Chronic viral hepatitis is a global health threat and financial burden. Hepatitis B and C viruses (HBV and HCV) are the most common causes of chronic viral hepatitis in the United States. Most cases are asymptomatic before adulthood. Research has resulted in effective therapy for HCV and the promise of effective therapies for HBV. For HCV, therapy is pegylated interferon and ribavirin. Clinical trials with effective direct-acting antiviral agents are underway in pediatrics. For HBV, approved agents are alpha-interferon, lamivudine, adefovir, tenofovir, and entecavir. However, treatment seldom results in functional cure and more effective therapies are urgently needed.
Key points
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The disease burden for both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in the pediatric population is high because most infected children acquire the virus via maternal fetal transmission.
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Without spontaneous viral clearance or indications to treat, most HBV-infected and HCV-infected children will become adults with chronic viral hepatitis and liver disease.
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The treatment goal for HCV infection is to achieve a sustained virologic response (ie, sustained viral clearance). The treatment goal for HBV infection is to achieve a functional cure, meaning that circulating markers of viral infection are negative but there may be residual covalently closed circular (ccc) HBV DNA in the liver.
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Successful antiviral treatment in adults with HBV and HCV infection gives promise to guide therapy in children; however, there are differences between adults and children with these infections, including in natural history, pharmacokinetics, responses to therapy, and short-term and long-term adverse effects of antiviral agents.
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Apart from antiviral therapies, prevention of these diseases is important because transmission largely occurs during the perinatal period.
Viral hepatitis has been a global health concern and economic burden for the past century. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most common causes of chronic viral hepatitis in the United States, as well as worldwide. However, the presentation depends on the type of virus and the age of the patients. Children with HBV rarely have acute severe hepatitis. Most children with HBV and HCV are asymptomatic during childhood but are at risk for developing cirrhosis and hepatocellular carcinoma (HCC) in adulthood. In this article, human immunodeficiency virus (HIV) coinfection is not discussed in depth.
Hepatitis B virus
Epidemiology and Natural History
The number of cases of chronic HBV (CHB) infection has been estimated at almost 400 million worldwide (∼5% of world’s population). HBV has 8 genotypes (A–H) which are associated with moderate differences in response to therapy. Children with CHB (genotypes B and C) have a high frequency of hepatitis B envelope antigen (HBeAg) positivity and high HBV DNA levels compared with those with other genotypes. The timing of HBeAg seroconversion in genotype C is more delayed compared with genotype B. Genotype C results in more aggressive hepatitis and is associated with an increased risk of HCC. However, the development of HCC was associated with genotype B in a Taiwanese pediatric study. The prevalence of CHB infection in pregnant women in urban areas of the United States varies by race and ethnicity. Although the highest rate was observed in Asian women (6%), the rates in black, white, and Hispanic women were 1, 0.6%, and 0.14%, respectively.
Maternal-fetal transmission is currently the most common route of HBV transmission because meticulous screening for HBV has been performed in individuals receiving transfusion of blood products. Perinatal transmission occurs at or close to the time of birth as a result of exposure to maternal blood and cervical secretions. Transplacental transmission is presumably responsible for perinatal infections, depending on risk factors, including maternal HBeAg positivity, hepatitis B surface antigen (HBsAg) titer, and HBV DNA level. Infants born to mothers positive for HBeAg and mothers with very high serum DNA levels (>= 10 9 copies per mL) are at risk for acquiring HBV despite receiving active and passive immunization within 24 hours postpartum. Transplacental transmission can occur due to leakage, such as during a threatened abortion. Amniocentesis in HBsAg-positive mothers can be another risk of HBV transmission. Although HBsAg and HBV DNA can be detected in the colostrum and breast milk of HBV-infected mothers, several studies have shown that there is no additional risk of transmission of HBV to breast-fed infants of infected mothers, provided that completed active and passive immunoprophylaxis is received.
Wang and colleagues compared outcomes among 3 groups of infants of HBsAg-positive mothers: 144 born by spontaneous vaginal delivery, 40 by forceps or vacuum extraction, and 117 by cesarean section, all of whom received the HBV vaccine and the hepatitis B immunoglobulin (HBIG). Because the response rates to recommended passive and active immunoprophylaxis were similar in all groups, in the 1-year-old infants, hepatitis B surface antibody (anti-HBs) was detected in 78.9% of the infants born by normal vaginal delivery, 84.6% by forceps or vacuum extraction, and 86.4% by cesarean section, with CHB incidence of 7.3%, 7.7%, and 6.8%, respectively. The mode of delivery does not likely influence HBV transmission. A higher incidence of low birth weight and prematurity has been reported in infants born to mothers infected with HBV compared with those born to uninfected mothers.
