Usually serum HBsAg positivity for more than 6 months is called chronic HBV infection. There are approximately 125 million people with chronic HBV infection in China, the vast majority of which are due to mother-to-child transmission or childhood infection. Despite the effectiveness of hepatitis B vaccine in preventing hepatitis B transmission, chronic HBV infection in children remains a serious social problem due to the large base of the infected population. Chronic hepatitis B refers to chronic necroinflammation of the liver caused by persistent HBV infection, as evidenced by elevated serum HBV-DNA with persistently or intermittently elevated ALT levels or liver biopsy showing chronic hepatitis (inflammatory necrosis score R4). Chronic hepatitis B can lead to cirrhosis and hepatocellular carcinoma. With the understanding of the natural history of chronic hepatitis B and the introduction of new anti-hepatitis B virus drugs, the concept of treatment and management of chronic hepatitis B has been revolutionized in recent years. Guidelines and consensus on chronic hepatitis B have been published and updated in the United States, Europe, and Asia Pacific, and in China, the “Guidelines for the Prevention and Treatment of Chronic Hepatitis B” were developed by the Chinese Medical Association’s Hepatology and Infectious Diseases Sections and published in 2005. New developments in the treatment of chronic hepatitis B in children are described as follows: (a) Evaluation and treatment indications for chronic HBV infection in children A detailed evaluation of patients with chronic HBV infection should be performed. The initial evaluation should include a systematic history and physical examination, with particular attention to the presence of high-risk factors such as co-infection, family history of HBV infection, and family history of liver cancer. Laboratory tests should include assessment of the extent of liver disease (routine blood work, liver function and prothrombin time) and HBV replication markers (HBeAg/anti-HBe, HBV-DNA), excluding HCV, HDV or HIV co-infection and ultrasound for liver cancer in those with high-risk factors. For those who meet the criteria for chronic hepatitis, liver biopsy should be performed to grade the inflammation, stage the fibrosis, and exclude other causes of liver disease. Anyone with chronic HBV infection who is not immune to hepatitis A should receive hepatitis A vaccination. The US AASLD guidelines use HBV-DNA >105copies/ml as an artificial criterion. Our guidelines use HBV-DNA ≥104copies/ml as one of the indicators for antiviral treatment in HBeAg-negative chronic hepatitis B. Some quantitative amplification methods can now detect HBV-DNA at 102copies/ml, but because the clinical significance of such low levels of HBV-DNA is unclear, the results must be interpreted with caution. HBeAg-positive patients with high levels of serum HBV-DNA (>105copies/ml) and normal ALT levels in an “immune tolerant” state should not be considered for treatment at this time, but ALT should be followed up every 3-6 months. The ALT level should be more closely followed up if it is found to be elevated, usually every 1-3 months for 3-6 months. If ALT is persistently elevated more than 2 times the upper limit of normal and is still HBeAg positive with HBV-DNA >105copies/ml after more than 3 months of continuous observation, liver biopsy should be considered and antiviral therapy should be given. Because liver disease may still be reactive after years of rest, inactive HBsAg carriers should be checked for ALT every 6 to 12 months, and if elevated ALT is found, serum HBV-DNA levels should be added and attention should be paid to exclude other causes of liver disease. Lamivudine antiviral therapy should be started immediately for children with chronic HBV infection who are at risk of liver function loss. (ii) Treatment goals The fundamental goal of chronic hepatitis B treatment is to remove or permanently suppress HBV, thereby reducing the pathogenicity and infectivity of the virus, reducing or suppressing necrotizing inflammation of the liver, delaying and stopping disease progression, reducing and preventing liver failure, cirrhosis, hepatocellular carcinoma and their complications, and thus improving quality of life and prolonging survival time. Antiviral therapy is the key to the treatment of chronic hepatitis B. (iii) Antiviral treatment drugs The drugs approved globally for the treatment of chronic hepatitis B include interferon, including common interferon and pegylated interferon, as well as the nucleoside analogs lamivudine, adefovir, entecavir, tipifudine, tenofovir, etc. Thymidine a1 is also approved for the treatment of chronic hepatitis B in China. Among them, common interferon has been widely used in children, and the US FDA has approved lamivudine for the treatment of chronic hepatitis B in children for several years, and recently approved adefovir for children over 12 years of age. However, because the long-term efficacy of current therapeutic measures remains limited, individualized treatment must be considered before treatment is initiated, taking into account the patient’s age, severity of disease, likelihood of achieving efficacy, and potential drug adverse effects and comorbidities, the cost of treatment, and the patient’s wishes. Both interferon a and lamivudine can be used as initial therapy for children with chronic hepatitis B unless there are contraindications or no response to prior treatment. 