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.

Study Overview

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

Detailed Description

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.

• Study Type: Interventional
• Enrollment: 1496
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • Bayamon, Puerto Rico, 00956
    • Ramon Ruiz Arnau Univ Hosp / Pediatrics
  • San Juan, Puerto Rico, 009367344
    • San Juan City Hosp
  • San Juan, Puerto Rico, 009365067
    • Univ of Puerto Rico / Univ Children's Hosp AIDS
  • San Juan, Puerto Rico, 009365067
    • UPR Children's Hosp / UPR School of Medicine
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Univ of Alabama at Birmingham
    • Birmingham, Alabama, United States, 35294
      • Univ of Alabama at Birmingham Schl of Med / Pediatrics
  • California
    • La Jolla, California, United States, 920930672
      • UCSD Med Ctr / Pediatrics / Clinical Sciences
    • Los Angeles, California, United States, 90033
      • Los Angeles County - USC 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
    • San Francisco, California, United States, 94110
      • San Francisco Gen Hosp
  • Colorado
    • Denver, Colorado, United States, 802181088
      • Children's Hosp of Denver
  • Connecticut
    • Farmington, Connecticut, United States, 06032
      • Univ of Connecticut / Farmington
    • Farmington, Connecticut, United States, 06032
      • Univ of Connecticut Health Ctr
  • District of Columbia
    • Washington, District of Columbia, United States, 20060
      • Howard Univ Hosp
  • Florida
    • Miami, Florida, United States, 33161
      • Univ of Miami (Pediatric)
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern Univ Med School
    • Chicago, Illinois, United States, 60612
      • Cook County Hosp
    • Chicago, Illinois, United States, 606143394
      • Chicago Children's Memorial Hosp
    • Chicago, Illinois, United States, 606371470
      • Univ of Chicago Children's Hosp
    • Chicago, Illinois, United States, 60612
      • Univ of Illinois College of Medicine / Pediatrics
  • Louisiana
    • New Orleans, Louisiana, United States, 701122699
      • Tulane Univ / Charity Hosp of New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hosp
    • 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, 02215
      • Beth Israel Deaconess Med Ctr
    • Boston, Massachusetts, United States, 021155724
      • Children's Hosp of Boston
    • Boston, Massachusetts, United States, 02118
      • Boston City Hosp / Pediatrics
    • Springfield, Massachusetts, United States, 01199
      • Baystate Med Ctr of Springfield
    • Worcester, Massachusetts, United States, 01655
      • Univ of Massachusetts Med Ctr
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hosp of Michigan
  • New Jersey
    • Newark, New Jersey, United States, 071032714
      • Univ of Medicine & Dentistry of New Jersey / Univ Hosp
    • Newark, New Jersey, United States, 071032714
      • UMDNJ - New Jersy Med School
    • Newark, New Jersey, United States, 071072198
      • Children's Hosp of New Jersey / UMDNJ - New Jersey Med Schl
  • New York
    • Albany, New York, United States, 12208
      • Children's Hosp at Albany Med Ctr
    • Bronx, New York, United States, 10461
      • Albert Einstein College Of Medicine
    • Bronx, New York, United States, 10457
      • Bronx Lebanon Hosp Ctr
    • Brooklyn, New York, United States, 11203
      • SUNY - Brooklyn
    • Brooklyn, New York, United States, 11203
      • SUNY / Health Sciences Ctr at Brooklyn / Pediatrics
    • New York, New York, United States, 10016
      • Bellevue Hosp / New York Univ Med Ctr
    • New York, New York, United States, 10021
      • Cornell Univ Med College
    • New York, New York, United States, 10032
      • Columbia Presbyterian Med Ctr
    • New York, New York, United States, 10029
      • Mount Sinai Med Ctr / Pediatrics
    • New York, New York, United States, 10003
      • Beth Israel Med Ctr / Pediatrics
    • Rochester, New York, United States, 14642
      • Univ of Rochester Medical Center
    • Stony Brook, New York, United States, 117948111
      • State Univ of New York at Stony Brook
    • Syracuse, New York, United States, 13210
      • SUNY Health Sciences Ctr at Syracuse / Pediatrics
    • Valhalla, New York, United States, 10595
      • Westchester Hosp
  • North Carolina
    • Chapel Hill, North Carolina, United States, 275997215
      • Univ of North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Med Ctr
    • Durham, North Carolina, United States, 277103499
      • Duke Univ Med Ctr
  • Ohio
    • Cincinnati, Ohio, United States, 452670405
      • Univ of Cincinnati
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 191044318
      • Children's Hosp of Philadelphia
    • Philadelphia, Pennsylvania, United States, 191075098
      • Thomas Jefferson Univ Hosp
    • Philadelphia, Pennsylvania, United States, 19104
      • Hosp of the Univ of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hosp / Brown Univ
  • South Carolina
    • Charleston, South Carolina, United States, 294253312
      • Med Univ of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 381052794
      • Saint Jude Children's Research Hosp of Memphis
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Med Ctr of Dallas
    • Houston, Texas, United States, 77030
      • Texas Children's Hosp / Baylor Univ
    • Houston, Texas, United States, 77030
      • Lyndon Baines Johnson Gen Hosp
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hosp of Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 60 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

