Pegylated Interferon, Ribavirin, Telaprevir in Hepatitis C Virus Infection in Orthotopic Liver Transplant Recipients

BACKGROUND:

Cirrhosis from HCV is the most common indication for OLT. Unfortunately, disease recurrence
in the allograft is virtually universal. The spectrum of disease recurrence ranges from
minimal inflammation to severe cholestasis as well as cirrhosis, leading to allograft
failure. Previous reports indicated a comparable survival rate between patients who received
OLT for HCV and those who received OLT for other indications. More recent data, however,
suggested that HCV-positive recipients have significantly impaired patient and allograft
survival following OLT as compared to HCV-negative recipients. Approximately 20% of patients
with recurrent HCV have cirrhosis at 5 years post-OLT.

Attempts to treat HCV recurrence in OLT recipients have had limited success. Sustained
virologic responses (SVR) have only been seen in up to 30% of patients with genotype 1
infection, whereas SVR has been higher at 42-46% for non-transplant counterparts. Most
recently, the addition of telaprevir to pegylated interferon and ribavirin to comprise the
triple therapy in the nontransplant HCV-infected population has led to significantly higher
sustained virologic response rate (SVR) of 75% when compared to 44% observed in the control
arm which received pegylated interferon and ribavirin. Its side effect profile was
acceptable to allow the FDA to approve the drug on May 23, 2011. However, there is no data
on the efficacy and safety of telaprevir in OLT recipients. In fact, its use in this
population is greatly hindered by a significant drug-drug interaction with the major
immunosuppressive agents used in OLT, namely tacrolimus and cyclosporine. Telaprevir
increases cyslosporine exposure by 4.6 fold and its half-life by 3.5 fold. It increases
tacrolimus exposure to 70 fold and its half-life by 4.9 fold. Clearly, the doses of these
immunosuppressive agents need to be adjusted at the start and end of telaprevir therapy.

The primary aim of our study is to determine the safety and efficacy of pegylated interferon
alfa-2a (Pegasys®), ribavirin, and telaprevir therapy in liver transplant recipients with
hepatitis C recurrence who are maintained on cyclosporine or tacrolimus-based
immunosuppression. We hypothesize that triple therapy will have better sustained virologic
response rates than the current standard of care, pegylated interferon and ribavirin, with
an acceptable side-effect profile.

STUDY DESIGN:

Prospective, open-label, single center pilot study. All patients will receive the study
drug along with the standard regimen of pegylated interferon and ribavirin.

DRUG DOSE AND TREATMENT DURATION:

Patients will be treated with pegylated interferon alfa-2a (Pegasys®) 180 mcg SQ per week,
ribavirin 800-1200 mg PO per day (weight-based) for 48 weeks. Telaprevir 750 mg PO tid will
be administered for the first 12 weeks. Following completion of therapy, patients will be
followed for another 24 weeks to determine sustained response.

*Doses lower than 800 mg/day may be used by the investigator in patients with renal
insufficiency (as ribavirin is renally excreted), at the investigator's discretion.

RESEARCH PROTOCOL:

This prospective study will include patients who have histologic evidence of recurrent HCV
infection who are maintained on cyclosporine-based immunosuppression.

Patients who qualify for the study will be identified from the Liver Transplant Clinic.
Patients will be treated with pegylated interferon alfa-2a (Pegasys®) 180 mcg SQ per week,
ribavirin 600-1200 mg PO per day, and telaprevir 750 mg tid (Incivek®) for 12 weeks,
followed by pegylated interferon alfa-2a (Pegasys®) and ribavirin for another 36 weeks.
Patients will be assessed at periodic intervals for safety and adverse effects as delineated
in the Schedule of Assessments (Appendix A). Growth factors such as erythropoietin and
filgastrim will be allowed in the event that signficiant anemia and thrombocytopenia
develops during therapy, at the discretion of the investigator.

The HCV RNA will be measured at baseline and weeks 2, 4, 8, 12, 24, 36 and 48 of therapy as
well as during follow-up. Response to therapy is defined by HCV RNA <1000 IU/ml at weeks 4,
8, and 12 of therapy, which will allow continuation of treatment. Telaprevir will be
discontinued if HCV RNA is >1000 IU/ml at weeks 4 or 8 of therapy, and pegylated interferon
and ribavirin will be discontinued if HCV RNA is still detectable by week 24 of therapy.

Cyclosporine or tacrolimus trough levels will be drawn at baseline, days 1,2, 3, 4,5, 8, and
to be continued every 2-3 days. The cyclosporine or tacrolimus dose will be cut by 50% at
baseline and cyclosporine or tacrolimus dose adjustments will be made to maintain the level
within the targeted therapeutic range. Once two consecutive levels within the targeted
therapeutic range have been achieved, levels will be drawn weekly for the first month then
biweekly until the end of telaprevir treatment. After the last dose of telaprevir,
cyclosporine or tacrolimus levels will be drawn on days 1, 3, 5, 7 and to be continued every
other day, and cyclosporine or tacrolimus dose adjustments will be made to maintain the
level within the targeted therapeutic range. Once two consecutive levels within the targeted
therapeutic range have been achieved, levels will be drawn in a week and then monthly for up
to week 24 of therapy. Patients who complete therapy will continue to be followed for 24
weeks to determine their sustained virologic response.

STATISTICAL ANALYSIS:

This is a pilot, single arm study that evaluates the efficacy and safety of triple therapy
in recurrent HCV. All clinical and laboratory data will be entered into a computer database.
Categorical variables will be expressed as proportions and continuous variables will be
expressed in mean values.

Inclusion Criteria:

- Male or female patients > 18 years of age.

- Detectable plasma HCV-RNA by qualitative PCR assay.

- HCV genotype 1 infection,

- Documented recurrent hepatitis C by liver biopsy within the past year.

- On cyclosporine or tacrolimus-based immunosuppression

- Negative urine pregnancy test before initiating the treatment for women of
childbearing potential.

- Willingness of the patient and all potentially childbearing partners to use a
reliable form of effective contraception during the study, unless the patient or
partner is surgically sterile or post-menopausal.

- Willingness to undergo provide informed consent and comply with study requirements.

Exclusion Criteria:

- Genotype non-1 HCV infection.

- Women who are pregnant or breast-feeding.

- Male partners of women who are pregnant.

- Evidence of co-infection with HIV or hepatitis B.

- History of severe psychiatric disease.

- History of immunologically mediated disease (e.g., inflammatory bowel disease, lupus
erythematosus, rheumatoid arthritis, etc.)

- History of clinically significant pulmonary disease.

- History of severe cardiac disease.

- History of malignancy where risk of recurrence is >20% within 2 years.

- History of uncontrolled seizure disorder.

- History of poorly controlled thyroid disease.

- History of poorly controlled diabetes mellitus.

- History of severe retinopathy.

- Active gout.

- History or evidence of severe medical illness that, in the opinion of the
investigator, makes the patient unsuitable for pegylated interferon alfa-2a treatment
(Pegasys®).

- Inability or unwillingness to abstain from alcohol throughout the entire study
period.