Immune profiling to detect viral hepatitis-related liver cancer in HIV-infected patients

免疫分析检测 HIV 感染者中病毒性肝炎相关肝癌

• 批准号: 10536532
• 负责人: Jose Daniel Debes
• 金额: $ 22.65万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536532
• 关键词: AFP gene; Address; Adherence; Africa; Age; Apoptosis; Biological; Biological Markers; Blood; Blood Tests; Blood Vessels; Brazil; CD4 Lymphocyte Count; Cancer Etiology; Cessation of life; Chronic; Cirrhosis; Collaborations; Data; Detection; Development; Diagnostic; Early Diagnosis; Enrollment; Environment; Europe; Future; Gastroenterology; Gender; Goals; Guidelines; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV/HCV; Hepatic; Hepatitis; Hepatitis B; Hepatitis B Infection; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; IL3 Gene; Immune; Immunologic Markers; Individual; Infection; International; Latin America; Lead; Liver; Liver Cirrhosis; Malignant Neoplasms; Malignant neoplasm of liver; Measurable; Measures; Nodule; Patients; Performance; Peripheral; Persons; Phase; Population; Primary carcinoma of the liver cells; Process; Prospective cohort; Proteins; Reporting; Research; Risk; Risk Factors; Sampling; Second Primary Neoplasms; Secondary to; Sensitivity and Specificity; Series; Serum; Site; South American; Standardization; TNFSF10 gene; Testing; Time; Training; Transplantation; Ultrasonography; United States; Validation; Variant; Vascular Endothelial Growth Factors; Viral hepatitis; Virus; Virus Diseases; Visual; chronic liver disease; co-infection; cohort; cytokine; differential expression; early detection biomarkers; hepatocyte injury; high risk; immunogenic; immunoreaction; innovation; interleukin-22; liver transplantation; novel; prospective; public health relevance; screening; tumor; ultrasound

Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver and the second most common cause of cancer-related death worldwide. HCC occurs in the setting of chronic liver disease, and infections with hepatitis B (HBV) and hepatitis C virus (HCV), are the most common underlying HCC risk factor worldwide. The risk of HCC is heightened in those infected with HIV. Indeed, HIV-positive individuals are frequently co- infected with HBV or HCV, priming them for liver-related complications. Moreover, studies have consistently shown that HIV-positive individuals living with HBV or HCV develop HCC at younger ages than their HIV- negative counterparts. Currently, individuals with HIV and co-infection with viral hepatitis at risk for HCC are advised to undergo ultrasonography of the liver every 6 months with the goal of “visually” identifying a tumor. This visual screening approach has poor adherence and is dependent on the ultrasound operator expertise. We hypothesize that a non-visual screening approach with standardized immune-related blood biomarkers may be a sensible alternative approach. Our group recently identified a series of immune markers detected in serum of patients with hepatitis that were able to predict the future development of HCC, even when the cancer occurred two years later. In this project, we will investigate whether a hyper-immune environment, product of the continuous presence of the virus in body, could lead to measurable immune analytes in serum so as to predict early HCC. Using our multinational on-going collaborations of the SALRN and ESCALON networks in Latin America, we propose to cross-sectionally and prospectively evaluate peripheral immune variations in HIV-infected individuals as markers to predict early HCC development. In Specific Aim 1, we will determine if novel immune signatures in the serum of persons co-infected with viral hepatitis B or C and HIV are differentially expressed in those with hepatocellular carcinoma (discovery phase). We will analyze serum samples collected via SALRN and ESCALON studies as a training set to evaluate if a pre-defined panel of immune analytes measured via multiplex cytokine analysis is differentially expressed in HIV-infected HCC cases compared to age-gender matched HIV controls without HCC. In Specific Aim 2, we will determine if immune signatures can accurately differentiate HIV-infected individuals co-infected with hepatitis B or C with hepatocellular carcinoma from those without tumor (validation phase). We will collect samples from HIV-infected subjects in a single HIV high-endemicity site in Brazil via the existing ESCALON study network as a validation set to determine the ability of the signature to detect HCC. This study will generate innovative data related to biomarkers for early detection of HCC in HIV-infected individuals and provide the basis for a larger prospective cohort for HCC biomarkers in HIV.

肝细胞癌 (HCC) 是最常见的肝脏恶性肿瘤，也是第二常见的肝脏恶性肿瘤 全世界癌症相关死亡的原因是慢性肝病和感染。 乙型肝炎 (HBV) 和丙型肝炎病毒 (HCV) 是全球最常见的潜在 HCC 危险因素。 事实上，HIV 阳性个体经常患有 HCC。 此外，研究一致表明，感染乙型肝炎病毒或丙型肝炎病毒的人容易出现肝脏相关并发症。 研究表明，感染 HBV 或 HCV 的 HIV 阳性个体比 HIV 感染者更年轻地患上 HCC。 目前，HIV 感染者和病毒性肝炎合并感染者有罹患 HCC 的风险。 建议每 6 个月进行一次肝脏超声检查，目的是“目视”识别肿瘤。 这种视觉筛查方法的依从性较差，并且依赖于超声操作员的专业知识。 我们追求一种采用标准化免疫相关血液生物标志物的非视觉筛查方法 我们的小组最近发现了一系列免疫标记物，这可能是一种明智的替代方法。 肝炎患者的血清能够预测 HCC 的未来发展，即使癌症已经发生 发生在两年后。 在这个项目中，我们将调查超免疫环境是否是持续存在的产物 体内的病毒可能会导致血清中产生可测量的免疫分析物，从而利用我们的方法预测早期肝癌。 拉丁美洲的 SALRN 和 ESCALON 网络正在进行的跨国合作，我们建议 横断面和前瞻性地评估 HIV 感染者的外周免疫变异 预测早期 HCC 发展的标志物。 在具体目标 1 中，我们将确定同时感染者的血清中是否存在新的免疫特征 乙型或丙型病毒性肝炎和 HIV 在肝细胞癌患者中存在差异表达 （发现阶段）我们将分析通过 SALRN 和 ESCALON 研究收集的血清样本作为训练集。 评估通过多重细胞因子分析测量的预定义免疫分析物组是否存在差异 与年龄性别匹配的无 HCC 的 HIV 对照相比，HIV 感染的 HCC 病例中表达。 在具体目标 2 中，我们将确定免疫特征是否可以准确区分 HIV 感染者 合并感染乙型或丙型肝炎且无肿瘤的肝细胞癌的个体 （验证阶段）我们将从一个艾滋病毒高流行地点的艾滋病毒感染者身上收集样本。 巴西通过现有的 ESCALON 研究网络作为验证集来确定签名的能力 检测肝癌。 这项研究将生成与生物标志物相关的创新数据，用于早期检测 HIV 感染者的 HCC 个体，并为 HIV 中 HCC 生物标志物的更大前瞻性队列提供基础。