Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine
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 e...
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Published in | AIDS (London) Vol. 19; no. 1; pp. 15 - 23 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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England
03.01.2005
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Abstract | 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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AbstractList | Objective: To determine if stavudine ( alpha 4T)-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. Design: 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. 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. |
Author | Hessenthaler, Siegrid M Lonergan, J Tyler Fisher, Robin L Ross, Steve T Paulsen, Denise M Williams, Vanessa C White-Owen, Cathy Hoppel, Charles L McComsey, Grace A Thompson, Katherine A Cherry, Catherine L Hernandez, Jaime E Ross, Lisa L |
Author_xml | – sequence: 1 givenname: Grace A surname: McComsey fullname: McComsey, Grace A email: mccomsey.grace@clevelandactu.org organization: Rainbow Babies and Children's Hospital bCase School of Medicine Center for AIDS Research, Cleveland, Ohio, USA. mccomsey.grace@clevelandactu.org – sequence: 2 givenname: Denise M surname: Paulsen fullname: Paulsen, Denise M – sequence: 3 givenname: J Tyler surname: Lonergan fullname: Lonergan, J Tyler – sequence: 4 givenname: Siegrid M surname: Hessenthaler fullname: Hessenthaler, Siegrid M – sequence: 5 givenname: Charles L surname: Hoppel fullname: Hoppel, Charles L – sequence: 6 givenname: Vanessa C surname: Williams fullname: Williams, Vanessa C – sequence: 7 givenname: Robin L surname: Fisher fullname: Fisher, Robin L – sequence: 8 givenname: Catherine L surname: Cherry fullname: Cherry, Catherine L – sequence: 9 givenname: Cathy surname: White-Owen fullname: White-Owen, Cathy – sequence: 10 givenname: Katherine A surname: Thompson fullname: Thompson, Katherine A – sequence: 11 givenname: Steve T surname: Ross fullname: Ross, Steve T – sequence: 12 givenname: Jaime E surname: Hernandez fullname: Hernandez, Jaime E – sequence: 13 givenname: Lisa L surname: Ross fullname: Ross, Lisa L |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/15627029$$D View this record in MEDLINE/PubMed |
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contributor: fullname: Nolan |
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Snippet | To determine if stavudine (alpha4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse transcriptase... Objective: To determine if stavudine ( alpha 4T)-associated mitochondrial toxicity could be reversed by substitution with another nucleoside reverse... |
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SubjectTerms | Adipocytes - drug effects Adipocytes - physiology Adipose Tissue - drug effects Adipose Tissue - metabolism Adult Apoptosis - drug effects Dideoxynucleosides - therapeutic use DNA, Mitochondrial - drug effects Electron Transport - drug effects Female HIV-Associated Lipodystrophy Syndrome - drug therapy HIV-Associated Lipodystrophy Syndrome - metabolism Human immunodeficiency virus Humans Leukocytes, Mononuclear - drug effects Male Middle Aged Mitochondria - enzymology Muscle, Skeletal - drug effects Reverse Transcriptase Inhibitors - adverse effects Reverse Transcriptase Inhibitors - therapeutic use Stavudine - adverse effects Stavudine - therapeutic use Zidovudine - therapeutic use |
Title | Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine |
URI | https://www.ncbi.nlm.nih.gov/pubmed/15627029 https://search.proquest.com/docview/17831771 |
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