Karin Nielsen, MD, MPH
During the opening session of
this year's ICAAC there were somber predictions that the highly active
antiretroviral therapy (HAART) of today could become the failed antiretroviral
therapy of tomorrow.[1] The
euphoric optimism of a few years ago, based on the development of potent
protease inhibitors, was dampened by the knowledge that there is no evidence of
eradication of disease, and that latent reservoirs promptly release virus upon
cessation of therapy.[2] Yet
amidst the concerns over therapy failure, drug toxicities, and development of
genotypic resistance mutations, one of the speakers reminded the audience of
the continuing success story that is the reduction of mother-to-child HIV
transmission via prompt identification and treatment of HIV-infected pregnant
women and their infants.[3]
Although great strides have
been made in the last 5 years, there are still many issues regarding the
optimal management of the pregnant woman with HIV, including identification of
the safest and most cost-effective approach, as well as complex issues of
implementation of these findings in developing countries where control of the
epidemic in women and children is desperately needed. Extensive information about
recent advances in the area of maternal-fetal transmission was reviewed,
including issues of medical care, obstetrical, virologic, and immunologic
factors involved in the pathogenesis of HIV perinatal transmission, recent
clinical trials, and antiretrovirals (including toxicity data). Dr. Carmen
Zorrilla from the University of Puerto Rico and Dr. Lisa Frenkel of the
University of Washington thoroughly summarized the available facts and
discussed recent controversies at a Meet-the-Experts Roundtable session.[4,5]
Starting in 1993, a dramatic
decline in mortality rates of HIV/AIDS patients was noted in the United States,
including the population of HIV-infected women of childbearing age, leading in
turn to higher numbers of pregnant women infected with HIV. The continued
heterosexual expansion of the epidemic also contributed to this finding.
Reviewing the overall management of pregnant women with HIV, Dr. Zorrilla
mentioned that prophylaxis of opportunistic infections during pregnancy should
not be different from that of the HIV-infected nonpregnant patient.
Trimethoprim-sulfamethoxazole for PCP prophylaxis and azithromycin for Mycobacterium
avium complex prophylaxis should be instituted where warranted. In
addition management of a wide spectrum of infectious diseases such as
tuberculosis, syphilis, and bacterial vaginosis should not differ in this
population.
Although opinions vary among
specialists in the field, there is consensus that HIV disease in pregnant women
should be treated with antiretroviral regimens that would not be considered
substandard in nonpregnant women. Many recommend treatment should be instituted
at a threshold HIV RNA level of 5000 to 10,000 copies/mL. Others recommend
treating all patients, regardless of HIV RNA levels. There is also ongoing
discussion on whether this threshold should be lowered, given that the
relationship between HIV RNA and risk of disease progression may differ in
women compared with men.
Regardless of this observation,
however, use of antiretroviral regimens during pregnancy has changed in the
last 5 years. Data on 1201 pregnant women in the WITS study showed that
vertical transmission rates were 18% in 1990, peaked at 23% in 1993, and fell
to 3.9% by 1998.[6] Analysis
of the specific antiretrovirals used in this population indicated that today
approximately one third of the women followed still receive zidovudine (ZDV)
monotherapy. ZDV and a second antiretroviral, usually lamivudine (3TC), are
used by another third of the population studied. The remaining 33% to 35% of
women enrolled in this study are being prescribed triple antiretroviral
regimens or HAART.
Zidovudine monotherapy is
still the official recommendation for management of HIV-infected pregnant women
whose health status is such that therapy would not normally be indicated.[7] However, official recommendations may
lag behind current clinical practice and emerging data. The use of ZDV and 3TC
during pregnancy has become popular in both North America and Europe since
there is a more substantial improvement of plasma virus load (a stronger
antiretroviral effect) and more protection against development of high-level
ZDV genotypic resistance mutations. Specialists agree that HAART is
unquestionably warranted when plasma HIV RNA levels reach a specific threshold.
Nevirapine has been used as part of HAART or as a single drug given to the
mother at the time of delivery and to the infant for prevention of
transmission, as seen in the HIVNET 012 study and the ongoing PACTG 316.[8] Yet, many questions arise about the
use of HAART during pregnancy:
º
Should HAART be offered to pregnant women for the
purpose of prevention of perinatal transmission?
