Management of hepatitis B virus infection in children and adolescents

INTRODUCTION — Hepatitis B virus (HBV) infection remains a global public health problem despite the availability of an effective vaccine. A substantial number of children are infected, even in countries where infants are routinely immunized against HBV. Infected children in these countries usually are adoptees, children of immigrants, or become infected during childhood.

Management of children with HBV infection involves a focused evaluation to determine the phase and severity of the liver disease, general measures such as counseling of the patient and family, surveillance for disease progression and development of complications, and consideration for treatment, as detailed in this topic review (algorithm 1) [1,2]. The clinical manifestations, screening, and diagnosis of HBV infection in this age group are discussed separately. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents".)

Detailed discussions of HBV infection in adults are presented separately. Some elements are applicable to children and are reflected in the discussion below. (See "Characteristics of the hepatitis B virus and pathogenesis of infection" and "Hepatitis B virus: Clinical manifestations and natural history" and "Hepatitis B virus: Screening and diagnosis in adults" and "Hepatitis B virus: Overview of management".)

POST-DIAGNOSIS EVALUATION — Initial evaluation of patients with chronic HBV infection includes:

History and physical examination — The history should emphasize risk factors for coinfection with hepatitis C virus (HCV) and/or HIV, use of alcohol, and family history of HBV infection, liver disease, and liver cancer.

The physical examination should assess for growth parameters and for signs of chronic liver disease (such as spider telangiectasias, palmar erythema, hepatosplenomegaly, jaundice, ascites, edema, wasting, and gynecomastia in boys).

Laboratory testing — Routine laboratory testing includes:

●Complete blood count with platelets, albumin, and prothrombin time. These tests are usually normal in children with chronic HBV. Low albumin or prolonged prothrombin time would suggest possible hepatic dysfunction. A low platelet count would raise the possibility of cirrhosis, which can cause portal hypertension and splenic sequestration.

●Liver biochemical tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], total bilirubin, alkaline phosphatase), and tests for HBV replication (hepatitis B e-antigen [HBeAg], hepatitis B e antibody [HBeAb], and HBV DNA). The results of these tests are used to determine the phase of HBV infection (figure 1A), which has important implications for selection of patients for antiviral treatment (algorithm 1). The phases of chronic HBV infection in children are described in detail separately. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Phases of chronic HBV infection'.)

●Testing for coinfection, which has important implications for disease progression, and selection of antiviral treatment. Selection of tests is based upon the presence of risk factors:

•HCV – Test for HCV in all children with HBV, unless HCV infection was previously excluded. Coinfection with HCV increases the risk for progressive liver disease, and also informs decisions about antiviral treatment, because of the risk of HBV reactivation during treatment for HCV [3]. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'HBV coinfection'.)

•Hepatitis A virus (HAV) – Test for immunity to HAV by measuring a serum HAV immunoglobulin G (IgG) in patients from high-endemicity areas who are not known to be immune. Patients who are not immune should be immunized against HAV.

•Hepatitis D virus (HDV) – Test for coinfection with HDV by measuring antibodies to HDV (anti-HDV) in patients with risk factors for HDV infection, including those from countries with a high prevalence of HDV coinfection (Eastern European, Mediterranean, and Central American countries), or with HIV infection, or people who engage in unprotected anal intercourse [3,4]. (See "Epidemiology, clinical manifestations and diagnosis of hepatitis D virus infection".)

•HIV – HIV testing is warranted for children with HBV infection and any risk factors for HIV, such as those born in countries with high HIV prevalence, or whose mother's HIV status is unknown, or adolescents who are injection drug users [5]. This is because HIV and HBV have similar modes of transmission and because coinfection with HIV increases the risk for rapid progression of disease and hepatocellular carcinoma (HCC). Moreover, coinfection has important implications for selection of antiviral therapies [3]. (See "Treatment of chronic hepatitis B in patients with HIV".)

Additional evaluation — Additional evaluation is appropriate for selected patients:

●Evaluation for other causes of liver disease should be performed in children with signs and symptoms that are atypical for HBV (eg, low albumin or prolonged prothrombin time, suggesting hepatic decompensation) or in those with risk factors for other types of liver disease. We do not routinely test for other causes if there is no heightened clinical suspicion for these disorders.

●We suggest surveillance for HCC for all children with chronic HBV infection, regardless of cirrhosis or other risk factors, at diagnosis and periodically thereafter. Some other experts take a more selective approach and propose HCC surveillance only for children with cirrhosis or a first-degree relative with HCC, while acknowledging that there are insufficient data to identify high-risk groups for HCC in children [1,3]. (See 'Hepatocellular carcinoma surveillance' below.)

●Liver biopsy for patients who are being considered for treatment of chronic HBV infection (generally only those who are in the immune-active phase) or for those with signs or symptoms of advanced hepatic disease. If the biopsy results have findings that are atypical for chronic HBV infection, further evaluation for other causes of liver disease may be warranted. (See 'Selection of patients for antiviral treatment' below.)

●Testing for HBV genotype is not necessary at the time of diagnosis, since the results do not affect treatment decisions for most patients. However, genotype testing may be useful later in the course for selected patients who are treated with nucleos(t)ide analogs and have loss of response, suggesting the possibility of resistance, or for patients who are otherwise undecided about the treatment options. (See 'Choice of treatment' below.)

