Worldwide, perinatal (i.e., mother to infant) transmission accounts for most human immunodeficiency virus (HIV) infections among children; in the United States, of the approximately 7000 infants born to HIV-infected mothers each year, 1000-2000 are HIV-infected (1). Strategies for reducing perinatally acquired HIV infection have included preventing HIV infection among women and, for HIV-infected women, avoiding pregnancy or refraining from breastfeeding their infants (2). On February 21, 1994, the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Child Health and Human Development (NICHD) announced preliminary results from a randomized, multicenter, double-blinded clinical trial of zidovudine (ZDV) to prevent HIV transmission from mothers to their infants (AIDS Clinical Trials Group [ACTG] protocol 076). This report summarizes the interim results of that trial, which indicate effectiveness of ZDV for prevention of perinatal transmission.*
The study was initiated in April 1991 by the Pediatric ACTG of NIAID in collaboration with NICHD and the National Institute of Health and Medical Research (INSERM) and the National Agency of Research on AIDS (ANRS), France. Eligible participants were HIV-infected pregnant women who had received no antiretroviral treatment during their current pregnancy, had no clinical indications for maternal antepartum antiretroviral therapy in the judgment of their health-care provider, and who had a CD4+ T-lymphocyte count greater than 200/uL at time of entry into the study. Enrolled women were randomized to receive either a ZDV or placebo regimen. The ZDV regimen included antepartum ZDV (100 mg given orally five times daily) initiated at 14-34 weeks' gestation and continued for the remainder of the pregnancy; intravenous ZDV during labor (administered intravenously as a loading dose of 2 mg per kg body weight given over 1 hour, followed by continuous infusion of 1 mg per kg body weight per hour until delivery); and oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg body weight per dose given every 6 hours) for the first 6 weeks of life, beginning 8-12 hours after birth (see box). The placebo regimen was given on the same schedule. Blood specimens were obtained for HIV culture from all infants at birth and at ages 12, 24, and 78 weeks. A positive viral culture was considered indicative of HIV infection. Infants also were tested for HIV-antibody at ages 15 and 18 months.
Eligibility Criteria and Zidovudine Regimen for HIV-Infected Pregnant Women and Their Infants Participating in AIDS Clinical Trials Group Protocol 076
Based on analysis of data for 364 births through December 1993, ZDV therapy was associated with a 67.5% reduction in the risk for HIV transmission; the estimated rates of transmission were 25.5% (95% confidence interval [CI]=18.3%-33.7%) among the 184 children in the group receiving the placebo regimen compared with 8.3% (95% CI=3.8%-13.8%) among the 180 children in the group receiving ZDV (Kaplan-Meier estimate at age 18 months; p=0.00006). Although the ZDV regimen was well tolerated by mothers and infants, hemoglobin levels were lower for infants in the ZDV group (mean decrease in hemoglobin was less than 1 g/dL); however, this problem resolved without therapy following completion of ZDV treatment. The incidence of reported side effects was similar among mothers and infants between the two randomized groups.
Based on these interim findings, NIAID accepted the recommendation of an independent data and safety monitoring board to terminate enrollment into the trial and to offer ZDV to women in the group who had received the placebo but had not yet delivered and to their infants aged less than 6 weeks. An NIAID Clinical Trials Alert summarizing the trial is available by calling (800) 874-2572.
Div of AIDS, National Institute of Allergy and Infectious Diseases; Center for Research for Mothers and Children, National Institute of Child Health and Human Development; National Institutes of Health.
This clinical trial demonstrated efficacy of ZDV in reducing perinatal HIV transmission when administered to HIV-infected women meeting the study's eligibility criteria (see box). However, these findings are subject to at least four limitations. First, the study did not assess the efficacy of ZDV among women with CD4+ T-lymphocyte counts less than or equal to 200 cells/uL or among women who had previously used ZDV for extended periods and who may be infected with ZDV-resistant strains of HIV. Second, this trial could not assess the relative or independent contributions of the antepartum treatment, intrapartum treatment, or treatment of the infant; therefore, the efficacy and side effects of ZDV regimens restricted to only one or two of these treatment periods is unknown. Third, the study did not evaluate the risk or benefit of ZDV use in the first trimester. Finally, the study has not yet provided information about long-term side effects for infants and mothers treated with ZDV, including infants who did not become infected with HIV; however, long-term follow-up of infants and mothers is being conducted to monitor for possible late side effects.
Based on the findings of ACTG protocol 076, the Public Health Service (PHS) provides the following interim recommendations**: 1) all health-care workers providing care to pregnant women and women of childbearing age should be informed of the results of ACTG protocol 076; 2) HIV-infected pregnant women meeting the protocol eligibility criteria should be informed of the potential benefits but unknown long-term risks of ZDV therapy as administered in ACTG protocol 076, and decisions to use ZDV for prevention of perinatal transmission should be made in consultation with their health-care providers (see box); 3) health-care providers should inform their patients that this ZDV regimen substantially reduced, but did not eliminate, the risk for HIV infection among the infants; and 4) until the potential risk for teratogenicity and other complications from ZDV therapy given in the first trimester can be assessed, ZDV therapy only for the purpose of reducing the risk for perinatal transmission should not be instituted earlier than the 14th week of gestation. PHS is developing further recommendations for the uses of ZDV for HIV-infected pregnant women whose clinical indications differ from the ACTG protocol 076 eligibility criteria and for counseling and HIV-antibody testing for women of childbearing age.
The international Antiretroviral Pregnancy Registry, sponsored by Burroughs Wellcome Co. (Research Triangle Park, North Carolina)*** and Hoffmann-LaRoche Foundation, Inc. (Nutley, New Jersey)***, is collecting observational, nonexperimental data on exposure to ZDV and dideoxycytidine (ddC) during pregnancy. Women who have been treated with either of these drugs at any time during pregnancy for any duration are eligible for registry enrollment. Patients can be enrolled by contacting the registry, telephone (800) 722-9292, extension 8465; fax (919) 315-8981.
* Single copies of this report will be available free until April 29, 1995, from the CDC National AIDS Clearinghouse, P.O. Box 6003, Rockville, MD 20849-6003; telephone (800) 458-5231.
** These recommendations do not reflect current Food and Drug Administration-approved labeling for ZDV.
*** Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services.