AZT May Reduce the Risk of Maternal Transmission of HIV

On February 21 the U.S. National Institutes of Health issued
a Clinical Alert announcing that AZT greatly reduced the risk
of HIV transmission from pregnant women to their babies,
according to preliminary results of the Federally-sponsored
trial ACTG 076; those who received the drug in the trial were
only a third as likely to transmit HIV to their children as
those who did not. As a result, AZT will be offered to all
currently enrolled pregnant women who remain in the study,
and also offered to their babies for the first 6 weeks of
life. It is also planned to follow all the infants who
participated in the study "to monitor for the possible
development of unknown late effects of study treatment."

The NIH points out that "there are currently 10-20,000 HIV-
infected children and approximately 7,000 infants born
annually to HIV-infected women in the United States; it is
estimated that by the year 2000, ten million children will
have been infected globally." Consequently, there are immense
implications arising from these preliminary trial results in
regard to the future standard of care for HIV-infected
pregnant women and their infants. As Peter Vink, M.D., the
doctor in charge of the site for this trial at the University
of Maryland School of Medicine in Baltimore, put it, "Until
this time there has been no equivalent to the clean needle or
condom for the pediatric population." Here we review the
background to the trial and discuss some of the implications
for future care which arise in relation to the preliminary
trial results.

This study, which began in April 1991, 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 the Institut National de la
Sant et de la Recherche Mdicale (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. Eligible patients were HIV-infected
women who were between 14 and 34 weeks pregnant; had had no
antiretroviral treatment, and had no clinical signs
indicating their need for AZT as part of their medical care,
during their current pregnancy; and had baseline T-helper
cell counts greater than 200. The women received either AZT
or placebo during the trial and neither the researchers or
the women knew which treatment arm the women had been
randomly assigned to.

While they were pregnant the mothers were given oral doses of
AZT and they also received it intravenously during labor.
They were seen frequently throughout their pregnancy and
delivery, and for 6 weeks after giving birth. They were also
carefully assessed for evidence of drug toxicity, HIV-disease
progression, and fetal well-being. The babies began receiving
AZT syrup 8-12 hours after they were born and for the
following 6 weeks; they were carefully monitored until they
were eighteen months old and were defined as HIV infected
based on one positive viral culture.

The preliminary results of the trial showed that 8.3 per cent
of babies were infected when both mothers and babies received
AZT, compared to 25.5 per cent of babies when the mothers and
babies had received a placebo. There was no difference in
birth defects between the two arms of the study and the rate
was the same as that for the population at large. Burroughs
Wellcome points to the same results from the pregnancy
register, which it established with the Centers for Disease
Control to document the use of AZT in pregnant women when AZT
was first released in 1987. While hemoglobin levels were
slightly lower for children in the AZT group these were not
significant enough to require transfusion and all resolved
themselves several weeks after completion of AZT therapy. AZT
was well tolerated by the mothers; of the 477 women enrolled
in the trial, only six discontinued therapy due to perceived
toxicity (three in the AZT group and three in the placebo
group).

While these results are certainly encouraging, there are
still many questions HIV-infected women who are pregnant, or
contemplating pregnancy, will need to consider in
collaboration with their caregivers -- this is not a cure,
eight per cent of babies are still infected and until more
data is available we do not know if there are any signs which
may indicate which women are at most risk from giving birth
to infected babies. Dr. Vink hails the results of this trial
as "tremendously exciting" but expresses cautions for future
standards of care. First, there is no conclusive evidence to
indicate whether babies are infected in the uterus or during
the birth process -- and whether babies whose mothers deliver
precipitously (and are thus unable to receive AZT
intravenously during labor) may be at greater risk of
infection than babies whose mothers are able to receive
intravenous AZT. Secondly, he points out that it is
imperative that the babies receive their first dose of AZT as
soon as possible after birth, are kept on their AZT regimen
for the first 6 weeks of their lives, and have their health
regularly monitored. In addition, there is no evidence as to
whether AZT would work as well if the mothers were to become
pregnant on subsequent occasions.

Rebecca Denison of WORLD (Women Organized to Respond to Life-
Threatening Diseases, a monthly newsletter written by and for
HIV-positive women to address concerns specific to women and
HIV disease; WORLD can be contacted at P.O. Box 11535,
Oakland, CA 94611, 510/658-6930) sees these preliminary
results as, "Wonderful if they hold up and there are indeed
no major side effects." She cautions, however, that women who
are contemplating pregnancy and have much higher T-helper
cell counts than the average for the women in the trial
(which was 586) may want to know more about whether they
should take AZT and how taking AZT would affect their own
health. She is concerned that there could be a danger that
the health of the mothers may not be considered to the same
degree as that of the babies. Laura Thomas of ACT UP San
Francisco agrees, pointing out that we really know very
little about the pregnancies of well HIV-positive women and
that until we have more research in this area it is difficult
for women to make informed choices on the use of AZT in
pregnancy. For instance, it may be that healthy women, or
women whose pregnancies are carefully monitored, are less at
risk for transmitting the virus to their babies anyway. There
is no data available so far to tell us whether the women who
had the highest viral loads were most at risk for
transmitting the virus.

Another area of concern is the one surrounding the testing of
pregnant women for HIV. Ms. Denison pointed out that many
women already sign a form for an array of tests, HIV just
being one of them, when they first become pregnant, without
being aware of the implications of a positive HIV result and
without receiving pre-test counseling. She and Dr. Vink both
expressed the hope that the trial results would not lead to
mandatory testing, but they also noted that, given supportive
counseling, most women are happy to be tested if they know a
positive result could lead to better care and a healthier
pregnancy.

While HIV-positive women now have more hope that transmission
of the virus to their babies is preventable, the preliminary
results of this study still leave many questions unanswered,
particularly for women anxious to weigh the risks before
deciding whether or not to become pregnant. However, as the
Clinical Alert from the National Institute of Allergy and
Infectious Diseases (NIAID) notes, "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 counseling and
testing of HIV-infection status of pregnant women, as well as
in the assessment and obstetrical care of individual women."
This leaves a major concern, though, as to how AZT will reach
those pregnant women who need it but are unable to afford it
and, of course, as Ms. Denison notes, many of the babies
being born to HIV-infected women are born to women in
countries where even basic health care is the exception
rather than the rule; for them AZT is not even likely to be
an option.

[Note: For copies of NIAID's ACTG 076 Questions & Answers,
the Clinical Alert, and the press release, call the AIDS
Clinical Trials Information Service, 800/TRIALS-A.]