5th Conference on Retroviruses and Opportunistic Infections


Chicago, IL - February 1-5, 1998



IMPAIRMENT OF STAVUDINE (d4T) PHOSPHORYLATION IN PATIENTS RECEIVING A COMBINATION OF ZIDOVUDINE (ZDV) AND d4T (ACTG 290)

Conf Retroviruses Opportunistic Infect 1998 Feb 1-5; 5th:79 (abstract no. 3)

Sommadossi JP, Zhou XJ, Moore J, Havlir DV, Friedland G, Tierney C, Smeaton L, Fox L, Richman D, Pollard R; NIAID Sponsored AIDS Clinical Trials Group, Bethesda, MD.

In the ACTG 881 substudy of 6 patients, we evaluated the underlying pharmacologic mechanisms possibly responsible for the observed lack of viral load response and decline in CD4 observed with a ZDV/d4T combination (comb) in ACTG 290. Plasma and intracellular phosphorylated metabolite concentrations of ZDV and d4T were determined in peripheral blood mononuclear cells. Plasma levels of d4T ranged between 210 and 860 ng/ml within 1 and 3 hr after drug administration among patients receiving d4T alone (n=4) and no difference was observed with d4T plasma levels measured in the ZDV/d4T comb (n=2). Plasma levels of ZDV were in the expected range (110-280 ng/ml) in the ZDV/d4T comb. Intracellular ZDV-monophosphate and ZDV-triphosphate (ZDV-TP) achieved expected concentrations of 350-500 and 40-70 fmole/106 cells, respectively. Intracellular d4T-triphosphate (d4T-TP) reached a mean of 65 fmole/106 cells in those receiving d4T alone and 10 fmole/106 cells in patients receiving d4T alone and ZDV/d4T comb, respectively. In one patient who received the d4T/ZDV comb for 42 weeks and subsequently a d4T monotherapy for 8 weeks, no d4T-TP was detected at 2, 4 and 6 weeks following ZDV discontinuation. These data suggest that in patients receiving a comb of ZDV/d4T, the intracellular phosphorylation of d4T to d4T-TP is hampered and this negative effect may be prolonged for several weeks after discontinuation of ZDV treatment.

Keywords: AEGIS, Stavudine, Zidovudine, Anti-HIV Agents, Viral Load, Reverse Transcriptase Inhibitors, Thymine Nucleotides, HIV Protease Inhibitors, 3′-azido-3′-deoxythymidine 5′-triphosphate, Human, diagnosis, AIDS

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1998-02-01
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