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

Open-labelled pilot clinical trial of Zepatier (MK-5172 and MK-8742/Grazoprevir + Elbasvir)
in 10 HCV-negative subjects receiving a lung transplant from a HCV-positive donor. Eligible
subjects will receive a lung transplant from a deceased-donor with genotype 1 or 4 HCV, and
then will receive 12 weeks of Zepatier after lung transplantation when infection with HCV is
confirmed in these lung transplant recipients. Treatment will be complete after 12 weeks.

Subject Selection Criteria

Inclusion Criteria:

- 18-65 years of age

- Obtained agreement for participation from the lung transplant team

- No evident contraindication to lung transplantation other than the underlying lung
disorder

- Lung allocation score ≤55

- Able to travel to the University of Pennsylvania for routine post-transplant visits
and study visits for a minimum of 12 months after transplantation

- No active illicit substance abuse

- 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 of birth control or
remain abstinent following transplant due to risk of HCV transmission

- Inclusion criteria for treatment (not for entry as study patient) will include any
detectable HCV RNA by week 4 post-lung transplantation

- Able to provide informed consent

Exclusion Criteria:

- Hepatocellular carcinoma

- HIV positive

- HCV RNA positive

- Hepatitis B surface antigen and/or DNA positive

- Any chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD)) that
is occurring in the setting of persistently elevated liver enzymes (patients with
Alpha-1-antitrypsin lung disease without hepatic involvement are eligible)

- Significant fibrosis (≥F2 on the Fibroscan)—for patients with cystic fibrosis, the
cutoff will be 11kPa (cutoff for F2 for patients with chronic cholestatic liver
disease), whereas for all other patients the cutoff will be 8kPa (the cutoff for fatty
liver disease used in the THINKER study).

- 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

- Patients with underlying liver disease with or without liver cirrhosis

- Patients with cystic fibrosis who have underlying liver disease

- Significant esophageal dysmotlity

- Patient with systemic sclerosis or other collagen vascular disease with underlying
significant esophageal dysmotility

- Re-transplant candidate

- Use of ECMO or mechanical ventilation as a bridge to lung transplantation

- Inability to provide study consent

- Chronic kidney disease with GFR<50

Relative contraindications for study subjects that will be reviewed on a case-by-case basis
by the Lung Transplant Selection Committee and the Principal Investigators:

- Evidence of end organ damage due to diabetes (e.g. retinopathy, nephropathy,
ulcerations) and /or brittle diabetes mellitus (e.g. history of diabetic ketoacidosis)
and/or uncontrolled diabetes as evidence by a HgbA1C of 7.5-8.5.

- Hematologic: Significant coagulation abnormalities, and/or bleeding diatheses.

- Active or recent solid or liquid malignancy in the past 5 years (apart from select
skin malignancies).

- Patient refusal to receive blood products or transfusions during lung transplant
surgery.

- Psychosocial: Profound neurocognitive impairment with absence of social support.

- Active mental illness or psychosocial instability

- Inadequate insurance and/or financial support for post-transplant care.

- Evidence of drug, tobacco or alcohol abuse within the past six months and failure to
satisfy recommended therapy/services/parameters as indicated by social work staff
and/or consult team.

- History of chronic non-adherence to medical recommendations and/or medications

- PRA >10%.

- Severe malnutrition, BMI <18

- Major chronic disabling comorbidity (e.g. lupus, severe arthritis, neurologic
diseases, previous stroke with profound residual).

- Symptomatic or severe vascular disease (History of CABG, Aorta-femoral surgery)

Donor Organ Selection Criteria

Broad goal: To include donors with confirmed genotype 1 or 4 HCV expected to have
acceptable post-transplant graft outcomes based on large retrospective lung transplant
studies.

Inclusion criteria for donors:

- Detectable HCV RNA

- Genotype 1 or 4 HCV

- Age ≤55 years

- PaO2/FiO2 ≥300 on FiO2 = 100% and PEEP=5

- Cigarette use history ≤20 pack years

- No evidence of cirrhosis

- No prior treatment of HCV with a DAA-based therapy

- Can be isolated hepatitis B Core IgG positive, but cannot have a detectable HBV Core
IgM, HBSAg, and/or HBV DNA (positive HBV NAT test)

Donor Exclusion Criteria:

- Donation after circulatory death determination (DCDD)

- HIV positive