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标题: 慢性乙型肝炎：应该是什么目标，为新的治疗方法？ [打印本页]

作者: StephenW 时间: 2015-7-9 18:52 标题: 慢性乙型肝炎：应该是什么目标，为新的治疗方法？

Antiviral Res. Author manuscript; available in PMC 2014 Apr 1.
Published in final edited form as:
Antiviral Res. 2013 Apr; 98(1): 27–34.
Published online 2013 Feb 4.  doi:  10.1016/j.antiviral.2013.01.006

PMCID: PMC3627746
NIHMSID: NIHMS440683

Chronic hepatitis B: What should be the goal for new therapies?Timothy M. Block,1,2,* Robert Gish,3 Haitao Guo,1 Anand Mehta,1 Andrea Cuconati,2 W. Thomas London,2,4 and  Ju-Tao Guo1

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Abstract

Chronic hepatitis B can currently be medically managed with either pegylated interferon-alpha (pegIFN-α) or one of the five nucleos(t)ide analogue Direct Acting Antivirals (DAAs) that inhibit the hepatitis B virus (HBV) DNA polymerase. While pegIFN-α is effective in approximately one-third of the treated patients, the polymerase inhibitors significantly reduce viral load in the vast majority of those treated. However, neither pegIFN-α nor nucleosid(t)e analogues are capable of reliably eliminating the virus and achieving a cure. Moreover, the interferons and polymerase inhibitors are recommended by US, European and Asian professional society practice guidelines for use in only a subset of those infected with HBV. This subset is the population with the greatest levels of circulating viral DNA and abnormal liver function. Although this is the population at the highest risk for cirrhosis and liver cancer, those who fall outside the treatment guidelines, with low levels of viral replication and normal serum ALTs, may also benefit from antiviral therapy. The questions are thus: are new classes of drugs needed to manage chronic hepatitis B? Is a cure possible? Is a cure even necessary? It is therefore important to define the meaning of a cure and determine what the goals of new therapies should be. In this article, we address those questions and propose two operational definitions of medically attainable cures. The first is a “functional cure” based on the clinical outcome, in which the patient’s life expectancy becomes the same as that of an individual who has resolved his HBV infection without therapy. Because such an outcome cannot be measured over the short term, we also define an “apparent virological cure,” based on the stable off-drug suppression of HBV viremia and antigenemia and the normalization of ALTs and other laboratory tests. We suggest that such a virological cure should be the goal of future therapeutics in all patients with chronic hepatitis B. The extent to which a virological cure predicts a functional cure will only be determined by long-term follow-up.

作者: StephenW 时间: 2015-7-9 18:52

抗病毒水库。作者的手稿;提供PMC 2014年4月1日。
发表在最后的编辑形式：
抗病毒水库。 2013年4月; 98（1）：27-34。
网上公布的2013 4月DOI：10.1016 / j.antiviral.2013.01.006
PMCID：PMC3627746
NIHMSID：NIHMS440683
慢性乙型肝炎：应该是什么目标，为新的治疗方法？
蒂莫西·M.座1,2，*罗伯特·吉什，3海涛郭，1阿南德·梅塔，1安德烈Cuconati，2 W.托马斯伦敦，2,4和鞠陶果1
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抽象

