                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                        November 18, 1994

               Women and HIV Infection (Part XIII)

     Zidovudine for the Prevention of HIV Transmission from
                        Mother to Infant

     Worldwide, perinatal (i.e., mother to infant) transmission
accounts for most human immunodeficiency virus (HIV) infections
among children; in the United States, of the approximately 7000
infants born to HIV-infected mothers each year, 1000-2000 are
HIV-infected (1). Strategies for reducing perinatally acquired HIV
infection have included preventing HIV infection among women and,
for HIV-infected women, avoiding pregnancy or refraining from
breastfeeding their infants (2). On February 21, 1994, the National
Institutes of Health's National Institute of Allergy and Infectious
Diseases (NIAID) and National Institute of Child Health and Human
Development (NICHD) announced preliminary results from a
randomized, multicenter, double-blinded clinical trial of
zidovudine (ZDV) to prevent HIV transmission from mothers to their
infants (AIDS Clinical Trials Group [ACTG] protocol 076). This
report summarizes the interim results of that trial, which indicate
effectiveness of ZDV for prevention of perinatal transmission.

     The study was initiated in April 1991 by the Pediatric ACTG
of NIAID in collaboration with NICHD and the National Institute of
Health and Medical Research (INSERM) and the National Agency of
Research on AIDS (ANRS), France. Eligible participants were
HIV-infected pregnant women who had received no antiretroviral
treatment during their current pregnancy, had no clinical
indications for maternal antepartum antiretroviral therapy in the
judgment of their health-care provider, and who had a CD4+
T-lymphocyte count greater than 200/uL at time of entry into the
study. Enrolled women were randomized to receive either a ZDV or
placebo regimen. The ZDV regimen included antepartum ZDV (100 mg
given orally five times daily) initiated at 14-34 weeks' gestation
and continued for the remainder of the pregnancy; intravenous ZDV
during labor (administered intravenously as a loading dose of 2 mg
per kg body weight given over 1 hour, followed by continuous
infusion of 1 mg per kg body weight per hour until delivery); and
oral administration of ZDV to the newborn (ZDV syrup at 2 mg per
kg body weight per dose given every 6 hours) for the first 6 weeks
of life, beginning 8-12 hours after birth (see box). The placebo
regimen was given on the same schedule. Blood specimens were
obtained for HIV culture from all infants at birth and at ages 12,
24, and 78 weeks. A positive viral culture was considered
indicative of HIV infection. Infants also were tested for HIV
antibody at ages 15 and 18 months.

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Eligibility Criteria and Zidovudine Regimen for HIV-Infected
Pregnant Women and Their Infants Participating in AIDS Clinical
Trials Group Protocol 076

Patient Eligibility:

*    Has not received antiretroviral treatment during current
     pregnancy

*    Has no clinical indications for maternal antepartum
     antiretroviral therapy in the judgment of her health-care
     provider

*    Has a CD4+ T-lymphocyte count greater than 200/uL at initial
     assessment

Zidovudine Regimen:

*    Oral administration of 100 mg zidovudine (ZDV) five times
     daily, initiated at 14-34 weeks' gestation and continued for
     the remainder of the pregnancy

*    During labor, intravenous administration of ZDV in a loading
     dose of 2 mg per kg body weight given over 1 hour, followed
     by continuous infusion of 1 mg per kg body weight per hour
     until delivery

*    Oral administration of ZDV to the newborn (ZDV syrup at 2 mg
     per kg body weight per dose given every 6 hours) for the first
     6 weeks of life, beginning 8-12 hours after birth

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     Based on analysis of data for 364 births through December
1993, ZDV therapy was associated with a 67.5% reduction in the risk
for HIV transmission; the estimated rates of transmission were
25.5% (95% confidence interval [CI]=18.3%-33.7%) among the 184
children in the group receiving the placebo regimen compared with
8.3% (95% CI=3.8%-13.8%) among the 180 children in the group
receiving ZDV (Kaplan-Meier estimate at age 18 months; p=0.00006).
Although the ZDV regimen was well tolerated by mothers and infants,
hemoglobin levels were lower for infants in the ZDV group (mean
decrease in hemoglobin was less than 1 g/dL); however, this problem
resolved without therapy following completion of ZDV treatment. The
incidence of reported side effects was similar among mothers and
infants between the two randomized groups.

     Based on these interim findings, NIAID accepted the
recommendation of an independent data and safety monitoring board
to terminate enrollment into the trial and to offer ZDV to women
in the group who had received the placebo but had not yet delivered
and to their infants aged less than 6 weeks. An NIAID Clinical
Trials Alert summarizing the trial is available by calling (800)
874-2572.

