Novel liver fibrosis test for early detection and classification

DESCRIPTION (provided by applicant): The overall goal of this application is to develop and validate a potential biomarker based assay to determine if it can be used as a noninvasive test to detect the stage of hepatic fibrosis and to predict fibrosis progression in HIV/HCV co-infected patients. Significant fibrosis and cirrhosis are premalignant conditions that greatly increase the risk of the development of hepatocellular carcinoma (HCC). We have recently reported increases in a glycoform of an antibody directed toward many gram negative and positive bacteria (lectin-reactive anti-Gal IgG, LRAGG) in patients with liver fibrosis. LRAGG has shown superior discriminatory ability, as compared to clinically available non-invasive markers of liver fibrosis, i.e.Fibrosure/Fibrospect, in differentiating mild fibrosis (not a pre-malignant conditio) from advanced fibrosis (a pre- malignant condition). The Fibrosure assay, and other algorithm based tests use a combination of several serum biomarkers and patented algorithms to measure fibrogenesis of the liver. Due to their complexity and limited available data in distinguishing stages of fibrosis, especially pre- malignant conditions, these tests are considered in the clinical diagnostic field as investigational andmedically not necessary. Therefore, simple easy to use high sensitive assays are needed to accurately detect and classify fibrosis in HIV/HCV co- and mono-infected patients. Based on the recent reports that have shown increased peripheral levels of bacterial endotoxin in patients with hepatic fibrosis, we hypothesize that chronic exposure to bacterial products, such as endotoxin, might occur in patients with advanced liver disease due to HCV or HCV/HIV co- infection, and promote increased production of LRAGG. Changes in glycosylation on LRAGG as hepatic fibrosis progresses interfere with normal bactericidal processes. The outcome of enhanced bacterial exposure is stimulation and perpetuation of the inflammatory and fibrogenic pathways. In this phase I proofof concept study, we propose to assess whether this biomarker has potential utility as noninvasive indicator of the stage of fibrosis as well as their utility as predictive marker for fibrosis progression and better performers than the existing fibrosis tests using archived serum samples. In phase II, we will collaborate with our clinical collaborators and perform prospective studies using this biomarker. Since we have accumulated large datasets in HCV mono-infected patients, this study will be conducted in HIV/HCV co- and HCV mono-infected patients undergoing clinical evaluation to assess the histological severity of HCV- associated liver disease. Success of this proposal will determine the feasibility of using LRAGG as a novel biomarker for liver fibrosisclassification, and form a strong foundation for developing a clinical diagnostic and prognostic test. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The over-all goal of this proposal is to develop a novel biomarker based non- invasive liver fibrosis diagnostic test to distinguish mild fibrosis (not a pr-malignant condition) from advanced fibrosis (a pre-malignant condition) as well as to predict fibrosis progression in patients with HIV/HCV co-infection. In our research, we have identifiedincreases in a glycoform of an antibody directed toward many gram negative and positive bacteria (lectin-reactive anti-Gal IgG, LRAGG) in patients with liver fibrosis. In this application we propose to validate the ability of this promising biomarker to differentiate among patients with different stages of fibrosis and demonstrate superior performance of this assay compared to the existing complex, technically challenging Fibrotest assay in liver fibrosis classification ad progression. Successful completionof this project will generate a simple and non-invasive test for liver fibrosis applicable to infection induced liver disease.