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					Recent Findings in PMTCT

      Elaine J. Abrams
     Columbia University
  Recent Findings in PMTCT
• Review: timing, risk, ART
• New findings in PMTCT
  – More about sd-NVP
  – PP transmission
     •   Replacement feeding
     •   Early weaning
     •   Exclusive breast feeding
     •   ART for prevention of post-natal transmission
Most Children Acquire HIV through MTCT
      (Estimated MTCT Rate 35-40%)

                                  Early Postpartum
  Early Antenatal                      (0-1 mo)
    (<36 wks)
                                             Late Postpartum

                       Labor &             Breast
                       Delivery            Feeding

                                          1-6 mos    6-24 mos
    Late Antenatal
   (36 wks to labor)
    0%        20%      40%      60%                    100%
                    Proportion of infections
Primary Factors Associated with MTCT are
Advanced Maternal Disease, Breast Feeding
               & ART Use
• Maternal Factors
   – Advanced Disease
       • High plasma viral load, low CD4,
         high viral load genital secretions
   – Acute infection
• Obstetrical Factors
   – Rupture of Membranes > 4hrs
   – Vaginal delivery
• Infant Factors
   – Prematurity < 37wks
• Breast Feeding
   – Maternal advanced disease
   – Duration of exposure
   – Acute maternal infection
   – Mastitis
• Maternal/infant Antiretroviral use
Women with High Viral Load are more
 likely to transmit HIV to their babies
Maternal HIV RNA                   N              Transmission N (%)

<1000                              57                  0 (0%)
1000-10,000                        193                32 (16.5%)
10,001-50,000                      183                39 (21.3%)
50,001-100,000                     54                 17 (30.9%)
>100,000                           64                 26 (40.6%)
  Mean VL transmitters 30,000 copies/ml (HIV-1 RNA)
  Mean VL nontransmitters 10,000 copies/ml (HIV-1

                                                        Garcia et al, NEJM 1999
   Women with Low CD4 are more likely to
transmit HIV infection during pregnancy, labor
               & breast feeding
                                                             84% of maternal deaths
                                                             82% of postnatal infections
   >500        3.9         4.5   1.9

 350-500       3.5 2.3           7.4

 200-350             7.6           7.3           13.3

   <200              7.6                 15.5                     20.8

           Percent Transmission
           0                     10             20           30          40           50

                                                IU      IP    PP

                                                                                  ZEBS, 2007
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
What’s new about sd-NVP?
   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
   – Crosses the placenta: provides prophylaxis to the
   – 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
 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
  – 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
Risk of treatment failure including death
similar for sd-NVP exposed & unexposed

                                Chi, AIDS, 2007
    VL response to HAART varies by
         time from sd-NVP (MASHI+)

HAART initiated <6mo postpartum

                                  HAART initiated >6mo postpartum

                                                      Lockman, NEJM 2007
 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
• No obvious impact on virologic efficacy for
  women who begin HAART > 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
 What can be done to reduce the risk of
selecting NNRTI resistance with sd-NVP?

 • During pregnancy
   – Identify pregnant women with advanced
   – Initiate HAART during pregnancy
 • At delivery
   – initiate AZT + 3TC ‘tail’ postpartum
   Lower Rates of NNRTI Resistance in
Mothers/Infected Babies with AZT/3TC ‘Tail’

               Mother Resistance at   Infant Resistance at
                2 or 6 Weeks PP         2 or 6 Weeks PP
                 N     % Resistant     N      % Resistant

 SD NVP        39/68      57%         7/9         78%
 SD NVP +      9/67       13%         1/8         13%
 4 d AZT/3TC
 SD NVP +      6/68        9%         0/7         14%
 7 d AZT/3TC

                                            McIntyre IAS Toronto 2005
What about the kids?
 Response to NVP-based HAART in 30
Infants with & without sd-NVP exposure

                               Lockman, NEJM 2007
Use of SD-NVP shifts the ratio of
       IU:IP transmission
• 740 babies with sd-NVP exposure
  – IU:IP 69%:31% (historical 30:70)
• 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
50% of children qualify for
HAART by 3 months of age

                         Mphatswe AIDS 2007
Anything new around HAART
   for pregnant women?
Time to ‘undetectable’ depends on
  baseline VL & HAART regimen
       VL <4log        VL >4log

                                  ECS, CID 2007
                                    Median CD4 cell count (IQR) since HAART
                                     initiation by gender-pregnancy status

CD4 cell count (cells/mm3)

                                                                                  Non-preg F
                                                                                  Preg F
                             600                                                  M



                                     0      6        12     18         24   30
                                            Months since HAART initiation
                                   1794   1418     1102      882      644   405
Conundrums around HAART use
      during pregnancy
• Balancing efficacy and toxicity when using NVP-
  based HAART
  – Starting CD4 < 250 vs. <350 cells/mm3
     • Increased risk of fulminant hepatitis >250
     • Significant risk of MTCT at 250-350 cells/mm3
• Alternatives
  – Efavirenz
  – Kaletra
  – 3 NRTI
• When do you stop? At delivery, at weaning,
What’s new in prevention of
Postnatal (Breast Feeding)
   2 recently completed studies
• ZEBS: Zambian      • KwaZulu Natal, South
  Exclusive Breast     Africa Vertical
  Feeding Study        Transmission Study

                     and a little bit more….
          ZEBS Questions
1. Is early weaning at 4mo safer (HIV-free
   survival - alive without HIV) than
   continued BF?

