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标题: 迈向有效预防和彻底治愈肝炎 [打印本页]

作者: StephenW 时间: 2022-7-22 13:05 标题: 迈向有效预防和彻底治愈肝炎

迈向有效预防和彻底治愈肝炎

电子生物医学

开放存取发布时间：2022 年 7 月 DOI：https://doi.org/10.1016/j.ebiom.2022.104156

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全球每 30 秒就有一人死于与肝炎有关的疾病。世卫组织估计，超过 3.54 亿人患有肝炎，其中乙型肝炎 (HBV) 和丙型肝炎 (HCV) 导致 96% 的肝硬化、肝细胞癌和肝移植，特别是在非洲和西太平洋地区.尽管疫苗和抗病毒药物发展迅速，但大多数国家未能如期实现到 2030 年消除病毒性肝炎的世卫组织目标。7 月 28 日举行的 2022 年世界肝炎日呼吁世界各地的人们提高认识并采取行动对抗肝炎。
消除病毒性肝炎的努力特别关注 HBV 和 HCV，因为它们代表了高死亡率和公共卫生负担。科学家和医生的共同努力，在开发有效的肝炎预防和治疗药物方面取得了很大进展。截至2018年底，HBV婴儿疫苗已在189个国家和地区推出。与此同时，针对病毒生命周期（如病毒进入、释放和复制）的新型直接作用抗病毒（DAA）药物已经出现。
HBV 的持久性、共价闭合环状 DNA (cccDNA) 形式被认为是根除 HBV 的目标。然而，没有一种可用的药物可以抑制 cccDNA 和基因组整合 DNA 中病毒基因的转录。 2021 年 10 月，Nature Medicine 发表了针对所有 HBV 信使 RNA 的贝匹罗韦森 2 期试验。该研究显示了可接受的安全性，以及 31 名 HBV 感染患者的 HBV 表面抗原 (HBsAg) 显着降低。在 2022 年国际肝病大会（6 月 22 日至 26 日，英国伦敦）上，葛兰素史克展示了他们在接受和停止稳定核苷酸类似物治疗的患者中使用贝匹罗韦森的最新数据（摘要编号 LB004A）。在同一次会议上，Vir Biotechnology Inc（美国加利福尼亚州旧金山）还更新了他们关于 VIR-2218 的 2 期试验数据，VIR-2218 是一种小型 n-乙酰半乳糖胺干扰核糖核酸（siRNA），用于慢性 HBV 感染的潜在功能性治愈。摘要编号 654）。 Vir-2218 旨在靶向 HBV 的保守 X 区域，使其能够沉默所有 HBV 转录物，包括 cccDNA 和所有 10 种 HBV 基因型的整合 DNA。由 Alexander Ploss（美国新泽西州普林斯顿大学）领导的一项研究于 2021 年 3 月在 Nature Communications 上发表，进一步详细介绍了 cccDNA 如何由松弛的环状 DNA (rcDNA) 形成，表明负链或正链损伤的修复rcDNA 需要不同的 DNA 修复因子组。更重要的是，该研究表明 FEN-1 和 RFC 是 cccDNA 形成中最限速的因素，这可能会导致消除 cccDNA 的新治疗靶点。
基因编辑方法也引起了广泛关注，以序列特异性方式靶向整合的 HBV 和 cccDNA。根据 5 月发表在 Molecular Therapy 上的临床前数据，Precision BioSciences（美国北卡罗来纳州达勒姆）开发的工程 ARCUS 核酸酶可有效靶向并降解小鼠和非人类灵长类动物模型中 85% 的 cccDNA。 Keith Jerome (Fred Hutchinson Cancer Research Center, WA, USA) 领导的另一项研究 (Mol Ther Methods Clin Dev) 检验了基于 CRISPR-Cas9 的疗法在小鼠模型中的安全性。在他们的研究中，HBV 特异性 AAV-SaCas9 疗法耐受性良好，并有效降低了肝脏总 HBV DNA 和 cccDNA。进一步优化基因编辑方法可以使我们更接近治愈 HBV 感染。