COUNSELING — Household members of children with chronic HBV should be vaccinated if they test negative for HBV serologic markers. Patients and their families should be counseled regarding the risk of transmission to others, including perinatal transmission and risk of environmental exposure from blood [3]. Household members should not share toothbrushes or razors, which may become contaminated with blood. Although HBV DNA has been detected in various bodily secretions of hepatitis B carriers, there is no firm evidence of HBV transmission via body fluids, so no special measures are called for to avoid inadvertent sharing of eating utensils. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Transmission of HBV'.)

Children with chronic HBV infection should be allowed to participate in all regular activities and should not be excluded from regular school and participation in sports [6]. No special arrangements need to be made other than practicing universal precautions in daycare centers, schools, sports clubs, and camps [3,7]. (See "Epidemiology, transmission, and prevention of hepatitis B virus infection", section on 'Prevention'.)

Adolescents with chronic HBV infection should be advised regarding prevention of sexual transmission (ie, vaccination of sex partners in individuals with monogamous partners and safe sex practice including use of condoms in subjects with multiple partners). They should also be advised that heavy use of alcohol (>40 g/day) and drug abuse has been associated with worsening liver disease and an increased risk of hepatocellular carcinoma (HCC). (See "Hepatitis B virus: Overview of management", section on 'Counseling and prevention' and "Prevention of sexually transmitted infections".)

Women with chronic HBV who are pregnant should inform their providers and have case management procedures put in place to prevent perinatal infection of their infant [8]. Their infants should receive hepatitis B immune globulin (HBIG) and vaccine immediately after delivery. Screening of pregnant women for HBV infection is discussed separately. (See "Hepatitis B and pregnancy" and "Hepatitis viruses and the newborn: Clinical manifestations and treatment", section on 'Hepatitis B'.)

MONITORING — Children in all phases of HBV infection should undergo regular laboratory testing to determine if and when antiviral therapy might be indicated, to monitor for disease progression and hepatic decompensation, and for surveillance of hepatocellular carcinoma (HCC) [1]. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Progression to cirrhosis' and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Hepatocellular carcinoma'.)

The frequency of monitoring depends upon the stage of infection, as outlined below (figure 1A). Frequent monitoring is important for children in the immune-active phase, as outlined below. Monitoring usually can be performed less frequently during the other phases of infection, as long as disease activity is mild.

Disease activity — The frequency and type of laboratory monitoring depends upon the phase of HBV:

●Immune-tolerant phase – Patients who are in the immune-tolerant phase of HBV infection (ie, hepatitis B surface antigen [HBsAg]-positive, hepatitis B e antigen [HBeAg]-positive, serum HBV DNA >20,000 copies/mL) should undergo monitoring of liver biochemical tests (serum alanine aminotransferase [ALT]) every 6 to 12 months, and HBeAg and hepatitis B e antibody (HBeAb) every 12 months (figure 1A). It is not necessary to monitor HBV DNA for these patients, because the result is likely to remain elevated and this finding will not change patient management.

●Immune-active, HBeAg-positive phase – If the ALT becomes elevated (>40 international units/L), biochemical tests and serologies should be measured more frequently (eg, every three to six months). In this case, the patient is probably entering an immune-active phase and may undergo spontaneous seroconversion, or become eligible for treatment. If there is clinical suspicion for hepatic decompensation (jaundice or systemic symptoms), the evaluation also should include testing for markers of hepatic synthetic function (prothrombin time and international normalized ratio), with close follow-up.

●Inactive chronic HBV – Patients who are in the inactive chronic HBV phase of hepatitis B infection (ie, HBsAg-positive, HBeAg-negative, HBeAb-positive, persistently normal ALT/aspartate aminotransferase [AST] levels, serum HBV DNA <10⁵ copies/mL) should undergo monitoring of liver biochemical tests (serum ALT) every 6 to 12 months, and HBeAg and HBeAb every 12 months (figure 1A) [9]. If the ALT becomes elevated, HBV serologies and HBV DNA should be measured. The disease may reactivate even after years of quiescence; 4 to 20 percent of inactive carriers have one or more conversions to the HBeAg-negative or HBeAg-positive state [10].

Hepatocellular carcinoma surveillance — We suggest surveillance for HCC in all HBsAg-positive children. Surveillance consists of ultrasonography approximately every six months, with serum alpha-fetoprotein (AFP) if practical. Because the risk for HCC increases with age, we monitor somewhat less frequently (eg, every two to three years) for young patients in the immune-tolerant phase, provided that the baseline AFP and ultrasound are normal.

This suggestion for HCC surveillance in all HBsAg-positive children, regardless of other risk factors, is based primarily on two case series with a total of 21 patients in whom HBV-associated HCC presented between 6 and 17 years, some of whom had no cirrhosis [11,12]. Because some children with HBV-associated HCC had normal liver enzymes and AFP, these reports also underscore the need to include imaging (ultrasound) as part of surveillance. A more selective approach was taken by an expert panel, which proposed monitoring for HCC only in children with advanced fibrosis or cirrhosis or those with a first-degree relative with HCC, while acknowledging that there are insufficient data to identify high-risk groups for HCC in children [3]. HCC surveillance in adults is summarized in a separate topic review. (See "Surveillance for hepatocellular carcinoma in adults".)

