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

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.

Adverse effects of chronic treatment with the Main subclasses of highly active antiretroviral therapy: a systematic review

“…A total of 21 articles were included in this study: 10 observational cohort studies , six clinical trials , two cross‐sectional studies , one experimental study , one observational prospective study and one case report .…”

“…Regarding drug combinations, the participants were initiating or switching to treatment with fusion inhibitors , C‐C chemokine receptor type 5 (CCR5) inhibitors or integrase inhibitors . The three studies showed the emergence of major adverse effects (Table ), with the highest incidence of major adverse effects found for exposure to CCR5 binding inhibitors and the lowest incidence of lipodystrophy found for integrase inhibitors . Circulating markers of liver damage were also observed .…”

“…Similarly, raltegravir, a viral integrase inhibitor, can be used to replace stavudine in patients who develop lipodystrophy. After 48 weeks, it was found in one study that, in the group receiving raltegravir in place of stavudine, there was a significant fat gain in the limbs, increased symmetrical distribution of body fat and an increase in the levels of gene markers associated with adipose tissue formation as a result of the lower mitochondrial toxicity of raltegravir.…”

Lipodystrophies: adipose tissue disorders with severe metabolic implications

“…New antiretroviral agents with milder AT toxicity have promising effects in lipodystrophy. In fact, switching from nucleoside reverse transcriptase inhibitors to Raltegravir, the first integrase inhibitor, was associated with recovery of subcutaneous AT mass [12]. Notoriously, beneficial effects on adipose mass do not necessarily correlate with improved insulin resistance [12].…”

Fat Matters: Understanding the Role of Adipose Tissue in Health in HIV Infection

“…In the SPIRAL parent study, switch to raltegravir was associated with significant reductions in hs-CRP, monocyte chemotactic protein (MCP)-1, IL-6, and TNF-α but not IL-10 or adiponectin, and it is not clear to what extent changes in adipose tissue explain the changes in inflammatory markers [128]. In contrast, a switch to raltegravir from stavudine therapy among lipodystrophic individuals resulted in improvements in whole body and limb fat quantity, trunk/limb fat ratio and fat mass index, with restoration of mtDNA and adiponectin levels [52]. …”