Clinical Trial to Evaluate the Efficacy of Pegylated Interferon-Ribavirin-Boceprevir Triple Therapy in Patients Infected With Genotype 1 HCV With Cirrhosis and Awaiting Liver Transplantation (ANRS HC 29 BOCEPRETRANSPLANT)

• Sustained Virologic Response (SVR) Rate [ Time Frame: Week 24 after the discontinuation of antiviral C treatment and at the time of liver transplantation or at the time of liver transplantation ] [ Designated as safety issue: No ]

  Evaluation of sustained virologic response to antiviral C treatment depends of time of liver transplantation that can be performed between week 16 and week 96 of the trial:

  • If the liver transplant is realized after the discontinuation of antiviral C treatment,sustained virologic response should be evaluated 6 months after the discontinuation of antiviral C treatment and at the time of liver transplantation.
  • If the liver transplant is realized before the discontinuation of antiviral C treatment,sustained virologic response should be evaluated at the time of liver transplantation.
  
  

• Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: From week 0 to week 144 ] [ Designated as safety issue: Yes ]
  Information on adverse events will be collected by the investigator during medical visits and reported in the CRF. Adverse events will be classified as: a) Flu-like symptoms b) Musculoskeletal symptoms c) Neurologic symptoms d) Psychiatric symptoms e) Constitutional symptoms
  
  
• Perceived symptoms [ Time Frame: at day 0, week 24, week 48 and every 24 week up liver transplant - post liver transplant: day 0, week 24 and week 48 ] [ Designated as safety issue: No ]
  Information on symptoms as perceived by the patients will be collected through self-administered questionnaires.
  
  
• Compliance rate. [ Time Frame: week 12, week 24, week 36, week 48, week 72 - after Liver transplant:Day 0 ] [ Designated as safety issue: No ]
  Treatment compliance will be assesses through a self-administered questionnaire reporting the number of medication doses prescribed and taken by the participants
  
  
• SVR prognosis factors [ Time Frame: Week-4 up week 144 ] [ Designated as safety issue: No ]
  Participants with undetectable plasma HCV-RNA 24 weeks after treatment cessation and/or liver transplantation will be considered as SVR. Factors potentially associated with SVR will be studied through a logistic regression analysis. These factors include demographical (age, gender), virological (baseline viral load), clinical (disease severity measured by MELD score) and genetic factors (IL28B polymorphism: TT, CT, or CC)
  
  
• The predictive value of on-treatment HCV RNA on SVR [ Time Frame: During weeks 1, 4, 5, 6, 7, 8, 12, 16, 20, and 24 (before transplantation) ] [ Designated as safety issue: No ]
  Quantitative assessment of HCV RNA during treatment will be performed at weeks 1, 4, 5, 6, 7, 8, 12, 16, 20, and 24 and correlated to SVR
  
  
• The percentage of virologic failure [ Time Frame: week 4 and week 48 ] [ Designated as safety issue: No ]
  Virological failure is defined as an increase of HCV RNA of at least 1 log IU/mL during treatment, or by the reappearance of positive viremia during treatment, after an initial negative result
  
  
• The percentage of relapse after transplantation [ Time Frame: Between week 16 and week 144 ] [ Designated as safety issue: No ]
  Virological relapse is characterized by an HCV RNA negative at the end of treatment but becoming detectable after cessation of therapy. The proportion of patients with virological relapse will be determined
  
  
• Boceprevir resistant mutations [ Time Frame: From week 5 to week 48 or after week 48 ] [ Designated as safety issue: No ]
  The proportion of patients with emergence of resistant mutations to boceprevir in case of detectable viral load during treatment (from W5) and after the discontinuation of treatment in the event of virologic failure will be assessed
  
  
• Resistant mutations in plasma and liver samples (both explanted liver and graft) [ Time Frame: Week 16 up to week 96 ] [ Designated as safety issue: No ]
  
