The purpose of this ACTG protocol is to examine, in HIV-seropositive patients, the safety and antiretroviral activity of hydroxyurea alone and in combination with DDI compared with DDI alone. The primary hypotheses are 1) that hydroxyurea will be safe and well tolerated at the two doses that will be examined alone and in combination with ddI and 2) that there will be a more favorable antiviral effect when ddI and hyroxyurea are used in combination as compared to either one used as monotherapy. This will be a 24 week, phase I/II, randomized, double-blind, dose-ranging study in HIV-infected adults, whose CD4 lymphocyte count is between 200-500. There will be two 12-week treatment periods and 5 study arms. Pharmacokinetic monitoring will be performed on all subjects. Specimens for quantitative HIV RNA levels, CD4+/CD8+ lymphocyte counts, and dATP measurements will be obtained on weeks 2, 4, 8, 12 and 24. The initial 12-week portion of the study is designed to gather data that will be used to perform an antiretroviral activity analysis. The five study arms are 1) hydroxyurea placebo qd plus ddI 200 mg bid, 2) hydroxyurea 1000 mg qd plus ddI placebo bid for 4 weeks, then hydroxyurea 1000 mg qd plus ddI 200 mg bid, 3) hydroxyurea 1500 mg qd plus ddI placebo bid for 4 weeks, then hydroxyurea 1500 mg qd plus ddI 200 mg bid, 4) hydroxyurea 1000 mg qd plus ddI 200 mg bid, and 5) hydroxyurea 1500 mg qd plus ddI 200 mg bid. The principal comparison used in the antiretroviral activity analysis will be between the hydroxyurea + ddI combination therapy arms and the ddI monotherapy arm. The Week 8 plasma HIV RNA levels will be used in this comparison. After the completion of Week 12, subjects on combination therapy will remain on their current therapy; and subjects on ddI monotherapy will remain on ddI and have hydroxyurea added at an assigned dose (1:1 randomization) of 1000 mg qd or 1500 mg qd. Randomization of subjects in the ddI monotherapy arm to low or high dose hydroxyurea + ddI combination therapy at Week 12 will have occurred at study entry. Therefore, all subjects will receive combination therapy during Weeks 12 to 24, with half receiving hydroxyurea at a dose of 1000 mg qd and half receiving hydroxyurea at a dose of 1500 mg qd. During Weeks 12 to 24, all study medication will be open label with no placebos. The study is ongoing and treatment arms remain blinded, therefore study conclusions and significance can not yet be discussed.
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