1. Interferon a Generic interferon a was one of the first approved anti-HBV therapeutic agents. Its advantages are a defined course of treatment, relatively long-lasting efficacy, and the absence of drug-resistant mutant strains. In children with elevated ALT, the HBeAg clearance rate was 10% in the control group and 30% in the interferon a treatment group, similar to the effect of adult hepatitis B treatment. A meta-analysis of 240 children showed that interferon a treatment increased HBV-DNA and HBeAg clearance (OR 2.2) and promoted ALT normalization (OR 2.3) compared to the control group. In China, thousands of chronic hepatitis B cases were treated with recombinant interferon a in recent years, and the average rate of HBeAg and HBV-DNA negative conversion was 30-40%. Follow-up for 4-8 years found that 80%-90% of patients who cleared HBeAg after interferon a treatment still remained HBeAg negative. A study in Taiwan showed that the incidence of hepatocellular carcinoma was also lower in the interferon a treatment group than in the control group, but most studies concluded that interferon treatment only accelerated HBeAg serological conversion and that the long-term benefits of treatment were uncertain and needed more in-depth evaluation. Effective interferon cases are mainly seen in patients with high pretreatment ALT levels, low serum viral levels, and non-maternal-to-child transmission infections. The “transient” increase in ALT that occurs in approximately 20% to 40% of HBeAg-positive chronic hepatitis B patients during treatment is thought to be the result of a treatment-induced immune response that attacks infected hepatocytes and is a precursor to a treatment response. The recommended dose for children is 3-6 MU/m2, with a maximum of 10 MU, administered subcutaneously three times a week. The recommended course of treatment for HBeAg-positive chronic hepatitis B is 16 weeks to 6 months, regardless of whether a treatment response has occurred, and a 12-month course is more beneficial for HBeAg-negative chronic hepatitis B. Because of the longer course required for HBeAg-negative chronic hepatitis B, AASLD prefers to recommend interferon a therapy. Follow-up should be continued for 6 to 12 months after the end of interferon a therapy to observe for delayed response and to clarify whether the response is durable so that the need for retreatment or other treatment can be determined. Interferon a is less effective in people with high viral levels and immunosuppression. Treatment of children with chronic HBV infection with normal ALT is also ineffective, with HBeAg clearance rates below 10%. Interferon a is contraindicated in patients with hepatic decompensation because of the potential for exacerbation of hepatitis during treatment. Interferon a has many side effects, of which flu-like symptoms, fatigue, leukopenia and depression are the most common. Flu-like symptoms tend to decrease or disappear after 1 week, but fatigue, nausea, hair loss, and mood swings can persist throughout the course of treatment and for several weeks after treatment ends. Interferon a can also cause an underlying immune disorder to flare up or worsen. Treatment of adults with chronic hepatitis B requires dose reduction due to side effects in about 1/3 of patients and early discontinuation in 5% of patients. PEGylated interferon, which combines interferon and pegylated glycol to slow the rate of interferon absorption and excretion, can be given as a weekly injection and was originally approved for the treatment of chronic hepatitis C. It is now approved for the treatment of chronic hepatitis B in adults and has been approved for the treatment of chronic hepatitis C in children in the US. There is a lack of information on the treatment of chronic hepatitis B in children, and it has not been approved for the treatment of chronic hepatitis B in children, but it is much speculated that it can be expected to replace regular interferon a for the treatment of chronic hepatitis B in children. If interferon a treatment fails in children, they can be treated with lamivudine. The advantage of lamivudine is that it is orally administered and well tolerated. Because the drug has a faster onset of action than interferon a, while no interferon a increases the risk of decompensation in patients with cirrhosis, lamivudine is particularly suitable for patients with decompensated cirrhosis or cirrhosis at risk of liver failure. The recommended dose of lamivudine for the treatment of chronic hepatitis B in children aged 2-17 years is 3 mg/kg/d, with a maximum dose of 100 mg/d. The HBeAg conversion rate at 1 year of lamivudine treatment was 23% compared with 13% in the control group. HBeAg serologic conversion occurred in another 21% of children who continued treatment for 1 year. The durability and long-term safety of the efficacy of lamivudine treatment in children with chronic HBV infection after discontinuation of the drug was recently reported. At 3-year follow-up, HBeAg seroconversion was maintained in 82% of cases discontinued at 1 year of lamivudine treatment and in 90% of cases discontinued at 2 or more years of treatment. In