JAC Advance Access originally published online on March 25, 2009
Journal of Antimicrobial Chemotherapy 2009 63(6):1244-1250; doi:10.1093/jac/dkp100
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Original research |
Mitochondrial function, morphology and metabolic parameters improve after switching from stavudine to a tenofovir-containing regimen
1 Hawaii AIDS Clinical Research Program, Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI 96816, USA 2 Division of Infectious Diseases, Feinberg School of Medicine, Northwestern University Chicago, IL 60611, USA 3 Abbott Laboratories, Chicago, IL, USA 4 Sigma Clinical, Chicago, IL, USA 5 Case Western Reserve University, Pediatric Infectious Diseases and Rheumatology, Cleveland, OH, USA
Received 3 December 2008; returned 19 January 2009; revised 24 February 2009; accepted 26 February 2009
* Corresponding author. Division of Infectious Disease, Northwestern University, 645 N. Michigan Avenue, Suite 900, Chicago, IL 60611, USA. Tel: +1-312-695-4994; Fax: +1-312-695-5088; E-mail: r-murphy{at}northwestern.edu
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®) 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.
Keywords: adipose , HIV , lipodystrophy , metabolic , mitochondria