慢性乙型肝炎目前可以用医学要么聚乙二醇化干扰素α（pegIFN-α）或五个核苷（酸）类似物IDE直接代理抗病毒药物（的DAA），抑制乙肝病毒（HBV）DNA聚合酶的一个管理。而pegIFN-α是有效的大约三分之一的治疗的患者中，聚合酶抑制剂显著减少病毒载量在这些处理中的绝大多数。然而，无论是pegIFN-α，也不nucleosid（T）电子类似物能够可靠地消除病毒，实现治愈。此外，干扰素和聚合酶抑制剂在那些感染了乙肝病毒的一个子集，建议由美国，欧洲和亚洲的专业社会实践指导使用。该子集是与循环病毒DNA和肝功能异常程度最高的人群。虽然这是在最高的风险为肝硬化和肝癌的人口，这些谁属于治疗准则外，与病毒复制和正常血清低价竞标低水平，也可以受益于抗病毒治疗。问题是这样的：有新的类来管理慢性乙肝需要什么药？一个治愈可能吗？甚至是必需治愈？因此，重要的是定义一种治疗的含义和确定的新疗法的目标应。在这篇文章中，我们解决这些问题，并提出了医学疗法达到两个运算的定义。第一个是基于所述的临床结果，其中，患者的预期寿命变得相同，谁已经未经治疗解决了HBV感染的个体的“功能性治疗”。因为这样的结果不能在短期内来衡量，我们也定义基于稳定的休药抑制HBV病毒血症和抗原和ALTS正常化等实验室检查的“明显的病毒学治愈”。我们认为，这种病毒学治愈应该是未来治疗的目标中的所有患者的慢性乙型肝炎向其中一个病毒学治愈预测的官能固化将仅由长期随访来确定的程度。

作者: StephenW 时间: 2015-7-9 18:54

4. Can current DAAs be curative?

Given enough time, treatment with DAAs might produce a “virological” cure of chronic hepatitis B. Indeed, despite the limitations of current therapies, up to 10% of patients, and in some studies up to 17%, appear to achieve stable off-drug suppression of viremia, and even the loss of HBsAg or anti-HBs seroconversion (Perrillo, Gish et al. 2006; Lok and McMahon 2009). It is therefore possible for DAAs, alone to eliminate all virological markers and achieve the clinical and biological benefits that, borrowing from HIV nomenclature, we have defined as a “functional” cure (Cohen 2011), in at least a sub-set of patients.

Hepatocytes are self-renewing, with a half-life in the healthy liver of approximately 6 months (Mason, Jilbert et al. 2005; Mason, Low et al. 2009; Mason, Liu et al. 2010). In HBV-infected individuals, in contrast, the half-life is dramatically shortened to only 3-30 days (Nowak 1996; Ciupe, Ribeiro et al. 2007). Therefore, as illustrated in Figure 1, if DAA therapy alone could absolutely block HBV replication, then inhibition at any step of the life cycle should eventually eliminate all viral replicative intermediates, resulting in a stable SVR once the treatment period has exceeded 10 hepatocyte half-lives (Fig. 2). Such an outcome should therefore be achieved by the currently used DAAs, even though they target the viral polymerase and have no direct effect on cccDNA. However, the reality appears to be more complicated (Fig. 2). Substantial HBsAg antigenemia may persist even after 5-10 years of DAA therapy, indicating the persistence of significant numbers of productively infected cells or virus reservoirs, making it impossible to discontinue treatment without a risk of rebound viremia (Lok 2011). This has certainly been the experience with monotherapy.
Figure 1
Figure 1
Inhibition of the HBV replication cycle
Figure 2
Figure 2
Reduction of the number of infected hepatocytes in treated HBV infection

The reason for the inability of current DAAs to reliably achieve a stable SVR, and thus “virologically” cure chronic hepatitis B (Table 1), may be due to their failure to completely suppress viral replication in vivo. Consistent with this notion is the observation that, while antiviral therapy often lowers the serum viral load by more than 6 logs, it only reduces intracellular HBV cccDNA and core DNA by 1 or 2 logs, respectively (Werle-Lapostolle, Bowden et al. 2004; Wursthorn, Lutgehetmann et al. 2006; Sung, Tsoi et al. 2008; Takkenberg, Terpstra et al. 2011). The reason for this disconnection between the reduction in circulating and intracellular forms of HBV DNA is unclear. One possibility is that the maturation of viral genomes to produce secreted virions is much more sensitive to the current polymerase inhibitor DAA therapy than the intracellular generation of immature virions. Alternatively, there might be drug-refractory viral “reservoirs,” with two possible scenarios. In the first, a subpopulation of infected cells is “off limits” to the current DAAs, creating sanctuaries from drugs. In the other, a percentage of HBV-infected cells are long-lived, and their nuclear cccDNA is quiescent and stable, serving as a persistent source of virus reactivation.

