Direct-acting antiviral (DAA)-induced HCV clearance conceivably leads to improved outcomes at all stages of liver disease. However, available data suggest that the maximum measurable benefit is obtained by treating patients before they reach the stage of compensated advanced chronic liver disease (cACLD). Ideally, all patients with chronic hepatitis C should be treated before they develop advanced fibrosis or cirrhosis, since even if sustained virologic response (SVR) reduces the risk of hepatic events (e.g. decompensation and hepatocellular carcinoma [HCC]) and improves survival, further progression of liver disease and adverse outcomes, including hepatic deaths, cannot be entirely avoided. The hepatic venous pressure gradient (HVPG) correlates closely with the stage of liver disease. Measurements of HVPG in patients with severe fibrosis or cirrhosis treated with DAAs show that those with the highest degree of portal hypertension have the lowest probability of a meaningful reduction of portal pressure after SVR, and remain at significant risk of decompensation. Reduced liver stiffness is commonly observed in patients with cACLD but its role in predicting prognosis is yet to be demonstrated. In patients with decompensated cirrhosis, prevention of further decompensation and of HCC is only weakly associated with SVR. Overall, the main clinical predictors of a high risk of HCC in patients who obtain SVR on DAAs are all indexes strongly reflecting advanced fibrosis and impaired hepatic function. Long-term follow-up of large real-life cohorts of patients treated at all stages of liver disease, but mainly those with mild to moderate fibrosis, will be needed to confirm the impact of SVR among diverse HCV-infected populations and, more importantly, to better stratify patients at higher risk of complications in order to define their correct surveillance. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Background & Aims: To date, studies evaluating the association between frailty and mortality in patients with cirrhosis have been limited to assessments of frailty at a single time point. We aimed to evaluate changes in frailty over time and their association with death/delisting in patients too sick for liver transplantation. Methods: Adults with cirrhosis, listed for liver transplantation at 8 US centers, underwent ambulatory longitudinal frailty testing using the liver frailty index (LFI). We used multilevel linear mixed-effects regression to model and predict changes in LFI (DLFI) per 3 months, based on age, gender, model for end-stage liver disease (MELD)-Na, ascites, and hepatic encephalopathy, categorizing patients by frailty trajectories. Competing risk regression evaluated the subhazard ratio (sHR) of baseline LFI and predicted DLFI on death/delisting, with transplantation as the competing risk. Results: We analyzed 2,851 visits from 1,093 outpatients with cirrhosis. Patients with severe worsening of frailty had worse baseline LFI and were more likely to have non-alcoholic fatty liver disease, diabetes, or dialysis-dependence. After a median follow-up of 11 months, 223 (20%) of the overall cohort died/were delisted because of sickness. The cumulative incidence of death/delisting increased by worsening DLFI group. In competing risk regression adjusted for baseline LFI, age, height, MELD-Na, and albumin, a 0.1 unit change in DLFI per 3 months was associated with a 2.04-fold increased risk of death/delisting (95% CI 1.35-3.09). Conclusion: Worsening frailty was significantly associated with death/delisting independent of baseline frailty and MELD-Na. Notably, patients who experienced improvements in frailty had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty, using the LFI, in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty. Lay summary: Frailty, as measured at a single time point, is predictive of death in patients with cirrhosis, but whether changes in frailty over time are associated with death is unknown. In a study of over 1,000 patients with cirrhosis who underwent frailty testing, we demonstrate that worsening frailty is strongly linked with mortality, regardless of baseline frailty and liver disease severity. Notably, patients who experienced improvements in frailty over time had a lower risk of death/ delisting. Our data support the longitudinal measurement of frailty in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty. (C) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.