to clarify the natural history and clinical staging characteristics of HBV infection in children, to provide higher quality evidence-based medical evidence for the diagnosis and treatment of CHB in children. Additionally, optimization and improvement of antiviral treatment regimens for children under 12 years old are still needed to clarify their long-term safety and effectiveness. Research on the safety and efficacy of existing antiviral medications for the treatment of HBV-infected infants under 2 years old is also necessary.
