WHAT IS STUDY ACTG 076?
ACTG 076 is a Phase III, randomized, double-blind, placebo-controlled clinical trial, designed to evaluate whether zidovudine (AZT) administered to HIV-infected pregnant women and their infants could reduce the rate of transmission from mother to infant.
The primary objective was to determine if zidovudine given to HIV-infected women during pregnancy and to their infants for the first six weeks of life can reduce the HIV infection rate in the infants. The study also evaluated the safety of AZT when administered to pregnant women and to their infants during the first 6 weeks of life.
WHY WAS ACTG 076 CONDUCTED?
Vertical transmission of HIV (infection of an infant through exposure to maternal virus during pregnancy or labor and delivery) accounts for the vast majority of HIV infection in infants and children worldwide. In the U.S. over 5000 children have developed AIDS. Approximately 7000 infants are born to HIV-infected women each year in the U.S. Not all infants born to infected women become infected. Vertical transmission rates vary in different regions and different patient populations. The overall transmission rate in the U.S. is about 20 to 25 percent.
WHAT WAS THE RATIONALE FOR THE TREATMENT REGIMEN USED IN THIS STUDY?
At the time ACTG 076 was designed there was very little information regarding when the greatest risk of transmission occurs during gestation and delivery. Since transmission is known to occur in some infants early in gestation, the investigators believed that institution of therapy as early as possible in pregnancy might be important in order to achieve the maximum possible effect on the transmission rate consistent with a reasonable safety profile. Thus, it was decided to begin treatment of the women no earlier than the end of the first trimester of pregnancy. Similarly, since one of the mechanisms which was hypothesized to be potentially important for a reduction in transmission was a reduction of the circulating HIV load in the mother, it was decided that women in the study should begin therapy no later than 34 weeks, so that most of the women would have at least four weeks of therapy before delivery.
Since there was some preclinical data to suggest that AZT could reduce the risk of infection in animal models when treatment occurs before exposure, it was thought important that the fetus and infant should be exposed to adequate levels of AZT during the period at risk. The intravenous AZT regimen during labor was designed to ensure these levels were maintained. The data to support the regimen was obtained in a phase I trial ACTG 082 conducted by the NIAID sponsored AIDS Clinical Trials Group.
A regimen of AZT for the six weeks following birth was included because of the potential for significant blood exposure and mixing at birth and because circulating maternal HIV infected cells might be present in the infant for some time after delivery. The oral treatment of the infant was started at 8-12 hours after delivery based on pharmacokinetic data on the half life of AZT in newborns. The dose used in the infants was derived from data obtained in the phase I trial of AZT in infants, ACTG 049.
WHAT ARE THE POSSIBLE MECHANISMS BY WHICH AZT REDUCES TRANSMISSION?
AZT causes a significant reduction in the level of infectious virus in the maternal circulation, and likely in other fluids such as vaginal secretions as well. It is probable that this reduces the amount of virus to which the infant is exposed.
The presence of AZT in the infant before and during exposure to virus may reduce the risk of an exposure resulting in an established infection.
There is no data to suggest which of these mechanisms plays the most significant role in the effect observed in this study.
WHO SPONSORED THE STUDY?
ACTG 076 was conducted by the AIDS Clinical Trials Group sponsored by the National Institute of Allergy and Infectious Diseases. Study trial sites contracted by the National Institute of Child Health and Human Development participated in the trial. In addition, women enrolled at sites under the auspices of the Institut National de la Sante et de la Recherches Medicale (INSERM), and Agence Nationale de Recherches sur le SIDA (ANRS), France. Burroughs Wellcome Co. provided zidovudine for the study.
WHEN AND WHERE WAS THE STUDY CONDUCTED?
Study enrollment opened in April 1991. The study was conducted at 59 sites of the AIDS Clinical Trials Group (ACTG). As of December 20, 1993, 477 women had been randomized and the births of 421 infants have been recorded in the database.
WHO PARTICIPATED IN THE STUDY?
The study was open to HIV-infected pregnant women who had not taken any antiretroviral therapy 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 women were between 14 and 34 weeks of their pregnancy when they entered the study.
WHAT WAS THE DESIGN OF THE STUDY?
