Purpose of This Document
This document provides information on the interim results of a randomized clinical trial of zidovudine (ZDV) for the prevention of transmission of HIV from infected mothers to their infants. The treatment regimen that was compared with placebo consisted of ZDV administered to HIV-infected pregnant women beginning between 14 and 34 weeks of gestation, continued intrapartum, and then to their infants during the first six weeks of life.
An interim analysis of the study demonstrated a highly significant reduction of the risk for transmission of HIV from mother to infant for the group who received ZDV. An independent Data Safety Monitoring Board recommended that women who have not yet delivered and infants who are less than six weeks of age in the study should be immediately offered ZDV. The board stressed the importance of long term follow-up of infants enrolled in the study to monit or for the possible development of unknown late effects of study treatment. The Pediatric ACTG Executive Committee and NIAID concurred with these recommendations.
This study was conducted by the Pediatric AIDS Clinical Trials Group (ACTG) of the National Institute of Allergy and Infectious Diseases (NIAID) in collaboration with the National Institute of Child Health and Human Development (NICHD), and Institut National de la Sante et de la Recherche Medicale (INSERM) and Agence Nationale de Recherches sur le SIDA (ANRS), France. There were 35 NIAID sponsored sites, 15 NICHD sponsored sites, and 9 centers in France.
This information is provided to you, as a health care publication of a formal peer-reviewed report in the medical literature.
ACTG 076 is a phase III double-blind placebo-controlled randomized clinical trial designed to evaluate the efficacy, safety and tolerance of ZDV for the prevention of maternal-fetal HIV transmission.
Eligible participants were HIV-infected pregnant women who had received no antiretroviral treatment during the current pregnancy, had no clinical indications for maternal antepartum ZDV therapy in the judgement of their caregiver, and had baseline CD4+ lymphocyte counts greater than 200 cells/mm3. Patients were randomized to either an active arm containing ZDV or a control arm containing placebo. The ZDV regimen consisted of antepartum ZDV (100 mg po 5 x daily) initiated between 14 and 34 weeks gestation and continued throughout the remainder of pregnancy, followed by intrapartum intravenous ZDV (loading dose 2 mg/kg starting in labor followed by continuous infusion 1 mg/kg/hour until delivery), followed by oral administration of ZDV (syrup 2 mg/kg q six hours for six weeks beginning 8 to 12 hours after birth) to the infant. The primary study endpoint, HIV infection of the infant, was defined by one positive viral culture obtained from peripheral blood. Specimens for viral culture were obtained from the infants at birth, and 12 and 78 weeks postpartum. A protocol modification added an additional viral culture at 24 weeks. HIV serology was also obtained at 15 and 18 months of age.
Four hundred seventy-seven women were enrolled at the time of the analysis. The median age was 25 years (range 15 to 43), the median CD4+ lymphocyte count was 550 cells/mm3 (range 200 to 1818), forty-one 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. Approximately 17% reported a history of intravenous drug use. The randomization resulted in balance between the arms for prognostic variables known to influence transmission.
Thus far, 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 to 43 weeks). Three sets of twins and 23 singletons were premature (<36 weeks gestation).
There were 364 infants with sufficient data to be included in the analysis, 180 in the ZDV group and 184 in the placebo group. As of this analysis, thirteen babies in the ZDV group and 40 in the placebo group were HIV infected (i.e., at least one positive culture). All babies with positive cultures were identified within the first 24 weeks of life. A total of 75 babies were culture and seronegative at or beyond 78 weeks.
The transmission rate in the placebo arm was 25.5 (+/- 7.2) percent and the rate in the ZDV arm was 8.3 (+/- 4.5) percent based on a Kaplan-Meier estimate at 18 months. This corresponded to a 67.5 percent relative reduction in transmission risk and was highly statistically significant (p=0.00006). Similar analysis using the more stringent criteria of two positive cultures yielded identical conclusions.
Reported maternal and infant side effects were balanced between the two randomized groups with the one exception that hemoglobin levels were lower for infants in the ZDV group. 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. There was no difference in the incidence of birth defects between the two arms, and the incidence reflected the baseline rate within the population.
Maternal therapy was well tolerated; six women discontinued therapy due to perceived toxicity (three in the ZDV group and three in the placebo group).
Maternal HIV disease progression was monitored through 6 months postpartum. At six months postpartum, there was no significant difference in CD4+ lymphocy te cell counts by treatment group. At 6 months post-delivery, 95% of women had CD4+ lymphocyte counts >300 cells/mm3. Only four women developed CD4+ cell counts below 200 cells/ mm3 during the course of the protocol, one on the treatment arm and three on placebo.
A regimen of ZDV administered to the mother during pregnancy and during labor and delivery, as well as to her infant during the first six weeks of life significantly reduced the risk of maternal infant transmission of HIV from 25.5 % to 8.3%.
The regimen was well tolerated by both mothers and infants, with no significant short term toxicities other than reversible mild anemia seen in some infants. There is no currently apparent adverse effect of the treatment regimen on the health of the women in the study or on the progression of their HIV disease.
This study currently provides no information regarding any late effects of ZDV on infants, including those who do not become infected with HIV. Continued long term follow-up of the infants in this trial, and of those who may subsequently be treated in a similar fashion, is a high priority.
Implications for Clinical Practice
The results are only directly applicable to women who initiate ZDV treatment between 14 and 34 weeks gestation, have received 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. This study was not designed to provide information regarding the efficacy of ZDV for the prevention of maternal-infant HIV transmission from infected pregnant women with clinical characteristics other than those described above.
The long term risks to those infants who are exposed to ZDV in utero and early infancy are not known although there is currently no information in humans to suggest such toxicities will occur. Pregnant women and their caregiver(s) who contemplate ZDV therapy to prevent maternal-infant transmission should give careful consideration to both the substantial potential benefit and the unknown long term risks. General recommendations regarding treatment must await broader consensus on the balance between known benefit and unknown risk.
When counselling patients regarding pregnancy related decisions it is important to provide information regarding the substantial 8.3 (+/- 4.5) percent risk of transmission despite therapy.
The study was not designed to discern the relative contributions of the antepartum treatment, intrapartum treatment, or treatment of the infant. The study provides no data regarding the efficacy and side effects of any other regimen for either mother or infant.
This study does not address the risk of ZDV use in the first trimester and ZDV therapy should not be instituted earlier than the 14th week of gestation solely for the prevention of maternal-infant transmission.
No information regarding the efficacy or risk of other agents such as ddI or ddC for this indication is available.
If a pregnant woman is infected with HIV, the therapy evaluated in this protocol may be of substantial benefit to her infant. These findings should therefore be considered in formulating policies or standard of care recommendations regarding counselling and testing of HIV infection status of pregnant women, as well as in the assessment and obstetrical care of individual women.