Recent Findings in PMTCT

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Recent Findings in PMTCT

• Elaine J. Abrams
• Columbia University

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Recent Findings in PMTCT

• Review timing, risk, ART
• New findings in PMTCT
• More about sd-NVP
• HAART and PMTCT
• PP transmission
• Replacement feeding
• Early weaning
• Exclusive breast feeding
• ART for prevention of post-natal transmission

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Most Children Acquire HIV through MTCT
(Estimated MTCT Rate 35-40)
Early Postpartum (0-1 mo)
Early Antenatal (lt36 wks)
Late Postpartum
Labor Delivery
Breast Feeding
1-6 mos
6-24 mos
Late Antenatal (36 wks to labor)
0
20
40
60
100
Proportion of infections
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Primary Factors Associated with MTCT are Advanced
Maternal Disease, Breast Feeding ART Use

• Maternal Factors
• Advanced Disease
• High plasma viral load, low CD4, AIDS,high viral
  load genital secretions
• Acute infection
• Obstetrical Factors
• Rupture of Membranes gt 4hrs
• Vaginal delivery
• Infant Factors
• Prematurity lt 37wks
• Breast Feeding
• Maternal advanced disease
• Duration of exposure
• Acute maternal infection
• Mastitis
• Maternal/infant Antiretroviral use

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Women with High Viral Load are more likely to
transmit HIV to their babies
Mean VL transmitters 30,000 copies/ml (HIV-1
RNA) Mean VL nontransmitters 10,000 copies/ml
(HIV-1 RNA)
Garcia et al, NEJM 1999
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Women with Low CD4 are more likely to transmit
HIV infection during pregnancy, labor breast
feeding
84 of maternal deaths 82 of postnatal infections
Percent Transmission
ZEBS, 2007
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Antiretroviral therapy to the mom baby reduces
the risk of MTCT

• ART for PMTCT
• Lowers maternal viral load
• Provides prophylaxis (pre and post exposure) to
  the infant
• Efficacy is enhanced
• Longer duration of therapy
• Combination therapy
• Addition of sd-NVP, usually

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Whats new about sd-NVP?

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Advantages of using sd-NVP

• In clinical trials, early transmission rates with
  sd-NVP generally reported at 10-15.
• Highly potent rapidly diminishes VL
• Reduces risk of intrapartum and early BF
  transmission
• Crosses the placenta provides prophylaxis to the
  infant
• Long half-life levels are detectable in maternal
  plasma for up to three weeks
• Inexpensive and easy to administer
• Sd-NVP can be a particularly effective
  intervention in settings where women access
  antenatal care late in pregnancy or at delivery

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Disadvantages of using sd-NVP

• sd-NVP has limited efficacy particularly for
  women with advanced disease
• sd-NVP failure more common with low CD4
• sd-NVP selects for NNRTI resistance mutations
• Higher risk for women with advanced disease
• NNRTI-based HAART is the recommended 1st-line
  therapy for adults and children
• May impact the efficacy of 1st-line treatment

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Risk of treatment failure including death similar
for sd-NVP exposed unexposed women
Chi, AIDS, 2007
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VL response to HAART varies by time from sd-NVP
(MASHI)
HAART initiated lt6mo postpartum
HAART initiated gt6mo postpartum
Lockman, NEJM 2007
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No difference in VL following treatment with
NNRTI regimen initiated gt18mo post-delivery,
Neverest
Kuhn, CROI 2007
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Impact of sd-NVP on efficacy of NNRTI-based HAART

• No clear impact on immunologic and clinical
  outcomes
• Suggestion of relationship to timing of HAART
  initiation
• No obvious impact on virologic efficacy for women
  who begin HAART gt 6-12 months after delivery
• Risk of early virologic failure is increased
  response for women who begin HAART within months
  of receipt of sd-NVP

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What can be done to reduce the risk of selecting
NNRTI resistance with sd-NVP?

• During pregnancy
• Identify pregnant women with advanced disease
• Initiate HAART during pregnancy
• At delivery
• initiate AZT 3TC tail postpartum

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Lower Rates of NNRTI Resistance in
Mothers/Infected Babies with AZT/3TC Tail
McIntyre IAS Toronto 2005
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What about the kids?

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Response to NVP-based HAART in 30 Infants with
without sd-NVP exposure
Lockman, NEJM 2007
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Use of SD-NVP shifts the ratio of IUIP
transmission

• 740 babies with sd-NVP exposure
• IUIP 6931 (historical 3070)
• VL higher in moms of IP vs IU infected infants
• Sd-NVP less effective for moms with high viral
  loads
• Peak infant VL higher in IP vs IU infected
  infants (5,160,000 vs 984,000 copies/ml)
• Children in this study were at very high risk for
  rapid disease progression
• 85 meeting WHO criteria for ART within 6 mo
• Risk of disease progression associated with peak
  VL, maternal VL and IU infection

Mphatswe AIDS 2007
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50 of children qualify for HAART by 3 months of
age
Mphatswe AIDS 2007
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Anything new around HAART for pregnant women?