HCC is rare in children with HBV [13] but has been reported [11,12,14]. It can develop in patients with HBV infection, regardless of whether the virus is actively replicating. Therefore, we maintain surveillance for HCC in individuals in all phases of HBV infection, including those who have undergone seroconversion (converted to HBeAg-negative), either spontaneously or after successful treatment. The benefit of surveillance for HCC has not been well established, but it is likely to be greatest in those children and adolescents with advanced fibrosis and cirrhosis or a first-degree relative with HCC; the latter information is not always available.

Monitoring for HCC is recommended for adults with cirrhosis and chronic HBV infection, using right upper quadrant ultrasound imaging every six months and/or AFP levels [3]. These recommendations are based upon observational data and expert opinion. (See "Surveillance for hepatocellular carcinoma in adults".)

SELECTION OF PATIENTS FOR ANTIVIRAL TREATMENT — The ultimate goal of treatment is to reduce the risks of progression to cirrhosis and of hepatocellular carcinoma (HCC). To date, the efficacy of treatment has only been measured through intermediate outcomes such as changes in short-term virologic, biochemical, and histologic parameters. Long-term outcomes are inferred from the intermediate virologic and biochemical outcomes of treatment trials, but are not clinically proven [3,15]. Because progression to cirrhosis appears to be associated with the intensity and duration of chronic inflammatory activity and hepatitis B e-antigen (HBeAg) positivity, it is reasonable to infer that successful treatment of HBV probably reduces the risk of cirrhosis [15]. It is not clear whether treatment reduces the risk for HCC. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Hepatocellular carcinoma'.)

Phase of chronic hepatitis B virus — Selection of patients for treatment is primarily driven by the phase of chronic HBV infection, which is summarized in these figures (figure 1A-B). This categorization leads to the following treatment recommendations, which are summarized in the algorithm (algorithm 1):

●Immune-tolerant phase – We suggest not treating patients in the immune-tolerant phase, which is characterized by normal or mildly elevated serum alanine aminotransferase (ALT) levels (<1.5 to 2 times the upper limit of normal [ULN]), with high HBV DNA levels (typically >20,000 international units/mL [approximately 10⁵ copies/mL]) [3,5]. In this phase, treatment with any of the currently available drugs does not result in higher rates of HBeAg seroconversion compared with no treatment [3,15-19]. Moreover, treatment of patients in this phase is associated with development of drug resistance, which could diminish responsiveness to the same or related medications at a later date, when hepatic injury is active. For these reasons, treatment of children in this phase should only be considered as part of a comprehensive clinical trial. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Immune-tolerant'.)

In exceptional clinical situations in which the child has cirrhosis or other signs of severe liver disease, a child may be considered for treatment even if the ALT levels are normal. This strategy is used for adults with cirrhosis and persistently elevated HBV DNA levels, regardless of the serum ALT level [3]. (See "Hepatitis B virus: Overview of management", section on 'Indications for antiviral therapy'.)

●Immune-active, HBsAg-positive (clearance) phase – For patients in the hepatitis B surface antigen (HBsAg)-positive immune-active phase, which is characterized by elevated ALT (>2 times the ULN, or >60 units/L, whichever is lower) and elevated HBV DNA levels, management depends on the magnitude and duration of these abnormalities:

•For patients with markedly elevated ALT values (>10 times the ULN), we suggest observation for several months. Laboratory testing should be performed at least every three months, including ALT, HBeAg and HBe antibody (HBeAb), HBsAg and HBs antibody (HBsAb), and HBV DNA. The markedly elevated ALT suggests that they are in the immune-active phase; HBV DNA is usually high (>20,000 international units/mL). There are three possible outcomes of this phase (figure 1A):

-Spontaneous seroconversion to inactive chronic HBV ("carrier" state), characterized by loss of HBeAg and normalization of ALT and low HBV DNA levels. In this case, treatment is not necessary or effective [20]. Patients with only moderately elevated HBV DNA levels may be in the process of seroconversion, or may have another cause of liver disease in addition to HBV.

-Persistent immune-active phase for more than three to four months, indicated by persistently elevated ALT and high HBV DNA levels. In this case, treatment is indicated.

-Spontaneous resolution of the HBV infection, heralded by clearance of HBsAg and appearance of HBsAb. This usually (but not always) indicates permanent resolution of HBV, although patients should be monitored for reactivation of infection and for HCC.

•We suggest treatment for patients who have persistently abnormal ALT (>2 times the ULN or >60 units/L, whichever is lower) and HBV DNA >20,000 international units/mL or 10⁵ copies/mL for at least four to six months [3,5,9]. Almost all of these children will be HBeAg-positive, but therapy can also be considered for the few in whom HBeAg is negative, provided that active HBV infection is documented by demonstration of viremia of >10⁴ copies/mL and ALT is persistently abnormal. If there is evidence of hepatic decompensation, such as jaundice or coagulopathy, treatment should be initiated earlier [21,22]. Interferon cannot be used in patients with decompensated disease. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Immune-active, HBeAg-positive (clearance)'.)

