Zepatier For Treatment Of Hepatitis C-Negative Patients Who Receive Kidney Transplants From Hepatitis C-Positive Donors (HCV)

Open-labelled pilot clinical trial of Zepatier (MK-5172 and MK-8742/Grazoprevir + Elbasvir)
in 40 HCV-negative subjects with end-stage renal disease receiving a kidney transplant from a
HCV-positive donor. Eligible subjects will receive a kidney transplant from a deceased-donor
with genotype 1 or 4 HCV, and then will receive 12 weeks of Zepatier after kidney
transplantation when infection with HCV is confirmed in these kidney transplant recipients.
Treatment will be complete after 12 weeks.

Subject:

Inclusion criteria

- Must be waitlisted for a kidney transplant (dialysis is not a requirement if a patient
is waitlisted)

- Listed for an isolated kidney transplant with ≤2555 days of accrued transplant waiting
time and/or ≤2555 days of dialysis time for blood group A, B, or O, by enrollment

- Listed for an isolated kidney transplant with ≤1825 days of accrued transplant waiting
time and/or ≤1825 days of dialysis time for blood group AB, by enrollment

- No available living kidney donor

- Between 30-65 years of age, by enrollment

- Have a panel reactive antibody level ≤97%

- eGFR <15ml/min/1.73m2 as calculated using the 4 variable MDRD equation

- Obtained agreement for participation from the patient's treating transplant
nephrologist

- Able to travel to the University of Pennsylvania for routine post-transplant visits
and study visits for a minimum of 6 months after transplantation

- No active illicit substance abuse

- Weigh at least 50kg

- Women must agree to use birth control in accordance with Mycophenolate Risk Evaluation
and Mitigation Strategy (REMS) following transplant due to the increased risk of birth
defects and/or miscarriage

- Both men and women must agree to use at least one barrier method to prevent any
secretion exchange

- Inclusion criteria for treatment (not for entry as study patient) will include any
detectable HCV RNA

- Able to provide informed consent

Exclusion criteria

- Hepatocellular carcinoma

- Patients with primary focal segmental glomerulosclerosis (FSGS), FSGS recurring after
previous transplant, or disease process with increased risk of causing early graft
failure as per the treating nephrologist

- HIV positive

- HCV RNA positive (can be isolated HCV antibody positive provided the subject has no
history of previously treated HCV)

- Hepatitis B surface antigen positive

- Any other chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD)
with abnormal liver enzymes

- Persistently elevated liver transaminases

- Significant hepatic fibrosis on screening elastography (≥f2 fibrosis)

- Pregnant or nursing (lactating) women

- Known allergy or intolerance to tacrolimus that would require post-transplant
administration of cyclosporine, rather than tacrolimus given the drug-drug interaction
between cyclosporine and Zepatier

- Waitlisted for a multi-organ transplant (e.g., pancreas-kidney, heart-kidney, etc.)

- Significant cardiomyopathy defined as either:

- Left ventricular ejection fraction <40% on most recent echocardiogram

- Left ventricular ejection fraction ≥40% but <50% on most recent echocardiogram
with an <5 METS of exercise tolerance

- Reversible ischemia on stress testing without revascularization

Donor Organ Selection:

Inclusion Criteria

- Detectable HCV RNA

- Genotype 1 or 4 HCV

- Age ≤60 years

- Study modified Kidney donor profile index (KDPI) score ≤0.856 - calculated as if the
kidney were HCV-negative
(https://optn.transplant.hrsa.gov/resources/allocation-calculators/kdpi-calculator/)

Exclusion Criteria

- Anatomical issues in the kidney allograft that raise the risk of post-transplant
complications (e.g., number or length of renal arteries or veins)

- Confirmed HIV positive

- Confirmed HBV positive (positive Hepatitis B surface antigen and/or HBV DNA)

- Known previously failed treatment for HCV using a regimen with a direct-acting
antiviral (can have received interferon monotherapy and/or interferon + ribavirin
combination therapy)