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Introduction and Aim: Cirrhotic patients with hepatitis C virus genotype 3 infection show unsatisfactory outcomes after 12 weeks' treatment with direct antiviral agents. The National Italian Drug Agency allows 24 weeks of therapy in difficult-to-treat patients, including genotype 3 cirrhotics. Aim of this study was to evaluate efficacy and safety of a 24-week course of sofosbuvir plus daclatasvir±ribavirin in this population., Materials and Methods: 106 consecutive cirrhotics (70.8% males, mean age 55.3±7.6 years) in 8 tertiary hepatology centers received sofosbuvir plus daclatasvir for 24 weeks. Ribavirin was administered in 85 (80.2%) based expected tolerability, at a mean dose of 964±202mg/day. Baseline Child-Pugh class was A 91.5%, B 6.6%, C 1.9%; mean baseline MELD was 8.5±2.7., Results: All patients completed 12-week follow-up post-treatment, and 104 (98.1%) obtained sustained virological response (100% in ribavirin -treated patients vs. 90.4% without ribavirin; p=0.04). No worsening in renal and liver function was observed, no serious adverse events occurred. Two virological failures showed resistance associated variants (Y93H and S282T)., Conclusion: An extended 24-week treatment with sofosbuvir plus daclatasvir+ribavirin obtained 100% efficacy in genotype 3 hepatitis C cirrhosis, with very limited side effects. The role of ribavirin seems crucial in this setting and should be administered if clinically feasible., (Copyright © 2019 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Background: In 2012, an Italian Named Patient Program began for hepatitis C virus (HCV)-infected liver transplant (LT) recipients with advanced fibrosis, before approval of direct antiviral agents (DAA), to benefit severely ill patients. The aim of this "real-life" study was to assess treatment efficacy and safety with an extended course of daclatasvir (DCV) plus sofosbuvir (SOF) with or without ribavirin (RBV)., Methods: All HCV LT recipients with severe fibrosis in 15 Italian transplant centers were treated with DCV+SOF±RBV for 24 weeks; sustained virological response was assessed at 12 weeks post-treatment (SVR12)., Results: Eighty-seven patients were enrolled (75.9% males, mean age 58.4 ± 7.2 years, 83.9% genotype 1, 81.6% cirrhosis); 52 (59.8%) received RBV. Overall, 79 obtained SVR12 (90.8%): 100% in F3 and 88.7% in cirrhotics (91.5% in Child-Pugh A, 83.3% in Child-Pugh B and C). According to the treatment group, SVR was 80% in DCV + SOF group and 98.1% in SOF + DCV + RBV. Two virological relapses occurred during follow-up in cirrhotic patients who received DCV + SOF. Four cirrhotic patients in DCV + SOF group and 1 in DCV + SOF + RBV group died on treatment., Conclusion: An extended course of SOF plus DCV for 24 weeks, with or without RBV, is effective and well tolerated for the treatment of post-LT HCV recurrence with severe fibrosis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and model of end stage liver disease (MELD) scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (P < 0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (P = 0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs. 8/189, P = 0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs. 6/10, P = 0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function., (© 2017 Steunstichting ESOT.)

