EASL Clinical Practice Guidelines

Treatment strategy

Currently, a finite-duration IFN-α therapy remains the treatment strategy of choice for HBeAg-positive children with elevated ALT levels (A1), as in this patient population seroconversion to anti-HBs is the main aim. IFN-α is the only available treatment offering a chance of sustained off-treatment VR. It is likely that, as soon as results of trials using PegIFN in children [89] are available, this medication will become the recommended drug. Although adverse effects may be serious and a clear benefit on the long-term remains to be confirmed, the use of IFN-α is not associated with the emergence of genotypic resistance. The recommended regimen is 5–10 million units per square meter, three times weekly for 6 months (A1). For PegIFN, studies in adults show the highest HBeAg seroconversion rate with 48-week treatment schedules [166] (A1). IFN-α is contraindicated in children with decompensated cirrhosis, cytopenia, autoimmune disorders, cardiac or renal failure, and in transplanted patients (B1) [68]. The possible benefit of priming with corticosteroids has not been proven (C2) [[110], [111], [112]]. On-treatment response was higher with the combination of IFN-α and lamivudine than with IFN-α alone, both in adults and in children, but no benefit was seen for off-treatment response rate [[76], [77],[78], [79], [80], [87], [88], [167]]. Thus, the combination is currently not recommended (C2). Furthermore, in adults combined IFN-α and telbivudine treatment has been reported to be associated with polyneuropathy (A1) [168]. IFN-α is the only treatment licensed for treating children younger than 3 years of age, who however rarely require therapy (A1). In this age group, the risk of IFN-related neurotoxicity (although mostly minor and transient) has to be taken into account [[59], [113]]. In case of no response, at least 6–12 months should elapse before considering other therapies, as VR may be achieved during the 6 months following the end of IFN-α treatment (B1).

NA used to be second-line therapies because of the high risk of emergence of resistant mutant strains. Nevertheless, the recent FDA approval of NA with higher genotypic barrier to resistance has opened the way for the use of such drugs as first-line treatment for adolescents. In patients older than 12 years of age, tenofovir (or entecavir for patients ⩾16 years old) is the best choice, as response rate is high and resistance is less likely (A1). The recommended dose for tenofovir is 300 mg once daily, and for entecavir is 0.5 mg once daily (for nucleoside-naïve patients) (A1). Although not yet approved for the treatment of CHB in patients <12 years of age, the use of tenofovir might be safe in younger children, as it is already widely used (and FDA-licensed) for patients older than 2 years of age with HIV infection. A phase 3 clinical trial in 2–11-year-old CHB patients is currently underway [189]. Since the approval of tenofovir for adolescents, adefovir is no more recommended because of the higher risk of resistance and the lower response rate (B1) [[61], [81]].

A finite-duration treatment with tenofovir or entecavir is possible if seroconversion to anti-HBe is achieved on treatment(C2). Duration of treatments with NA has not been established, but they should be continued for at least 12 months after reaching undetectable HBV DNA levels and HBeAg seroconversion (B1) [[8], [169]]. As an important proportion of adult patients was shown not to maintain their serological and virological response, treatment up to HBsAg clearance could be a safer choice for patients with histological evidence of severe fibrosis (C2) [170]. Patients should be monitored after discontinuation because of the possibility of post-treatment flares (B1).

Patients who do not undergo HBeAg seroconversion on treatment, the rare children with HBeAg-negative chronic hepatitis and cirrhotic patients need long-term treatment with NA (B1). Tenofovir or entecavir, if allowed by the age, are the first choice (A1). Long-term efficacy and safety data in adults support such a strategy, but no data are available for adolescents as yet [[173], [174], [175], [176]]. During long-term treatment with NA, HBV DNA levels should be monitored every 3 months, as HBV DNA reduction to undetectable level is of paramount importance to avoid resistance (B1).

Although guidelines in adults do not recommend the use of lamivudine monotherapy [[6], [8]], the risk of the emergence of resistant strains has to be balanced against the fact that lamivudine is the only NA currently approved for younger children. Its use should be limited to the rare young children unresponsive to IFN-α and requiring immediate treatment and to special populations (see below) (C1). The recommended treatment dose for lamivudine is 3 mg/kg/day (maximum 100 mg/day), administered orally once daily (A1) [114]. Optimal treatment duration is more difficult to determine. Treatment should be continued until VR is achieved, and possibly for 12 months after seroconversion (B1) [[75], [169]]. As longer treatment duration leads to higher resistance rates, it is recommended to discontinue lamivudine after 6 months if a complete suppression of viral replication is not achieved or if resistant mutations emerge (B1). As post-treatment ALT flares are possible, children should be carefully monitored and a reinstitution of lamivudine treatment (in patients who have not developed resistance) or an alternative therapy (tenofovir if possible for the age) should be started in the rare cases with severe and protracted ALT elevation (A1) [115]. For children with cirrhosis, who need antiviral treatment to be continued, switch to tenofovir (if ⩾12 years of age), alone or in combination with entecavir (if ⩾16 years of age) or maintenance of lamivudine (if <12 years of age) despite an incomplete VR is recommended (C2) [[171], [172]]. Combination therapy with IFN-α and lamivudine is promising, but further data are needed in children (C2). Combination therapy with adefovir and lamivudine has been tried only in children not responding to adefovir monotherapy, and its efficacy has not been compared to monotherapy [81].

Although no data are available from pediatric studies, current guidelines in adults suggest that, for HBeAg-negative patients who have persistently elevated ALT values (at least 3 measurements in 12 months) and high HBV DNA levels, the same treatment algorithm applied to HBeAg-positive children should be considered (C1) [[6], [8]]. Nevertheless, attention should be paid to the higher relapse rate and the longer duration of treatment needed [[116], [117], [118]].