The Department of Veterans Affairs is the single largest hepatitis C virus infection health care provider in the United States. Since the introduction of direct acting antivirals for the treatment of HCV infection in 2014, VA has cured over 100,000 Veterans. Due to the high rate of comorbidities in the veteran population, including HIV co- infection, alcohol use, and obesity and metabolic syndrome, rates of severe liver fibrosis prior to DAA therapy are high and likely to persist despite cure. While sustained virologic response (SVR), a virologic surrogate of HCV cure, is associated with decreased risk of hepatic decompensation (i.e., ascites, spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), esophageal variceal bleed), hepatocellular carcinoma (HCC), and liver-related mortality, Veterans with severe liver fibrosis prior to cure remain at high risk for such events and all-cause mortality. To date there are no reliable laboratory tests or biomarkers to differentiate patients with the greatest risk of post-SVR decompensation events, HCC, and liver-related death. We have discovered a group of lipid and lipid-related metabolites that accurately predict risk of liver-related complications in people with HIV and HCV co-infection, approximately 2 years prior to the incident event. We propose to validate this biomarker in a cohort of patients who have achieved HCV cure. Once validated, we propose to test the biomarker in a real- world Veteran cohort to ensure generalizability. Successful validation of the metabolite profile will support translational investigations to gain an understanding of the fundamental biology associated with the metabolites and potential pathways for therapeutic targets of fibrosis and HCC. For Aim 1 we will validate a biosignature of circulating lipid and lipid-related metabolites that is predictive of incident hepatic decompensation events and HCC in patients with cirrhosis who achieve HCV cure with DAA therapy. We will conduct a nested case-control study, leveraging a pre-existing cohort of patients with HCV and cirrhosis who achieved cure with DAA therapies and are followed prospectively for liver-related complications. We will perform comprehensive targeted metabolomic profiling to validate a prognostic metabolic profile. For Aim 2 we will develop integrated “clinico- metabolic” models incorporating clinical variables and metabolite biomarkers that identify Veterans at greatest risk of hepatic decompensation events and HCC after achieving HCV cure with DAA therapy. We will enroll Veterans with severe liver disease into a prospective, observational study, conducted at two VA sites, after DAA- induced HCV cure. Using a nested case-control design we will complete comprehensive targeted metabolite profiling to develop optimized models to predict liver-related events. For Aim 3 we will use an integrated high- dimensional biology approach of peripheral blood and liver tissue to optimize blood-based predictive mo...