The Safety and Effectiveness of Zidovudine Plus Lamivudine, Used With and Without 1592U89, in HIV-1 Infected Children Who Have Taken Anti-HIV-1 Drugs

A Double-Blind, Randomized, Multicenter Trial to Evaluate the Safety and Efficacy of the Combination of 1592U89/Zidovudine (ZDV)/Lamivudine (3TC) Versus the Combination of Zidovudine (ZDV)/Lamivudine (3TC) in HIV-1 Therapy-Experienced Pediatric Patients.

To compare the safety, tolerance, durability of the viral load response and the antiviral activity of the 1592U89/zidovudine(ZDV)/lamivudine (3TC) regimen vs. ZDV/3TC regimen. To determine the clinical efficacy of the two regimens as measured survival, disease progression, weight growth velocity, and neuropsychological or neurological changes. To assess the development of viral resistance and relative pharmacokinetics associated with each regimen.

Patients are randomized to receive blinded treatment with ZDV/3TC alone or in combination with 1592U89, orally for 16 weeks. If after the 16-week period certain criteria are met, patients may have the option to switch to open-label treatment for the remainder of the study period.

Inclusion Criteria

Concurrent Medication:

Allowed:

• Intravenous immunoglobulin G, erythropoietin, G-CSF and GM-CSF.
• Opportunistic infection prophylaxis.

Patients must have:

• HIV-1 infection documented by:

< 18 months of age:

• one positive viral test culture and one other positive viral test (culture, PCR, p24 antigen, or Immune Complex Dissociation p24 antigen) on two different specimens.

>= 18 months of age:

• two positive viral tests as stated above, one or both of which may be determined by a federally documented ELISA and confirmed by Western blot or Indirect Fluorescent Antibody test.
• Any of the CDC Categories:
• 1, 2, 3, and N, A, B, and C of the 1994 Revised Classification System for HIV Infection in Children Less than 13 Years of Age.
• CD4+ count >= 15% within 14 days prior to study drug administration.
• No active or ongoing AIDS-defining opportunistic infection that precludes absorption of study drug or observation of a study parameter.
• Signed, informed consent from parent or legal guardian for patients under 18 years of age.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions or symptoms are excluded:

• Serious bacterial infection that precludes absorption of study drug or observation of a study parameter.
• Documented hypersensitivity to a nucleoside analog.
• Co-enrollment in certain opportunistic infection protocols is not exclusionary if approval is obtained.
• Malignancy.
• Life-threatening infection or other chronic disease that may compromise patient safety.
• Grade 3/4 clinical or laboratory toxicity or current grade 2 or higher pancreatic amylase or lipase toxicity as defined by the ACTG Toxicity Tables within 14 days prior to study entry.

Concurrent Medication:

Excluded:

• Other anti-HIV therapy.
• Probenecid.
• Biologic response modifier (unless listed under included concurrent medication) and megestrol acetate.
• Human growth hormone.
• Immunomodulators and cytotoxic chemotherapeutic agents.
• Systemic corticosteroids > 14 days without approval.
• Investigational agents.

Concurrent Treatment:

Excluded:

Radiation therapy.

Patients with the following prior conditions are excluded:

• History of clinically relevant pancreatitis or hepatitis within the past 6 months.
• Participation in a vaccine trial.

Prior Medication:

Excluded:

• Protease inhibitor therapy within 2 weeks prior to randomization.
• Interleukins or interferons within 30 days prior to study drug administration.
• Investigational drugs within 14 days prior to randomization.
• HIV vaccine dose within past 30 days.

Required:

> 12 weeks prior antiretroviral therapy and unchanged therapy 12 weeks prior to screening.