This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Lipoatrophy - loss of body fat from particular areas of the body, especially the arms, legs, face, and buttocks - is an important problem in HIV. The management of HIV has been complicated by lipoatrophy, a distressing long-term complication of antiretroviral therapy (ART) associated with decreased quality of life, disincentive for adherence to therapy, as well as possibly increased risk of cardiovascular disease. A proposed mechanism for the development of lipoatrophy is mtDNA depletion in subcutaneous adipose tissue caused by thymidine analogue nucleoside analogues (zidovudine [ZDV] or stavudine [d4T]). Unfortunately, no therapy is available for clinical lipoatrophy. To date, several strategies have been unsuccessful in reversing this condition. The most successful intervention has been the replacement of d4T with abacavir. However, about 5% of people experience serious hypersensitivity reactions on abacavir. Recent studies have reported similar improvement in peripheral fat after replacement of drT or ZDV with tenofovir. Additionally, many ART-experienced persons are not suitable candidates for this nucleoside substitution strategy due to underlying nucleoside resistance. Pilot data on uridine supplementation in NRTI-related mitochondrial toxicity support the use of uridine in conditions associated with mtDNA depletion. Fibroblasts depleted of mtDNA by long-term exposure to the polymerase g inhibitor ethidium bromide became more dependent upon uridine for growth. Uridine also improved the survival and neurite outgrowth of neuronal cells exposed to dideoxycytidine (ddC) and reversed the toxicity of ZDV to bone marrow progenitors.This study hypothesizes that supplementation with uridine in the form of NucleomaxX will reverse the fat mitochondrial abnormalities, leading to an increase of limb fat content. The primary objective is to examine the effect of uridine supplementation on limb fat in HIV-1-infected subjects with clinical lipoatrophy by comparing changes from baseline to week 48 in DEXA (dual-energy x-ray absorptiometry)-measured limb fat between the uridine arm and placebo arm.This is a phase II/III, randomized, double-blind, placebo-controlled study. It will examine the effect of NucleomaxX on limb fat in HIV-1-infected subjects receiving stable ART containing d4T or ZDV. The study will also asses the safety and tolerability of NucleomaxX in this population. The duration will be 48 weeks. The sample size is 164 (82 per arm). The population will be HIV-infected men and women 18 years of age or greater with clinical lipoatrophy and a cumulative duration of thymidine NRTI (ZDV or d4T) treatment for at least 24 weeks prior to study entry.At study entry, subjects will be randomized 1:1 to one of the following:Arm A: NucleomaxX, one sachet (36 g) orally three times per day, every other day.Arm B: Placebo for NucleomaxX, one sachet (36 g) orally three times per day, every other day.
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