REPORTED BY: 

     Div of AIDS, National Institute of Allergy and Infectious
Diseases; Center for Research for Mothers and Children, National
Institute of Child Health and Human Development; National
Institutes of Health.

EDITORIAL NOTE: 

     This clinical trial demonstrated efficacy of ZDV in reducing
perinatal HIV transmission when administered to HIV-infected women
meeting the study's eligibility criteria (see box). However, these
findings are subject to at least four limitations. First, the study
did not assess the efficacy of ZDV among women with CD4+
T-lymphocyte counts less than or equal to 200 cells/uL or among
women who had previously used ZDV for extended periods and who may
be infected with ZDV-resistant strains of HIV. Second, this trial
could not assess the relative or independent contributions of the
antepartum treatment, intrapartum treatment, or treatment of the
infant; therefore, the efficacy and side effects of ZDV regimens
restricted to only one or two of these treatment periods is
unknown. Third, the study did not evaluate the risk or benefit of
ZDV use in the first trimester. Finally, the study has not yet
provided information about long-term side effects for infants and
mothers treated with ZDV, including infants who did not become
infected with HIV; however, long-term follow-up of infants and
mothers is being conducted to monitor for possible late side
effects.

     Based on the findings of ACTG protocol 076, the Public Health
Service (PHS) provides the following interim recommendations*: 1)
all health-care workers providing care to pregnant women and women
of childbearing age should be informed of the results of ACTG
protocol 076; 2) HIV-infected pregnant women meeting the protocol
eligibility criteria should be informed of the potential benefits
but unknown long-term risks of ZDV therapy as administered in ACTG
protocol 076, and decisions to use ZDV for prevention of perinatal
transmission should be made in consultation with their health-care
providers (see box); 3) health-care providers should inform their
patients that this ZDV regimen substantially reduced, but did not
eliminate, the risk for HIV infection among the infants; and 4)
until the potential risk for teratogenicity and other complications
from ZDV therapy given in the first trimester can be assessed, ZDV
therapy only for the purpose of reducing the risk for perinatal
transmission should not be instituted earlier than the 14th week
of gestation. PHS is developing further recommendations for the
uses of ZDV for HIV-infected pregnant women whose clinical
indications differ from the ACTG protocol 076 eligibility criteria
and for counseling and HIV-antibody testing for women of
childbearing age.

     The international Antiretroviral Pregnancy Registry, sponsored
by Burroughs Wellcome Co. (Research Triangle Park, North
Carolina)** and Hoffmann-LaRoche Foundation, Inc. (Nutley, New
Jersey)**, is collecting observational, nonexperimental data on
exposure to ZDV and dideoxycytidine (ddC) during pregnancy. Women
who have been treated with either of these drugs at any time during
pregnancy for any duration are eligible for registry enrollment.
Patients can be enrolled by contacting the registry, telephone
(800) 722-9292, extension 8465; fax (919) 315-8981.

REFERENCES

1. CDC. National HIV serosurveillance summary: results through
1991. Vol 3. Atlanta: US Department of Health and Human Services,
Public Health Service, 1994.

2. CDC. Recommendations for assisting in the prevention of
perinatal transmission of human T-lymphotropic virus type
III/lymphadenopathy-associated virus and acquired immunodeficiency
syndrome. MMWR 1985;34:721-6,731-2.


*    These recommendations do not reflect current Food and Drug
     Administration-approved labeling for ZDV.

**   Use of trade names and commercial sources is for
     identification only and does not imply endorsement by the
     Public Health Service or the U.S. Department of Health and
     Human Services.

(Centers for Disease Control and Prevention. Morbidity and
Mortality Weekly Report. 1994;43(16):285-87.)

      Task Force to Study Implications of AZT in Pregnancy

     The U.S. Public Health Service has established a task force
to explore the medical and policy implications of the recently
announced findings of a National Institutes of Health clinical
trial that tested the effectiveness of AZT in preventing
transmission of the human immunodeficiency virus (HIV) from
pregnant women to their babies.

     Preliminary findings from randomized, blind clinical trials
showed a 67.5 percent effectiveness rate in blocking HIV
transmission to newborn infants through the use of AZT, with little
apparent adverse effect on the women or on the progression of their
disease.

     Perinatal transmission is responsible for the majority of HIV
infections in children in the United States and throughout the
world. 

     "The challenge of the task force will be to develop a rational
approach in translating the results of this clinical trial into
appropriate policy and practices," said Dr. Philip R. Lee, HHS
assistant secretary for health and director of the U.S. Public
Health Service. "Under the leadership of the National Institutes
of Health, the efforts of the task force will address critical
questions regarding treatment, testing, monitoring and resource
needs, which are raised as a result of this study.  The task force 
has begun moving expeditiously because of the urgency of these
issues for the community and for the health care providers."

