National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Level 2, 376 Victoria St, Darlinghurst NSW 2010, Sydney, Australia
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Abstract |
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Keywords: HIV , lipodystrophy , antiretroviral therapy , body composition , hyperlipidaemia
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Lipodystrophy |
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Protease inhibitors |
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Nucleoside reverse transcriptase inhibitors |
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In vitro, NRTIs inhibit mitochondrial DNA polymerase-, an important enzyme involved in replication of mitochondrial DNA (mtDNA), leading to mtDNA depletion.13
As mitochondria are abundant in subcutaneous adipose tissue, it has been proposed that this mechanism leads to depletion of mtDNA in subcutaneous fat, resulting in cellular dysfunction and increased apoptosis.14
Several studies have demonstrated reduced mtDNA in subcutaneous adipose tissue of subjects treated with tNRTIs, particularly stavudine.1518
In one study, in addition to mtDNA depletion, subjects treated with stavudine also showed significantly lower expression of PPAR-
compared with controls.16
Where reversibility in body fat has been described, the most compelling data comes from tNRTI withdrawal studies, particularly the MITOX study.1923 The MITOX study was a large, prospective, randomized controlled trial, examining the strategy of switching from a tNRTI to abacavir, with the primary endpoint being change in limb fat.19 Participants were randomized to switch from zidovudine or stavudine to abacavir or continue their current thymidine-containing HAART regimen. At the end of the initial 24 week phase, limb fat improved by 11% (or 0.4 kg) in the switch group; a benefit which, although statistically significant (P=0.02), was not noticeable clinically. For the extension phase (2 years) participants initially randomized to continue their tNRTI were allowed to switch to abacavir, giving rise to three groups; those who commenced abacavir at baseline, those that switched at week 24 and those that remained on stavudine or zidovudine. At 104 weeks, those who switched at baseline experienced a 35% increase in limb fat (or 1.3 kg; P=0.001), an effect that was clinically noticeable.20 Those switching at week 24 increased limb fat by 15% (0.6 kg; not clinically noticeable). In contrast, those remaining on stavudine or zidovudine only gained 0.2 kg of limb fat over the 2 year period.20 Multivariate analysis indicated that improvement in limb fat was significantly associated with reduced usage of stavudine on-study. These and other switch studies demonstrate the central role of thymidine analogues in the pathogenesis of lipoatrophy.2123 However, the potential benefits of switching need to be weighed against the potential to introduce new toxicities from alternative antiretrovirals, together with the increased risk of virological failure. For example, in the MITOX study, 10% of those who initially switched to abacavir experienced a hypersensitivity reaction.
In addition to switch strategies, studies have investigated initial antiretroviral regimens that avoid the use of tNRTIs. In one substudy of 96 subjects randomized to an NRTI backbone of stavudine/didanosine (n=46) or the tNRTI-sparing backbone of abacavir/lamivudine (n=50), those on the tNRTI-sparing regimen experienced slower rates of change in body composition as measured using anthropometry.24 In a larger, randomized study of stavudine/lamivudine versus the tNRTI-sparing regimen of tenofovir/lamividine in 262 antiretroviral-naive subjects, subjects randomized to the tNRTI-sparing arm had 2.9 and 4.1 kg more limb fat after 96 and 144 weeks of therapy, respectively (both P < 0.01).25 Such strategies may delay the onset of lipoatrophy in populations of antiretroviral-naive subjects, but may be difficult to implement outside developed countries owing to limitations of cost and availability of drugs.
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Thiazolidinediones |
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Surgical correction of facial lipoatrophy |
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Alternative therapeutic approaches |
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Conclusions |
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Acknowledgements |
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References |
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