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.

退伍军人事务部是全国最大的丙型肝炎病毒感染医疗保健提供者 美国。自2014年推出治疗丙型肝炎病毒感染的直接作用抗病毒药物以来，退伍军人管理局 治愈了10万多名退伍军人。由于退伍军人人群中的高并存率，包括艾滋病毒联合感染 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 很高，尽管治愈了，但很可能会持续下去。虽然持续病毒学应答(SVR)是一种病毒学替代品 治愈丙型肝炎病毒与降低肝脏失代偿(即腹水、自发性细菌)的风险有关 腹膜炎(SBP)、肝性脑病(HE)、食道静脉曲张出血、肝细胞癌、 和肝脏相关的死亡率，在治愈之前有严重肝纤维化的退伍军人仍然是此类事件的高危人群， 全因死亡。到目前为止，还没有可靠的实验室测试或生物标志物来区分患者和 SVR后失代偿事件、肝细胞癌和肝脏相关死亡的风险最大。我们发现了一群人 准确预测HIV感染者肝脏相关并发症风险的脂质和脂质相关代谢物 和丙型肝炎病毒混合感染，大约在事件发生前2年。我们建议验证这个生物标记物 在一组已治愈丙型肝炎病毒的患者中。一旦得到验证，我们建议在真实的- 世界经验丰富的队伍，以确保可推广性。代谢物图谱的成功验证将支持 翻译研究以了解与代谢物相关的基础生物学 以及肝纤维化和肝细胞癌治疗靶点的潜在途径。对于目标1，我们将验证生物签名 循环脂质和脂质相关代谢物可预测发生的肝脏失代偿事件和 用DAA疗法治愈丙型肝炎病毒的肝硬变患者的肝细胞癌。我们将进行嵌套病例对照研究 这项研究利用了通过DAA疗法治愈的先前存在的丙型肝炎和肝硬变患者队列 并对肝脏相关并发症进行前瞻性随访。我们将全面有针对性地进行 代谢组谱分析以验证预测代谢谱。对于目标2，我们将开发综合的“临床-- 结合临床变量和代谢物生物标记物的新陈代谢模型，最大限度地识别退伍军人 用DAA疗法治愈丙型肝炎后发生肝脏失代偿事件和肝细胞癌的风险。我们将招收 将患有严重肝病的退伍军人纳入一项前瞻性、观察性研究，该研究在两个VA站点进行，在DAA- 诱导丙型肝炎治愈。采用嵌套式病例对照设计，完成全面靶向代谢物 分析以开发预测肝脏相关事件的优化模型。对于AIM 3，我们将使用综合高音- 外周血和肝组织的空间生物学方法优化血液学预测模型 退伍军人SVR后发生肝癌并确定新的生物途径以指导未来的治疗目标 发展。用DAA疗法治愈丙型肝炎后发生肝癌的退伍军人的肝组织 我们将整合转录组、代谢组学和蛋白质组学，以确定新的生物途径 可以开发出血浆中的哪些代谢物生物标志物。这项初步研究将产生生物学方面的知识 将作为疾病生物标记物和未来研究的新疗法的靶点的途径。