Entecavir Plus Pegylated Interferon and Sequential HBV Vaccination Increases HBsAg Seroclearance: a Randomized Controlled Proof-of-Concept Study

BACKGROUND: HBsAg seroclearance is considered a functional cure for patients with chronic hepatitis B, but is rarely achievable with oral nucleos(t)ide analogs alone. We conducted a randomized controlled proof‐of‐concept trial to evaluate the impact of adding pegylated interferon (Peg‐IFN) alfa‐2a plus sequential or concomitant hepatitis B virus (HBV) vaccination. METHODS: A total of 111 patients who achieved serum HBV DNA <20 IU/mL and quantitated HBsAg (qHBsAg) <3,000 IU/mL with entecavir were randomly assigned (1:1:1) to the E+sVIP group (entecavir + Peg‐IFN alfa‐2a [180 µg every week over 48 weeks] + sequential HBV vaccination [20 µg of HBsAg on weeks 52, 56, 60, and 76]), E+cVIP group (entecavir + Peg‐IFN alfa‐2a + concomitant HBV vaccination [weeks 4, 8, 12, and 28]), or the control group (entecavir only). The primary endpoint was HBsAg seroclearance at week 100 and secondary endpoints included safety. RESULTS: No differences in baseline qHBsAg were observed among the groups. The E+sVIP group in the intention‐to‐treat analysis showed a significantly higher chance of HBsAg seroclearance during week 100 than the control group (16.2% vs. 0%, P=0.025), but the E+cVIP group (5.4%) failed to reach a significant difference (P=0.54). Adverse events were significantly more frequent in the E+sVIP (81.1%) or E+cVIP group (70.3%) than the control group (2.7%) (both P<0.0001). However, the frequency of serious adverse events did not differ significantly among three groups (2.7%, 5.4%, and 2.7%, respectively; P=1.00). CONCLUSIONS: Entecavir plus an additional Peg‐IFN alfa‐2a treatment followed by sequential HBV vaccination under an intensified schedule significantly increases the chance of HBsAg seroclearance compared to entecavir alone.