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Background: There are few data on the efficacy and safety of pegylated interferon treatment in adolescents with chronic hepatitis B. Aim: We conducted a pilot study in 13 adolescents with chronic hepatitis B treated with peginterferon alfa-2a at 100 µg/m2 once weekly for 48 weeks. Methods: HBV DNA was assessed by qPCR method. Results: After four weeks of treatment six adolescents had undetectable HBV DNA (<12 IU/mL). Seven adolescents - including five HBV negatives at week 4 - had undetectable HBV DNA (<55 IU/mL) at week 24, and seven adolescents - including all HBV DNA negatives at week 4 - had undetectable HBV DNA at week 48 of treatment (<55 IU/mL). Five adolescents had undetectable HBV DNA (<55 IU/mL) after 24 weeks of follow-up (sustained viral response). HBeAg seroconversion was achieved in one patient. HBsAg loss was documented at the end of therapy in two of the six adolescents HBV DNA negative at week 4 of treatment. Three adolescents withdrew from the treatment (two because of adverse events, one because of withdrawal of parental consent). Leukopenia was reported in seven adolescents and three individuals experienced thrombocytopenia. Except for one patient who discontinued treatment due to leukopenia, no dose modifications for adverse events or laboratory abnormalities were required. Conclusion: This pilot study shows that 48 weeks of treatment with peginterferon alfa-2a can result in sustained HBV DNA suppression, HBeAg seroconversion and HBsAg loss in adolescents with CHB. Larger and longer trials are now required to better define the magnitude of the benefit in this group of patients.