与可用于 HBV 的抗病毒治疗相比，HCV 的抗病毒治疗要有效得多。特定的 DAA 治疗方案已被批准作为每种 HCV 基因型的一线治疗。然而，由于 HCV 的高度遗传多样性，很少有 HCV 疫苗进入临床试验。 2021 年 2 月发表的一项随机试验 (N Engl J Med) 由 Andrea Cox（美国马里兰州约翰霍普金斯大学医学院）领导，评估了重组黑猩猩腺病毒 3 载体引发疫苗接种和重组改良后的安全性和有效性。牛痘安卡拉促进。尽管该疫苗可以引发针对 HCV 蛋白的 T 细胞反应，但不幸的是，与安慰剂相比，它未能降低慢性 HCV 感染的发生率。为加快丙肝疫苗研究，2022年3月，美国国家过敏和传染病研究所举办了一场关于丙肝疫苗研发最新研究的研讨会（Vaccines against Hepatitis C virus: Harnessing Immunity to Eliminate Global Chepatitis）。讨论了 HCV 免疫学的新发现和新疫苗平台（如 mRNA）的出现。
特别是，来自 Scripps Institute（CA，USA）的 Mansun Law 介绍了开发基于 HCV 包膜糖蛋白 E1E2 的疫苗抗原的挑战。斯坦福大学（美国加利福尼亚州）的 Bali Pulendran 分享了他对快速评估受辉瑞 BNT162b2 mRNA 疫苗开发启发的 HCV 候选疫苗的看法。尽管障碍依然存在，但科学家们期待未来十年 HCV 疫苗的成功。
距离世界卫生组织消除肝炎的目标还剩不到 10 年的时间。随着世界试图从 COVID 大流行中恢复过来，一种神秘的肝炎突然席卷了许多国家。自英国出现首例病例以来，截至 2022 年 6 月 7 日，已报告了 700 多例不明原因急性肝炎的儿科病例。实验室测试已经排除了所有已知的肝炎病毒。腺病毒与该疾病之间的潜在关联已在英国医院广泛讨论，目前正在调查中。其他风险因素，例如当前或以前感染 SARS-COV-2，或 SARS-CoV-2 疫苗的副作用，也在研究中。到目前为止，这些假设都不能完全解释这种儿童急性肝炎的严重临床表现。有趣的是，与英国的报告相反，由美国疾病控制和预防中心（美国乔治亚州）的 Anita Kambhampati 领导的 6 月发布的一项调查（MMWR Morb Mortal Wkly Rep）显示，与肝炎相关的紧急情况的数量没有增加与 COVID-19 大流行前的水平相比，2021 年 10 月至 2022 年 3 月期间 0 至 11 岁儿童的科室就诊或住院情况。因此，不明原因肝炎病例是代表一种新型肝炎还是只是一种长期存在的不明肝炎类型，仍存在争议。现在疫情正在受到密切监测。
尽管在预防和治疗方面做出了令人瞩目的努力，但仍存在重大挑战，阻碍了消除肝炎的目标。除了药物开发，还需要关注医疗保健服务的不公平，这对于肝炎的早期诊断和治疗至关重要。 eBioMedicine 作为 The Lancet Discovery Science 的一部分，继续作为关于人类疾病（包括肝炎）的转化研究的出版平台。
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发布时间：2022 年 7 月
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DOI：https://doi.org/10.1016/j.ebiom.2022.104156
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© 2022 作者。由 Elsevier B.V. 出版

