Highlights from the Conference
on Global Strategies on the Prevention of Mother-to-Child HIV Transmission
Leslie Hanna
More than 700 people, including a large contingent from Africa, attended
the Global Strategies on the Prevention of Mother-to-Child HIV Transmission
conference in Washington, DC, in September. Despite the optimism suggested
by the conference's title, a more appropriate name might have been "The
Lack of Global Strategies on the Prevention of Mother-to-Child HIV Transmission."
Although the conference drew attendees from around the world and there
was much discussion of the critical HIV-related needs of women and children
worldwide, there are no strategies yet that can be applied worldwide.
The availability of resources was a predominant and recurrent theme of
the conference. The challenge to provide HIV-related information and health
care to women and children is global. Even in the U.S. and western Europe,
there are many HIV positive women who do not receive adequate health care,
including prenatal care, despite the comparative wealth of these regions
and the generally better access to perinatal HIV transmission (PHT) prevention
strategies that exists there.
Social, economic and political factors have many implications for the
design and conduct of research protocols relating to PHT prevention. This
regrettable situation has led to recent public battles among scientists
and researchers from around the world about the ethics of conducting research
on HIV-infected women in developing nations of Africa and Southeast Asia,
where the challenge of providing of HIV-related care is very large.
In November, the Joint United Nations Programme on HIV/AIDS (UNAIDS)
announced the first phase of a promising collaboration between pharmaceutical
companies and health officials in developing nations that will attempt
to increase delivery of HIV-related drugs to HIV-infected residents. Pharmaceutical
companies that have thus far pledged their commitment are Glaxo Wellcome,
Hoffmann-LaRoche and Virco; the countries targeted for the pilot program
are Chile, Cote d'Ivoire, Uganda and Viet Nam. A new infrastructure will
be created in each country to execute the program's goals, and will include
a national HIV/AIDS Health Advisory Board and nonprofit companies charged
with the purchase and importation of drugs at subsidized prices. Ideally,
the pilot programs will prove successful and be expanded.
In order to devise the most effective strategies to prevent mother-to-child
HIV transmission, certain social, economic and political realities must
be faced. No matter how pristine the concept or beautiful the science,
medical innovations can only be implemented in "the real world."
To disregard this may delay finding truly effective global strategies.
Interventions that can be useful in the developing world must be cheap
and easy to use (i.e., no intravenous AZT infusions as the 076 regimen
demands), and must require the shortest possible time. Since many women
continue to breast-feed in the developing world, the ideal intervention
would benefit both breast-feeding and non-breast-feeding mothers.
Primary Prevention of HIV in Women and Children
The best way to prevent mother-to-child HIV transmission is to prevent
HIV infection in women. During the conference, presenters reviewed factors
that increase the risk of HIV infection in women. Cultural and societal
factors known to increase the risk of HIV infection in women include high-risk
behavior of sex partner(s), substance abuse, cultural practices such as
wife inheritance, domestic violence and sexual abuse (including the inability
of many women to refuse unsafe sex), lack of employment opportunities
and low education levels. The presence of untreated sexually transmitted
diseases (STD) in women as well as in their partners is known to increase
the risk of HIV infection. Anatomical factors such as cervical ectopy,
which is more common in younger women, also increase risk.
Knowledge of these factors propels research on how to prevent infection.
Vaginal microbicides continue to be a prevention priority, yet at this
conference there was no clinical news. Some agents have recently moved
into small clinical trials. Presenters reiterated that nonoxynol-9 failed
to prove effective in large clinical trials, and recommended testing specific
antiviral compounds for topical microbicidal use.
Ultimately, vaccines are likely to be the most effective approach for
preventing primary HIV infection as well as for preventing HIV infection
of infants born to HIV positive mothers. Several presentations were updates
on the status of candidate vaccines and the vaccine development process.
Currently, 3 vaccine clinical trials involving more than 2,000 HIV negative
participants are underway through the NIH. Although vaccine development
is controversial and is proceeding slowly, it is a research item of great
significance.
PHT Facts and Figures
The following updated facts and figures were presented at the conference:
- 1,000 infants are infected with HIV each day around the world
- 500 infants are infected with HIV each year in the U.S. (compared
to 2,000 per year before 1994/1995)
- The results of AIDS Clinical Trials Group (ACTG) 076 were released
in 1994, showing that a perinatal regimen of AZT used by mothers and
also by infants could reduce the risk of PHT by two-thirds. The cost
of the 076 regimen today is $1,000.00 U.S.
