A Phase I /II Study of the Protease Inhibitor Indinavir (MK-0639) in Children With HIV Infection

This is a phase I/II study to determine the safety and tolerance of the protease inhibitor indinavir (MK-0639), alone and then in combination with HIV reverse transcriptase inhibitor therapy in children with HIV infection. Indinavir sulfate (the capsule formulation) has been shown to have potent antiviral activity and an acceptable safety profile in adults. HIV-infected children who have not received prior antiretroviral therapy, and children who have become refractory to prior therapy, or who have experienced toxicity to prior therapy, will be included. In addition, we will explore viral and CD4 cell kinetics before starting therapy and following exposure to antiretroviral agents.

The study will be conducted in three parts.

1. In order to help interpret the antiviral activity of indinavir, the virologic and immunologic profile of children will be studied within 2 weeks prior to starting the therapeutic part. For children who have never been treated, this will be before the initiation of any antiretroviral therapy and for children who have already received antiretroviral therapy, this will be done during the initial "wash-out" phase that is routinely interposed between two different treatment regimens.
2. The initial 16 weeks of therapy will then evaluate the toxicities, pharmacokinetics, and preliminary efficacy of single drug therapy with indinavir.
3. Subsequently, all children who are able to tolerate the combination of zidovudine and lamivudine (i.e., have no prior history of intolerance to one of these two agents) will be treated with these two reverse transcriptase inhibitors in addition to the protease inhibitor indinavir. Zidovudine and lamivudine will be added after 16 weeks at a fixed dosage. Toxicity, pharmacokinetics, and preliminary efficacy of indinavir will also be investigated after combination therapy. All patients who wish to remain in this study after 96 weeks of therapy and who do not meet off study criteria will be permitted to receive extended treatment with their current indinavir combination therapy for an additional 48 weeks. The study will determine the pharmacokinetic profile of indinavir, given as single drug or in combination with zidovudine and lamivudine. It will assess the preliminary antiviral and clinical activity by monitoring clinical status, viral burden in plasma, and markers of immunologic status. Based on safety and preliminary efficacy results from studies performed in adults, we will study three dose levels which are expected to result in drug levels above the IC95 of HIV-1 for all or most of the dosing interval.