Understanding why current polymerase inhibitor DAA therapy fails to resolve chronic HBV infection holds the key to achieving a “virological cure” For example, if the incomplete suppression of HBV replication results from the failure of metabolic activation of nucleoside/nucleotide analogues in a small percentage of infected hepatocytes, then combination therapy with drugs that target both the viral DNA polymerase and other steps in DNA synthesis might be beneficial.
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5. How great a decline in viral load is needed for clinical benefit?

Kinetic studies have shown that HBV viremia declines in a multistep, at least biphasic manner in most patients treated with DAAs (Nowak 1996; Ciupe, Ribeiro et al. 2007). Based on such reports (Tsiang, Rooney et al. 1999; Lewin, Ribeiro et al. 2001; Wang, Holte et al. 2004), we have graphed some ”hypothetical” effects of the current polymerase inhibitor DAAs on viral and HBsAg load (Fig. 3). The responses can be divided into four groups. Unless an individual is infected with a drug-resistant virus, all four response groups show an initial, rapid drop in viral load (circulating viral DNA), usually within the first 4 weeks, followed by a slower decline which varies among patients. In some, the second period of decline is gradual but steady, ending up below the level of detection (Fig. 3a). In others, although the viral load declines, it either does not go below (Fig. 3b) or stabilizes just above (Fig. 3c) or significantly above (Fig. 3d) the level of detection.
Figure 3
Figure 3
Hypothetical kinetics of HBV viremia and HBs antigenemia during DAA therapy

In marked contrast to the HBV DNA level, which may drop more than 5 logs during the first year of nucleoside/nucleotide analogue therapy, the level of HBsAg rarely falls more than 1 log (Fig. 3). (An apparent exception is telbivudine, which can produce a >1 log decline in HBsAg after 4 years of treatment (Wursthorn, Jung et al. 2010; Chan, Thompson et al. 2011)). Even though DNA polymerase inhibitors do not directly suppress viral transcription or HBsAg synthesis, a decline in the number of infected cells should cause a decrease in HBsAg. It thus appears that, even after virus production has been inhibited for a year by current DAA therapy, a significant number of infected cells remain. This observation is consistent with previously cited reports of the continued presence of intracellular replicative forms of viral DNA and cccDNA, long after the viral load has fallen near the level of detection (Werle-Lapostolle, Bowden et al. 2004; Sung, Wong et al. 2005; Wursthorn, Lutgehetmann et al. 2006; Pan, Hu et al. 2012). In this regard, it should be noted, as illustrated in the graphs of hypothetical outcomes in Fig. 4, that pegIFN-α therapy may cause a more rapid decline in circulating HBsAg, associated with the loss of HBeAg and the eventual loss of detectable HBsAg, or even anti-HBs seroconversion, producing a stable off-drug benefit (Moucari, Mackiewicz et al. 2009; Ma, Yang et al. 2010; Thompson, Nguyen et al. 2010; Liaw 2011; Chen, Jeng et al. 2012). These data suggest that long-term efficacy is related to the kinetics of the drug-induced reduction in viral gene products. In chronic hepatitis C, a rapid reduction in viral load is an excellent predictor of a beneficial outcome (Poordad, Reddy et al. 2008). Perhaps the same is true for HBV infection.
Figure 4
Figure 4
Hypothetical kinetics of HBV viremia and HBs antigenemia during therapy with pegIFN-α

