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Perinatal Transmission and HIV:
Two Realities“National and International
Perspectives”
Tanya Zangaglia, MDMedical Director, Project Streetbeat
Curriculum Coordinator, NY/VI AETCColumbia Univ. School of Public Health
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What has been the most
significant accomplishment
of the HIV/AIDS era?
Perinatal Transmission and HIV:
Two Realities
3
The number of women living with HIV/AIDS
is growing
Perinatal Transmission and HIV:
Two Realities
4
Over four-fifths of all HIV-
infected women in the U.S.
are of childbearing age
Perinatal Transmission and HIV:
Two Realities
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HIV positive women are:
• Living longer• Feeling more hopeful• Choosing life
Perinatal Transmission and HIV:
Two Realities
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HIV positive women are choosing to become
pregnant
Perinatal Transmission and HIV:
Two Realities
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Perinatal Transmissioncontinues to exist in the
United States
Perinatal Transmission and HIV:
Two Realities
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Perinatal Transmission has
declined by at least 80%between 1992 and 1999
JAMA1999; 282:531
Perinatal Transmission and HIV:
Two Realities
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It is now possible to achieve
Perinatal Transmission rates
as low as 1-2%… this contrasted to 25-
30% a decade ago
The Hopkins HIV ReportJean R. Anderson, MD
July 2001; p2
Perinatal Transmission and HIV:
Two Realities
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Many women who arepregnant are not offeredcounseling and testing
andremain undiagnosed –
manyof these women are not
perceived to be “at risk”
Perinatal Transmission and HIV:
Two Realities
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• Conducted in 7 states
• Found that 20% of women with HIV-infection were not diagnosed before delivery
• Reported that 36% of HIV-infected women using illicit drugs during pregnancy had no prenatal care
HIV SURVEILLANCE REPORT
Wortley, et. al.MMWR 2001; 50:RR6-17
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Universal HIV testing with patient
notification as a routine part of Prenatal care is currently
supportedby the:
– Institute of Medicine– American College of
Obstetricians and Gynecologists
MANDATORY HIV TESTING OF PREGNANT
WOMEN
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Maternal plasma viral load is
viewed as perhaps the most
important correlate of perinatal
transmission in both antiretroviral
treated and naïve womenGarcia, et. al. NEJM 1999; 341:394
Mofensen et. al.NEJM 1999; 341:385
MATERNAL VIRAL LOAD
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MATERNAL VIRAL LOAD• A meta-analysis of 7 European
and U.S. prospective studies examined mother-to-child transmission when maternal viral load was < 1000 c/ml
• The study found that the risk of HIV transmission was lowered from 9.8% in untreated women to 1% in women treated with antiretroviral therapy (generally AZT alone)
Ionnides, et. al. J. Infect Diseases
2001; 183:539
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In the past decade the clinicalthinking has shifted from
beingreluctant to treat HIV positive
pregnant women to nowrecommending antiretrovirals
for allpregnant women with HIVregardless of CD4 count or
viral load
MATERNAL VIRAL LOAD
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PACTG 076STUDY PROTOCOL
• AZT administered from week 14 of gestation
• AZT continued throughout pregnancy
• AZT given as an IV infusion to the mother during labor
• AZT given to the newborn for 6 weeks
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• Anger, skepticism, thoughts of genocide, reluctance
• Adverse fetal effects
• Unethical to withhold AZT from some women who might receive direct benefit themselves, but instead were randomized to receive a placebo
PACTG 076EARLY CONCERNS
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• Study stopped prematurely
• Review by the data and safety Monitoring board found a highly significant difference in transmission rates between women who received AZT and those randomized to placebo
PACTG 076EARLY RESULTS
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• VT was reduced by 66%
• VT decreased from 22.6% (in placebo recipients) to 7.6% (in those receiving AZT)
