Boceprevir in End Stage Renal Disease (ESRD)

Hepatitis C (HCV) remains the most common chronic infection in the United States with about
3 million people chronically infected. The majority of these patients in the U.S. have
genotype 1 HCV infection, which has been the most difficult genotype to treat with the
traditional regimen of pegylated-interferon (P-IFN) and ribavirin, leading to sustained
virologic response (SVR) in less than 50% of cases. HCV is also an established risk factor
for chronic kidney disease (CKD) and end-stage renal disease (ESRD) and unfortunately the
treatment is even less successful in these patients mainly limited by increased medication
toxicity.

In spring of 2011, the FDA approved two new direct acting antivirals (DAA) for the treatment
of chronic genotype 1 HCV, boceprevir and telaprevir, to be used in combination with Peg-IFN
and ribavirin. This 'triple therapy' approach has significantly increased the response rate
(increased SVR rates to about 80% in those patients who had never been previously treated)
representing a significant advance in the field. In addition, several response-guided
therapy approaches were tested to determine if treatment duration could be shortened based
upon the virologic response on treatment.

To date, there have been no studies evaluating the safety and efficacy of triple therapy in
patients with ESRD. However, a single dose pharmacokinetic study of boceprevir in subjects
with ESRD on hemodialysis demonstrated that the mean maximum concentration achieved by
boceprevir (Cmax) and bioavailability (AUC) were comparable in patients with ESRD and in
healthy subjects. Mean t½, median Tmax and mean apparent oral total clearance (CL/F) values
were also similar in healthy subjects and patients with ESRD. Boceprevir exposure was also
similar on dialysis and non-dialysis days. These data suggest that boceprevir does not need
to be adjusted in patients with ESRD on dialysis, and that it is not removed by
hemodialysis. To date, there are no studies of telaprevir in ESRD patients.

The investigators therefore aim to study the safety and efficacy of triple therapy using
boceprevir in combination with P-IFN and ribavirin in patients with stage 5 CKD (defined as
glomerular filtration rate (GFR) < 15 mL.min.1.73m2 on permanent hemodialysis for stage 5).
In addition, given the significant toxicity of treatment in this particular patient
population, the investigators aim to study the efficacy of response guided therapy in those
patients who are eligible for response-guided therapy based on prior studies (treatment
naïve patients, and well documented history of relapse with prior treatment with P-IFN and
ribavirin).

Inclusion Criteria:

1. Adult (ages 18-75)

2. Hepatitis C Virus ribonucleic acid (HCV RNA) 1000 IU/mL or greater

3. Hepatitis C Virus (HCV) genotype 1

4. End stage renal disease on hemodialysis

5. Females of child bearing potential must be using an adequate method of contraception
throughout the study and must have a negative pregnancy test prior to the start of
treatment.

Exclusion Criteria:

1. Intolerance to peg-IFN or ribavirin with prior treatment course.

2. Prior treatment with protease inhibitor (telaprevir or boceprevir) or experimental
protease inhibitor

3. Significant cytopenias:

1. Absolute neutrophil count (ANC) < 1000/mm3, OR

2. Hemoglobin (Hgb) <10.5 g/dL, or

3. Platelet count < 50,000/mm3

4. Significant laboratory abnormalities

1. Direct bilirubin > 1.5 x upper limit of normal (ULN)

2. Total bilirubin > 1.6 mg/dL unless due to Gilbert's disease

3. Prothrombin time (PT)/Partial thromboplastin time (PTT) > 10% above laboratory
reference range

4. Thyroid Stimulating Hormone (TSH) > 1.2 x ULN or < 0.8 x lower limit of normal
(LLN)

5. Uncontrolled depression or psychiatric disease

6. Uncontrolled cardiopulmonary or cardiovascular disease

7. Autoimmune diseases except for treated thyroid disease

8. Active substance abuse within 6 months of initiation of treatment

9. Recent (within 4 weeks) episode of infection requiring systemic antibiotics

10. Any medical condition that would be predicted to be exacerbated by therapy or that
would limit study participation

11. Any medical condition requiring or likely to require chronic systemic administration
of corticosteroids or other immunosuppressive medications during the course of this
study

12. Human immunodeficiency virus (HIV) or Hepatitis B Virus (HBV) co-infection

13. Hepatocellular carcinoma (HCC) (Patients with HCC who are listed for liver
transplantation may be included.)

14. Other significant chronic liver disease diagnosis

15. Evidence of decompensated liver disease

16. Solid organ transplant recipient (Patients who have a history of renal transplant,
and have experienced kidney graft loss, and are not on immunosuppression may be
included.)