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Background & Aims: There are limited data on patients with chronic HCV infection in whom combination voxilaprevir (VOX), velpatasvir (VEL), sofosbuvir (SOF) retreatment fails. Thus, we aimed to assess treatment failure and rescue treatment options in these patients., Methods: Samples from 40 patients with HCV genotypes (GT) 1-4 in whom VOX/VEL/SOF retreatment failed were collected within the European Resistance Study Group. Population-based resistance analyses were conducted and clinical parameters and retreatment efficacies were evaluated retrospectively in 22 patients., Results: Most VOX/VEL/SOF failure patients were infected with HCV GT3a (n = 18, 45%) or GT1a (n = 11, 28%) and had cirrhosis (n = 28, 70%). Previous treatments included an NS3-inhibitor (30%), an NS5A-inhibitor (100%) and SOF (85%). Baseline RAS data from a subgroup of patients before VOX/VEL/SOF retreatment (78%) showed few NS3 RASs apart from Q80K in GT1a (40%), typical NS5A RAS patterns in most patients (74%) and no S282T in NS5B. Sequencing after VOX/VEL/SOF failure was available in 98% of patients and showed only minor changes for NS3 and NS5A RASs. In 22 patients, rescue treatment was initiated with glecaprevir, pibrentasvir alone (n = 2) or with SOF±ribavirin (n = 15), VOX/VEL/SOF±ribavirin (n = 4) or VEL/SOF and ribavirin (n = 1) for 12 to 24 weeks. Sustained virologic response was achieved in 17/21 (81%) patients with a final treatment outcome. Of these, 2 GT3a-infected patients had virologic failure after rescue treatment with VEL/SOF or glecaprevir/pibrentasvir+SOF+ribavirin, and 2 patients with cirrhosis died during treatment or before reaching SVR12., Conclusions: VOX/VEL/SOF failure was mainly observed in HCV GT3- and GT1a-infected patients with cirrhosis and was not associated with specific RAS patterns within NS3, NS5A or NS5B target regions. Rescue treatment with multiple targeted therapies was effective in most patients., Lay Summary: The advent of direct-acting antivirals has enabled the effective cure of chronic hepatitis C in most patients. However, treatment failure occurs in some patients, who are often retreated with a combination regimen called VOX/VEL/SOF, which is associated with very high rates of cure. However, VOX/VEL/SOF retreatment also fails in some patients. Herein, we analysed samples from patients in whom VOX/VEL/SOF retreatment failed and we assessed the efficacy of different rescue therapies, showing that rescue treatment is effective in most patients (81%)., Competing Interests: Conflict of interest Julia Dietz: Research support from Gilead. Dolores Merino: Speaking and/or consulting fees from Gilead, ViiV Health Care, Merck/MSD, Janssen. Johannes Vermehren: Speaking and/or consulting fees from Abbott, AbbVie, Gilead, Bristol-Myers Squibb, Medtronic, Merck/MSD, and Roche. Andreas E. Kremer: Speaking and/or consulting fees: AbbVie, Beiersdorf, Bristol-Myers Squibb, CymaBay, Eisai, Falk, Gilead, GSK, Intercept, Lilly, MSD, and Zambon. Heinz Zoller: Speaking and/or consulting fees: Abbott, AbbVie, Bristol-Myers Squibb, Gilead, Merck/MSD, Pharmacosmos, Roche, Vifor. Grant support from Abbvie, Gilead, Pharmacosmos, and Vifor. Elisabetta Degasperi: Speaking and/or consulting fees: AbbVie, Gilead, MSD. Laura Sighinolfi: Speaking and/or consulting fees: Merck/MSD, ViiV Healthcare. Elisa Fernández-Fuertes: Speaking and/or consulting fees: Abbvie, Gilead, Merck/MSD, Janssen, ViiV. Leopoldo Muñoz-Medina: Speaking and/or consulting fees: AbbVie, Gilead, Janssen, ViiV. Rudolf Stauber: Speaking and/or consulting fees: AbbVie, Bayer, BMS, Eisai, Ipsen Gilead, Roche. Pietro Lampertico: Speaking and/or consulting fees: AbbVie, Alnylam, Arrowhead, BMS, Eiger, Gilead, GSK, Janssen, MSD, MYR, Roche, Spring Bank. Stefan Zeuzem: Speaking and/or consulting fees: Abbvie, BMS, Gilead, Janssen, Merck/MSD. Francesca Ceccherini-Silberstein: Speaking and/or consulting fees: Abbvie, Gilead, Janssen, Merck/MSD, ViiV Healthcare. Federico García: Speaking and/or consulting fees: Abbvie, Gilead, Hologic, Merck/MSD, Roche, Qiagen. Christoph Sarrazin: Speaking