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: 10703227
• 负责人: Jose Daniel Debes
• 金额: $ 17.4万
• 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/10703227
• 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; 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; Recommendation; Reporting; Research; Risk; Risk Factors; Sampling; 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; viral detection

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， 全球癌症相关死亡的原因。HCC发生在慢性肝病的背景下，并且感染 B型肝炎（HBV）和C型肝炎病毒（HCV）是全世界最常见的潜在HCC危险因素。 感染HIV的人患HCC的风险更高。事实上，艾滋病毒阳性的人往往是共同的， 感染HBV或HCV，引发肝脏相关并发症。此外，研究表明， 显示，HIV阳性的HBV或HCV感染者发生HCC的年龄比他们的HIV感染者更年轻， 消极的对应。目前，HIV感染者和合并病毒性肝炎感染者有患HCC的风险， 建议每6个月进行一次肝脏超声检查，目的是“视觉上”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。 我们假设，采用标准化免疫相关血液生物标志物的非视觉筛查方法 可能是一个明智的替代方法。我们的研究小组最近发现了一系列免疫标记物， 肝炎患者的血清能够预测HCC的未来发展，即使癌症 发生在两年后 在这个项目中，我们将研究是否一个超免疫环境，产品的持续存在， 体内的病毒，可以导致血清中可测量的免疫分析物，从而预测早期HCC。使用我们 在拉丁美洲，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， 标志物来预测早期HCC的发展。 在具体目标1中，我们将确定是否在合并感染的人的血清中存在新的免疫特征， 病毒性肝炎B或C和HIV在肝细胞癌患者中的差异表达 （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 为了评估通过多重细胞因子分析测量的预定义的一组免疫分析物是否与通过多重细胞因子分析测量的免疫分析物有差异， 与年龄性别匹配的无HCC的HIV对照组相比，HIV感染的HCC病例中的表达。 在《特定目标2》中，我们将确定免疫特征是否能准确区分艾滋病毒感染者和非感染者。 合并感染B或C型肝炎和肝细胞癌的个体与无肿瘤个体 （验证阶段）。我们将从一个艾滋病毒高流行地区的艾滋病毒感染者中收集样本， 巴西通过现有的ESCALON研究网络作为验证集，以确定签名的能力， 检测HCC。 这项研究将产生与HIV感染者中HCC早期检测生物标志物相关的创新数据。 并为HIV中HCC生物标志物的更大前瞻性队列提供基础。