PACTG 076IMPACT ON VERTICAL TRANSMISSION (VT)
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• Immediate action taken
• Study protocol became the standard of care for pregnant women with HIV infection
PACTG 076PUBLIC HEALTH RESPONSE
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• Original study cohort consisted of women with CD4 > 200 cells/mm3 and no prior AZT exposure
• Subsequent observational studies confirmed the effectiveness of 076 in women with more advanced disease who were not antiretroviral naive
PACTG 076
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• Many women do not present for care until much later in pregnancy (ex: 3rd trimester rather than 2nd trimester)
• IV catheters are not available to women in labor in a large part of the world where HIV predominates
• The cost of the 076 regimen is prohibitive for all but a few of the worlds’ nations
PACTG 076ONGOING DEBATE
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• In this study AZT was started as late as 36 weeks of pregnancy
• AZT was given orally in labor
• There was no neonatal component
Lancet Shaffer, et. al.1999; 353:773
THAI SHORT-COURSE AZT STUDY
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• Still achieved significant reductions in mother-to-child transmission
• 50% decline noted compared to placebo in a non-breast feeding population
Lancet Shaffer, et. al.1999; 353:773
THAI SHORT-COURSE AZT STUDY
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• Study also found that both plasma and genital tract viral load were suppressed by AZT treatment
• Both were independently correlated with transmission
J. Infectious DiseasesChuachoowong, et. al
2000; 181:99
THAI SHORT-COURSE AZT STUDY
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• Showed that the length of maternal treatment is a significant variable in reducing HIV transmission
• Therapy started at 28 weeks gestation is far superior to therapy started at 35 weeks
NEJMLallemont, et. al.2000; 343:1036
OTHER SHORT-COURSE AZT STUDIES
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• Studies highlighted the fact that approximately 1/3 of transmission occurs earlier in pregnancy
• Also studies demonstrated that the effectiveness of therapy is blunted by breastfeeding
NEJM Lallemont, et. al.2000; 343:1036
THAI SHORT-COURSE AZT STUDY
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• A single oral dose of Nevirapine was given to a pregnant women at the onset of labor
• A single oral dose of Nevirapine was given to her newborn within 48-72 hours of birth
Lancet Guay, et. al.
1999; 354:795
HIV NET 012 TRIAL
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• Results show an approximate 50% reduction in transmission compared with oral AZT given intrapartum and to the infant for one week
Lancet Guay, et. al.
1999; 354:795
HIV NET 012 TRIAL
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• Less expensive
• Offers the most realistic option for the developing world
• Allows women to be treated who first present for medical care in labor
• It can be given as directly observed therapy (DOT) Lancet
Guay, et. al.1999; 354:795
HIV NET 012 TRIALTHE REGIMENTS
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• No clinical trials evaluating HAART for the purpose of reducing perinatal transmission have been completed
• Yet and still, HAART is the standard of care in the majority of HIV positive pregnant women in the U.S.
• This is especially true in women who require HAART for their own infection
HAART
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• HAART is effective in reducing Viral Load to undetectable levels
• This in turn further lowers the likelihood of transmission between mother and fetus
HAART
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• International Phase III trial
Compares:
• Standard antiretroviral therapy (2-3 drug regimen)
Plus 2-dose NevirapineVS
• Standard antiretroviral therapyPlus placebo
8th CROI [Abstract LB7]Dorenbaum, et. al.
Chicago 2/01
PACTG 316
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• Very low rates of transmission in both study arms
• 1.5% NVP
• 1.4% Placebo
• Study concludes:– Effective treatment of mom
allows for effective prophylaxis of the fetus
8th CROI [Abstract LB7]Dorenbaum, et. al.
Chicago 2/01
PACTG 316
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Is Cesarean Section an appropriate
choice/option for “preventing”
Perinatal HIV Transmission?
