治疗慢性乙型肝炎感染管理的进展

StephenW

Therapeutic Advances in the Management of Chronic Hepatitis B Infection
Johanne Brooks, MBChB, BSc, MRCP, William Gelson, MA, MD, MBBS, MRCP, Simon M. Rushbrook, MBBS, MRCP, PhD
Disclosures

Ther Adv Chronic Dis. 2013;4(4):157-166.
治疗慢性乙型肝炎感染管理的进展
约翰妮布鲁克斯，内外全科医学士，理学士，MRCP，MA，MD，MBBS，MRCP，西蒙·Rushbrook，MBBS，MRCP，博士，威廉杰尔松
披露

进一步进阶慢性疾病。 2013，4（4）:157-166。

HBV Immunity and HBV Viral Escape

Hepatocellular injury in HBV is immune-mediated, with human leukocyte antigen (HLA) class I restricted CD8 cells recognizing HBV peptide fragments processed and presented on hepatocytes. Direct cell killing by CD8 cytotoxic T lymphocytes then occurs, in association with noncytolytic inhibition of virus replication. However, the activation of the CD8+ T-cell adaptive immune response only occurs once the innate immune system has recognized HBV along with assistance from activated CD4+ T cells. Several studies have highlighted the role of type 1 interferon (IFN) in the production of the antiviral state in acute HBV [Fletcher et al. 2012], with Toll-like receptors (TLRs) [Tjwa et al. 2012] mediating the production of IFN. HBeAg has been shown to induce a tolerogenic effect by acting as an immune decoy for the core antigen and also by downregulating cell signalling suppressing TLR-induced IFN beta activation [Visvanathan et al. 2007]. By mechanisms that are as-yet unclear, HBV-infected cells have been shown to have downregulation of signal transducer and activator of transcription-1, thereby reducing the antiviral state further [Lutgehetmann et al. 2011]. HBeAg is not alone in its immunomodulatory effects: Protein X downregulates mitochondrial antiviral signalling [Bouchard et al. 2003] by suppressing the retinoic acid inducible gene I (RIG-I) [Civril et al. 2011; Luo et al. 2011] and SVPs have been shown in vitro to inhibit TLR-9 mediated IFN alpha production by dendritic cells [Xie et al. 2009].


乙肝病毒免疫和乙肝病毒逃逸

乙肝是免疫介导的肝细胞损伤，与人类白细胞抗原（HLA）I类限制性CD8细胞识别HBV肽片段对肝细胞处理和呈现。然后直接CD8+细胞毒性T淋巴细胞的细胞杀伤时，与非溶细胞抑制病毒的复制。然而，只发生一次的先天免疫系统已确认HBV随着援助由活化的CD4+ T细胞活化的CD8 + T细胞的适应性免疫反应。几项研究已经强调了1型干扰素（IFN）的作用在急性HBV[Fletcher等人的抗病毒状态，在生产中。 2012]，Toll样受体（TLRs的）[Tjwa等。 2012]介导产生IFN。 e抗原已被证明通过作为核心抗原的免疫诱饵，并通过下调细胞信号转导抑制TLR诱导干扰素beta的激活[Visvanathan医师等，以诱导耐受性的效果。 2007]。通过机制尚不清楚，HBV感染的细胞已被证明有下调信号转导子和转录激活转录-1，从而降低了抗病毒状态进一步Lutgehetmann等。 2011]。 HBeAg的不单单是其免疫调节作用：蛋白质X下调线粒体抗病毒信号[布沙尔等。 2003]抑制视黄酸诱导基因I（RIG-I）[等Civril。 2011年罗等人。 2011]的SVP已被证明在体外抑制TLR-9介导的树突状细胞[谢等人干扰素α生产。 2009]。

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Phases of HBV Infection

Chronic hepatitis B (CHB) natural history is regarded as consisting of four phases: immune tolerant (high DNA, HBeAg+, normal alanine transaminase [ALT]), immune clearance (HBeAg+, abnormal ALT, high DNA), inactive (low DNA, HBeAg–, normal ALT) and immune escape (HBeAg–, high DNA, abnormal ALT). Finally, HBsAg may be lost with or without the development of anti-HBs (1% of patients per year). The four phases are not sequential and any patient can move in any direction along the phases. Patients in immune clearance and immune escape phases are candidates for antiviral therapy, the aim being to prevent cirrhosis and development of hepatocellular carcinoma (HCC).

HBeAg seroconversion is predictive of a substantial reduction in HBV DNA levels, a decrease in intrahepatic inflammation and improved prognosis [Chen et al. 2002; Neiderau et al. 1996]. The level of HBV DNA is also thought to have prognostic value, as a chronically high level of HBV DNA is associated with an increased risk of progression to cirrhosis and HCC [Chen et al. 2011]. Whilst no threshold of HBV viraemia has been determined for predictive value of outcome at an individual level, a titre of 2000–20,000 IU/ml of HBV DNA is often recommended as a cut off [Chevaliez et al. 2012]. Hence, HBeAg seroconversion, a reduction in HBV DNA and HBsAg loss are important clinical treatment endpoints.

In the immune clearance/immune escape phases, therapy is often considered if the HBV DNA is >2000 IU/ml along with either an ALT > 2× the reference range or either moderate inflammation or moderate liver fibrosis on liver biopsy.

