Longitudinal associations between antiretroviral treatments and quantification of tissue mitochondrial DNA from ambulatory subjects with HIV infection
Cherry, C., Nolan, D., James, I., Mallal, S., McKinnon, E., French, M., Hammond, E., Gahan, M., McArthur, J. and Wesselingh, S. (2003) Longitudinal associations between antiretroviral treatments and quantification of tissue mitochondrial DNA from ambulatory subjects with HIV infection. In: 10th Conference on Retroviruses and Opportunistic Infections, 10 - 14 February 2003, Boston, U.S.A.
Background: The proposed basis for NRTI-associated clinical toxicities involves cellular mitochondrial DNA (mtDNA) depletion and mitochondrial dysfunction. Critical questions remain about optimal monitoring for mitochondrial toxicity. Results are presented from two Australian sites investigating effects of antiretroviral treatment on mtDNA depletion in adipose tissue (Perth and Melbourne) and peripheral blood (Melbourne) using real time-PCR assays.
Methods: Adipose samples were prospectively collected in Perth via suprailiac excisional biopsy (72 study visits, 60 patients [pts]) and in Melbourne via punch biopsies at the thigh and calf (160 study visits, 62 pts). Concurrent peripheral blood mononuclear cell (PBMC) samples were obtained from Melbourne pts. mtDNA copies/cell were determined using real time-PCR. Statistical analyses were performed using linear mixed effects models, accounting for multiple measures on individuals.
Results: mtDNA was lower in all tissues from those receiving at least one dideoxynucleotide (dNRTI, d4T, ddI or ddC) (p < 0.005). Current dNRTI use was the only treatment association with lowered mtDNA in limb fat. mtDNA in suprailiac fat was also lower in those on AZT than those on neither AZT nor dNRTIs (p = 0.0002). In PBMCs, mtDNA tended to be lower in those on ddI or ddC than those in whom d4T was the only dNRTI (p = 0.07). There was no effect of age, CD4 cell count, viral load, treatment with protease inhibitors, or duration of known HIV infection on mtDNA in any tissue examined. Among subjects who initiated (n = 5) or ceased (n = 13) dNRTI therapy on study, mtDNA was lower in fat samples taken on dNRTIs (p = 0.02), but there was no effect of time on current treatment on mtDNA in any tissue, suggesting that any changes in mtDNA occur rapidly.
Conclusions: The findings of these independent studies involving 232 biopsy samples are concordant in demonstrating significant mtDNA depletion in adipose tissue associated with dNRTI therapy, consistent with clinical data implicating choice of NRTI as an important determinant of lipodystrophy risk. mtDNA depletion occurs rapidly on exposure to dNRTIs, and this is reversible on cessation of drug.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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