     The task force members are:

     Chairwoman Lynne Mofenson, M.D., associate chief of the
     pediatric, adolescent and maternal AIDS branch, Center for
     Research for Mothers and Children, National Institute of Child
     Health and Human Development, NIH.

     James Balsley, M.D., Ph.D., chief of the pediatric medicine
     branch of the Division of AIDS, National Institute of Allergy
     and Infectious Diseases, NIH. 

     Martha Rogers, M.D., chief of the epidemiology branch of the
     Division of AIDS, Centers for Disease Control and Prevention.
     Helene D. Gayle, M.D., Ph.D., chief of the HIV/AIDS division,
     CDC.

     David Feigal, M.D., director of the anti-viral drug product
     division, Food and Drug Administration.

     Patricia S. Fleming, special assistant to the secretary, HHS.

     Frances Page, RN, MN, public health adviser, Office of
     National AIDS Policy.

     Patricia Salomon, M.D., associate director for clinical
     affairs, Bureau of Primary Health Care, Health Resources and
     Services Administration.

     David Lanier, M.D., health policy analyst, Agency for Health
     Care Policy and Research.

     The task force will also make use of outside experts,
including academic researchers, clinicians, HIV-infected women,
representatives of professional societies, state and local public
health officials and ethicists.

(Press Release. Public Health Service. National Institutes of
Health. May 10, 1994.)

        Ethical Challenges Posed by Zidovudine Treatment
             to Reduce Vertical Transmission of HIV

     Despite the prospect of great benefits from the study showing
that the use of zidovudine (AZT) can help reduce maternal-infant
transmission of HIV, many ethical questions remain unanswered. The
most important issue is whether AZT will put at risk the 70 to 80
percent of children who, though born to infected women, would not
have been infected themselves.  Many clinicians argue that the case
for testing pregnant women for HIV is now stronger than ever, but
many AIDS and women's rights advocates are skeptical about the
claims on behalf of AZT treatment during pregnancy.  The underlying
fear is that the new findings would be used to undermine the
privacy rights of pregnant women at risk for HIV--the majority of
whom are poor, black, or Hispanic women. Mandatory screening of
children could be justifiable if therapeutic interventions could
significantly extend the lives of infected children because
treatment would be necessary, despite parental objections. 
Mandatory screening of pregnant women, however, is problematic
because mandatory treatment of competent adults is rarely
acceptable.  Also, no recommendation for HIV testing would be
ethical if access to the necessary therapy and counseling were not
guaranteed.  The daily five-dose AZT regimen would be too difficult
and too expensive to enforce. (Bayer R. New England Journal of
Medicine. 1994 Nov 3;331(18):1223.)

