HCV Treatment Immune Response With Grazoprevir/Elbasvir Before or After Renal Transplant

The study will be a pilot, prospective, single-center, open-label, non-randomized,
non-controlled, parallel clinical trial. 50 HCV genotype 1 infected patients with CKD defined
as a glomerular filtration rate (GFR) <50, with approximately 25 pre- transplant and 25
post-transplant patients, will be enrolled in the study. Recruitment will be conducted
through the renal transplant and nephrology outpatient clinics at the University of Maryland.

The study will involve two cohorts of patients:

- Pre-renal transplant

- Post- renal transplant

The pre-transplant cohort will include patients with GFRs < 50, regardless of whether they
are listed for transplant. These patients will be recruited from the University of Maryland's
transplant and general nephrology clinics, infectious diseases clinics, or dialysis center.
The transplant nephrology clinic is a multidisciplinary clinic that incorporates
nephrologists, pharmacists to aid in medication management, infectious disease and
coordinators to assist the patients in coordination of care.

The post-transplant cohort will include renal transplant recipients of both living donor and
deceased donor organs infected with HCV prior to their transplantation with GFRs <50 with
active HCV viremia. These patients will also be recruited from the University of Maryland's
multidisciplinary transplant nephrology clinic or infectious disease clinic.

Screening All patients will be screened at the Institute of Human Virology (IHV) Clinical
Research Unit. At this visit, all patients will have screening labs drawn and a history and
physical examination performed. Additional requirements will be genotype testing prior to
enrollment, but after transplant for the post-transplantation cohort, and disease staging
within 12 months of enrollment by liver biopsy, elastography, or biochemical testing. For
those who do not have a genotype or disease staging within the specified time frame,
genotyping and elastography will be repeated as part of the study screening work up.
Eligibility will be determined based upon these results within 6 weeks of starting the study
drugs.

Given the reduced efficacy of this regimen in patients with genotype 1a with the presence of
baseline NS5A resistance-associated variants (RAVs), the investigators will screen patients
for RAVs in patients with HCV genotype 1a at the time of enrollment. Any patient with
genotype 1a HCV found to have NS5A RAVs will undergo 16 weeks of therapy according to current
treatment guidelines.

Starting therapy Study drugs will be administered starting on day 0 after a history and
physical examination is performed and safety labs are checked. All patients will sign an
informed consent as approved by our Institutional Review Board (IRB) prior to administration
of study drugs.

Study visits during treatment Patients will be followed every 4 weeks while they are
receiving study drugs. HCV viral load (VL), safety labs and hepatic panel will be performed
at each of these visits. Patients will also be advised about study adherence and monitored
for adverse events.

Safety and adverse event monitoring At each study visit, research nurses will inquire about
adverse events that may or may not be related to study drugs. Any unfavorable medical
occurrences will be recorded, whether or not considered related to the patient's
participation in the research, temporally associated with the patient's participation in the
research. Adverse events (AEs) classified as grade 3 or higher will be reported to the IRB
and principal investigator. Any grade 3 or 4 AEs and all serious adverse events (SAEs) will
be reviewed as they occur by the study team.

Safety labs will also be drawn at these visits. Levels of immunosuppressive agents will also
be determined at these visits as appropriate. The need for dose modification of the patient's
immunosuppression in the time between visits will be recorded.

End of treatment visit Patients will be seen 12 weeks after starting study drugs (or 16 weeks
in the case of genotype 1a patients with baseline NS5A RAVs) for an end of study visit. HCV
VL, safety labs and hepatic panel will be performed at this visit. Patients will also be
counseled about study adherence and the investigators will inquire about adverse events.

Post treatment follow up visits Patients will be followed every 4 weeks for 12 weeks after
they complete treatment. HCV VL, safety labs and a hepatic panel will be performed at these
visits.

Inclusion Criteria:

- At least 18 years of age at the time of screening

- Have stable renal function for one month (30 days) prior to enrollment

- Have Chronic HCV infection prior to transplantation with documented HCV viremia ≥
1,000 IU/ml at screening and either documented HCV Ab positivity or HCV viremia ≥
1,000 IU/ml at least 6 months prior to enrollment.

- Documented genotype 1 HCV infection prior to enrollment and after their transplant in
the post-transplantation cohort

- HCV disease staging within 12 months prior to enrollment by liver biopsy, transient
elastography, or biochemical testing

- Be able to give informed consent and comply with study guidelines

- Women of childbearing age will be required to have a negative pregnancy test at
enrollment and use birth control throughout the duration of treatment.

Inclusion Criteria Specific to the Pre-transplant Arm

Patients will either be:

- On the transplant waiting list followed by the University of Maryland's nephrology
clinic or the Baltimore VA's nephrology clinic

- On chronic hemodialysis not yet on the transplant list and followed in the
University's hemodialysis center or in the University's nephrology clinic

- Have chronic kidney disease with GFR <50

Inclusion Criteria Specific to the Post-transplant Arm

• Patients will have undergone renal transplantation no greater than five years prior to
enrollment and will be followed in our University's nephrology and infectious disease
clinic. They will all have stable renal function at the time of enrollment.

Exclusion Criteria:

- Documented positive hepatitis B (HBV) surface antigen, and/or HBV DNA prior to
enrollment

- Any prior exposure to HCV protease inhibitor therapy

- HIV co-infection if on a protease inhibitor based regimen

- Increase in creatinine of 15% or greater within one month (30 days) of the screening
visit

- Evidence of hepatocellular carcinoma at the time of enrollment

- Liver disease caused by an etiology other than HCV

- F4 or decompensated cirrhotic patients

- Child Pugh class B or C

- AST or ALT >350 within 6 months prior to enrollment

- Albumin < 3g/dL at the time of enrollment

- Platelet count < 75 at the time of enrollment

- History of clinically significant allergy or adverse event with protease inhibitors

- Evidence of the acquisition of HCV at the time of or after transplantation

- Pregnant or breastfeeding women

- Cyclosporine; St. John's Wort; Efavirenz; Phenytoin; Carbamazepine; Bosentan; HIV
protease inhibitors; modafinil; ketoconazole; or rifampin use within 7 days of
enrollment

- Coadministration of more than 20 mg atorvastatin; 10 mg rosuvastatin; 20 mg of
fluvastatin, lovastatin or simvastatin