Longitudinal effects on subcutaneous fatmass of initiating or switching stavudine and zidovudine-based antiretroviral therapy
James, I., Nolan, D., Hammond, E., McKinnon, E. and Mallal, S. (2003) Longitudinal effects on subcutaneous fatmass of initiating or switching stavudine and zidovudine-based antiretroviral therapy. In: 5th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 8 - 11 July, Paris, France.
OBJECTIVES/AIMS: To examine the progression of subcutaneous fat wasting (lipoatrophy) among Western Australian HIV cohort participants initiating stavudine (d4T) or zidovudine (AZT), as well as the effects of switching between these drugs. In these non-linear mixed effects analyses fat wasting is considered as a continuous process of variable rate and/or severity, rather than as a dichotomous clinical end-point.
METHODS: Longitudinal profiles of %leg fat relative to body mass index (%leg fat/BMI) were analysed in 72 treatment-naïve white males with sequential DEXA scans after highly active antiretroviral therapy (HAART) (average 3.7/patient). Fifty-five patients received protease inhibitor (PI) therapy (24/33 d4T; 31/39 AZT) and 61 received lamivudine (23/33 d4T; 38/39 AZT). Associations between %leg fat/BMI and mitochondrial DNA (mtDNA) depletion were also investigated in patients with fat biopsy data (9 d4T, 13 AZT; 103 DEXA scans). Further analysis investigated the effects of switching from d4T to AZT (n=12; 63 DEXA scans), compared with ongoing d4T therapy.
RESULTS: For patients aged >35 years %leg fat/BMI decreased exponentially from baseline (average=0.98) after commencing HAART, with significant differences between d4T and AZT groups (P=0.02). Estimated decreases from baseline in %leg fat after 36 months were 30% for AZT and 45% for d4T. Patients <35 years had lower baseline %leg fat/BMI (average=0.85, P=0.04) and experienced less fat loss over time (average .%leg fat=25%, P=0.01), although no age-dependent effects were detected for patients >35 years (P=0.4). Switching from d4T to AZT was associated with stable %leg fat/BMI over time, compared with ongoing fat loss in d4T patients matched for duration of therapy (P=0.01). Among patients with biopsy data, %leg fat/BMI was associated with adipocyte mtDNA depletion (P=0.01) and duration of nucleoside reverse transcriptase inhibitor (NRTI) therapy (P<0.001). Use of PI therapy, didanosine and baseline CD4 T cell count provided no significant effect in analyses.
CONCLUSION: Choice of d4T versus AZT in the first HAART regimen, and in subsequent switching strategies, is associated with differential effects on fat wasting over time. These drug-specific effects may manifest through NRTI-associated mitochondrial DNA depletion and adipose tissue mitochondrial toxicity.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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