Pre-Transplant Treatment to Prevent Recurrence of Hepatitis C 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:

Baseline

• History and Physical Examination
• Vital signs: Weight, blood pressure (BP), heart rate (HR), Temperature
• Fundoscopic exam in all patients. In patients with hypertension or diabetes exam should be performed with pupils dilated
• Quality of Life and Depression Assessment (SF-36V2, Beck Depression Inventory)
• Functional status evaluation
• Symptom assessment
• HCV RNA
• HCV Genotype
• Urinalysis
• Pregnancy Test
• HIV Test
• Other blood tests, including: complete blood count (CBC), International Normalized. Ratio (INR), Liver Panel, Creatine, Sodium Alpha-fetoprotein, triglycerides, iron studies, uric acid, thyroid stimulating hormone (TSH), antinuclear antibody (ANA)
• Ultrasound (US), computed tomography (CT), and/or magnetic resonance imaging (MRI) (some or all are probably done in LDLT evaluation)

Week 0 (Randomization and/or Treatment Start)

• Confirm eligibility
• Initiate treatment for all genotype 2, 3 patients and genotype 1, 4, 5 or 6 patients randomized to treatment group
• Repeat CBC, chemistries, INR

After randomization

• Week 1 and 3: CBC (for treated patients only, may be performed in local labs)
• Every 2 weeks up to 12 weeks: CBC, chemistries
• Weeks 4 and 8: Focused physical exam (signs and symptoms of liver disease) vital signs, urinalysis and symptom assessment
• Every 4 weeks from 12 to 48 weeks: Full physical exam and vital signs, urinalysis and symptom assessment, CBC, chemistries.
• Every 12 weeks up to 48 weeks: INR, TSH, urine or serum pregnancy test female (treated subjects of childbearing capacity only)
• At 12 Weeks: HCV RNA is measured. Patients without a 2-log or more drop in HCV RNA level are declared nonresponders and treatment is discontinued.
• After 12 weeks: HCV RNA is measured every 12 weeks on treatment by quantitative tests.
• At the time of LDLT or DDLT: CBC, INR, chemistries, quantitative and qualitative HCV RNA, Medications, adverse events (AE)
• Blood samples will be collected at Treatment Weeks 4, 8, 12, 24, 48 and at time of transplantation for subsequent HCV RNA testing in a central lab
• Quality of life (QOL) assessment at week 12, 24 and 48: Beck Depression Inventory (BDI) and SF-36V2
• Patients who discontinue treatment early due to adverse events will be followed according to the study schedule until 12 months after transplant or 48 weeks after randomization.

Post-LT (LDLT or DDLT) Follow-up

• Week 12, 24 and 52: CBC, INR, chemistries, HCV RNA by quantitative testing (part of A2ALL prospective study)
• Week 12, 24 and 52: Full physical exam and vital signs, urinalysis and symptom assessment
• Week 12: TSH and urine or serum pregnancy test (treated subjects of childbearing capacity only)
• Week 12, 24 and 52: QOL Assessment (BDI, and SF-36V2)
• Week 12 and 52: Liver Biopsy (part of A2ALL prospective study). Pathologists reading the 3 and 12 month biopsies will be blinded to the patients' clinical course and treatment.
• Blood samples will be collected at Week 12, 24 and 52 for subsequent HCV RNA testing in a central laboratory

Follow-up of Patients completing 48 weeks of Treatment without Transplantation

• Week 12, 24 and 48: CBC, INR, chemistries, HCV RNA by quantitative testing
• Week 12, 24 and 48: Full physical exam and vital signs, urinalysis and symptom assessment
• Week 12: TSH and urine or serum pregnancy test (treated subjects of childbearing capacity only)
• Week 12, 24 and 48: QOL Assessment (BDI, and SF-36V2)
• Blood samples will be collected at Week 12, 24 and 48 for subsequent HCV RNA testing in a central laboratory

NOTE: As a result of LADR Protocol Amendment III, patients with hepatocellular carcinoma (HCC) and tumor stage T2 awaiting DDLT are now eligible to participate in the LADR study. The following inclusion criteria was added:

• Candidates for DDLT who are listed for transplantation and meet United Network for Organ Sharing (UNOS) criteria for MELD upgrade for HCC

HCC DDLT candidates will not have their transplant delayed if a liver becomes available even if they have not completed 12 weeks of Rx.