Eligible women were randomized to either an active drug arm containing ZDV or a control arm containing placebo. The zidovudine regimen included 100 mg capsules five times a day initiated between the 14th and 34th weeks of pregnancy and continued throughout the remainder of pregnancy. During labor, intravenous ZDV was administered (loading dose 2 mg/per kilogram of body weight followed by continuous infusion 1 mg/kg/hour until delivery). When the mothers received ZDV, their infants received ZDV, and when mothers received the placebo, their infants received the placebo. The zidovudine regimen for the infants (syrup 2 mg/kg by mouth every six hours) began 8 to 12 hours after birth and continued for 6 weeks.
The ability of zidovudine to prevent the transmission of HIV in infants born to HIV-infected mothers was evaluated by comparing the rates of HIV infection in infants born to mothers who had received zidovudine and those who received placebo.
WHAT WERE THE RESULTS OF THE STUDY?
As of December 1993, 421 infants were born to women enrolled in the trial. Of those, 364 infants had at least one culture result available.
Of the 364 evaluable infants, 53 had HIV infection. Of those 53, 13 had received zidovudine and 40 had received the placebo. The estimated rate of transmission in the group that in the group that received the placebo was 25.5%. These results are statistically significant (p=.00006) and indicate that if zidovudine is used in a similar population, only 8 out of 100 infants will be infected, compared to 25 out of 100 infants when zidovudine is not used. All 53 HIV-infected infants had at least one HIV-positive culture. There was no evidence that zidovudine delayed time to detection of infection.
There were no significant short time side effects to either mother or infants resulting from AZT use other than mild anemia in the infants which reversed shortly after treatment ended.
There is no information regarding any long term effects on the infants or mothers treated in this study.
HOW WAS HIV INFECTION DETECTED IN THE INFANTS?
All infants were checked for evidence of HIV infection at birth and at 12, 24, and 78 weeks. A positive viral culture was considered indicative of HIV infection. Infants were also tested for HIV antibodies at 15 and 18 months.
HOW OLD WERE THE WOMEN IN THE TRIAL AND WHAT WERE THEIR CD4+ CELL COUNTS?
The average age of the women who participated in the trial was 25.6 years old. The average CD4+ cell count was 586 cells/cubic millimeter of blood (mm3). Forty-one percent of women had CD4+ lymphocyte counts between 200 and 500 cells/mm3.
WHAT WERE THE ETHNIC BACKGROUNDS OF THE WOMEN ENROLLED?
Of the women enrolled, 51% were African American, 29% Hispanic and 0.2% Asian. The ethnic and racial distribution of the trial participants is comparable to that in the population of HIV-infected women in the U.S.
WERE SIGNIFICANT SIDE EFFECTS SEEN IN THE MOTHER THAT COULD BE ASSOCIATED WITH ZIDOVUDINE USE?
The drug was tolerated well by women enrolled in the trial. No significant differences in side effects between the zidovudine and placebo groups were reported. The most common side effects reported were blood related toxicities with equal numbers reported in both groups. Six women discontinued treatment due to toxicities. Three of these were receiving zidovudine and the other three were receiving placebo.
WERE SIGNIFICANT SIDE EFFECTS SEEN IN THE INFANTS THAT COULD BE ASSOCIATED WITH ZIDOVUDINE USE? Overall, zidovudine was tolerated well. During the six weeks of treatment the most common side effects reported for both treatment groups were low hemoglobin (anemia), low white blood cells (neutropenia) and a high bilirubin level. While significant anemia was rare, the values of hemoglobin for the zidovudine group were lower than those for the placebo. However, the mean decrease in hemoglobin was less than one gram/dl, did not require transfusion, and resolved within several weeks after completion of ZDV therapy.
WERE ANY CONGENITAL ANOMALIES IN THE INFANTS ASSOCIATED WITH ZIDOVUDINE USE?
Congenital anomalies were seen equally in the ZDV treated and placebo groups of infants (7 infants and 8 infants, respectively). The rate of congenital anomalies that did occur does not differ from what one would expect in the general population. No congenital anomalies were believed to be related to ZDV.
HAVE ANY WOMEN OR INFANTS ON THE STUDY DIED?
No women on the study have died. Most women on ACTG 076 are at a relatively early stage of HIV disease. Seven infants in the treatment group and seven infants in the control group died. Infant deaths were attributed to serious congenital anomalies present at birth or were due to rapid progression of HIV disease.