-

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Glaxo Wellcome
• Investigators: Study Chair: R Sperling

Publications and helpful links

General Publications

• Frenkel LM, Cowles MK, Shapiro DE, Melvin AJ, Watts DH, McLellan C, Mohan K, Murante B, Burchett S, Bryson YJ, O'Sullivan MJ, Mitchell C, Landers D. Analysis of the maternal components of the AIDS clinical trial group 076 zidovudine regimen in the prevention of mother-to-infant transmission of human immunodeficiency virus type 1. J Infect Dis. 1997 Apr;175(4):971-4. doi: 10.1086/514003.
• Edathodu J, Halim MM, Dahham MB, Alrajhi AA. Mother-to-child transmission of HIV: experience at a referral hospital in Saudi Arabia. Ann Saudi Med. 2010 Jan-Feb;30(1):15-7. doi: 10.4103/0256-4947.59367.
• Connor EM, Sperling RS, Gelber R, Kiselev P, Scott G, O'Sullivan MJ, VanDyke R, Bey M, Shearer W, Jacobson RL, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994 Nov 3;331(18):1173-80. doi: 10.1056/NEJM199411033311801.
• Sperling RS, Shapiro DE, Coombs RW, Todd JA, Herman SA, McSherry GD, O'Sullivan MJ, Van Dyke RB, Jimenez E, Rouzioux C, Flynn PM, Sullivan JL. Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1996 Nov 28;335(22):1621-9. doi: 10.1056/NEJM199611283352201.
• Sperling RS, Shapiro DE, McSherry GD, Britto P, Cunningham BE, Culnane M, Coombs RW, Scott G, Van Dyke RB, Shearer WT, Jimenez E, Diaz C, Harrison DD, Delfraissy JF. Safety of the maternal-infant zidovudine regimen utilized in the Pediatric AIDS Clinical Trial Group 076 Study. AIDS. 1998 Oct 1;12(14):1805-13. doi: 10.1097/00002030-199814000-00012.
• Wiznia AA, Crane M, Lambert G, Sansary J, Harris A, Solomon L. Zidovudine use to reduce perinatal HIV type 1 transmission in an urban medical center. JAMA. 1996 May 15;275(19):1504-6.
• Rouzioux C. Prevention of maternal HIV transmission. Practical guidelines. Drugs. 1995;49 Suppl 1:17-24; discussion 38-40. doi: 10.2165/00003495-199500491-00006.
• Dickover RE, Garratty EM, Herman SA, Sim MS, Plaeger S, Boyer PJ, Keller M, Deveikis A, Stiehm ER, Bryson YJ. Identification of levels of maternal HIV-1 RNA associated with risk of perinatal transmission. Effect of maternal zidovudine treatment on viral load. JAMA. 1996 Feb 28;275(8):599-605.
• Culnane M, Fowler M, Lee SS, McSherry G, Brady M, O'Donnell K, Mofenson L, Gortmaker SL, Shapiro DE, Scott G, Jimenez E, Moore EC, Diaz C, Flynn PM, Cunningham B, Oleske J. Lack of long-term effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA. 1999 Jan 13;281(2):151-7. doi: 10.1001/jama.281.2.151.
• Shearer WT, Quinn TC, LaRussa P, Lew JF, Mofenson L, Almy S, Rich K, Handelsman E, Diaz C, Pagano M, Smeriglio V, Kalish LA. Viral load and disease progression in infants infected with human immunodeficiency virus type 1. Women and Infants Transmission Study Group. N Engl J Med. 1997 May 8;336(19):1337-42. doi: 10.1056/NEJM199705083361901.
• Newell ML, Gray G, Bryson YJ. Prevention of mother-to-child transmission of HIV-1 infection. AIDS. 1997;11 Suppl A:S165-72. No abstract available.

Study record dates

Study Major Dates

• Study Completion (Actual): June 1, 1994

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): October 29, 2021
• Last Update Submitted That Met QC Criteria: October 28, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Pregnancy; AIDS-Related Complex; Zidovudine; Pregnancy Complications, Infectious; Administration, Oral; Prenatal Exposure Delayed Effects
• 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 076; 11050 (Other Identifier: Ethical committe of the Kanton Lucerne, Switzerland)