Lipoatrophy is a highly prevalent complication of antiretroviral therapy, associated with decreased quality of life, disincentive for adherence to antiretroviral therapy, as well as possibly an increased risk of coronary artery disease. Lipoatrophy has been shown to correlate with reduced fat mitochondrial DNA (mtDNA) content and mitochondrial dysfunction. Additionally, recent work from our group suggested an association between oxidative stress and lipoatrophy. Reactive oxygen species (ROS) contribute to oxidative stress and are produced principally by the mitochondria during oxidative phosphorylation (OXPHOS). ROS damages mtDNA, lipids, and proteins leading to a decrease in expression of mtDNA-related products involved in OXPHOS, and subsequent decrease in ATP synthesis. Whether the finding of increased oxidative stress represents the consequence of or the cause of this mitochondrial dysfunction is unclear. An additional potential mechanism for nucleoside analogue reverse transcriptase inhibitors (NRTI) induced mitochondrial toxicities was recently revealed; NRTI-induced mitochondrial dysfunction may inhibit dihydroorotate dehydrogenase and lead to depletion in natural pyrimidines; if the latter is true, providing exogenous uridine would reverse mitochondrial DNA content and function. ? ? Recent trials have shown that reversal of lipoatrophy is very slow to occur even after switching off antiretroviral therapy. Other strategies for treating lipoatrophy have been disappointing. In recent investigations, uridine supplementation was able to reverse mtDNA depletion and mitochondrial dysfunction in adipocytes treated with NRTIs. In this proposed study, we will assess the efficacy and safety of NucleomaxX, a nutritional supplement which contains high levels of nucleosides, in HIV lipoatrophy. We hypothesize that by improving mitochondrial DNA content and function, uridine supplementation will be able to improve fat content and oxidative markers in NRTI-treated HIV-infected subjects with established lipoatrophy. The study has already been approved by the AIDS Clinical Trials Group (ACTG study 5229) and will use ACTG resources for patient recruitment, safety assays, virologic and immunologic assays, data management, and statistical assistance. ? ? All patients will be enrolled in the first 18 months of funding. On-study subjects will continue to be followed per study protocol for a total of 12 months. The last 6 months of the grant will be dedicated to processing of samples and analysis of all data. ? ?
| McComsey, Grace A; O'Riordan, MaryAnn; Choi, Julia et al. (2012) Mitochondrial function, inflammation, fat and bone in HIV lipoatrophy: randomized study of uridine supplementation or switch to tenofovir. Antivir Ther 17:347-53 |
| McComsey, Grace A; Walker, Ulrich A; Budhathoki, Chakra B et al. (2010) Uridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229. AIDS 24:2507-15 |
