The Safety and Effects of 1592U89 Used Alone or in Combination With Other Anti-HIV Drugs in HIV-Infected Infants and Children

On the basis of the preclinical and clinical studies, 1592U89 appears to be a promising agent for treatment of HIV infection in children, either as an alternative to currently employed agents, or in combination therapy regimens. A liquid formulation of the drug is available; thus concurrent development of 1592U89 for children and adults is possible.

In part 1, patients will receive 1592U89 monotherapy for 12 weeks. Patients will be assigned initially to a low dose of 1592U89 (Dose A). Those patients who tolerate the drug for at least six weeks without a toxicity of grade 3 or above attributable to study drug will have their 1592U89 dose increased (Dose B). If none of those patients experience a life threatening event attributable to study drug, subsequent enrollees will be assigned initially to Dose B. In part 2, each participant will be assigned randomly (1:1:1:1) within their age and Part 1 regimen stratum to one of the four agents: Zidovudine (ZDV), Stavudine (d4T), Didanosine (ddI) or Lamivudine (3TC) in combination with 1592U89.

Inclusion criteria

Concurrent Medication:

Allowed:

• IVIG.
• Erythropoietin, granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor (for management of hematologic toxicity).

Patients must have:

• Documented HIV-1 infection.
• Laboratory evidence of immunosuppression or symptomatic HIV disease.
• Parent or legal guardian able and willing to provide signed informed consent.

Prior Medication: Required:

• HIV infected infants and children will be eligible for the trial if they have received greater than 56 days of previous antiretroviral therapy.

NOTE:

• Those children who participated in the single dose phase I study of 1592U89 and satisfy all other criteria for inclusion may have received <= 56 days of previous antiretroviral therapy.

Exclusion criteria

Co-existing Condition:

Patients with the following symptoms and conditions are excluded:

• Grade 3 or greater abnormalities in any toxicity monitoring laboratory tests at baseline.
• Presence of an acute opportunistic infection requiring therapy at the time of enrollment.
• Intractable or chronic diarrhea or vomiting.

Concurrent Medication:

Excluded:

• Chemotherapy for active malignancy.
• Concurrent use of antiretroviral agents other than those provided by the study, biologic response modifiers, human growth hormone, systemic corticosteroids (>= 14 days duration), probenecid, I.V. pentamidine, immunomodulators (other than intravenous immunoglobulin), or other investigational drugs.

Patients with any of the following prior conditions or symptoms are excluded:

• History of intolerance to any of the study drugs.