With the universalization of hepatitis B vaccination, there has been a significant decrease in HBV infection in children, and children at high risk of HBV infection include infants born to chronically HBV-infected mothers, children who did not receive the hepatitis B vaccine properly due to a variety of factors, and children who were born prior to the universal implementation of the hepatitis B vaccination. Before the universal implementation of hepatitis B vaccination, about half of the children with chronic HBV infection in China were due to mother-to-child transmission. After the universalization of hepatitis B vaccination, more than 90% of children with chronic HBV infection are due to mother-to-child transmission. Chronic HBV infection is defined as serum HBsAg positivity for at least 6 months. Its natural history can be divided into 4 phases: immune tolerance, HBeAg-positive immune activity (also known as immune clearance), inactivity, and reactivation. Most children with chronic HBV infection will remain in the immune-tolerant phase until older childhood or adolescence, and severe liver disease is rare. However, they are at increased risk of developing chronic severe liver disease, including cirrhosis and hepatocellular carcinoma, later in life. Children with chronic HBV infection due to mother-to-child transmission tend to have a longer period of immune tolerance and a low rate of spontaneous HBeAg seroconversion (disappearance of HBeAg and positivity for anti-HBe), <2% per year before 3 years of age, and 4% to 5% per year thereafter. Patients with CHB are routinely monitored for disease progression, including physical examination, laboratory tests for ALT, AFP, HBeAg with anti-HBe, and HBV DNA, and occasionally a complete set of liver functions and platelets. Usually an elevated AST to ALT ratio suggests liver fibrosis, especially if the AST is greater than the ALT. In rare cases, such as alcoholic liver disease, this may confound the interpretation of the results. If the AST is greater than the ALT in a child with chronic HBV infection, it suggests the possibility of cirrhosis. In this case, further investigations and, if necessary, a liver biopsy are required. It is important to note that the AST and ALT ratios are affected by occasional alcohol consumption and strenuous activity, so both should be excluded prior to evaluation for liver fibrosis. Thrombocytopenia may be an early sign of splenomegaly due to portal hypertension.Children with CHB who show signs of active hepatitis or have a family history of HBV-related liver disease, especially hepatocellular carcinoma, should be seen by a pediatric hepatologist. Children with CHB who are immunologically active often have abnormal ALTs and histologic findings of liver inflammation and necrosis without clinical symptoms. Studies in adults have found that the length of the immunoactive phase is strongly associated with cirrhosis and hepatocellular carcinoma, so chronically HBV-infected children should be monitored throughout their lives and given treatment at the appropriate time. CHB Treatment Goals and Challenges in Children The goals of anti-HBV therapy in children with CHB are to suppress viral replication, reduce liver inflammation, and reverse liver fibrosis, thereby protecting the liver. Suppression of viral replication should be achieved at a level undetectable by sensitive PCR methods, and HBeAg-positive children should achieve HBeAg serological conversion; reduction of hepatic inflammation is manifested by the return of ALT to normal. The ultimate goal of anti-HBV therapy is to reduce the risk of progressive liver disease, cirrhosis, and hepatocellular carcinoma. However, many factors are involved in determining whether a child with CHB needs treatment, such as age, severity of liver disease, other medical factors, and the presence of a family history of liver disease or liver cancer. The child's compliance must also be taken into account. The pediatrician has to decide which patients need treatment, in addition to when to treat them and the length of the course of treatment. The biggest challenge is that there are only a limited number of drugs that have been studied in pediatric CHB patients and approved for use in pediatric patients. Selection of patients requiring antiviral therapy The main indicators of the need for anti-HBV therapy include ALT levels, HBV DNA levels, and liver histology. Serum ALT levels are a useful indicator of liver injury or disease, but the range of normal values is often debated, especially in children. The prevailing view is that an ALT above the upper limit of laboratory normal reference value (ULN) or >40 U/L (whichever is lower) should be considered abnormal. There have also been some recent studies suggesting that for children, the ALT normal values currently used underestimate the proportion of children with truly abnormal liver function. There is general agreement both nationally and internationally that antiviral therapy should be considered for adult patients with CHB who have a persistent ALT >2 x ULN. This consensus document states that antiviral therapy needs to be considered for ALT >1.5 × ULN or >60 U/L (whichever is lower), at least 2 times for 6 months in children (1 year of age or older) with HBeAg-positive CHB, and at least 3 times for 12 months in children (1 year of age or older) with HBeAg-negative CHB. The requirement of persistent ALT abnormalities for more than 6 months in children with HBeAg-positive CHB is intended to avoid treating children who are undergoing spontaneous serologic conversion that would not otherwise require treatment.The 1.5-fold ULN was proposed with reference to the inclusion criteria used in the 3 large prospective, randomized, controlled pediatric studies. There was actually insufficient evidence to support a particular ALT value as an indication for treatment. The panel set the standard for ALT lower than before because of inaccurate normal values for this age group, limited information on histologic abnormalities, and the fact that previous registry studies used