EASL Clinical Practice Guidelines

Who and when to treat

Decision to treat must take into account the mild evolution of the disease during childhood, the risk of disease progression later in life, the development of severe complications in few, not yet well identified children, the efficacy of current antivirals, their side effects, and the limited number of drugs labeled for use in this age group. A treatment algorithm is proposed in Fig. 1.


Fig. 1
Treatment algorithm for pediatric patients with CHB (modified from [1])
. ∗Recommendation valid until results of ongoing trials on the treatment of immunotolerant children are available. ∗∗It is likely that PegIFN will replace IFN-α as the first-line treatment for CHB once the results of ongoing clinical trials are available.

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The need for treatment should be evaluated at each follow-up visit, in order to initiate antiviral drugs at the earliest signs of liver damage (C2). Children with CHB should undergo physical examination and measurement of serum ALT and HBeAg/anti-HBe levels every 6 months (C1). In HBeAg-positive patients with persistently elevated ALT, their levels should be monitored every 3 months for at least one year (B1). In HBeAg-negative patients, ALT and HBV DNA levels should be measured 4-monthly within the first year to rule out HBeAg-negative hepatitis. After confirmation of the inactive carrier status (normal ALT and HBV DNA <2000 IU/ml), patients should be monitored every 6 months (B1). Full blood count and liver function tests should be performed yearly (C1). HCC surveillance with liver ultrasound should be done every 6–12 months, depending on the stage of fibrosis [190]. Alpha-fetoprotein (AFP), although widely used, was recently shown to provide insufficient sensitivity and specificity for effective surveillance [[191], [192]]. Lifetime follow-up is warranted even for inactive carriers, because of the risk of cirrhosis, HCC and reactivation of HBV infection, with seroreversion to HBeAg-positive status or progression to HBeAg-negative hepatitis (C1) [[49], [58]].

Currently, decision to start treatment is based on ALT levels (which reflect ongoing liver damage), HBeAg positivity, HBV DNA levels, liver histology, family history of HCC, co-existing liver diseases and patient's treatment history.

As the upper limit of normal (ULN) for ALT levels in pediatric age has not been established yet, it is advised that a patient should be considered for antiviral treatment if ALT levels are more than 1.5 times the laboratory ULN or more than 60 IU/L (value used as inclusion criterion in the three largest trials in children [[59], [60], [61]]), whichever is lower (C2) [9]. Patients with lower transaminases have fewer chances to achieve serological response [[59], [60]]. A lower threshold based on larger pediatric cohorts may be used in future studies to avoid underestimation of liver damage, but this approach may reduce the overall rate of serological response and increase the need of prolonged treatment of patients with maintained VR under antiviral drugs [62].

Antivirals should be considered for children with elevated serum ALT levels for at least 6 months (12 months if HBeAg-negative), in order to avoid treating patients who are undergoing spontaneous HBeAg seroconversion (C1).

In the presence of high ALT levels, assessment of serum HBV DNA levels is important, as high HBV DNA values warrant antiviral treatment, whereas low levels should instigate investigations to exclude other causes of liver disease. The cut-off value for HBV DNA, however, has not been defined for children. As young patients have a higher HBV replication rate than adults, a value of 20,000 IU/ml has been chosen by different authors [[7], [63]]. However, lower values have been associated with progressive liver disease in adults, and latest management guidelines for adult patients identified 2000 IU/ml to be a more reliable cut-off [[6], [8]]. Such a cut-off appears to be appropriate for children as well (C1).

In patients older than 40 years of age, antiviral treatment is advocated in the presence of a high viral load in isolation, as this is an independent risk factor for cirrhosis and HCC [[42], [43]]. No data exist in children to support such an approach. Therefore, as response to currently available antivirals in children is partial and limited to specific subgroups, histologic assessment of the degree of inflammation and of the stage of fibrosis is recommended before considering treatment (A1). Response to both interferon(IFN)-α and NA is more likely when at least moderate necroinflammation or moderate fibrosis is found at liver histology (A1) [[59], [64]]. Although the benefit of treatment has not been established for children with mild inflammation or fibrosis, a family history of HCC may warrant treatment even in children with mild histological changes, as they are at increased risk of developing HCC (B2) [4].

Although still not fully validated, non-invasive methods to assess the degree of hepatic fibrosis, such as FibroScan, could prove useful to avoid liver biopsy, especially during follow-up [[8], [162], [163], [164], [165]]. However, no sufficient data are available in children and, at present, these non-invasive methods cannot substitute for liver biopsy in the decision to treat a child or an adolescent with chronic hepatitis B, as these methods evaluate more fibrosis than necroinflammatory activity(C2).

Antiviral treatment with NA should be instituted in HBV infected children undergoing liver transplantation or in recipients of grafts from anti-HBc-positive donors to prevent (or treat) recurrent HBV infection (C1). Prophylactic anti-HBV therapy should also be administered to HBsAg-positive patients who are going to receive immunosuppressive or cytotoxic treatment, as it decreases the risk of mortality and morbidity related to HBV reactivation (B1) [65]. Children with cirrhosis, HBV-related glomerulonephritis, or co-infection with HDV, HCV or HIV are at increased risk for a rapid progression of liver disease. These patients might benefit from treatment even if ALT, HBV DNA levels, and liver histology do not match the criteria listed above (C2).

If antiviral treatments were able to achieve complete viral control (i.e., anti-HBs seroconversion), the ideal children to treat would be those tolerant to HBV, in order to obtain the production of neutralizing antibodies before the onset of complications. These children, who have normal or mildly elevated ALT levels and a high viral load, have been shown not to respond to isolated interferon treatment [[59], [60], [66], [67], [68]] and are not good candidates for current NA therapy because of the risk of developing antiviral resistance [69]. A pilot open study in small cohort of tolerant children has shown promising results with a combined protocol, in which 8 weeks of lamivudine treatment to decrease the viral load were followed by 44 weeks of combined lamivudine and IFN-α treatment [70]. On the basis of this study, two controlled trials in tolerant children are currently being conducted in the UK (lamivudine/pegylated IFN-α) and in the USA (entecavir/pegylated IFN-α) [[71], [72]]. Until the results of these studies become available, children in the immunotolerant phase should not be treated, but should be monitored, and treated only if an increase of ALT levels reveals immune activation (A1).