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 question
Authors: Shaolong Chen, Wenhong Zhang
Journal: Journal of Hepatology (2014)

Switching 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 An integration of deep viral suppression with sequential immune modulation (cocktail therapy) to restore antiviral capacity: The future of chronic hepatitis B?Journal of HepatologyVol. 62Issue 1PreviewWe 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. Full-Text PDF Open Access We read with great interest the paper by Ning et al. [[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 (197) Google Scholar] 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. The authors indicated that HBeAg loss and seroconversion were less likely to occur in patients with prior long-time exposure to a nucleos(t)ide analogue (NUC) compared with treatment-naïve patients. However, “add-on” PegIFN alfa to a current NUC therapy has been shown to lead to a high rate of HBsAg loss in some small cohort studies [2Kittner 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 (46) Google Scholar, 3Ouzan 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 (45) Google Scholar]. Moreover, the complete response (HBeAg loss and HBV DNA <2000 IU/ml) and HBsAg loss rates were much higher in patients with sequential combination therapy in our recent retrospective study. In the sequential combination therapy cohort, PegIFN alfa-2a was added to HBeAg-positive CHB patients who had received NUC for at least two years. It showed that complete response and HBsAg loss rates in the “add-on” PegIFN alfa-2a cohort were 60.2% and 27.7% at week 72 (48 week treatment and 24 week follow-up), respectively [[4]Li G, Yu Y, Chen S, Fan, P, Zhang W. Sequential combination therapy with NUCs and Peg-IFN In HBeAG positive CHB patients with prior long-term exposure to NUCs. EASL 2014, O117.Google Scholar]. Since the study design and inclusion criteria are different, we can hardly draw the conclusion that sequential combination therapy with PegIFN alfa (“add-on”) is better than “switch-to” PegIFN alfa in patients with prior long-time exposure to NUC. Nevertheless, some recent studies have further found that PegIFN alfa therapy may benefit more from the combination therapy with NUC. First, PegIFN alfa therapy induced the expansion of natural killer (NK) cell populations, which was detrimental to CD8 T cells [5Micco L. Peppa D. Loggi E. Schurich A. Jefferson L. Cursaro C. et al.Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B.J Hepatol. 2013; 58: 225-233Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar, 6Peppa D. Gill U.S. Reynolds G. Easom N.J. Pallett L.J. Schurich A. et al.Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell-mediated deletion.J Exp Med. 2013; 210: 99-114Crossref PubMed Scopus (264) Google Scholar] and conversely, NUC playing a role in the restoration of adaptive antiviral responses had already been proven in an earlier study [[7]Boni 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 (292) Google Scholar]. Thus, it was suggested that the combination with NUC addresses the limitation of the PegIFN alfa therapy. Second, chronic HBV patients became refractory to multiple doses of PegIFN alfa, which could be reduced by the combination of PegIFN alfa and tenofovir [[8]Tan 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 (73) Google Scholar]. Third, the combination therapy might avoid the replenishment of nuclear cccDNA after degradation [[9]Lucifora J. Xia Y. Reisinger F. Zhang K. Stadler D. Cheng X. et al.Specific and nonhepatotoxic degradation of nuclear hepatitis B virus cccDNA.Science. 2014; 343: 1221-1228Crossref PubMed Scopus (715) Google Scholar]. Although early and recent clinical trials showed no extra benefit of simultaneous combination therapy compared to PegIFN alfa monotherapy, more evidence had shown that sequential combination therapy with late “add-on” PegIFN alfa to an ongoing NUC treatment instead of simultaneous combination therapy might be more beneficial [[10]Thimme R. Dandri M. Dissecting the divergent effects of interferon-alpha on immune cells: time to rethink combination therapy in chronic hepatitis B?.J Hepatol. 2013; 58: 205-209Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar]. With increasing data finding an extra benefit of combination therapy, we suggest that “add-on” may be more suitable than “switch-to” PegIFN alfa therapy for patients with prior exposure to NUC in clinical practice. Obviously, large clinical trials are needed to further clarify the above hypothesis and its underlying mechanism. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.