Hydroxyurea is an antineoplastic agent which inhibits DNA synthesis. In vitro hydroxyurea decreases levels of a cellular competitor of didanosine (ddI) and synergizes the antiretroviral effect of the drug. Hydroxyurea also directly inhibits replication of HIV by lowering concentrations of intracellular deoxynucleotides essential for viral DNA synthesis. Initial clinical trials of hydroxyurea in HIV-infected adults have shown promising results. The objectives of the present study are: (1) to assess the steady-state pharmacokinetic features, tolerance, and safety of orally administered hydroxyurea, added to existing therapy which includes ddI and/or stavudine (d4T), in HIV-infected children; and (2) to evaluate addition of hydroxyurea to existing antiretroviral therapy, with respect to changes from baseline in plasma HIV RNA concentrations, total lymphocyte counts, and CD4+ lymphocyte counts. This will be a 48-week open, dose-escalating study of hydroxyurea added to existing antiretroviral therapy which includes didanosine and/or stavudine. Approximately 15 HIV-infected children aged 12 months to 16 years will be enrolled. Children will be evaluated clinically and with laboratory studies at screening, entry, and every four weeks thereafter. A four-hour pharmacokinetic study will be conducted on study day one; single timed blood samples will be collected subsequently during routine clinic visits for determination of pharmacokinetic parameters by sparse sampling methodology. Temporary interruption of dosing will be outlined for hydroxyurea-associated grade 3 toxicities. Permanent discontinuation of dosing will be prescribed for drug-associated persistent grade 3 or grade 4 toxicities.
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