作者: StephenW 时间: 2015-7-9 18:54

4.可目前的DAA是治疗？

给予足够的时间，用的DAA治疗可能产生慢性乙型肝炎的“病毒学”治愈事实上，尽管目前的治疗方法的局限性，高达10％的患者，在某些研究中高达17％，出现实现稳定场外病毒血症的药物抑制，与HBsAg或抗-HBs阳转（Perrillo，基希等，2006;乐和2009年麦克马洪）甚至丧失。因此，有可能的DAA，独自消除所有的病毒学指标和实现这一目标，艾滋病毒命名借款，我们定义为“功能性”治疗（科恩2011年）的临床和生物的好处，至少在一个子集患者。

肝细胞自我更新，具有半衰期在约6个月的肝脏健康（梅森Jilbert等人2005;梅森，Low等2009;梅森，Liu等人，2010年）。在HBV感染的个体，与此相反，半衰期显着地缩短到仅3-30天（诺瓦克1996; Ciupe，里贝罗等人，2007）。因此，如示于图1中，如果DAA疗法能够单独绝对方框HBV复制，然后抑制在生命周期中的任何步骤最终应消除所有的病毒复制中间体，从而得到稳定的SVR一次治疗期间已超过10肝细胞半生命（图2）。这样的结果因此，应该由目前使用的DAA来实现，即使它们针对病毒聚合酶和对cccDNA的没有直接的影响。然而，现实情况似乎是更复杂（图2）。实质性的HBsAg抗原可能持续即使经过5 - 10年的DAA治疗，表明显著号码富有成效感染细胞或病毒储层的持久性，从而不可能中止治疗无反病毒血症的风险（乐2011）。这无疑是与单药治疗的经验。
图1
图1
乙肝病毒复制周期的抑制
图2
图2
在治疗HBV感染减少感染的肝细胞的数量

其原因目前的DAA的无法可靠地实现稳定的SVR，因而“病毒学”治愈慢性乙型肝炎（表1），可能是由于其未能完全抑制体内病毒的复制。与此相一致的概念是，虽然抗病毒治疗常常超过6日志降低血清病毒载量的观察，它仅被1或2个数量级，分别为（Werle-拉波斯托勒，鲍登等降低细胞内的HBV cccDNA的和核心的DNA。2004年; Wursthorn，Lutgehetmann等，2006;宋，蔡等人2008; Takkenberg，特普斯特拉等2011）。究其原因，减少循环和HBV DNA的细胞形态之间的断线目前还不清楚。一种可能性是，病毒基因组以产生分泌的病毒粒子的成熟是到当前聚合酶抑制剂的DAA疗法比胞内产生未成熟的病毒粒子更敏感。另外，有可能是药物难治性病毒“水库”，有两个可能的方案。在第一阶段，被感染的细胞的一个亚群是“关闭的限制”，以当前的DAA，创建从药物避难所。在其它方面，乙肝病毒感染的细胞的百分比是长寿命的，并且它们的核cccDNA的是静态稳定的，作为病毒再活化的持久源。

理解为什么当前聚合酶抑制剂治疗DAA未能解决慢性HBV感染是关键，以实现“病毒学治愈”举例来说，如果从核苷/核苷酸类似物代谢活化的失败HBV复制的结果的一小部分不完全抑制感染的肝细胞，然后联合治疗药物靶两者的病毒DNA聚合酶和DNA合成其他步骤可能是有益的。
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5.如何在巨大的病毒载量的下降是必要的临床益处？

动力学研究显示，在一个多步该乙肝病毒血症的下降，在大多数患者的DAA治疗至少双相方式（诺瓦克1996; Ciupe，里贝罗等人，2007）。基于这样的报告（蒋，鲁尼等人1999;卢因，李义等人2001;王，霍尔特等人2004年），我们绘制了当前聚合酶抑制剂的DAA对病毒和乙肝表面抗原负载一些“假设”效应（图3）。该反应可分为四组。除非一个人被感染了抗药性病毒，所有四个响应组显示中的病毒载量（循环病毒DNA）的初始，快速下降，通常在第4周，接着是较慢的下降而变化的患者。在有些国家，下降的第二个时期是渐进而稳定，结束了低于检测水平（图3a）。在其他国家，虽然病毒载量下降，它要么不走下面（图3b）或稳定的正上方（图3c）或显著上述（图3d）检测水平。
图3
图3
HBV病毒血症和HBs抗体抗原的DAA治疗期间假设动力学