WHAT HAPPENED TO THE WOMEN AFTER THEY DELIVERED?
The mothers' health was monitored for six months after delivery. At six months postpartum, there was no significant difference in CD4+ T lymphocyte cell counts by treatment group and 95% of women had CD4+ lymphocyte counts >300 cells/mm3.
HOW WILL THE MANAGEMENT OF MOTHERS AND THEIR INFANTS WHO ARE NOW IN THE STUDY CHANGE?
All participants will be informed of the study results. Women who are currently enrolled in Study ACTG 076 will be informed of the trial results and be offered zidovudine for the remainder of their pregnancy and for their infants during the first six weeks of life. Infants within the first 6 weeks of life in both the ZDV and placebo groups also will be offered zidovudine. Data will continue to be collected as outlined in the protocol. This means that all women will be seen at six months after delivery and their infants will be followed until they are 18 months old. Infants also will be followed for an extended period of time for potential late-appearing side effects of treatment.
WHAT ARE THE IMPLICATIONS OF THE RESULTS? The results of this study indicate zidovudine treatment as administered in this study can greatly reduce the risk of transmission of HIV infection from mother to infant. However, because long term effects of therapy on infants exposed to the treatment regimen used in this trial are unknown, general recommendations regarding treatment must await consensus on the balance between known benefit and unknown risk.
DOES THIS MEAN THAT ALL PREGNANT HIV-INFECTED WOMEN SHOULD BE TREATED WITH ZIDOVUDINE?
The results of this study are directly applicable only to women who initiate ZDV treatment between 14th and 34th weeks of pregnancy, receive no other antiretroviral treatment during the current pregnancy, have baseline CD4+ lymphocyte counts greater than 200 cells/mm3, and have no clinical indications for maternal antepartum ZDV therapy.
Many clinical situations will differ from that of the women who were treated in ACTG 076. However, the study provides no data that directly address either alternative clinical situations or therapeutic regimens.
Answers to questions that involve other treatments and other patient populations will require additional research.
DOES THIS NOW MEAN THAT AN HIV-INFECTED WOMAN CAN DECIDE TO HAVE A CHILD AND BE SURE IT WILL BE BORN WITHOUT HIV INFECTION?
No. In this study population, 8 out of every 100 infants born were infected with HIV even though both mothers and infants received zidovudine.
WILL THERE BE LATE CONSEQUENCES FOR WOMEN AFTER USING ZDV DURING PREGNANCY TO REDUCE PERINATAL TRANSMISSION?
Further studies are needed to address questions about ZDV efficacy and safety in mothers for whom ZDV will be indicated at a later time, following an interval off-treatment after their treatment during pregnancy.
WILL USING ZIDOVUDINE CAUSE CANCER OR SOME OTHER PROBLEMS LATE IN LIFE?
There are no human data to answer the question of whether treatment with zidovudine may cause unforeseen problems later in life. Infants who have been followed for at least one year in ACTG 076, show no indication of a late side effect associated with zidovudine, but it is far to soon after therapy to draw any conclusions regarding the long term effects, if any. Additional data are absolutely essential from longer follow-up of more infants. The NIAID and ACTG long term follow-up for all the infants who have participated in this study. Through this long term follow-up, data will be gathered on possible long term effects of zidovudine.
CAN THE RESULTS OF ACTG 076 BE EXTRAPOLATED TO OTHER SITUATIONS IN WHICH PREEXPOSURE OR POSTEXPOSURE PROPHYLAXIS MIGHT BE CONSIDERED?
There are no useful data to extrapolate from this study to other situations where one is trying to prevent transmission. The transmission of virus from mother to infant is a unique route of infection.
WHERE IS MORE INFORMATION AVAILABLE?
Further information about this trial is available from the AIDS Clinical Trials Information Services, 1-800-TRIALS-A.
General information about HIV disease, testing or treatment options may be obtained from your health care provider, your local and state health department or by calling any of the national organizations. Some of these include:
o National AIDS Information Hotline (1-800-342-AIDS) o National AIDS Information Clearinghouse(1-800-458-5231) o National Pediatric HIV Resource Center(1-800-362-0071)