º
Should there be a lower threshold for institution of
HAART (for instance 1000 HIV RNA copies/mL plasma)?
º
Should HAART be interrupted postpartum in women with
HIV RNA less than 5000 copies/mL, especially since there are valid concerns
about adherence to more complex regimens during the postpartum period?
Many studies have reported
the strong association between an increased virus load and an increased risk of
perinatal transmission.[9-13]
To date a number of relatively small studies from developed countries have
shown that perinatal transmission in women who are receiving HAART and have
undetectable HIV RNA levels is zero. For example, Dr. Zorrilla highlighted a
study by Morris and colleagues[14]
which reviewed protease inhibitor use in 89 pregnancies; data were available
for 85 deliveries and the HIV transmission rate was zero. Similar small
European studies were recently presented at the Global Strategies Conference
for Prevention of HIV Transmission from Mothers to Infants held in Montreal in
September 1999. PACTG 185, a study comparing HIV-specific immunoglobulin
(HIVIG) vs placebo in women receiving zidovudine[15] also reported no perinatal transmission in women with
HIV RNA levels below the detectable range. There was no added benefit of HIVIG
and both arms reported transmission rates of approximately 4%.[16] Although these studies have
indicated that transmission of HIV with undetectable HIV RNA levels appears to
be an extremely rare event, a definite HIV RNA threshold below which no
vertical transmission occurs has not been identified.
If HAART achieves the goal of
reducing HIV load to undetectable levels and virus load is a significant risk
factor for perinatal transmission, then HAART in pregnancy may be the way to
go. However, there is controversy about stopping potent antiretroviral therapy
in women postpartum. Some specialists fear an increase in virus replication
following total suppression could lead to development of resistance, while
others counter that poor adherence during the postpartum period could
contribute to antiretroviral resistance.
Untreated women with undetectable
virus loads are NOT the same as treated women with undetectable virus loads,
since in untreated women there is no postexposure prophylaxis benefit to the
infant and there is always the risk that virus levels may increase at any given
moment. Dr. Zorrilla suggested that one should consider antiretroviral therapy
in this population, at least at the time of delivery so that the infant may
receive antiretroviral prophylaxis.
Because of so many unknowns
concerning the use of antiretrovirals during pregnancy, Dr. Zorrilla reminded
the conveners of the creation of the Antiretroviral Pregnancy Registry
approximately 2 years ago. Such registries are pivotal for monitoring potential
adverse effects, including maternal toxicities and teratogenicity. The Antiretroviral
Pregnancy Registry may be contacted at 1-800-258-4263 (US and Canada) or 1-910
251-9087 (international).
In February of this year, Dr.
Stephan Blanche presented data from his prospective perinatal cohort at the
Retrovirus Conference in Chicago.[17]
At the time he described two cases of fatal mitochondrial toxicity syndromes in
HIV-exposed infants who were uninfected and had been exposed to ZDV plus 3TC in
utero. These data were recently published, and the French researchers have
described 8 HIV uninfected children within their cohort (including the 2
patients above) with relatively diverse clinical findings attributable to
mitochondrial dysfunction syndrome.[18] Five
patients have had neurologic findings and the other 3 are symptom-free.
Persistent lactic acidosis was demonstrated in 5 patients.
These data generated
significant concern and prompted an extremely thorough review of CDC,
NIH/PACTG, and WITS databases in the US. The nucleoside safety review is
ongoing, but of 15,229 children exposed in utero to antiretrovirals,
no deaths within the cohort could be attributed to mitochondrial toxicity
syndrome. This led the researchers to conclude that there is no evidence for
fatal mitochondrial toxicity in children perinatally exposed to nucleoside
analogue antiretrovirals in the US.[19] Given
the very diverse and nonspecific findings of mitochondrial toxicity syndrome,
however, careful monitoring of perinatally exposed cohorts is warranted.
A recent publication has
reviewed data on 234 infants exposed to intravenous ZDV in 076. After 4.2 years
of follow-up, no deaths or cancers were noted, no effect on growth or cognitive
development was described. Two children had ophthalmic involvement and 1 child
had cardiomyopathy.[20] Animal
studies to evaluate antiretrovirals for potential toxicity and teratogenicity
are also crucial. Efavirenz, for instance, has been associated with gross
neurologic abnormalities in primate studies, and its use is contraindicated
during pregnancy. It is unknown whether teratogenicity occurs in humans.
