Universal hepatitis B vaccination has reduced the number of HBV-infected children by tens of millions, but due to the large population in China, the HBV-infected population base is large, and most HBV infections in children are mainly through the mother-to-child transmission route and are generally immune-tolerant. Therefore, the antiviral treatment of chronic hepatitis B (CHB) in children remains a concern. To date, there are no guidelines for the prevention and treatment of CHB in children in China, and the 2015 edition of our Guidelines for the Prevention and Treatment of Chronic Hepatitis B only briefly describes the drugs and doses of anti-HBV therapy in children with CHB. This article summarizes and analyzes the latest research results of antiviral therapy for children with CHB at home and abroad in recent years, hoping to help clinicians gain a deeper understanding of the issues of antiviral therapy for children. Goals and treatment endpoints of antiviral therapy in children with CHB The 2013 guidelines of the European Society for Pediatric Gastroenterology and Hepatology Nutrition (ESPGHAN) state that the overall goals of antiviral therapy for CHB in children are the same as those for adults, namely to reduce liver disease progression, reduce the risk of cirrhosis and hepatocellular carcinoma (HCC), improve long-term survival and improve quality of life through antiviral therapy. Regarding the endpoints of anti-CHB therapy in children, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) express the same, i.e., HBeAg-positive patients on antiviral therapy achieve sustained HBeAg serologic conversion, alanine transaminase (ALT) normalization, and improvement in liver histology (satisfactory treatment endpoints); a proportion of patients achieve HBsAg elimination and/or (or) serologic conversion (the desired treatment endpoint), i.e., clinical cure, thus achieving the ultimate goal of CHB antiviral therapy. Sustained virologic remission (undetectable HBV DNA) during antiviral therapy is an acceptable basic treatment endpoint if a durable response after drug discontinuation is not achieved. Timing of antiviral treatment and selection of treatment targets in children with CHB World Health Organization (WHO) guidelines emphasize the importance of good monitoring of the disease throughout the course of HBV infection in children older than 2 years of age, with regular checks for HBV DNA and changes in liver function. Children with persistent HBV infection resulting in active HBV replication, elevated HBV DNA levels, liver showing necroinflammation, persistent or intermittent elevation of ALT levels above 2 times the upper limit of normal, and exclusion of other factors causing ALT elevation, or liver biopsy confirming inflammation or fibrosis of liver tissue need antiviral therapy. the WHO guidelines for antiviral therapy in patients with compensated cirrhosis are more positive than The WHO guidelines are more aggressive than previous guidelines in recommending treatment for adults and adolescents with clinically documented compensated or decompensated hepatitis B cirrhosis and for children, regardless of ALT level, HBeAg status, or HBV DNA level. It has been well documented that early antiviral therapy can stop disease progression and reverse fibrosis and cirrhosis, improving prognosis. Selection of antiviral therapy for children with CHB The disease progresses slowly in childhood, and the risks and benefits of treatment should be fully evaluated before antiviral therapy, and the treatment regimen should be selected according to the current disease status of the child. The 2015 edition of our Guidelines for the Prevention and Treatment of Chronic Hepatitis B summarizes the U.S. Food and Drug Administration (FDA) and WHO medications and doses for anti-HBV therapy in children. Currently, there are two major classes of drugs available for anti-HBV treatment, namely interferon analogs and nucleoside (acid) analogs (NAs). Interferons The interferon class includes regular interferon (IFN) and pegylated interferon (Peg IFNα), of which IFNα has been approved for use in children over 1 year of age, but Peg IFNα has not been approved for the treatment of children with CHB to date, and Peg IFNα-2a is in phase IIIb clinical trials in children over 3 years of age worldwide. 2010, Zhang Hongfei from China reported at the Asia Pacific Liver Disease In 2010, Zhang Hongfei from China reported the results of the extended course (96 weeks) of Peg IFNα-2a in 45 HBeAg-positive CHB children aged 8-16 years at the annual meeting: the HBeAg conversion rate was 23.8% at 48 weeks of treatment and up to 91.9% at 96 weeks. The recommended dose of IFNα is 3-6 MU/m2 body surface area, with a maximum dose of 10 MU/m2 every other day. IFN regimen is generally 1 year, but most experts now believe that CHB IFNα regimen in Chinese children, at least 1 year to obtain better efficacy, and prolonging the regimen can improve HBeAg and HBsAg clearance. IFNα therapy can lead to liver failure, therefore, decompensated cirrhosis is a contraindication to IFNα therapy. Due to factors such as the high number of adverse effects during Peg IFNα treatment and the high price, WHO guidelines do not recommend priority use for patients in low- and middle-income areas. Nucleoside (acid) analogues (NAs) NAs include lamivudine (LAM), adefovir (ADV), entecavir (ETV), telbivudine (LDT), tenofovir (TDF), and emtricitabine (ETC). Among