Hepatitis
C Virus-Specific T-Cell Reactivity During Interferon and
Ribavirin
Treatment in Chronic Hepatitis C
CTL
responses to HCV antigen appears important in one's ability to respond to
treatment. Response occurs 4-8 weeks following initiation of therapy and may be
key to phase 2 viral decay response.
*
Institute of Liver Studies, King's College Hospital, London, England; ß
Institute of Hepatology, University College London, London, England; and
Department of Gastroenterology, Mannheim, Germany
GASTROENTEROLOGY 2000;118:346-355
Abstract
Background
& Aims: The
role of virus-specific T-helper lymphocyte reactivity in determining the
therapeutic response in chronic hepatitis C virus (HCV) infection is not fully
understood.
Methods: We studied CD4+ T lymphocyte proliferation together
with interferon (IFN)- and interleukin (IL)-10 production from peripheral blood
mononuclear cells in response to 4 HCV antigens (core, NS3, NS4, and NS5) in 25
patients with chronic hepatitis C undergoing antiviral therapy with IFN alone or
in combination with ribavirin, prospectively, before, during, and after
treatment.
Results: HCV-specific T-cell reactivity was uncommon at
baseline but increased markedly during antiviral therapy, peaking around
treatment weeks 4-8. Resolution of hepatitis C viremia was significantly more
likely in patients who developed HCV-specific T-cell proliferation with
increased IFN- production. The main difference in T-cell reactivity of patients
treated with IFN plus ribavirin was a significantly lower production of IL-10,
whereas lymphocyte proliferation was similar to that in patients receiving IFN
monotherapy.
Conclusions:
Treatment-induced control of hepatitis C viremia is associated with the
development of HCV-specific T-cell responses with enhanced IFN- and low IL-10
production. The greater efficacy of combination therapy with IFN- plus ribavirin
may be related to its ability to suppress HCV-specific IL-10 production.
The
results show that virological response to treatment is associated with
activation of HCV-specific Th cell reactivity, particularly in the early phase
between weeks 4 and 8 of treatment. Patients with sustained HCV clearance show
much stronger and long-lasting enhancement of virus-specific T-cell reactivity,
which correlates with increased IFN- production at week 4 of treatment. In
contrast, treatment nonresponders show only weak or absent lymphoproliferation
with production of IL-10 rather than IFN- at week 4.
Introduction
Chronic
infection with hepatitis C virus (HCV) is a major cause of liver disease and
liver cancer worldwide. Effective treatment is needed not only to stop viral
replication and progression of liver damage in individual patients, but in
addition it would have an important role in the overall control of HCV
infection. Until recently, the sole therapeutic option available has been
treatment with interferon (IFN)-, which results in sustained remission only in a
minority of cases. Three patterns of therapeutic response to IFN- have been
recognized. Approximately 50% of patients are nonresponders with failure to
normalize serum aminotransferase levels and to lose detectable HCV RNA in the
serum. Among the other 50% who do have an initial response to treatment with
normalization of aminotransferases, at least half will relapse shortly after
treatment is discontinued (relapse patients), thus leaving only 25% of IFN-treated
patients with normal aminotransferase levels in the long term (sustained
biochemical responders). When the virological endpoint is considered, the
sustained response rate is even poorer, with HCV RNA remaining undetectable in
the serum at 6 months after stopping treatment in 15% or less of those treated.
Recently, 2 major multicenter clinical trials have established that the
combination of IFN- with ribavirin (IFN+R) markedly increases the sustained
biochemical and virological response rates in previously untreated patients with
chronic hepatitis C to about 40% overall and as high as 64% in cases infected
with HCV genotype 2 or 3.
