The Safety and Effectiveness of Zidovudine in HIV-Infected Pregnant Women and Their Infants

A Phase III Randomized Placebo-Controlled Trial to Evaluate the Efficacy, Safety and Tolerance of Oral Zidovudine (AZT) in Pregnant HIV Infected Women and Their Infants

To determine whether the rate of HIV transmission from mother to infant can be reduced by continuous oral zidovudine (AZT) treatment to HIV infected pregnant women, intravenous AZT during childbirth, and oral AZT treatment of the newborn infant from birth to six weeks of age. The study is also designed to evaluate the safety of AZT for both the pregnant woman and the newborn infant.

No method exists to prevent transmission of HIV from an infected mother to her newborn infant. Giving an antiviral agent (such as AZT) to the mother and to the newborn could in theory decrease the risk of infection to the newborn by reducing the exposure of the fetus to maternal virus, or by preventive treatment of the fetus before exposure.

No method exists to prevent transmission of HIV from an infected mother to her newborn infant. Giving an antiviral agent (such as AZT) to the mother and to the newborn could in theory decrease the risk of infection to the newborn by reducing the exposure of the fetus to maternal virus, or by preventive treatment of the fetus before exposure.

Patients are enrolled during their pregnancy, between 14 and 34 weeks of gestation. They are chosen by random selection to receive AZT or placebo. Treatment continues until labor at which time they begin to receive continuous intravenous study drug. Study drug treatment is discontinued after the umbilical cord is clamped. AZT is then offered all women as per labeled indications for 6 weeks postpartum, while appropriate medical followup is being arranged. Mothers who develop an AIDS defining illness or whose CD4+ cell counts decrease to less than 200 cells/mm3 during pregnancy are offered open-label drug at that time. The mother is followed by her primary obstetrician at an AIDS Clinical Trials Unit (ACTU) or subunit facility. The mother may deliver at the ACTU or a non-ACTU site. Treatment of the infant is started in the newborn nursery and continues on an outpatient basis. Infants receive the same study treatment as the mother for 6 weeks, and are monitored to week 78.

Inclusion Criteria

Concurrent Medication:

Allowed for infants:

• Treatment for signs of drug withdrawal (e.g., phenobarbital, chlorpromazine, tincture of opium, paregoric, or Valium).
• Treatment for nonserious conditions (e.g., syphilis treatment, hepatitis B vaccine).
• All essential supportive treatment for conditions that are nonlife threatening as deemed by the on-site pediatrician.
• Acetaminophen.
• Standard immunizations.
• Allowed for women:
• All medications/treatments as required for normal OB care of HIV+ women, except as noted under exclusions.
• Pneumocystis prophylaxis as indicated.
• Topical steroids. Parenteral and oral steroids for 6 or fewer days.

Concurrent Treatment:

Allowed for pregnant woman:

Blood transfusion for anemia (hemoglobin less than 7 g/dl).

Allowed for infant:

- Blood transfusions for anemia except if attributed to study drug.

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Patients must:

• Have HIV infection.
• Intend to carry pregnancy to term.
• Be willing to be followed by a participating ACTG center for duration of the study.
• Be able to provide informed consent (if available, father of the fetus must also provide informed consent).
• Infants may enroll simultaneously in other pediatric protocols after completing the initial 6 weeks of study treatment.
• Inclusion age for women is 13 years old or more or IRB local age of consent.
• Inclusion age for infants is 0 to 20 months.

Exclusion Criteria

Co-existing Condition:

Infants with the following conditions or symptoms are excluded:

• Requiring treatment for hyperbilirubinemia (except phototherapy).

Concurrent Medication:

Excluded:

• Infants:
• Antiretroviral drugs or vaccines.
• Excluded during current pregnancy:
• Zidovudine (AZT).
• Other antiretroviral agents (e.g., rCD4, CD4-IgG, d4T, didanosine (ddI), dideoxycytidine (ddC)), passive immunotherapy (e.g., HIVIG), anti-HIV vaccines, cytolytic chemotherapeutic agents.
• Corticosteroids for equal to or more than 7 days.

Patients with the following are excluded:

• Evidence of preexisting fetal anomalies that may (1) result in a high probability that the fetus/infant will not survive to the end of the study period (e.g., anencephaly, renal agenesis, or Potter's syndrome); or (2) increase the fetal tissue concentration of zidovudine (AZT) or its metabolites to a toxic level (e.g., neural tube or ventral wall defects).
• Baseline sonogram completed within 28 days prior to randomization that demonstrates 2nd trimester findings of anencephaly or oligohydramnios, or 3rd trimester findings of unexplained polyhydramnios, fetal hydrops, ascites or other evidence of preexisting in-utero anemia.
• History of intolerance to AZT dose of 500 or less mg/day prior to this pregnancy that resulted in discontinuation of treatment for more than 4 weeks.
• Recipient of AZT during current pregnancy for any indication or meet criteria for AZT as defined by this protocol (CD4+ cell counts less than 200 cells/mm3 or AIDS).
• Infants not having parent/guardian available to give informed consent if necessary.

Prior Treatment:

Excluded during current pregnancy:

• Radiation therapy.