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

摘要肝细胞癌是肝脏最常见的恶性肿瘤，也是第二常见的恶性肿瘤。 全球与癌症相关的死亡原因。肝细胞癌发生在慢性肝病的背景下，感染 乙肝病毒(乙肝)和丙型肝炎病毒(丙型肝炎病毒)是全球最常见的潜在肝癌危险因素。 那些感染艾滋病毒的人患肝癌的风险更高。事实上，艾滋病毒阳性的人经常是共同的 感染了乙肝病毒或丙型肝炎病毒，为肝脏相关的并发症做好了准备。此外，研究一致地表明 研究表明，携带乙肝病毒或丙型肝炎病毒的艾滋病毒阳性者比他们的艾滋病毒携带者患肝癌的年龄更早。 消极的对应物。目前，感染艾滋病毒和合并感染病毒性肝炎的人有患肝癌的风险 建议每6个月进行一次肝脏超声检查，以“肉眼”识别肿瘤。 这种目视筛查方法依从性差，并且依赖于超声操作员的专业知识。 我们假设一种带有标准化免疫相关血液生物标志物的非目视筛查方法 这可能是一种明智的替代方法。我们的小组最近发现了一系列免疫标志物，在 肝炎患者的血清能够预测肝细胞癌的未来发展，即使当癌症 发生在两年后。 在这个项目中，我们将调查一种超免疫环境，即持续存在的 体内的病毒，可导致血清中可测的免疫分析，从而预测早期肝细胞癌。使用我们的 SALRN和Escalon网络在拉丁美洲正在进行的跨国合作，我们建议 横断面和前瞻性评估HIV感染者的外周免疫变异 预测早期肝细胞癌发展的标志物。 在特定的目标1中，我们将确定联合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与HIV在肝细胞癌中的差异表达 (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培训集 评估通过多重细胞因子分析测量的预定义免疫分析物小组是否具有差异性 在感染艾滋病毒的肝细胞癌病例中的表达与年龄性别匹配的未患肝细胞癌的艾滋病毒对照相比。 在具体目标2中，我们将确定免疫特征是否能准确地区分艾滋病毒感染者 无肿瘤患者合并乙型或丙型肝炎合并肝细胞癌患者 (验证阶段)。我们将在一个艾滋病毒高流行地点收集艾滋病毒感染者的样本 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 检测肝细胞癌。 这项研究将产生与生物标记物相关的创新数据，用于早期检测艾滋病毒感染的肝细胞癌 并为HIV中更大规模的肝癌生物标记物的前瞻性队列奠定了基础。

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.