• The Effect of Hydroxyurea (HU) on Intracellular Deoxy- and Dideoxynucleoside Triphosphate Ratios in Naive Subjects Receiving ZDV, ABC, 3TC+- NVP over 48 Weeks -- CHARM Phosphorylation Substudy (Poster 747)
  Authored by D. Back, P. Hoggard, A. Maherbe, R. Wood, S. Kwen, S. Sales, S. Khoo, C. De Vries, and J. Gould
  View the original abstract

All nucleoside analogs are pro-drugs. They have to enter the cell and get phosphorilated and be converted to triphosphates in order to work. Once that has happened, the reverse transcriptase of HIV takes them instead of the "real" triphosphate, and the DNA that is made cannot continue to grow. Hydroxyurea is a ribonucleotidese reductase inhibitor. What it does is reduce the amount of "real" triphosphate (dATP), so the ratio between "real" triphosphates and the nucleoside analog triphosphates (mainly ddI) is altered, so the reverse transcriptase is more likely to get one of the nucleoside triphosphates and screw up HIV viral replication, which is the goal here. At least that is what we know from in vitro studies. Hydroxyurea probably also plays an immunomodulator role that may be related to its antiviral activity when used as part of combination regimens.

This was a 24-patient study. These patients were enrolled in a larger trial comparing a triple-nucleoside-analog regimen of Trizivir (ZDV+3TC+abacavir) with or without nevirapine or hydroxyurea. The investigators wanted to know if the addition of hydroxyurea could affect the phosphorylation of the nucleosides used in the trial.

In general, it did not happen, which suggests that hydroxyurea does not increase the antiviral activity of this combination regimen (if this is the mechanism of action of this drug). However, there were two unexpected findings of the trial that caught my eye. One finding was that, in the arm receiving abacavir, there seemed to be an increased ratio of abacavir triphosphate vs. dGTP, something that the authors could not explain, and, of course, neither can I (that effect would be something similar to what mycophenolic acid does to abacavir triphosphate levels). The second unexpected finding was that the levels of dATP did not change a lot after the administration of hydroxyurea, which questions the whole issue of how hydroxyurea works.

Hydroxyurea has become less "fashionable" nowadays. After study A5025 (see abstract 456, 7th CROI, 2000) almost nobody wants to talk about it anymore. There is a current trial in the ACTG using hydroxyurea, which is struggling. Two years ago, when the "Berlin" patient was reported (a patient in Berlin who remained undetectable after stopping a regimen that contained hydroxyurea) everybody wanted to take this drug, but now it is like a bad poison.

HU is a monument to the huge "pendulum" swings that characterize the whole field of HIV. I really think the truth about hydroxyurea is somewhere in the middle. I also think it deserves to be looked at more carefully in trials, however that is something very unlikely to happen.