Background & Aims: Hepatitis C virus (HCV) re-infection following liver transplant (LT) is associated with reduced graft and patient survival. Before transplant, Sofosbuvir/Ribavirin (SOF/R) treatment prevents recurrent HCV in 96% of those patients achieving viral suppression for at least 4 weeks before transplant. We evaluated whether a bridging SOF-regimen from pre- to post-transplant is safe and effective to prevent HCV recurrence in those patients with less than 4 weeks of HCV-RNA undetectability at the time of transplant., Methods: From July 2014 SOF/R was given in 233 waitlisted HCV cirrhotics with/without hepatocellular carcinoma (HCC) within an Italian Compassionate Program. One hundred patients were transplanted and 31 patients (31%) treated with SOF/R bridging therapy were studied., Results: Liver transplant indication in bridge subgroup was HCC in 22 and decompensated cirrhosis in 9. HCV-genotype was 1/4 in 18 patients. SOF 400 mg/day and R (median dosage 800 mg/day) were given for a median of 35 days before LT. At transplant time, 19 patients were still HCV-RNA positive (median HCV-RNA 58 IU/mL). One recipient had a virological breakthrough at week 4 post-transplant; one died, on treatment, 1-month post-transplant for sepsis and 29/31 achieved a 12-week sustained virological response (94%). Acute cellular rejection occurred in three recipients. On September 2016, 30 recipients (97%) were alive with a median follow-up of 18 months (range 13-25)., Conclusions: In patients with suboptimal virological response at LT, a bridging SOF/R regimen helps avoiding post-transplant graft reinfection., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Fibrosis in liver transplant recipients with recurrent HCV is fast, yet, different patterns of progression are recognized., Aims: To investigate histological findings associated with maintenance ribavirin monotherapy in patients with recurrent HCV transplanted > or =4 years earlier., Methods: 14 recipients at high risk of progression (fibrosis progression rate >0.33 units/year and/or persistently elevated ALT) were assigned to receive ribavirin for 3 years. 11 patients at lower risk of progression (FPR < or =0.33 units/year and normal ALT) as controls. Biopsies were obtained yearly since transplant and 7 consecutive biopsies were evaluated., Results: Improved necroinflammation (reduction > or =2 grading) was observed in 7 treated with ribavirin and 3 untreated patients, while 1 and 3 patients worsened respectively. Fibrosis improved (reduction >1 staging) in 2 ribavirin-treated patients, unchanged in 10 and worsened (increase > or =1 staging) in 2. Fibrosis progression decreased from 0.48+/-0.27 observed during the 3-year pre-treatment period to 0.04+/-0.31 units/year (p=0.003) during the 3 years of ribavirin. Among untreated fibrosis remained unchanged in 1 and worsened in 10 (p<0.001), yearly fibrosis progression rate increasing from 0.15+/-0.17 units/year to 0.42+/-0.39 units/year (p=0.10)., Conclusions: Maintenance ribavirin monotherapy delays fibrosis progression in high risk patients, offering an alternative strategy for those failing to respond to conventional treatment., (Copyright (c) 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: On-treatment predictors during antiviral therapy of HCV are useful because they allow discontinuation of an unnecessary treatment in non-responders. Our aim was to evaluate the usefulness of plasma and erythrocyte ribavirin levels in predicting sustained virological response (SVR) in HCV genotype 1 patients undergoing antiviral treatment., Methods: A total of 40 HCV genotype 1 patients treated with pegylated interferon-alpha2a 180 microg weekly plus ribavirin 1,000 or 1,200 mg daily (according to body weight) were included in the study. Plasma and erythrocyte ribavirin levels were evaluated in all patients at week 12 by HPLC. At week 24, ribavirin levels were reassessed in those achieving early virological response (EVR)., Results: A total of 27 patients achieved EVR, whereas 17 achieved SVR. There was no difference among EVR and non-EVR patients in terms of plasma and erythrocyte ribavirin concentrations at week 12. At week 24, EVR patients obtaining SVR exhibited higher mean +/-sd levels of ribavirin in plasma and lower levels in erythrocytes compared with non-SVR patients (in plasma 12.8 +/-10 versus 5.8 +/-4 microM [P<0.02] and in erythrocytes 1,053 +/-504 versus 1,613 +/-589 microM [P<0.03]). When the plasma ribavirin/erythrocyte ribavirin x100 ratio was compared, the difference was enhanced (1.5 +/-1.3 versus 0.4 +/-0.3 microM; P<0.01). Receiver operating characteristic curve analysis identified a cutoff for plasma ribavirin/erythrocyte ribavirin x100 ratio in predicting SVR of 0.71 with a negative predictive value of 0.8 and a positive predictive value of 0.9, whereas those related to EVR were 1 and 0.6, respectively., Conclusions: Plasma ribavirin/erythrocyte ribavirin x100 ratio at week 24 seems to be a good indicator of SVR in HCV genotype 1 patients achieving EVR.

