Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine.
OBJECTIVE
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.


METHODS
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.


METHODS
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
Substitution of stavudine with abacavir or zidovudine improves mitochondrial indices and fat apoptosis in the setting of lipoatrophy.
McComsey
Grace A
GA
Rainbow Babies and Children's Hospital bCase School of Medicine Center for AIDS Research, Cleveland, Ohio, USA. mccomsey.grace@clevelandactu.org
Paulsen
Denise M
DM
Lonergan
J Tyler
JT
Hessenthaler
Siegrid M
SM
Hoppel
Charles L
CL
Williams
Vanessa C
VC
Fisher
Robin L
RL
Cherry
Catherine L
CL
White-Owen
Cathy
C
Thompson
Katherine A
KA
Ross
Steve T
ST
Hernandez
Jaime E
JE
Ross
Lisa L
LL
D017667:Adipocytes / Q000187:drug effects / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D015224:Dideoxynucleosides / Q000627:therapeutic use*; D004579:Electron Transport / Q000187:drug effects; D005260:Female; D039682:HIV-Associated Lipodystrophy Syndrome / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D018482:Muscle, Skeletal / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D018119:Stavudine / Q000009:adverse effects* / Q000627:therapeutic use; D015215:Zidovudine / Q000627:therapeutic use*; D000099227:Abacavir
D004272:DNA, Mitochondrial; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D015215:Zidovudine; D000099227:Abacavir