Safety of add on Interferon-alpha-2a in hepatitis B patients receiving effective nucleos(t)de therapy: Interim results from the German multicenter PADD-ON trial

Background: Treatment of chronic hepatitis B (cHB) with nucleos(t)ide analogues or Interferon-alpha (IFN) monotherapy regularely fails persistent immune control and HBsAg elimination. Hence, we initiated a prospective multicenter trial (PADD-ON) to investigate the addition of IFN to an ongoing nucleos(t)ide treatment. Here we report the study protocol and interim safety data obtained during ongoing study recruitment. Methods: HBeAg negative cHB patients (HBsAg > 100 IU/ml) showing stable HBV suppression (HBV-DNA < 20 IU/ml) for > 1 year under nucleos(t)ide analogue administration are randomized (2:1) to receive additional open-label pegylated-IFN-alpha-2a (180 µg, Pegasys®, Roche) once weekly or no additional treatment. Adverse events are reported via electronic case report forms and classified according to MedDRA. Results: During a median follow up of 17 (range 3 – 48) weeks of study treatment 121 adverse events were observed in patients receiving IFN add-on. Fatigue (n = 12, 9.9%), Pyrexia (n = 7, 5.5%), headache (n = 7, 5.8%), myalgia (n = 6, 5.0%), arthralgia (n = 5, 4.1%) and injection site erythema (5, 4.1%) were the most commonly reported events. Leucopenia (n = 1, 3.4%), thrombocytopenia (n = 1, 3.4%) and elevated transaminases (n = 1, 3.4%) were rarely identified. Intriguingly, anemia did not occur during IFN add on treatment so far. Patients in the treatment group were affected in 69% by general symptoms and musculoskeletal symptoms were reported in 37.9%. Serious adverse events (foot contusion and thoracic pain) were observed, respectively, but were not directly related to IFN therapy. Patients receiving nucleos(t)ide treatment did not show any treatment related side effects. Discussion: IFN add on therapy is relatively well tolerated in cHB patients receiving efficient nucleos(t)ide therapy. The toxicity profile hereby clearly differs from patients receiving IFN/ribavirin treatment for hepatitis C, as it did not induce relevant hematologic toxicity, requiring dose adjustments.