An integration of deep viral suppression with sequential immune modulation (cocktail therapy) to restore antiviral capacity: The future of chronic hepatitis B?
Authors: Di Wu, Meifang Han, Qin Ning
Journal: Journal of Hepatology (2014)

A response-guided approach based on HBsAg kinetics may identify patients with the greatest chance of successJournal of HepatologyVol. 62Issue 1PreviewWe read with interest the paper by Ning et al. entitled "Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomised open-label trial (OSST trial)" in the latest issue of the Journal of Hepatology [1]. The authors conducted a randomized open study (randomization: 1:1; peginterferon alfa-2a 180 μg/week or entecavir [ETV] 0.5 mg/day for 48 weeks) in HBe antigen (HBeAg)-positive CHB patients who had received ETV for 9–36 months, with HBeAg <100 PEIU/ml and HBV DNA ⩽1000 copies/ml. Full-Text PDF Open AccessSwitching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomised open-label trial (OSST trial)Journal of HepatologyVol. 61Issue 4PreviewDurable post-treatment response is uncommon in chronic hepatitis B (CHB) patients on nucleos(t)ide analogue therapy. Response, response predictors and safety were assessed in patients who switched from long-term entecavir (ETV) to peginterferon alfa-2a. Full-Text PDF HBeAg-positive chronic hepatitis B patients with prior long-time exposure to nucleos(t)ide analogues: "Switch-to" or "add-on" PegIFN alfa, that is the questionJournal of HepatologyVol. 62Issue 1PreviewWe read with great interest the paper by Ning et al. [1] about the efficacy of switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B (CHB). In this prospective study, hepatitis B e antigen-positive CHB patients who had received entecavir for 9–36 months were randomized 1:1 to switch to PegIFN alfa-2a or to continue with entecavir for 48 weeks. It showed that only 14.9% patients achieved HBeAg seroconversion and 8.5% patients achieved HBsAg loss in the PegIFN alfa-2a cohort at week 48. Full-Text PDF Open Access We are pleased about the interest of Zhang and Chen as well as Halfon et al. and many others in our recent publication entitled "Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: A randomized open-label trial (OSST trial)" in the Journal of Hepatology. An important question now has arisen: What is the optimal way to combine nucleos(t)ide analogue (NA), IFN, and perhaps potential regimens other than the two above for the better treatment of chronic hepatitis B (CHB)? CHB patients who do not experience HBeAg seroconversion after more than one year of treatment with a potent NA may be considered "difficult to treat", despite having achieved HBV DNA suppression because of the failure to seroconvert and the high likelihood that they will require lifelong therapy. The OSST trial enrolled subgroups of these patients and achieved a significantly higher rate of HBeAg seroconversion and, what is more interesting, an increased rate of HBsAg loss of up to 8.5% after an alteration of treatment strategy [[1]Ning Q. Han M. Sun Y. Jiang J. Tan D. Hou J. et al.Switching from entecavir to PegIFN alfa-2a in patients with HBeAg-positive chronic hepatitis B: a randomised open-label trial (OSST trial).J Hepatol. 2014; 61: 777-784Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar]. We believe that this study has a practical implication as Halfon et al. has highlighted. Data from the one year follow-up showed that response rates of HBeAg seroconversion increased from 17.7% (11/62) at the end of treatment to 38.7% (24/62) at the end of follow-up and HBsAg loss was durable [[2]Han M, Jiang J, Hou J, Tan D, Sun Y, Zhao M., et al. Sustained immune control In HBeAg-positive chronic hepatitis B patients who switched from long-term entecavir therapy to peginterferon Alfa-2a (40KD): 1-year follow-up of the OSST Study. AASLD 2013; Poster 954.Google Scholar]. It is important for the design of future clinical trials to understand the mechanism, regarding how the "switch-to" or "add-on" PegIFN therapy received the extra benefit, compared to the continuous ETV monotherapy. In the OSST study we found an early significant restoration of the impaired innate and adaptive immune response, including Tregs, NKG2C+ NK cells and TLR2+ monocytes in PegIFN alfa-2a responders, which was associated with a higher probability of seroconversion and HBsAg loss (manuscript under review). Several studies have investigated the possibility that high levels of HBV replication can not only actively suppress the innate immune response, especially type I IFN induction through the action of different viral proteins, but also extend to blocking its antiviral activity [3Bertoletti A. Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection.Gut. 2012; 61: 1764Crossref Scopus (365) Google Scholar, 4Tan A.T. Hoang L.T. Chin D. Rasmussen E. Lopatin U. Hart S. et al.Reduction of HBV replication prolongs the early immunological response to IFNalpha therapy.J Hepatol. 