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Differential effects of nucleoside reverse transcriptase inhibitor (NRTI) regimens on adipocyte mitochondrial DNA depletion in HIV-infected patients

Hammond, E., Nolan, D., McKinnon, E., James, I. and Mallal, S. (2004) Differential effects of nucleoside reverse transcriptase inhibitor (NRTI) regimens on adipocyte mitochondrial DNA depletion in HIV-infected patients. In: 6th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 25 - 28 October 2004, Washington DC, U.S.A.


BACKGROUND: Clinical trials data have provided strong evidence that NRTI therapy significantly influences risk of lipoatrophy. Here we examine associations between stavudine, zidovudine and non-thymidine NRTI regimens, as well as demographic and HIV disease-related variables, and adipocyte mitochondrial DNA (mtDNA) depletion.

METHODS: Adipocyte mtDNA depletion was assessed using real-time PCR in 130 subcutaneous fat samples from 87 HIV+ individuals, including 34 ART-naïve samples and 96 NRTI-exposed samples. Current NRTI therapy: 35 stavudine, 42 zidovudine and 19 non-thymidine NRTI (abacavir or tenofovir). Linear regression models were utilized with adjustment for multiple measurements in individuals.

RESULTS: Among ART-naïve (n=34), median mtDNA content was 1427 copies/cell (range: 413–6570). No significant correlations were detected between mtDNA levels and age (mean ±SD, 45 ±10), race (non-white: 15%), CD4 T-cell count (357 ±403) or HIV RNA (4.59 ±1.1) (P>0.1). Among NRTI-treated individuals, zidovudine was associated with mtDNA depletion compared with ART-naïve (median 761, range: 94–2846 copies/cell, P=0.0001), while mtDNA depletion was even more marked with stavudine (median 250, range: 61–2287 copies/cell) compared with ART-naïve or zidovudine groups (P<0.0001). A significant decline in mtDNA levels was also observed within 2–12 months of commencing stavudine or zidovudine therapy (n=14, mean reduction from ART-naïve baseline: 263 copies/cell/month, P=0.005).

In contrast, non-thymidine regimens were associated with similar mtDNA levels to ART-naïve controls (median 1675, range: 916–4180 copies/cell, P=0.8), and initiating these regimens was not associated with significant changes in mtDNA over time (mean reduction of 69 copies/cell/month, P=0.6). Among NRTI-experienced patients, switching from stavudine to zidovudine or abacavir was associated with a marked increase in adipocyte mtDNA (3–11-fold increase, P=0.01) over 1–24 months (median 6 months). After adjustment for effects of choice of NRTI therapy in a mixed effects analysis, no significant effects of HIV protease inhibitor therapy (current PI: 38%, P=0.7) nor age (P=0.9) were detected.

CONCLUSION: These data are concordant with evidence that lipoatrophy risk is differentially and specifically associated with stavudine or zidovudine use, providing further evidence that NRTI-induced mitochondrial toxicity is central to lipoatrophy pathogenesis. Alternative NRTI regimens were not associated with adipocyte mtDNA depletion in this study, nor were demographic/disease-related factors.

Publication Type: Conference Item
Murdoch Affiliation: Centre for Clinical Immunology and Biomedical Statistics
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