them, LAM and ETV are approved for antiviral treatment in children over 2 years of age, and ADV and TDF are used for antiviral treatment in children over 12 years of age. Entecavir (ETV) and tenofovir (TDF) have a strong inhibitory effect on HBV DNA and a high resistance barrier, but short-term treatment has a low rate of HBeAg serologic conversion, and long-term treatment can achieve HBV DNA below the lower limit of detection in more than 90% of CHB patients, and it can improve liver tissue inflammation necrosis and fibrosis, reduce the incidence of liver failure and HCC, and decrease the morbidity and mortality rate. A recent study completed by Jonas et al. at Boston Children’s Hospital found that entecavir (ETV) treatment in children with CHB resulted in better outcomes. It was a phase III randomized controlled study with the primary endpoints of HBeAg serologic conversion and HBV DNA <50 IU/mL at week 48 of treatment. after week 48, patients who experienced HBeAg serologic conversion continued blinded treatment, and patients who did not experience HBeAg serologic conversion were switched to open-label ETV therapy. A total of 180 patients were enrolled in the study and randomized in a 2:1 ratio to receive ETV or placebo. 25%, 25%, and 50% of children aged 2 to 6, 6 to 12, and 12 to 18 years, respectively, were treated with ETV at a dose of 0.015 mg?kg-1?d-1 orally, with a maximum dose of 0.5 mg/d for children with a body mass ≥32.6 kg. The incidence of the primary endpoint at week 48 was significantly higher in the ETV-treated group than in the placebo group [24.2% (29/120) vs. 3.3% (2/60), P = 0.0008]. The cumulative incidence of drug resistance was 0.6% and 2.6% at 1 and 2 years of ETV application, respectively. Patients tolerated ETV well compared with the application of placebo, and no differences in adverse events or changes in growth were observed. Tenofovir (TDF) has been recommended for antiviral therapy in children with HIV infection at 2 years of age with a good safety profile, but clinical data are scarce for the treatment of children with CHB. Murray et al. reported a double-blind, randomized, controlled clinical study of TDF in adolescent patients >12 years of age. A total of 106 patients were enrolled in the study, of whom 85% were treated and 91% were HBeAg-positive. 52 were treated with TDF at a dose of 300 mg/d and 54 were treated with placebo. By 72 weeks of treatment, 89% of patients in the TDF-treated group had a virological response, significantly higher than in the placebo group (0, P<0.001). 74% of ALT was normalized in the TDF-treated group, also significantly higher than in the placebo group (31%, P<0.001). TDF resistance was not detected and was safely tolerated. Based on the available findings, the 2015 WHO guidelines recommend tenofovir disoproxil (TDF) and entecavir (ETV) as first-line antiviral therapy for adults, adolescents, and children with CHB ≥12 years of age who have an indication for antiviral therapy, and ETV is recommended for children 2 to 11 years of age. low resistance barrier NAs (LAM, ADV, or LDT) can lead to drug resistance and are not recommended (strong recommendation, moderate quality evidence). For CHB patients with proven or suspected resistance to ETV and second-line antivirals LAM, ADV, or LDT (i.e., previous history of drug exposure or primary non-response), switching to TDF therapy is recommended (strong recommendation, low-quality evidence). Regarding the dose of NAs, the doses of ETV and TDF for the treatment of children with CHB are detailed in the 2015 edition of our guidelines. China is the largest developing country in the world, with uneven economic development and differences in population income. For children in the western region who do not have priority access to ETV/TDF for economic or other reasons, second-line antiviral therapy with close monitoring of drug resistance and safety may be an option. According to the 2015 edition of the AASLD guidelines, the standard oral dose of lamivudine (LAM) for pediatric patients over 2 years of age is 3 mg?kg-1?d-1, with a maximum dose of 10 mg?kg-1?d-1; adefovir (ADV) for adolescent CHB patients over 12 years of age is administered orally at a dose of 10 mg/d. Once resistance is detected during dosing, it should be Rescue therapy should be given as early as possible, and it is advisable to choose nucleoside (acid) analogues without cross-resistance sites for combination therapy and to avoid single-drug sequential therapy with drugs with low resistance barriers. Discontinuation and management of antiviral therapy in children with CHB The discontinuation and management of antiviral therapy in children with CHB should follow the protocol for adults with CHB. Special emphasis should be placed on close monitoring of disease progression in children who do not meet the recommended indications for antiviral therapy and in those with HBV/HIV co-infection; in patients on treatment or followed up after treatment discontinuation, monitoring should be done at least once every 3 months in the first year; progressive (compensated or decompensated cirrhosis) patients need even closer monitoring of disease progression. Patients on long-term treatment with tenofovir (TDF) or entecavir (ETV) should have their renal function monitored annually. In addition, because children are still growing, monitoring of their growth and development should also be enhanced during antiviral therapy and follow-up.