The Safety and Effectiveness of Zidovudine in the Treatment of HIV-Infected Children With Mild to Moderate Symptoms

A Multicenter Placebo-Controlled Trial To Evaluate the Safety and Efficacy of Oral Zidovudine in the Treatment of Children Infected With Human Immunodeficiency Virus With Mild to Moderate Symptoms (Including LIP)

To determine the safety and usefulness of zidovudine (AZT) for the treatment of children 3 months to 12 years of age. This study is designed to determine if children who are infected with HIV and who have a special type of lung disease called lymphocytic interstitial pneumonitis (LIP) or other early symptoms of HIV infection may derive benefit from treatment with AZT. It is hoped that this drug will prevent children from developing additional symptoms and infections and will help resolve already existing symptoms.

AZT has been shown in the laboratory to inhibit the infection of cells by HIV. AZT has been shown to decrease the mortality and the frequency of opportunistic infections in certain adult patients with symptomatic HIV infection. It is, therefore, likely that symptomatic HIV-infected children may also benefit from specific antiviral therapy.

Study Overview

• Status: Completed
• Conditions: HIV Infections
• Intervention / Treatment: Drug: Zidovudine

Detailed Description

AZT has been shown in the laboratory to inhibit the infection of cells by HIV. AZT has been shown to decrease the mortality and the frequency of opportunistic infections in certain adult patients with symptomatic HIV infection. It is, therefore, likely that symptomatic HIV-infected children may also benefit from specific antiviral therapy.

Children who participate in the study are evaluated at a hospital outpatient clinic and are under the care of a specialist in pediatrics. Of the children who participate in the study, half receive AZT syrup and half receive a placebo (sugar solution). The investigator does not know which medication each child receives as this is decided by a random process. The children take the medication in a strawberry-flavored clear syrup every 6 hours (4 times a day), for a period of 2 years or 104 weeks. The children are monitored on an outpatient basis while receiving therapy and the tests performed on admission to the study are repeated several times during treatment. Blood samples are obtained once a week for the first 4 weeks, every other week for the next 4 weeks, and then monthly until the end of the study. At certain sites, Cerebrospinal fluid (CSF) is collected by lumbar puncture every 52 weeks to evaluate infection involving the brain and nervous system. An independent committee reviews the data collected on the children every 6 months. The drug is stopped or the dose reduced if unacceptable side effects develop. AMENDED: As of August 7, 1989 the study blind was broken, the placebo arm discontinued and the study closed to accrual as of September 25, 1989. The 6 children enrolled in the study have been offered AZT.

• Study Type: Interventional
• Enrollment: 224
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Downey, California, United States, 902422814
      • Kaiser Permanente / UCLA Med Ctr
    • Long Beach, California, United States, 90801
      • Long Beach Memorial (Pediatric)
    • Los Angeles, California, United States, 900276016
      • Children's Hosp of Los Angeles/UCLA Med Ctr
    • Los Angeles, California, United States, 905022004
      • Harbor - UCLA Med Ctr / UCLA School of Medicine
    • Los Angeles, California, United States, 900951752
      • UCLA Med Ctr / Pediatric
    • Los Angeles, California, United States, 900593019
      • Martin Luther King Jr Gen Hosp / UCLA Med Ctr
    • Menlo Park, California, United States, 94025
      • Stanford Univ School of Medicine
    • Oakland, California, United States, 946091809
      • Children's Hosp of Oakland
    • San Diego, California, United States, 92103
      • UCSD Treatment Ctr
    • San Francisco, California, United States, 94143
      • Northern California Pediatric AIDS Treatment Ctr / UCSF
  • Florida
    • Miami, Florida, United States, 331361013
      • Univ of Miami School of Medicine
    • Miami, Florida, United States, 33136
      • Univ of Miami School of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Cook County Hosp
    • Chicago, Illinois, United States, 606143394
      • Chicago Children's Memorial Hosp
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane Univ School of Medicine
    • New Orleans, Louisiana, United States, 70112
      • Charity Hosp / Tulane Univ Med School
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Univ of Maryland at Baltimore / Univ Med Ctr
    • Baltimore, Maryland, United States, 212874933
      • Johns Hopkins Hosp - Pediatric
  • Massachusetts
    • Boston, Massachusetts, United States, 021155724
      • Children's Hosp of Boston
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Univ of Minnesota
  • New Jersey
    • Newark, New Jersey, United States, 071072198
      • Children's Hosp of New Jersey / UMDNJ - New Jersey Med Schl
  • New York
    • Bronx, New York, United States, 10465
      • Jack Weiler Hosp / Bronx Municipal Hosp
    • Elmhurst, New York, United States, 11373
      • City Hosp Ctr at Elmhurst / Mount Sinai Hosp
    • New York, New York, United States, 10016
      • Bellevue Hosp / New York Univ Med Ctr
    • New York, New York, United States, 10029
      • Mount Sinai Med Ctr
    • New York, New York, United States, 10037
      • Harlem Hosp Ctr
    • New York, New York, United States, 10003
      • Beth Israel Med Ctr / Pediatrics
    • New York, New York, United States, 10032
      • Columbia Univ Babies' Hosp
  • North Carolina
    • Durham, North Carolina, United States, 277103499
      • Duke Univ Med Ctr
  • Ohio
    • Columbus, Ohio, United States, 432052696
      • Columbus Children's Hosp
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 170330850
      • Milton S Hershey Med Ctr
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
    • Houston, Texas, United States, 77030
      • Hermann Hosp / Univ Texas Health Science Ctr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 months to 12 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

Concurrent Medication:

Allowed:

• Prophylaxis for Pneumocystis carinii pneumonia (PCP) in children with AIDS or CD4 cell count = or < 500 cells/mm3.