●Inactive chronic HBV phase – Patients who undergo spontaneous seroconversion (HBeAg-positive to HBeAg-negative, with subsequent HBV DNA <2000 international units/mL) should not be treated, but should be monitored. In this state, HBeAb is usually positive. Monitoring consists of measuring ALT every six months, and HBeAg and HBeAb every 12 months. HBV DNA should be measured if ALT becomes elevated. (See "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Inactive chronic hepatitis B virus'.)

These patients have inactive disease but should be monitored periodically because some reactivate into an HBeAg-negative immune-active phase, as discussed below, while others revert to the immune-active phase (HBeAg-positive). If this state is persistent, treatment is warranted to reduce the risk of progressive hepatic damage.

●Immune-active, HBeAg-negative (reactivation) phase – Some individuals in the inactive chronic HBV phase reactivate into an HBeAg-negative immune-active phase, characterized by elevated HBV DNA, ALT that is intermittently or persistently elevated, and negative HBeAg. This condition is rare in children. Most of these patients have HBV variants with precore or core promoter mutations. Patients in this phase tend to have virulent liver disease, and close monitoring is indicated. Antiviral therapy is indicated to minimize liver damage, although long-term clearance of HBV from serum is rare. Adults with this condition are typically treated indefinitely. There are no pediatric-specific guidelines about management of this phase because it is uncommon in childhood. (See "Hepatitis B virus: Overview of management", section on 'HBeAg-negative chronic hepatitis'.)

Other considerations — Several other considerations may be relevant to treatment decisions for individual patients:

●Patients who are coinfected with hepatitis C virus (HCV), hepatitis delta virus (HDV), or HIV – These patients require special considerations for timing and selection of treatments. (See "Hepatitis B virus: Overview of management", section on 'Patients with hepatitis C coinfection' and "Treatment and prevention of hepatitis D virus infection" and "Treatment of chronic hepatitis B in patients with HIV".)

●Patients who will be undergoing immunosuppressive, cytotoxic, or biologic modifier therapy (eg, chemotherapy, antitumor necrosis factor alpha treatments, or organ transplantation) – Treatment is appropriate for these patients, even if they are in the immune-tolerant or inactive chronic HBV phase of HBV infection. In this case, a nucleos(t)ide is often used in an effort to prevent reactivation; these drugs may be discontinued after the immunosuppressive therapy is complete and if HBV DNA remains <20,000 units/mL and ALT is normal [23]. Issues related to screening and prophylaxis are described separately. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

CHOICE OF TREATMENT — Treatment options for chronic HBV in children typically include interferon (IFN), or the nucleos(t)ide analogs entecavir or tenofovir (table 1). Each of these drugs is a reasonable choice for first-line treatment, and the selection depends primarily on the patient's age and the values and preferences of the patient and family. Therefore, we engage the family and patient in a discussion of the relative advantages and disadvantages of these agents before choosing, as follows:

●IFN has the advantage of a finite duration of treatment. Thus, IFN is a good choice for the patients who are most likely to respond, ie, for patients with serum alanine aminotransferase (ALT) more than twice the upper limit of normal (ULN), have positive hepatitis B e antigen (HBeAg), who are willing to undertake the regimen of subcutaneous injections, and have no comorbid diseases that might be exacerbated by an immunostimulatory agent. IFN is not associated with the development of resistant variants. IFN is not a good option for patients with an underlying autoimmune disorder, organ transplant, decompensated liver disease, or serious neuropsychiatric disease, due to its side effects [21]. (See 'Interferon alfa' below.)

●Entecavir or tenofovir are good options for patients who prefer long-term treatment with an oral agent (indefinite length of treatment, except in the minority of patients who undergo seroconversion) rather than finite treatment with IFN by injection (typically six months of treatment). These drugs are also appropriate for those who do not respond to IFN (defined by detectable HBV DNA and elevated serum ALT six months after completion of the course of IFN alfa) or for those who have a contraindication to IFN. The choice between entecavir and tenofovir depends primarily on the patient's history of prior nucleos(t)ide treatment, if any:

•Entecavir has a low rate of drug resistance in nucleoside-naïve patients (adult data), but this is higher in patients previously exposed to lamivudine, so it generally should be avoided in this group of patients. In the United States, entecavir is approved for use in children two years and older [24]. (See 'Entecavir' below.)

•Tenofovir disoproxil fumarate (TDF) is licensed in the United States and Europe for children ≥2 years, and tenofovir alafenamide (TAF) is licensed for individuals ≥12 years. Either of these forms is a reasonable first-line alternative to entecavir [3]. They do not appear to induce viral resistance and are often effective for patients who have developed resistance when treated with other nucleos(t)ide analogs. Although there are concerns about nephrotoxicity and decreases in bone mineral density with TDF, only mild changes were demonstrated in the large clinical trial, so it is generally considered safe and a good alternative for children with lamivudine experience or demonstrated entecavir-resistant HBV. TAF has less renal or bone toxicity. (See 'Tenofovir' below.)

Other drugs that are licensed for use in children are lamivudine and adefovir dipivoxil. Lamivudine is not a preferred drug, due to high rates of resistance; adefovir is not preferred, due to weak antiviral activity. (See 'Less preferred drugs' below.)

