Protocol Number: 07-I-0105

Title:

Pioglitazone for Hepatic Steatosis in HIV

Number:

07-I-0105

Summary:

This study will determine whether pioglitazone (Actos, a drug approved to treat diabetes, can benefit HIV-infected people with fatty liver. Fatty changes of the liver (also known as steatosis) have been linked to diabetes and long-term liver damage in some patients. Pioglitazone has been shown to improve fatty liver in people without HIV; this study will see if it is beneficial for people with HIV as well.

HIV-infected patients 18 years of age and older with increased fat in the liver may be eligible for this study. Screening includes a CT scan and liver biopsy (withdrawal of a small sample of liver tissue through a needle).

Participants are randomly assigned to take either 45 mg of pioglitazone or placebo (sugar pill) by mouth once a day for 48 weeks. At the end of 48 weeks, all participants stop taking their medication and are followed for an additional 48 weeks to see what, if any benefits, of pioglitazone persist after treatment is stopped. In addition to taking the study medication, participants undergo the following procedures:

-Visits to the NIH Clinical Center over a period of approximately 2 years at day 0 and weeks 2, 8, 16, 24, 32, 40, 48, 52, 72, and 96. Most visits take about 1 hour and include blood drawing for various laboratory tests.

-Insulin clamp test at day 0 and weeks 24 and 48 to see how the body processes glucose. This test takes 4 to 6 hours and may include an overnight stay at the Clinical Center. A catheter (plastic tube) is placed in a vein in the arm to infuse insulin and another is placed in a vein on the back of the hand to draw blood samples. Blood sugar is checked frequently and glucose is given to keep blood sugar at normal values.

-Nutrition evaluations at day 0 and weeks 24 and 48. Subjects write down all the food they eat and drink for 4 days before the visit. They meet with a nutritionist to review the food record and to complete simple measurements of body fat and shape.

-CT scan of liver and abdomen at weeks 24, 48, 72 and 96.

-Liver biopsy at week 48.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1. Men and women, 18 years of age or greater.

2. Confirmed HIV infection by ELISA and Western blot.

3. No changes in antiretroviral regimen within the prior 3 months. Individuals not currently taking antiretroviral therapy will be eligible.

4. Liver-to-spleen attenuation ratio less than 1 determined by CT and hepatic steatosis on liver biopsy within the past 1 year scored grade 1 or greater (i.e. greater than or equal to 5 percent of hepatocytes).

5. Fasting glucose less than 126 mg/dL.

6. Platelets greater than 50,000/microliters.

7. Willingness to avoid medications and herbal supplements that may increase the risk of bleeding for one week prior to and one week following liver biopsy (e.g. aspirin, NSAIDs and ginko biloba).

8. Willingness to restrict physical activity 72 hours after liver biopsy.

9. Willingness to use 2 effective forms of contraception during the study to avoid pregnancy.

10. Have a primary care physician.

EXCLUSION CRITERIA:

1. Current thiazolidinedione use or use in the last 6 months; known allergy or sensitivity to a thiazolidinedione.

2. Use of insulin or other oral hypoglycemics, or known diabetes.

3. Current pregnancy, breast feeding, or pregnancy within the past 6 months.

4. MELD score greater than 9 or previously diagnosed cirrhosis.

5. ALT greater than 3 times the upper limit of normal.

6. Current or history of heart failure (NYHA Class III or IV cardiac status).

7. Hemoglobin level less than 9g/dL.

8. Active or ongoing infection with Hepatitis A, B, or C.

9. Known or suspected liver disease such as autoimmune hepatitis, Wilson's disease, alpha-1-antitrypsin deficiency, cystic fibrosis, hemachromatosis, glycogen storage disease, amyloidosis, primary biliary cirrhosis, sclerosing cholangitis or any primary or secondary hepatic tumor.

10. Current alcohol/substance abuse or mean alcohol consumption greater than 24g/day over past year.

11. Use of growth hormone, prednisone or other anabolic agents (except for physiologic testosterone replacement) currently or within the past 6 months. One day or less of corticosteroid within the prior 90 days of screening is allowed as is stable dose inhalation corticosteroids.

12. Concurrent use of ketoconazole.

13. Active opportunistic infection (except thrush) or neoplasm (except Kaposi's sarcoma, skin cancer, cancer of the cervix or anus).

14. Any known contraindications to percutaneous liver biopsy including elevated PT/PTT.

15. Severe psychiatric illness that would interfere with adherence to protocol requirements.

16. Known history of insulin secreting tumor or symptomatic hypoglycemia.

17. Current use or a history of treatment with interleukin-2, interferon-alpha, or other investigational agent(s) within the past 6 months. (This does not pertain to ARV's obtained through expanded access).

18. Any medical condition for which the investigator believes a liver biopsy may be contraindicated.

Special Instructions:

Currently Not Provided

Keywords:

Pioglitazone

Hepatic Steatosis

Liver Toxicity

Liver Biopsy

Recruitment Keyword(s):

HIV

Condition(s):

HIV Infections

Hepatic Steatosis

Insulin Resistance

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Drug: Pioglitazone

Supporting Site:

National Institute of Allergy and Infectious Diseases

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Jain MK, Skiest DJ, Cloud JW, Jain CL, Burns D, Berggren RE. Changes in mortality related to human immunodeficiency virus infection: comparative analysis of inpatient deaths in 1995 and in 1999-2000. Clin Infect Dis. 2003 Apr 15;36(8):1030-8. Epub 2003 Apr 2.

Carr A, Samaras K, Chisholm DJ, Cooper DA. Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet. 1998 Jun 20;351(9119):1881-3. Review.

Carr A, Miller J, Law M, Cooper DA. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS. 2000 Feb 18;14(3):F25-32.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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