HBV感染阶段

慢性肝炎乙（CHB）视为自然史包括四个阶段：免疫宽容（高DNA，HBeAg+的，正常谷丙转氨酶[ALT]），免疫间隙（大三阳+，异常癖好，高脱氧核糖核酸），无效（低DNA，HBeAg的 - ，转氨酶正常）和免疫逃逸（大三阳，DNA，ALT异常）。最后，乙肝表面抗原有或没有抗-HBs（1％的患者每年）的发展，可能会丢失。这四个阶段是不连续的，任何患者都沿任意方向移动的阶段。患者在免疫清除和免疫逃逸阶段候选人进行抗病毒治疗，其目的是防止肝硬化和肝细胞癌（HCC）的发展。

HBeAg血清转换是HBV DNA水平大幅减少，减少肝内炎症和改善预后[Chen等人的预测。 2002等; Neiderau。 1996]。 HBV DNA水平也被认为有预后价值，作为一个长期的高HBV DNA水平是与风险增加发展为肝硬化和肝癌[Chen等。 2011]。虽然没有门槛的HBV病毒血症的结果的预测值已被确定在个人层面，2000-20,000 IU/ ml的HBV DNA滴度通常建议作为切断[Chevaliez等。 2012]。因此，HBeAg血清转换，HBV DNA和HBsAg消失的减少是重要的临床治疗终点。

在免疫清除/免疫逃逸阶段，通常被认为是治疗，如果HBV DNA>2000 IU/ ml的一个ALT>2×参考范围或任意的中度炎症或中度肝纤维化肝组织活检。

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Future Developments

Clevudine is licensed in South Korea. In a 48-week follow up head-to-head comparison with entecavir, the reduction in viral load was similar for both drugs in HBeAg-positive and -negative patients, with a similar number reaching undetectable viral DNA levels. Clevudine however was associated with a higher virologic breakthrough rate and clinical myopathy [Shin et al. 2011]. This was further correlated in a 2-year follow up [Yoon et al. 2011].

MIV-210 a prodrug of 3'-fluoro-2',3'-dideoxy-guanosine has been shown with woodchuck hepatitis virus to produce a rapid virological response and is currently undergoing further phase II trials [Michalak et al. 2009].

LB80380 is a nucleoside analogue that has been tested in 65 HBeAg-positive patients with lamivudine resistance. It was shown to be safe over 12 weeks [Yuen et al. 2010].

AGX-1009 is a prodrug of tenofovir that is currently completing preclinical trials in China, with an aim to start phase I trials in 2013.

Nonnucleos(t)ide antivirals that are in current phase II trials include Myrcludex B, which is an entry inhibitor shown to prevent viral spread among human hepatocytes in UPA mice [Barek et al. 2011]. Other interesting compounds in phase I trials include Bay 41-4109, which is a heteroaryldihydropyrimidine (HAP) antiviral compound that accelerates and misdirects viral capsid production, leading to unstable viral capsid production [Stray and Zlotnick, 2006]. Rep 9AC which is an HBsAg release inhibitor is undergoing a proof-of-concept trial to show it can elicit a sustain virological response [Al-Mahtab et al. 2011] and nitazoxanide has been shown to modulate host antiviral pathways via activation of a protein kinase involved in cellular antiviral response.

Finally, immune modulators such as IL-7, GS9260 (a TLR7 agonist) are still in phase I trials, but there is more evidence for their use in T-cell reconstitution in the treatment of HIV [Levy et al. 2012].

Summary

These are exciting times with regard to the pathobiology of hepatitis B and the new virologic tools becoming available to allow for more exacting standards of care. The greater understanding of this virus, with the technology and drugs with better resistance profiles, should allow for a reduction in cirrhosis and the development of HCC in patients with CHB infection.

未来发展

克拉夫定在韩国的许可。在48周随访头对麦芒的比较恩替卡韦，病毒载量的减少是HBeAg阳性和阴性患者两种药物类似的，具有类似数达到检测不到病毒DNA水平。然而，克拉夫定具有较高的病毒学突破率和临床肌病[Shin等相关联。 2011]。这是2年随访[Yoon等密切相关。 2011]。

MIV-210的前体药物，3'-氟-2'，3'-二脱氧 - 鸟苷已被证明土拨鼠肝炎病毒以产生一个快速病毒学反应，目前正进行更多的II期临床试验[Michalak先生等人。 2009]。

LB80380是一种核苷类似物，已经过测试，在65例HBeAg阳性拉米夫定耐药患者。它被证明是安全的，超过12周袁等。 2010]。

AGX-1009是一种药替诺福韦目前完成临床前试验，在中国启动I期临床试验，目的是在2013年。

Nonnucleos（T）是在当前的II期临床试验的IDE抗病毒药物包括Myrcludex B，这是一个进入抑制剂，以防止病毒传播，在人类肝细胞在UPA小鼠[Barek等。 2011]。其他有趣的化合物，在I期试验包括湾41-4109，这是一个heteroaryldihydropyrimidine的（HAP）的抗病毒化合物加速和误导病毒衣壳生产，导致不稳定的病毒衣壳生产流浪Zlotnick的，2006]。代表9AC这是一个乙肝表面抗原的释放抑制剂正处于一个概念证明试验显示，它可以引起持续病毒学应答[铝马赫塔卜等。 2011]和硝噻醋柳胺已被证明是通过激活细胞抗病毒反应中涉及的蛋白激酶调节宿主的抗病毒途径。

最后，仍然是免疫调节剂，如IL-7，GS9260（TLR7激动剂）在Ⅰ期临床试验中，但它们在T细胞重建的治疗艾滋病毒[Levy等有更多的证据。 2012]。

总结

这是激动人心的时刻与病理学乙肝病毒学的工具和新的可允许更严格的标准，护理方面。更好地了解这种病毒，具有更好的抗型材的技术和药物，应允许减少慢性乙型肝炎感染患者肝硬化和肝癌的发展。

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