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Background and Objectives: The pangenotypic single tablet regimen of NS5B inhibitor sofobuvir (SOF) and NS5A inhibitor velpatasvir (VEL) is advised for 12 weeks in HCV-infected patients including those with compensated cirrhosis. Addition of ribavirin (RBV) may be considered in genotype 3 (GT3) with compensated and is recommended in decompensated cirrhosis. Real-life results with SOF/VEL are limited. To evaluate efficacy and safety in a large real-world-cohort including patients with different GTs and various fibrosis stages., Design: In total, 1429 patients were treated with SOF/VEL 400/100 mg for 12 weeks in the Puglia registry between June 2017 and May 2018. 1319 (92.3%) reached week 12 post-treatment (SVR12) at the moment. Only 41 received RBV. Diagnosis of cirrhosis was based on transient elastography and/or APRI or FIB-4 scores. Sensitivity analysis in the population including all patients except non virological failure was conducted. Primary efficacy endpoint was the percentage of patients with SVR12., Results: Patients' mean age was 63.8 years, 42.3% had GT1. The majority were naïve and 735 (55.5%) F0/F2. Of the remaining 587, 282 had cirrhosis. SVR12 was 98.5%, 98.0% in GT1, 99.4% in GT2, 97.1% in GT3, 100% in GT4. Overall, SVR12 by sensitivity analysis was 99.4%; 99.7% among F0-F1. Among 218 PWID, SVR12 was 94.5%. Discontinuation rates were 3.7% among PWID and 0.7% among non-PWID (p = 0.004)., Conclusions: SOF/VEL treatment of chronic HCV infection reaches very high cure rates in a variety of patients; including those with F0/F1 and PWID., Competing Interests: AM has received grant and research support from Merck, Gilead Sciences, Janssen, and Intercept and consulting fees from Gilead Science, Merck and Janssen. This does not alter our adherence to PLOS ONE policies on sharing data and materials. The other Authors have nothing to declare.

In clinical trials, a sofosbuvir/velpatasvir (SOF/VEL) pangenotypic single-tablet regimen was associated with high sustained virological response (SVR) rates at 12 weeks (SVR12) after the end of treatment, regardless of genotype and fibrosis stage. No real-life data on genotype 3 (GT3) cirrhotic patients with portal hypertension are available. The aim of this study was to assess the effectiveness of SOF/VEL in GT3 cirrhotics with portal hypertension. Patients with GT3 and advanced cirrhosis were treated for 12 weeks with SOF/VEL without ribavirin at five different centers in Italy from June 2017 to August 2018 and their SVR12 was assessed. Of the 227 GT3 cirrhotics evaluated, 205 met the inclusion criteria and 111 had transient elastography results ≥20 KPa. SVR12 was 97.6% (95% CI 94.4-98.9), rates were 99.1% (95% CI 95.7-99.8) in patients with ≥20 KPa and 95.8% (95% CI 89.5-98.3) in those with <20 KPa (p = 0.18). Analyzed by presence of esophageal varices, the SVR12 rates were 98.4% (95% CI 91.4-99.7) and 97.1% (95% CI 92.9-98.9) in patients without and with varices, respectively (p = 1.0). In real life, SOF/VEL GT3 cirrhotic patients with evidence of portal hypertension can achieve SVR12 levels comparable to those of patients without portal hypertension. These SVR12 rates are similar to what is reported in compensated cirrhosis treated within clinical trials., Competing Interests: The authors declare no conflict of interest

Background: Treatment of GT3 remains challenging compared to other genotypes., Aims: To explore real life SVR rates and to identify predictors of virological failure across the most recently used Direct acting antiviral (DAA) regimens in a large cohort of Italian patients with cirrhosis or advanced fibrosis (F3 or F4)., Methods: Between May 2015 and June 2017, the combinations of sofosbuvir (SOF) plus daclatasvir (DCV) ± RBV and SOF plus velpatasvir (VEL) ± RBV become available in our Country. Patients were treated following Italian guidelines within a protocol implemented by 11 centers working together on genetics., Results: Of 336 patients, 38.1% were Peg/IFN-experienced. SOF/DCV was used in 65.1%, SOF/VEL in the remaining. Overall SVR12 was 90.2% ranging from 87.2% after SOF/DCV to 95.7% after SOF/VEL (p = 0.012). No additional benefits of RBV use were observed for both regimens. 155 patients (46.1%) had cirrhosis. SVR12 was 87.1% (135/155) for cirrhotic patients and 92.8% (169/182) for non-cirrhotic (p = 0.09). NS5A-RASs were present at baseline in 6.4% of patients, PNPLA3GG and IL28BCC genotypes in 7.3% and 33.0%, respectively. No association between favorable genetics and SVR12 was observed. Predictors of relapse were: history of Peg/IFN/RBV failure (OR = 6.34, 95% CI 2.04-19.66, P = .001), baseline NS5A-RASs (OR = 8.7, 95% CI 1.58-47.92, P = 0.013) and treatment regimen (OR = 5.57 95% CI 1.64-18.95.96, P = 0.006)., Conclusions: Our real-world results validate the efficacy of current GT3 IFN-free regimens suggesting that, among patients with severe disease, Peg/IFN/RBV experience and NS5A associated RASs are predictors of relapse. Their relevance can be expected to decline with the use of SOF/VEL. (250)., Competing Interests: Alessandra Mangia declares the following conflicts: Advisory for Gilead Sciences, MSD, Janssen, BMS; Research funding: MSD, Gilead Sciences, Janssen; Speaking and Teaching: MSD, Gilead Sciences, BMS. The other authors have no conflicts of interest to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

