Chronic Hepatitis C
Conditions
Keywords
HCV, T cells, cytokines, cytotoxicity, proliferation
Brief 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
Detailed description
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.
Interventions
DRUGBoceprevir
In the experimental arm boceprevir (800 mg orally three times daily), PEG-IFN and ribavirin will be given for 24 weeks after the lead-in; the patients who will have undetectable HCV-RNA at week 8 will stop treatment at week 28; those who will be HCV-RNA positive at any visit between week 8 and 24 will receive an additional 20 weeks of PEG + RBV. Treatment will be discontinued if HCV-RNA is positive at week 24. Immunological analysis will be performed longitudinally at the following time points: week -4, 0, 4 (end of lead-in), 8, 12, 24, 48, week 24 of follow-up. HCV-RNA will be quantified at the same time points and viremia will be correlated with immunological data.
Sponsors
Azienda Ospedaliero-Universitaria di Parma
Study design
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Levels of HCV-specific T cell functions before, during and after therapy to measure functional restoration induced by therapy | 2 years | Capacity of expansion, cytokine production (IFN-γ, IL-2 and TNF-α) and cytotoxicity expressed by HCV-specific T cells will be analyzed longitudinally at different time points before, during and after therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Correlation of quality and intensity of pre-treatment HCV-specific T cell responses with outcome of therapy | 2 years | To assess whether different levels of efficiency of pre-treatment antiviral T cell responses can predict response to treatment. |
Countries
Italy
Outcome results
None listed