title: Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study).
abstract: Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add-on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg-IFN add-on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6-14.0; P = 0.004). Eleven (13%) of the add-on-treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add-on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg-IFN add-on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated.
  
  
  CONCLUSIONS
  Although the primary endpoint was not reached, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add-on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg-IFN add-on therapy may facilitate the discontinuation of nucleos(t)ide analogs.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
authors.forename: Willem Pieter
authors.initials: WP
authors.lastname: Brouwer
authors.forename: Qing
authors.initials: Q
authors.lastname: Xie
authors.forename: Milan J
authors.initials: MJ
authors.lastname: Sonneveld
authors.forename: Ningping
authors.initials: N
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.forename: Fehmi
authors.initials: F
authors.lastname: Tabak
authors.forename: Adrian
authors.initials: A
authors.lastname: Streinu-Cercel
authors.forename: Ji-Yao
authors.initials: JY
authors.lastname: Wang
authors.forename: Ramazan
authors.initials: R
authors.lastname: Idilman
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: Reesink
authors.forename: Mircea
authors.initials: M
authors.lastname: Diculescu
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Simon
authors.forename: Mihai
authors.initials: M
authors.lastname: Voiculescu
authors.forename: Meral
authors.initials: M
authors.lastname: Akdogan
authors.forename: Wlodzimierz
authors.initials: W
authors.lastname: Mazur
authors.forename: Jurrien G P
authors.initials: JG
authors.lastname: Reijnders
authors.forename: Elke
authors.initials: E
authors.lastname: Verhey
authors.forename: Bettina E
authors.initials: BE
authors.lastname: Hansen
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006513:Hepatitis B e Antigens / Q000097:blood*; D019694:Hepatitis B, Chronic / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D000998:Antiviral Agents; D006513:Hepatitis B e Antigens; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C413685:entecavir; D006147:Guanine; C417083:peginterferon alfa-2b