Ribavirin Pre-treatment Followed by Combined Standard Therapy in Hepatitis C Virus (HCV) Recipients (RBV)

Ribavirin Pre-Treatment Study Protocol

1. Introduction:

   • Recurrence of hepatitis C infection and liver transplant:

   Recurrence of hepatitis C after liver transplant is almost universal. After liver transplantation, the progression of chronic hepatitis C is more aggressive and an high percentage of recipients develop cirrhosis and rapid liver decompensation (1). Recent studies have shown that the long-term-survival-rate is significantly lower compared with non-HCV infected recipients (2). Other studies founded that antiviral treatment improves survival in these patients. Thus, the treatment of hepatitis C patients after LT is a priority for transplant units.

   To date, the rate of sustained virologic response (SVR) in patients with recurrent hepatitis C after liver transplantation is about 20% with standard IFN and increases to 30% with pegylated IFN and Ribavirin (3). Lack in tolerability and low compliance to the antiviral therapy may represent an important limiting factor in order to improve the SVR. Severe myelosuppression is frequent in these patients, due to the additional effect of immunosuppressive therapy, being an additional reason to reduce antiviral drug dosage (3).

   • Ribavirin:

   Recent studies have evaluated the effects of a ribavirin priming before the standard combined antiviral therapy in immuno-competent patients with chronic hepatitis C (4-7). The conclusion of these studies may suggest that ribavirin pre-treatment may be a way to improve the SVR.

2. Aim of the study:

   The study is a randomized un-blind multicenter project to compare the efficacy of antiviral treatment with a RBV priming vs standard antiviral treatment in patients with recurrent hepatitis C after liver transplantation.

   Ribavirin pre-treatment may:

   • Ameliorate therapy-compliance
   • Avoid a concomitant drugs-related hematological side effects
   • Modify the intra-hepatic cytokine pattern toward a better antiviral action
   • Improve the SVR.

   This controlled trial is not sponsored by a drug company.

3. Patients:

   The protocol of the study needs to be approved by the local ethic committee. Patients are enrolled in the study after been informed of the purpose and protocol of treatment and need to sign a written informed consent.

4. Statistical analysis, sample size and randomization:

   Sample size calculations were performed using EVR as the primary outcome measure. We assumed that 48 weeks intended treatment with pegylated interferon and ribavirin in transplant patients with recurrent hepatitis C induced EVR in about 60% of patients (10). In our pilot study ribavirin priming followed by 48 weeks of pegylated interferon and ribavirin obtained EVR in 92% of patients. To show an improvement of EVR from 60 to 92% , assuming an alpha level of 0.05, and 90% power ( beta =0.20) fifty patients per group are needed.

   Patients will be randomized after inclusion in the study, using an opaque envelope technique to be assigned to their treatment by a predetermined sequence at the Coordinator Center. Randomization will be stratified for genotype 1 and non1 to decrease the likelihood that uneven distribution of underlying disease severity would bias the results. Randomization will occur in blocks of four.

5. Definitions:

   The following definitions are going to be used; during the study:

   • Rapid Virological Response: complete viral clearance at week 4
   • Early Virologic Response: viral reduction > 2 log after 12 weeks of combined therapy.
   • Complete Early Virological Response: complete viral clearance after 12 weeks of combined therapy.
   • End of treatment Virologic Response: complete viral clearance at the end of the treatment period
   • Sustained Virologic Response: complete viral clearance 24 weeks after the end of treatment
   • Non Responder: Absence of virological response after 12 weeks
   • Relapse: recurrence of viral replication after a complete clearance during treatment time or after the conclusion of it.
6. Protocol of the study:

Basal Evaluation:

• Liver biopsy within the last 6 months
• Complete biochemical assessment (liver function tests, renal function, blood tests, levels of immunosuppressive therapy)
• HCV-RNA quantitative determination

Randomization: Patient are randomized to treatment A or Treatment B):

• Treatment A:

Pre-treatment:

Ribavirin is started at 600 mg/day (or 400mg/ day if < 60 kg) and increased to 10,4 mg/kg within week 2, the therapy is continued for 8 complete weeks.

Biochemical assessment is repeated at week 2, 4, 8. Samples are stored at the same times.

HCV-RNA quantitative determination is repeated at week 8. Drug reduction is allowed when hemoglobin level is below 10 g/dL though EPO administration or whenever it is considered necessary.

Combined antiviral therapy:

For 48 weeks patients are treated with Ribavirin (same dosage) and IFN alfa2b (1,5 mcg/kg/week).

Patients are followed monthly or more frequently if required. Biochemical and virological assessment is recorded at week 4, 12, 24, 48. Surveillance is performed for any collateral effects and dose adjustment or growth factor need.

Ribavirin reduction is required when hemoglobin level is below 10 g/dL though EPO use.

IFN weekly administration should be reduced when neutrophiles count is < 750 in spite of G-CSF administration.

IFN interruption is required when neutrophiles are < 500 or platelets are < 35000.

• Treatment B:

For 48 weeks patients are treated with Ribavirin (10 mg/kg ) and pegylated IFN alfa2b weekly.

Ribavirin is started at 600 mg/day and increased to 10 mg/kg within week 2. Pegylated IFN alfa2b is administered weekly at a dose of 1,5/kg/week. Patients are followed twice monthly in the first month and at least monthly thereafter (more frequently whenever is required).

Biochemical and virological assessment is recorded at week 4, 12, 24, 48. Surveillance is performed for any collateral effects and dose adjustment or growth factor need.

Ribavirin reduction is required when hemoglobin level is below 10 g/dL though EPO use.

IFN weekly administration should be reduced when neutrophiles count is < 750 in spite of G-CSF administration.

IFN interruption is required when neutrophiles are < 500 or platelets are < 35000.

End-points of the study:

• Rapid Virological Response ( week 4)
• Early Virological Response (week 12)
• Complete Early Virological Response (week 12)
• End of treatment Virological Response (week 48)
• End of treatment Biochemical Response (week 48)
• Sustained Virological Response (Six months after the end of therapy)

Collateral effects, dose adjustment and use of growth factors are recorded.