While direct-acting antivirals (DAAs) cure chronic hepatitis C virus (HCV) infection in almost all patients, some patients remain at risk of liver disease despite HCV cure. In order to identify risk factors indicating liver-related morbidity and death after viral cure, we included 6982 patients from the national multicenter real-world German Hepatitis C Registry with regular follow-up visits for up to 7 years after DAA therapy. Definitions for normal liver function tests (in women/men) were alanine aminotransferase (ALT; <= 35/<= 50 U/L), ALT according to American Association for the Study of Liver Diseases (AASLD; <= 19/<= 30 U/L), and gamma-glutamyltransferase (GGT; <= 40/<= 60 U/L). In our cohort, 97.4% of patients achieved sustained virologic response (SVR). At 24 weeks after SVR (SVR24), elevated ALT occurred in 657/6982 (9.4%), elevated ALT (AASLD) in 2609/6982 (37.4%), and elevated GGT in 1777/6982 (25.5%) patients. Risk factors for increased ALT at SVR24 were obesity, alcohol, cirrhosis, elevated baseline ALT, and non-SVR. Increased GGT at SVR24 was significantly (p < 0.05) and independently associated with male sex (odds ratio [OR], 2.12), higher body mass index (OR, 1.04), age >50 years (OR, 1.60), liver cirrhosis (OR, 3.97), alcohol consumption (OR, 2.99), diabetes (OR, 1.63), non-SVR (OR, 8.00), and elevated GGT at baseline (OR, 17.12). In multivariate regression analysis, elevated GGT at SVR24, particularly in combination with cirrhosis, was the best predictor for hepatic decompensation, hepatocellular carcinoma development, and death, followed by elevated ALT (AASLD) and standard ALT, which predicted hepatic decompensation. Despite successful HCV therapy, elevated GGT at SVR24 and to a lesser extent ALT are predictive of the future clinical outcome and linked with liver-associated comorbidities. This may highlight the relevance of nonalcoholic fatty liver disease, diabetes mellitus, alcohol, and cirrhosis for the clinical outcome in a vulnerable population, even after HCV cure.