Combination therapy (eg, IFN with a nucleos[t]ide analog, or the combination of two nucleos[t]ide analogs) has not been shown to improve clinical outcomes compared with monotherapy, based on studies in adults. (See "Hepatitis B virus: Overview of management".)

Genotype testing is not an established factor for making the choice between IFN and nucleos(t)ide therapy. However, genotype testing may be useful for HBeAg-positive patients who are otherwise undecided about the choice of treatment since patients with genotype A and B have a more favorable response to IFN and those with genotype C generally are less likely to respond. Response to entecavir or tenofovir does not differ among the four major genotypes (A, B, C, and D). (See "Hepatitis B virus: Overview of management" and "Clinical significance of hepatitis B virus genotypes".)

ANTIVIRAL AGENTS

Interferon alfa — Interferon (IFN) alfa is a good choice for the patients who are willing to undertake the regimen of subcutaneous injections and have no comorbid diseases that might be exacerbated by an immunostimulatory agent. The likelihood of hepatitis B e-antigen (HBeAg) seroconversion and of hepatitis B surface antigen (HBsAg) seroconversion with IFN is somewhat greater than for the nucleos(t)ide analogs. As for all treatments for HBV, IFN treatment should be limited to patients in the immune-active phase (serum alanine aminotransferase [ALT] more than twice the upper limit of normal [ULN] and positive HBeAg), except in unusual circumstances.

Standard interferon — IFN alfa-2b (Intron A) was the first treatment approved for chronic HBV infection in most countries. It leads to a beneficial response in 30 to 40 percent of patients with chronic HBV infection, but is expensive and may be accompanied by frequent and unpleasant side effects. Standard interferon has largely been replaced by pegylated interferon, where available. (See 'Pegylated interferon' below and "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

Pegylated interferon — Pegylated interferon alfa-2a (PegIFN) is now approved for use in children three years and older with HBV in the United States and Europe [25,26]. The dose in children is 180 micrograms/1.73 m² body surface area (maximum dose 180 micrograms), given subcutaneously once weekly for 48 weeks [3].

A positive response to treatment is defined as conversion to the inactive chronic HBV state, ie, the loss of serum HBV DNA and HBeAg (in patients who were HBeAg-positive). The 48-week course of treatment is followed by an observation period of 6 to 12 months since seroconversion may be delayed. A small minority of patients convert to HBsAg-negative, HBs antibody (HBsAb)-positive. Those who do not achieve HBeAg seroconversion may be considered for treatment with nucleos(t)ide analogs, or observed if the disease activity is mild. (See 'Nonresponders to interferon' below.)

Efficacy — A randomized trial of PegIFN reported moderate efficacy at 24 weeks post-treatment for each of the following outcomes: HBeAg seroconversion (25.7 percent for PegIFN, 6 percent for controls), HBsAg clearance (8.9 percent for PegIFN, 0 percent for controls), and suppression of HBV DNA <2000 international units/mL (28.7 percent for PegIFN, 2 percent for controls) [27]. Similar efficacy and safety outcomes for PegIFN were reported for a small group of patients with advanced fibrosis. The study was conducted at more than 37 sites across the globe; 56 percent of the subjects were Asian (primarily from China). A subsequent meta-analysis that included this trial reported somewhat better outcomes (HBV DNA <2000 international units/mL: 60 percent, 95% CI 30-87) [28]. However, the analysis was limited by heterogeneity in study design, including nonrandomized studies, dual therapy with entecavir, and inclusion of patients in the immune-tolerant phase. (See "Pegylated interferon for treatment of chronic hepatitis B virus infection".)

The lower response rate in populations from Asian countries is primarily explained by the higher proportion of individuals who were infected at birth and tend to have a prolonged immune-tolerant phase of infection. For reasons that are incompletely understood, such patients appear to be less likely to respond to antiviral treatment with IFN. In addition, HBV genotype C is more common among Asian populations and may be associated with lower rates of seroconversion and response to treatment compared with HBV genotype B. Whether immune tolerance and genotype exert independent effects on seroconversion has not been established. (See "Hepatitis B virus: Clinical manifestations and natural history" and "Clinical significance of hepatitis B virus genotypes".)

HBeAg seroconversion is generally associated with histologic improvement in studies of adults. There are relatively few studies showing histologic changes in children since a repeat liver biopsy after treatment is uncommonly performed. One such study involved 10 paired-biopsy samples, six of which were from responders [29]. The histologic activity index improved significantly in all responders. It also improved in two of the nonresponders but worsened in the other two.

Side effects — Treatment with IFN is associated with multiple side effects. Nevertheless, most children are able to complete their course of therapy, although not always with the initial dose.

Approximately 15 percent of children experience flu-like symptoms (eg, fever, myalgia, headache, arthralgia, and anorexia), which usually remit after a few doses [27]. Prophylactic acetaminophen and/or ibuprofen may be used to mitigate these symptoms.