- In 1995 the Centers for Disease Control and Prevention (CDC) issued
guidelines recommending that all pregnant women be counseled about HIV
and offered HIV testing
- Between 1992 and 1996, new cases of pediatric AIDS decreased 47%
- The prevalence of HIV infection in pregnant women varies from approximately
0.01% in northern European countries to 10% in Caribbean countries to
40% in some sub-Saharan countries
- The United Nations reports that nearly half the new HIV infections
in 1996 occurred in women
- The World Health Organization (WHO) reports that 3.1 million new HIV
infections occurred in 1996. Approximately 3,750 women were infected
daily during 1996
- The WHO estimates that nearly 22 million adults are living with HIV
infection; 90% of people living with HIV infection live in the developing
world.
Drug Strategies and Chemo-prophylaxis against PHT
The regimen that was shown in ACTG 076 to reduce the risk of PHT by two-thirds
is the "gold standard," as well as the only approved strategy.
The standard of care in the U.S. and in Europe for all pregnant HIV positive
women is the ACTG 076 protocol (hereafter called the 076 regimen), which
involves AZT use during and after pregnancy as well as during labor and
delivery. The study, results and subsequent recommendations have been
discussed extensively in previous articles (see the September 1994 issue
of BETA for complete coverage).
Researchers assert that the regimen essentially works by protecting the
fetus against HIV infection. While the regimen has some ability to lower
maternal plasma viral load, this is not considered the sole or even primary
reason for the regimen's efficacy. Other factors not yet well understood
and undergoing investigation are felt to be involved. A better understanding
of what effectively reduces risk or prevents PHT would permit the development
of more effective strategies, including short-course chemotherapeutic
approaches for use in the developing world.
Secondary risk factors also appear to increase the risk of PHT. These
include advanced maternal HIV disease, the presence of other STD, maternal
intravenous drug use and lack of prenatal care (which may arise from lack
of access or from a pregnant woman's lack of awareness of her HIV status).
Other known risk factors are obstetrical instruments and procedures used
during pregnancy or birth, such as fetal scalp sampling and the use of
internal fetal and labor monitoring.
Vaginal births appear to involve a higher risk of PHT than cesarean sections.
However, study results are inconclusive and have not shown that the tentative
benefits outweigh the risks associated with cesarean sections, especially
postoperative complications to the mother's health. The length of time
between rupture of membranes and birth also increases the risk of PHT.
Several studies indicate that rupture of membranes longer than 4 hours
is associated with a significantly elevated risk of PHT. However, cesarean
sections are not universally recommended when rupture of membranes is
4 hours or longer; facilitating labor may be preferable. Researchers recommend
against artificially inducing labor.
Limitations to the AZT 076 regimen exist. First, the regimen does not
reduce the risk of PHT to 0%, that is, it does not always prevent PHT.
Critics of the AZT monotherapy regimen are legion. One of the biggest
concerns stems from the risk of AZT resistance that is incurred through
monotherapy. Since AZT monotherapy is now considered substandard care
for people with HIV, many advocates question the appropriateness of recommending
substandard therapy for an entire group of HIV-infected persons: pregnant
women.
For women who are already taking combination antiretroviral therapy before
their pregnancy, decisions about what to take during pregnancy can be
very complicated. It is not clear whether stopping highly active antiretroviral
therapy (HAART) in order to follow the 076 regimen will be more beneficial
or more detrimental. Benefits would include reduced fetal exposure to
drugs with unknown effects on fetal development; detriments might include
worsening of maternal health and return of a high viral load, which consequently
might increase the risk of PHT. Pregnancy-related treatment decisions
must encompass the woman's health status and history of antiretroviral
drug use, as well as personal choices about the inherent risks of treatment.
Several of the powerful combination antiretroviral regimens that are
now the standard of care for the treatment of HIV infection are being
evaluated for their ability to prevent PHT. Some triple combination PHT-related
trials underway in the U.S. are:
- ACTG 353: nelfinavir (Viracept), AZT and 3TC
- ACTG 354: ritonavir (Norvir), AZT and 3TC
- ACTG 357: abacavir (1592), AZT and 3TC
- ACTG 358: indinavir (Crixivan), AZT and 3TC
The expectation is that these preventive regimens will prove more effective
than AZT monotherapy for preventing PHT.