Background/aims: We performed a randomized trial on pegylated interferon alfa-2a (Peg-IFNalpha) monotherapy vs Peg-IFNalpha and ribavirin in non-cirrhotic liver transplant recipients with recurrent hepatitis C., Methods: Forty-two patients transplanted for HCV-related cirrhosis 12-96 months earlier were randomized to Peg-IFNalpha monotherapy (180 microg weekly) or Peg-IFNalpha and ribavirin, up to the maximum tolerated dose, for 48 weeks., Results: Early virological response (EVR, i.e., HCV-RNA2 log drop at week 12) occurred in 76% of the monotherapy and 71% of the combination groups, respectively (intention-to treat). Sustained virological response (SVR) occurred in 8 (38%) and 7 (33%) patients, respectively. EVR had a positive predictive value for SVR of 50% and 47%, respectively, and a 100% negative predictive value in both groups. Six drop-outs occurred in the monotherapy (including 3 rejections) and 7 in the combination groups (including one rejection). Peg-INFalpha dose was reduced in 7 and 8 patients, respectively. The average daily dose of ribavirin was 435 mg/day., Conclusions: Peg-IFNalpha-2a, with or without ribavirin, induces SVR in one-third of transplant recipients with recurrent hepatitis C. Treatment cessation is indicated in patients without EVR. The low SVR rate is mainly due to inability to sustain full doses of antivirals and lack of the booster effect of ribavirin.

Background & aims: We investigated the HCV‐RNA amount, variability and prevalence of resistance‐associated substitutions (RASs), in plasma, hepatic tumoral and non‐tumoral tissue samples in patients undergoing liver‐transplant/hepatic‐resection (LT/HR), because of hepatocellular carcinoma and/or cirrhosis. Methods: Eighteen HCV‐infected patients undergoing LT/HR, 94.0% naïve to direct‐acting antivirals (DAAs), were analysed. HCV‐RNA was quantified in all compartments. NS3/NS5A/NS5B in plasma and/or in tumoral/non‐tumoral tissues were analysed using Sanger and Ultra‐deep pyrosequencing (UDPS, 9/18 patients). RASs prevalence, genetic‐variability and phylogenetic analysis were evaluated. Results: At the time of LT/HR, HCV‐RNA was quantifiable in all compartments of DAA‐naïve patients and was generally lower in tumoral than in non‐tumoral tissues (median [IQR] = 4.0 [1.2‐4.3] vs 4.3[3.1‐4.9] LogIU/µg RNA; P = 0.193). The one patient treated with sofosbuvir + ribavirin represented an exception with HCV‐RNA quantifiable exclusively in the liver, but with higher level in tumoral than in non‐tumoral tissues (51 vs 7 IU/µg RNA). RASs compartmentalization was found by Sanger in 4/18 infected‐patients, and by UDPS in other two patients. HCV‐compartmentalization resulted to be associated with HBcAb‐positivity (P = 0.013). UDPS showed approximately higher genetic‐variability in NS3/NS5A sequences in all compartments. Phylogenetic‐analysis showed defined and intermixed HCV‐clusters among/within all compartments, and were strongly evident in the only non‐cirrhotic patient, with plasma and non‐tumoral sequences generally more closely related. Conclusions: Hepatic compartments showed differences in HCV‐RNA amount, RASs and genetic variability, with a higher segregation within the tumoral compartment. HBV coinfection influenced the HCV compartmentalization. These results highlight HCV‐strain diversifications within the liver, which could explain some of the failures occurring even today in the era of DAAs. [ABSTRACT FROM AUTHOR]