Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen

Abstract

Objectives: HIV-associated lipoatrophy has been associated with mitochondrial dysfunction induced by nucleoside reverse transcriptase inhibitor therapy. We hypothesize that lipid profiles and markers of mitochondrial function will improve in HIV-lipoatrophic patients switched to the nucleotide analogue tenofovir.

Methods: Ten patients receiving stavudine, lamivudine and lopinavir/ritonavir (Kaletra(R)) for over 6 years were switched from stavudine to tenofovir for 48 weeks. Subcutaneous fat tissue biopsies, fasting metabolic tests, HIV RNA, CD4 cell count and whole body dual energy X-ray absorptiometry (DEXA) scans were obtained at study entry and week 48. Mitochondrial DNA (mtDNA) copies/cell and mitochondrial morphology were assessed in adipose tissue biopsies, mtDNA 8-oxo-deoxyguanine in peripheral blood mononuclear cells, and glutathione (GSH) and F2-isoprostane in plasma.

Results: There was no change in limb fat mass by DEXA; however, trunk fat mass increased by 18.9% (P = 0.01). Fasting total cholesterol decreased by 33 mg/dL (P = 0.005) and serum glucose decreased by 4 mg/dL (P = 0.039). mtDNA copies/cell increased from 386 to 1537 (P < 0.001). Transmission electron microscopy showed that mitochondrial cristae were lacking or poorly defined at study entry, whereas mitochondrial inner structures were more well defined and outer membranes were intact at 48 weeks. Oxidative damage decreased in 8/10 patients, GSH increased and F2-isoprostane decreased.

Conclusions: The results from this study demonstrate that systemic and peripheral fat mitochondria improve in patients switched to tenofovir following long-term exposure to stavudine, while continuing protease inhibitor therapy.

Figures

Figure 1

Morphological assessment of mitochondria in subcutaneous adipose tissue at study entry and week 48. Transmission electron micrographs depicting mitochondria with poorly defined inner membrane structures and broken outer membranes, see arrows, at ×16 000 magnification (a and b) in gluteal subcutaneous adipose tissue from patients at study entry. Mitochondrial morphology dramatically improves demonstrating membrane structural integrity at ×16 000 (c) and ×31 500 magnification (c) 48 weeks following tenofovir substitution.