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Improvements
in Lipoatrophy, Mitochondrial DNA Levels and Fat Apoptosis after
Replacing Stavudine with Abacavir or Zidovudine
The objective of the current study was to determine
if stavudine/
d4T (Zerit)-associated
mitochondrial
toxicity could be reversed by substitution
with another nucleoside
reverse transcriptase inhibitor (NRTI).
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
(Ziagen)
or zidovudine
(Retrovir) 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.
Results
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.
Conclusions
The
authors conclude, ““Substitution of stavudine with abacavir or zidovudine
improves mitochondrial indices and fat apoptosis in the setting
of lipoatrophy.”
Rainbow Babies and Children's
Hospital, Case School of Medicine Center for AIDS Research, Cleveland,
Ohio; GlaxoSmithKline; University of California, San Diego, California;
Monash University; and the Burnet Institute, Melbourne, Australia.
01/10/05
Reference
G
A McComsey and others. Improvements in lipoatrophy, mitochondrial
DNA levels and fat apoptosis after replacing stavudine with abacavir
or zidovudine. AIDS 19(1):15-23. January 3, 2005.
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