Interleukin
10 Treatment Reduces Fibrosis in Patients With
DAVID R.
NELSON,* GREGORY Y. LAUWERS,* JOHNSON Y. N. LAU, and GARY L. DAVIS*
*
Section of Hepatobiliary Diseases and Department of Pathology, University of
Florida College of Medicine, Gainesville, Florida; and
Department of Antiviral Therapy, Schering Plough Research Institute,
Kenilworth, New Jersey
Published
online 10 March 2000
GASTROENTEROLOGY 2000;118:655-660
RAPID COMMUNICATIONS
Abstract
Background
& Aims: Interleukin (IL)-10 is a cytokine that down-regulates the
proinflammatory response and has a modulatory effect on hepatic fibrogenesis.
The aim of this study was to determine the effect of IL-10 on hepatic injury in
patients with chronic hepatitis C.
Methods:
Twenty-four
patients with chronic hepatitis C who had not previously responded to
interferon-based therapy were enrolled in a randomized, double-blinded 2-dose
trial in which they received either 4 or 8 µg/kg IL-10 subcutaneously daily for
90 days. Liver biopsies were performed before and at the end of therapy.
Results:
IL-10
was well tolerated with 22 patients completing the study. Serum ALT levels
normalized in 19 of 22 patients by the end of therapy and were sustained in 5 of
22. Hepatic inflammation decreased in 19 of 22 patients, with 11 having a
decrease by 2. Fibrosis decreased in 14 of 22 patients (mean change, 3.6-2.6; P=
0.001). There was no change in serum HCV RNA levels. IL-10 therapy was
associated with changes in serological markers, suggesting a reduction of immune
response and fibrogenesis. The degree of regression of liver fibrosis and
histological improvement observed after only 12 weeks of IL-10 in this pilot
study is similar to that previously reported in treatment-naive patients with
chronic hepatitis C who responded to 48 weeks of IFN-based therapy.
Conclusions:
IL-10
therapy is safe and well tolerated in patients with chronic hepatitis C.
Although it has no apparent antiviral activity, IL-10 normalizes serum ALT
levels, improves liver histology, and reduces liver fibrosis in a large
proportion of patients receiving treatment. Therefore, IL-10 may have
therapeutic potential in patients with chronic hepatitis C patients who do not
respond to interferon-based therapy.
DISCUSSION:
improvements in liver condition (histology), side effects
(excerpts
from the published article in Gatroenterology)
Hepatitis
C virus (HCV) infection is common and may cause insidious and progressive liver
damage in many infected patients. Of those who develop chronic infection,
20%-50% will eventually progress to cirrhosis, and 4% of these will experience
hepatic failure each year. Interferon (IFN)- (with or without ribavirin) is
currently the only effective treatment for chronic HCV infection, although only
30%-40% of treated patients have sustained virological responses. There is no
treatment that prevents the progression of liver disease in patients who do not
respond to IFN-based therapies. Alternative options are needed.
The
pathogenesis of hepatocellular injury in HCV infection is not fully understood,
but there is increasing evidence to implicate immune-mediated mechanisms. CD4+
and CD8+ T cells, as well as their inflammatory and regulatory cytokines, have
been implicated in both the hepatocellular damage and the perpetuation of
chronic HCV infection. CD4+ cell responses are polarized into T helper (Th)1 and
Th2 types. Th1 cells secrete interleukin (IL)-2 and IFN-, which are required for
host antiviral immune responses. Th2 cells produce IL-4, IL-5, IL-13, and IL-10,
which facilitate antibody production and limit Th1 response. The interplay
between Th1 and Th2 cytokines may be important in regulating hepatocellular
damage and disease progression in chronic HCV infection. Patients with chronic
HCV infection have an activated T-cell response cytokine pattern, with elevated
levels of serum IL-2, IL-4, IL-10, tumor necrosis factor (TNF)-, and IFN-. Those
with severe chronic hepatitis or cirrhosis have enhanced expression of both IFN-
and IL-2 messenger RNA that correlates with fibrosis and portal inflammation,
We
hypothesize that in vivo administration of IL-10 may tilt the balance away from
Th1 cytokine dominance, thereby reducing the hepatocellular injury that
characterizes HCV infection. Human IL-10 has both anti-inflammatory and
immune-suppressive properties. Of particular importance is the capacity of IL-10
to down-regulate production of proinflammatory cytokines, such as TNF-, IL-1,
and IFN-, and IL-2 from T cells. In fact, endogenous IL-10 reduces the
intrahepatic inflammatory response and limits hepatotoxicity in several models
of liver injury.
Patients
Adult
subjects who had previously not responded to IFN-based treatment were enrolled
to assess the effect of recombinant IL-10 in chronic hepatitis C. Nonresponse to
IFN-based treatment was defined as detectable HCV RNA and persistently elevated
serum
Study
Design and Treatment Regimens
The
study was a randomized, double-blind, 2-dose trial. Twenty-four subjects were
randomized (1:1; 12 subjects per group) to receive recombinant human interleukin
(rIL-10; Schering Plough Research Institute, Kenilworth, NJ) subcutaneously at a
daily dose of either 4 or 8 µg/kg for 90 consecutive days. Each subject
underwent liver biopsy before the first dose of rIL-10 and at the end of 12-week
treatment period. Participants were monitored as outpatients on a weekly basis
during therapy, and 1 and 3 months after treatment. Serum was collected and
stored under conditions previously shown to optimize HCV RNA for detection and
quantitation.
