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Assessing the contribution of ART, HIV and host factors to adipose tissue changes occurring in HIV-infected individuals: Risk profile for lipoatrophy

Hammond, E., Nolan, D., McKinnon, E., Pace, C., Metcalf, C. and Mallal, S. (2005) Assessing the contribution of ART, HIV and host factors to adipose tissue changes occurring in HIV-infected individuals: Risk profile for lipoatrophy. In: 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 13 - 16 November 2005, Dublin, Ireland

Abstract

Objectives: For HIV-infected individuals receiving antiretroviral therapy (ART), the development of lipoatrophy significantly impacts clinical management. To identify critical risk factors for lipoatrophy, we assessed in vivo adipose tissue changes occurring longitudinally in HIV-infected patients.

Methods: Subcutaneous fat (n=68 biopsies; n=32 individuals) was paraffin processed and stained by immunohistochemistry for scoring of macrophage numbers and adipocyte-specific protein expression of cytokines (IL-18, IL-6, TNFa, IL-8, IL-12). Data was analysed cross-sectionally and for changes over time (median=7.0, IQR=5.9–10.1 months). Data included samples from individuals initiating [zidovudine (AZT) n=6; stavudine (d4T) n=7; abacavir (ABC)/non-thymidine n=6], switching (d4T onto AZT/ABC n=8; AZT onto ABC n=2) or continuing therapy (n=7). Mitochondrial DNA (mtDNA) content and relative transcriptional expression of caspase I, IL-18, IL-6, TNFa, adiponectin and PPAR-g were also measured in frozen biopsies (AZT n=6; d4T n=10; naive n=14; ABC n=13). The influence of ART, disease and host-related factors on these endpoints was investigated. Results: Cross-sectional analysis revealed protein expression of all cytokines correlated with current ART (all P<0.03), with each other (all P<0.001), %leg fat/BMI (all P<0.05), %leg fat (all P<0.01), and macrophage count (all P<0.001). Neither cytokine expression nor macrophage count was independently associated with viral load, age, BMI, CD4 or HOMA score, although, TNFa expression correlated with BMI (P=0.04) in ART-naïve individuals. Initiating d4T or AZT was associated with increases in mtDNA depletion (P=0.003), macrophage count (P=0.006) and protein expression of cytokines (TNFa, IL-6, IL-8, IL-12 all P<0.03, IL-18 P=0.06). Initiating ABC (in the absence of thymidine therapy) was not associated with any outcomes (P>0.2). No significant effect of protease inhibitor therapy was detected. Switching from d4T or AZT was associated with modest improvements in tissue morphology and improvements in mtDNA depletion (P=0.008), macrophage numbers and expression of all cytokines, but significance was restricted to IL-8 (P=0.008). Fat gain (positive changes in % leg fat/BMI) was undetectable. Gene expression data failed to show significant correlations with protein expression (all P>0.05). Dublin, Ireland 13–16 November 2005 Conclusions: Profiling of adipose tissue morphology, cytokine protein expression and mtDNA depletion identified ART [d4T>AZT>ABC (without d4t/AZT)= naive], but not viral or host variables, as risk factors for lipoatrophy.

Results: Cross-sectional analysis revealed protein expression of all cytokines correlated with current ART (all P<0.03), with each other (all P<0.001), %leg fat/BMI (all P<0.05), %leg fat (all P<0.01), and macrophage count (all P<0.001). Neither cytokine expression nor macrophage count was independently associated with viral load, age, BMI, CD4 or HOMA score, although, TNFa expression correlated with BMI (P=0.04) in ART-naïve individuals. Initiating d4T or AZT was associated with increases in mtDNA depletion (P=0.003), macrophage count (P=0.006) and protein expression of cytokines (TNFa, IL-6, IL-8, IL-12 all P<0.03, IL-18 P=0.06). Initiating ABC (in the absence of thymidine therapy) was not associated with any outcomes (P>0.2). No significant effect of protease inhibitor therapy was detected. Switching from d4T or AZT was associated with modest improvements in tissue morphology and improvements in mtDNA depletion (P=0.008), macrophage numbers and expression of all cytokines, but significance was restricted to IL-8 (P=0.008). Fat gain (positive changes in % leg fat/BMI) was undetectable. Gene expression data failed to show significant correlations with protein expression (all P>0.05).

Conclusions: Profiling of adipose tissue morphology, cytokine protein expression and mtDNA depletion identified ART [d4T>AZT>ABC (without d4t/AZT)= naive], but not viral or host variables, as risk factors for lipoatrophy.

Publication Type: Conference Paper
Murdoch Affiliation: Centre for Clinical Immunology and Biomedical Statistics
URI: http://researchrepository.murdoch.edu.au/id/eprint/15692
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