肝胆相照论坛

标题: 深病毒抑制序贯免疫调节（鸡尾酒疗法）的整合，恢复抗病 [打印本页]

作者: StephenW 时间: 2014-11-18 17:13 标题: 深病毒抑制序贯免疫调节（鸡尾酒疗法）的整合，恢复抗病

本帖最后由 StephenW 于 2014-11-18 17:19 编辑

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

Department and Institute of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

Published Online: October 09, 2014
DOI: http://dx.doi.org/10.1016/j.jhep.2014.10.002
Publication stage: In Press Corrected Proof

To the Editor:

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 [[url=]1[/url]]. 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 [[url=]2[/url]].

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 [[url=][3][/url], [url=][4][/url], [url=][5][/url]]. 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 [[url=]6[/url]]. 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 [[url=][7][/url], [url=][8][/url]]. 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 [[url=]9[/url]]. 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 [[url=]10[/url]]. 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.

Fig. 1Underlying mechanism of current treatment options and newly developed therapeutic regimens in the treatment of CHB. Current treatment options involve the use of NAs, which efficiently inhibit the HBV DNA polymerase and thus block the viral replication pathway, and IFN which has been shown to have both direct antiviral and immunomodulatory effects. Besides, IL-2 and GM-CSF have been explored in the treatment of CHB as they can enhance the function of APC and T cells. Some newly developed therapeutic regimens will appear in the near future, including HBV entry blockers, Toll-like receptor agonists, PD1/PD1-L pathway blockages and therapeutic vaccines, it is conceivable that use of these additional immunomodulators rather than IFN, might be of synergic benefit in the restoration of the innate and adaptive immune responses in CHB patients.

作者: StephenW 时间: 2014-11-18 17:14

深病毒抑制序贯免疫调节（鸡尾酒疗法）的整合，恢复抗病能力：慢性乙型肝炎的未来？
狄乌
，
梅芳汉
，
秦Ningemail
部和传染病华中科技大学研究院，同济医学院附属同济医院，武汉，中国
发布时间：2014年10月9日
DOI：http://dx.doi.org/10.1016/j.jhep.2014.10.002
出版阶段：按更正证明

抽象
全文
图片
参考文献

文章概要

财政支持
利益冲突

要编后语：

我们很高兴张某和陈某的利益，也有Halfon等。和其他许多人在我们最近发表的题为“恩替卡韦治疗HBeAg阳性慢性乙型肝炎切换到PegIFN干扰素α-2a的患者：一项随机开放标签试验（OSST试行）”，在肝病学杂志。

一个重要的问题，现在已经出现了：什么是要结合核苷（酸）类似物IDE（NA），干扰素，也许潜在的方案比两个以上的更好的治疗慢性乙型肝炎（CHB）等的最佳方法是什么？

慢性乙型肝炎患者谁后一年以上具有强效的NA处理不经历血清转换可以被认为是“难以治疗的”，尽管已达到，因为未能血清转化和高似然性，他们将需要终生治疗的HBV DNA的抑制。该OSST试验入选的患者亚组，取得了显著较高的HBeAg血清学转换，并且什么是更有趣，乙肝表面抗原亏损高达8.5％的治疗策略[1]的变更后增加的速度。我们认为，这项研究具有实际意义的Halfon等。突显。从单年的随访数据显示，HBeAg血清转换的应答率17.7％（62分之11）增加了在治疗结束38.7％（六十二分之二十四）在随访结束，HBsAg消失了耐用[2]。

它为将来的临床试验设计，以了解该机制是很重要的，关于如何将“切换到”或“附加”PegIFN疗法收到了额外的好处，相比于连续ETV单药治疗。在OSST研究中，我们发现了一个早期显著修复受损的先天和适应性免疫应答，包括调节性T细胞，NKG2C+ NK细胞和TLR2+单核细胞在PegIFNα-2a中反应，将其用的血清转化和HBsAg消失（手稿下一个更高的概率相关联的评审）。几项研究已经调查了可能性，高水平乙型肝炎病毒复制，不仅可以有效抑制先天性免疫应答，特别是通过不同的病毒蛋白的作用，I型干扰素诱导，而且还延伸到阻断其抗病毒活性[[3]，[4 ]，[5]。两者合计，这些结果提供了一个可能的解释为OSST试验，这表明显著恢复的先天和适应性免疫反应的结果，以“切换到”PegIFNalfa治疗患者之前长期暴露于ETV。

