Effect of hydroxyurea and dideoxyinosine on intracellular 3'-deoxyadenosine-5'-triphosphate concentrations in HIV-infected patients.

Author(s): Bakshi RP, Hamzeh F, Frank I, Eron JJ Jr, Bosch RJ, Rosenkranz SL, Cramer YS, Ussery M, Flexner C

Affiliation(s): Division of Clinical Pharmacology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, USA.

Publication date & source: 2007-11, AIDS Res Hum Retroviruses., 23(11):1360-5.

Publication type: Comparative Study; Multicenter Study; Randomized Controlled Trial; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Hydroxyurea (HU) significantly enhances the antiretroviral effects of the adenosine analog reverse transcriptase inhibitor dideoxyinosine (ddI). This is believed to be due to a reduction in intracellular de-oxyadenosine triphosphate (dATP) concentrations resulting from HU-mediated inhibition of ribonucleotide reductase (RnR). The effect of combined HU-ddI treatment on intracellular dATP pools in vivo has not been examined. We measured intracellular dATP concentrations in peripheral blood mononuclear cells (PBMCs) from 69 HIV-infected patients receiving 1000 or 1500 mg HU daily for 14 days, 200 mg ddI twice daily for 14 days, or a combination of the two drugs. Median intracellular dATP concentrations decreased from base-line to day 14 by 46% in the ddI + 1000 mg HU arm and by 62% in the ddI + 1500 mg HU arm. When compared to the HU monotherapy arms, these changes proved statistically significant (p = 0.018; stratified Wilcoxon rank-sum test). These findings support reduced intracellular dATP as the mechanism of ddI-HU synergistic activity, and indicate that changes in intracellular nucleotides contribute to HU activity and toxicity in patients. Since a significant reduction in dATP was measurable only when ddI was combined with HU, the antiretroviral activity of ddI may be more complex than previously assumed.