Since regimens involving multiple drugs may have disadvantages, including
an increased risk of side effects, high cost and complicated dosing schedules,
other studies will look at simpler regimens. ACTG 332 will evaluate the
safety and pharmacokinetics of the combination of d4T and 3TC in women
during pregnancy and in infants. ACTG 316 is a new, placebo-controlled
trial of nevirapine (Viramune) for preventing perinatal transmission from
women beginning in their third trimester of pregnancy. ACTG 324 will study
a simpler, shorter AZT regimen than the one used in ACTG 076. This study
will evaluate the pharmacokinetics and tolerance of an oral AZT regimen
given to HIV positive women only during labor and delivery.
Many presenters urged greater utilization of the Antiretroviral
Pregnancy Registry, which collects observational data on the
use of antivirals by pregnant women. Providers may call 800-722-9292,
extension 38465, to report data. Information is available by
calling the same number.
Nutritional Interventions
Most HIV-related studies of nutritional interventions fall into 2 categories,
pertaining either to dietary intake or to biochemical markers (serum levels).
In most studies of dietary intake, deficiencies of certain nutrients have
been associated with disease progression. For example, in the Multicenter
AIDS Cohort Study (MACS), those with the lowest intake of vitamins B,
C and E were most likely to progress to AIDS. On the other hand, dietary
zinc was associated with progression to AIDS in MACS, a finding that complicated
the issue of supplementation. In the second type of study, low serum levels
of vitamins E and B and certain minerals were associated with disease
progression. Mariana Baum, MD, and colleagues conducted much of this seminal
research at the University of Miami. In the August 15, 1997 issue of AIDS,
Baum published her most recent finding: selenium deficiency is an independent
predictor of decreased survival in people with HIV.
Both types of studies have limitations. In the first type of study, confounding
variables were introduced when it was discovered that adjustments were
not made for "big eaters," or for those with high or at least
adequate dietary nutrient intake. Nor was time since seroconversion factored
into the analysis. In the second type, biochemical markers for vitamin
A, selenium and zinc may not be predictive; they may reflect disease status.
That is, HIV infection may be driving the depletion of nutrients, not
vice versa. These issues about nutrient status and HIV infection have
yet to be fully clarified.
In dietary studies enrolling pregnant HIV positive women, vitamin A supplementation
has been associated with decreased PHT. A study by Richard Semba, MD,
and others from Johns Hopkins University, published in 1994, paved the
way for the current round of studies. The striking results of the 1994
study showed that vitamin A deficiency was strongly linked with PHT; the
greater the deficiency, the greater the rate of PHT. That study was conducted
in Malawi. Since then, pregnant women in the U.S. have been cautioned
to be careful about nutrient supplementation; vitamin A in high doses
taken during the first trimester can cause birth defects. Since most women
in the U.S. are not vitamin A-deficient, the maximum amount recommended
is 8,000 International Units (IU) daily during pregnancy.
Today, several trials of nutritional interventions attempting to reduce
the risk of PHT by giving pregnant women vitamin/mineral supplements are
underway, with results expected in 1998. Many are evaluating vitamin A
supplementation. Other micronutrients being evaluated are folic acid,
zinc and iron. Studies of nutritional interventions are primarily being
conducted in developing countries, where nutritional deficiencies are
more common and where supplementation, which is less costly than antiviral
treatment, may be more helpful. Research questions include: will vitamin
A supplementation for women during pregnancy and lactation reduce the
transmission of HIV? slow the progression of HIV disease? reduce viral
load? improve humoral and cellular immunity?
Breast-Feeding
Breast-feeding is a significant route of PHT. Although estimates vary,
a significant proportion of HIV positive children worldwide are believed
to have been HIV-infected after birth in this way. Risk is estimated to
range from 14% to 22% in some developing countries.
Over the past few years, researchers have begun to look more intently
at breast-feeding risks and options including different feeding methods
such as nutritionally adequate breast milk substitutes. Currently, there
is great interest in the timing of transmission through breast-feeding,
i.e., if PHT through breast-feeding is more or less likely in intervals
such as just after birth or by 12 months of age.