The spontaneous seroconversion rates of HBeAg (loss of HBeAg and development of the HBe antibody [anti-HBe]) for children infected via perinatal transmission are less than 2% per year for those under age 3 years, and 4% to 5% per year in those older than 3 years; whereas children infected after the perinatal period have higher rates of spontaneous HBeAg seroconversion, up to 70% to 80% over 20 years. The time to HBeAg clearance for individuals with HBV genotype C is longer than in patients with other genotypes. Since the early 1990s, the incidence of acute HBV in the United States has declined.
About one-third of older children and adolescents with acute HBV infection will develop classic symptoms of hepatitis. Cirrhosis and HCC, mostly in adulthood, may be anticipated in about 25% of those who acquire HBV infection during infancy or childhood. Approximately 90% of children infected as infants will develop CHB infection. The risk decreases to 25% to 50% for children who become infected after early infancy but before age 5 years and to only 5% to 10% for children who become infected in adolescence or adulthood. Most children with CHB are asymptomatic, growing and developing normally. Like adults, children and adolescents who are immune-active with persistent elevation of alanine aminotransferase (ALT) and histologic findings of liver inflammation and fibrosis have an increased risk of cirrhosis and HCC compared with those without evidence of hepatic inflammation.
Diagnosis and Tests
The diagnosis of acute hepatitis B is based on the detection of HBsAg as an initial serologic marker and immunoglobulin (Ig)-M antibody to hepatitis B core antigen (anti-HBc). Early in the course of acute infection, HBeAg and HBV DNA are detected and are markers of active viral replication. As patients recover, serum HBV DNA significantly declines but may remain detectable by polymerase chain reaction (PCR) assay for up to several decades. Anti-HBc IgM is the initial antibody, which usually persists for several months. During the window period anti-HBc IgM may be present as the only marker of acute HBV infection (after HBsAg is cleared and before anti-HBs is detected). The development of anti-HBc IgG and anti-HBs indicates recovery from acute HBV infection. Seroconversion (HBeAg to anti-HBe) occurs and is followed by a decrease in serum HBV DNA levels and, eventually, HBsAg becomes undetectable. Persistence of HBsAg for longer than 6 months indicates an HBV carrier or progression to CHB. During the early phase of CHB, HBeAg and high serum HBV DNA levels are markers of HBV replication.
Different serologic patterns are observed at various phases of CHB ( Table 1 ): immune tolerant phase, immune-active phase, inactive (HBeAg-negative), inactive (loss of HBsAg), and HBeAg-negative immune reactivation phase. The immune tolerant phase is characterized by normal or mildly elevated serum aminotransferases (ALT <1.5 times the upper limit of normal) and evidence of active HBV replication (HBV DNA >20,000 IU/mL or 10 5 copies/mL). HBsAg and HBeAg are positive. Children with maternal-fetal transmission may remain in this phase for up to several decades and are less likely to respond to antiviral therapies compared with immune-active children. Immune-active hepatitis is characterized by elevated serum aminotransferases (ALT>1.5–2 times the upper limit of normal) and active HBV replication (HBV DNA is typically >20,000 IU/mL or 10 5 copies/mL). HBsAg and HBeAg are positive. During this phase children are more likely to clear HBeAg spontaneously or to respond to antiviral therapies. Inactive CHB phase (HBeAg-negative), also known as the nonreplicative or latent phase, is characterized by normal levels of serum aminotransferases and low or undetectable levels of HBV replication. HBsAg is positive but HBeAg is negative. Up to 20% of children with the nonreplicative phase undergo reversions to the immune-active phase, and 20% to 30% reactivate into HBeAg-negative HBV. Inactive CHB (loss of HBsAg) occurs in a minority of children who clear HBeAg, as well as the HBV infection (clearance of HBsAg and appearance of anti-HBs). However, the state of negative serologic markers of active infection, including loss of HBsAg, is now referred to as a functional cure because such individuals probably have residual covalently closed circular (ccc) HBV DNA and, therefore, remain at risk for reactivation which receiving immunosuppressants such as chemotherapy for cancer. During the HBeAg-negative immune reactivation phase, children have increased HBV DNA levels with normal or elevated serum aminotransferases and have more virulent liver disease.