It is for these reasons that
large-scale, long-term follow-up studies like PACTG 219 exist, where infants
exposed perinatally to antiretrovirals are followed until 21 years of age.
Perhaps even longer-term follow-up is warranted, since pathology could still be
found after decades of exposure. One has to remember, however, that the vast
majority of perinatally HIV-infected children in the developing world do not
have the luxury of decades of survival. The benefits of avoiding perinatal HIV
infection clearly outweigh potential theoretical risks of exposure.
Perinatal transmission of
antiretroviral-resistant strains of virus is reason for concern and has been
shown to occur, although only rarely to date. In ACTG 076, after a mean 3
months of exposure to ZDV, a 1% rate of low-level resistance mutations to ZDV
was observed in pregnant women. High-level resistance mutations were not seen.
Previous studies have
demonstrated that advanced maternal illness, maternal drug use, low vitamin A
levels (in African studies), preterm deliveries, and breastfeeding have been
associated with an increased risk of mother-to-child transmission. Vertical transmission
rates in African countries, where antiretrovirals are not routinely used during
pregnancy, have been approximately 25%. These rates are higher than those in
countries where HIV-infected mothers do not breastfeed, even in the absence of
antiretroviral therapy, reflecting the fact that breastfeeding is generally
estimated to carry an excess transmission risk of 14%.[21] Studies in Africa indicate that the
risk appears to be highest in the first weeks of life, carrying a 4% to 6% risk
between 6 weeks to 6 months.[22]
However, there is risk present throughout the duration of breastfeeding. A
study by Miotti and colleagues reported a .7% monthly risk of acquisition of
infection between 1 to 5 months of age, .6% between 6 to 11 months, .3% between
12 to 17 months, and .2% from 18 to 23 months.[22]
The declining rate of transmission could be an indication that the more
susceptible infants are infected in early life, rather than that there is a
lower risk of acquisition of infection later.
Mastitis has been shown to
also increase the risk of transmission of HIV by breastfeeding. Virus load in
breast milk was shown to be higher in transmitting mothers with mastitis.[23] A recently published study conducted
in Durban, South Africa, demonstrated higher rates of vertical transmission in
infants who received mixed feedings, compared with exclusive breastfeeding.[24] At day 1 of life, all infants had
similar perinatal transmission rates of approximately 6%, which reflected in
utero infection. By 3 months of age, 15% of exclusively breastfed infants
were infected, versus 24% of infants who received breast milk and dietary
supplementation and 19% of exclusively formula-fed infants. A possible
explanation of these controversial data is that a higher rate of gastrointestinal
infections prompted by the use of formula would facilitate transmission of the
virus present in breast milk in the population receiving mixed feeds. A second
study from Africa conducted in Nairobi compared transmission rates between
formula-fed and breastfed infants.[25]
This study observed an excess transmission risk of 16.2% in the breastfed arm;
37% of breastfed infants versus 20% of formula-fed infants were HIV infected on
long-term follow-up. Transmission via breast milk was highest in the first
weeks of life, and by 6 months of age 75% of breast milk infections had already
occurred. At 24 months of age mortality rates were comparable between both arms
(24% for breastfed infants vs 20% for formula-fed).
In summary, breastfeeding is
associated with a significant risk of HIV transmission, and limits the
potential of short-course antiretroviral regimens to minimize HIV transmission
rates in the developing world (see below). Creative strategies for reduction of
breast milk transmission in the developing world, particularly in Africa, are a
MUST if this epidemic is too be contained.
HIV perinatal transmission
risk factors of particular concern in industrialized countries include maternal
virus load at delivery, mode of delivery (higher rates with vaginal or
nonelective Cesarean sections), prolonged rupture of amniotic membranes. and
presence of chorioamnionitis. The placenta is recognized as a functional
barrier, since without concurrent use of antiretrovirals it prevents at least
75% of perinatal HIV infections. There have been reports that the placenta is
able to downregulate CXCR4 expression.[26]
Placental histologic pathology appears to facilitate HIV transmission from
mother to infant.