2014; 60: 54-61Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 5Boni C. Laccabue D. Lampertico P. Giuberti T. Vigano M. Schivazappa S. et al.Restored function of HBV-specific T cells after long-term effective therapy with nucleos(t)ide analogues.Gastroenterology. 2012; 143: e969Abstract Full Text Full Text PDF Scopus (279) Google Scholar]. Taken together, these findings provide a possible explanation for the results of the OSST trial, which showed significant restoration in both innate and adaptive immune responses, using "switch-to" PegIFNalfa therapy for patients with prior long-term exposure to ETV. Earlier studies, which evaluated PegIFN alfa-2a in combination with LAM did not demonstrate significantly improved rates of post-treatment response in CHB patients [[6]Marcellin P. Lau G.K. Bonino F. Farci P. Hadziyannis S. Jin R. et al.Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.N Engl J Med. 2004; 351: 1206-1217Crossref PubMed Scopus (1067) Google Scholar]. In those studies, PegIFN alfa-2a and a less potent NA were started simultaneously. Recently, another concept of combination therapy, late add-on PegIFN alfa-2a strategy, was demonstrated to have improved response [7Ouzan D. Penaranda G. Joly H. Khiri H. Pironti A. Halfon P. Add-on peg-interferon leads to loss of HBsAg in patients with HBeAg-negative chronic hepatitis and HBV DNA fully suppressed by long-term nucleotide analogs.J Clin Virol. 2013; 58: 713-717Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 8Kittner J.M. Sprinzl M.F. Grambihler A. Weinmann A. Schattenberg J.M. Galle P.R. et al.Adding pegylated interferon to a current nucleos(t)ide therapy leads to HBsAg seroconversion in a subgroup of patients with chronic hepatitis B.J Clin Virol. 2012; 54: 93-95Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar]. It seems that" add-on" combination therapy of PegIFN alfa-2a to an ongoing NA therapy may lead to a high rate of response. However, due to small cohort numbers, lack of a control group, different study design and inclusion criteria, we cannot speculate whether an "add-on" approach is superior to a "switch-to" PegIFN alfa-2a therapy at this stage, for patients with prior long-time exposure to NA. This point was highlighted by Zhang and Chen. Nevertheless, these studies introduced a new approach to combination therapy, which requires larger comparative, prospective trials with comprehensive analyses of the immune system to further investigate and understand its efficacy and safety. Current data supports that monitoring of HBsAg levels may help to predict therapeutic outcome, guide treatment options and determine stopping rules [[9]HönerZuSiederdissen C. Cornberg M. The role of HBsAg levels in the current management of chronic HBV infection.Ann Gastroenterol. 2014; 27: 105-112Google Scholar]. Our OSST trial also found that the combination of HBeAg loss and HBsAg <1500 IU/ml at the time of switching was associated with high rates of HBeAg seroconversion (37.5%) and HBsAg loss (25.0%) following PegIFN alfa-2a therapy. Patients with HBsAg <200 IU/ml at week 12 had the highest likelihood of responding to PegIFN alfa-2a. These data are consistent with previous reports, demonstrating that HBsAg quantification early during treatment is a useful predictor of response in CHB patients [[10]Piratvisuth T. Marcellin P. Popescu M. Kapprell H.P. Rothe V. Lu Z.M. Hepatitis B surface antigen: association with sustained response to peginterferon alfa-2a in hepatitis B e antigen-positive patients.Hepatol Int. 2013; 7: 429-436Crossref PubMed Scopus (79) Google Scholar]. Exploratory analyses into predictors of response were conducted using a small number of patients, and therefore, the results should be interpreted with caution, will require validation by large prospective trials before incorporation into daily clinical practice. This approach will define baseline cut-off values to permit individualizing treatment. We are pleased to learn that this hypothesis was confirmed by Halfon et al. in their clinical practice. In summary, the combination therapy of PegIFN alfa-2a and NA can be beneficial, but the optimal strategies for combination remains to be determined. With newly developed therapeutic regimens appearing in the near future, including cytokines, HBV entry blockers, Toll-like receptor agonists, and therapeutic vaccines, it is conceivable that use of these additional immunomodulators rather than IFN, might be of synergic benefit in the restoration of innate and adaptive immune responses in CHB patients (Fig. 1). Currently two randomized, multicentre, comparative and prospective clinical trials (Endeavor and Anchor study), involving combination therapies of IFN, NA and immunomodulators (cocktail therapy) for NA-treated CHB patients, are under way in China to explore this hypothesis. This work was supported by the National Natural Science Foundation (No. 81030007), and the National Twelfth Five-Year Plan (No. 2013ZX10002-003, 2012ZX10002003). The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We thank Prof. Stephen Locarnini for his intellectual discussion and comments.