Stratified Medicine to Optimise Treatment for Hepatitis C Virus Infection

分层医学优化丙型肝炎病毒感染的治疗

• 批准号: MR/K01532X/1
• 负责人: Eleanor Barnes
• 金额: $ 531.1万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK01532X%2F1
• 关键词: Stratified; Medicine; Optimise; Treatment; Hepatitis

Stratified Medicine is a type of personalised medicine where treatments are directed specifically at people who are most likely to respond to them, often using detailed information about individuals. We believe that the treatment of patients with hepatitis C virus (HCV) would benefit enormously from this approach. About 300,000 people in the UK are infected with HCV, only half of whom have been diagnosed as carrying the virus. The virus has a high tendency to persist as the body's immune system is usually unable to clear infection. HCV infects the liver, causing liver cirrhosis (scarring), liver failure and liver cancer. HCV exists in different genetic forms called genotypes. In the UK, most infections are caused by either genotype 1 or 3, which occur at about equal frequency. Treatment for HCV has consisted of two drugs interferon and ribavirin. Approximately half of patients receiving treatment respond and are successfully cured of infection. Until recently, no additional drugs were available to treat those who failed treatment. The number of people who develop severe liver disease from HCV is expected to continue to rise over the next two decades. Those who develop liver failure can be given a transplant but the transplanted organ is rapidly infected with the virus and often becomes diseased within a few years.New drugs, which directly act against the virus (called DAAs), are being used in combination with interferon and ribavirin in NHS patients for the first time in the clinic in 2012. DAA drugs increase the cure rate to 70%. However, there are drawbacks: the drugs are very expensive costing in excess of £20,000 per patient; the virus can become resistant to new drugs, rendering them useless and increasing the frequency of resistant strains in the community; the first wave of new drugs are effective against genotype 1 but not genotype 3 strains; additional side effects can be associated with the new drugs, so that treatment may be stopped before the virus is eliminated.We have developed a team of experts in the clinical care of HCV patients, who will work with HCV scientists, in partnership with industry. Combining expertise in this way should serve to benefit patients. The group is already working well together collecting blood samples and information from 10,000 people across the UK into a single bio-bank, supported by government infrastructure. We aim to assess the genetic make up of both the virus and the infected person. We will also look at the way in which the immune system responds to the virus, and measure protein markers in the blood. We will assess these in patients receiving therapy and also in those with serious liver disease to try to work out in advance who will develop further complications of their disease. A unique feature of our group will be the ability to draw all these strands together. We will develop new technologies so that we rapidly obtain the host and viral sequence in thousands of infected people. In this way we hope to improve treatment options for patients so that the right therapies are given to patients who are most likely to benefit from them. We will focus our efforts especially on HCV genotype 3, which is a particular problem in UK patients, and also on patients with more serious liver disease, who are more difficult to treat with the new therapies. Ultimately we hope to predict the likelihood of treatment response in individuals, and possibly through our investigations develop new therapies. This could bring considerable cost-savings to the NHS and means that drugs are given to HCV-infected people who are most likely to respond to them.

