EASL Clinical Practice Guidelines

Special populations

Treatment strategies for special populations of HBV infected children are rarely based on strong evidence. Indications and type of treatment are decided on the basis of few available case reports and are often extrapolated from evidence obtained in adult patients. Such children should be referred to specialized tertiary centers where individualized treatments (even with off-label newer antivirals) can be administered.

Immunocompromised children

All children candidate for chemotherapy or immunosuppressive therapy should be screened for HBsAg, anti-HBs, and anti-HBc, and seronegative patients should be vaccinated (A1). Prophylactic treatment with NA should be considered for inactive carriers requiring immunosuppressive therapy (transplanted patients, patients undergoing cytotoxic chemotherapy, corticosteroids treatment, rituximab, anti-TNF-α or other monoclonal antibody therapies), in order to prevent reactivation(A1) [[6], [120]]. NA treatment should be continued for 12 months after cessation of the immunosuppressive therapy (C1). NA with high genetic barriers to resistance should be used for patients with CHB and for inactive carriers requiring long or repeated cycles of immunosuppressive therapy (C1). Lamivudine could be sufficient for children with low viral load or requiring a short duration of immunosuppression (C2). HBsAg-negative, anti-HBc-positive children (prior infection) should be treated as HBsAg-positive subjects if they have detectable HBV DNA (C2). If they have undetectable HBV DNA levels, they should be followed and treated upon reactivation of HBV infection (C2). Prophylaxis with lamivudine should be administered to HBsAg-negative, anti-HBc-positive children receiving rituximab or combined regimens for hematological malignancies or undergoing bone marrow or stem cell transplantation (C1) [[177], [178], [179], [180], [181]].

Organ transplantation

If the recipient has been successfully immunized before surgery, the risk of HBV infection after transplantation of non-hepatic solid organs from HBsAg-negative, anti-HBc-positive donors (i.e., with past HBV infection) is low, despite immunosuppression [121]. The risk of infection is higher after liver transplantation from anti-HBc-positive donors, with a 10% rate of de novo hepatitis in successfully vaccinated recipients and 69% recurrence rate in HBsAg-positive recipients [[122], [123], [124]]. Presence of anti-HBs antibodies per se does not guarantee protection against de novo HBV infection, whereas the achievement of a high anti-HBs titer (>200 mIU/ml) is protective [125]. Therefore, immunization (with the achievement of an adequate anti-HBs titer) and prophylaxis with lamivudine, tenofovir or entecavir (according to patient's age) for an indefinite period of time, and HBIG are recommended when transplanting an anti-HBc-positive liver to an HBV naïve recipient (C1) [126]. Anyway, because of the long post-transplant life expectancy, HBc-positive liver grafts should be discarded when transplanting pediatric patients (C2).

Co-infection with HIV, HCV or HDV

HIV infection should be ruled out in children from high-prevalence countries, as well as in adolescents who are injection drugs users. HBV/HIV-co-infected patients are at increased risk of disease progression [127]. Furthermore, they are at increased risk of developing resistance against lamivudine if used as monotherapy [128]. Because of the risk of inducing HIV resistance, entecavir should only be used in patients receiving effective antiretroviral therapy [129] (A1). In HBV/HIV-co-infected adult patients, the combination of tenofovir (approved for HIV-infected children ⩾2 years old) and emtricitabine or lamivudine is the recommended treatment (A1). Tenofovir monotherapy should not be administered to co-infected patients because of the risk of HIV resistance (A1). Until stronger pediatric evidence is available, such recommendations may be extrapolated to co-infected children (C2) [[130], [131]]. The indications for therapy are the same as in HIV-negative patients. According to HHS pediatric guidelines, no HIV treatment is required if the CD4 count is ⩾500 cells/mm3 in children ⩾5 years of age (⩾750 if aged 3 to <5 years and ⩾1000 if aged 1 to <3 years) [182]. In these cases, HBV may be treated before the institution of an anti-HIV therapy with drugs inactive against HIV (such as IFN-α or PegIFN) (C2).

HBV/HCV co-infection is rare, and few data are available. IFN-α (at doses recommended for HBV treatment) and ribavirin may be a good option (C2). HBV/HDV co-infected children have more severe liver disease than those with HBV alone. IFN-α is also the drug of choice for these patients, although the only pediatric study available has shown a transient effect with no therapeutic benefit in the long-term (24 months) compared to medium-term (12 months) treatment (C2) [[132], [133]].

Acute hepatitis B

Acute symptomatic infection is rare in pediatric age, and it can vary from a mild to a fulminant hepatitis. Classic symptoms are present in 30–50% of older children and adolescents with acute hepatitis B and include fever, jaundice, nausea and vomiting, abdominal pain, liver tenderness, and fatigue, which last approximately 2–3 months. Less than 10% of infants born to HBeAg-positive mothers develop acute hepatitis, and jaundice may be the only sign [[183], [184]]. Fulminant hepatitis is uncommon in infants and children but it is associated with a more than 40% mortality rate without liver transplantation [[185], [186]]. Therefore, patients with fulminant hepatitis must be evaluated for liver transplantation (A1). Such patients may benefit from treatment with entecavir, tenofovir (according to the age of the patient) or lamivudine (C2)[187]. Although the duration of treatment is not defined, continuation of antiviral therapy for at least 3 months after anti-HBs seroconversion or 1 year after anti-HBe seroconversion may be recommended (C2) [8].

Pregnant women

No antiviral agent has been approved by the FDA for use in pregnancy. Lamivudine and entecavir are classified pregnancy class C by the FDA, while both tenofovir and telbivudine are class B. Although interference with organogenesis secondary to the activity of the drug on replication of mitochondrial DNA cannot be excluded, data from the Antiretroviral Pregnancy Registry has shown no increased incidence of birth defects with the use of lamivudine (3.1% when used during the first trimester and 2.7% during the second or third trimester) or tenofovir (2.4% and 2%, respectively) compared to the CDC's population-based birth defects surveillance system (2.72% of total prevalence) [134]. PegIFN is contraindicated during pregnancy (A1). Children of lamivudine-treated mothers have 13–23% lower incidence of intrauterine infection and 1–2% lower mother-to-child transmission rate [[135], [136]]. Treatment with telbivudine during the third trimester of pregnancy has proven effective in reducing maternal viral load and preventing perinatal transmission (0% vs. 8% in controls) [137]. No studies are yet available for tenofovir. Nevertheless, in order to reduce the risk of mother-to-child transmission, treatment of highly viraemic (serum HBV DNA >106 IU/ml) HBsAg-positive women during the last trimester of pregnancy with tenofovir is currently recommended because of its high genetic barrier to resistance and the possibility to continue therapy post-partum if needed (B1) [8]. Although no studies have been conducted in pregnant teens, the same recommendations for treatment in the third trimester of pregnancy may apply (C1).

Household contacts

The extreme resilience of HBV, which allows its survival for more than a week on dry surfaces, is the cause of the significant risk of horizontal intrafamilial transmission. Counseling of HBV carriers and vaccination of uninfected household members are therefore essential [[33], [138]]. Surprisingly, although between 8% and 24% of household contacts of HBV infected subjects (children and adults) have been reported to be HBsAg-positive [[139], [140], [141], [142], [143]], vaccination coverage in this high-risk group is still low (15–25%) even in developed countries [[141], [144], [145], [146]]. All household contacts of an HBV infected child should be screened for HBsAg, HBsAb, and HBcAb in order to offer vaccination to those without protective antibody levels and diagnose those with a previously unknown infection (C1).