Continued use of a thymidine analogue may limit benefit from rosiglitazone when used to treat lipoatrophy

Previous articles in HTB have tracked the rationale for potential benefit of rosiglitazone (RSG), a PPARg agonist and transcription regulator, to reverse lipoatrophy, together with reports from several studies that found conflicting clinical results, but generally found no benefit.

HIV-positive patients with lipoatrophy have decreased PPAR-g and rosiglitazone has increased limb fat in HIV-negative adults with Type-2 Diabetes Mellitis (who also have reduces PPAR-g). A report from last years Lipodystrophy Workshop highlighted a study from Patrick Mallon showing that thymidine analogues could work downstream of any beneficial effect, negating any potential benefit. [1]

Dr Mallon brought new data to the Retrovirus meeting that analysed responses to rosiglitazone by continued use of background thymidine analogue that appears to confirm this finding clinicallly.

Mallon reported on 44 men (4mg RSG BID n = 21; placebo n = 23) to a sub-study of the 48 week ROSEY rosiglitazone study. 21 were receiving the thymidine analogues (tNRTI) zidovudine (AZT) (n = 3) or stavudine (d4T) (n = 18) at baseline. Changes in mitochondrial RNA (mRNA) in fat biopsies and lipid metabolism genes were analysed at 0, 2 and 48 weeks.

At week 2, only those randomized to RSG in the no-tNRTI group experienced a significant rise in PPAR-g expression (p = 0.046). Similar significant increases in PPAR-g co-activator 1 (PGC-1) expression were also observed in the RSG no-tNRTI group. At week 48, PPAR-g expression was significantly higher only in the no-tNRTI group, regardless of randomised treatment allocation (p = 0.04), with RSG having no effect in the tNRTI group.

However, no significant correlations were observed between changes in PPAR-g or PGC-1 expression and change in limb fat.

Comment

Although it is disappointing that no clinical benefit could be seen even when increased levels of PPAR-g were achieved without the use of thymidine analogues, this may be a reason to look again at this class of drugs, perhaps using pioglitazone, which does not increase cholesterol or triglycerides.