作者: StephenW 时间: 2022-7-22 13:06

Towards effective prevention and a complete cure for hepatitis

eBioMedicine

Open AccessPublished:July, 2022DOI:https://doi.org/10.1016/j.ebiom.2022.104156

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Every 30 seconds there is a person who dies of a hepatitis-related disease globally. WHO estimates that more than 354 million people are living with hepatitis, among whom hepatitis B (HBV) and hepatitis C (HCV) are responsible for 96% of liver cirrhosis, hepatocellular carcinoma, and liver transplantation, especially in Africa and the western Pacific region. Despite the fast development of vaccines and antiviral drugs, most countries are not on track to achieve the WHO target of eliminating viral hepatitis by 2030. The 2022 World Hepatitis Day, which takes place on July 28, calls on people across the world to raise awareness and take action against hepatitis.
Efforts towards eliminating viral hepatitis are particularly focused on HBV and HCV, owing to the high mortality and public health burden they represent. Combined efforts from scientists and physicians have made great progress in the development of effective prophylaxis and therapeutics against hepatitis. By the end of 2018, the HBV infant vaccine was introduced in 189 countries and regions. Meanwhile, novel direct-acting antiviral (DAA) drugs that target viral life cycles, such as viral entry, release, and replication, have emerged.
The persistent, covalently closed circular DNA (cccDNA) form of HBV is regarded as a target for HBV eradication. However, none of the available drugs can inhibit the transcription of viral genes from cccDNA and genome-integrated DNA. In October, 2021, Nature Medicine published a phase 2 trial of bepirovirsen that targets all HBV messenger RNAs. The study showed acceptable safety, as well as a significant reduction of HBV surface antigen (HBsAg) in 31 patients with HBV infection. At the International Liver Congress 2022 (June 22–26, London, UK), GSK presented their updated data of bepirovirsen in patients with on and off stable nucleotide analogue therapy (abstract number LB004A). At the same meeting, Vir Biotechnology Inc (San Francisco, CA, USA) also updated their phase 2 trial data about VIR-2218, a small n-acetylgalactosamine interfering ribonucleic acid (siRNA), for the potential functional cure of chronic HBV infection (abstract number 654). Vir-2218 is designed to target the conserved X region of HBV so that it can silence all HBV transcripts, including cccDNA and integrated DNA of all ten HBV genotypes. A study published in Nature Communications in March, 2021, led by Alexander Ploss (Princeton University, NJ, USA), showed further details about how cccDNA is formed from relaxed circular DNA (rcDNA), indicating that the repair of minus or plus strand lesions of rcDNA require different set of DNA repair factors. More importantly, the study suggests that FEN-1 and RFC are the most rate-limiting factors in cccDNA formation, which could lead to new therapeutic targets for cccDNA elimination.
Gene-editing approaches have also attracted wide interest for targeting integrated HBV and cccDNA in a sequence-specific manner. According to the preclinical data published in May in Molecular Therapy, an engineered ARCUS nuclease developed by Precision BioSciences (Durham, NC, USA) efficiently targeted and degraded 85% of the cccDNA in mouse and non-human primate models. Another study (Mol Ther Methods Clin Dev) led by Keith Jerome (Fred Hutchinson Cancer Research Center, WA, USA) examined the safety of CRISPR-Cas9-based therapy in mouse models. In their study, HBV-specific AAV-SaCas9 therapy was well tolerated and efficiently decreased total liver HBV DNA and cccDNA. Further optimisation of gene editing approaches could bring us closer to a cure for HBV infections.
The antiviral therapy of HCV is much more efficient compared with those available for HBV. Specific DAA treatment regimens have been approved as first-line therapy for each HCV genotype. However, very few HCV vaccines have progressed to clinical trials owing to the high genetic diversity of HCV. A randomised trial (N Engl J Med) published in February, 2021, led by Andrea Cox (Johns Hopkins University School of Medicine, MD, USA) evaluated the safety and efficacy of a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost. Although the vaccine could elicit T-cell responses against HCV proteins, it unfortunately failed to lower the incidence of chronic HCV infection compared with placebo. To accelerate the research in HCV vaccines, the National Institute of Allergy and Infectious Diseases hosted a symposium (Vaccines against hepatitis C virus: Harnessing Immunity to Eliminate Global Hepatitis C) in March, 2022, on the latest research related to HCV vaccine development. New findings in HCV immunology and the emergence of new vaccine platforms, such as mRNA, were discussed.
In particular, Mansun Law from Scripps Institute (CA, USA) introduced the challenges in developing vaccine antigens based on HCV envelope glycoproteins E1E2. Bali Pulendran at Stanford University (CA, USA) shared his thoughts about rapid assessment of HCV vaccine candidates that are inspired by the development of Pfizer BNT162b2 mRNA vaccine. Although obstacles remain, scientists look forward to the success of HCV vaccines in the next decade.
Fewer than 10 years remain to reach the WHO goal of hepatitis elimination. As the world tries to recover from the COVID pandemic, a mysterious hepatitis has suddenly swept across many countries. As of June 7, 2022, more than 700 paediatric cases of an unexplained acute hepatitis have been reported since the first case appeared in the UK. Laboratory tests have ruled out all known hepatitis viruses. The potential association between adenovirus and the disease, which has been widely discussed in hospitals in the UK, is under investigation. Other risk factors, such as current or previous infection with SARS-COV-2, or side-effects of SARS-CoV-2 vaccines, are also being examined. So far, none of these hypotheses can fully explain the severe clinical manifestations of this acute hepatitis in children. Interestingly, contrary to reports from the UK, a survey published in June (MMWR Morb Mortal Wkly Rep) led by Anita Kambhampati of the US Centers for Disease Control and Prevention (GA, USA) showed no increase in the number of hepatitis-related emergency department visits or hospitalisation between Oct, 2021, and March, 2022, among children aged between 0 and 11 years, compared with pre-COVID-19 pandemic levels. Thus, whether the cases of unexplained hepatitis represent a new type of hepatitis or only one unidentified hepatitis type that has long existed, remains controversial. Now the outbreak is under close monitoring.
Regardless of impressive efforts made in prevention and treatment, major challenges still stand in the way of the goal of hepatitis elimination. In addition to drug development, attention also needs to be paid to inequities in health-care delivery, which is crucial for early diagnosis and treatment of hepatitis. eBioMedicine, as part of The Lancet Discovery Science, continues to serve as a publishing platform for translational studies about human diseases, including hepatitis.
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Published: July 2022
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DOI: https://doi.org/10.1016/j.ebiom.2022.104156
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© 2022 The Author(s). Published by Elsevier B.V.

