The royal wedding in chronic hepatitis B: The haves and the have‐nots for the combination of pegylated interferon and nucleos(t)ide therapy

Abstract

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...

Expression of Interferon Effector Gene SART1 Correlates with Interferon Treatment Response against Hepatitis B Infection

“…These patients are prone to life threatening complications such as HBV acute-on-chronic liver failure (ACLF) [3], cirrhosis, and hepatocellular carcinoma (HCC) [4]. There are currently two classes of agents approved for the treatment of chronic hepatitis B (CHB): nucleos(t)ide analogues and standard or pegylated interferon- α (Peg-IFN- α ) [5].…”

“…There are currently two classes of agents approved for the treatment of chronic hepatitis B (CHB): nucleos(t)ide analogues and standard or pegylated interferon- α (Peg-IFN- α ) [5]. IFN- α is an important cytokine of the innate immune and adapt immune response embracing both immunomodulatory and antiviral activity [4–6]. IFN- α binds to its receptor, activates the JAK-STAT signaling pathway, and transcriptionally induces interferon-stimulated genes (ISGs) including “classical ISGs” myxious resistance protein (MxA) [7], 2,5-oligoadencylate sythase (OAS), and RNA-dependent protein kinase (PKR) [8, 9], which have been found to mount antiviral effect against HBV and other viruses [10].…”

Phase IIb trial ofin vivoelectroporation mediated dual-plasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy

“…Indeed, treatment guidelines suggest that therapy may be discontinued after 2-3 years of consolidation therapy in HBeAg-positive non-cirrhotic CHB patients that achieve HBeAg seroconversion during an antiviral therapy[25]. It was reported by recent studies that patients with NUC therapy either switching to or adding peg-IFN achieve higher rates of sustained response than those continuing NUC monotherapy[21,26,27]. Combination therapy of antivirals and immunomodulators, either to improve response to NUCs, IFN, or newly developed therapeutic vaccines, is considered crucial for investigators to achieve “functional” cure of HBV, defined as HBsAg loss or off-therapy immune control[27].…”

“…It was reported by recent studies that patients with NUC therapy either switching to or adding peg-IFN achieve higher rates of sustained response than those continuing NUC monotherapy[21,26,27]. Combination therapy of antivirals and immunomodulators, either to improve response to NUCs, IFN, or newly developed therapeutic vaccines, is considered crucial for investigators to achieve “functional” cure of HBV, defined as HBsAg loss or off-therapy immune control[27]. The present study suggests that for patients receiving long-term therapy, it might be possible to enhance the chances of HBeAg seroconversion by adding a finite course of immunomodulatory therapy, especially an HBV-specific one.…”

Hepatitis B: Working Towards a Cure

“…Although combination NA and PEG-IFN therapy is currently not recommended due to unproven superior efficacy in earlier trials, recent published studies as well as those presented at 2014 AASLD shed light on novel ways to combine these drugs using either an Badd-on^or Bswitch to^approach [29].…”