HBeAg阳性慢性乙型肝炎患者事先长时间曝光来核苷（酸）类似

StephenW

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
Shaolong Chen,Wenhong Zhang
Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
Open Access
DOI: http://dx.doi.org/10.1016/j.jhep.2014.08.056
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To the Editor:

We 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. 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 [[2], [3]]. 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]. 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 [[5], [6]] and conversely, NUC playing a role in the restoration of adaptive antiviral responses had already been proven in an earlier study [7]. 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]. Third, the combination therapy might avoid the replenishment of nuclear cccDNA after degradation [9]. 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]. 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.
Conflict of interest

The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.
References

    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: 777–784
        View in Article
    Kittner, 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: 93–95
        View in Article
    Ouzan, D., Penaranda, G., Joly, H., Khiri, H., Pironti, A., and 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: 713–717
        View in Article
    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.
        View in Article
    Micco, 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: 225–233
        View in Article
    Peppa, 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: 99–114
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    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: e969
        View in Article
    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: 54–61
        View in Article
    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: 1221–1228
        View in Article
    Thimme, R. and 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: 205–209
        View in Article

© 2014 European Association for the Study of the Liver. Published by Elsevier Inc.

StephenW

HBeAg阳性慢性乙型肝炎患者事先长时间曝光来核苷（酸）类似物：“切换到”或“附加”PegIFN阿尔法，这是个问题
少龙陈，张文红
传染病，华山医院，上海复旦大学，中国科
开放获取
DOI：http://dx.doi.org/10.1016/j.jhep.2014.08.056
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给编辑：

我们宁等人阅读饶有兴趣的文件。 [1]关于从恩替卡韦HBeAg阳性慢性乙型肝炎（CHB）切换到PegIFN干扰素α-2a的患者的疗效。在这项前瞻性研究中，接受了恩替卡韦的9-36个月，谁乙型肝炎e抗原阳性慢性乙型肝炎患者被随机分为1：1，切换到PegIFNα-2a或继续恩替卡韦治疗48周。它表明，只有14.9％的患者达到HBeAg血清转换和8.5％的患者在PegIFN干扰素α-2a队列在48.作者周实现HBsAg消失表明，HBeAg消失和血清学转换是不太可能发生在患者的前长时间曝光来一个核苷（酸）类似物IDE（NUC）治疗初治患者相比。然而，“附加”PegIFN阿尔法到电流NUC疗法已显示导致HBsAg消失率高于一些小队列研究[[2]，[3]]。此外，完全应答（HBeAg消失和HBV DNA<2000国际单位/毫升）与HBsAg损失率分别为患者顺序组合疗法在我们最近的回顾性研究中要高得多。在顺序组合治疗组中，PegIFN干扰素α-2a加至HBeAg阳性收到NUC为至少两年谁CHB患者。它表明，在完全应答和HBsAg消失率“附加”PegIFN干扰素α-2a的队列分别为60.2％，并在72周（48周的治疗和24周随访）27.7％[4]。由于研究设计和入选标准是不同的，我们很难得出这样的结论序贯联合治疗PegIFNα（“附加”）是不是“切换到”PegIFN阿尔法患者之前长时间曝光来NUC更好。

然而，最近的一些研究已经进一步发现，PegIFN阿尔法治疗可能更多地从联合治疗NUC获益。首先，PegIFN阿尔法疗法诱导的自然杀伤（NK）细胞群的膨胀，这是不利的CD8 T细胞[5]，[6]]，相反地，NUC发挥自适应抗病毒反应的恢复作用早已经被证明在早先的研究[7]。因此，有人提出，与国统会的结合解决了PegIFN阿尔法疗法的局限性。第二，慢性HBV患者变得难治多个剂量PegIFN阿尔法的，这可以通过PegIFN阿尔法和替诺福韦[8]的组合来降低。第三，所述组合疗法可避免核cccDNA的后降解[9]的补给。虽然早期和近期的临床试验显示，同时联合治疗没有额外的好处相比，PegIFN阿尔法单药治疗，更多的证据表明，序贯联合治疗晚期“附加”PegIFN阿尔法到正在进行的NUC治疗，而不是同时联合治疗可能会更有益[10]。随着越来越多的数据发现联合治疗的一个额外的好处，我们建议“附加”可能更适合比“切换到”PegIFN阿尔法治疗的患者事先接触到NUC在临床实践中。很显然，需要大量的临床试验，以进一步明确上述假设及其机制。
利益冲突

作者宣称，他们没有什么要披露有关资金或利益冲突相对于这个手稿。
参考

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    Micco，L.，Peppa，D.，Loggi，E.，Schurich，A.，杰斐逊，L.，Cursaro，C等。差的先天免疫和适应性抗病毒反应在慢性乙型肝炎肝脏病学杂志的PEG化干扰素治疗提高。 2013; 58：225-233
        鉴于文章
    Peppa，D.，吉尔，美国，雷诺，G.，Easom，新泽西州，Pallett，LJ，Schurich，A等。上调的死亡受体呈现抗病毒的T细胞易受NK细胞介导的缺失。实验医学杂志。 2013; 210：99-114
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©2014年欧洲协会为肝脏的研究。发布时间由Elsevier公司

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