| Phases | Other Terms | Serum Aminotransferases | HBV Replication | HBV DNA | HBsAg | HBeAg | Anti HBs | Covalently Closed Circular (ccc) DNA | Spontaneous Clearance | Response to Antiviral Therapy |
|---|---|---|---|---|---|---|---|---|---|---|
| Immune tolerant | Normal or mildly elevated (ALT <2 times the upper limit of normal) | Active | >20,000 IU/mL or 10 5 copies/mL | Positive | Positive | Negative | Positive | Less likely | Less likely | |
| Immune-active | Elevated serum aminotransferases (ALT>1.5–2 times the upper limit of normal) | Active | >20,000 IU/mL or 105 copies/mL | Positive | Positive | Negative | Positive | Possible | Highly possible | |
| Inactive | Nonreplicative or latent phase | Normal | Inactive | Low or undetectable levels | Positive | Negative | Negative | Positive | Possible (Up to 20% of children with the nonreplicative phase undergo reversions to the immune-active phase) | Possible (Up to 20% of children with the nonreplicative phase undergo reversions to the immune-active phase) |
| HBsAg or HBeAg-negative immune reactivation | Normal or elevated | Active | Increased | Becoming positive | Becoming positive | Negative | Positive | Less likely | Less likely | |
| Inactive with loss of HBsAg | Functional cure | Normal | None | Undetected | Negative | Negative | Positive | Positive | ||
| Inactive with loss of HBsAg | Clinical cure | Normal | None | Undetected | Negative | Negative | Positive | Negative |
Screening tests for HBV are recommended for children and adolescents with clinical signs of hepatitis or unexplained elevation of serum aminotransferases; for all internationally adopted children; for all pregnant adolescents; for adolescents who engage in high-risk behaviors, including the use of intravenous or intranasal drugs or unprotected sex with an infected partner or more than 1 partner; for men who have sex with men; and for those with a history of sexually transmitted disease, immigrants from high prevalence areas (HBsAg prevalence is >2%), including Africa and Asia, the Cape Verde islands, most of Eastern and Mediterranean Europe, the Caribbean, and parts of South America; for children living in communities where HBV is endemic; and for children born to immigrant parents from endemic areas. Because approximately 5% of infants born to HBsAg-positive mothers develop CHB even after optimal immunoprophylaxis, anti-HBs and HBsAg should be tested at 9 to 12 months of age, or 1 to 2 months after the last dose of hepatitis B vaccine given to an at-risk infant.
Hepatitis delta (D) (HDV) infection can occur with CHB and an enzyme immunoassay for anti-HDV is commercially available. Negative anti-HBc IgM, positive HBsAg, and presence of anti-HDV suggest the diagnosis of HDV superinfection. Anti-HDV may take several weeks to develop. Acute and convalescent sera may be required. IgM anti-HDV is not useful because it can persist several months during chronic infection.
Prevention and Treatment
The combination vaccination strategy (HBIG and HBV vaccine series) for high-risk neonates significantly prevents vertical transmission to neonates born to HBV-infected mothers. Children and adolescents with CHB should be immunized against hepatitis A, if not already immune.
Not all children with CHB will benefit from antiviral therapy due to potential side effects and the development of antiviral resistance. Treatment should be considered for children with immune-active CHB regardless of HBe Ag status, or if liver biopsy shows moderate-to-severe inflammation or the presence of fibrosis. The treatment goal for CHB is to suppress HBV replication, reduce liver inflammation, reverse hepatic fibrosis, and prevent the development of cirrhosis and HCC. There are currently several oral antivirals approved by the US Food and Drug Administration (FDA) for CHB in adults: 3 nucleoside drugs (lamivudine, entecavir, and telbivudine) and 2 nucleotides (adefovir dipivoxil and tenofovir disoproxil fumarate).
The first treatments for children with CHB to be FDA approved are thrice-weekly interferon (IFN)-alpha and daily lamivudine for 16 to 24 weeks for children between age 2 and 18 years.