the control group, HBeAg seroconversion was maintained in 75% of cases with spontaneous seroconversion. No side effects related to long-term treatment, including effects on growth and development, were found, and no cases of severe hepatitis occurred after discontinuation of the drug. The recommended course of treatment for HBeAg-positive chronic hepatitis B is now generally considered to be at least 1 year: those with established HBeAg conversion (at least 2 months between tests) should continue treatment for 6 months to reduce relapse after discontinuation; those without HBeAg conversion need to be analyzed on an individual basis according to the patient’s clinical/virological response and severity of disease before deciding to discontinue or continue treatment. Long-term treatment with lamivudine increases resistant mutant strains. Adult studies have reported up to 20% resistant mutants at 1 year of treatment and up to 70% resistant mutants at 5 years of treatment. The emergence of resistant mutants can exacerbate the disease in some patients. The most common mutant strain is the YMDD mutation, with a mutation incidence of 19% at 1 year of treatment and 64% at 2 years of treatment in pediatric data. The treatment effect is significantly lower in mutated cases than in non-mutated cases. There are two options for those who develop breakthrough infection due to lamivudine-resistant strains: individuals with normal immune function without cirrhosis can be discontinued under close observation; individuals with underlying cirrhosis or immunosuppression should be switched or added to other nucleoside analogs that are effective against mutant strains; pediatric safety data are available only for adefovir. Patients who are HBeAg-negative should be treated for more than 1 year; the ideal duration of therapy cannot be determined at this time, and the endpoint of therapy needs to be determined based on the patient’s clinical response and the severity of liver disease. For patients with immunosuppression, lamivudine therapy is preferred. Interferons are often ineffective or even harmful in organ transplant patients. Patients who are HBsAg-positive and on immunosuppression or receiving chemotherapy need to be monitored closely for viral rebound and lamivudine therapy must be started promptly before the onset of decompensation. 3, Adefovir Adefovir (ADV) is a purine analogue that has been approved for safe and effective use for several years as first-line therapy or treatment of lamivudine-resistant cases in adults with chronic HBV infection. The first randomized, double-blind, placebo-controlled trial in children and adolescents was published last year with 173 patients enrolled at 12 centers in the United States and 14 centers in Europe. The study population was divided into three age groups: 2-6 years (35 patients), 7-11 years (55 patients) and 12-17 years (83 patients). Asian patients comprised approximately 25% of the study population, with slightly more than half having received prior antiviral therapy. more than 90% were HBeAg-positive patients with serum ALT levels exceeding 1.5 times the upper limit of normal. Patients were randomly divided into treatment and control groups in a 2:1 ratio, with similar pre-treatment HBV-DNA concentrations and other indicators in the treatment and control groups. The primary endpoint was a reduction in HBV-DNA to less than 1000 copies/ml at 48 weeks of treatment and a normal ALT. ADV was most effective in the 12-17 year old group. The primary treatment endpoint was achieved in 23% of the treatment group and 0% of the placebo control group at the end of 48 weeks of treatment. When all age groups were analyzed together, 19% of the treatment group met the primary treatment endpoint compared to 1.7% of the placebo control group. More cases in the 7-11 and 2-6 year old ADV groups met the primary treatment endpoint (7-11 year old group, 17% vs. 0%; 2-6 year old group, 13% vs. 8%), but did not reach statistical significance. Secondary endpoints included changes in HBV-DNA levels, changes in ALT levels, disappearance of HBeAg and appearance of anti-HBe, and disappearance of HBsAg. Throughout the treatment period, all ADV-treated patients showed statistically significant decreases in HBV-DNA. ALT recurrence was higher in ADV-treated patients than in controls in the 7-11 and 12-17 age groups (58% vs. 16% in the 7-11 age group and 64% vs. 22% in the 12-17 age group). There was no statistical difference in the proportion of HBeAg disappearances or serological conversion rates in the treatment and control groups compared to each age group, but there was an effective trend with a 16% e-seroconversion rate in the treatment group and 5% in the control group (p=0.051). 1 case of S-antigen seroconversion occurred in the ADV group. Adefovir was generally well tolerated in children and adolescents, with only mild to moderate side effects reported and not related to treatment. No viral resistance occurred in the study. However, it is important to note that adult studies reported a 1-year resistance rate of 1%, rising to a 5-year resistance rate of 29%. Additional clinical trials are necessary to study the durability of efficacy of ADV, its effectiveness in children under 12 years of age, and the incidence of mutations in children on long-term dosing. It is currently not recommended as first-line treatment for younger children unless there are conditions such as cirrhosis. 