Pioglitazone in Hepatitis C

RESEARCH PLAN:

Chronic hepatitis C is a leading cause of cirrhosis and hepatocellular carcinoma in the U.S.
and is the most common cause for liver transplantation. Treatment of chronic hepatitis C
remains problematic and unsatisfactory. Several factors influence the response to treatment
most importantly hepatitis C virus (HCV) genotype (sustained virological response/SVR seen
in 40-45% vs. 75-80% using pegylated IFN + ribavirin combination therapy genotype 1 vs.
2/3). Recently, the presence of hepatic steatosis has been shown to be an important
predictor of disease progression and also response to antiviral therapy especially in
patients with genotype 1 infection. The mechanisms of hepatic steatosis in HCV are
multi-factorial; the presence of insulin resistance (IR) appears to be a key factor
especially in genotype 1 (metabolic steatosis) similar to that seen in patients with
non-alcoholic fatty liver disease (NAFLD). Whereas metabolic steatosis appears to be a
factor in resistance to antiviral therapy, viral steatosis (direct viral induced as in
genotype 3) is reduced in those who achieve an SVR. We recently also observed that IR is
common in type 1 HCV infection even at low BMIs and is present even in the non-steatotic
hepatitis C patients, suggesting a direct effect of viral infection on insulin sensitivity
and that IR may precede hepatic steatosis. We hypothesize that in patients with HCV genotype
1 infection, therapy aimed at improving insulin sensitivity in conjunction with standard
antiviral therapy may not only reduce the insulin resistance in hepatitis C but also improve
hepatic steatosis, decrease expression of pro-inflammatory cytokines and reduce oxidative
stress thereby preventing disease progression. In addition, we also hypothesize that
improvement in IR and hepatic steatosis may also result in improved virological response to
antiviral therapy.

This study introduces a novel concept of using the insulin sensitizing thiazolidinedione
agent pioglitazone to improve insulin sensitivity, improve hepatic steatosis and possibly
result in a higher rate of virological response when given in conjunction with standard
antiviral therapy in treatment naïve patients with genotype 1 infection. Our main goals are
to study the effect of pioglitazone on insulin sensitivity and hepatic steatosis in addition
to its effect on SVR along with confirming the safety of pioglitazone in patients with
hepatitis C. To our knowledge, this is the first randomized, placebo-controlled study of an
insulin sensitizing agent in the treatment of patients with chronic hepatitis C. We hope
that the findings in this study will shed new light into the mechanisms associated with the
pathogenesis of hepatitis C and lead to new and effective treatments in the management of
this very important disease.

Insulin resistance (IR), a key factor in the development of steatosis, is a common finding
in patients with hepatitis C virus (HCV) infection. In patients with genotype 1 infection,
IR has been noted in up to 80% of patients in some studies. In patients with non-alcoholic
fatty liver disease (NAFLD) who have evidence of nonalcoholic steatohepatitis (NASH), the
role of IR leading to decreased fatty acid oxidation, increased production of
pro-inflammatory cytokines and increased oxidative stress had been proposed as an important
mechanism leading to steatosis and subsequent liver cell injury. Recently, an association
between steatosis and hepatic fibrosis has been emphasized in HCV infection, similar to that
described in patients with NAFLD. While IR and hepatic steatosis are common findings in
patients with HCV infection, the latter with prevalence rates of 40% to 70%, and different
HCV genotypes confers distinct risks for steatosis; a greater degree of steatosis is seen in
patients with genotype 3 infection compared to others. Similar to that seen in patients with
NAFLD, patients infected with genotype 1 HCV show a relationship between body mass index
(BMI) and risk for steatosis. However, in up to 30% of patients with HCV infection and
hepatic steatosis, no other risk factors for steatosis can be identified. The investigators'
preliminary data will show that even in HCV infected individuals with low BMI and no
steatosis, there is IR and the risk for steatosis is increased when directly compared to
NAFLD patients. Recent data also suggest that the presence of hepatic steatosis is an
independent predictor of decreased response to antiviral therapy even when controlling for
genotype. This is especially important in patients with type 1 infection.

The investigators hypothesize that in patients with HCV genotype 1 infection, treatment with
antiviral therapy will have a partial effect on reducing insulin resistance (IR) and
steatosis and this is augmented by the addition of an insulin sensitizing thiazolidinedione
(TZD) agent such as pioglitazone to the treatment regimen. The investigators also
hypothesize that the rate of sustained virological response (SVR) will be higher in the
antiviral regimen + pioglitazone treated group compared to patients receiving antiviral
therapy alone.

The investigators' specific aims are the following:

1. To assess the improvement in insulin sensitivity in patients with treatment naïve
genotype 1 chronic hepatitis C treated with standard antiviral therapy + pioglitazone
or placebo

2. To assess the improvement in hepatic steatosis in patients with treatment naïve
genotype 1 chronic hepatitis C after treatment with standard antiviral therapy +
pioglitazone or placebo

3. To assess the rates of sustained virological response (SVR) among patients with
treatment naïve genotype 1 chronic hepatitis C treated with standard antiviral therapy
+ pioglitazone compared to standard antiviral therapy + placebo

CLINICAL STUDY DESIGN AND METHODS

Overview:

This is a randomized, double-blind, placebo-controlled study of pioglitazone given in
combination with standard antiviral therapy for the treatment of genotype 1 infected
hepatitis C patients who are treatment naïve. We will determine the rates of improvement in
homeostasis model assessment of insulin resistance (HOMA-IR) and hepatic steatosis after 48
weeks of therapy compared to baseline along with determining the rate of SVR in the two
treatment groups. In addition, we will also assess the safety of pioglitazone in patients
with chronic hepatitis C infection.

All eligible patients will have undergone a percutaneous liver biopsy within 6 months of
enrollment to assess the severity of hepatitis C, steatosis and features of steatohepatitis
by the study pathologist. A period of 6 months prior to enrollment was selected in order to
have a more recent representation of the degree of steatosis and histologic severity of
hepatitis C as the effect of therapy on these histologic features is one of the important
aims in this study. A HOMA index value of > 2.0 was selected to define IR in this study (see
below: Inclusion criteria) as this value is considered abnormal and indicative of decreased
insulin sensitivity. Histological severity of chronic hepatitis C will be done using the
modified histological activity index (HAI) scoring system by Ishak for grading and staging
chronic viral hepatitis and that for steatosis and steatohepatitis will be done using the
scoring system that is currently being used in the NIH-funded Virahep-C study, which the PI
is currently a member.

We currently have an IRB approved protocol at the University of Michigan to collect a sample
of liver tissue at the time of liver biopsy in all patients with hepatitis C and NAFLD to
study fat gene expression. We will collect samples on patients being considered for this
study who are undergoing a liver biopsy at initial evaluation. We will also collect similar
samples at the time of repeat liver biopsies in this study. This will give us a unique
opportunity to study the effect of pioglitazone on fat-related gene expression and its
relationship to responses being studied in this study (changes in IR and steatosis and
virological response to therapy).

Given that this is a pilot study of pioglitazone in patients with hepatitis C and the
potential hepatotoxicity of this drug in hepatitis C is not well known due to limited
available data, we plan to enroll treatment-naïve patients with evidence of at least some
fibrosis on liver biopsy (a minimum Ishak fibrosis score of 1) although we do not have any
reason to expect any significant drug induced liver injury with this drug. Patients with
evidence of cirrhosis on liver biopsy (Ishak fibrosis score 5 and 6) will be excluded since
cirrhosis itself can be associated with IR and thereby bias the findings. Although we do not
expect to see any increased hepatotoxicity due to pioglitazone in patients with hepatitis C
in general, whether cirrhosis increases potential risk is unknown at this time.

Similarly, we also plan to exclude patients with known diabetes mellitus (DM) to minimize
any bias especially since interferon therapy itself can affect glucose tolerance and may
lead to difficult control in patients with pre-existing diabetes. In our hepatitis C patient
population, although prevalence of DM is less than 15%, the addition of diabetic patients
may also confound the analysis unless we stratify randomization based on presence or absence
of DM and since this is a pilot study with a limited sample size, we decided to exclude
diabetics. Another factor would be correcting the influence of glucose controlling agents on
insulin sensitivity during the study.

