Applying an 'omics' approach to predict hepatic decompensation events and hepatocellular carcinoma in veterans after HCV cure with direct acting antiviral therapy

应用“组学”方法预测退伍军人在使用直接作用抗病毒疗法治愈 HCV 后的肝失代偿事件和肝细胞癌

• 批准号: 10548114
• 负责人: Cynthia A Moylan
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548114
• 关键词: Alcohol consumption; Amino Acids; Antiviral Agents; Antiviral Therapy; Ascites; Bile Acids; Biological; Biological Markers; Biology; Blood; Caring; Ceramides; Cessation of life; Cirrhosis; Clinical; Development; Disease; Enrollment; Ensure; Esophagus; Etiology; Event; Fibrosis; Future; Goals; HCV Cirrhosis; HIV; HIV/HCV; Health; Health Personnel; Hemorrhage; Hepatic; Hepatic Encephalopathy; Hepatitis C; Hepatitis C Therapy; Hepatitis C co-infection; Hepatitis C virus; Knowledge; Laboratories; Lecithin; Lipids; Liver; Liver Fibrosis; Liver diseases; Mediating; Membrane Lipids; Metabolic; Metabolic syndrome; Modeling; Nested Case-Control Study; Obesity; Observational Study; Pathogenesis; Pathway interactions; Patients; Peripheral; Peritonitis; Persons; Pilot Projects; Plasma; Primary carcinoma of the liver cells; Proteins; Proteomics; Residual state; Risk; Site; Sphingomyelins; Subgroup; Testing; Tissues; Transcript; Translational Research; United States; United States Department of Veterans Affairs; Validation; Veterans; Viral; acylcarnitine; biomarker validation; biosignature; case control; clinical predictors; co-infection; cohort; comorbidity; design; fatty acid oxidation; follow-up; high dimensionality; high risk; improved; lipid metabolism; liver cancer model; liver injury; metabolic profile; metabolomics; military veteran; mortality; multiple omics; new therapeutic target; non-alcoholic fatty liver disease; novel; novel marker; novel therapeutics; peripheral blood; predict clinical outcome; predictive modeling; prognostic; prospective; response; risk prediction; risk stratification; therapeutic target; transcriptomics

The Department of Veterans Affairs is the single largest hepatitis C virus infection health care provider in the United States. Since the introduction of direct acting antivirals for the treatment of HCV infection in 2014, VA has cured over 100,000 Veterans. Due to the high rate of comorbidities in the veteran population, including HIV co- infection, alcohol use, and obesity and metabolic syndrome, rates of severe liver fibrosis prior to DAA therapy are high and likely to persist despite cure. While sustained virologic response (SVR), a virologic surrogate of HCV cure, is associated with decreased risk of hepatic decompensation (i.e., ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), esophageal variceal bleed), hepatocellular carcinoma (HCC), and liver-related mortality, Veterans with severe liver fibrosis prior to cure remain at high risk for such events and all-cause mortality. To date there are no reliable laboratory tests or biomarkers to differentiate patients with the greatest risk of post-SVR decompensation events, HCC, and liver-related death. We have discovered a group of lipid and lipid-related metabolites that accurately predict risk of liver-related complications in people with HIV and HCV co-infection, approximately 2 years prior to the incident event. We propose to validate this biomarker in a cohort of patients who have achieved HCV cure. Once validated, we propose to test the biomarker in a real- world Veteran cohort to ensure generalizability. Successful validation of the metabolite profile will support translational investigations to gain an understanding of the fundamental biology associated with the metabolites and potential pathways for therapeutic targets of fibrosis and HCC. For Aim 1 we will validate a biosignature of circulating lipid and lipid-related metabolites that is predictive of incident hepatic decompensation events and HCC in patients with cirrhosis who achieve HCV cure with DAA therapy. We will conduct a nested case-control study, leveraging a pre-existing cohort of patients with HCV and cirrhosis who achieved cure with DAA therapies and are followed prospectively for liver-related complications. We will perform comprehensive targeted metabolomic profiling to validate a prognostic metabolic profile. For Aim 2 we will develop integrated “clinico- metabolic” models incorporating clinical variables and metabolite biomarkers that identify Veterans at greatest risk of hepatic decompensation events and HCC after achieving HCV cure with DAA therapy. We will enroll Veterans with severe liver disease into a prospective, observational study, conducted at two VA sites, after DAA- induced HCV cure. Using a nested case-control design we will complete comprehensive targeted metabolite profiling to develop optimized models to predict liver-related events. For Aim 3 we will use an integrated high- dimensional biology approach of peripheral blood and liver tissue to optimize blood-based predictive models of post-SVR incident HCC in Veterans and identify novel biologic pathways to inform future therapeutic target development. Using liver tissue from Veterans who develop incident HCC after HCV cure with DAA therapies we will integrate transcriptomic, metabolomic, and proteomic profiling to identify novel biologic pathways for which metabolite biomarkers in the plasma can be developed. This pilot study will generate knowledge of biologic pathways that will serve as the target for disease biomarkers and novel therapeutics for future study.

