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

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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.