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Time to undetectable depends on baseline VL
HAART regimen
VL lt4log
VL gt4log
ECS, CID 2007
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(No Transcript)
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Conundrums around HAART use during pregnancy

• Balancing efficacy and toxicity when using NVP-
  based HAART
• Starting CD4 lt 250 vs. lt350 cells/mm3
• Increased risk of fulminant hepatitis gt250
• Significant risk of MTCT at 250-350 cells/mm3
• Alternatives
• Efavirenz
• Kaletra
• 3 NRTI
• When do you stop? At delivery, at weaning,
  never.

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Whats new in prevention of Postnatal (Breast
Feeding) Prevention?

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2 recently completed studies

• ZEBS Zambian Exclusive Breast Feeding Study

• KwaZulu Natal, South Africa Vertical Transmission
  Study (VTS)
• and a little bit more.

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ZEBS Questions

• Is early weaning at 4mo safer (HIV-free survival
  - alive without HIV) than continued BF?
• Does EBF reduce transmission?
• Is abrupt weaning safer than slow weaning?

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ZEBS Study Profile
1 mo of age
ABRUPT WEANING AT 4 MONTHS
WEANING AS USUAL (16mo)
Successful Follow-up 85
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ZEBS Questions

• Is early weaning at 4m safer (HIV-free survival)
  than continued BF?
• Does EBF reduce transmission?
• Is abrupt weaning safer than slow weaning?

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Overall HIV-free Survival among Children without
HIV still Breastfeeding at 4 Months of Age by
Group Assignment
There is No Overall Benefit to Early Weaning
Compared with Continued Breastfeeding
Early weaning
Group A
HIV-neg at 4m still BF
Group B
P 0.21
Continued BF
Sinkala et al, CROI 2007
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Formula Feeding is associated with less HIV
transmission but higher rates of early death in
Mashi Study (Botswana)
Thior et al, JAMA 2006

• HIV transmission was higher in the breast fed
  (BF) group
• Early mortality was higher in the formula fed
  (FF) group
• Overall, no difference in 18 month HIV-free
  survival
• HIV or death at 18 months 14.2 in FF vs.
  15.6 in BF

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ZEBS Questions

• Is early weaning at 4m safer (HIV-free survival)
  than continued BF?
• Does EBF reduce transmission?
• Is abrupt weaning safer than slow weaning?

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Exclusive Breastfeeding is associated with
Decreased Early Postnatal Transmission
ZEBS
Only including postnatal transmission rates
Sinkala et al, CROI 2007
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The Risk of Postnatal HIV Transmission Is Lowest
in Infants Who Exclusively Breastfeed
6wks-6 mo
6-18 mo
20
15
10
HIV TRANSMISSION
9.5
5.6
5
5.6
4.4
3
1.3
0
Mixed
EXCLUSIVE
PREDOMINANT
Iliff PJ et al. AIDS 2005
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ZEBS Questions

• Is early weaning at 4m safer (HIV-free survival)
  than continued BF?
• Does EBF reduce transmission?
• Is abrupt weaning safer than slow weaning?

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VL in Breast Milk 2 wks after Cessation of BF
vs. Postpartum-matched Controls
Longitudinal analysis among 29/31
weaners Median VL copies Before 353 2 wk
after 15,822 Range 38 to gt 750,000
Thea et al. AIDS. 2006
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Zambia Exclusive Breast Feeding Study

• No net benefit to early BF cessation among
  HIV-exposed children living in resource-poor
  areas.
• EBF in the first 4 months significantly reduces
  HIV transmission through breastmilk.
• Abrupt weaning may increase HIV-transmission.

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Vertical Transmission Study, KwaZulu Natal, South
Africa

• Aim To assess transmission risk associated with
  exclusive breast feeding and other types of
  feeding

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Vertical Transmission Study

• 1132 infants initiated EBF for a mean duration of
  159 days
• 89RF, 415 EBF, 434 MF at 26 weeks
• Sd-NVP for PMTCT
• Infants who received MF (Mixed feeds) were 10.5
  times as likely to become infected vs. EBF
  infants
• 3 mo mortality was 6.1 in EBF vs. 15.1 in RF
  group

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Early Introduction of Solids is Associated with a
Higher Risk of HIV Transmission
This study includes cumulative transmission
rates
Coovadia , Lancet, 2007
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VTS No significant difference in HIV-survival
between EBF RF
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Women with Advanced Maternal Disease are at
Higher Risk of Transmitting MTCT
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Vertical Transmission Study, KwaZulu Natal, South
Africa

• EBF reduces the risk of postnatal transmission
• Increased risk of introducing solids and liquids
  during the first 6 months of life
• Very high risk of postnatal transmission for
  women with advanced disease.
• Feasibility of EBF with supportive counseling

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ART for prevention of BF transmission

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Not much yet.

• HAART during breast feeding may reduce the risk
  of postnatal transmission
• AMARTA
• MITRA
• NVP to infants for 6 weeks reduces the risk of
  transmission and death at 6 weeks and 6 months

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Summary

• Infants born to women with advanced disease are
  at highest risk of acquiring HIV infection during
  pregnancy, delivery and breast feeding
• ART reduces the risk of MTCT
• Exclusive breast feeding is associated with a
  lower the risk of postnatal transmission compared
  with mixed feeding.

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Translation Where does this leave us?

• All women should receive ART for PMTCT
• Identify women with advanced disease
• Monitor CD4 during BF for ART elgibility
• Support exclusive breast feeding for prevention
  of postnatal transmission