Effects of Switching from Stavudine to Raltegravir on Subcutaneous Adipose Tissue in HIV-Infected Patients with HIV/HAART-Associated Lipodystrophy Syndrome (HALS). A Clinical and Molecular Study

Pere Domingo,Joan Villarroya,Francesc Villarroya,Ferran Torres,Gracia María Mateo,José Miguel Gallego-Escuredo,Ignacio De Los Santos,Luis Del Rio,Marta Giralt,Joan Carles Domingo,Vicente Estrada,María Del Mar Gutierrez

doi:10.1371/journal.pone.0089088

Abstract

HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P<0.0001) increased from baseline. Trunk/limb fat ratio (P = 0.0022), fat mass ratio (P = 0.0020), fat mass index (P = 0.0011) and percent leg fat normalized to BMI (P<0.0001) improved after 48 weeks. Relative abundance of mtDNA, expression of PPAR gamma, adiponectin, Cyt b, and MCP-1 genes increased, whereas Cox IV, TNF alpha, and CD68 did not change significantly from baseline. Switching from d4T to RAL in patients with HALS is associated with an increase in limb fat mass and an improvement in markers of adipocyte differentiation and mitochondrial function in SAT.

Highlights

The landscape of HIV-1 infection has been changed forever by the availability, in developed countries, of highly active antiretroviral therapy (HAART) since 1996
That associated with the use of nucleoside reverse transcriptase inhibitors (NRTI) stands out [2]
HIV-1/ HAART-associated lipodystrophy syndrome (HALS) is one of the most severe adverse effects related to NRTI use, especially with stavudine (d4T) for which there is overwhelming epidemiological evidence linking its use to the development of HALS [1,3]

Summary

Introduction

The landscape of HIV-1 infection has been changed forever by the availability, in developed countries, of highly active antiretroviral therapy (HAART) since 1996. The doubtless efficacy of HAART is still shadowed by significant toxicity, especially long-term toxicity [1]. That associated with the use of nucleoside reverse transcriptase inhibitors (NRTI) stands out [2]. HIV-1/ HAART-associated lipodystrophy syndrome (HALS) is one of the most severe adverse effects related to NRTI use, especially with stavudine (d4T) for which there is overwhelming epidemiological evidence linking its use to the development of HALS [1,3]. Among partially successful strategies, switching between NRTI, especially from thymidine analogues to abacavir (ABC) or tenofovir (TDF) has been associated with significant limb fat gains [4,5]

Methods

Results

Conclusion