EASL Clinical Practice Guidelines

Context

Epidemiology and prevention

Since the WHO recommended global immunization programs for HBV in 1991, the prevalence of HBV infection has declined worldwide [[5], [10], [11], [12]]. Although among children born in Western Europe and North America HBsAg-positivity is rare, pediatricians are confronted with an increasing number of children adopted from higher prevalence countries, 2–5% of whom are still infected with HBV and often carry HBV genotypes which expose them to a higher risk of complications [[1], [13], [14], [15]].

In countries where donor screening and blood testing have been implemented, the current risk of acquiring HBV infection after blood transfusion is estimated at 1 in 500,000 per unit exposure [[16], [17]]. Nevertheless, as HBV nosocomial transmission is still a critical problem, vaccination status of children needs to be checked regularly and all preventive measures have to be strictly respected [18].

Mother-to-child transmission accounts for more than 50% of chronic infections in highly endemic areas. After exposure, the risk of chronicity is higher for newborns (90%), infants and children younger than 5 years (25–30%) than for adolescents or adults (<5%) [[19], [20]].

Vaccination is the most effective measure to prevent hepatitis B transmission. In highly endemic areas, it is also the most cost-effective medical intervention, offering the higher benefit-cost ratio, whereas in low-endemicity countries, such cost-effectiveness is not as clear [[21], [22], [23], [24]]. Recombinant vaccine induces a seroprotective response (anti-HBs ⩾10 mIU/ml) in about 95% of subjects vaccinated with three doses [[25], [26]]. The first dose of monovalent vaccine should be administered intramuscularly within 24 hours of birth, and should be followed by 2 or 3 doses (monovalent or combined) with a minimum interval of 4 weeks (A1) [26]. Preterm infants weighting <2000 g should receive 3 doses after the birth dose(B1) [[26], [147]]. Postvaccination testing for a protective concentration of anti-HBs is recommended only for high-risk populations (infants born to HBsAg-positive mothers and HIV-infected or other immunocompromised subjects), and should be performed 1–2 months after the end of the vaccination schedule (A1) [26]. Revaccination with further 3 doses induces protective anti-HBs response in the majority of non-responders [[27], [28]]. Immunocompromised subjects should be tested annually and revaccinated if anti-HBs <10 mIU/ml (C1) [148]. Although anti-HBs levels have been shown to decrease over time, long-lasting protection has been observed in vaccinated subjects with undetectable anti-HBs, and at present there is no clear evidence for recommending the administration of a booster dose in immunocompetent individuals [[149], [150]]. Testing for coeliac disease, HIV or other causes of immune deficiency might be advisable for non-responders (C2) [[29],[30], [151]].


Vaccine failure and mother-to-child transmission of hepatitis B affect 17% of infants born to HBeAg-positive mothers [25]. The high viral load related to HBeAg-positivity seems to be the most important factor for breakthrough infection [[25], [31]]. Moreover, when the mother is infected by genotype C HBV, intrauterine infection may occur before vaccination can be administred, in addition to hyporesponsivness to vaccination [[31], [32]]. When the mother is a chronic carrier, vaccination at birth is not sufficient to avoid vertical transmission, and concurrent intramuscular administration of 0.5 ml of hepatitis B immunoglobulin (HBIG) is recommended to give immediate passive immunity to the newborn [[26], [33]]. Administration of both the vaccine and HBIG to newborns of HBeAg-positive mothers within 12–24 h of birth allows the achievement of 90% protection rate (98% when mothers are HBeAg-negative), compared to vaccine alone [[25], [26], [34]]. Administration of both vaccine and HBIG is recommended for newborns of HBeAg-positive mothers (A1). Although a clear benefit has not been shown for newborns of HBeAg-negative mothers, a reduction of the incidence of fulminant hepatitis justifies HBIG administration to all infants born of HBsAg-positive mothers [25], regardless of the maternal HBeAg status (C2). High breakthrough infection (17%) and chronicity (54%) rates have been reported in newborns of HBeAg-positive mothers despite concomitant active and passive immunization at birth [25]. As breakthrough infection rates are directly correlated to maternal viral load (as well as to HBV genotype C, high HBsAg titer, vaginal delivery, hyporesponsiveness to vaccine and vaccine escape mutants) [[25], [31], [152]], treatment with nucleos(t)ide analogues (NA) of highly viraemic women during the last trimester of pregnancy is currently recommended to prevent vertical transmission (B1, see below) [8].

Breastfeeding has been shown not to contribute significantly to HBV transmission from infected mothers to infants who have received active and passive immunoprophylaxis [[153], [154]]. In the absence of cracked or bleeding nipples, breastfeeding of properly immunized infants is encouraged (B2). Unlike interferon (IFN), which is not excreted in breast milk, lamivudine and tenofovir are excreted (although no data are available yet for tenofovir in humans), but the dose adsorbed by the infants is negligible compared to standard oral doses [[155], [156]]. Nevertheless, no systematic study has been conducted to evaluate the effects of nucleos(t)ide analogues (NA) absorbed from maternal milk on breastfed infants. Though there are data suggesting that breastfeeding while on lamivudine and tenofovir is safe [156] at present, breastfeeding cannot be recommended, and the risk of potential long-term effects on the infant should be weighed against the risk of stopping the antiviral therapy. Entecavir has not been studied in pregnant women as yet, but was shown to be excreted in breast milk in rats and to have carcinogenic potential both in mice and rats after placental transfer. No data are available yet for telbivudine.

