• Tolerance induction [ Time Frame: 6 months following immunosuppression withdrawal ] [ Designated as safety issue: No ]
• Laboratory tests indicative of successful withdrawal [ Time Frame: 6 months following immunosuppression withdrawal ] [ Designated as safety issue: No ]
• Hepatitis C immune response and graft injury [ Time Frame: Random assignment to immunosuppression withdrawal ] [ Designated as safety issue: Yes ]
• Definition of rejection profiles from laboratory tests [ Time Frame: Post-immunosuppression withdrawal ] [ Designated as safety issue: No ]

• Tolerance induction
• Laboratory tests indicative of successful withdrawal
• Hepatitis C immune response and graft injury
• Definition of rejection profiles from laboratory tests

In order to prevent organ rejection, patients receiving liver transplants currently require life-long treatment with immune system-suppressing medications to prevent the rejection of the transplanted liver. However, these medications can cause long-term side effects, such as infection, kidney problems, diabetes, and cancer. In patients infected with hepatitis C virus (HCV), these medications may increase the risk of HCV infection in the transplanted liver. The purpose of this study is to determine whether a slow withdrawal of immune system-suppressing medications is safe. The study will also look at whether slow withdrawal will help reduce the long-term side effects of immune system-suppressing medications and decrease the chance for HCV infection of the new liver in transplant patients with HCV.

More than 60% of liver transplants are done in patients who are infected with HCV. Following organ transplants, immunosuppressive medications are used to prevent the patient's immune system from rejecting the transplanted organ. In general, these antirejection medications are prescribed for the remainder of the transplant recipient's life. However, in patients infected with HCV, these same medications are believed to be associated with a rapid reoccurrence of HCV, which can lead to failure of the transplanted liver, severe hepatitis, cirrhosis, and other serious conditions. This study will evaluate how safe it is to slowly withdraw antirejection medications without the rejection of the transplanted liver in patients with HCV-related liver failure receiving a liver transplant. The study will also determine if the risk for HCV infection in the transplanted liver decreases with this regimen in these patients.

Participants will undergo liver transplantation and receive immunosuppression medications consistent with current standard practices. Study participants will be treated with standard of care antirejection medications after transplant. This includes a 3-month course of corticosteroids and maintenance therapy with one or two antirejection medications (tacrolimus or cyclosporine and/or mycophenolate mofetil). Participants will be tapered off corticosteroids in the first 3 months but will continue maintenance immunosuppression for 1 year. Participants will be regularly monitored for recurrence of hepatitis and for evidence of allograft rejection.

One year after transplantation, participants who meet certain criteria for immunosuppressive withdrawal will be randomly assigned to either the immunosuppression withdrawal group or the control group. Only study participants who are taking one immunosuppressive drug will qualify for the random assignment. Participants assigned to the drug withdrawal group will have their dose of immunosuppressive drug tapered off over the course of 1 year. The control group will be maintained on normal levels of their assigned immunosuppressive drugs. Immunosuppressive drugs will not be provided by this study.

During and after the withdrawal phase, participants will be closely monitored for liver function, signs of rejection, levels of HCV in the blood and liver, and for the response of the immune system to the withdrawal of immunosuppression. Participants will be followed for a minimum of 1 year after the completion of withdrawal, possibly up to 4 years.

• Hepatitis C
• Hepatitis C, Chronic

• Procedure: Continuous maintenance immunosuppressive therapy
• Procedure: Immunosuppression withdrawal
• Procedure: Liver transplant

• Experimental: Liver transplant, followed by tapered withdrawal of immunosuppressive therapy over the course of 1 year
• Active Comparator: Liver transplant, followed by maintenance doses of continuous immunosuppressive therapy over the course of 1 year

Inclusion Criteria:

• Active hepatitis C virus (HCV) infection with genotype 1 OR nonimmune, nonviral liver disease
• Needs liver transplant
• Willing to use acceptable forms of contraception

Exclusion Criteria:

• Previous transplant
• Multiorgan or split liver transplant other than a right trisegment
• Living donor transplant
• Donor liver from a donor positive for antibody against hepatitis B core antigen
• Donor liver from a donor positive for antibody against hepatitis C
• Donor liver from a non-heart-beating donor
• Liver failure due to autoimmune disease
• Fulminant liver failure
• Hepatitis B virus infection or HCV infection with a genotype other than genotype 1
• Stage III or higher hepatocellular cancer
• History of cancer. Patients with hepatocellular cancer, adequately treated in situ cervical carcinoma, adequately treated basal or squamous cell carcinoma of skin, or other cancer judged to have a 5-year risk of recurrence less than 10% are not excluded.
• Active systemic infection at the time of transplantation
• Clinically significant chronic kidney disease
• Clinically significant cardiovascular or cerebrovascular disease
• HIV infected
• Pregnancy