Perinatal Transmission and HIV: Two Realities “National and International Perspectives” Tanya Zangaglia, MD Medical Director, Project Streetbeat Curriculum

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

2

What has been the most

significant accomplishment

of the HIV/AIDS era?


Two Realities

3

The number of women living with HIV/AIDS

is growing


Two Realities

4

Over four-fifths of all HIV-

infected women in the U.S.

are of childbearing age


Two Realities

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HIV positive women are:

• Living longer• Feeling more hopeful• Choosing life


Two Realities

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HIV positive women are choosing to become

pregnant


Two Realities

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Perinatal Transmissioncontinues to exist in the

United States


Two Realities

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Perinatal Transmission has

declined by at least 80%between 1992 and 1999

JAMA1999; 282:531


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


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”


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


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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


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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


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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


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


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?


DEVELOPED WORLD

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Issues in the developing world

are much more basic, yet more

overwhelming


DEVELOPED WORLD

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The majority of AIDSORPHANS reside in thedeveloping world and isestimated at 13.2 million

globally


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


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


DEVELOPING WORLD

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– 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


DEVELOPING WORLD

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– 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


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


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


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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Documents

Perinatal Transmission and HIV: Two Realities “National and International Perspectives” Tanya Zangaglia, MD Medical Director, Project Streetbeat Curriculum