早期的研究中，其评价PegIFNα-2a中结合林没有表现出慢性乙型肝炎患者[6]中的后处理反应的显著改善率。在这些研究中，PegIFNα-2a和较低效力的NA被同时开始。最近，组合治疗的另一个概念，后期附加PegIFNα-2a中的策略，被证明具有改善的响应[[7]，[8]。看来PegIFNα-2a的“附加”组合疗法对正在进行的NA治疗可能导致反应率较高。然而，由于小样本数，缺乏对照组，不同的研究设计和入选标准，我们不能猜测是否是“附加”的方式要优于一个“切换到”PegIFN干扰素α-2a治疗在这个阶段，患者之前长时间曝光到的NA。这一点强调了张某和陈某。然而，这些研究引入了一个新的方法来联合治疗，这需要比较大的，前瞻性与免疫系统的综合分析试验，以进一步研究和了解它的疗效和安全性。

当前的数据支持该监测HBsAg水平可以有助于预测治疗结果，指导治疗方案，并确定停止规则[9]。我们OSST试验还发现，HBeAg消失与HBsAg<1500 IU/毫升，在切换时的组合与HBeAg血清学转换（37.5％）和HBsAg消失（25.0％）之后PegIFN干扰素α-2a治疗率高有关。患者的HBsAg<200 IU / ml的在第12周有响应PegIFNα-2a的最高可能性。这些数据与以前的报道一致，这表明HBsAg的量化处理过程中的早期是响应慢性乙型肝炎患者[10]中的一个有用的指标。探索性分析到响应的预测利用少数患者进行的，因此，其结果应谨慎解释，将需要通过验证大型前瞻性研究纳入日常临床实践之前。这种方法将定义基线的临界值以允许个体化治疗。我们很高兴地得知，这一假说是由Halfon等人的证实。在临床实践中。

总之，PegIFNα-2a和NA的组合治疗可以是有益的，但对于组合中的最优策略仍有待确定。与出现在不久的将来新开发的治疗方案，包括细胞因子，乙肝条目阻滞剂，Toll样受体激动剂和治疗性疫苗，可以想象的是，使用这些额外的免疫调节剂，而不是干扰素，可能的协同效益中的恢复慢性乙型肝炎患者固有免疫和适应性免疫应答（图1）。目前两项随机，多中心，对照和前瞻性临床试验（努力和锚的研究），包括干扰素，NA和免疫调节剂（鸡尾酒疗法）的NA治疗的慢性乙肝患者的联合治疗，是根据中国的方式来探讨这个假设。
图的缩略图。 1.打开大图
图。 1

当前的治疗选择潜在的机制和新开发的治疗方案在慢性乙型肝炎的治疗。当前的治疗方案包括使用的NA，从而有效地抑制HBV DNA聚合酶，从而阻止病毒复制的通路，和IFN已显示出具有直接的抗病毒和免疫调节作用。此外，IL-2和GM-CSF已探索在慢性乙型肝炎的治疗，因为它们可增强APC和T细胞的功能。一些新开发的治疗方案将出现，在不久的将来，包括乙型肝炎病毒条目阻滞剂，Toll样受体激动剂，PD1 / PD 1-L路径堵塞和治疗性疫苗，可以想象的是，使用这些额外的免疫调节剂，而不是干扰素，可能是协同效益在慢性乙型肝炎患者的固有免疫和适应性免疫应答的修复。

作者: 齐欢畅2 时间: 2014-11-18 19:09

极好的。哈哈

作者: xiazhifeng0009 时间: 2014-11-19 16:52

什么极好的。

作者: StephenW 时间: 2014-11-19 17:09

回复 xiazhifeng0009 的帖子

目前两项随机，多中心，对照和前瞻性临床试验（Endeavor和Anchor），包括干扰素，NA和免疫调节剂（鸡尾酒疗法）的联合治疗，正在中国进行中

作者: 使命123 时间: 2014-11-21 10:17

免疫调节剂和抗病毒药连用不用干扰素？

作者: StephenW 时间: 2014-11-21 11:46

回复使命123 的帖子

我找不到Anchor临床试验信息. 根据Endeavor(chictr-trc-13003249)临床试验，是IL2(Interleukin 2)+治疗性疫苗 v 干扰素.
我的希望是口服TR7 angonist（GS9620）可以取代干扰素, 或短期干扰素.

作者: hao2014 时间: 2014-11-21 18:19

9620现在效果未知数
2015年底才能出部分数据

要是也来个2a2b，那就有得等了

作者: MP4 时间: 2014-11-21 18:56

http://www.chictr.org/cn/proj/show.aspx?proj=4864
http://www.chictr.org/cn/proj/show.aspx?proj=4480

作者: MP4 时间: 2014-11-21 18:57

普通干扰素-α2b+阿德福韦脂+粒-巨细胞集落刺激因子+乙肝疫苗

干扰素α-2b（ 600万IU，隔日一次，皮下注射）治疗48周，联用恩替卡韦（ 0.5mg，一天一次，口服）自开始到第8周结束，同时接受IL-2（25万IU，隔日一次，皮下注射）治疗自开始至12周结束，并联用乙肝疫苗（60ug，一月一次，肌肉注射）治疗自开始至48周结束

