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PEGINTERFERON ALPHA-2A ALONE OR IN COMBINATION WITH RIBAVIRIN ENHANCES
RESTORATION OF THE HCV SPECIFIC T CELL RESPONSES IN PATIENTS WITH CHRONIC
HEPATITIS C
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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.
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