• Sepsis according to Systemic Inflammatory Response System (SIRS) Criteria [ Time Frame: From day 0 to week 72 ] [ Designated as safety issue: Yes ]
  
• Cirrhosis impairment [ Time Frame: From day 0 to week 72 ] [ Designated as safety issue: Yes ]

  Cirrhosis impairment will be assessed by studying:

  • the mean variation of MELD score between baseline and end of therapy
  • the proportion of patients with a MELD score increased by at least 3 points (in case of baseline MELD>15) or 5 points (in case of baseline MELD<15)
  
  
• Survival after transplantation [ Time Frame: Week 16 up to week 96 ] [ Designated as safety issue: Yes ]
  
• Survival rate within one year after liver transplantation [ Time Frame: week 64 up to week 144 ] [ Designated as safety issue: Yes ]
  
• The mean time elapsed between registration on the transplantation list and the date of transplantation [ Time Frame: Week16 up to week 96 ] [ Designated as safety issue: No ]
  
• Measurement of the residual plasma concentration (Cres) of ribavirin [ Time Frame: at Week 4 and Week 8 ] [ Designated as safety issue: No ]
  
• Area Under the Plasma Concentration Time Curve (AUC) From 0-8h of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  
• Maximum Plasma Concentration (Cmax) of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  
• Time of Maximum Plasma Concentration (Tmax) of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  
• Minimum Plasma Concentration (Cmin) of Boceprevir [ Time Frame: At week 16 and at week 24 and if the MELD score has changed by more than three points ] [ Designated as safety issue: No ]
  
• Correlation study between the presence of an elevated level of IP-10 during triple therapy and the absence of sustained virologic response [ Time Frame: From week 4 to week 48 ] [ Designated as safety issue: No ]
  Plasma aliquots will be performed in all patients of the trial at day 0 before liver transplant and day 0 post liver transplant to measure IP10. Evaluation will be performed at the end of the trial for all patients recruited. The association between IP-10 level and SVR will be assessed
  
  
• Histological severity of HCV recurrence after liver transplantation [ Time Frame: At week 20 up to week 100, at week 40 up to week 120, at week 64 up to week 144 ] [ Designated as safety issue: No ]

  Histological severity will be assessed by the METAVIR score at 1 month (if early recurrence), at 6 months, 1 year after transplantation in case of non-response/relapse before transplantation .

  Liver transplantation can be performed between week 16 and week 96

  
  
• Insulin Resistance (HOMA-IR) [ Time Frame: At baseline, week 48 and at the last follow-up visit ] [ Designated as safety issue: No ]
  
• Virological Response in participants with and without Insulin Resistance [ Time Frame: At week 4, 8, 16, 28 and 48 during therapy ] [ Designated as safety issue: No ]
  
• Relationship between the presence of a polymorphism in the IL28B gene (donor and recipient) and SVR [ Time Frame: After week 144 ] [ Designated as safety issue: No ]
  Whole blood aliquots (DNA bank) will be performed at the Day 0 visit to measure IL28B polymorphism. Evaluation will be performed at the end of the trial for all patients recruited. The SVR rate will be compared between the different IL28B phenotypes (CC, CT and TT).
  
  
• Relationship between the presence of a polymorphism to the ITPA gene and the onset of hemolytic anemia [ Time Frame: After week 144 ] [ Designated as safety issue: No ]
  Whole blood aliquots (DNA bank) will be performed at the Day 0 visit for ITPA gene measure. Evaluation will be performed at the end of the trial for all patients recruited. The proportion of patients with occurrence of hemolytic anemia will be compared according to the ITPA polymorphism
  
  

Evaluation of sustained virological response defined as the proportion of patients with undetectable hepatitis C virus RNA 24 weeks after discontinuation of therapy and/or after liver transplantation in patients with genotype 1, who are treatment-naive, have relapsed, or are non-responders with cirrhosis and awaiting liver transplantation, with a MELD score less than or equal to 18