                    Mother and Child and AZT
                     by Elizabeth B. Cooper

     In February 1994, a federal Data Safety and Monitoring
Committee announced that, based on preliminary data, it would halt
enrollment in clinical trial ACTG 076, a study designed to examine
whether mother-to-child (vertical) transmission of HIV could be
reduced if the mother and newborn were given AZT.  To the surprise
of many observers, initial data projections indicated that there
was a 67 percent reduction in maternal HIV transmission among trial
participants given AZT.
     ACTG 076 was a double-blind, placebo-controlled trial in which
women were given AZT or a placebo beginning in the second or third
trimester and intravenously during labor, with infants receiving
AZT syrup for the first six weeks of life.  The women enrolled had
CD4 counts above 200, no other need for AZT treatment, and no prior
experience with the drug.  Additional preliminary investigation
indicated similarly low levels of birth defects and mortality in
the newborns given AZT and those given the placebo.  It is not yet
possible to know the long-term effects of AZT on children (e.g.,
with regard to growths, cancers, or other medical complications)
or mother (e.g., with regard to AZT resistance).
     ACTG 076 was begun under the cloud of significant community
concern that adequate protections for the women enrolled were not
established and that the trial was not well-designed.  For example,
it was only after much community agitation that researchers
recently agreed to examine the long-term impact of AZT use during
pregnancy among women; initially, follow-up studies were to focus
solely on the newborns.
     While the results of this trial bring hope to HIV-positive
women who wish to bear children, they spark a host of questions as
well.  Many have raised concerns about the lessons to be gleaned
from this study.  Because the trial involved women in good health
with CD4 counts averaging above 500, it is not known whether the
protocol will be effective for women with more advanced HIV
disease, previous use of AZT, or AZT-resistant virus.  The protocol
involved the intake of AZT at three different points: gestation,
delivery, and after birth.  Yet we remain unsure of the point at
which AZT was most effective in helping to reduce transmission. 
It is likely that the significantly reduced transmission rates
experienced in the controlled environment of the ACTG 076 trial may
not be achieved in the "real world" of limited access to health
care.
     The Public Health Service has issued guidelines on the
counseling of HIV-positive women on the use of AZT during pregnancy
yet many are concerned that health care workers may attempt to
coerce women into taking AZT.  In addition, as a result of ACTG
076, calls for the mandatory HIV-antibody testing of pregnant women
and newborns have increased.  Legislation to this effect has been
introduced, but thus far tabled or defeated, in New York, Michigan,
Pennsylvania, Florida and the U.S. Congress.  Because the women
primarily affected by this issue are likely to be low-income women
of color, the political landscape of the study and its
ramifications must be examined.
     While it is important that women have the option of learning
their serostatus during pregnancy and delivery (if not before), we
must carefully consider the methods by which this option is
presented.  First, many more women may already know their status
than health care providers are aware; others may choose not to know
of their status.  The reasons for ignorance of HIV status and non-
disclosure are ongoing:  fears of breaches of confidentiality, a
perception of insufficient access to care and services for those
who test positive, and continuing discrimination against people
(and families) with HIV.
     As we have seen throughout the epidemic, mandatory testing
programs consistently frighten people away from services.  For
example, when New York City required newborns to be screened for
drug metabolites there was a significant increase in the number of
babies not taken home from the hospital; many women either feared
prosecution or assumed that their children would be taken from them
regardless.
     Furthermore, legal experts conclude that such a mandatory
testing program--whether focusing on pregnant women, women who have
just delivered, or newborns--would likely be found to violate many
of a woman's constitutional and statutory rights, including her
right to privacy (with regard to consent to testing as well as
privacy of personal medical information), equal protection,
informed consent, and the right to make medical decisions on behalf
of her children.  It would be highly unethical--and illegal--to
force a woman to take AZT without her full voluntary and informed
consent.  Absent extraordinary circumstances, not present in this
context, a woman cannot legally be forced to accept medical
intervention she does not wish to have.  In addition, she must be
counseled with regard to the possible risks and benefits of this
potentially toxic treatment.  It would be inappropriate to yield
to the expectations of some that every HIV-infected pregnant women
should take AZT regardless of her own treatment decisions.
     Early identification of HIV infection is important, but it is
not enough.  We must shift the focus of the debate to the need for
accessible, comprehensive health care.  What has worked--quite
effectively--is access to HIV-related counseling that provides
links to confidential pre-natal care and well-baby services.  A
woman's consent for HIV testing and treatment decisions is
dependent on this education and counseling, which must be
universally incorporated into pre-natal and pre-pregnancy care. 
Although it is useful for a woman to learn her serostatus following
delivery, learning it before she becomes pregnant or during
pregnancy will give her a wider range of prevention, treatment and
reproductive options.  As important, decent quality of care should
not be tied to a woman's decision to be tested or not tested.
     In reality, neither mandatory testing nor "mandatory
treatment" will accomplish what their adherents claim:  access to
care for the child or mother.  Rather, such programs are likely to
drive a wedge between the woman and health care provider,
undermining this critical relationship and, in turn, undermining
the care that must be provided.  If we devote our attention solely
to the child--at the expense of providing care to both mother and
child--a woman's role as the critical component of her baby's
health is reduced to that of carrier and deliverer.
     By building policy on the assumption that a pregnant woman,
including an HIV-positive pregnant women, is interested in giving
birth to a health baby, we foster, rather than undermine, the
essential parent-child loving bond and the critical provider-
patient trust relationship.  Notably, this conclusion also has been
reached by divisions of the American Medical Association, the
American Academy of Pediatrics, the American Public Health
Association, the National Academy of Science/Institute of Medicine,
and the American College of Obstetricians and Gynecologists (NY).
     This more comprehensive approach both respects the individual
and protects the public health--thereby benefitting both mother and
child--which, indeed, is our goal.

                          Editor's Note

     The article above is reprinted from The Active Voice (Autumn
1994, pp. 1,5), a publication of The National Association of People
with AIDS Public Policy and Education Department (NAPWA, 1413 K
Street, N.W., Washington DC 20005. Phone: 202-898-0414 or fax: 202-
898-0435).  Information contained in this publication is for
educational purposes only and does not constitute an endorsement. 
Permission to duplicate is granted and encouraged; please
acknowledge the source.
     The author of the article, Elizabeth B. Cooper, is a clinical
instructor at the Brooklyn School of Law in New York City and Co-
Chair of the New York Task Force on Women and AIDS.
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