A Phase II Rolling Arm Master Protocol (PRAM) of Novel Antiretroviral Therapy in Stable Experienced HIV- Infected Children; PRAM-1: ZDV+3TC vs. d4T+Ritonavir vs. ZDV+3TC+Ritonavir; PRAM-1, Step 2: d4T+Nevirapine+Ritonavir; PRAM-1, Step 3: d4T+Indinavir vs. ZDV+3TC+Indinavir

For PRAM-1: Evidence supports combination therapy with 2 or more antiviral agents as beneficial in the long-term management of HIV. The possibility exists that combination therapy may result in a synergistic or additive activity over a prolonged period of time. Also hypothesized is that the development of resistance to individual agents will be developed if viral replication is significantly decreased.

AS PER AMENDMENT 10/20/97: For PRAM-1, Step 2: Interim analysis at 12 weeks on PRAM-1 indicates that the proportion of children reaching undetectable RNA levels on the ZDV + 3TC arm is significantly less than the other two arms. The protocol, therefore, has been modified (Step 2) to permit children in the ZDV + 3TC arm with RNA copy number >= 10,000 the opportunity to change to a novel therapeutic regimen (d4T + nevirapine + ritonavir).

The Master PRAM is a Phase II, multicenter, randomized, open-label trial of a standard therapeutic regimen in current use versus experimental therapies administered over 48 weeks. It is designed to allow new therapeutic arms to be studied as "rolling screens" through multiple generations of PRAM. Each PRAM generation compares 2 novel therapeutic arms with a linking arm that allows for an indirect comparison of included therapies. Once accrual to PRAM-1 is complete a new treatment comparison opens for accrual (PRAM-2). The linking arm to be used in PRAM-2 is decided by the Pediatric Primary Scientific Committee. PRAM-2 will continue to accrue patients while PRAM-1 patients continue therapy.

For PRAM-1: This study compares the following three treatment arms:

Arm I: ZDV plus 3TC Arm II: d4T plus ritonavir Arm III: ZDV plus 3TC plus ritonavir. Prior to randomization to one of the three arms, patients are stratified based on CD4 percents: either less than 15% or greater than or equal to 15%. The first 8 patients randomized to Arms II and III participate in a real-time Phase I pharmacokinetic study (16 patients total). After the first 45 (15 per arm) patients entered are followed for 24 weeks, an interim analysis is done. Patients are treated for 48 weeks [AS PER AMENDMENT 1/5/98: 72 weeks].