Comparison of New Anti-HIV Drug Combinations in HIV-Infected Children Who Have Taken Anti-HIV Drugs

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: To evaluate zidovudine (ZDV) + lamivudine (3TC) vs. stavudine (d4T) + ritonavir vs. ZDV + 3TC + ritonavir with respect to the change in plasma HIV-1 RNA copy number from baseline to 48 weeks [AS PER AMENDMENT 1/5/98: 72 weeks; AS PER AMENDMENT 7/17/98: 48 weeks] in stable HIV-infected children with >= 16 weeks of prior continuous antiretroviral therapy. To evaluate the safety and tolerance of ZDV + 3TC vs. d4T + ritonavir vs. ZDV + 3TC + ritonavir based upon laboratory and clinical toxicities.

AS PER AMENDMENT 10/20/97: For PRAM-1, Step 2: To evaluate d4T + nevirapine + ritonavir with respect to change in plasma HIV-1 RNA copy number from baseline to 48 weeks in children who have received at least 12 weeks of therapy on the PRAM-1 ZDV/3TC arm and have over 10,000 viral copies at weeks 12, 24, or 36. To evaluate the safety and tolerance of d4T + nevirapine + ritonavir based upon laboratory and clinical toxicities. [AS PER AMENDMENT 10/23/98: To evaluate safety and tolerance of a switch from d4T + ritonavir vs. ZDV + 3TC + ritonavir to d4T + indinavir vs. ZDV + 3TC + indinavir in stable, HIV-infected children with RNA values <= 10,000 copies/ml.] 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).

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].

AS PER AMENDMENT 10/20/97:

PRAM-1, Step 2:

Patients initially assigned to Arm I (ZDV plus 3TC) who have RNA values greater than 10,000 copies at week 12, 24, or 36 are assigned to switch protocol treatment to d4T + ritonavir + nevirapine. Patients may enroll in Step 2 no later than week 38 of PRAM-1. [AS PER AMENDMENT 1/5/98: Patients initially assigned to Arm 1 with viral load greater than 100,000 copies may also switch to Step 2 or discontinue therapy. Patients originally assigned to Arms I or II with viral load greater than 10,000 may continue their current drugs or discontinue study therapy; those with viral load greater than 100,000 should discontinue study drugs.] [AS PER AMENDMENT 7/17/98: PRAM-1 has been extended to permit long-term follow-up of clinically stable, HIV-infected children for a total of 120 weeks. Patients still on initial treatment assignment for all three treatment arms are eligible for this extension, as are children from PRAM-1, Step 2. Step 2 is now closed to enrollment. Patients on 3TC/ZDV who reach virologic failure must discontinue study therapy].

[AS PER AMENDMENT 10/23/98: PRAM-1, Step 3: This amendment substitutes indinavir (IDV) capsules for ritonavir capsules in PRAM-1. The regimens will switch from d4T plus ritonavir versus ZDV plus 3TC plus ritonavir to d4T plus IDV versus ZDV plus 3TC plus IDV. All patients will be followed for 48 weeks. Patients eligible for this change in regimens are those taking ritonavir capsules who have RNA values less than or equal to 10,000 copies/ml (as demonstrated by the most recent viral load test) after at least 72 weeks on PRAM-1, Step I. Twelve patients with RNA values less than or equal to 400 copies/ml will immediately join the study; 6 will receive d4T plus IDV and 6 will receive ZDV plus 3TC plus IDV. Additional patients may be added based on toxicity and viral load results. A total sample size of 53 evaluable patients (37 with RNA values less than or equal to 400 copies/ml and 16 with RNA values of greater than 400 to 10,000 copies/ml) is anticipated. PRAM-1 Step 2 patients are not eligible for Step 3. PRAM-1, Step 2 patients currently taking liquid ritonavir should continue their study drug; those taking ritonavir capsules will switch to liquid ritonavir or go off study.

Inclusion Criteria

Concurrent Medication:

Allowed:

• IVIG and opportunistic infection prophylaxis will be allowed.
• Erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony- stimulating factor (GM-CSF) will be allowed for the management of hematologic toxicity.
• Treatment with trimethoprim is allowed at the discretion of the principal investigator.

Patients must have:

• Laboratory evidence (at least 2 viral tests) of HIV-1 infection.
• Clinical and immunological stability [maintained CDC category 1 or 2 immunologic status for past 4 months and no new CDC category (diagnosis within the past year)].
• Patients must have received continuous antiretroviral therapy for the past 16 weeks (missing no more than 6 weeks of therapy during the previous 16 weeks).

AS PER AMENDMENT 10/20/97: For PRAM-1, Step 2:

• Viral load >= 10,000 and < 100,000 copies/ml at week 12, 24, or 36 in children initially assigned to Arm I (ZDV + 3TC) of PRAM-1 and currently on study.

Prior Medication:

Required:

• Patients must have received continuous antiretroviral therapy for the past 16 weeks.

Allowed:

• Patients who have received immunomodulator therapy as part of perinatal clinical trials or in trials for HIV- exposed infants are eligible.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Current grade 3/4 clinical or laboratory toxicity and/or current grade 2 or higher amylase/lipase toxicity.
• Active opportunistic infection and/or serious bacterial infection.
• Current diagnosis of malignancy.

Concurrent Medication:

Excluded:

• Current antiretroviral therapy identical to any of the following regimens:
• ZDV + 3TC, d4T + ritonavir and ZDV + 3TC + ritonavir.
• Concurrent therapy with any other anti-HIV-1 therapy, biologic response modifiers (EPO, G-CSF and GM-CSF allowed), human growth hormone and megestrol acetate.
• Use of continuous systemic corticosteroids (>= 14 days duration) is not allowed.
• Medications that are incompatible with ritonavir.
• Probenecid and daily intravenous pentamidine.

[AS PER AMENDMENT 10/23/98: The following are excluded in patients receiving indinavir:

• terfenadine, astemizole, cisapride, rifampin, rifabutin, triazolam, ketoconazole, clarithromycin, carbamazepine, phenobarbital, phenytoin, calcium channel blockers, midazolam, and ergot derivatives.]

Patients with the following prior conditions and symptoms are excluded:

• Documented hypersensitivity to a therapy included in any of the treatment arms.

Prior Medication:

Excluded:

Investigational drug therapy within 2 weeks prior to randomization.

NOTE:

• Co-enrollment in ACTG 219, ACTG 220 and certain ACTG opportunistic infection protocols is allowed.