Improved adipose tissue function with initiation of protease inhibitor-only ART

<span class="paragraphSection"><div class="boxTitle">Objectives</div>Use of ART containing HIV PIs has previously been associated with toxicity in subcutaneous adipose tissue (SAT), potentially contributing to the development of lipodystrophy and insulin resistance. However, the effect of PIs on SAT function in ART-naive patients independent of other ART classes is unknown. This study aimed to elucidate the effect of initiating PI-only ART on SAT function in ART-naive subjects.<div class="boxTitle">Methods</div>In the HIVNAT-019 study, 48 HIV-infected, ART-naive Thai adults commencing PI-only ART comprising lopinavir/ritonavir/saquinavir for 24 weeks underwent assessments of fasting metabolic parameters and body composition. In a molecular substudy, 20 subjects underwent SAT biopsies at weeks 0, 2 and 24 for transcriptional, protein, mitochondrial DNA (mtDNA) and histological analyses. ClinicalTrials.gov registration number: NCT00400738.<div class="boxTitle">Results</div>Over 24 weeks, limb fat increased (+416.4 g, <span style="font-style:italic;">P </span>= 0.023), coinciding with larger adipocytes as indicated by decreased adipocyte density in biopsies (−32.3 cells/mm², <span style="font-style:italic;">P </span>= 0.047) and increased mRNA expression of adipogenesis regulator <span style="font-style:italic;">PPARG</span> at week 2 (+58.1%, <span style="font-style:italic;">P </span>= 0.003). Increases in mtDNA over 24 weeks (+600 copies/cell, <span style="font-style:italic;">P </span>= 0.041), decreased <span style="font-style:italic;">NRF1</span> mRNA expression at week 2 (−33.7%, <span style="font-style:italic;">P </span>< 0.001) and increased COX2/COX4 protein ratio at week 24 (+288%, <span style="font-style:italic;">P </span>= 0.038) indicated improved mitochondrial function. Despite decreased <span style="font-style:italic;">AKT2</span> mRNA at week 2 (−28.6%, <span style="font-style:italic;">P </span>= 0.002) and increased <span style="font-style:italic;">PTPN1</span> mRNA at week 24 (+50.3%, <span style="font-style:italic;">P </span>= 0.016) suggesting insulin resistance, clinical insulin sensitivity [by homeostasis model assessment (HOMA-IR)] was unchanged.<div class="boxTitle">Conclusions</div>Initiation of PI-only ART showed little evidence of SAT toxicity, the changes observed being consistent with a return to health rather than contributing to lipodystrophy.</span>

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