this standard, but in reality, to make a treatment decision, it is necessary to rely not only on ALT, but also to take into account age, hepatic puncture biopsy, the presence of obesity, and the presence of a family history of CHB-associated hepatocellular carcinoma. For example, in obese children, it is necessary to rule out whether the elevated ALT is due to fatty liver disease or due to HBV. Children with elevated ALT need to be tested for HBV DNA, and if HBV DNA is >2000 IU/mL, liver histology should be further evaluated and other causes should be excluded.The level of HBV DNA follows the current adult standard. Typically, children who are immunologically active often have HBV DNA levels greater than 20,000 IU/mL, and more information is needed to determine the most appropriate criteria for children. For the vast majority of children in the compensated phase of liver disease, liver biopsy is recommended prior to treatment. Liver histology evaluates the degree of hepatic inflammation and fibrosis and aids in treatment selection. Typically, moderate to severe inflammation and/or more than moderate portal fibrosis require antiviral therapy. However, because a family history of HCC is a high-risk factor for a child to develop HCC in the future, some experts have suggested that the histologic criteria could be lowered for treatment selection in children with CHB who have a family history of HCC. The panel’s recommendations for selecting children who require antiviral therapy are shown in Figure 1.Anti-HBV therapy is not recommended in general for immunotolerant children with normal ALTs and inactive HBsAg carriers. However, there are specific children with CHB who need to be considered for short- or long-term anti-HBV therapy, regardless of HBV DNA and ALT levels. These indications include: (i) rapid deterioration of hepatic synthetic function; (ii) compensated or decompensated cirrhosis; (iii) glomerulonephritis caused by HBV infection; (iv) prevention or treatment of recurrence of HBV infection after liver transplantation; (v) anti-HBc positivity in liver transplant donors; (vi) need for immunosuppression or chemotherapy; (vii) overlapping infections (HBV and HIV, HBV and HCV, and HBV and HDV); (viii) a family history of hepatocellular carcinoma in an immunoactive children; ⑨ high viral load pregnant women in the second trimester of pregnancy, especially transient mothers who have failed previous perinatal hepatitis B immunoblockade. Drug choices for the treatment of CHB in children The U.S. Food and Drug Administration (FDA) has approved four drugs for the treatment of pediatric (<18 years of age) patients with CHB: lamivudine (LAM) can be used for children 3 years of age and older, adefovir (ADV) for children 12 years of age and older, entecavir (ETV) for children 16 years of age and older, and common interferon (IFN) for children 12 months of age and older. and older children. No drugs are approved for use in infants under 1 year of age-often this age group also does not need antiviral treatment. IFN-aIFN-a-2b has been used to treat chronic HBV infection for more than 10 years. Many experts, including this panel of experts, suggest that this drug can be used in children aged 1 to 12 years with chronic compensated CHB. Studies in Western countries have shown virologic responses in 20% to 50% of children, significantly higher than in controls. A large multicenter, randomized controlled trial showed that after IFN-a treatment, 26% of children with CHB showed HBeAg conversion and HBV DNA reduced to below detectable levels; this percentage increased to 35% in children with ALT above 2×ULN, while only 11% of children in the control group showed HBeAg conversion, and the HBsAg conversion rate was 10% and 1% in the treatment and control groups, respectively. The HBsAg conversion rate was 10 percent in the treatment group and 1 percent in the control group. It has also been shown that children under 5 years of age respond better to IFN-a. Polyethylene glycolated interferon (PEG-IFN) has not been approved for use in children with hepatitis B in the United States, but PEG-IFN has been recommended in Sweden for the treatment of CHB in children. Standard IFN-a treatment is 3 times per week for 6 months, and no resistance has been found. Evaluation of treatment results should be done 6 to 12 months after the end of treatment, because some children will still show a response to the drug 6 months after the end of treatment. As in adults, children treated with IFN-a may experience adverse effects such as flu-like symptoms, gastrointestinal reactions, neutropenia, and weight loss, all of which are reversible after discontinuation of the drug. Adverse reactions of affective disorders and personality changes have also been reported. Cirrhosis is a contraindication to IFN-a therapy, especially in patients with decompensated liver disease. Nucleoside (Acid) Analogues Based on the antiviral effects of the drugs and the risk of resistance, the ideal sequence of nucleoside (acid) analog choices that have been approved for the treatment of CHB in children is ETV, ADV, and LAM. however, at present, ETV is approved only for adolescents 16 years of age and older, and ADV is used for those 12 years of age and older. ADV and LAM are no longer recommended as first-line therapeutic agents for CHB in adults in countries such as Europe and the United States due to their weak efficacy or susceptibility to drug resistance. Antiviral therapy will change the natural history of HBV infection, and these drugs have not been used in children for a long time, and further observation is needed to see the effect of serologic conversion on future adulthood after antiviral therapy in childhood. (1) LAMLAM is approved for use in children aged 3 years and older with chronic hepatitis B. In a randomized controlled trial of 288 children, after 52 weeks of treatment with LAM, 23% achieved a virologic response (reduction of HBV DNA to below detectable levels and HBeAg conversion) compared to 13% in the control group. Among children with ALT ≥2 × ULN, the