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1994-04-25
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Clinical Alert: Important Therapeutic Information on the Benefit of
Zidovudine (AZT) for the Prevention of the Transmission of HIV from
Mother to Infant.
Source: National Institute of Allergy and Infectious Diseases (NIAID)
Summary:
This document provides information on the interim results of a
study 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. The study was 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 and 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 monitor for the possible development
of unknown late effects of study treatment. The Pediatric ACTG Executive
Committee and NIAID concurred with these recommendations.
There were 35 NIAID-sponsored sites, 15 NICHD-sponsored sites, and
9 centers in France.
This information is being provided to health care practitioners to
serve as preliminary information pending the publication of a formal
peer-reviewed report in the medical literature.
To receive a copy of the full Clinical Alert and Executive Summary,
call the AIDS Clinical Trials Information Service at 1- 800-TRIALS-A.
This 800 number can be reached from Canada as well.
Command-language searchers may receive the full text of this Alert
online by issuing a PRINT DL or a PRINT FT.
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 monitor 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 practitioner,
to serve as preliminary information pending the publication of a formal
peer-reviewed report in the medical literature.
Objective:
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.
Methods:
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.
Results:
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+ lymphocyte 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.
Conclusions:
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.
For more information about the Zidovudine study, please call 1-800-
TRIALS-A. This 800 number can be reached from Canada as well.
The full text of this alert has been mailed to all libraries that
are members of the National Network of Libraries of Medicine.