Peroxisome Proliferator‐Activated Receptor γ Agonists and the Treatment of HIV‐Associated Lipoatrophy: Unraveling the Molecular Mechanism of Their Shortcomings

The recognition of metabolic complications associated with the use of antiretroviral therapy (ART), including dyslipidemia, lipoatrophy, and dysregulation of glucose homeostasis, followed close on the heels of the introduction and widespread use of potent combination ART for the treatment of HIV infection. Our understanding of the role of specific drug classes and of individual antiretroviral agents in these metabolic disturbances has evolved over time and has helped to inform clinical care practices to both preventandtreatthesecomplications.Inthis issue of the Journal, Mallon et al. [1] present data that provide another important step forward in understanding the mechanismsoflipoatrophyinassociation with exposure to nucleoside reversetranscriptase inhibitors (NRTIs) and offer insight into why treatment with the peroxisome proliferator-activated receptor(PPAR)agonistshasoftenfailedto produce clinically significant gains in adipose tissue mass in trials involving HIVassociated lipoatrophy. The potential role of mitochondrial toxicity associated with NRTIs, in particular the potent effects of thymidine analogues (tNRTIs), was recognized early in the study of lipodystrophy and ART tox