Study
Patients: previous treatment and baseline characteristics
The 2
treatment groups were well matched. Collectively, 20 of 24 (83%) patients had
genotype 1a/1b, the mean serum HCV RNA level was 17.4 ± 3.9 ? 106 Eq/mL, and 18
of 24 patients had at least focal bridging fibrosis on initial liver biopsy. The
previous treatment regimens were a single course of Intron A monotherapy (Schering
Plough; n = 12; median duration of therapy, 24 weeks; range, 12-48 weeks) or
Rebetron therapy (Schering Plough; n = 8; median duration of therapy, 24 weeks;
range, 12-48
Treatment
Responses
Serum
ALT:
Serum
ALT levels normalized by the end of treatment in 19 of 22 (86%) treated
subjects: in 8 of 11 patients given 4 µg/kg and in all 11 patients given 8 µg/kg
(difference not significant). Two patients did not complete the study and were
not included in this analysis (1 completed 1 week of rIL-10 therapy with a
decrease of serum ALT from 136 to 63 U/L, and the other completed 3 weeks of
therapy with normalization of ALT from 76 to 35 U/L). As a group, the mean ALT
level decreased from 90 ± 9 to 32 ± 4 U/L during therapy (P = 0.001) and
returned to a level of 75 ± 7 U/L (P = 0.1) by the 3-month follow-up. Normal
ALT was sustained throughout the 3-month follow-up period in 5 patients (23%), 2
at the 4-µg/kg dose and 3 at the 8-µg/kg dose. Serum ALT levels did not
increase during treatment in any patient.
Liver
histology:
Paired
pretreatment and posttreatment liver biopsy specimens were available from all 22
patients who completed therapy. The histological activity index (HAI) decreased
in 19 of 22 subjects, and improved by at least 2 points in 11 of 22 (Figure 2A).
The mean HAI score for the entire group decreased from 4.3 ± 0.3 to 2.7 ± 0.3
(P = 0.001), with significant reductions in all components of the inflammatory
score (portal, periportal, and lobular). The Ishak fibrosis score decreased in
14 of 22 (Figure 2B) with a mean change from 3.6 ± 0.4 to 2.6 ± 0.4 (P =
0.001). The HAI and fibrosis score improvements were observed with both the 4-
and 8-µg/kg doses.
Adverse
Events:
Safety
analysis was performed on all 24 patients who received study medication.
Symptoms experienced during treatment are listed in Table 3. rIL-10 was well
tolerated with minimal side effects. The most frequent clinical adverse events
during treatment with rIL-10 were headache, dry mouth, and insomnia. These were
not dose limiting in any patient. Mild anemia occurred during the first 4 weeks
of therapy in most subjects with an average decrease in hemoglobin level of 2.2
± 0.3 g/dL. Hemoglobin levels stabilized without dose reduction and returned to
baseline after completion of treatment. The platelet count decreased slightly
during therapy (by 14,000/dL; P = NS), and there was no effect on neutrophil
counts. Anecdotally, most patients reported improvement in arthralgias, myalgias,
fatigue, and disturbed sleep patterns during treatment, but these symptoms
returned when the drug administration was stopped. Of 12 patients receiving
higher dose of 8 ug/ml daily subcutaneously, 9 experienced headaches, 3 dry
mouth/thirst, 2 sleep disturbances, 1 abdominal pain/nausea, 2 rash, 1 anxiety.
Summary
by authors:
Although
combination therapy has significantly improved the sustained response rate,
approximately 60% of patients are nonresponders and are at continued risk for
disease progression. Progression to cirrhosis is common in patients who already
have hepatic fibrosis, and this is associated with an increased risk of liver
decompensation, hepatocellular carcinoma, and death. Therapy that is able to
slow or reverse liver injury and fibrosis would provide significant clinical
benefit.
We now show that 3 months of rIL-10 therapy is safe, well tolerated, and decreases hepatocellular injury in patients with chronic hepatitis C. These effects were observed at both the 4- and 8-µg/kg doses. Hepatic inflammation scores decreased in most patients (11 with significant improvement [HAI 2]) and was attributed to improvement in all 3 parameters of inflammation, namely, portal, periportal, and lobular inflammation. Fibrosis decreased in 14 of 22 treated subjects. Importantly, this study selected refractory patients with chronic hepatitis C who had not responded to one or several courses of treatment with interferon alone or in combination with ribavirin. The degree of regression of liver fibrosis and histological improvement observed after only 12 weeks of IL-10 in this pilot study is similar to that previously reported in treatment-naive patients with chronic hepatitis C who responded to 48 weeks of IFN-based therapy.