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Session 90 Poster Presentations
Interventions for Prevention or Treatment of Lipodystrophy Syndromes
Session Day and Time: Thursday 1:30 - 3:30 pm
Room: Hall B


729
Changes in Mitochondrial DNA in PBMCs from Patients with Lipoatrophy Randomized to Switch to Abacavir or Continue Thymidine Analogue-containing ARV Regimens
J. F. Hoy*1,2,5, M. E. Gahan2, A. Carr3, S. R. Lewin4, D. Smith5, D. A. Cooper3,5, S. L. Wesselingh1,6
1Alfred Hosp, Melbourne, Australia; 2Monash Univ, Melbourne, Australia; 3St Vincent's Hosp, Sydney, Australia; 4Univ of Melbourne, Australia; 5Natl Ctr In HIV Epid and Clin Res (NCHECR), Univ of New South Wales, Sydney, Australia; and 6Burnet Inst, Melbourne, Australia

Background: Thymidine analogues (TA) inhibit mitochondrial DNA (mtDNA) polymerase gamma in vitro, causing a reduction in mtDNA copy number per cell. Reductions in the per cell amount of mtDNA has been suggested as the cause of a wide range of NRTI toxicity. In the MITOX study, substitution of TA with abacavir resulted in a significant increase in limb fat of 0.39 kg over 24 wks. The hypothesis was that switching from a TA to abacavir is associated with a significant increase in mtDNA in PBMC from patients (pts) with lipoatrophy.

Methods: We randomized 111 pts to continue or switch TA for 24 wks. A real-time PCR assay with a low coefficient of variation (2.7%) was used to quantify mtDNA copy numbers per cell in PBMCs. MtDNA was assayed at weeks 0, 4, 12, and 24 in 94 pts. Changes in mtDNA from baseline were compared between the 2 treatment strategies, and relationships between variables including peripheral body fat and plasma lactate were evaluated.

Results: mtDNA results were obtained from 39 pts randomized to change the TA component to abacavir (34 stavudine, 5 zidovudine) and 55 pts who continued TA (45 stavudine, 10 zidovudine). Mean baseline mtDNA copy number was 582.44 ±356.48 for the switch group and 540.41 ±428.5 for the TA group. There was no significant difference in baseline mtDNA copy numbers, plasma lactate, peripheral limb fat between groups, and no significant difference in mtDNA copy number at weeks 4, 12, and 24 between those switched to abacavir or those continuing TA. The mean (SD) changes from baseline in mtDNA at weeks 4, 12, and 24 were 54.8 (350.4), 76.6 (414.2), and 48.8 (431.61) for the switch group, compared with -38.0 (267.7), -15.3 (344.7), and –85.3 (390.4) for the continue TA group. The mean difference in mtDNA (95% CI) between groups was 92.8 (-36.7, 222.2), 91.9 (-67.3, 251.2) and 134.1 (-43.3, 311.5) at weeks 4, 12, and 24, respectively. There was no correlation between change in mtDNA with change in peripheral subcutaneous fat measured by DEXA scan (r = -0.005, p = 0.97), or changes in lactate levels (r = 0.19, p = 0.08).

Conclusions: Despite the low coefficient of variation of the assay, a wide range of mtDNA copies/cell was identified between pts. There was a non-significant trend to increased mtDNA copy number in those who switched to abacavir compared with those who continued on TA. Currently, there is limited clinical utility of quantifying mtDNA in PBMCs from an individual to assess NRTI toxicity.