Rosiglitazone loses its lustre: Data on HAART-associated lipodystrophy not encouraging

This article is more than 22 years old. Click here for more recent articles on this topic

At the close of the Ninth Annual Retroviruses Conference in Seattle today, researchers from Helsinki presented data from the first controlled study to evaluate the use of rosiglitazone as a treatment for the lipodystrophic changes which occur as a side-effect of anti-HIV therapy. Whilst the drug’s use in this context remains under investigation, the results of this small Finnish study were disappointing.

Rosiglitazone is an insulin-sensitising agent used in the treatment of diabetes. It’s one of a relatively new class of drugs, termed PPAR-gamma agonists, and has been shown to improve lipodystrophic symptoms in HIV-negative patients. A small study at last year’s Lipodystrophy Workshop from Visnegarwala and colleagues reported apparently beneficial results following the drug’s administration to HIV-positive people with facial fat loss. Other trials involving rosiglitazone are ongoing, including the HALT trial in London, details of which can be found here at aidsmap.com.

The Finnish study involved twenty five men and five women on stable HAART, with self-reported lipodystrophy, which was investigator-confirmed in all cases. Participants were randomised in a blinded fashion to receive either 8mg rosiglitazone or matching placebo for the 24 week study period.

Glossary

lipodystrophy

A disruption to the way the body produces, uses and distributes fat. Different forms of lipodystrophy include lipoatrophy (loss of subcutaneous fat from an area) and lipohypertrophy (accumulation of fat in an area), which may occur in the same person.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

insulin

A hormone produced by the pancreas that helps regulate the amount of sugar (glucose) in the blood.

matched

In a case-control study, a process to make the cases and the controls comparable with respect to extraneous factors. For example, each case is matched individually with a control subject on variables such as age, sex and HIV status. 

blinding

When a clinical trial is blinded, the participants are unaware as to whether they are receiving the experimental drug or a placebo (or another drug). Double blinding refers to the participant, their doctor and researchers running the trial not knowing which treatment is received by each group until all data have been recorded. Blinding is done to reduce bias in clinical trials.

Lipodystrophic parameters were measured at baseline and at 24 weeks by a series of sixteen MRI scans around the body, spectroscopy of liver fat, skinfold thickness, serum leptin (a correlate of body fat mass), bioimpedence analysis, and self-assessment. Blood lipid and liver enzyme levels were also determined.

At the end of the 24 week treatment period, there were no changes observed in any morphologic parameter in either treatment arm. In other words, there was no evidence that rosiglitazone improved body fat changes. Self-assessment showed improvements in both fat loss and gain, but this only reached statistical significance in those receiving the inactive placebo.

Rosiglitazone appeared to improve insulin resistance. However, unexpectedly, the drug was also associated with a significant increase in both cholesterol and triglyceride levels, causing one individual to discontinue treatment early.

In seeking to explain the study’s negative findings, presenting author Dr Sutinen offered several possible explanations – inadequate dosing, inadequate treatment duration, or perhaps the small sample size. Professor David Cooper, a leading Australian physician, questioned the power of such a small study to detect a difference between treatment arms. According to Sutinen, powering was based on the 34% increase in subcutaneous fat observed when rosiglitazone was administered to HIV-negative patients.

Of course, another explanation is that 24 weeks is simply too soon to see a clear resolution of body fat changes. When discussing the results of the MITOX study earlier this week, which reported a seemingly marginal improvement in lipodystrophy following replacement of d4T or AZT with abacavir, Andrew Carr said of lipodystrophy: “If it took five years to develop, it may take five years to go away”.

References

Sutinen J et al. Rosiglitazone in the treatment of HAART-associated lipodystrophy (HAL): a randomized, double-blind, placebo-controlled study. Ninth Retroviruses Conference, abstract LB13, Seattle, 24-28 February, 2002.

Carr A et al. Switching stavudine or zidovudine to abacavir for HIV lipoatrophy: a randomised, controlled, open-label, multicentre, 24-week study. Ninth Retroviruses Conference, abstract 32, Seattle, 24-28 February, 2002.