Although lamivudine is well-tolerated in young children, drug resistance is common in approximately 20% of patients per year; therefore, its use is currently rare. There have been promising results with pegylated-IFN (PEG-IFN) for adults with CHB and this treatment is currently being studied in children. Adefovir dipivoxil, a nucleotide analog, is approved for children 12-years-old and older but probably has a limited role because higher antiviral activity and lower rates of viral resistance compared with newer agents, such as PEG-IFN and entecavir. Entecavir and tenofovir are FDA-approved for adults with CHB and tenofovir disoproxil is FDA-approved for children 12 years and older. The pediatric approval for entecavir was based primarily on a phase 3 randomized trial ( NCT01079806 ) in 180 children between 2 and 18 years of age who had not been previously treated with a nucleoside/nucleotide analog.
Side effects from nucleos(t)ide analogues usually are minimal during clinical trials but more have been reported after postmarketing surveillance. These analogues have activity against human mitochondrial DNA (mtDNA) polymerase gamma and can lead to mitochondrial dysfunction. All 5 approved agents carry an FDA black box warning of potential mitochondrial toxicity. Myopathy and neuropathy are commonly reported with lamivudine, nephrotoxicity is fairly common with adefovir and tenofovir, and pancreatitis may be associated with the use of lamivudine or adefovir. Antiviral therapy with nucleos(t)ide analogues for children in the immune-tolerant phase has not been associated with benefits but poses a theoretic risk for the development of antiviral drug resistance or adverse side effects.
The best strategy to control HBV infection in children and adolescents is to implement a universal vaccination program. For newborn infants born to mother with CHB, the current recommendation is the administration of prophylaxis (HBIG and completion of hepatitis B vaccine series with the first dose of hepatitis B vaccine given within 12 hours of birth). The efficacy of the combination of HBIG and HBV vaccine series is not yet 100% but somewhat higher (85%–95%) than that of HBV vaccine alone (65%–95%). The risk of maternal-fetal transmission exists despite double vaccination of infants born to mothers with positive HBeAg and/or a high HBV DNA level. The American Association for the Study of Liver Diseases (AASLD) suggests antiviral therapy to reduce the risk of perinatal transmission of hepatitis B in HBsAg-positive pregnant women with a high viral load. Increasing evidence of the safety of exposing infants to antiviral therapy during pregnancy is available but long-term follow-up is required. However, the exact viral load threshold and the timing of when to start therapy during the third trimester have not been clearly addressed. Mothers with CHB who have cracked nipples should avoid breastfeeding and should not donate their breast milk.
After a routine series of HBV vaccination, a circulating anti-HBs level of greater than 10 mIU/mL is considered to be seroprotective. In immune-competent children, seroprotective levels are achieved in at least 95% after 1 course of HBV vaccine. Peak vaccine-induced anti-HBs level is directly related to the waning of the antibody over time, which could increase the risk of HBV infection and of CHB carriage.
Following an additional dose of a new HBV vaccine series (the fourth dose), 15% to 20% of patients who fail to respond to the first complete HBV vaccine series will develop a protective antibody response and 50% to 75% will develop such a response after 3 additional doses. Therefore, another complete 3-dose series of the HBV vaccine is recommended for nonresponders to routine HBV vaccination. Nonresponders after 3 additional doses are less likely to have any benefit after the sixth dose and should be tested for HBsAg to determine the possibility of CHB. Immunosuppression and certain genetic factors (both HLA and non-HLA genes) may explain such nonresponsiveness to routine and additional HBV vaccination.
Special Considerations
The influence of age, mode of acquisition, ethnicity, and/or HBV genotype on the natural history of CHB in children is variable. Genotype testing is not routinely recommended in clinical practice. HBV genotyping may be considered for HBeAg-positive children who are being considered for IFN therapy. A response to IFN was more likely observed in genotype A and B than genotype C. HBV genotype may influence HCC development in children differently than in young adults.
The risk for HCC in children increases with age due to the duration of disease, the degree of histologic injury, and the replicative state of the virus (HBV DNA levels). HCC can occur even after viral replication ceases or early HBeAg seroconversion. It is unclear how to monitor disease progression and the development of HCC in children. The monitoring protocol for HCC for adults with HBV that is recommended is the combined use of liver ultrasound and serum alpha-fetoprotein (AFP) every 12 months or more often in those with elevated AFP, cirrhosis, or a family history of HCC.
The financial burden for children with CHB is undoubtedly high due to long-term exposure to the virus and risks of cirrhosis and HCC. To reduce the financial burden, an effective combination therapy using antiviral drugs is required to target the viral replication cycle rather than merely achieving prolonged suppression of viral replication.
Efforts have also focused on searching for natural products, such as alternative medicines with low cost and safety, for the antiviral therapy. In recent decades, a large number of clinical trials and preclinical studies using Chinese medicine have demonstrated potential benefit in several aspects of treatment of CHB. Many concerns include study design the quality of clinical trials and the inconsistent and unknown active ingredient components of Chinese medicines in the regimen.
Hepatitis B virus
Epidemiology and Natural History
The number of cases of chronic HBV (CHB) infection has been estimated at almost 400 million worldwide (∼5% of world’s population). HBV has 8 genotypes (A–H) which are associated with moderate differences in response to therapy. Children with CHB (genotypes B and C) have a high frequency of hepatitis B envelope antigen (HBeAg) positivity and high HBV DNA levels compared with those with other genotypes. The timing of HBeAg seroconversion in genotype C is more delayed compared with genotype B. Genotype C results in more aggressive hepatitis and is associated with an increased risk of HCC. However, the development of HCC was associated with genotype B in a Taiwanese pediatric study. The prevalence of CHB infection in pregnant women in urban areas of the United States varies by race and ethnicity. Although the highest rate was observed in Asian women (6%), the rates in black, white, and Hispanic women were 1, 0.6%, and 0.14%, respectively.
Maternal-fetal transmission is currently the most common route of HBV transmission because meticulous screening for HBV has been performed in individuals receiving transfusion of blood products. Perinatal transmission occurs at or close to the time of birth as a result of exposure to maternal blood and cervical secretions. Transplacental transmission is presumably responsible for perinatal infections, depending on risk factors, including maternal HBeAg positivity, hepatitis B surface antigen (HBsAg) titer, and HBV DNA level. Infants born to mothers positive for HBeAg and mothers with very high serum DNA levels (>= 10 9 copies per mL) are at risk for acquiring HBV despite receiving active and passive immunization within 24 hours postpartum. Transplacental transmission can occur due to leakage, such as during a threatened abortion. Amniocentesis in HBsAg-positive mothers can be another risk of HBV transmission. Although HBsAg and HBV DNA can be detected in the colostrum and breast milk of HBV-infected mothers, several studies have shown that there is no additional risk of transmission of HBV to breast-fed infants of infected mothers, provided that completed active and passive immunoprophylaxis is received.
Wang and colleagues compared outcomes among 3 groups of infants of HBsAg-positive mothers: 144 born by spontaneous vaginal delivery, 40 by forceps or vacuum extraction, and 117 by cesarean section, all of whom received the HBV vaccine and the hepatitis B immunoglobulin (HBIG). Because the response rates to recommended passive and active immunoprophylaxis were similar in all groups, in the 1-year-old infants, hepatitis B surface antibody (anti-HBs) was detected in 78.9% of the infants born by normal vaginal delivery, 84.6% by forceps or vacuum extraction, and 86.4% by cesarean section, with CHB incidence of 7.3%, 7.7%, and 6.8%, respectively. The mode of delivery does not likely influence HBV transmission. A higher incidence of low birth weight and prematurity has been reported in infants born to mothers infected with HBV compared with those born to uninfected mothers.
The spontaneous seroconversion rates of HBeAg (loss of HBeAg and development of the HBe antibody [anti-HBe]) for children infected via perinatal transmission are less than 2% per year for those under age 3 years, and 4% to 5% per year in those older than 3 years; whereas children infected after the perinatal period have higher rates of spontaneous HBeAg seroconversion, up to 70% to 80% over 20 years. The time to HBeAg clearance for individuals with HBV genotype C is longer than in patients with other genotypes. Since the early 1990s, the incidence of acute HBV in the United States has declined.
About one-third of older children and adolescents with acute HBV infection will develop classic symptoms of hepatitis. Cirrhosis and HCC, mostly in adulthood, may be anticipated in about 25% of those who acquire HBV infection during infancy or childhood. Approximately 90% of children infected as infants will develop CHB infection. The risk decreases to 25% to 50% for children who become infected after early infancy but before age 5 years and to only 5% to 10% for children who become infected in adolescence or adulthood. Most children with CHB are asymptomatic, growing and developing normally. Like adults, children and adolescents who are immune-active with persistent elevation of alanine aminotransferase (ALT) and histologic findings of liver inflammation and fibrosis have an increased risk of cirrhosis and HCC compared with those without evidence of hepatic inflammation.
