Assessing the risk of adipose tissue mitochondrial toxicity in HIV-infected individuals on contemporary NRTI regimens
Hammond, E., Nolan, D., McKinnon, E., Pace, C. and Mallal, S. (2006) Assessing the risk of adipose tissue mitochondrial toxicity in HIV-infected individuals on contemporary NRTI regimens. In: 8th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, 23 - 26 September 2006, San Fransisco, U.S.A.
Data examining the contribution of drug, HIV and host demographic covariates to changes occurring in adipose tissue of HIV infected patients indicates that the dominant risk factor for lipoatrophy is the choice and duration of stavudine and to a lesser extent zidovudine, NRTI therapy. The risk of adipose tissue toxicity and clinical lipoatrophy for patients initiating or switching to non-thymidine based analogues is less well defined. Our research suggests that early changes in adipose tissue in mitochondrial DNA content, cytokine expression and macrophage recruitment predict the onset of this syndrome. We have therefore evaluated lipoatrophic risk on contemporary antiretroviral drug regimens based on changes in parameters that include these tissue markers. Subcutaneous fat biopsies (n=217) were obtained from HIV infected patients (n=140). Samples were obtained from patients who were treatment naïve (n=50), untreated (n=9), or treated with zidovudine (AZT, n=66), stavudine (d4T, n=37), abacavir (ABC, n=45), or on other therapy (n=10). Mitochondrial DNA per cell was quantified using real time PCR. In a subset of longitudinal samples (n=32, 68 samples) from patients initiating or switching NRTI therapy, cytokine protein expression (IL-6, IL-8, IL-12, IL-18 and TNF) and adipose tissue macrophage content were also assessed. Cross sectional analyses revealed that mitochondrial DNA depletion was significantly associated with stavudine and zidovudine (23 and 49% of treatment naïve values, respectively; P-values both <0.001), but not abacavir or other drug regimens (82% and 75% of treatment naïve values, respectively, P>0.1). These findings were also observed in paired biopsy samples obtained from ART-naïve patients commencing abacavir-based regimens (n=10), in which adipocyte mitochondrial DNA was not significantly influenced by treatment (P=0.2). Thymidine analogues associated with increased pro-inflammatory cytokine expression and macrophage infiltration (P<0.05). No significant effects of patient demographic factors, HIV disease severity, or concurrent HIV therapy (PI versus NNRTI) were detected. Our study found no evidence of increased lipoatrophic risk for HIV infected patients initiating their first antiviral drug treatment with abacavir based therapies in the absence of stavudine or zidovudine. Changes in adipocyte mtDNA, adipose tissue cytokine expression and inflammation associated with stavudine (and zidovudine), independent of PI therapy use or HIV disease severity, indicate that changes in these parameters may underpin clinical lipoatrophy via a common pathogenic mechanism.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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