E-mail Abstract Author Session Search Abstracts Program

Session 91 Poster Presentations
Incidence, Prevalence, and Impact of Body Composition Abnormalities
Session Day and Time: Thursday 1:30 - 3:30 pm
Room: Hall B


739
Relation between Use of Nucleoside Reverse Transcriptase Inhibitors, Mitochondrial DNA Depletion, and Severity of Lipoatrophy: Results from a Randomized Trial Comparing Stavudine and Zidovudine-based Antiretroviral Therapy
M. van der Valk*1, M. Casula1, J. P. Ruiter2, C. van Kuijk2, B. L. F. van Eck-Smit2, G. J. Weverling2, H. J. Hulsebosch2, A. van Eeden3, K. Brinkman4, J. M. A. Lange1,2, R. J. Wanders2, A. de Ronde5, P. Reiss2
1Intl Antiviral Therapy Evaluation Ctr, Amsterdam, The Netherlands; 2Academic Med Ctr, Amsterdam, The Netherlands; 3Jan van Gooyen Kliniek, Amsterdam, The Netherlands; 4Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands; and 5Primagen, Amsterdam, The Netherlands

Background: Reverse Transcriptase Inhibitors (nRTI) are implicated in the development of Lipoatrophy (LA), maybe resulting from mitochondrial toxicity. The incidence of LA has been suggested to be higher with the use of Stavudine (d4T) compared to Zidovudine (ZDV). We assessed LA and mtDNA in a cross-sectional study of all traceable and consenting patients (pts) who years before as therapy-naοve pts had participated in a 72-wk randomized trial of d4T+3TC versus ZDV+3TC, with IDV added at wk 12 if wk 8 HIV-RNA > 500 c/ml. Post-trial treatment was at the discretion of the treating physician.

Methods: LA was assessed by standardized questionnaire completed by one physician blind to their medical history. DEXA and abdominal CT were performed and Mitochondrial (mt) DNA was measured both in peripheral blood mononuclear cells (PBMC) and in subcutaneous fat biopsies taken from the lower back. MtDNA was also measured in PBMC cryopreserved prior to the initiation of randomized therapy. ITT analysis was done with all data expressed as median (IQR).

Results:

 

D4T (n = 17)

ZDV (n = 11)

p

No (%) pt with clinical LA

14/17 (82%)

1/11 (9%)

0.0001

PI exp (months)

45 (24–48)

31 (21–53)

 ns

NVP exp (months)

24 (17–25)

19 (17–26)

 ns

SAT by CT (cm2)

75 (54–95)

131 (105–149)

0.04

SAT:TAT

0.35 (0.30–0.44)

0.50 (0.41–0.62)

0.005

kg peripheral fat (DEXA)

2.4 (1.9–3.2)

4.8 (3.2–6.3)

0.005

Peripheral:total fat (DEXA)

0.33 (0.27–0.38)

0.37 (0.34–0.49)

0.04

PBMC mtDNA/cell

pre-Rx

362 (300–464)

322 (248–452)

ns

PBMC mtDNA/cell

current study

96 (84–118)

120 (108–147)

0.01

sc fat mtDNA/cell

571 (440–760)

707 (542–802)

0.23

 

Despite similar exposure to d4T or ZDV (51 and 50 mos) the frequency of clinical LA was 82% compared to 9%. DEXA and CT supported this, showing more severe LA in those allocated to d4T. Adjustment for duration of PI use did not alter these findings. PBMC mtDNA had decreased significantly compared to before starting therapy. This decrease was significantly greater in the d4T-arm (73% vs 63%, p = 0.01). A statistically significant relation was found between the mtDNA content in PBMCs with SAT:TAT (p = 0.003), the ratio of peripheral over total fat by DEXA (p = 0.04) and with mtDNA in fat (p = 0.002).

Conclusions: In this population randomly allocated to d4T or ZDV, d4T use was associated with both a greater frequency and objectively assessed severity of LA and a stronger decrease in PBMC-mtDNA content. LA severity measured both by DEXA and CT was related to mtDNA content in PBMC.