icon-folder.gif   Conference Reports for NATAP  
  DDW Liver Conference
San Francisco, May 19-22, 2002
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  Sanaa M. Kamal, Jutta E. Fehr, Bernd Roesler, Thomas Peters, Jens Rasenack, Freiburg, Germany
This study compares the immune response and correlates it to HCV RNA response in patients with HCV mono-infection receiving inteferon a-2a monotherapy, Pegasys (pegylated interferon alone), or Pegasys+ribavirin. There were 14 patients in each treatment group. Biopsies were performed. The study authors reported that sustained viral responders achieved histologic responses in all 3 treatment arms. Nonresponders were also able to achieve a histologic response. It appeared that the Pegasys/RBV arm had the highest percentage of patients experiencing histologic response among nonresponders followed by Pegasys monotherapy, and then by IFN monotherapy.
During the 72 weeks of following the patients the HCV specific CD4+ T-cell response appeared to correlate with viral response to therapy. Patients receiving Peg+RBV had the biggest CD4 responses and the best viral response. Pegasys alone had a better CD4 response than interferon monotherapy. Sustained viral responders had much better CD4 responses than either partial responders or nonresponders. The nonresponders had no CD4 response. The partial responders had a small response that quickly faded. The sustained responders's CD4 response increased after treatment ended and was sustained for the full 72 week follow-up leading to comment by authgor that this response accompanies a sustained response. Suggesting that relapsers may not be able to sustain this CD4 response. The cytokine production (IFN-gamma, IL-4, IL-10) was much better in thePeg/RBV group. The Peg monotherapy group had less of a response and it faded. Sustained responders also had much stronger and sustained cytokine responses than both other treatment groups. The CTL response (cytotoxic lymphocyte response, also an immune response meant to control the virus, was more sustained in the Peg/RBV arm. The Peg monotherapy arm had a response but it faded. The IFN monotherapy arm had very little CTL response.
The authors summarized: Pegasys/RBV and Pegasys are associated with more vigorous multispecific immune responses compared to standard IFN a-2a. The efficacy of anti-viral therapy in inducing higher rates of sustained viral responses may be due to enhancement and restoration of HCV specific T CD4+ helper 1 and CTL responses.
I think a message from this study is that the ability to achieve histologic improvement may be tied to the strength of the immune response. And the strength of the immune response is tied to the ability to achieve a sustained viral response. Still, the authors reported that nonresponder patients and partial responders were able to achieve a histologic improvement.
BACKGROUND/AIMS: Pegylated interferons without or with ribavirin were shown in phase III studies to improve sustained virological response compared to standard interferon alpha-2a therapy. This study investigated if the greater efficacy of pegylated interferons might be related to modulation of immunological responses.
PATIENTS & METHODS: HCV-specific CD4+ T-cell responses, cytotoxic CD8+ T cell response and cytokine production to various HCV proteins (ELISPOT assay) in peripheral blood mononuclear cells were prospectively assessed in 42 patients receiving IFN alpha-2a monotherapy, peginterferon alpha-2a monotherapy or peginterferon alpha-2a plus ribavirin and correlated to the outcome of therapy.
RESULTS: The sustained virological response rate was significantly higher in the peginterferon groups (42% in peginterferon alpha-2a monotherapy, 57% in peginterferon alpha-2a/ribavirin combination) than in the standard IFN alpha-2a group (14%). Patients with HCV genotype 1 infection benefited most from peginterferon alpha-2a/ribavirin combination therapy (SVR 48%). Pre-treatment HCV specific CD4+ responses and CD8+ cytotoxic responses were either absent or weak in all patients. Peginterferon alone or combined with ribavirin induced significant increase in the frequency, strength and breadth of HCV-specific CD4+ T-helper 1 responses; while interferon alpha-2a monotherapy was associated with lower, fluctuating, short lived responses. Sustained responders developed strong multi-specific maintained HCV specific CD4+ T cell responses with enhanced IFN-gamma production and IL-10 suppression. Relapsers and partial responders initially displayed significant HCV specific CD4+ T cell responses, which waned or were lost. CTL responses were more common in sustained responders compared to non-responders.
CONCLUSION: the results indicate that the efficacy of peginterferon alpha-2a alone or in combination with ribavirin in inducing high rates of sustained virological response may be to restoration and maintenance of significant multi-specific HCV-specific CD4+T helper 1 and CTL responses.