effect of boceprevir on hcv-specific t cell responses

Conditions: Chronic Hepatitis C

Summary: 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.

Eligibility criteria:
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

Keywords: hcv t cells cytokines cytotoxicity proliferation