形成鲜明对照的HBV DNA的水平，这可能会在核苷/核苷酸类似物治疗的第一年下降超过5日志，HBsAg的水平很少下降超过1日志（图3）。（一个明显的例外是替比夫定，能产生> 1日志下降乙肝表面抗原经过4年的治疗（Wursthorn，Jung等2010;陈，汤普森等人2011））。即使DNA聚合酶抑制剂不直接抑制病毒转录或HBsAg的合成，在感染的细胞的数量的下降应引起的HBsAg的降低。因此，看来，即使病毒的生产已被禁止了一年通过电流DAA疗法，显著数感染细胞的存在。这一观察是一致的与前面引用的病毒DNA和cccDNA的，经过长期的病毒载量下降近检测（Werle-拉波斯托勒，鲍登等人2004年的水平的细胞内复制形式的继续存在的报告;宋，Wong等人。2005; Wursthorn，Lutgehetmann等，2006;潘，胡等人2012）。在这方面，应该指出，如图中所示假想的结果的曲线图。 4，即pegIFN-α治疗可能会导致更快速的下跌循环的HBsAg，HBeAg的带的损失和检测HBsAg的最终损失，甚至抗-HBs阳转相关，产生稳定的休药福利（Moucari，Mackiewicz等2009年人;马，杨等人2010;汤普森，阮等人2010;廖2011;陈钲等2012）。这些数据表明，长期功效有关，在病毒基因产物的药物诱导减少的动力学。在慢性丙型肝炎，迅速减少病毒载量是一个有益的结果（Poordad，Reddy等人，2008年）优异的预测值。或许也是如此HBV感染。
图4
图4
HBV病毒血症和HBs抗体抗原的治疗pegIFN-α期间动力学假设

作者: StephenW 时间: 2015-7-9 18:56

作者: StephenW 时间: 2015-7-9 18:56

作者: StephenW 时间: 2015-7-9 19:00

Figure 1
Inhibition of the HBV replication cycle

Major steps in the life cycle of the hepatitis B virus in an infected cell. The steps targeted by currently used antiviral drugs are indicated, as well as possible drug targets. The figure indicates how inhibition of any step in the life cycle, if complete, prevents all downstream virological events, the production of new progeny virus and new rounds of infection.
图1
乙肝病毒复制周期的抑制

在B型肝炎病毒的生命周期中被感染的细胞主要步骤。通过目前使用的抗病毒药物的目标的步骤指出的，以及可能的药物靶标。该图显示了如何抑制在生命周期的任何一步，如果完整，防止所有下游病毒学事件，生产新的子代病毒新发感染。

Figure 2
Reduction of the number of infected hepatocytes in treated HBV infection

A. An infected liver, with infected cells colored in red, and virions indicated by red circles. B. In theory, preventing the production of progeny virus should, after 10-20 hepatocyte half-lives, result in the death of all infected cells, so that no detectable virus-infected cells remain. In reality, however, infected nests of cells persist even after 5 years, or more than 20-50 half lives of polymerase therapy.
图2
在治疗HBV感染减少感染的肝细胞的数量

A.被感染的肝，与受感染的细胞染成红色，和病毒粒子用红色圆圈表示。 B.在理论上，防止生产子代病毒应，10-20肝细胞的半衰期后，导致所有感染的细胞的死亡，从而没有可检测到病毒感染的细胞仍然存在。然而在现实中，细胞的感染巢坚持即使5年后，或聚合酶治疗超过20-50个半衰期。

