The royal wedding in chronic hepatitis B: The haves and the have‐nots for the combination of pegylated interferon and nucleos(t)ide therapy
Authors: Pietro Lampertico
Journal: Hepatology (2015)

Potential conflict of interest: Dr. Lampertico advises and is on the speakers' bureau for Roche, Bristol‐Myers Squibb, Gilead, MSD, and GlaxoSmithKline. See Article on Page 1512 Combination 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 hepatology1 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 Therapy Both 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 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 = 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 levels was significantly higher in the ETV group (98% vs 72%, P < 0.0001; 91% vs 58%, P < 0.0001, respectively), serological response rates were significantly greater in the Peg‐IFN group (HBeAg seroconversion 15% vs 6%; HBsAg loss 8% vs 0%; HBsAg <10 IU/mL 16% vs 0%; HBsAg <100 IU/mL 27% vs 4%). However, the price for these results was safety as viral rebound or virological breakthroughs (40% of the patients), one or more adverse events (64%), adverse events leading to drug discontinuation (8%), serious adverse events (6%), ALT flares (10%), and significant decreases of platelets, neutrophils, and white blood cells were observed only in Peg‐IFN–treated patients. The "late add‐on" Peg‐IFN strategy has been recently investigated by two European studies enrolling only HBeAg‐negative patients with HBV replication fully suppressed by long‐term NUC treatment. In a multicenter Italian study in genotype D patients (HERMES study), 70 HBeAg‐negative patients (100% Caucasians with genotype D) with stable quantitative HBsAg levels on NUC and HBV DNA fully suppressed for >12 months (median 3 years) by ETV or TDF monotherapy, received a 48‐week course of add‐on Peg‐IFN. At the 24‐week interim analysis, median quantitative HBsAg declined by 36% (P < 0.0001 vs baseline) and one patient (1.4%) cleared HBsAg.5 In a multicenter French study (PEGAN study), 183 HBeAg‐negative chronic hepatitis B patients (40% Caucasian, different viral genotypes) with undetectable HBV DNA for an average of 198 weeks (range 1‐1074) while on NUC were randomized to either continue NUC or add on Peg‐IFN for 48 weeks.6 At week 48, HBsAg loss rates were significantly higher in the combo than in the NUC group (8% vs 1%, P < 0.0327). Although these studies indeed show that "late add‐on" Peg‐IFN does significantly reduce HBsAg levels, with some patients even achieving HBsAg loss, in fully suppressed HBeAg‐negative patients "add‐on" combination therapy for HBV will not rely on Peg‐IFN forever. In a phase II dose ranging study, a single intravenous injection of a small interfering RNA–based therapeutic (ARC‐520) at the dose of 2 mg/kg reduced HBsAg levels by 40% for up 43 days in six Chinese HBeAg‐negative chronic hepatitis B patients fully suppressed by long‐term ETV,7 indicating that new promising alternative approaches may soon became part of the game. To Improve IFN Therapy Of HBeAg‐positive and ‐negative patients treated with a 48‐week course of Peg‐IFN treatment, 20%‐40% achieve a stable off‐therapy immune control status, defined as the combination of HBV DNA <2000 IU/mL, anti‐HBe positivity, and normal ALT levels, leading to HBsAg clearance in 20%‐30% of the responders during long‐term posttreatment follow‐up. Two recent studies designed to increase the virological response rates are worth mentioning. In the NEED study,8 naive HBeAg‐positive Taiwanese patients were randomized to receive a 48‐week course of Peg‐IFN or this treatment preceded by 4 weeks of ETV or adefovir. At week 72, i.e., 24 weeks posttreatment, the HBeAg seroconversion rates, the primary endpoint of the study, were similar among groups (36% vs 28% vs 23%, respectively), demonstrating that a 4‐week pretreatment with ETV or adefovir did not improve the outcome. Once again, someone may argue that a 4‐week NUC pretreatment is too short of a period to impact the outcome. A "de novo" Peg‐IFN and NUC combination study has been one of the protagonists of the recent American Association for the Study of Liver Diseases 2014 meeting in Boston.9 In a multicenter international study, a 48‐week course of Peg‐IFN was compared to a 48‐week course of Peg‐IFN+TDF given to naive HBeAg‐positive and ‐negative patients. The combination arm was indeed superior to the Peg‐IFN arm as the HBsAg loss rates (the primary endpoint) were three times higher in the combo than in the monotherapy group (Kaplan‐Meier estimates, 9% vs 2.8%, P = 0.003) at week 72, 24 weeks posttreatment. However, the rescue rates with TDF were similar between groups (54% vs 61%) as were the HBeAg loss rates (29% vs 25%), the HBeAg seroconversion rates (25% vs 24%), and the proportion of patients with HBV DNA <15 IU/mL (7% vs 3.2%). Surprisingly, the most important endpoint of any IFN‐based therapy, the off‐therapy immune control rate, was not reported, which makes this study very interesting from a biological point of view but not translatable into clinical practice yet. All of these studies have been designed to provide clear‐cut, final answers. Actually, they just pose new questions, in part because of methodological issues such as suboptimal study designs, small sample size, and questionable endpoints. For studies aimed to improve the off‐therapy sustained immune control provided by IFN‐based strategies, neither of the two quoted studies really provided additional benefits over Peg‐IFN monotherapy, although for the second study9 only preliminary results are available. By contrast, for those studies aimed at improving response to potent and high genetic barrier drugs, i.e., ETV and TDF, the whole issue is really about stopping rules rather than improving efficacy. How much more are the payers and we ready to spend just to reduce duration of NUC therapy from several years to a few years? How many side effects are patients willing to face to achieve a faster HBsAg decline? How many of these new strategies designed just to reduce duration of NUC therapy for countries where duration of therapy is the problem today because of reimbursement rules, cost, and compliance issues or just the HBV burden will be easily available and transferable to those countries? Also, there is the fact that ETV and TDF will soon became generic and thereby even more easily available worldwide at a minimal cost. In conclusion, while any new strategy to shorten duration of NUC therapy is more than welcome from both a biological and a clinical point of view, it is important not to forget that long‐term suppression of viral replication by ETV and TDF is incredibly successful at improving patients' survival, without the need to achieve low HBsAg levels or HBsAg loss. This is a crucial point: a low HBsAg level or HBsAg loss is not a required endpoint to prevent complications and extend patient survival. "Functional" cure of HBV, defined as HBsAg loss or off‐therapy immune control, is indeed a noble and fascinating endpoint that we never even dreamed about just a few years ago; but it might not be so easy to achieve given the biology of the HBV life cycle. And the price to be paid in terms of added value, side effects, cost, and monitoring might be just too high for some patients and/or some countries where the main unsolved urgent problem is still to keep viral replication under control, rather than to develop new stopping rules for NUC‐treated patients. The "royal" wedding must be postponed once more. After so many years of loyal and faithful engagement, the two betrothed are thinking about other partners. To remain single might be a good option too.