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.

退伍军人事务部是美国最大的丙型肝炎病毒感染医疗保健提供者 美国自 2014 年推出直接作用抗病毒药物治疗 HCV 感染以来，VA 已 治愈了超过 100,000 名退伍军人，因为退伍军人中合并症的发生率很高，包括艾滋病毒合并症。 感染、饮酒、肥胖和代谢综合征、DAA 治疗前严重肝纤维化的发生率 持续病毒学应答（SVR）是病毒学替代指标，尽管治愈，但仍较高且可能持续存在。 HCV 治愈与肝功能失代偿风险降低相关（即腹水、自发性细菌感染） 腹膜炎 (SBP)、肝性脑病 (HE)、食管静脉曲张出血、肝细胞癌 (HCC)、 和与肝脏相关的死亡率，治愈前患有严重肝纤维化的退伍军人仍然面临此类事件的高风险， 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 后失代偿事件、HCC 和肝脏相关死亡的最大风险。 脂质和脂质相关代谢物可准确预测艾滋病毒感染者肝脏相关并发症的风险 和 HCV 混合感染，大约在事件发生前 2 年，我们建议验证该生物标志物。 一旦验证，我们建议在一组已实现 HCV 治愈的患者中测试该生物标志物。 世界退伍军人队列确保代谢物概况的成功验证将支持。 转化研究以了解与代谢物相关的基础生物学 对于目标 1，我们将验证纤维化和 HCC 治疗靶点的潜在途径。 循环脂质和脂质相关代谢物可预测发生的肝代偿失调事件和 通过 DAA 治疗实现 HCV 治愈的肝硬化患者的 HCC 我们将进行巢式病例对照。 该研究利用了一组已通过 DAA 疗法治愈的 HCV 和肝硬化患者 并对肝脏相关并发症进行前瞻性随访。 代谢组学分析以验证预后代谢分析 对于目标 2，我们将开发集成的“临床-”。 代谢”模型结合了临床变量和代谢生物标志物，最大程度地识别退伍军人 通过 DAA 治疗实现 HCV 治愈后发生肝失代偿事件和 HCC 的风险 我们将参加。 患有严重肝病的退伍军人参加了一项前瞻性观察性研究，该研究在 DAA 后在两个 VA 地点进行 使用嵌套病例对照设计，我们将完成全面的靶向代谢物治疗。 对于目标 3，我们将使用集成的高通量分析来开发优化模型来预测肝脏相关事件。 外周血和肝组织的三维生物学方法，以优化基于血液的预测模型 退伍军人 SVR 事件后 HCC 并确定新的生物学途径以告知未来的治疗目标 使用 DAA 疗法治愈 HCV 后发生 HCC 的退伍军人的肝组织。 我们将整合转录组学、代谢组学和蛋白质组学分析，以确定新的生物学途径 可以开发血浆中的哪些代谢生物标志物。这项试点研究将产生生物知识。 途径将作为疾病生物标志物和未来研究的新疗法的目标。