Executive Summary: Abstract ACTG 076. A Phase III Randomized, Placebo-Controlled Trial to Evaluate the Efficacy, Safety and Tolerance of Zidovudine (ZDV) for the Prevention of Maternal-Fetal Transmission
Currently, there are approximately 10-20,000 HIV-infected children and approximately 7,000 infants are born annually to HIV-infected women in the United States. It is estimated that by the year 2000, 10 million children globally will have been infected.
The vast majority of HIV-infected infants and children acquire the virus by maternal-infant transmission; either in utero, during labor and delivery, or postpartum via breastfeeding. In the developed world, antepartum and intrapartum routes account for nearly all of the cases. The risk of matern al-infant HIV transmission in pregnant women has been associated with advanced disease stage, low CD4+ lymphocyte count, and high viral burden.
Zidovudine (ZDV) has been demonstrated to be an effective treatment to decrease viral burden and delay disease progression for HIV-infected adults and children. An uncontrolled survey of some pregnant women treated with ZDV for their own medical care revealed no significant untoward effect.
The risk of maternal-infant transmission of HIV theoretically could be reduced by ZDV treatment of pregnant women. To test this hypothesis, in April 1991, a Phase III randomized, double-blind, placebo- controlled clinical trial (ACTG 076) was initiated to evaluate whether ZDV therapy could reduce the risk of maternal-fetal transmission in HIV- infected pregnant women. An additional study objective was to evaluate the safety of the ZDV regimen for mothers a nd infants.
Eligible patients were HIV-infected pregnant women (between 14 and 34 weeks gestation) who had no antiretroviral treatment during the current pregnancy, had baseline CD4+ lymphocyte counts greater than 200 cells/ mm3, and had no clinical indications for maternal antepartum ZDV therapy. The target sample size was 748 women (636 fully assessable mother-infant pairs). This was chosen so as to provide 80 percent power to detect a reduction in the probability of transmission to 20 percent for the ZDV group compared with 30 percent for the placebo group, using a two-sided, alpha=0.05 test. Women were stratified according to gestational age (14-26 weeks; >26 weeks) and randomized to receive either ZDV or placebo.
The ZDV regimen consisted of antepartum ZDV (100 mg p.o. five times daily) plus intrapartum ZDV (IV loading dose, 2 mg/kg, followed by continuous infusion, 1 mg/kg/hr, until delivery) plus newborn ZDV (syrup, 2 mg/kg q. 6 hr for six weeks beginning 8-12 hours after birth). Pregnant women were seen frequently during pregnancy, through delivery, and for six months postpartum, and were carefully assessed for evidence of drug toxicity, HIV disease progression, and fetal well-being. Infants were carefully monitored through 78 weeks of age for evidence of HIV infection and to assess safety. HIV infection status was determined by viral culture from the infants at birth, 12 weeks, and 78 weeks of life, and samples were obtained for HIV serology at 72 and 78 weeks. A protocol modification added an additional culture at 24 weeks. Infants were defined as HIV infected for the primary analysis based on one positive viral culture obtained from peripheral blood.
On February 17, 1994, the ACTG Data and Safety Monitoring Board (DSMB) reviewed the interim analysis based on information in the database as of December 20, 1993, and concluded that there was significant evidence of treatment efficacy. On February 18, 1994, the Pediatric AIDS Clinical Trials Group Executive Committee approved the DSMB recommendations to: (1) discontinue new patient enrollment; (2) offer open-label ZDV as per protocol regimen to all individuals on the study; and (3) continue long term follow-up of all infants participating in ACTG 076 to monitor for possible development of unknown late effects of the study treatment.
Thirty-five NIAID sponsored sites, 15 NICHD sponsored sites, and nine centers in France enrolled patients in ACTG 076. Four hundred seventy- seven women were enrolled as of the December 20, 1993 data cut-off. The median age was 25 years (range, 15-43), the median CD4+ lymphocyte count was 550 cells/mm3 (range, 200-1818), and 41 percent of women had CD4+ lymphocyte counts between 200 and 500 cells/mm3. The median age was 25 years (range, 15-43), the median CD4+ lymphocyte count was 550 cells/mm3 (range, 200-1818), and 41 percent of women had CD4+ lymphocyte counts between 200 and 500 cells/mm3. The median gestational age at entry was 26 weeks. Maternal demographics revealed a predominantly minority population: only 19 percent were white/non-Hispanic.
Four hundred twenty-one babies have been born; 409 singletons and 6 sets of twins. The median gestational age at delivery was 39 weeks (range, 27-43 weeks). Three sets of twins and 23 singletons were premature (<36 weeks gestation). The median 1-minute Apgar score was 8 (range, 0-10), the median 5-minute Apgar was 9 (range, 5-10), and the median birth weight was 3160 gr ams (range, 1040-5267 grams). Seven infants (1.7 percent) weighed <1500 grams at birth, 14 (3.4 percent) weighed between 1500 and 2000 grams, and 44 (10.7 percent) weighed between 2000 and 2500 grams.
Three hundred sixty-four births were included in this interim efficacy analysis, 180 in the ZDV group and 184 in the placebo group. Two hundred thirty-three infants had information about HIV infection status as of 24 weeks of life, and 75 of these had confirmation at 18 months. Thirteen babies in the ZDV group and 40 in the placebo group were defined as HIV-infected. The estimated percentages infected based on Kaplan-Meier analysis were 8.3 percent (s.e.: 2.25 percent) in the ZDV group and 25.5 percent (s.e.: 3.60 percent) in the placebo group. The estimated absolute difference in percentage infected between the two groups was 17.2 percent, with 95 percent confidence interval 8.9 to 25.5 percent. This corresponded to a 67.5 relative reduction in transmission risk. This risk reduction is highly statistically significant (z=4.03; two-sided p=0.000056).
Reported maternal and infant side effects were balanced between the two randomized groups, with one exception that hemoglobin levels were lower for infants in the ZDV group. The mean decrease in hemoglobin was less than 1 g/dl, did not require transfusion, and resolved after completion of ZDV therapy.
A treatment regimen consisting of ZDV given to the mother both antepartum and intrapartum, as well as to the newborn during the first six weeks of life, significantly reduced the risk of maternal-infant transmission of HIV for women with baseline CD4+ lymphocyte counts >200 cells/mm3. Further follow-up of mothers and infants is being conducted to determine if there are any late adverse effects of this treatment regimen. Any decision to institute therapy regimens for the prevention of maternal-fetal transmission must be made after careful consideration of the potential unknown long term risks.
Prepared by: Richard D. Gelber, Ph.D. Pavel Kiselev, Ph.D. Edward Connor,C.R.N.P. Bethann Cunningham, M.S.