Children must demonstrate the following clinical and laboratory findings:

• Laboratory evidence of HIV infection as demonstrated by either a positive viral culture or detectable serum p24 antigen or = or > two positive tests for HIV antibody, which must be determined by a federally licensed ELISA test and confirmed by Western blot.
• Children < 15 months of age, who are thought to have acquired HIV through perinatal transmission and whose only laboratory evidence of HIV infection is a positive antibody test, must also have one or more of the following laboratory criteria indicative of immunologic abnormality:
• hypergammaglobulinemia (IgG or IgA) defined as greater than the upper limit of normal for age-adjusted normals; absolute depression in the CD4+ cells to = or < 500 cells/mm3; decreased helper/suppressor ratio < 1.0; depressed in vitro mitogen response to at least one antigen/mitogen.
• Absence of serious bacterial infections as defined in Exclusion Criteria requiring therapy at the time of entry.
• Hemophiliacs are included.

Exclusion Criteria

Co-existing Condition:

Children will be excluded for the following reasons:

• Recurrent or life-threatening toxicity. Several allergic reactions such as exfoliative erythroderma, anaphylaxis, or vascular collapse. The presence of one or more of the indicator diseases of AIDS, such as opportunistic infections, malignancy, recurrent bacterial infections, or encephalopathy. Development of two or more episodes of recurrent varicella zoster infection or chronic zoster defined as = or > 30 days duration. Development of AIDS related complex, with failure to thrive, persistent or recurrent oral candidiasis, plus at least one of the following:
• Diarrhea that is either persistent or recurrent, lymphadenopathy at two or more noncontiguous sites, organomegaly, nephropathy manifested by nephrotic syndrome without evidence of renal failure, two or more episodes of herpes stomatitis or one or more episodes of herpes zoster within a 1 year period; plus at least one of the following:
• hypergammaglobulinemia, depression in the CD4+ cells to = or < 500/mm3, decreased helper/suppressor ratio < 1.0, depressed in vitro mitogen response to at least one antigen/mitogen.

Concurrent Medication:

Excluded:

• Hepatotoxic drugs.
• Steroids for lymphocytic interstitial pneumonitis (LIP).
• Prophylaxis for oral candidiasis, or otitis media.
• Immunoglobulin therapy.
• Chronic use of drugs that are metabolized by hepatic glucuronidation.

Concurrent Treatment:

Excluded:

• Supplemental oxygen treatment for lymphocytic interstitial pneumonitis (LIP).

Children will be excluded from the study for the following reasons:

• AIDS-defining opportunistic infection or neoplasm.
• Unexplained recurrent, serious bacterial infections (= or > 2 within a 2-year period) including sepsis, meningitis, pneumonia, abscess of an internal organ, and bone/joint infections caused by Haemophilus, Streptococcus, or other pyogenic bacteria.
• Encephalopathy.
• One or both of the following:
• Failure to thrive, defined as a child who crosses two percentile lines on the growth chart or a child who is less than the fifth percentile and does not follow the curve; and/or persistent (= or > 2 months) oral candidiasis despite appropriate topical therapy.
• Children with lymphocytic interstitial pneumonitis (LIP) who are steroid dependent or requiring supplemental oxygen or who have a pretreatment PaO2 < 70 mmHg.
• Children who qualify for the entrance criteria to open-label zidovudine (AZT) or AZT plus or minus gammaglobulin.

Prior Medication:

Excluded:

• Rifampin or rifampin derivatives.
• Antiretroviral agents.
• Zidovudine (AZT).
• Excluded within 2 weeks of study entry:
• Other experimental therapy.
• Drugs which cause prolonged neutropenia or significant nephrotoxicity.
• Excluded within 4 weeks of study entry:
• Immunomodulating agents including immunoglobulin, interferon, isoprinosine, and IL-2.

Prior Treatment:

Excluded within 4 weeks of study entry:

• Lymphocyte transfusions.

Active alcohol or drug abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Masking: Double

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Study Chair: P Weintrub

Study record dates

Study Major Dates

• Study Completion (Actual): September 1, 1992

Study Registration Dates

• First Submitted: November 2, 1999
• First Submitted That Met QC Criteria: August 30, 2001
• First Posted (Estimate): August 31, 2001

Study Record Updates

• Last Update Posted (Actual): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: AIDS-Related Opportunistic Infections; Zidovudine; Pulmonary Fibrosis
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites; Zidovudine
• Other Study ID Numbers: ACTG 052; 11026 (Registry Identifier: DAIDS ES Registry Number)