Plasma concentrations of zidovudine (ZDV) and other nucleoside analog drugs have shown little correlation with clinical events. Because they must be metabolized intracellularly to elicit a biological effect, intracellular concentrations of the phosphorylated metabolites of nucleoside analogs might correlate with drug effects. The studies herein propose to use a sensitive and reproducible radioimmunoassay method, suitable for routine monitoring of total phosphorylated ZDV in peripheral blood mononuclear cells (PBMC), to define the pharmacokinetics of ZDV phosphorylation in PBMC from patients receiving ZDV, and examine the relation between intracellular concentrations and certain prognostic indicators of HIV disease. This includes a two armed study with a total of 40 patients. One arm will examine the rate of ZDV phosphorylation in ZDV-naive patients and the length of time required to reach steady-state concentrations while on standard dose ZDV (500 mg/day). The second arm will investigate the dose-response in patients on an escalating dose regimen. A two-year study combined both patient groups, and investigates the effects of long-term ZDV therapy on intracellular pharmacokinetics, including clearance and phosphorylation upon re-introduction of drug. Concurrent measurements of the prognostic indicators will be made. This study may suggest that longer dosing intervals and/or lower doses of ZDV are adequate to maintain intracellular concentrations. Additionally, an HPLC/RIA method will be validated and used to determine pharmacokinetics of ZDV triphosphate. this 10 patient study will be nested into the larger study because of practical limitations of the method, but the same parameters will be investigated. Similarly, a pilot study investigating the pharmacokinetic differences of ZDV phosphorylation in patients on combination ZDV/dideoxycytidine will also be performed in an effort to investigate synergistic efficacy. This study will be nested in site patients enrolled in ACTG 155. Finally, the development of new assays for measurement of intracellular nucleoside analog metabolites is planned. Eventually, modifications of dose to maximize effect might be possible through routine intracellular monitoring of nucleoside analog metabolites.

Project Start
1998-01-01
Project End
1998-12-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Type
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Grady, Benjamin J; Torstenson, Eric S; McLaren, Paul J et al. (2011) Use of biological knowledge to inform the analysis of gene-gene interactions involved in modulating virologic failure with efavirenz-containing treatment regimens in ART-naïve ACTG clinical trials participants. Pac Symp Biocomput :253-64
Sherman, Kenneth E; Rouster, Susan D; Stanford, Sandra et al. (2010) Hepatitis C virus (HCV) quasispecies complexity and selection in HCV/HIV-coinfected subjects treated with interferon-based regimens. J Infect Dis 201:712-9
Bhattacharya, Debika; Umbleja, T; Carrat, F et al. (2010) Women experience higher rates of adverse events during hepatitis C virus therapy in HIV infection: a meta-analysis. J Acquir Immune Defic Syndr 55:170-5
Zhao, Yu; Navia, Bradford A; Marra, Christina M et al. (2010) Memantine for AIDS dementia complex: open-label report of ACTG 301. HIV Clin Trials 11:59-67
Fichtenbaum, Carl J; Yeh, Tzu-Min; Evans, Scott R et al. (2010) Treatment with pravastatin and fenofibrate improves atherogenic lipid profiles but not inflammatory markers in ACTG 5087. J Clin Lipidol 4:279-87
Winham, Stacey J; Slater, Andrew J; Motsinger-Reif, Alison A (2010) A comparison of internal validation techniques for multifactor dimensionality reduction. BMC Bioinformatics 11:394
Butt, Adeel A; Tsevat, Joel; Leonard, Anthony C et al. (2009) Effect of race and HIV co-infection upon treatment prescription for hepatitis C virus. Int J Infect Dis 13:449-55
Tsevat, Joel; Leonard, Anthony C; Szaflarski, Magdalena et al. (2009) Change in quality of life after being diagnosed with HIV: a multicenter longitudinal study. AIDS Patient Care STDS 23:931-7
Skowron, Gail; Spritzler, John G; Weidler, Jodi et al. (2009) Replication capacity in relation to immunologic and virologic outcomes in HIV-1-infected treatment-naive subjects. J Acquir Immune Defic Syndr 50:250-8
Velilla, P A; Shata, M T; Lages, C S et al. (2008) Effect of low-dose IL-2 immunotherapy on frequency and phenotype of regulatory T cells and NK cells in HIV/HCV-coinfected patients. AIDS Res Hum Retroviruses 24:52-61

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