Other risk factors include
immunologic factors. Decreased CD4+ cell counts have long been reported to be
associated with an increased likelihood of transmission. A recent study found
that there is an increased risk of vertical transmission of HIV with higher
concordance rates in class I HLA types between mother and child.[27] The researchers hypothesize that the
infant's immune cells are more likely to react against infected maternal cells
that are genetically distinct and in this way circumvent infection. Another
study has indicated that genetic polymorphisms in the regulatory region of CCR5
may also influence transmission.[28]
The results of the widely
publicized meta-analysis on mode of delivery and perinatal HIV transmission
were reviewed.[29] With data
on more than 8000 patients, this study demonstrated a significant difference in
perinatal transmission rates (19% to 10%) between vaginal and nonelective
Cesarean sections versus elective C-sections in patients who did not receive
antiretroviral therapy. With concurrent use of antiretroviral therapy (the full
076 regimen) differences in transmission rates between both groups were 7%
versus 2%. Data from the 15 contributing studies were obtained at a time when
HAART were not available. Hence, there is no information as to whether elective
C-sections would provide any added benefit for women on HAART with undetectable
HIV RNA levels.
In a randomized trial of mode
of delivery, Semprini and colleagues also reported significantly lower rates of
HIV transmission among women randomized to elective C-sections.[30] Fever, bleeding, and anemia rates
were not significantly different between both groups. An analysis of the WITS
study data demonstrated a 19% total morbidity rate for elective C-sections,
with an 11% infection rate.[31]
Vaginal deliveries had infection rates of 8% for instrumented deliveries and 4%
for noninstrumented deliveries. The odds ratio (OR) for infection was 3.0 for
elective C-sections, 6.0 for nonelective C-sections, and 4.7 for diabetes. Dr.
Zorrilla commented that the population of women in this study changed over time
(the study started in 1989) since initially study participants tended to be
women with higher-risk behaviors more prone to medical complications.
If given the choice between
elective C-sections and antiretroviral treatment, it is clear that the latter
is a much better choice, since treatment prevents in utero infection
and also provides postexposure prophylaxis to the infant. Women who might benefit
from elective C-sections include those who were antiretroviral-naive at
delivery, those who had persistent or rising HIV RNA titers, and those with
concerns regarding adherence to the antiretroviral regimen during pregnancy.
Unquestionably, for all women, postpartum morbidity is higher with C-sections.
Yet the procedure is relatively well accepted by women living with HIV. The
possibility of an elective C-section should be discussed with patients, and
with balanced information provided by their physicians, they should ultimately
be the ones to decide whether they want an elective procedure. Dr. Zorrilla
recommended that postpartum morbidity data should not be the single factor to
be considered in the decision-making process.
Since the results of PACTG
076 were first reported, many perinatal intervention trials have been and
continue to be conducted around the world. The classic 076 trial showed the
efficacy of the three-part ZDV-containing regimen (to the mother during
gestation, intrapartum, and 6 weeks to the infant) in reducing vertical
transmission rates from 25.5% to 8.3%.[32]
The recent Thailand trial demonstrated a 51% reduction of vertical transmission
from 18.9% in the placebo group to 9.4% in the ZDV group when this drug was
initiated at >/= 36 weeks of gestation and orally every 3 hours during
labor. There was no breastfeeding in the study population and no drug was
delivered to the infant for postexposure prophylaxis.[33] A similar trial was conducted in
Abidjan, but in a population of breastfeeding women. The efficacy of ZDV in
reducing perinatal transmission in this trial was 37%. At 6 months of age, HIV
infection rates were 18% in the ZDV group of infants and 27.5% in the placebo
group.[34] A recent follow-up
presentation demonstrated that the efficacy of the short-course peripartum ZDV
regimen in this breastfeeding population fell to 30% by 450 days of age (21% in
the ZDV arm vs 31% in the placebo arm).[35]
The Petra trial, also
conducted in Africa (Uganda, Tanzania, and South Africa), evaluated the use of
ZDV in combination with 3TC in a three-arm regimen in 1447 women.[36] The first group of women initiated
therapy at 36 weeks and received intrapartum drugs, with the infant receiving
treatment for 1 week. In the second arm, treatment was started intrapartum and
the infant received 1 week of combination therapy. The third arm received only
intrapartum treatment, and a fourth group received placebo. Breastfeeding rates
approached 100% in Uganda and Tanzania but were 60% in Durban and 25% in
Johannesburg. The overall rate for the cohort was 69%. Transmission rates at 6
weeks were 7.8%, 10.2%, 15.7%, and 16.5% for first, second, third, and placebo
arms, respectively. Thirty-two percent of deliveries were via C-section. A
multivariate logistic regression analysis demonstrated that C-section had a
protective effect in the first and second arms (OR of 0.48 and 0.60,
respectively), but no protective effect in arm 3 and the placebo group.[37] This analysis saw no effect of
breastfeeding on perinatal transmission rates at 6 weeks, but the duration of
breastfeeding at that point was potentially too short to influence the efficacy
of perinatal antiretroviral regimens. CD4+ cell count was also found to be an
independent predictor of vertical transmission of HIV.