Natural history

Chronic hepatitis B, defined as positivity for HBsAg for 6 months or longer, is a mild disease in childhood [1]. Most infected children are asymptomatic, with a normal growth and a normal physical examination [35]. The great majority of perinatally infected subjects are HBeAg-positive, with high serum levels of HBV DNA and normal serum alanine aminotransferases (immunotolerant phase). Transplacental transfer of maternal HBeAg has been suggested to elicit HBe/HBcAg-specific Th cell tolerance in utero [[157], [158], [159], [160]]. Such mechanism could explain the different chronicity rates between neonatal and adult infection, as well as the higher chronicity rate in babies born to HBeAg-positive mothers, in whom high-level viral replication leading to large amount of HBeAg would maintain the tolerance to HBV [56]. This immunotolerant phase, which lasts 10–30 years, is usually marked by high viral replication and little liver damage. Nevertheless, 1.7–4.5% of children and adolescents infected at birth have cirrhosis at liver biopsy [[35], [36]].

Over time, HBV DNA levels fluctuate and ALT levels rise, reflecting the histologic finding of necroinflammation of liver parenchyma. This phase of active hepatitis leads to seroconversion to anti-HBe antibodies in 60–95% of patients on long-term follow-up [[36], [37]]. ALT levels increase before HBeAg clearance and may remain elevated (with flare-ups in 20% of subjects) for 6–12 months after seroconversion [[11], [35], [38], [39]]. Most HBsAg-positive, HBeAg-negative, and anti-HBe-positive patients (i.e. those who undergo HBeAg seroconversion) are defined as inactive carriers, have absent or low viral replication (HBV DNA <2000 IU/ml) and usually inactive liver histology, with normal ALT levels. Over a long-term follow-up (24–29 years), inactive carriers with no signs of cirrhosis at seroconversion do not show disease progression, whereas 1–5% of HBeAg-positive children develop cirrhosis [[2], [35], [36]].

Although the incidence of HCC in high HBV prevalence areas has been significantly reduced by global immunization programs, between 0.01% and 0.03% of children with CHB develop HCC during childhood (32 per 100,000 person-year) [[14], [36], [40], [41]]. Children developing HCC are more likely to be males (70%), with cirrhosis (80%), and to have undergone early seroconversion (suggesting that necroinflammation during seroconversion to anti-HBe may be severe enough to lead to cirrhosis and HCC) [[14], [36], [40]]. In adult patients, the long-term risk of both HCC and cirrhosis is directly correlated to serum HBV DNA levels and HBeAg positivity [[42], [43], [44]]. No conclusion can be drawn from pediatric studies because of the rarity of HCC during childhood [[36], [40]]. The role of viral genotype on the risk of developing HCC is still to be clarified in the pediatric population (80% of HCC are in cirrhotic genotype B children, whereas in adults, genotypes C and F are considered at increased risk) [[14], [45], [46], [47], [48]]. Furthermore, the risk of HCC is higher in individuals with a family history of HCC [4]. Seroconversion to anti-HBe reduces the risk of developing HCC, but 0.2% of HBeAg-negative adults and 1.6% of asymptomatic HBsAg carriers still develop HCC [49].


A subgroup of anti-HBe-positive subjects has active viral replication with abnormal ALT levels and histologically active hepatitis (HBeAg-negative chronic hepatitis). HBeAg-negative hepatitis affects about 10% of pediatric patients, who show a more severe disease progression and have a higher incidence of HCC than HBeAg-negative patients in sustained remission [49].
Between 7% and 25% of inactive carriers lose HBsAg and become anti-HBs-positive over a 20-year follow-up [50]. Unfortunately, spontaneous seroconversion to anti-HBs is a rare event in childhood (0.6–1%/year) [[35], [36], [38]]. Such an event marks resolution of HBV infection, and leads to an improved liver histology. HBsAg seroclearance, if it occurs before the development of cirrhosis or HCC and in the absence of concomitant infections, has an excellent long-term prognosis [51]. Nevertheless, covalently closed circular DNA (cccDNA) persists indefinitely in hepatocytes, and low-level viral replication or reactivation upon immunosuppression is always possible. Moreover, the HBV genome may integrate in the host genome, increasing the risk of HCC development even after HBsAg seroclearance [[52], [53]].


As a reflection of the transcriptional activity of cccDNA, HBsAg levels decrease with age and disease progression, being higher during the immunotolerance phase, lower after seroconversion to anti-HBe, and reaching the lowest levels in inactive carriers [161].