CESAREAN SECTION
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• Randomized clinical trial comparing:
– Scheduled C-Section vs. Vaginal Delivery
– Transmission Rates:• 1.8% in women randomized to
planned C-Section• 10.6% in women with planned vaginal
deliveryLancet
The European Mode of Delivery Collaboration1999; 353:1035
CESAREAN SECTION
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• Observational data from 15 prospective cohort studies examined in a meta-analysis
• A total of 7,800 mother-infant pairs in the study
NEJMThe International Perinatal HIV Group
1999; 340:9770
CESAREAN SECTION
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• The study found that women undergoing C-Section before the onset of labor or ruptured membranes had significantly lower Perinatal HIV Transmission
NEJMThe International Perinatal HIV Group
1999; 340:9770
CESAREAN SECTION
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• These rates were compared to those women having Vaginal Delivery or C-Section after membrane rupture, regardless of AZT use
NEJMThe International Perinatal HIV Group
1999; 340:9770
CESAREAN SECTION
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• Current data is insufficient to evaluate potential benefits of planned C-Sections in women treated with antiretroviral therapy with viral loads less than 1000 c/ml
The Hopkins HIV ReportJean R. Anderson, MD
July 2001
CESAREAN SECTION
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• Resistance is increasing in frequency, even among antiretroviral-naïve individuals…the implication for perinatal transmission is unknown
• The role of C-Sections in women with low viral loads or with short duration of ruptured membranes is not yet established
• Should serum concentrations of antiretrovirals in pregnant women be monitored for purposes of safety and for efficacy?
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPED WORLD
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• Are drugs toxicities more common in HIV positive pregnant women?
• What, if any, long term effects will we see in exposed but uninfected infants?
• What are the issues involved in the use of rapid tests to make a diagnosis of HIV in labor?
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPED WORLD
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Issues in the developing world
are much more basic, yet more
overwhelming
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPED WORLD
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The majority of AIDSORPHANS reside in thedeveloping world and isestimated at 13.2 million
globally
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPING WORLD
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• Issues of access to antiretroviral therapy continue to arise:
– Resources are needed to offer HIV counseling and testing
– Affordable and available drugs are needed
– A healthcare infrastructure is needed to allow for proper distribution and education
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPING WORLD
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• Breastfeeding (BF)
– The mode of transmission in up to 50% of newly infected children world-wide
– Affordable alternatives are not widely available
– The general benefits in infant nutrition and infant morbidity and mortality are established
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPING WORLD
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• Breastfeeding (BF)
– BF vs. formula feeding (FF) in Kenya• FF prevented 44% of infant infections
• FF was associated with HIV-free survival
• But FF is expensive
• Clean water and the ability to sterilize appropriately is not ubiquitous
Nduati, et. al.JAMA 2000; 283:1167
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPING WORLD
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• Breastfeeding (BF)
– In areas of the world where BF is common and HIV remains highly stigmatized a real social pressure exists for women to BF
– By not BFing women signal that something is wrong and alienation from their families and their communities ensues
– So the debate no longer centers exclusively on whether or not to BF in these countries, but perhaps how long to BF and how best to BF
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPING WORLD
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• It has been shown that the longer the duration of BF the higher the risk of HIV transmission
• It has also been shown that mixed-feeding versus exclusive breastfeeding also leads to a higher risk of HIV transmission
• The conclusion from studies conducted to date suggest that exclusive breastfeeding with early weaning may be an appropriate alternative
Leroy et. al. Lancet 1998; 353:597 Coutsoudis et. al. Lancet 1999; 354:471
OUTSTANDING ISSUES/ ONGOING DILEMNAS
DEVELOPING WORLD
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“In the past, I never allowed myself to think about having a baby or even look at a baby. I was just waiting to
die. But now, everything has changed, and I suddenly have the
opportunity to have a child.”Dr. Prager –
A New Yorker living in Istanbul
…She was infected with HIV 15 years ago after being pricked by a needle during her medical residency…
The New York Times, Health & Fitness
Tuesday, August 7th,2001 pF7
Perinatal Transmission and HIV:
Two Realities
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• AIDS 1998; 12:5241, Lorenzi, et al.
• Obstet Gynecol 1999; 94:641, McGowan, et al.
• Internat J. STD AIDS 2000; 11:200, Clarke, et al.
• NEJM 1999; 341:205 Beckerman, et al.
• The Women & Infants Transmission Study Investigators
XIII International Conference 2000 Abstract LBOr4
• Society for Maternal Fetal Medicine Annual Meeting 2000, Abstract 289, Helfgott, et al.
REFERENCES
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U.S. Public Health Task Force Guidelines for the Management of
HIV in pregnancy:
http://www.hivatis.orghttp://hopkins-aids.edu
WEB RESOURCES
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