Thompson K, McComsey G, Paulsen D, Cherry C, Lonergan T, Hessenthaler S, Williams V, Fisher R, Wesselingh S, Hernandez J, Ross L; Conference on Retroviruses and Opportunistic Infections.
Abstr 10th Conf Retrovir Oppor Infect Feb 10 14 2003 Hynes Conv Cent Boston Mass USA Conf Retrovir Oppor Infect 10th 2003 Boston Mass. 2003 Feb 10-14; 10: abstract no. 728.
Monash Univ, Alfred Hosp, Melbourne, Austrailia
BACKGROUND: Recent studies have suggested that nucleoside reverse transcriptase inhibitors (NRTIs), with Stavudine (d4T) > Zidovudine (ZDV) > Abacavir (ABC), may be associated with lipoatrophy (LA) through mitochondrial (Mt) dysfunction. We hypothesize that apoptosis, driven by Mt dysfunction, may be involved, and examine the effect of substitution within NRTIs on fat apoptosis. Adipose tissue apoptosis, mt content, and change in body fat were assessed in 13 subjects with HIV-1 RNA < 400 c/mL on d4T-based regimens for > 2 yrs who enrolled with symptoms of LA, hyperlactatemia or both, and who substituted ABC or ZDV (as Combivir) for d4T.METHODS: Regional body fat was analyzed by DEXA. Adipose Mt DNA levels were determined at week 0 and 48 using real-time PCR and compared to uninfected controls. Subcutaneous adipocyte apoptosis was assessed semi-quantitatively by terminal deoxynucleotidyl transferase dUTP-digoxigenin nick end labeling (TUNEL) in blinded and randomized slides from controls and subjects. Duplicate slides were scored from 0-3 and slide scores were averaged.RESULTS: Of the 13 subjects, 12 replaced d4T with ABC, 1 with ZDV. By wk 48, DEXA results (n = 13) indicated median increases from week 0 in arm, leg and trunk fat of 25%, 15%, and 23%, respectively. Median patient week 0 Mt DNA/fat cell was 214 (n = 13) compared to 863 for controls (n = 20), but rose at wk 48 to 462 (n = 8). TUNEL results indicated that at baseline, median patient (n = 13) adipocyte apoptosis was greater (2.0) than that observed in controls tissue (0.5, n = 20). Median adipocyte apoptosis decreased after d4T discontinuation (1.25, n = 10). The interquartile range (25th and 75th quartiles) for the apoptosis assays were 1 and 2.5 at baseline and 0.5 and 2.5 at wk 48. Increased levels of adipocyte apoptosis and decreased Mt numbers were noted in adipose tissue from subjects on d4T-containing regimens relative to uninfected controls. Fat biopsies from HIV infected subjects showed increased Mt DNA content and a reduction in adipocyte apoptosis with regional body fat increases by DEXA 48 weeks after d4T discontinuation. These findings suggest adipocyte apoptosis secondary to mitochondrial toxicity may contribute to d4T associated LA, and this toxicity is reversible on substitution of ABC or ZDV for stavudine.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Adipocytes
- Adipose Tissue
- Anti-HIV Agents
- Antiretroviral Therapy, Highly Active
- Apoptosis
- Combivir
- DNA, Mitochondrial
- Dideoxynucleosides
- HIV
- HIV Infections
- HIV Protease Inhibitors
- Humans
- In Situ Nick-End Labeling
- Lamivudine
- Lipodystrophy
- Reverse Transcriptase Inhibitors
- Stavudine
- Zidovudine
- abacavir
- drug therapy
- therapy
Other ID:
UI: 102261368
From Meeting Abstracts