Breast-feeding recommendations for HIV positive women continue to differ,
depending on whether the woman lives in the developed world, where breast-feeding
is eschewed, or the developing world, where breast-feeding is still recommended
despite the known HIV-related risk. This is primarily because of high
risk to the child of other illness or death from malnutrition if breast-feeding
is withheld. Many in the HIV community are growing more and more uneasy
about breast-feeding in the developing world, and studies are examining
alternatives, including reduced duration of breast-feeding (e.g., 6 months
instead of the average 2 years) and formula-feeding.
Attitudes in the developing world will play an important role in devising
new strategies. Thus far, many women are resistant to deviating from the
average 2 years of breast-feeding because doing so simply is not the norm.
At the conference, African women and their advocates expressed fear of
drawing attention to themselves if they were to refrain from breast-feeding
their infants. A primary concern is that refraining from breast-feeding
could alert others in their community to their positive HIV serostatus.
Thus, empowering women to make fully informed decisions and support to
implement their decisions will be an important part of strategies that
seek to reduce risk of PHT via breast-feeding.
Another large task facing those in the developing world will likely be
the ensurance of high-quality breast milk substitutes for mothers who
choose not to breast-feed. Not only must an uninterrupted supply of infant
formula be assured, but techniques must be taught (e.g., providing assistance
to mothers whose infants have trouble "latching," a common problem
that may lead to colic and malnutrition). The ability to prepare the formula
also must be ensured. This requires a hygienic environment, clean water
to mix formula and to wash bottles, and the ability to boil water (i.e.,
availability of electricity or fuel) to sterilize bottles.
Most studies are being conducted in developing countries. Some data already
available shows variable rates of PHT through breast-feeding depending
on the age of the child. One of the biggest studies so far was conducted
in South Africa, where Glenda Gray, MD, and others divided 163 HIV positive
mothers into 2 groups: those who exclusively breast-fed and those who
(reported that they) exclusively bottle-fed. Final results were based
on the infants' serostatus at 18 months of age. Infants who were breast
fed were twice as likely to become infected with HIV, i.e., the relative
risk for breast-feeding was two-fold.
In Abidjan, Cote d'Ivoire, 138 infants who were born to HIV positive
mothers were evaluated. All were breast-fed. At 6 months of age, 24% of
the children were HIV positive. Of the 76% who were HIV negative at 6
months of age, 84 were followed until age 4 years. At some time after
age 6 months, another 12% seroconverted and tested HIV positive by age
4 years. In Brazil, of 103 infants born to HIV positive mothers, 19% of
those infants who were exclusively bottle-fed were HIV positive by age
2 years, compared to 49% who were breast-fed.
Other Interventions
Other interventions being evaluated were reviewed at the conference,
although little new data were reported. Other interventions include cesarean
section births, vaginal and newborn cleansing, short-course AZT and immunotherapeutic
strategies, namely the administration of protective antibodies (HIVIG
or IVIG). As discussed above, studies involving cesarean section to date
are inconclusive; some have suggested that having a cesarean section reduces
the risk of PHT, while others have suggested that cesarean sections make
no difference. Concern remains moderately high over the risk of post-cesarean
section infections and complications to the mother. Many of these studies
were presented in Vancouver last summer at the XI International Conference
on AIDS.
Presenters also discussed the results of studies that show that cleansing
the vagina and then the newborn, after birth, with an antiseptic solution
made with chlorhexidine effectively reduces the incidence of post-delivery
infections (primarily due to Group B streptococcus), hospitalizations
and deaths among both infants and mothers. The results of a 7,000-person
trial that took place in Malawi were published in the July 26, 1997 issue
of The British Medical Journal, and are similar to the preliminary results
involving a smaller number of participants that were reported in Vancouver.
PHT was reduced in association with use of 0.25% chlorhexidine when the
woman's membranes were ruptured for greater than 4 hours.
An ACTG study of HIVIG vs IVIG for reducing PHT was halted earlier this
year because transmission rates were 4.8% for both arms, which is extremely
low, considering that the women on average had more advanced disease than
the 076 participants. Most took antiviral drugs and began taking the 076
regimen early in pregnancy, at about 2 months. Thus, results could not
be compared or analyzed.
