A Study of Azidothymidine in HIV-Infected Children
Condition: Encephalopathies; HIV Infections
MeSH terms: Infections; HIV Infections; Acquired Immunodeficiency Syndrome; Brain Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      AMENDED 07/07/93: To evaluate whether continuous infusion AZT will impact neurodevelopmental
      deficits associated with HIV infection or alter rate of encephalopathy progression in
      children who have failed to improve or shown progression of these deficits despite optimal
      AZT therapy.

      AMENDED: To assess whether didanosine (ddI) will be better tolerated than AZT administered by
      either continuous intravenous delivery or oral administration (ddI arm removed per amended
      version).To determine whether ddI will achieve comparable clinical efficacy as the continuous
      intravenous route of delivery of AZT, and to assess whether either or both of these regimens
      are superior to that achieved with an intermittent AZT dosage schedule. To determine whether
      there are differences in patient or parent (guardian) compliance between the three treatment
      regimens. Original design: To determine whether the pharmacokinetic profile (bloodstream
      levels) of zidovudine (AZT) influences its effectiveness on HIV infection in children. That
      is, the study seeks to find out whether there is a difference in the effect of AZT when given
      as a continuous intravenous infusion (and, if available, an oral sustained release dose)
      compared to an intermittent (not continuous) dose given orally every 6 hours. The study also
      plans to determine (1) whether there are differences in the tolerance and side effects
      associated with AZT when given on an intermittent schedule as opposed to a steady-state
      schedule; (2) the extent of variation from patient to patient in AZT levels and whether the
      plasma and cerebrospinal fluid levels of AZT are related to the degree of therapeutic
      effectiveness; and (3) whether there are differences in the response of children who acquired
      HIV infection perinatally (just before, during, or just after the time of birth) versus those
      who acquired HIV infection by transfusion.

      One of the most serious effects of HIV disease in children is neuropsychological
      deterioration (relating to mental and nervous system functioning). This complication affects
      the vast majority of HIV infected children. A previous study of continuous intravenous
      administration of AZT in pediatric patients with HIV infection showed consistent and dramatic
      improvements of symptoms in all patients that had shown neurodevelopmental deficits or
      abnormalities. These improvements were seen within 3 to 4 weeks after AZT treatment was
      started. Neurodevelopmental improvements have been sustained on AZT, usually showing steady
      improvement which, in some patients, was associated with restoration of pre-HIV intellectual
      and neurological function. This study also showed an increase in the IQ scores of children
      receiving continuous infusion of AZT who did not have overt clinical evidence of
      encephalopathy (disease of the brain). Thus changes in cognitive function may be among the
      earliest signs of AIDS encephalopathy and underscores the need to start therapies that will
      treat the central nervous system in patients who appear to be clinically intact. A study
      comparing continuous infusion to intermittent dosing of AZT showed a significant increase in
      IQ scores for those children receiving the continuous dose compared to those treated with the
      intermittent schedule. Although a portable infusion pump allows patients to receive
      continuous infusion of AZT, a sustained release oral formulation that could provide a
      continuous release of AZT into the bloodstream would be highly desirable.
    

Detailed description: 
      One of the most serious effects of HIV disease in children is neuropsychological
      deterioration (relating to mental and nervous system functioning). This complication affects
      the vast majority of HIV infected children. A previous study of continuous intravenous
      administration of AZT in pediatric patients with HIV infection showed consistent and dramatic
      improvements of symptoms in all patients that had shown neurodevelopmental deficits or
      abnormalities. These improvements were seen within 3 to 4 weeks after AZT treatment was
      started. Neurodevelopmental improvements have been sustained on AZT, usually showing steady
      improvement which, in some patients, was associated with restoration of pre-HIV intellectual
      and neurological function. This study also showed an increase in the IQ scores of children
      receiving continuous infusion of AZT who did not have overt clinical evidence of
      encephalopathy (disease of the brain). Thus changes in cognitive function may be among the
      earliest signs of AIDS encephalopathy and underscores the need to start therapies that will
      treat the central nervous system in patients who appear to be clinically intact. A study
      comparing continuous infusion to intermittent dosing of AZT showed a significant increase in
      IQ scores for those children receiving the continuous dose compared to those treated with the
      intermittent schedule. Although a portable infusion pump allows patients to receive
      continuous infusion of AZT, a sustained release oral formulation that could provide a
      continuous release of AZT into the bloodstream would be highly desirable.

      AMENDED 07/07/93: Children with progressive encephalopathy who have received a minimum of 3
      months of oral or intermittent AZT or who have failed to improve following 6 months of
      optimal AZT will receive continuous infusion AZT via a portable infusion pump.

      AMENDED: The oral sustained release has been dropped and is now oral ddI. Added has been a
      planned stratification for randomization for patients who received any antiretroviral therapy
      4 or more weeks prior to study entry. The informed consent was modified to reflect ddI
      toxicities from adult studies. Computerized Tomography radiation dosimetry is now included.

      AMENDED: Dropping the ddI component and open only to children with encephalopathy meaning
      they are losing milestones, this is equal to a P2 CDC rating . Testing the difference in
      intermediate vs continuous AZT. 12/1990. Original design: Children are first evaluated for
      randomization according to whether they have or do not have evidence of neurodevelopmental
      deficits at the time of the initial pretreatment evaluation. Patients are assigned to 1 of 3
      groups, to receive AZT (1) by continuous infusion; (2) by oral, intermittent (every 6 hours)
      dosing; or (3) by oral sustained-release dosing. If the oral sustained-release formulation is
      not available when this study begins, it will begin with only the first 2 groups. The
      sustained release preparation will be evaluated as soon as it is available. Patients will be
      tested to measure physical or biological improvement in neurodevelopmental function.
    

Intervention name(s): Zidovudine; Didanosine
Intervention type(s): Drug; Drug
Intervention MeSH terms: Zidovudine; Didanosine
Primary purpose: Treatment
Keywords: Central Nervous System Diseases; Acquired Immunodeficiency Syndrome; Zidovudine