Increases in serum ALT are frequent during treatment. In a trial of PegIFN, ALT flared >10 times the ULN in 20 percent of subjects in the treatment arm (versus 8 percent in controls) and >5 times the ULN in 34 percent of treated subjects (versus 22 percent in controls) [27]. Bone marrow suppression, especially neutropenia, is observed in approximately 20 to 40 percent of children [29,30]. Severe neutropenia resulting in infections is rare. In one of the largest controlled trials, the dose was reduced because of bone marrow suppression or fever in 23 percent of children [29].

A variety of other side effects have been described:

●Growth attenuation [27,31,32]. Data are conflicting regarding whether these effects are reversible. In a clinical trial of PegIFN in 111 children with HBV, the proportion of children with >15 percent decrease in height-for-age percentile compared with baseline was 6 percent at 48 weeks of treatment, then increased to 12 percent at 24 weeks post-treatment and 18 percent at five years post-treatment [33]. A similar trend was seen for weight-for-age percentiles. Long-term effects were less prominent in studies of children treated with PegIFN for hepatitis C virus (HCV) infection. Residual effects on height were detected in approximately 15 percent of patients two years after the end of treatment, but, by six years after the end of treatment, there were no consistent significant effects on height [34].

●Changes in personality (mostly irritability and temper tantrums), which are reversible upon withdrawal of treatment [29,30]. There are no studies regarding use of antidepressant medications in children receiving IFN. It is prudent to refer children for evaluation if they develop moderate depression or behavioral symptoms. Treatment should be stopped in children who develop severe depression.

●Fevers are common after the first few doses of IFN alfa in children [27,35].

●Decreased quality of life because of medication side effects and fear of injections [30]. Quality of life reverts to baseline within three months of cessation.

Nonresponders to interferon — The majority of patients treated with IFN do not achieve seroconversion. The long-term outcome of such patients has not been well described. Small studies suggest that the disease remains relatively stable in the short term [36].

Treatment options for such patients could include entecavir and tenofovir. A second course of IFN alfa therapy does not appear to increase the rates of seroconversion [37].

Nucleos(t)ide analogs — The preferred choices for oral therapy are tenofovir and entecavir, both of which are licensed in the United States for children two years and older.

Tenofovir

●Formulations – Tenofovir is administered orally as one of two prodrugs:

•Tenofovir disoproxil fumarate (TDF) – Tenofovir disoproxil fumarate is licensed for use in children ≥2 years (and ≥10 kg body weight) with chronic HBV in the United States and Europe [38]. It is an orally administered nucleotide analog with excellent viral suppression and a good safety profile; it is It can be used either as primary therapy or as secondary therapy for patients with lamivudine resistance. Studies of this formulation in adults and adolescents have shown no evidence that it induces resistance. Safety considerations include renal toxicity, reductions in bone density, and risk of severe acute exacerbation of HBV if TDF is discontinued.

•Tenofovir alafenamide (TAF) – Tenofovir alafenamide is licensed for use in individuals ≥12 years with chronic HBV in the United States and Europe [39,40]. It appears to have less renal and bone toxicity than tenofovir disoproxil fumarate, based on indirect evidence from adults with HBV and adults and children with HIV. (See "Tenofovir and adefovir for the treatment of chronic HBV infection", section on 'Safety'.)

●Dosing and administration

•TDF – For patients ≥2 years and ≥17 kg body weight, TDF dosing with tablets is:

-≥17 to 22 kg – 150 mg tablet orally daily

-≥22 to 28 kg – 200 mg tablet orally daily

-≥28 to 35 kg – 250 mg tablet orally daily

-≥35 kg – 300 mg tablet orally daily, which is the same dose used for adults

For children ≥2 years and ≥10 kg, TDF dosing with oral powder is 8 mg/kg body weight (up to a maximum of 300 mg) once daily.

•TAF – For children ≥12 years and adults, the TAF dose is 25 mg once daily.

●Efficacy – The efficacy of TDF in a pediatric population was demonstrated in a 72-week randomized trial in adolescents 12 to <18 years of age who [41]. HBV DNA decreased to <400 copies/mL in 89 percent (46 of 52) of patients who received TDF, compared with 0 percent (0 of 54) of those who received placebo. HBeAg seroconversions were rare during the study period. Data regarding HBeAg seroconversion with longer treatment are lacking, but studies in adults report long-term seroconversion rates of approximately 20 percent, similar to entecavir. For children 2 to 11 years, efficacy and safety were evaluated in a randomized trial of 89 HBV-infected treatment-experienced children. After 48 weeks, HBV DNA had decreased to <400 copies/mL in 77 percent of the subjects treated with TDF, versus 7 percent of those treated with placebo; the trial continues in an open-label extension (NCT01651403) [38]. In both of these pediatric trials, TDF had adverse effects on bone mineral density (mean change in total body bone mineral density Z-score -0.18 for TDF versus +0.22 for placebo). The long-term effects on bone health or growth have not been evaluated.

For TAF, the US Food and Drug Administration approval for adolescents with HBV was based on a 24-week trial that showed similar safety, pharmacokinetics, and effectiveness compared with adults [39]. A study in younger children is in progress (NCT02932150).

The experience with tenofovir in adults is described separately. (See "Tenofovir and adefovir for the treatment of chronic HBV infection".)