The recently published HIVNET
012 trial conducted in Uganda compared the efficacy of short courses of
zidovudine versus nevirapine (NVP) for prevention of perinatal transmission.[8] Women were randomized to one dose of
nevirapine at onset of labor and one dose of the drug to infants within 72
hours of birth, versus a loading dose of oral ZDV at onset of labor followed by
ZDV every 3 hours until delivery and 1 week of drug twice daily to the infant.
At 3 days of age transmission rates were equivalent for ZDV and NVP (10.4% and
8.2%) which reflects in utero transmission. At 6-8 weeks of age, rates
were 21.3% and 11.9% for ZDV and NVP, respectively, and by 14-16 weeks, rates
were 25.1% and 13.1%. The efficacy of NVP when compared with ZDV was 47%
greater. This trial has generated potential controversy with regard to issues
of implementation. Some argue that in populations where HIV seroprevalence is
extremely high it will be cost-effective to treat all pregnant women without
prior counseling and testing, although this view has been subject to much
debate.
It is clear from these
studies and others that antiretroviral therapy can reduce rates of perinatal
HIV transmission if instituted within 48 hours of birth. The postexposure
prophylaxis of the infant was critical to the success of nevirapine in the
HIVNET trial. Wade and collaborators also demonstrated the importance of
initiating therapy with ZDV within 48 hours of life in order to decrease
perinatal HIV transmission rates.[38]
In this analysis, women who received full 076 compatible regimens had
transmission rates of 6%, but transmission rates were 10% if treatment was
started with labor and continued in the infant, and 9% if given only to the
infant within the first 2 days. After that period transmission rates were
18.4%, statistically comparable to no treatment at all (26.6%).
At the end of the session it
was evident that so much progress has been achieved in the prevention of HIV
mother-to-child transmission, yet so much still remains to be achieved.
Progress is slowly being transformed into practice.
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3. Lange
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4. Zorrilla
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5. Frenkel,
L. Therapeutic issues pertaining to HIV-1 infected pregnant women in developed
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6. Garcia
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14. Morris A, Zorrilla
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18. Blanche S, Tardieu
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to antiretroviral nucleoside analogues. Lancet 1999; 354:1084-1089.
19. Smith M. Ongoing
nucleotide safety review of HIV-experienced children in the US. Programs and
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20. Culnane M, Fowler
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25. Ndauti R. The
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28. Kostrikis LG,
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CCr5 influence perinatal transmission of HIV. Programs and abstracts from the 6th
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4, 1999; Chicago, Ill, Abstract 263.
29. The International
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31. Read J, Kpamegan
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683.
32. Connor EM,
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33. Shaffer N,
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353:773-780.
34. Dabis F, Msellati
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regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed
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35. The DITRAME
Project Trial Study Team. Update on the DITRAME Trial. Programs and abstracts
from the 2nd Conference on Global Strategies for the Reduction of
Mother to Child Transmission of HIV; September 1-5, 1999; Montreal, Canada,
Oral presentation.
36. Saba J. Interim
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prevent mother to child transmission of HIV-1: the PETRA trial. Programs and
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37. Mcintyre JA, Gray
GE, and the Petra Trial Study Team. Programs and abstracts from the 39th
ICAAC; September 26-29, 1999; San Francisco, Calif. Abstract 585.
38. Wade NA, Birkhead
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perinatal transmission of the human immunodeficiency virus. N Engl J Med 1998;
339:1409-1414.