Metabolic Consequences of Thymidine Sparing Regimens

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DESCRIPTION (provided by applicant): Lipoatrophy is a highly prevalent complication of antiretroviral (ARV) therapy, associated with decreased quality of life, disincentive for adherence to AVR therapy, as well as possibly an increased risk of coronary artery disease. Our group has shown that subcutaneous adipose tissue from lipoatrophic patients have mitochondrial DNA (mtDNA) depletion, apoptosis, and increased oxidative stress systemically. It is known that the use of thymidine-analogue nucleoside reverse transcriptase inhibitors (NRTI) agents is associated with a high incidence of lipoatrophy and mitochondrial toxicity. Laboratory investigations have shown that non-thymidine analogue NRTIs carry a lower risk for inducing mtDNA depletion; this leads us to hypothesize that thymidine analogue sparing regimens will result in minimal or no effect on mitochondria and consequently minimal or no effect on fat apoptosis and fat content. Since there is no treatment for established lipoatrophy, prevention of this complication by the use of "mitochondrion-friendly" NRTIs may prevent substantial morbidity. Mechanistically, we believe that reactive oxygen species (ROS) produced principally by the mitochondria during oxidative phosphorylation, could damage mtDNA and mitochondrial proteins and as such could contribute to the pathogenesis of lipoatrophy. Our long-range goal is to understand the metabolic consequences of treatment using thymidine analogue sparing ARV regimens. This will be assessed in a 2 year longitudinal study of 50 subjects who are starting their first ARV regimen as part of the Adult AIDS Clinical Trials Group trial # 5202, in which they will be randomized to receive tenofovir/FTC or abacavir /3TC (in combination with either atazanavir/ritonavir or efavirenz). Another group of 25 patients will serve as the control group; these previously treatment-naive patients will enroll in a similarly designed trial in which they will receive thymidine analogue containing ARV regimens (ZDV or d4T + 3TC) and will have similar evaluations performed. Subcutaneous fat biopsies will be obtained from all 75 patients prior to, and after two years of therapy. We will assess mtDNA, mitochondrial function, fat apoptosis and lipid and mitochondrial oxidative damage markers. In addition, we will evaluate metabolic parameters using the clinical/imaging data obtained as part of the parent ACTG study.