A Study of Ritonavir (an Anti-HIV Drug) in HIV-Positive Infants and Children

A Phase I/II Study of Ritonavir Therapy in HIV-1 Infected Infants and Children

The study examines the safety and effectiveness of ritonavir (an anti-HIV drug), alone and in combination with other anti-HIV drugs, in HIV-positive children under 2 years of age. This study will also determine the most effective doses of ritonavir for future pediatric HIV studies.

Infants infected with HIV by their mothers experience faster disease progression than adults or older children. Treatment with anti-HIV drugs administered at an early age may slow disease progression in infant populations.

As a group, vertically infected children experience more rapid disease progression than children infected at an older age or adults. The early administration of potent antiretroviral regimens might significantly impact the course of vertical HIV-1 infection.

Infants and children are stratified by age, representative of the developmental differences related to drug metabolism (Group I: at least 6 months - 2 years, Group II: 3-6 months, Group IIIA: 1 month - 10 weeks, IIIB: 1 month - less than 3 months). Within each age group there will be two possible dosage cohorts. All age groups will be enrolled simultaneously into dosage Cohort I, at the initial drug dosage. Progression to Cohort II (at a higher or lower drug dosage) will be decided according to safety, tolerance or viral load in Cohort I. All therapy for Group I/II, whether in Cohort I or II, will be introduced as follows: single dose of ritonavir on Day 0, ritonavir monotherapy through Day 7 AM and combination therapy from Day 7 PM through Week 104. All therapy for Group IIIA & IIIB, whether in Cohort I or II, will be introduced as follows: single dose of ritonavir on Day 0 AM and transition to combination therapy Day 0 PM through Week 104. NOTE: Progression to combination therapy for Group IIIA infants is dependent upon the results of the single-dose ritonavir pharmacokinetics (PK). If the patient is no longer at least presumed to be HIV-infected, he/she will be discontinued from the study. Replacement infants, who will not receive the single dose of ritonavir, will be acquired from Group IIIB infants; new infants that are either presumed HIV infected or have already been shown to be HIV-infected. Clinical evaluations are conducted and blood and urine samples collected regularly during the treatment period in order to quantify HIV-1 levels and determine body chemistries. Pharmacokinetic studies require additional blood sampling up to Week 16. [AS PER AMENDMENT 6/30/98: Pharmacokinetics data from Cohort I showed that the proposed Cohort II starting dose was too low. The dose for Cohort II is now increased. All subjects in Groups I, II, and III will begin combination therapy on Day 0 at the increased dose.] [AS PER AMENDMENT 3/13/00: The study has been extended for an additional 104 weeks, provided the patient's viral load is undetectable (below 400 copies/ml) at the end of the initial study period. While on the treatment extension, patients must continue their current schedule for study drug administration and completion of study visits.]

Inclusion Criteria

Children may be eligible for this study if they:

• Are HIV-positive. (Infants under 3 months old presumed to be HIV-positive are eligible to participate in the single-dose phase of the study.)
• Are between the ages of 4 weeks and 2 years (consent of parent or guardian required).

Exclusion Criteria

Children will not be eligible for this study if they:

• Have an opportunistic (AIDS-related) infection within 2 months of study entry.
• Are allergic to 3TC and/or ZDV.
• Have received anti-HIV drugs for 6 to 12 weeks.
• Have any infections requiring treatment.
• Are experiencing wasting (significant weight loss).
• Have any malignancies (cancer).
• Have certain immune diseases, are being fed through a tube, or have HIV-related encephalopathy (a degenerative disease of the brain).