Effect of Boceprevir on HCV-specific T Cell Responses (Boce-Par)

Effect of Boceprevir Therapy on HCV-specific T Cell Responses: Perspectives of Immune Monitoring and Immune Therapy

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

Study Overview

• Status: Completed
• Conditions: Chronic Hepatitis C
• Intervention / Treatment: Drug: Boceprevir

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.

• Study Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Italy
  • Parma, Italy, 43126
    • Unit of Infectious Diseases and Hepatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Naïve genotype 1 chronic hepatitis C patients

Description

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

Study Plan

How is the study designed?

Design Details

• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Chronic hepatitis C; 10 naïve genotype 1 chronic hepatitis C patients treated with PEG plus RBV (control arm); 20 naïve genotype 1 chronic hepatitis C patients treated with a response guided therapy consisting of Boceprevir in combination with PEG plus RBV (experimental arm)

Drug: Boceprevir; 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.; Other Names: Peginterferon alfa-2b and ribavirin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Levels of HCV-specific T cell functions before, during and after therapy to measure functional restoration induced by therapy	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	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of quality and intensity of pre-treatment HCV-specific T cell responses with outcome of therapy	To assess whether different levels of efficiency of pre-treatment antiviral T cell responses can predict response to treatment.	2 years

Collaborators and Investigators

• Sponsor: Azienda Ospedaliero-Universitaria di Parma
• Investigators: Principal Investigator: Carlo Ferrari, MD, Azienda Ospedaliero-Universitaria di Parma

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): October 1, 2013

Study Registration Dates

• First Submitted: July 26, 2011
• First Submitted That Met QC Criteria: July 26, 2011
• First Posted (Estimate): July 27, 2011

Study Record Updates

• Last Update Posted (Estimate): November 6, 2013
• Last Update Submitted That Met QC Criteria: November 5, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: HCV; cytokines; proliferation; T cells; cytotoxicity
• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Hepatitis C; Hepatitis C, Chronic; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites; Ribavirin; Peginterferon alfa-2b
• Other Study ID Numbers: AZOSPA