C ombination therapy of oral nucleos(t)ide analogues (NUC) and pegylated interferon-alpha 2a (Peg-IFN) is not currently recommended by international guidelines because of unproven superior efficacy. However, this position might be subverted by recent studies, one of which has been published in this issue of HEPATOLOGY 1 including for the first time potent and high genetic barrier NUC, entecavir (ETV), and tenofovir (TDF). There are different ways to combine IFN and NUC, "de novo" meaning simultaneous administration of the two drugs in naive patients versus "add-on" or "switch to" strategies in patients already on therapy. There are also different reasons to combine immunomodulators and antivirals, either to improve response to NUC or to improve response to IFN.
To Improve NUC TherapyBoth ETV and TDF halt viral replication in >95% of naive patients over 5-8 years of treatment, preventing progression to cirrhosis, portal hypertension, and clinical decompensation and reducing, in selected patients, the attack rates of hepatocellular carcinoma. Since the only disadvantage of this strategy is the low rate of hepatitis B surface antigen (HBsAg) clearance, the best and safest current stopping rule, 2,3 recent studies have addressed if the combination with Peg-IFN may reduce the duration of NUC therapy. The study by Brouwer et al., published in this issue of HEPATOLOGY, 1 explores the "early add-on" Peg-IFN strategy by comparing a 48-week course of ETV versus 24 weeks of ETV followed by 24 weeks of "add-on" Peg-IFN for naive hepatitis B e antigen (HBeAg)-positive patients. At week 48, the two treatment groups showed similar HBeAg seroconversion (9% vs 17%), HBsAg <1000 IU/mL (18% vs 28%), and hepatitis B virus (HBV) DNA <20 IU/mL rates (50% vs 61%), while alanine aminotransferase (ALT) normalization rates were higher in the ETV monotherapy group (78% vs 49%, P < 0.001). However, when the kinetics of HBV DNA, HBsAg, and HBeAg levels between weeks 24 and 48 were compared, add-on Peg-IFN significantly improved virological and serological declines. At week 72, with all patients on ETV monotherapy in both groups, HBeAg seroconversion rates were indeed lower in patients always treated with ETV versus those who received a 24-month course of Peg-IFN add-on (11% vs 26%, P 5 0.012), but the rates of HBsAg <1000 IU/mL, HBV DNA <20 IU/mL, and normal ALT levels were similar (18% vs 25%, 57% vs 57%, 83% vs 86%, respectively). Someone may argue that a 24-week add-on period was too short to provide strong evidence in favor of this strategy, which remains for the time being difficult to export into clinical practice.Other studies have been designed to improve either on-or off-therapy response for patients already treated for years with NUC. The "early switch to" approach has been explored in 192 Chinese HBeAg-positive patients (OSST trial) who, after 20 months of ETV, were randomized to either continue ETV or "switch to" Peg-IFN for 48 weeks.4 By week 48, while the proportion of patients with HBV DNA <1000 copies/ mL and with normal ALT...