McComsey GA, Paulsen DM, Lonergan JT, et al. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine

University of California, San Diego, San Diego, California, United States
AIDS (Impact Factor: 5.55). 02/2005; 19(1):15-23. DOI: 10.1097/00002030-200501030-00002
Source: PubMed


To determine if stavudine (alpha4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse transcriptase inhibitor. As apoptosis and dysfunction of electron transport chain (ETC) activities may underlie mitochondrial toxicity, these parameters were also evaluated.
The 16 participants (on d4T for >3 years; with lipoatrophy and/or hyperlactatemia) substituted abacavir or zidovudine for stavudine in their antiretroviral regimen. Key parameters including dual-energy X-ray absorptiometry (DEXA) scans, fat apoptosis, mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMC), skeletal muscle and fat, as well as skeletal muscle mitochondrial ETC activities were evaluated at study entry and at 48 weeks after the substitution.
Quantitative PCR was used to evaluate mtDNA levels and the presence of deletions/rearrangements; CLIA-validated methods for ETC activities; terminal deoxynucleotidyl transferase dUTP-digoxigenin nick-end labeling assays to evaluate adipocyte apoptosis; and DEXA scans to measure changes in body fat.
MtDNA was depleted at study entry in muscle, adipose tissue and PBMC but levels rebounded with respective mean increases of 141%, 146%, and 369% at week 48. Corresponding fat improvements were noted with DEXA increases of 21%, 11%, and 16% in arm, leg, and trunk, respectively. Quantitative adipocyte apoptosis were significantly increased at baseline (P < 0.01 versus HIV-negative controls), with a significant reduction at week 48 (P < 0.05 versus baseline). Mean values for seven mitochondrial enzyme activities assays at entry indicated substantial loss of function (48% to 85% of controls) with significant improvement of complex I activity by week 48.
Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.

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Available from: Jaime Hernandez, Oct 29, 2015
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    • "Currently used NRTIs, such as tenofovir (a nucleotide RTI) and abacavir, have been shown to be essentially free from pol γ inhibition in vitro and to cause no significant mtDNA depletion in vivo [5], [6]. If a patient’s therapy is switched away from a pol γ inhibiting NRTI, the impairment of mtDNA replication is removed and mtDNA content returns to normal [7]. Therefore, although most patients are no longer exposed to pol γ inhibiting NRTIs, a significant cohort of long-term patients will have extensive prior exposure to such drugs. "
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