and/or consulting fees: Abbvie, Gilead, Merck/MSD, Research support: Abbvie, Gilead. All other authors report no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Sofosbuvir/velpatasivr/voxilaprevir (SOF/VEL/VOX) is approved for retreatment of patients with HCV and a previous failure on direct-acting antivirals (DAAs), however real-life data are limited. The aim of this study was to assess the effectiveness and safety of SOF/VEL/VOX in a real-life setting., Methods: All consecutive patients with HCV receiving SOF/VEL/VOX between May-October 2018 in 27 centers in Northern Italy were enrolled. Bridging fibrosis (F3) and cirrhosis (F4) were diagnosed by liver stiffness measurement: >10 and >13 kPa respectively. Sustained virological response (SVR) was defined as undetectable HCV-RNA 4 (SVR4) or 12 (SVR12) weeks after the end-of-treatment., Results: A total of 179 patients were included: median age 57 (18-88) years, 74% males, median HCV-RNA 1,081,817 (482-25,590,000) IU/ml. Fibrosis stage was F0-F2 in 32%, F3 in 21%, F4 in 44%. HCV genotype was 1 in 58% (1b 33%, 1a 24%, 1nc 1%), 2 in 10%, 3 in 23% and 4 in 9%; 82% of patients carried resistance-associated substitutions in the NS3, NS5A or NS5B regions. Patients received SOF/VEL/VOX for 12 weeks, ribavirin was added in 22% of treatment schedules. Undetectable HCV-RNA was achieved by 74% of patients at week 4 and by 99% at week 12. Overall, 162/179 (91%) patients by intention to treat analysis and 162/169 (96%) by per protocol analysis achieved SVR12, respectively; treatment failures included 6 relapsers and 1 virological non-responder. Cirrhosis (p = 0.005) and hepatocellular carcinoma (p = 0.02) were the only predictors of treatment failure. Most frequent adverse events included fatigue (6%), hyperbilirubinemia (6%) and anemia (4%)., Conclusions: SOF/VEL/VOX is an effective and safe retreatment for patients with HCV who have failed on a previous DAA course in a real-life setting., Lay Summary: This is the largest European real-life study evaluating effectiveness and safety of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) in a large cohort of consecutive patients with hepatitis C virus infection and a prior direct-acting antiviral failure, who were treated within the NAVIGATORE Lombardia and Veneto Networks, in Italy. This study demonstrated excellent effectiveness (98% and 96% sustained virological response rates at week 4 and 12, respectively) and an optimal safety profile of SOF/VEL/VOX. Cirrhosis and hepatocellular carcinoma onset were the only features associated with treatment failure., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Transarterial chemoembolization (TACE) is the standard of care for intermediate stage hepatocellular carcinoma (HCC) and it is the most commonly used treatment for HCC worldwide. However, no prognostic indices, designed to select appropriate candidates for repeat conventional TACE, have been incorporated in the guidelines., Methods: From January 2007 to April 2012, 139 consecutive HCC patients, mainly with an alcohol- or viral-induced disease, were treated with TACE. Using a regression model on the prognostic variables of our population, we determined a score designed to help for repeat TACE and we validated it in two cohorts. We also compared it to the ART score., Results: In the multivariate analysis, four prognostic factors were associated with overall survival: BCLC and AFP (>200 ng/ml) at baseline, increase in Child-Pugh score by ⩾2 from baseline, and absence of radiological response. These factors were included in a score (ABCR, ranging from -3 to +6), which correlates with survival and identifies three groups. The ABCR score was validated in two different cohorts of 178 patients and proofed to perform better than the ART score in distinguishing between patients' prognosis., Conclusions: The ABCR score is a simple and clinically relevant index, summing four prognostic variables endorsed in HCC. An ABCR score ⩾4 prior to the second TACE identifies patients with dismal prognosis who may not benefit from further TACE sessions., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)