Clinical trial NCT00441272
Conditions: HIV Infections Hepatic Steatosis Insulin Resistance
Keywords: Pioglitazone Hepatic Steatosis Liver Toxicity Liver Biopsy HIV Treatment Experienced Treatment Naive
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2007-02-01; Completion date: 2008-10-01
Enrollment: 100 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Detailed description:
While the introduction of antiretroviral therapy for HIV/AIDS has transformed HIV disease into a chronic infection for many, the use of antiretroviral therapy is also often associated with metabolic abnormalities including insulin resistance, central fat accumulation and peripheral fat atrophy. Fatty infiltration of the liver or hepatic steatosis may be an important consequence of these metabolic derangements or may represent a direct toxicity associated with HIV infection and/or antiretroviral medications. Preliminary data suggests that hepatic steatosis may be very common and perhaps present in up to 50 percent of HIV-infected patients receiving antiretroviral therapy. Hepatic steatosis represents one step in the potential progression towards hepatocellular injury, non-alcoholic steatohepatitis (NASH), and, in a small percentage of patients, subsequent fibrosis and cirrhosis. In addition, hepatic fat content is closely associated with impaired insulin resistance and type 2 diabetes, conditions increasingly recognized among HIV-infected patients. In the setting of type 2 diabetes mellitus and NASH, thiazolidinediones such as pioglitazone, have been shown to reduce hepatic steatosis, lower transaminase levels and improve insulin sensitivity.

In order to determine the potential benefits of pioglitazone therapy in the setting of HIV infection and hepatic steatosis, we will conduct a 96-week, double-blind, randomized placebo controlled trial of pioglitazone (45 mg/day) in 50 HIV-infected men and women, with 48 weeks of active treatment and 48 weeks of observational follow-up after study treatment ends. We anticipate needing to screen 100 subjects 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 score, liver-to-spleen ratio, which is calculated from CT scan of the abdomen. 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 sensitivity measured by hyperinsulinemic euglycemic clamp. All participants will be followed for 48 weeks after discontinuing study treatment to evaluate the short-term natural history of steatosis in those who received placebo and to assess the durability of any potential benefits of pioglitazone upon withdrawal. In this way, important information about the efficacy of pioglitazone to treat hepatic steatosis and improve the metabolic profile in HIV-infected patients will be obtained, as well as preliminary data on whether benefits of pioglitazone are sustained after treatment is discontinued.

Interventions: intervention 1: Pioglitazone
Intervention descriptions: intervention 1: None

Protocol documents: