The Adult-to-adult Living Donor Liver Transplantation Cohort Study (A2ALL) Low Accelerated Dosing Regimen (LADR) Protocol: Pre-Transplant Treatment to Prevent Recurrence of Hepatitis C Virus (HCV) After Liver Transplantation

Patients awaiting deceased donor liver transplant will be asked to enroll in this protocol at the time of identification of a potential living liver donor (see note note at end of description). Patients randomized to treatment arm will be encouraged to delay living donor liver transplant (LDLT) until they have received 12 weeks of treatment to allow for a treatment response, if any, to occur. The pros and cons of immediate versus delayed LDLT will be discussed with each patient; the timing of LDLT for patients randomized to no treatment will be determined by clinical need. There will be separate treatment strategies depending upon HCV genotype. Preliminary data and experience strongly suggests that interferon-based treatment clears HCV RNA in the majority of patients with genotypes 2 and 3, even at lower than standard doses (79% on-treatment response and 50% SVR). In contrast, clearance rates for genotype 1 patients with advanced cirrhosis may only be 28% on-treatment with an 11% SVR. In addition, treatment may be associated with significant side effects, intolerance, and increased risk of complications of liver disease. The HCV Committee for A2ALL strongly agreed that monitoring safety of pre-transplant antiviral therapy was essential and advised inclusion of an untreated control group. For these reasons, all patients with HCV, genotypes 1, 4, 5, & 6 infection will be randomized 2:1 to either treatment or control (no treatment). Randomization will be web-based to avoid prior knowledge of treatment assignment at any site. In contrast to the randomized design for patients with genotypes 1, 4, 5, and 6, all patients with genotypes 2 and 3 HCV will receive treatment. All genotypes will be included in the analysis of safety, tolerance, and complications occurring during pre-transplant treatment.

Treatment is continued up to the time of LDLT or deceased donor liver transplant (DDLT), or to a maximum of 48 weeks of continuous treatment. Both peginterferon and ribavirin will be stopped if transplantation is expected to occur within 24 hours. Patients whose liver disease stabilize and are no longer in need of a liver transplant will complete a full 48 weeks of treatment with the aim of achieving SVR. These patients will be followed by measurement of HCV RNA, biochemical tests, hematology, and clinical evaluation at 3, 6, and 12 months post-treatment. If relapse occurs when treatment is discontinued after 48 weeks of therapy, institution of retreatment will be at the discretion of the investigator.

Deferral of LDLT while antiviral therapy is continued will be considered in patients who have undetectable HCV RNA, tolerate treatment well, lack evidence of HCC or ongoing hepatic decompensation, and have had stabilization or improvement in clinical or biochemical measures of liver disease: Child-Turcotte-Pugh (CTP) and Model for End-stage Liver Disease (MELD) scores. These patients should lack uncontrolled or ongoing bleeding from portal hypertension, ascites, systolic blood pressure (SBP), or encephalopathy. The decision to defer transplantation and to continue antiviral therapy will be made at the transplant center by the clinical investigator in consultation with the patient.

Based upon the kinetics of early virologic response in the peginterferon + ribavirin clinical trials, the researchers anticipate that a minimum of 12 weeks treatment is necessary to achieve a virologic response. However, the optimum duration of pre-transplant antiviral therapy that yields the highest rates of prevention of post-transplant HCV recurrence is unknown. Prolongation of antiviral therapy beyond 12 weeks may be advantageous in this regard, but prolonged therapy may also increase the risk of development of intercurrent complications of liver disease or side effects of treatment. In addition, patients with stable liver disease who achieve virologic remission may experience hepatic improvement and avoid transplantation.

All patients, treated and untreated controls will be followed and tested at the same intervals unless specified. Unscheduled visits and additional tests may be performed if clinically indicated, the findings at these visits and results of additional tests will be recorded in the database. The following details the schedule of visits and the tests/procedures to be performed at each visit: