Fletcher CV, Kawle SP, Page LM, Remmel RP, Acosta EP, Henry K, Erice A, Balfour HH Jr; University of Minnesota, Minneapolis, MN.
The intracellular triphosphate anabolites of zidovudine (ZDV-TP) and related nucleoside agents are responsible for the inhibition of HIV reverse transcriptase (RT). Therefore, triphosphate concentrations, rather than plasma concentrations of the parent drug, may be a better predictor of anti-HIV effect. We have been conducting a 24-week randomized crossover evaluation of concentration-controlled (CC) vs. standard-dose (S) ZDV therapy in antiretroviral-naïve persons. In the context of this study, intracellular ZDV-TP was measured at weeks 0, 2, 6, 10, 12 (crossover point), 14, 18, and 22 in 16 patients. ZDV-TP was quantitated based upon the inhibition of 3H-TTP incorporation in the template primer by RT. CD4 cell counts and plasma HIV-RNA were also determined. Clinical response (R) or no response (NR) was defined as % change in CD4 count greater than 0 or less than or equal to 0, respectively. ZDV-TP concentrations were higher in CC vs. S recipients: 164 vs. 94 fmols/10(6) PBMCs for weeks 0-12, and 146 vs. 94 fmols/10(6) PBMCs for weeks 12-22. 100% (9/9) of CC recipients vs. 57% (4/7) of S patients had CD4 R (p is less than 0.05) for weeks 0-12; CD4 % increase was greater (33 vs. 5, p is less than 0.05) in CC vs. S patients. After crossover, the % change in CD4 for weeks 12-24 was 20 vs. -0.7 during CC and S therapy, respectively. For patients with NR compared with R: CD4 % change was -18 vs. 30 (p is less than 0.05); HIV-RNA was -0.22 vs. -0.56 log; and ZDV-TP was 26 vs. 158 fmols/10(6) PBMCs (p is less than 0.05). The % change in CD4 count was related to ZDV-TP concentrations (Emax model, r(2)=0.47), but not plasma; the 50% effect concentration ([approx] 10% increase) was 29 fmols/10(6) PBMCs. These findings support the theory that intracellular concentrations are a more precise determinant of anti-HIV effect, and suggest that achieving a certain threshold concentration may reduce the heterogeneity in clinical response. Supported by: NIAID RO1 AI33835 and MO1 RR00400
Keywords: AEGIS, HIV, Zidovudine, Thymine Nucleotides, Anti-HIV Agents, CD4 Lymphocyte Count, Reverse Transcriptase Inhibitors, HIV Infections, Polyphosphates, HIV Protease Inhibitors, HIV-1 Reverse Transcriptase, Antigens, CD4, 3'-azido-3'-deoxythymidine 5'-triphosphate, thymidine 5'-triphosphate, triphosphoric acid, Human, AIDS