退伍军人事务部是最大的丙型肝炎病毒感染医疗保健提供者 美国。自从2014年引入直接作用抗病毒药以治疗HCV感染以来 治愈了100,000多名退伍军人。由于退伍军人人口的合并症率很高，包括HIV共同 DAA治疗之前，感染，饮酒以及肥胖和代谢综合征，严重的肝纤维化速率 很高，可能会持续存在目的地治疗。虽然持续的病毒学反应（SVR），但 HCV治疗与肝脏代表性降低的风险降低有关（即腹水，赞助的细菌 腹膜炎（SBP），肝脑病（HE），食管静脉体出血，肝细胞癌（HCC）， 和肝有关的死亡率，治愈前具有严重肝纤维化的退伍军人仍处于此类事件和 全因死亡率。迄今为止，还没有可靠的实验室测试或生物标志物来区分患者 SVR后代理事件，HCC和与肝有关的死亡的最大风险。我们发现了一个小组 脂质和脂质相关的代谢产物，可准确预测HIV患者的肝脏相关并发症的风险 和HCV共感染，大约在事件事件发生前2年。我们建议验证这种生物标志物 在达到HCV治疗的一群患者中。一旦得到验证，我们建议在实现中测试生物标志物 世界退伍军人队列以确保普遍性。代谢物概况的成功验证将支持 转化投资以了解与代谢物相关的基本生物学 以及纤维化和HCC热靶标的潜在途径。对于目标1，我们将验证一个生物签名 循环脂质和脂质相关的代谢产物可预测出现肝功能失调事件和 肝硬化患者的HCC可以通过DAA治疗获得HCV治疗。我们将进行嵌套的情况对照 研究，利用HCV和Cirrhosis患者的既有队列均可治愈DAA疗法 并遵循与实时相关并发症的前瞻性。我们将执行全面的目标 代谢组分析以验证预后的代谢谱。对于AIM 2，我们将开发综合的“诊所 - 代谢”模型，结合了临床变量和代谢物生物标志物，这些模型识别出最大的退伍军人 通过DAA治疗实现HCV治疗后，肝功能不全事件和HCC的风险。我们将注册 患有严重肝病的退伍军人进入了一项前瞻性，观察性研究，在两个VA部位进行，在DAA-之后 诱导HCV治疗。使用嵌套的情况对照设计，我们将完成全面的靶向代谢物 分析以开发优化的模型以预测与肝脏相关的事件。对于AIM 3，我们将使用一个集成的高级 外周血和肝组织的维度生物学方法，以优化基于血液的预测模型 SVR后事件HCC在退伍军人中，并确定新的生物学途径，以告知未来的治疗靶点 发展。使用来自DAA疗法的HCV治疗后出现事件HCC的退伍军人的肝组织 我们将整合转录组，代谢组和蛋白质组学分析，以鉴定新的生物学途径 可以开发血浆中哪种代谢物生物标志物。该试点研究将产生有关生物学的知识 将作为疾病生物标志物的靶标和未来研究的新疗法的途径。