EASL Clinical Practice Guidelines

Treatment failure and antiviral resistance

Partial response to NA or primary non-response is often due to the emergence of genotypic resistant strains or to patient non-adherence to treatment. In non-responders, HBV genotypic analysis is warranted in order to differentiate between resistance and patient non-compliance (C1). Non-compliance may be a major issue in adolescents, especially if long-term treatment is required to maintain response.

In responders, virologic breakthrough (which may be followed by biochemical breakthrough) is usually secondary to genotypic resistance. Likelihood of virologic breakthrough depends on the intrinsic barrier to resistance of the specific NA (lamivudine >telbivudine >adefovir >entecavir >tenofovir). All children receiving NA should be monitored for virologic breakthrough by measuring HBV DNA levels every 3 months (C1). Ideally, identification of virologic breakthrough and consequent adaptation of treatment should be performed as early as possible, before ALT levels rise [[6], [69]]. Because of the low number of effective drugs approved, when resistance to an NA develops in children, the decision on therapy adjustment is based on liver biopsy and the patient's age. If mild hepatitis is present, he/she should be switched to either entecavir (for adefovir-resistant, ⩾16 years old and lamivudine-naïve patients) or tenofovir (for ⩾12 years old, lamivudine-resistant patients or adefovir-resistant patients previously treated with lamivudine) (C2). For younger children, for whom no other NA other than lamivudine is approved at the moment, switching to IFN-α (PegIFN when approved) can be a possibility (C2). Treatment with lamivudine should be stopped and the child should be followed up in the eventuality of post-treatment flares (C2). In case of moderate hepatitis/fibrosis, the patient should be switched to tenofovir if ⩾12 years old, or, if younger, to IFN-α (C2). If severe hepatitis is found at liver biopsy, switching to tenofovir is the only available choice (as monotherapy or associated to entecavir if the child is ⩾16 years old and has high viral load) (C2) [[171], [172]]. Both tenofovir and entecavir are effective in lamivudine-resistant patients [69], but an increased resistance rate has been observed for entecavir (8% after 2-year treatment) and higher dose (1 mg daily) is required (B1) [[84], [119]]. Lamivudine should therefore be discontinued when switching to entecavir to decrease the risk of emergence of resistant mutants (C2)[6]. Tenofovir can be used in lamivudine-resistant mutant strains, as their activity is not hampered by such mutations (B1)[[69], [81]].

In patients with partial virological response at week 24 (for those receiving lamivudine) or 48 (for those receiving adefovir), switch to tenofovir or entecavir (if allowed by the age) is recommended (B1). The strategy for children younger than 12 years of age is difficult to define. Patients could be switched to IFN-α (or PegIFN) if not tried yet (C1), or lamivudine could be either continued up to the 12th birthday (the only choice in those with severe fibrosis or cirrhosis) or stopped (with proper post-treatment follow-up) (C2).

As the emergence of resistant mutant strains is becoming a major public health problem, pediatric practitioners should not treat children who are not likely to benefit from a licensed therapy and consider waiting for market approval of more effective drugs (C1).