HIV Infections Clinical Trial
Official title:
Pioglitazone for Hepatic Steatosis in HIV
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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