All eligible patients who are interested in the study will be invited to come to the GCRC at
regular intervals for study assessment. During these visits, a brief physical examination
will be performed and blood will be collected and stored for future research purposes. The
current standard treatment for chronic hepatitis C patients with genotype 1 infection is a
combination of pegylated interferon and ribavirin for 48 weeks. Treatment response is
defined as follows:

- Sustained Virological Responder (SVR) - undetectable HCV RNA in serum during therapy
and at 24 weeks follow-up;

- Relapser - undetectable HCV RNA in serum during and end of treatment and reappearance
of RNA once therapy is stopped; we expect less than 15% of initial responders to
relapse after stopping treatment;

- Non-Responder - presence of HCV RNA in serum at the end of therapy and during
follow-up.

Although patients with genotype 1 who have detectable HCV RNA at 24 weeks of therapy are
usually labeled as non-responders and treatment is stopped in clinical practice, all
patients in this study will complete 48 weeks of treatment unless the regimen has to be
stopped due to side effects or patient preference. This is because of potential beneficial
effects of therapy (addition of pioglitazone to antiviral therapy) on IR and hepatic
steatosis and possibly even fibrosis even among viral non-responders when treated for 48
weeks.

Once treatment is completed, all patients will be invited to come to GCRC 12 weeks following
the end of treatment to undergo a repeat liver biopsy. Total follow-up once treatment is
stopped will be 24 weeks in all patients.

Patient Population:

All eligible adult patients with compensated liver disease due to chronic infection with HCV
and genotype 1 infection who are treatment naïve will be enrolled into the study. All racial
and ethnic groups will be recruited into this study. Patients with cirrhosis and
decompensated liver disease and any patient, in whom a liver biopsy is contraindicated, will
be excluded. Race (African American/Black or non-Hispanic white or other) will be assigned
based on the information given by the patient. It reflects the individual's recognition in
the community. This assignment of race/ethnicity will be similar to that practiced by
governmental agencies including the U.S. Census Bureau and the Center for Disease Control.
All patients will sign an IRB approved HIPAA compliant consent form before enrolling into
the study.

Inclusion Criteria:

- All eligible adult patients with compensated liver disease due to chronic infection
with HCV and genotype 1 infection who are treatment naïve will be enrolled into the
study.

- All racial and ethnic groups will be recruited into this study.

- Males and females: age > 18 years

- Chronic hepatitis C: history of serum positive for HCV antibody (anti-HCV) and HCV
RNA. Patients should have evidence of chronic hepatitis with a minimum fibrosis score
of 1 on liver biopsy done within 6 months of enrollment.

- Insulin resistance based on HOMA index value (HOMA-IR) of > 2.0 during screening.
HOMA-IR is a well recognized and validated index of insulin resistance in both
non-diabetic and diabetic populations and has been shown to have a good correlation
with 'clamp' techniques that are intensive. HOMA is also used routinely to assess
longitudinal changes including assessment of the effects of treatment. In general, a
HOMA-IR value of > 1.5 is considered abnormal based on repeat testing measurements
performed by both HOMA assessment and by euglycemic clamp technique and is considered
representative of decreased insulin sensitivity. Although insulin secretion is
pulsatile, the correlation between HOMA computed from repeat sampling (using a mean
of three samples taken at 5-minute intervals to compute HOMA) and the value obtained
from a single basal sample to determine insulin sensitivity has been shown to be near
perfect even in patients with type 2 diabetes (r = 0.99, p < 0.0001). The
investigators will use a HOMA-IR value of > 2.0 as part of the inclusion criteria in
this study.

- Able and willing to provide written informed consent

Exclusion Criteria:

- Hepatitis C patients who underwent previous therapy for their liver disease

- Genotype other than type 1

- Histological evidence of cirrhosis or confirmed hepatocellular carcinoma (HCC)

- Patients with cirrhosis and decompensated liver disease and any patient, in whom a
liver biopsy is contraindicated, will be excluded.

- Evidence of other causes of chronic liver disease

- Diabetes mellitus

- New York Heart Association (NYHA) functional classification for cardiac disease:
class III and IV patients

- Human immunodeficiency virus (HIV) antibody positive

- Patients with solid organ transplants

- Pregnancy or breast feeding

- Participation in any other clinical trial within 90 days of entry into this trial.

- Unwilling to consent to the study