作者: StephenW 时间: 2015-7-9 19:02

Hypothetical kinetics of HBV viremia and HBs antigenemia during DAA therapy

The graphs indicate four different responses to treatment of chronic hepatitis B patients with the currently available DAAs (lamivudine, tenofovir or barraclude), as reflected in circulating levels of HBV viral DNA and HBsAg (Lok and McMahon 2009). The time of treatment 0 to 52 weeks. The values of viral load and HBsAg are relative and arbitrary, although the scale for viral load is in logs (usually covering at least 8 logs) and antigen levels as percentage of baseline (0-100%, or 2 logs). The solid bar stemming from the y axis (LOD) indicates the limit of detection of viral DNA, and shows that in many patients it stabilizes at or above the LOD.
HBV病毒血症和HBs抗体抗原的DAA治疗期间假设动力学

该图显示四个不同的反应，治疗慢性乙型肝炎患者的当前可用的DAA（拉米夫定，替诺福韦或barraclude），这反映在循环的HBV病毒DNA与HBsAg（乐和麦克马洪2009年）的水平。治疗0至52周的时间。病毒载量和HBsAg的值是相对的，任意的，虽然规模为病毒载量是在原木（通常涵盖至少8日志）和抗原水平为基线的百分比（0-100％，或2个数量级）。固体棒从y轴（LOD）词干表示检测病毒DNA的限制，并表明，在许多患者它稳定在或高于检测限。

作者: StephenW 时间: 2015-7-9 19:04

Hypothetical kinetics of HBV viremia and HBs antigenemia during therapy with pegIFN-α

As in Fig. 3, the plots are summaries, sub-categorizing data from original papers such as (Moucari, Mackiewicz et al. 2009; Ma, Yang et al. 2010; Thompson, Nguyen et al. 2010; Chen, Jeng et al. 2012). The information is based on only HBeAg+ patients. Circulating viral DNA and HBsAg levels are depicted in arbitrary units on the y axis (where, as in Fig. 3, the scale for viral load values is 0-8 logs and for antigen, 2 logs) as a function of time of IF treatment (indicated by the bar), which was usually 28-42 weeks. Hypothetical profile for individuals treated with pegIFN-α who (a) did not experience a rapid reduction of circulating HBsAg and have the least likelihood of eliminating circulating HBV viral DNA load and losing HBeAg and (b) those who do experience a “rapid” decline of HBsAg and thus have the greatest likelihood of eliminating circulating detectable viral DNA load and HBeAg sero-conversion. Solid horizontal line: limit of detection of viral DNA. Dotted line: HBV DNA level in the blood. Hashed line: HBsAg level in the blood.

HBV病毒血症和HBs抗体抗原的治疗pegIFN-α期间动力学假设

如在图3，该地块是摘要，分归类数据从原来的纸张，如（Moucari，Mackiewicz等，2009;马，杨等人2010;汤普森，阮等人2010;陈钲等2012）。该信息是根据仅的HBeAg +的患者。循环病毒DNA和HBsAg水平是在y轴上（其中，如在图3中，标度为病毒载量的值是0-8日志和抗原，2原木）作为中频治疗时间的函数示出以任意单位，这是通常28-42周（由条表示）。假想的轮廓与pegIFN-α治疗的个人谁（一）没有经历一个迅速减少循环的HBsAg，并有消除循环HBV病毒DNA载，失去HBeAg和的可能性最小（B）做的那些经历了“迅速”衰落谁的HBsAg，因而具有消除循环检测的病毒DNA载和HBeAg血清转化的可能性最大。水平实线：检测病毒DNA的限制。虚线：血液中的HBV DNA水平。散列行：血液中的乙肝表面抗原水平。

作者: StephenW 时间: 2015-7-9 19:05

整篇文章，推荐

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3627746/

作者: 相信会幸福 时间: 2015-7-9 19:12

辛苦啦

作者: zgct 时间: 2015-7-9 21:59

反思

好文

作者: 遥望曙光 时间: 2015-7-20 19:33

嗨，看不太懂呢！

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