Zidovudine phosphorylation detemined at intervals over 12 months in naïve and antiretroviral experienced HIV+patients.
Originally Published on January 1, 1998
Back DJ, Hoggard PG, Gibbons SE, Lloyd J, Khoo SH, Wilkins EG, Merry C, Barry MG.
5th Conference on Retroviruses and Opportunistic Infections, February 1-5, 1998, Chicago, Illinois. LB 10 page 224.
ABSTRACT:
Nucleoside analogues (NA) require intracellular phosphorylation to the active triphosphate prior to the inhibition of HIV replication. Emergence of viral drug resistance is a central problem for the success of antiviral therapy and while the main focus has been a virological mechanism of resistance it is important to consider that pharmacological mechanisms (i.e. decreased intracellular phosphorylation of NA with time) may play a key role. We have determined the intracellular concentrations of ZDV and its mono-, di-, and tri- phosphates in PNMCs at intervals over 12 months in HIV+ patients receiving combination therapy of ZDV/ddl or ZDV/3TC. Twenty four subjects (both antiretroviral naïve and ZDV experienced) have been recruited and blood samples collected at 0, 1, 2, 3, 6, 9 and 12 months. Intracellular nucleotides are measured by a validated combined HPLC-RIA method. We report data on 10 patients who have completed the trial to 12 months.
There was no significant difference from baseline for either intracellular total ZDV phosphates (AUC 0-2 h, 2.05 1.47, 2.73 1.79, 2.20 1.46, 2.17 1.35, 1.83 0.95, 2.49 2.14, 1.56 0.89, 3.40 1.89 pmoles/10^{6} cells.h; mean s.d. at day 0, 2 weeks, 1, 2, 3, 6, 9 & 12 months) or ZDV triphosphate (0.08 0.05, 0.10 0.07, 0.09 0.08, 0.13 0.10, 0.09 0.07, 0.12 0.07, 0.06 0.05, 0.10 0.07 pmoles/10^{6} cells.h; mean s.d. at day 0,2 weeks, 1, 2, 3, 6, 9 & 12 months).
From this interim analysis there is no evidence of i) a systematic decrease in intracellular phosphorylation of ZDV with time or ii) a difference between naïve and experienced patients, suggesting that altered phosphorylation is not a key factor governing the emergence of resistance.
