A new study published in The Lancet has dashed hopes that a class of drugs used to treat diabetes – the glitazones – may reduce fat wasting associated with antiretroviral therapy. Nevertheless, this drug class may have some utility in improving insulin sensitivity and reducing fatty liver among HIV-infected people on treatment.
One hundred and eight HIV-positive people with lipoatrophy who were taking combination antiretroviral therapy were randomised to rosiglitazone 4mg twice daily or placebo. Conducted by an Australian team led by Dr Andrew Carr, the study was powered to detect as little as a half kilogram difference in limb fat between the groups.
After 48 weeks of treatment, rosiglitazone had no significant impact on subcutaneous fat mass, as measured by dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT) scan. Limb fat increased by 0·14kg and 0·18kg in the rosiglitazone and placebo groups, respectively. Moreover, rosiglitazone had no significant impact on any other measure of lipodystrophy.
Carr and colleagues found that rosiglitazone cannot be recommended as a therapy for HIV-associated lipoatrophy. In an accompanying commentary, Drs Graeme Moyle and Jussi Sutinen concur with this assessment.
“The remaining management options,” Moyle and Sutinen state, “are to switch from thymidine-nucleoside analogues, an approach that yielded modest and slowly accrued benefit in three randomised studies but is not available to everyone, and to resort to surgical correction of obvious morphological manifestations.”
The non-existent impact of rosiglitazone on lipoatrophy seems at odds with the boost in levels of adiponectin – a cellular messenger involved in fat cell maturation and function. Rosiglitazone is also known to enhance the activity of a cell receptor called PPAR-gamma which is also involved in fat cell differentiation.
The researchers do not understand exactly why these effects failed to translate into an increase in fat cells in people with HIV-associated lipoatrophy. Possibilities include that therapy may destroy new fat cells, too few PPAR-gamma receptors may exist as targets for rosiglitazone, or that lipoatrophy may not be the result of interference with PPAR-gamma after all.
Background therapy had no impact on response to rosiglitazone, although there was some suggestion that ongoing use of AZT or d4T was associated with a poorer response to rosiglitazone. Comparing the presence or absence of AZT or d4T among people taking rosiglitazone, there was a significant difference in fat gain at week 24 (no AZT or d4T +0.48 kg versus AZT or d4T -0·06 kg; p=0·05) but this difference was not maintained at week 48. The authors dismiss this finding as either an error or a short-term effect with no clinical relevance.
On a positive note, rosiglitazone did improve insulin sensitivity and liver function. But in HIV-positive people, in contrast to the effect in HIV-negative diabetics, the ability of the liver to make and secrete more triglycerides has not translated into increased fat storage within fat cells.
Unfortunately, the most common side-effects seen among those taking rosiglitazone were elevated triglycerides (mean increase 0·9 mmol/l at week 48; p=0·04) and elevated cholesterol (1·5 mmol/l; p=0·001).
The findings of Carr and colleagues support the results of a smaller study by Finnish researchers presented in 2002.
Two glitazones have been given marketing approval in Europe for the treatment of diabetes: Avandia or rosiglitazone and Actos or pioglitazone.
Carr A et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet 363 (9407): 429-438, 2004.
Moyle G and Sutinen J. Managing HIV lipoatrophy - commentary. Lancet 363 (9407): 2004.
Sutinen J et al. Rosiglitazone in the treatment of HAART-associated lipodystrophy (HAL): a randomized, double-blind, placebo-controlled study. Ninth Conference on Retroviruses and Opportunistic Infections, Seattle, abstract LB13, 2002.