Mechanisms of PHT
Not many new data were presented on the mechanisms of PHT. Researchers
have begun to become more interested in and to scrutinize the placenta
for a better understanding of its role in preventing or facilitating HIV
transmission. Currently, it appears desirable for drugs taken during pregnancy
to cross the placenta to protect the fetus against HIV.
Viral load is believed to be a factor in transmission, but may not have
as much significance as previously suspected. Several studies have shown
that women with very high viral loads are more likely to transmit HIV
to their infants. However, conflicting evidence challenges this finding.
For instance, there are many documented cases to the contrary, and PHT
in most studies is seen to occur across a broad range of viral loads.
Therefore, while maternal viral load still concerns researchers, as well
as clinicians and patients, the current recommendation is to regard high
viral load primarily as an indicator of the mother's antiretroviral treatment
needs.
Most PHT is felt to occur during labor and delivery. Furthermore, more
children than previously suspected are now believed to be infected via
breast-feeding. The goal of research is to develop a keener understanding
of when and how PHT occurs, in order to develop the most efficient and
effective interventions to prevent PHT.
PHT Strategies and Issues in Developing Countries
The lack of economic and other resources in the developing world means
that the PHT reduction/prevention strategies that will be most widely
used in developing countries will differ from those commonly used in North
America and western Europe.
The topic of PHT-related research in the developing world is highly charged.
Critics have raised questions about the ethics of testing PHT prevention
strategies in regions of the world that simply could not afford to pay
for them, were they to be approved. Such therapies are likely not to be
available outside of the research setting after the study ends even if
the therapy is proved effective. Opponents decry the lack of ethics of
conducting placebo-controlled trials of potential PHT reduction therapies
in developing countries, when it is already established that there is
a better option than placebo for reducing PHT (the 076 regimen). The downside
of conducting placebo-controlled trials of PHT strategies is clear. Since
placebo-controlled trials of this kind would not be conducted in the U.S.
or other wealthier nations, critics contend that it is unethical to conduct
them anywhere.
On the other hand, other experts claim that giving active drug or therapy
in developing-world settings is what is exceptional. Most if not all pregnant
women would receive no treatment anyway, proponents reason. Thus, placebo-controlled
trials in the developing world are not as abhorrent as charged. The standard,
agreeable or not, is no treatment for pregnant women. If in the context
of a placebo-controlled clinical trial, in spite of all its disadvantages,
an affordable strategy relevant to the setting -- e.g., a short course
of oral AZT which would likely not compare favorably to the 076 regimen
-- is found better than no treatment (placebo), then the welfare of women
in that region has been bettered.
Nevertheless, in late October, Johns Hopkins University postponed a planned
trial that would have involved giving placebo to HIV positive pregnant
women in Ethiopia, constituting one of the latest rejoinders in a debate
that is far from over.
Leslie Hanna is Associate Editor of BETA.
Conference Quotes
"If one does a trial where one compares 076 to something else and
076 turns out to be the most effective therapy, what therapy can that
country use, if they can't possibly use the 076 regimen? We need to study
in developing countries regimens that [let us], in the end, leave the
country with something they can use."
---Lynn Mofenson, MD, National Institute of Child Health and Human Development
"The fact is that treatment is not the same in one country as it
is in every other, due to the grim realities of economic inequities. Acceptance
of this tragedy as a reality that cannot be changed is not acceptable
morally, not realistic practically and not defensible intellectually."
---Helene Gayle, MD, MPH, CDC National Center for HIV, STD and TB Prevention
Selected Sources
A book of unnumbered, unindexed abstracts from
the Global Strategies conference may be available in some libraries.
American Foundation for AIDS Research (AmFAR).
A Conference on Global Strategies for the Prevention of HIV Transmission
from Mothers to Infants. Washington, DC. September 3-6, 1997.
Lurie P and Wolfe SM. Unethical trials of interventions
to reduce perinatal transmission of the human immunodeficiency virus in
developing countries. The New England Journal of Medicine 337(12):
853-856. September 18, 1997.
Pitt J and Cotton D. Treating the HIV-infected
pregnant woman and her child. AIDS Clinical Care 9(12). December
1997.
Taha TE and others. Effect of cleansing the birth
canal with antiseptic solution on maternal and newborn morbidity and mortality
in Malawi: clinical trial. British Medical Journal 315: 216-220.
July 26, 1997.
Page last updated 05 February 1998
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