Effect of Boceprevir on HCV-specific T Cell Responses
Effect of Boceprevir on HCV-specific T Cell Responses
Analysis of HCV-specific T cell responses in patients treated with boceprevir to assess
 whether therapy can induce restoration of the T cell function and to what extent this
 recovery can be achieved
Reconstitution of the antiviral T cell function may represent a component of the anti-viral
 effect of protease inhibitors. If T cell responsiveness is restored under therapy,
 potentiation of anti-viral T cell functions by exogenous T cell stimulation might be
 exploited to complement and to further improve response to available therapies. Monitoring
 the T cell function might also be useful to predict more accurately response to therapy.

 To address these issues, phenotype and function of HCV-specific T cells will be analyzed
 longitudinally before, during and after therapy in naïve genotype 1 chronic hepatitis C
 patients treated with peginterferon plus ribavirin or with peginterferon and ribavirin plus
 boceprevir. To analyze the global CD4 and CD8 reactivity against all structural and
 non-structural HCV proteins a wide panel of peptides corresponding to the whole HCV genome of
 genotype 1 will be employed. To further analyze CD8 reactivity, HLA-A2/peptide tetramers will
 be used in HLA-A2 positive patients to directly quantify ex vivo HCV-specific CD8 cells
 circulating in the peripheral blood.The T cell function will be analyzed as capacity of
 expansion in vitro, cytokine production and cytotoxicity.
Inclusion Criteria:

 Subjects must meet all of the following inclusion criteria to be eligible for participation
 in this study.

 -  Male or female, aged from 18 to 70 years old, inclusive.

 -  Willing and able to provide written informed consent

 -  Chronic HCV infection for at least 6 month prior to baseline (Day 1) in subjects
 currently positive for HCV-RNA and anti-HCV antibody documented by:

 -  A positive anti-HCV antibody test, positive HCV-RNA assay, or HCV genotype test at
 least 6 month prior to baseline (Day 1) or

 -  A liver biopsy performed prior to baseline (Day 1) with evidence of chronic HCV
 infection

 -  Subjects must have liver biopsy results (performed no more than two years prior the
 screening) indicating the absence of cirrhosis

 -  HCV infection limited to genotype 1

 -  Detectable plasma HCV-RNA at screening

 -  BMI between 18 and 36 Kg/m2

 -  Eligible subjects must also be HCV treatment-naïve, defined as no prior exposure to
 PEG-INF and ribavirin, and must be eligible to standard of care therapy with PEG/RBV

 -  Subjects must have the following laboratory parameters at screening:

 ALT and AST ≤ 5 x upper limit of normal range (ULN) Hemoglobin (Hb) ≥ 12 g/dl WBC ≥ 2.500
 cells/μL with absolute neutrophil count ≥ 1500 cells/μL If a woman of childbearing
 potential, must have negative serum β-human chorionic gonadotropin (β-HCG) pregnancy test
 documented at the screening visit and a negative serum or urine pregnancy test before the
 first dose of study drug to ensure that they are not pregnant at the time of starting
 treatment A female subjects of childbearing potential and nonvasectomized male subjects
 with a female partners of childbearing potential must agree that they and their partner
 will use effective contraception (two separate forms of contraception simultaneously, one
 of which must be a male condom with spermicide) from screening throughout the duration of
 study treatment and for at least 7 months

 Exclusion Criteria:

 -  Pregnant women or women who may wish to become pregnant during the course of the study

 -  Male with a female who is pregnant or is planning to become pregnant within seven
 month the study of anticipated last dose of ribavirin

 -  Evidence of infection or co-infection with a no-genotype 1 HCV-strain

 -  History of hemoglobinopathy

 -  History of sarcoidosis

 -  History of invasive malignancy diagnosed or treated within 5 years.

 -  Untreated or significant psychiatric illnesses including severe depression,
 schizophrenia, psychosis, history of a suicide attempt

 -  Co-infection with HBV or HIV

 -  Chronic use of systemic immunosuppressive agents

 -  Presence of autoimmune disorders; subjects with treated hypothyroidism with normal TSH
 may be enrolled

 -  History of significant cardiac disease

 -  Clinical evidence of chronic pulmonary disease

 -  Known cirrhosis

 -  History of solid organ transplantation

 -  Suspicion of hepatocellular carcinoma

 -  Chronic liver disease of a non-HCV etiology

 -  Ongoing alcohol abuse

 -  History of clinical relevant drug abuse

 -  Positive urine screen for cocaine, opiate etc, or methadone use