The
mechanisms by which either IFN monotherapy or IFN+R bring about resolution of
infection remain poorly understood. IFN- has direct antiviral effects and a
number of immunomodulatory activities that can enhance antiviral immune
responses.5 Ribavirin is a nucleoside analogue that inhibits the replication of
DNA and RNA viruses, although when used alone in patients with chronic hepatitis
C it has no significant effect on HCV replication, despite reducing the levels
of liver enzymes. 6-9 HCV-specific T-helper (Th) cell responses have been
shown to be important in the resolution of acute HCV infection with strong
T-cell reactivity found in patients who clear HCV spontaneously and weak
responses in those progressing to chronic infection.10,11 Furthermore, strong
and multispecific Th responses have been found in HCV antibody-positive patients
without detectable viremia, but not in those with chronic HCV infection and
persistent viremia, thus indicating the role of virus-specific T-cell reactivity
in the long-term control of viremia.12 Several studies on virus-specific T-cell
reactivity in association with IFN treatment have found increased numbers of
patients with chronic hepatitis C with demonstrable HCV-specific Th responses
either during treatment or after a sustained therapeutic response.13-16 These
findings raise
the
possibility that enhancement of HCV-specific T-cell reactivity may be one
mechanism for successful antiviral treatment. So far, no study has prospectively
evaluated the evolution of Th responses during antiviral treatment in standard
protocol samples. In this study, we investigated whether the variable
therapeutic responses in patients with chronic hepatitis C are associated with
different patterns of virus-specific T-cell reactivity. In addition, we looked
for differences in the effects of IFN alone compared with combination treatment
of IFN+R. We have followed up serially HCV-specific Th cell responses before,
during, and after treatment in a group of HCV-infected patients receiving either
IFN- alone or IFN+R.
Patients
who demonstrated HCV-specific Th reactivity on treatment were more likely to
have a virological response to treatment (i.e., undetectable HCV RNA) than those
who did not. Of the 18 patients with an end of treatment response, 11 had HCV-specific
Th cell reactivity at the time of completion of treatment compared with 1 of the
7 treatment nonresponders (2 = 4.43, P = 0.035; Figure 2). Over the entire study
period, the 18 patients with a virological response to treatment showed
significant HCV-specific Th cell reactivity on 108 occasions of a total of 508
(21.3%) test points, compared with 15 of 192 (7.8%) test points in the 7
treatment nonresponders (2 = 17.4, P = 0.00003).
The
induction of persistent HCV-specific Th cell reactivity (defined as significant
T-cell reactivity detected on a minimum of 3 time points during treatment) was
found
transient
treatment response, whereas none were treatment nonresponders (P = 0.01 for
sustained vs. nonresponders; P = NS for transient vs. nonresponders, Fisher
exact test). Both patients showing significant Th reactivity before treatment
had a sustained response to treatment with HCV-specific Th reactivity maintained
throughout the study and an increase in the SI on treatment.
The
present study shows in a prospective manner that antiviral therapy of patients
with chronic hepatitis C is associated with enhancement of HCV-specific CD4+
T-cell
reactivity.
In some cases, this immune reactivity is maintained for at least 24 weeks after
stopping treatment. These findings are in keeping with previous studies showing
that most patients with a sustained virological response after IFN treatment
have a significant T-cell proliferative reactivity to HCV antigens, unlike
nonresponders to treatment. Serial testing of T-cell proliferation to HCV core
protein before and during IFN treatment in 2 groups of patients infected with
HCV genotypes 1b and 2 has also shown
IFN-induced enhancement of T-cell responses, which was greater in patients with
genotype 2 than in patients infected with genotype 1b.
An interesting observation in the present study is the change of T-cell reactivity in patients with posttreatment relapse. Among these transient responders, 5 of 7 cases had HCV-specific CD4+ T-cell reactivity detectable during but not before treatment; in 4 of them, this was maintained during posttreatment follow-up. This differs from the pattern observed in treatment nonresponders, who showed no HCV-specific Th reactivity either before or after treatment, and may indicate one factor contributing to the success of a second course of IFN+R in transient responders, although there is very little benefit in nonresponders.