virologic response rate was 35%. The LAM resistance rate in children with CHB treated with LAM for 3 years was 64%. The above studies found that children with CHB tolerated 52 weeks of therapy well.The optimal duration of LAM therapy is not clear, and treatment should generally be continued for more than 6 months after HBeAg seroconversion has occurred. The rate of viral resistance increases with longer treatment duration. Therefore, when pediatricians see incomplete viral suppression after 24 weeks of treatment with LAM, especially in the absence of significant liver disease, discontinuation should be considered. For children who are poorly treated with LAM and have cirrhosis, there is the option of adding ADV or switching to ETV, which has not been formally approved for use in younger children.This option is not appropriate for LAM-resistant children with only mild chronic liver disease because of the potential for induction of multidrug-resistant strains of the virus.Children with LAM-treated CHB need to be closely followed up with ALT.② ADVADV is approved for for adolescents 12 years of age and older, with a preference for use in adolescents 12 to 15 years of age because ETV is an option for larger adolescents A multicenter randomized controlled study enrolled 173 children 2 to 17 years of age with CHB who had a 1.5-fold elevated ALT. In the 12- to 17-year-old group, ADV showed a significant antiviral effect (HBV DNA dropped below detectable levels and HBeAg turned negative), whereas in the 2- to 11-year-old group, the comparison between the study and control groups was not statistically significant. No ADV resistant variants were found in the study and the drug was well tolerated by children in all age groups. However, since the drug has a weaker antiviral effect than other drugs, it is not often recommended by adult hepatologists as there are more drug options for adults. After 48 weeks of ADV use, fewer antiviral-resistant strains than LAM were produced, and LAM-resistant variants remained susceptible to ADV. However, HBV containing rtA181T/V-resistant strains had a reduced response to ADV.The optimal course of ADV remains less clear, with the largest study treating children for 48 weeks and continuing antiviral therapy for an additional 2 years in a follow-up study in children who did not seroconvert, and analysis of the data is ongoing.HBeAg-positive children should be continued for more than 6 months after seroconversion to HBeAg occurs. treatment should be continued for more than 6 months. Similarly, after 24 weeks of treatment with ADV, if viral suppression is incomplete, discontinuation of the drug needs to be considered unless the liver disease improves. It is important to follow up closely for a period of time after discontinuation, as exacerbations have been reported in adults after discontinuation. (iii) ETV and other new drugs. A phase IIb clinical trial of ETV in children with CHB over the age of 2 years is currently underway, and another phase III study has begun.A cohort study of TDF in adolescents with CHB is also underway. In addition, pediatric clinical studies of tibivudine are being planned. Because the risk of resistance is higher in children, and the lifelong adverse consequences of developing resistance may outweigh the therapeutic benefits, it is appropriate to refer children with severe liver disease to specialists for treatment with ETV or TDF (off-label application, off-label). Management of drug resistance Strict indications are the best way to minimize drug resistance.LAM monotherapy is actually unwise because of the very high rate of resistance that results. If the patient has been treated with LAM for more than 24 weeks, HBVDNA is still detectable or persistently elevated, and liver biopsy suggests stage 2 or more liver fibrosis, there are three options: (1) stop antiviral therapy and observe closely; (2) add other drugs such as ADV; and (3) switch to interferon. When hepatitis is severe, it is better to add an antiviral drug. It should be noted that interferon is contraindicated in decompensated cirrhosis. Similarly, if the patient is resistant to initial ADV therapy and has only mild hepatitis, it is recommended to discontinue the antiviral drug; in case of moderate hepatitis, it is recommended to discontinue the antiviral drug and monitor closely; in case of severe hepatitis, it is recommended to switch to IFN, or to add LAM (if LAM has never been used). Discontinuation of Nucleoside (Acid) Analogs In general, nucleoside (acid) analog therapy should be maintained for at least 12 months in the absence of evidence of drug resistance and in the absence of serious adverse events requiring discontinuation, and often longer - even if applied off-label. Similar to adults, HBeAg-positive children need at least 6 months of consolidation therapy after achieving a complete response, but the optimal duration of therapy is uncertain; the duration of therapy for HBeAg-negative children is even more uncertain. However, for specific nucleoside analogs, resistance is not an absolute indication for discontinuation, and histologic evidence of the severity of liver disease is an important indicator of the decision to discontinue therapy, change regimen, or pursue combination therapy. Regardless of the reason for discontinuation, children should be tested every 1 to 3 months in the coming months to prevent recurrence of hepatitis, followed by follow-up monitoring every 6 months. Future Research Directions Limited therapeutic tools and research data are the major obstacles currently facing the treatment of CHB in children, and many questions need to be addressed, such as: how well do existing drugs work in children with immune tolerance? Are there other effective means? What is the significance of HBV genotyping for treatment? Are there non-invasive biomarkers of liver fibrosis for children? What are the factors that predict response to treatment? What is the impact of family history of liver disease and HCC on treatment choices? What is the management of non-response and overlapping infections?