Official Title: “Pioglitazone for Hepatic Steatosis in HIV/HCV Co-Infection”

This study will evaluate the effectiveness of pioglitazone in reducing liver fat content in patients with HIV and hepatitis C virus (HCV) infections. Fatty liver and accompanying insulin resistance in patients with HIV and HCV co-infections is associated with inflammatory changes, liver fibrosis and a poorer response to HCV treatment. Pioglitazone is a drug that helps to reduce the body's resistance to insulin. It is approved by the Food and Drug Administration to treat diabetes.

Patients with HIV and HCV co-infections who have hepatic steatosis (fatty liver) may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, magnetic resonance imaging (MRI) of the liver to measure liver fat and, if needed, a liver biopsy to confirm the diagnosis of liver steatosis. - Participants are randomly assigned to take either pioglitazone therapy or placebo for 48 weeks. This is followed by a second 48-week treatment period in which all participants take pioglitazone. - There are approximately 12 visits during the 96 weeks of the study. Participants will receive a physical assessment, blood and urine tests at each visit. In addition, periodic assessments of dietary habits, body composition, oral glucose tolerance testing, and health related quality of life questionnaires will be completed. - A repeat MRI of the liver is performed at 48 weeks and at the end of the study to evaluate any potential changes in liver fat and inflammation. In addition, there is a follow-up liver biopsy at 48 weeks and an optional liver biopsy at 96 weeks.

Study Type: Interventional

Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Efficacy Study

Following the introduction of effective antiretroviral therapy for HIV, the management of co-morbidities such as hepatitis C virus (HCV) has taken on increasing significance in the care and health maintenance of chronically infected patients. HCV co-infection is common in HIV, with an estimated prevalence of 30 percent among HIV-infected adults in the US.

Further, the reported prevalence of hepatic steatosis in HIV/HCV co-infection is between 40-67 percent.

In recent years, the significance of hepatic steatosis and accompanying insulin resistance in HCV has gained increasing recognition. For example, steatosis is associated with increased rates of necro-inflammatory change and fibrosis in HIV/HCV co-infected patients.

Furthermore, studies showed that, among non-HIV infected HCV patients, the presence of steatosis and/or insulin resistance was associated with poorer response to HCV therapy. These observations have led to research interest in treating hepatic steatosis in HCV, particularly in the context of pegylated interferon and ribavirin therapy.

Administration of the thiazolidinedione, pioglitazone, leads to significant reductions in hepatic steatosis, inflammation and in some cases fibrosis in patients with non-alcoholic steatohepatitis (NASH). Therefore, the potential benefits of pioglitazone therapy in the setting of HIV/HCV co-infection and hepatic steatosis will be determined. The proposed study is a 48-week, double-blind, randomized placebo-controlled trial of pioglitazone (45 mg/day) in 50 HIV/HCV-infected men and women. After the 48-week randomized portion of the trial, all participants will enter a 48-week open treatment extension arm irrespective of original randomization. It is anticipated that 100 subjects will be needed to be screened to identify a sufficient number of eligible participants to enroll in the study.

The primary outcome variable of interest in this trial will be the change in hepatic fat content measured by magnetic resonance (MR) spectroscopy. Important secondary outcomes will be histologic improvement on liver biopsy performed at baseline and 48 weeks, as well as improvements in transaminase levels and insulin resistance. The open treatment extension will allow all participants an opportunity to receive active study medication and it will allow the potential benefits of additional pioglitazone therapy to be assessed. In this way, important information about the efficacy of pioglitazone to treat hepatic steatosis and improve the metabolic profile in HIV/HCV co-infected patients will be obtained.

Intervention(s) in this Clinical Trial

• Drug: Pioglitazone
  • N/A

Primary Measures

• To determine the efficacy of pioglitazone to reduce hepatic steatosis and possibly improve hepatic inflammation/fibrosis in HIV/HCV co-infected patients with steatosis.
  • Time Frame: 48 weeks and 96 weeks
    Safety Issue?: Yes

Secondary Measures

• To assess the effects of pioglitazone on insulin resistance in HIV- and HCV-infected patients with steatosis compared to placebo and to evaluate the potential relationship between improvements in steatosis and changes in insulin resistance in this set.
  • Time Frame: 48 weeks and 96 weeks
    Safety Issue?: Yes

INCLUSION CRITERIA:

• Men and women, 18 years of age or greater
• Confirmed HIV infection by ELISA and Western blot
• No changes in antiretroviral regimen within the prior 3 months--Individuals not currently taking antiretroviral therapy will be eligible
• Confirmed HCV infection, and no current or recent (within the past 3 months) HCV treatment and no plans to start HCV antiviral therapy in the foreseeable future.
• H-MRS liver fat content greater than 5 percent and confirmed steatosis on liver biopsy within 1 year
• Fasting glucose less than 126 mg/dL
• Platelets greater than 50,000/uL
• Willingness to avoid medications and herbal supplements which may increase the risk of bleeding for one week prior to and one week following liver biopsy (e.g. aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and ginko biloba).
• Willingness to restrict physical activity 72 hours after liver biopsy
• Willingness to use 2 effective forms of contraception during the study to avoid pregnancy.
• Reliable methods of birth control include hormonal drugs (e.g., pills, patches, or shots), condoms with spermicide, diaphragms with spermicide, and intrauterine devices (IUD).
• Have a primary care physician
• Willingness to have specimens stored.

EXCLUSION CRITERIA:

• Current thiazolidinedione use or use in the last 6 months, known allergy or sensitivity to a thiazolidinedione
• Use of insulin or other oral hypoglycemics, or known diabetes
• Current pregnancy, breast feeding, or pregnancy within the past 6 months or desire to become pregnant within the next 2 years.
• Child-Pugh-Turcotte (CPT) score greater than class A
• ALT greater than 4 times the upper limit of normal
• Current or history of heart failure (New York Heart Association [NYHA] Class III or IV cardiac status)
• Hemoglobin level less than 9g/dL
• Active or ongoing infection with Hepatitis A or B
• Known or suspected liver disease such as autoimmune hepatitis, Wilson's disease, alpha-1-antitrypsin deficiency, cystic fibrosis, hemochromatosis, glycogen storage disease, amyloidosis, primary biliary cirrhosis, sclerosing cholangitis, or any primary or secondary hepatic tumor
• Current alcohol/substance abuse
• Use of growth hormone, prednisone or other anabolic agents (except for physiologic testosterone replacement) currently or within the past 3 months. One day or less of corticosteroid within the prior 90 days of screening is allowed as is stable dose inhalation corticosteroids
• Concurrent use of ketoconazole
• Active opportunistic infection (except thrush) or neoplasm (except Kaposi's sarcoma, skin cancer, cancer of the cervix or anus)
• Any known contraindications to percutaneous liver biopsy including elevated PT/PTT
• Severe psychiatric illness that would interfere with adherence to protocol requirements
• Current treatment with interleukin-2, interferon-alpha, or other investigational agent(s) within the past 6 months (This does not pertain to ARVs obtained through expanded access)
• Any significant medical condition for which the investigator believes a liver biopsy or participation in the research protocol may be contraindicated
• Any contraindication to MRI scan, including excess body size

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Overall Clinical Trial Officials and Contacts

Overall Contact: Patient Recruitment and Public Liaison Office (800) 411-1222 prpl@mail.cc.nih.gov

Information obtained from ClinicalTrials.gov on November 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00742326

Study ID Number: 080201

ClinicalTrials.gov Identifier: NCT00742326

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page