作者: newchinabok 时间: 2022-7-22 19:59

本帖最后由 newchinabok 于 2022-7-22 19:59 编辑

还过十年，乙人生老病死，还有几个乙肝病人？乙肝不就攻克了吗

作者: tim889 时间: 2022-7-23 04:00

newchinabok 发表于 2022-7-22 03:59
还过十年，乙人生老病死，还有几个乙肝病人？乙肝不就攻克了吗

是的就怕再过十年药厂越来越没有动力搞新药

作者: newchinabok 时间: 2022-7-23 06:09

本帖最后由 newchinabok 于 2022-7-23 06:14 编辑

tim889 发表于 2022-7-23 04:00
是的就怕再过十年药厂越来越没有动力搞新药

有时去治愈，常常去帮助，总是去安慰，医学不就是这样吗？以前痨病，鲁迅，林徽因又有什么办法。现在乙肝和痨病不是一样吗

作者: sky8989 时间: 2022-7-23 15:43

newchinabok 发表于 2022-7-23 06:09
有时去治愈，常常去帮助，总是去安慰，医学不就是这样吗？以前痨病，鲁迅，林徽因又有什么办法。现在乙肝 ...

量子计算机不是出来了，对于研制新的药物也有着极大的优势，量子计算机能描绘出万亿计的分子组成，并且选择出其中最有可能的方法，这将提高人们发明新型药物的速度，并且能够更个性化的对于药理进行分析。目前的问题应该是根本就没完全了解乙肝病毒，不然借助于量子计算机应该挺快的啊，不至于搞个几十年。其他肝炎病毒都被攻克，就乙肝患者可怜啊。

作者: newchinabok 时间: 2022-7-23 16:43

本帖最后由 newchinabok 于 2022-7-23 16:44 编辑

sky8989 发表于 2022-7-23 15:43
量子计算机不是出来了，对于研制新的药物也有着极大的优势，量子计算机能描绘出万亿计的分子组成，并且选 ...

乙肝本质上是免疫疾病，为什么有的急性自愈，有的慢性化。病人免疫千差万别，攻克乙肝难度太大，研发新药这么多，没治好一个人，除了干挠素老牛拉破车

作者: sky8989 时间: 2022-7-23 18:45

增强乙肝感染者针对乙肝病毒的特异性免疫反应。细胞疗法、治疗性疫苗、PD-1 / PD-L1阻断剂等没有一个能治愈的

作者: pppq123 时间: 2022-7-23 22:17

悲哀的乙人
卑微地活着
都他妈是命
一声叹息。

作者: tim889 时间: 2022-7-24 00:29

靶点都不知道你量子计算个啥

作者: tim889 时间: 2022-7-24 01:25

要从根本上解决问题只能寄希望于CRISPR （需要进一步降低脱靶效应，提升安全性，以及提升药物递送效率）。或者类似CAR T这种细胞治疗

作者: lancas 时间: 2022-7-24 07:57

我觉着现在至少有降HBSAG的手段，综合治疗或许可以对病友治愈的几率再提升~
只要不同的药物研发不断推进，乙肝这部分也会被辐射到的。而且免疫性疾病虽然难，但是一旦攻破可能会得到除治疗乙肝之外更好的收益。
至于等不等的到

~~如N兄所说的“咱们一出生就没打算活着离开”，有条件的在正规医院试下干扰素，或许趁有时间找点乐子好了~~

作者: 乙肝人1949 时间: 2022-7-24 22:39

这个问题不重要，不热闹。

作者: tim889 时间: 2022-7-25 04:24

lancas 发表于 2022-7-23 15:57
我觉着现在至少有降HBSAG的手段，综合治疗或许可以对病友治愈的几率再提升~
只要不同的药物研发不断推进， ...

美国HBV研究的grant肯定是比HIV差远了。缺乏基础科学的支持很难有本质上的进展尤其是涉及复杂免疫系统的研究都是需要及其长期的投入没法指望药企

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