This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Combinations of antiretroviral drugs that include nucleoside analog-reverse transcriptase inhibitors (NRTI) have prolonged the lives of patients with HIV, but drug-toxicities are major clinical issues. The rate of NRTI toxicities is higher in women than men, and in advanced versus less-advanced HIV infection, but the basis for these differences in toxicities is unknown. NRTIs are activated by phosphorylation in host cells to NRTI-triphosphates, some of which can interfere with mitochondrial DNA replication to elicit toxicity. Our laboratory has developed methods to quantify NRTI-triphosphate concentrations in peripheral blood mononuclear cells. In preliminary studies, we found that women and subjects with advanced HIV-infection had higher NRTI-triphosphate concentrations than men and those with less-advanced HIV-infection, respectively. The work proposed in this application will prospectively answer three critical questions: Are NRTI-triphosphate concentrations sex-dependent? Are NRTI-triphosphate concentrations dependent on HIV disease stage? And, is there a relationship between NRTI-triphosphate concentrations and NRTI toxicity? Research in this area is important and relevant to human health because NRTI-toxicities can be painful, disfiguring, and life-threatening. There is currently no adequate clinical approach to address sex- and disease-dependent NRTI-toxicity. The US Dept. of Health and Human Services warns of NRTI-toxicity in women, but the only recommendation is to avoid certain NRTIs during pregnancy. More comprehensive strategies are needed. Also, the increased NRTI-toxicity risk in advanced disease is not yet weighed in the current debate of early versus late initiation of NRTI-based treatments. Our preliminary work provides a rational pharmacologic basis to evaluate sex- and disease-dependent NRTI-triphosphate concentrations, and the concentration-effect relationship to NRTI-toxicity. The knowledge to be gained addresses our long-term objective to discover the determinants of drug responses and to utilize the information to improve drug safety
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