Diagnosis and Tests
The diagnosis of acute hepatitis B is based on the detection of HBsAg as an initial serologic marker and immunoglobulin (Ig)-M antibody to hepatitis B core antigen (anti-HBc). Early in the course of acute infection, HBeAg and HBV DNA are detected and are markers of active viral replication. As patients recover, serum HBV DNA significantly declines but may remain detectable by polymerase chain reaction (PCR) assay for up to several decades. Anti-HBc IgM is the initial antibody, which usually persists for several months. During the window period anti-HBc IgM may be present as the only marker of acute HBV infection (after HBsAg is cleared and before anti-HBs is detected). The development of anti-HBc IgG and anti-HBs indicates recovery from acute HBV infection. Seroconversion (HBeAg to anti-HBe) occurs and is followed by a decrease in serum HBV DNA levels and, eventually, HBsAg becomes undetectable. Persistence of HBsAg for longer than 6 months indicates an HBV carrier or progression to CHB. During the early phase of CHB, HBeAg and high serum HBV DNA levels are markers of HBV replication.
Different serologic patterns are observed at various phases of CHB ( Table 1 ): immune tolerant phase, immune-active phase, inactive (HBeAg-negative), inactive (loss of HBsAg), and HBeAg-negative immune reactivation phase. The immune tolerant phase is characterized by normal or mildly elevated serum aminotransferases (ALT <1.5 times the upper limit of normal) and evidence of active HBV replication (HBV DNA >20,000 IU/mL or 10 5 copies/mL). HBsAg and HBeAg are positive. Children with maternal-fetal transmission may remain in this phase for up to several decades and are less likely to respond to antiviral therapies compared with immune-active children. Immune-active hepatitis is characterized by elevated serum aminotransferases (ALT>1.5–2 times the upper limit of normal) and active HBV replication (HBV DNA is typically >20,000 IU/mL or 10 5 copies/mL). HBsAg and HBeAg are positive. During this phase children are more likely to clear HBeAg spontaneously or to respond to antiviral therapies. Inactive CHB phase (HBeAg-negative), also known as the nonreplicative or latent phase, is characterized by normal levels of serum aminotransferases and low or undetectable levels of HBV replication. HBsAg is positive but HBeAg is negative. Up to 20% of children with the nonreplicative phase undergo reversions to the immune-active phase, and 20% to 30% reactivate into HBeAg-negative HBV. Inactive CHB (loss of HBsAg) occurs in a minority of children who clear HBeAg, as well as the HBV infection (clearance of HBsAg and appearance of anti-HBs). However, the state of negative serologic markers of active infection, including loss of HBsAg, is now referred to as a functional cure because such individuals probably have residual covalently closed circular (ccc) HBV DNA and, therefore, remain at risk for reactivation which receiving immunosuppressants such as chemotherapy for cancer. During the HBeAg-negative immune reactivation phase, children have increased HBV DNA levels with normal or elevated serum aminotransferases and have more virulent liver disease.
| Phases | Other Terms | Serum Aminotransferases | HBV Replication | HBV DNA | HBsAg | HBeAg | Anti HBs | Covalently Closed Circular (ccc) DNA | Spontaneous Clearance | Response to Antiviral Therapy |
|---|---|---|---|---|---|---|---|---|---|---|
| Immune tolerant | Normal or mildly elevated (ALT <2 times the upper limit of normal) | Active | >20,000 IU/mL or 10 5 copies/mL | Positive | Positive | Negative | Positive | Less likely | Less likely | |
| Immune-active | Elevated serum aminotransferases (ALT>1.5–2 times the upper limit of normal) | Active | >20,000 IU/mL or 105 copies/mL | Positive | Positive | Negative | Positive | Possible | Highly possible | |
| Inactive | Nonreplicative or latent phase | Normal | Inactive | Low or undetectable levels | Positive | Negative | Negative | Positive | Possible (Up to 20% of children with the nonreplicative phase undergo reversions to the immune-active phase) | Possible (Up to 20% of children with the nonreplicative phase undergo reversions to the immune-active phase) |
| HBsAg or HBeAg-negative immune reactivation | Normal or elevated | Active | Increased | Becoming positive | Becoming positive | Negative | Positive | Less likely | Less likely | |
| Inactive with loss of HBsAg | Functional cure | Normal | None | Undetected | Negative | Negative | Positive | Positive | ||
| Inactive with loss of HBsAg | Clinical cure | Normal | None | Undetected | Negative | Negative | Positive | Negative |
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