AEGiS-10CROI: 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.

10th Conference on Retroviruses and Opportunistic Infections

Boston, MA USA - February 10 -14, 2003

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.

Conf Retroviruses Opportunistic Infect 2003 Feb 10-14;10th: abstract no. 739
van der Valk M, Casula M, Ruiter JP, van Kuijk C, van Eck-Smit BL, Weverling GJ, Hulsebosch HJ, van Eeden A, Brinkman K, Lange JM, Wanders RJ, de Ronde A, Reiss P; Intl Antiviral Therapy Evaluation Ctr, 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-naïve 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: [table: see text] 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.

Keywords: AEGIS, Stavudine, Reverse Transcriptase Inhibitors, Zidovudine, Lipodystrophy, Nucleosides, Lamivudine, Anti-HIV Agents, HIV Infections, DNA, Mitochondrial, HIV-1 Reverse Transcriptase, HIV, Drug Therapy, Combination, HIV Protease Inhibitors, Antiretroviral Therapy, Highly Active, Cross-Sectional Studies, Human, therapy, drug therapy

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Copyright © 2003 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.