作者: StephenW 时间: 2014-11-21 20:04

Also this:
http://clinicaltrials.gov/show/NCT01878565

The Treatment With HBIG+GM-CSF+HBV Vaccine for Chronic Hepatitis B Patients With HBeAg Seroconversion
This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2013 by Beijing 302 Hospital
Sponsor:
Beijing 302 Hospital
Information provided by (Responsible Party):
Fu-Sheng Wang, Beijing 302 Hospital
ClinicalTrials.gov Identifier:
NCT01878565
First received: June 12, 2013
Last updated: July 23, 2013
Last verified: July 2013

Purpose

The host immunity has been generally recognized as the main factors to determine the outcome of chronic hepatitis B virus (HBV) infection; however, previous studies have shown that HBV-specific T cell and B cell function are exhausted in chronic hepatitis B (CHB) patients. Recently, It is suggested that hepatitis B surface antigen (HBsAg) may play a key role in the immune tolerance or immune exhaustion. Anti-HBV immune responses are partially recovered when patients achieved hepatitis B e antigen (HBeAg) seroconversion during antiviral therapy, and can be nearly recovered during HBsAg seroconversion. However, it is still difficult to achieve the ideal terminal, HBsAg seroconversion. For this reason, immunotherapy would be helpful to enhance the anti-HBV immunity and acquire higher HBsAg seroconversion. Here, the investigators propose a hypothesis that hepatitis B immune globin (HBIG)+granulocyte-macrophage colony-stimulating factor (GM-CSF)+HBV vaccine can enhance anti-HBV immune responses and improve HBsAg seroconversion in CHB patients who has achieved HBeAg seroconversion using nucleoside analogues treatment.
Experimental: Drug treatment
Drug: Given four times in week 0, 4, 12 and 24. At each time of treatment, the patients will be hospitalized and treated with 800 unit of HBIG intramuscularly at day 0, 1, 2, 3 and 4, then were treated with 75 μg of GM-CSF subcutaneously at day 2, 3, 4, 5 and 6, and finally were injected 20μg of HBV vaccine subcutaneously at day 6.

GM-CSF control
GM-CSF was given four times as control in week 0, 4, 12 and 24. At each time of treatment, the patients will be hospitalized and treated with GM-CSF intramuscularly or subcutaneously at day 2, 3, 4, 5, 6.

同时这的：

治疗用乙肝免疫球蛋白+ GM-CSF+乙肝疫苗治疗慢性乙型肝炎患者HBeAg血清转换
这项研究目前正在招募参与者。（见联系方式和地点）
证实2013年7月由北京302医院
主办单位：
北京302医院
由（责任方）提供的信息：
王福生，北京302医院
ClinicalTrials.gov标识符：
NCT01878565
第一次收到：2013年6月12日
最后更新：2013年7月23日
最后证实：2013年7月

目的

宿主免疫已被公认为是主要的因素来确定的慢性乙型肝炎病毒（HBV）感染的结果;然而，先前的研究已经表明，HBV特异性T细胞和B细胞的功能被耗尽在慢性乙型肝炎（CHB）的患者。最近，有人建议，乙肝表面抗原（HBsAg），也可以在免疫耐受或免疫耗竭起到关键的作用。抗HBV免疫反应部分恢复，当患者在抗病毒治疗实现乙肝e抗原（HBeAg）血清学转换，并且可以在乙肝表面抗原血清学转换几乎被收回。然而，它仍然是难以达到理想的终端，HBsAg的血清转换。出于这个原因，免疫疗法将是有益的，以提高抗HBV免疫和获得更高的HBsAg血清转换。在这里，研究人员提出了一个假设，即乙肝免疫球蛋白（HBIG）+粒细胞 - 巨噬细胞集落刺激因子（GM-CSF）+乙肝疫苗能增强抗HBV免疫应答，提高乙肝表面抗原血清学转换在慢性乙肝患者谁取得了HBeAg血清转换使用核苷类似物治疗。
实验：药物治疗
药物：由于在第0周，第4，第12和244倍。在治疗的每一次中，将患者住院并用800单位球蛋白的肌肉内，在0天，1个，2个，3个和4个处理，然后分别与处理75 GM-CSF的皮下注射微克在第2天，3，4，5和6，最后注射的乙肝疫苗皮下注射20μg的第6天。

GM-CSF控制
GM-CSF给予四倍控制在0周，第4，第12和24.在治疗的每一次中，将患者住院，并与GM-CSF的肌内注射或皮下注射在第2天，3个，4个，5个，6个处理。

欢迎光临肝胆相照论坛 (http://hbvhbv.info/forum/)