Background & Aims: Sofosbuvir (SOF) and weight-based ribarivin (RBV) represented until recently the standard of care in hepatitis C virus (HCV) genotype (GT)2 patients. In registration studies 12-16weeks duration were associated with a 90% sustained virological response at 12weeks (SVR12). Real life cohorts showed lower SVR12 rates., Methods: SVR12 rates attained in an Italian real life cohort and possible benefits of a duration extended up to 20weeks was investigated in HCV GT2 patients with cirrhosis. The role of 2k/1b chimeras as potential predictor of treatment failure was also analysed., Results: Overall, 291 HCV GT2 infected patients with bridging fibrosis or cirrhosis were evaluated. Median age was 68years (18-87); 163 were treatment naïve. Of 168 cirrhotic patients, 149 had Child-Pugh score A and 19 B, 50 platelets count <100,000/mm 3 and 62 albumin <3.5g/dl. SVR12 were 95.53% overall, with 99.15% in non-cirrhotic patients and 93.06% in cirrhotic patients. In patients who completed treatment, SVR rates for cirrhotic patients resulted in 94.51%, and 94.94% after 16 or 20weeks respectively. Predictors of SVR were low platelet count and esophageal varices (OR 7.2; 95% CI 1.67-31.25; p=0.0022 and OR 0.1; 95% CI 0.01-0.72; p=0.0079, respectively). Anemia was mild in 12.4%, moderate in 3.4%, and severe in 2.4% of cases. Anemia was slightly more frequent among longer duration but not associated with treatment discontinuations. No 2k/1b strains or genotypes different from those at baseline were identified at relapse., Conclusions: In GT2 cirrhotic patients, SOF/RBV for 16 or 20weeks is associated with real life SVR12 rates of 95%., Lay Summary: A duration of treatment of 16-20weeks was recommended for treatment of HCV GT2 patients using the combination of sofosbuvir and ribavirin. Real life experiences, where patients received 12weeks of treatment regardless of the severity of liver disease, suggested that response rates are lower than expected, in particular in patients with liver cirrhosis. A misleading genotyping of a 2k/1b strain as GT2 was also hypothesized as a further explanation for less effectiveness. We demonstrated that using the recommended extended duration in patients with more severe disease 95% of patients with severe liver disease including cirrhosis can be cured and that 2k/1b strain plays only a secondary role in specific countries like Germany. Although this combination has been recently replaced by sofosbuvir and velpatasvir fixed dose combination as the standard of care for treating HCV GT2 patients, our findings may inform physicians from countries where the new regimen is not yet available., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The current standard-of-care for treatment of HCV genotype 2 (GT-2) patients is the combination of sofosbuvir (SOF) with weight-based ribavirin (RBV). Patients with HCV GT-2 infection and ribavirin contraindications require the use of SOF plus NS5A inhibitor daclatasvir (DCV) which is not reimbursed everywhere., Methods: We conducted an open-label observational, prospective study on a subgroup of GT-2 patients either naïve or treatment experienced (TE) with contraindications to the use of RBV. Patients with cirrhosis of Child-Pugh-Turcotte (CPT) class A and B or advanced fibrosis with comorbidities were included. They were assigned to receive 12 or 24 weeks of SOF/DCV. The primary end point of the study was sustained virological response (SVR) defined as HCV RNA levels <12 IU/ml, 12 weeks post treatment., Results: Out of 106 patients with GT-2 who received treatment at our unit from July 2014 to June 2015, 20 (18.8%) patients, whose treatment could not be deferred, were ribavirin intolerant; 19 received SOF/DCV combination for 12 or 24 weeks. The majority of the patients was men, 58% had cirrhosis, and 58% were TE. All treated patients achieved SVR regardless of treatment duration. The most common adverse events (AEs) were fatigue, headache and nausea. No discontinuations due to AEs were observed. Two patients had oesophageal bleeding but continued treatment and achieved SVR; one patient developed HCC 12 weeks post treatment, but remained HCV RNA undetectable., Conclusions: This study supports the use of SOF/DCV for 12 weeks in non-cirrhotics or 24 weeks in cirrhotic GT-2 patients who cannot tolerate RBV, including those with decompensated disease., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)