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

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.

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”.