ADEFOVIR DIPIVOXIL, INDINAVIR, ZIDOVUDINE, LAMIVUDINE IN VARIOUS DOSE

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This protocol describes a stratified, randomized, open-label study of the safety and efficacy of adefovir dipivoxil with indinavir as quadruple therapy in combination with zidovudine and lamivudine or as triple combination administered with either zidovudine or lamivudine or stavudine for a maximum of 48 weeks in the treatment of HIV-infected patients with CD4 cell counts > or = 100/mm3 and a HIV-1 RNA baseline copy number > or =5,000 copies/mL. There are two phases of enrollment planned for this study. In phase I, approximately 130 patients will be randomized to one of five treatment regimens in a 1:1:1:1:1 ratio. Patients will be randomized to adefovir dipivoxil and indinavir and zidovudine and lamivudine or to adefovir dipivoxil and indianvir and a nucleoside inhibitor (randomly assigned to receive zidovudine, lamivudine or stavudine) or to triple combination therapy with indinavir, zidovudine and lamivudine. Additionally, a daily dose of L-carnitine 500 mg is administered to all patients randomized to an arm containing adefovir dipovoxil. In the second phase, additional patients will be randomized to one of three treatment regimens in approximately a 2:2:1 ratio to a sample size of 100, 100, and 50 in the arms containing adefovir dipivoxil and indinavir and lamivudine or to zidovudine and indinavir and lamivudine or to adefovir dipivoxil, indinavir, zidovudine and lamivudine, respectively. As in the first phase, a daily dose of L-carnitine 500 mg will be administered to all patients randomized to the arms containing adefovir dipivoxil. Treatment will be for an intended duration of 48 weeks. Plasma HIV 1 RNA and CD4 cell counts will be measured to determine anti-HIV activity. Physical examination and laboratory tests will be used to monitor patient safety. Patients with plasma HIV-1 RNA concentrations below the lower limit of quantification at week 20 will be eligible to continue on study treatment for a total of 48 weeks. Patients with plasma HIV-1 RNA concentrations that are not sustained below the lower limit of quantification (after an initial response) and confirmed by a second plasma HIV-1 RNA concentration drawn at least 14 days later will be discontinued. In addition, patients unable to tolerate any of the assigned study medication of full dose will also be discontinued at the week 24 visit.