Patients receiving combination antiretroviral therapy with indinavir, zidovudine, (or stavudine) and lamivudine experience sustained viral suppression for periods of two years or more. In these patients, HIV RNA cannot be detected in the plasma, but virus can be cultured in vitro from long lived latently infected memory CD4 cells. The ACTG 343 trial demonstrated that a certain level of antiviral potency must be maintained to sustain viral suppression. Nearly one quarter of individuals who discontinued either zidovudine (or stavudine) and lamivudine or indinavir after achieving viral suppression with all three drugs experienced prompt rebound of HIV RNA levels in the plasma. Paradoxically, those individuals who had greater increases in CD4 cells with triple therapy were at the higher risk for loss of viral suppression on less intensive therapy. Hydroxyurea (HU) inhibits ribonucleotide reductase, thereby diminishing intracellular nucleosides and augmenting the activity of nucleoside analogues such as ddI. HU also inhibits the S phase of the cell cycle and can potentially reduce cellular activation in the cell pool that is susceptible to HIV infection. Previous studies have found that when HU is administered alone, there is no antiviral effect. When HU is administered with either ddI or ddI and d4T, HIV RNA levels in the plasma diminish more than that of ddI and HU and for this reason, ddI and d4T will be evaluated in this study.
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