Entecavir — Entecavir is an orally administered nucleoside with potent activity against HBV; in the United States, it is approved for use in children two years and older [24]. Entecavir is a good option for patients who meet criteria for antiviral treatment (see 'Selection of patients for antiviral treatment' above) and prefer long-term treatment with an oral agent (usually an indefinite length of treatment) rather than finite treatment with IFN by injection (typically one year of treatment). It is also appropriate for those who have a contraindication to IFN or for those who do not respond to IFN (defined by detectable HBV DNA and elevated serum ALT six months after completion of the course of IFN alfa). For patients previously treated with lamivudine, entecavir is associated with high rates of resistance. Therefore, tenofovir is preferred for this group of patients, but if tenofovir is not available, entecavir can be used at twice the usual dose. (See "Entecavir in the treatment of chronic hepatitis B virus infection".)

●Dosing and administration – Entecavir dosing is based on body weight for children weighing less than 30 kg. For treatment-naïve patients, doses start at 0.15 mg once daily for children weighing 10 kg (using a liquid formulation) and increase up to a maximum of 0.5 mg daily for children weighing 30 kg or more [24]. If entecavir is selected for patients previously treated with lamivudine, it is given at twice this dose.

●Efficacy – In adults with HBeAg-positive HBV who have not previously been treated with nucleoside/nucleotide analogs, treatment with entecavir achieves HBeAg seroconversion in approximately 20 percent of patients, with substantial reduction in mean HBV DNA levels and corresponding improvement in liver histology. Outcomes of entecavir treatment in children were shown in a randomized trial of 180 children between 2 and 18 years of age who had not been previously treated with a nucleos(t)ide analog [42]. After 48 weeks of treatment with entecavir, 24 percent achieved both seroconversion and HBV DNA <50 international units/mL, compared with 3.3 percent of subjects treated with placebo. ALT normalized in 68 percent of subjects treated with entecavir, versus 23 percent of those treated with placebo. Between 48 and 96 weeks of treatment, additional virologic and biochemical responses were observed.

●Viral resistance – For treatment-naïve patients undergoing long-term treatment with entecavir, the rate of virologic resistance is around 1 percent, with up to five years of follow-up. For patients who were previously treated with lamivudine, entecavir is less effective and is more likely to induce resistance. For such patients, tenofovir is recommended rather than entecavir. If tenofovir is not available, entecavir may be used if additional therapy is warranted, but the recommended dose is twice that for lamivudine-unexposed individuals and monitoring for development of resistance needs to be instituted.

Monitoring — After initiating nucleos(t)ide therapy, response to treatment should be assessed with periodic laboratory monitoring. We use the following approach [43]:

●Measure serum aminotransferase levels, HBV DNA, electrolytes, blood urea nitrogen, and creatinine at baseline and every three months during the first year of therapy, then every six months thereafter. Patients with impaired renal function may require dose adjustments.

●Measure HBsAg at baseline and annually thereafter if HBV DNA is undetectable.

●If HBsAg clears, check anti-HBs antibodies.

Treatment duration — Most pediatric patients who are candidates for nucleos(t)ide therapy have HBeAg-positive chronic hepatitis without cirrhosis. For these patients, treatment duration depends upon the patient's response to therapy [2,3]:

●Patients with persistent HBeAg – For the majority of patients, treatment with TDF or entecavir will result in low viremia (HBV DNA <2000 international units/mL) with persistent HBeAg, in which case, the treatment usually should be continued indefinitely.

●Patients who become HBeAg-negative – For the minority of patients who undergo seroconversion during treatment with these drugs (converting to HBeAg-negative, the inactive chronic HBV phase), the optimal duration of therapy has not been defined. Practice in adults is to continue treatment for at least one year after seroconversion and sometimes indefinitely [3,44]. Children who stop antiviral therapy should be monitored every three months for at least one year to detect flares, reactivation, or decompensation.

Discontinuation of treatment should only be considered for patients who become HBeAg-negative and have HBV DNA <2000 international units/mL (which is the case for almost all patients after seroconversion) and agree with close monitoring. Patients who discontinue treatment should be closely monitored for evidence of viral relapse (ALT, HBV DNA, and HBeAg) for at least one year, though relapses can occur after this.

Other biomarkers of sustained virologic response have been explored, but none have established roles for making decisions regarding treatment duration, particularly in children. The predictive value of quantitative HBsAg (qHBsAg) was assessed in a systematic review of studies in adults who stopped nucleos(t)ide treatment [45]. Approximately 10 percent of those with qHBsAg <100 international units/mL at the end of treatment had a virologic relapse at 12 to 24 months off of therapy, compared with 30 to 87 percent of those with qHBsAg >100 international units/mL. (See "Hepatitis B virus: Overview of management", section on 'Patients without cirrhosis'.)

Further details about these decisions and management of patients with other characteristics (cirrhosis and/or HBeAg-negative chronic hepatitis) are discussed separately. (See "Hepatitis B virus: Overview of management", section on 'Duration and treatment endpoints'.)

Less preferred drugs — Lamivudine and adefovir dipivoxil are now rarely used as first-line agents for treatment of chronic HBV due to limited efficacy and high rates of drug resistance. They have generally been supplanted by the newer and more effective nucleos(t)ide analogs, entecavir and tenofovir. Entecavir or tenofovir are also preferred for patients who are at risk for HBV reactivation because of immunosuppressive, cytotoxic, or biologic modifier therapy [23]. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy" and "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogs'.)

