Impact of Immune Responses in Chronic Hepatitis C Genotype 1 Virus Infected Patients during Treatment with Peg-Interferon-alpha-2b and Ribavirin.

Background
Treatment of chronic hepatitis C (HCV) has shown a remarkable success. However,
genotype 1 patients have reduced response rates (1-4). A better understanding
and improvement of these results can now be considered the greatest challenge.

In chronically infected patients, HCV-specific T-cell responses are generally
weak, narrowly focused, and often dysfunctional. The presence of HCV-specific
regulatory CD4+ T-lymphocytes (Treg) that are able to suppress the activity of
HCV-specific CD4+ helper and CD8+ cytotoxic T cells (5, 6) and dysfunction of
DC (dendritic cells) are possible mechanisms responsible for this impaired
immune response.

Another recent study by our group (9) showed an increased expression of FoxP3
in the liver of HCV-positive liver transplantation recipients as compared to
non-HCV recipients. FoxP3 is a key transcription factor expressed in Treg.
Furthermore, we found that the expression of the immunosuppressive cytokine
IL-10, was enhanced in the liver but not in peripheral blood of HCV-positive
patients. These results indicate increased Treg frequency and immunoregulatory
activity, locally in the liver, as a result of HCV re-infection. Hence, these
Data highlight the importance of monitoring intrahepatic immune responses in
addition to peripheral immune responses. Using the minimally-invasive technique
of fine-needle aspiration biopsy (FNAB), it is now possible to obtain safe and
frequent liver samples to monitor local antiviral immune responses in chronic
HCV patients during antiviral therapy (10)

Rationale of the study
Our previous studies and current literature support the concept that Treg may
contribute to HCV persistence by suppressing HCV-spec immune responses. The
current study is designed to examine if peginterferon and ribavirin therapy
affects the activity of Treg and DC, and if this results in enhanced
HCV-specific immune responses.

Primary aim
To evaluate the effects of peginterferon and ribavirin therapy on the immune
response in chronic HCV genotype 1 patients before, during and after treatment.

Secondary aims
1. To determine if differential modulation of Treg activity or DC function
during treatment may contribute to response to treatment of chronic HCV
patients.
2. To determine if, and to what extent, HCV-specific immune responses in blood
reflect the intrahepatic immune response.

Design (type of trial)
Monocenter, translational open label study with one arm of 20 patients.

Possible risks and discomforts

Since extra blood is drawn at the same time as the collection blood for regular
bloodtesting, there is no additive risk involved in the retrieval of extra
blood.
Normally, a venapunture can give the patient the sensation of minor pain and
cause a small swelling, bruise and/or infection. Furthermore, a FNAB can also
give the patient the sensation of minor pain and cause a small swelling, bruise
and/or infection. Other burdens or risks have not occured in our clinic, nor
have they been described in the international literature.