2. Does EBF reduce transmission?

3. Is abrupt weaning safer than slow
                  ZEBS Study Profile
                                    1112 live births

                 154 not randomized
                   (incl. 14 deaths)

                                    958 randomized
                                                                1 mo of age
ABRUPT WEANING                                                         WEANING AS USUAL
  AT 4 MONTHS                                                              (~16mo)

                    Group A n=481                      Group B n=477

 77 lost or withdrawn             66 lost or withdrawn

                  404 study endpoint
                (HIV, death, 24 months)
                                                   411 study endpoint
                                                 (HIV, death, 24 months)    Successful
                                                                           Follow-up: 85%
          ZEBS Questions
1. Is early weaning at 4m safer (HIV-free
   survival) than continued BF?

2. Does EBF reduce transmission?

3. Is abrupt weaning safer than slow
There is No Overall Benefit to Early Weaning
 Compared with Continued Breastfeeding
      Overall HIV-free Survival among Children without HIV & still
       Breastfeeding at 4 Months of Age by Group Assignment

                                                        Early weaning

                                              Group A
             HIV-neg at 4m
               & still BF
                                    Group B             P = 0.21

                 Continued BF

                                                              Sinkala et al, CROI 2007
 Formula Feeding is associated with less
   HIV transmission but higher rates of
  early death in Mashi Study (Botswana)
                              Formula (FF)   Breast + AZT
          % Mortality

                                             9.3%                   8.5%
                               4.3%                  4.9%

                               1 Month         7 Months      18 Months
                                              Infant age                 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
          ZEBS Questions
1. Is early weaning at 4m safer (HIV-free
   survival) than continued BF?

2. Does EBF reduce transmission?

3. Is abrupt weaning safer than slow
   Exclusive Breastfeeding is associated with
    Decreased Early Postnatal Transmission

                           Non-exclusive BF


                                        Exclusive BF

                                      Only including postnatal transmission rates

Sinkala et al, CROI 2007
The Risk of Postnatal HIV Transmission Is
         Lowest in Infants Who
         Exclusively Breastfeed
                                          6wks-6 mo   6-18 mo



                          EXCLUSIVE   PREDOMINANT     Mixed

                                                                Iliff PJ et al. AIDS 2005
          ZEBS Questions
1. Is early weaning at 4m safer (HIV-free
   survival) than continued BF?

2. Does EBF reduce transmission?

3. Is abrupt weaning safer than slow
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 > 750,000

                             Abrupt   Cont BF   P value
Mat fever since last visit   31%      7.5%      0.01
Mastitis                     16.1%    2.5%      0.04
                                                           Thea et al. AIDS. 2006
     Zambia Exclusive Breast
         Feeding Study
1. No net benefit to early BF cessation
   among HIV-exposed children living in
   resource-poor areas.
2. EBF in the first 4 months significantly
   reduces HIV transmission through
3. Abrupt weaning may increase HIV-
Vertical Transmission Study,
KwaZulu Natal, South Africa
  Aim: To assess transmission risk
  associated with exclusive breast
 feeding and other types of feeding
 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
Early Introduction of Solids is Associated
 with a Higher Risk of HIV Transmission

          Method of Feeding                        HIV prevalence
                                                  rates at 26 weeks

 EBF (n=362)                                           55 (15%)
 MBF (solids introduced <14                            89 (27%)
 wks; n=332)
 ‘MBF (solids introduced >14                           61 (26%)
 weeks; n=239)
 * This study includes cumulative transmission rates

                                                          Coovadia , Lancet, 2007
VTS: No significant difference in
HIV-survival between EBF & RF
 Women with Advanced Maternal
  Disease are at Higher Risk of
      Transmitting MTCT
 Estimated Transmission Rate at 6mos in Exclusively
   Breastfed Infants born to HIV infected mothers
         (includes all routes of transmission)

Maternal CD4 count

<200                           34.1%
>200                           17.0%
   Vertical Transmission Study,
   KwaZulu Natal, South Africa
• EBF reduces the risk of postnatal
• 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
ART for prevention of BF
          Not much yet….
• HAART during breast feeding may reduce
  the risk of postnatal transmission
• NVP to infants for 6 weeks reduces the
  risk of transmission and death at 6 weeks
  and 6 months
• 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.
   Translation: Where does this
             leave us?
• All women should receive
   – Identify women with
     advanced disease
   – Monitor CD4 during BF for
     ART elgibility
• Support exclusive breast
  feeding for prevention of
  postnatal transmission