4.Thymidine a1 Thymidine a1 is an artificially synthesized immunomodulatory drug. The clinical study conducted in China showed that the rate of HBV-DNA and HBeAg conversion in the group treated with thymidine a1 alone was 47%, the rate of HBV-DNA and HBeAg conversion in the group treated with thymidine a1 combined with interferon a was 61%, and the rate of HBV-DNA and HBeAg conversion in the group treated with interferon a alone was 39%. Foreign clinical trials using thymidine a1 failed to achieve consistent results, however a meta-analysis found that although there was no significant difference in response rates between the thymidine a1 and control groups at the end of treatment, the late response rate was significantly higher in the thymidine a1 group than in the control group 6 to 12 months after the end of treatment. Because thymidine a1 is well tolerated, thymidine a1 can be used when treating HBeAg-positive chronic hepatitis B patients who have indications for antiviral therapy but are unable or unwilling to receive interferon a or lamivudine. Dosing is 1.6 mg subcutaneously once daily, changing to twice weekly after 12 to 14 days for 6 months. Newer agents such as pegylated interferon and other nucleoside analogs have not been studied in children with chronic HBV infection, but are generally considered to be similarly effective to adults with chronic hepatitis B. In children, more attention should be paid to the long-term safety and drug resistance of the drugs. Recent long-term follow-up studies suggest that interferon therapy provides limited long-term benefit compared to untreated children. Therefore, given the current limited evidence of long-term treatment benefits and possible risks after initiation of treatment, some experts recommend that treatment should not be recommended unless there is an absolute indication, such as a potential or imminent liver failure. 5, combination therapy Given the unsatisfactory results of monotherapy for chronic HBV infection, many studies have turned to combination therapy. Although interferon and nucleoside analogs, or a combination of different nucleoside analogs, have shown a trend toward reducing the emergence of resistant strains, there is not enough to recommend interferon in combination with lamivudine, or lamivudine in combination with ADV for the treatment of children with HBeAg-positive or negative chronic hepatitis B. Some studies have achieved better results with 8 weeks of lamivudine followed by 10 months of interferon and lamivudine combination therapy in immune-tolerant children with chronic HBV infection, but the number of cases is small and further validation is needed. Combination therapy with lamivudine and thymidine a1 has been reported to improve durable response rates, but again further confirmation is needed. (iv) Monitoring during treatment Relevant indicators should be regularly monitored and followed up during antiviral therapy. Biochemical indicators, including ALT, should be monitored once a month for 3 consecutive times after the start of treatment and at least once every 3 months thereafter as the disease improves; virological markers, such as HBsAg, HBeAg, anti-HBe and HBV-DNA, should be tested every 3 months after the start of treatment. The patient should also be monitored before and during the course of treatment. Those treated with lamivudine should have their blood count, creatinine phosphate and serum creatinine monitored as needed. ALT levels and HBV markers (including HBV-DNA) should be monitored monthly for early relapse for the first 3 months after the end of treatment, and then every 3 months (for patients with cirrhosis and those with persistent HBeAg/HBV-DNA positivity) or 6 months (for those with treatment response). In non-responders, further monitoring should be performed to determine if there is a delayed response and to retreat if indicated. Summary The treatment of chronic hepatitis B in children has made great progress in recent years. Antiviral therapy should be considered in children aged 2-17 years with chronic HBV infection who have persistent elevations of blood ALT more than 2 times the upper limit of normal with active viral replication lasting more than 3 months. Both lamivudine and interferon can be considered for children over 2 years of age, but attention should be paid to the side effects of interferon and lamivudine resistance. adv is less effective in children under 12 years of age, but the incidence of drug resistance is low. It is worth noting that in China, there is no pediatric form of lamivudine so far, and the current domestic guidelines only recommend it for children over 12 years of age with indications. PEGylated interferon and other nucleoside analogs, including entecavir, tipifudine, and tenofovir, have not been studied in pediatric patients with chronic HBV infection. The costs and benefits of various treatment strategies have yet to be evaluated in depth. How to manage more effectively the large number of carriers in the immune tolerance phase or those with mildly elevated ALT levels (less than 2 times the upper limit of normal) to reduce their long-term complications is an even more urgent research question.