分层医学是一种个性化医学，治疗针对最有可能对其有反应的人，通常使用关于个人的详细信息。我们相信丙型肝炎病毒(丙型肝炎病毒)患者的治疗将从这一方法中受益匪浅。在英国，大约有30万人感染了丙型肝炎病毒，其中只有一半人被诊断为携带病毒。由于身体的免疫系统通常无法清除感染，这种病毒有很高的持久性。丙型肝炎病毒感染肝脏，导致肝硬变(疤痕形成)、肝功能衰竭和肝癌。丙型肝炎病毒以不同的基因形式存在，称为基因类型。在英国，大多数感染是由1型或3型引起的，这两种感染的发生频率大致相同。丙型肝炎病毒的治疗包括两种药物干扰素和利巴韦林。接受治疗的患者中约有一半对感染有反应并成功治愈。直到最近，还没有其他药物可用于治疗那些治疗失败的人。在接下来的20年里，感染丙型肝炎病毒而患上严重肝病的人数预计将继续上升。那些出现肝功能衰竭的人可以接受移植，但移植的器官很快就会感染病毒，通常在几年内就会患病。2012年，NHS患者首次在临床上使用直接对抗病毒的新药(称为DAA)与干扰素和利巴韦林联合使用。DAA药物将治愈率提高到70%。然而，这些药物也有缺点：药物非常昂贵，每个患者的成本超过20,000 GB；病毒可能对新药产生抗药性，使它们无用，并增加社区中耐药株的频率；第一波新药对基因1株有效，但对基因3株无效；新药可能会产生额外的副作用，因此可能在病毒被消灭之前停止治疗。我们已经开发了一个丙型肝炎患者临床护理专家团队，他们将与丙型肝炎病毒科学家合作，与产业界合作。以这种方式结合专业知识应该会让患者受益。该组织已经很好地合作，在政府基础设施的支持下，将英国各地1万人的血液样本和信息收集到一个单一的生物库中。我们的目标是评估病毒和感染者的基因构成。我们还将研究免疫系统对病毒的反应方式，并测量血液中的蛋白质标记物。我们将对接受治疗的患者和患有严重肝病的患者进行评估，试图提前找出谁会进一步发展为他们的疾病的并发症。我们团队的一个独特功能将是将所有这些链结合在一起的能力。我们将开发新技术，以便快速获得数千名感染者的宿主和病毒序列。通过这种方式，我们希望改善患者的治疗选择，以便为最有可能从中受益的患者提供正确的治疗。我们将把重点放在丙型肝炎病毒3型上，这在英国患者中是一个特殊的问题，也将集中在更严重的肝病患者上，这些患者更难用新的疗法治疗。最终，我们希望预测个体治疗反应的可能性，并可能通过我们的研究开发新的治疗方法。这可能会为NHS带来相当大的成本节约，并意味着药物被给予最有可能对药物产生反应的丙型肝炎病毒感染者。

项目成果

Genome-To-Genome Virus-Host Analysis Reveals HCV Genotype 3 Viral Polymorphisms Linked Viral Load and to Host HLA Class-I/II and IL28B Alleles

基因组到基因组病毒宿主分析揭示 HCV 基因型 3 病毒多态性与病毒载量以及宿主 HLA I/II 类和 IL28B 等位基因相关

• DOI: 10.1016/s0168-8278(16)00675-9
• 发表时间: 2016
• 期刊: Journal of Hepatology
• 影响因子: 25.7
• 作者: Azim Ansari M

Targeted reconstruction of T cell receptor sequence from single cell RNA-seq links CDR3 length to T cell differentiation state.

• DOI: 10.1093/nar/gkx615
• 发表时间: 2017-09-19
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Afik S;Yates KB;Bi K;Darko S;Godec J;Gerdemann U;Swadling L;Douek DC;Klenerman P;Barnes EJ;Sharpe AH;Haining WN;Yosef N
• 通讯作者: Yosef N

Genome-to-genome analysis highlights the effect of the human innate and adaptive immune systems on the hepatitis C virus.

• DOI: 10.1038/ng.3835
• 发表时间: 2017-05
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Ansari MA;Pedergnana V;L C Ip C;Magri A;Von Delft A;Bonsall D;Chaturvedi N;Bartha I;Smith D;Nicholson G;McVean G;Trebes A;Piazza P;Fellay J;Cooke G;Foster GR;STOP-HCV Consortium;Hudson E;McLauchlan J;Simmonds P;Bowden R;Klenerman P;Barnes E;Spencer CCA
• 通讯作者: Spencer CCA

ve-SEQ: Robust, unbiased enrichment for streamlined detection and whole-genome sequencing of HCV and other highly diverse pathogens.

• DOI: 10.12688/f1000research.7111.1
• 发表时间: 2015
• 期刊: F1000Research
• 作者: Bonsall D;Ansari MA;Ip C;Trebes A;Brown A;Klenerman P;Buck D;STOP-HCV Consortium;Piazza P;Barnes E;Bowden R
• 通讯作者: Bowden R

N-Glycosylation of the Na+-Taurocholate Cotransporting Polypeptide (NTCP) Determines Its Trafficking and Stability and Is Required for Hepatitis B Virus Infection.

Na+ - taurochaly共转运多肽（NTCP）的N-糖基化决定了其运输和稳定性，并且是乙型肝炎病毒感染所必需的。

• DOI: 10.1371/journal.pone.0170419
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Appelman MD;Chakraborty A;Protzer U;McKeating JA;van de Graaf SF
• 通讯作者: van de Graaf SF