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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI065348-02
Application #
7167149
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Brobst, Susan W
Project Start
2006-01-01
Project End
2010-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
2
Fiscal Year
2007
Total Cost
$212,299
Indirect Cost
Name
Case Western Reserve University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Gupta, S K; Kitch, D; Tierney, C et al. (2015) Markers of renal disease and function are associated with systemic inflammation in HIV infection. HIV Med 16:591-8
Longenecker, Chris T; Kitch, Douglas; Sax, Paul E et al. (2015) Reductions in Plasma Cystatin C After Initiation of Antiretroviral Therapy Are Associated With Reductions in Inflammation: ACTG A5224s. J Acquir Immune Defic Syndr 69:168-77
Erlandson, Kristine Mace; Kitch, Douglas; Tierney, Camlin et al. (2014) Impact of randomized antiretroviral therapy initiation on glucose metabolism. AIDS 28:1451-61
McComsey, Grace A; Kitch, Douglas; Sax, Paul E et al. (2014) Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202. J Acquir Immune Defic Syndr 65:167-74
Erlandson, Kristine M; Kitch, Douglas; Tierney, Camlin et al. (2013) Weight and lean body mass change with antiretroviral initiation and impact on bone mineral density. AIDS 27:2069-79
McComsey, Grace A; Daar, Eric S; O'Riordan, MaryAnn et al. (2013) Changes in fat mitochondrial DNA and function in subjects randomized to abacavir-lamivudine or tenofovir DF-emtricitabine with atazanavir-ritonavir or efavirenz: AIDS Clinical Trials Group study A5224s, substudy of A5202. J Infect Dis 207:604-11
Eckard, Allison Ross; Leong, Traci; Avery, Ann et al. (2013) Short communication: High prevalence of vitamin D deficiency in HIV-infected and HIV-uninfected pregnant women. AIDS Res Hum Retroviruses 29:1224-8
Grant, Philip M; Kitch, Douglas; McComsey, Grace A et al. (2013) Low baseline CD4+ count is associated with greater bone mineral density loss after antiretroviral therapy initiation. Clin Infect Dis 57:1483-8
Eckard, Allison Ross; Tangpricha, Vin; Seydafkan, Shabnam et al. (2013) The relationship between vitamin D status and HIV-related complications in HIV-infected children and young adults. Pediatr Infect Dis J 32:1224-9
Ross, A C; Leong, T; Avery, A et al. (2012) Effects of in utero antiretroviral exposure on mitochondrial DNA levels, mitochondrial function and oxidative stress. HIV Med 13:98-106

Showing the most recent 10 out of 16 publications