MANAGEMENT OF ACUTE HEPATITIS B VIRUS — Acute HBV infection in children is generally treated with supportive management alone. There are no data on treatment of children with acute infection. For those with severe acute hepatitis, treatment with a nucleos(t)ide analog might be considered. For individuals with fulminant hepatitis caused by HBV, liver transplant may be necessary. The risk of reinfection with HBV after transplantation for fulminant HBV is relatively low, in contrast with the higher risk for reinfection after liver transplantation for chronic HBV. (See "Hepatitis B virus: Overview of management", section on 'Acute infection' and "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients", section on 'Determining risk of HBV reinfection post-transplant'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diagnosis of hepatitis B" and "Society guideline links: Hepatitis B vaccination" and "Society guideline links: Management of hepatitis B".)

SUMMARY AND RECOMMENDATIONS

●Pretreatment evaluation

•Determine phase of hepatitis B virus (HBV) – The phase of HBV infection has important implications for treatment decisions. The phase is determined by measuring serum alanine aminotransferase (ALT), HBV DNA, and hepatitis B e-antigen (HBeAg) and hepatitis B e antibody (HBeAb) (figure 1A). (See 'Phase of chronic hepatitis B virus' above and "Clinical manifestations and diagnosis of hepatitis B virus infection in children and adolescents", section on 'Phases of chronic hepatitis B virus infection'.)

•Evaluate for coinfection – In addition, evaluate for the possibility of coinfection with hepatitis C virus (HCV), hepatitis D virus (HDV), and HIV. The first step is a focused history for risk factors for these infections, followed by serologic testing if risk factors are present. Coinfections with these viruses has important implications for disease progression and selection of antiviral treatment. (See 'Post-diagnosis evaluation' above.)

●Selection of patients for treatment – The decision about whether to treat depends primarily on the presence of persistently abnormal ALT levels (algorithm 1):

•Immune-tolerant or inactive phases – We suggest that patients in these phases of chronic HBV not be treated (Grade 2B). These phases are characterized by positive hepatitis B surface antigen (HBsAg) and normal or minimally elevated serum ALT levels. In the immune-tolerant phase, HBV DNA levels are high, usually with positive HBeAg and negative HBeAb. In the inactive carrier phase, HBV DNA levels are low, usually with negative HBeAg and positive HBeAb. Children in these phases should undergo monitoring of liver biochemical tests every 6 to 12 months to assess for immune activation or reactivation after HBeAg seroconversion (figure 1A). (See 'Selection of patients for antiviral treatment' above and 'Monitoring' above.)

•Immune-active, HBeAg-positive ("clearance") phase – We suggest that patients in this phase be treated (algorithm 1) (Grade 2B). This phase is defined as persistently abnormal ALT >2 times the upper limit of normal (ULN) with markedly elevated HBV DNA (typically >20,000 international units/mL or 10⁵ copies/mL) (figure 1A). Those with markedly elevated ALT levels (greater than 10 times the ULN) and low HBV DNA levels may be in the process of spontaneous seroconversion and thus should be observed for several months before initiating treatment. (See 'Selection of patients for antiviral treatment' above.)

●Choice of treatment – When a decision to treat has been made, first-line treatment options include (see 'Choice of treatment' above):

•Pegylated interferon (PegIFN) – This is a good choice for patients who wish to avoid long-term treatment and are willing to adhere to the regimen of subcutaneous injections. However, PegIFN should not be used for patients with comorbid diseases that might be exacerbated by an immunostimulatory agent. Duration of treatment is typically one year. (See 'Interferon alfa' above.)

•Tenofovir or entecavir – Patients who prefer an orally administered medication and are willing to adhere to indefinite duration of treatment are likely to choose a nucleos(t)ide analog. These drugs are also appropriate for patients who do not respond to or have a contraindication to PegIFN.

Of the available agents, we suggest tenofovir or entecavir rather than other nucleos(t)ide analogs (Grade 2C). These agents are preferred because they have potent antiviral activity and are at low risk of selecting for drug-resistant virus. Their efficacy for achieving seroconversion (ie, converting to HBeAg-negative) is probably somewhat less than for PegIFN. Entecavir generally should not be used for patients previously treated with lamivudine or other nucleos(t)ide analog, due to viral resistance. For the majority of patients, treatment should be continued indefinitely. (See 'Tenofovir' above and 'Entecavir' above and 'Treatment duration' above.)

●Monitoring for hepatocellular carcinoma (HCC) – Children with chronic HBV are at risk of developing HCC and should undergo periodic surveillance for this complication. The risk is particularly high in patients with advanced fibrosis and cirrhosis or a first-degree relative with HCC.

HCC surveillance consists of a right upper quadrant ultrasound, with or without an alpha-fetoprotein (AFP) level. We typically perform surveillance annually in adolescents and every six months in those with advanced fibrosis or cirrhosis or a family history of HCC. Less frequent screening is appropriate for younger children or for those in the immune-tolerant phase of HBV. (See 'Hepatocellular carcinoma surveillance' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Maureen M Jonas, MD, who contributed to earlier versions of this topic review.