Pioglitazone in Hepatitis C
Condition: Chronic Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis
Study type: Interventional
Phase: Phase 4

Summary: 
      The presence of insulin resistance (IR) appears to be a key factor in the development of
      steatosis and disease progression in patience with Hepatitis C virus (HCV) genotype-1
      infections similar to levels in Non-alcoholic fatty liver disease (NAFLD). The objective of
      this study is to determine whether Pioglatizone, when given along with Interferon and
      Ribavirin, reduces insulin resistance and lowers HCV viral levels and improved response in
      patients who have HCV genotype-1 infection when compared to a placebo.
    

Detailed description: 
      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.
    

Intervention name(s): Pioglitazone; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): 30 mg, taken orally, once per day, for 48 weeks; Sugar Pill, taken orally, once per day, for 48 weeks
Other intervention name(s): Actos
Intervention MeSH terms: Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Hepatitis C; Genotype 1; Insulin Resistance; Pioglitazone