Mother To Child HIV Transmission:

1
Mother To Child HIV Transmission Research Study
Update
Lynne M. Mofenson, M.D. Pediatric, Adolescent and
Maternal AIDS Branch National Institute of Child
Health and Human Development National Institutes
of Health
10/12/07
2
Studies on Mode of Infant Feeding
3
Modifying Infant Feeding Practices

• Exclusive breastfeeding vs mixed feeding
• Rationale S. African study suggests exclusive BF
  associated with less transmission than mixed
  feeding
• Timing and duration of breastfeeding cessation
• Rationale Earlier BF cessation reducing period
  of mixed feeding with shorter weaning duration
  might reduce risk of transmission
• Exclusive Breastfeeding study (Vertical
  Transmission Study, VTS) - Kwazulu Natal, South
  Africa
• ZEBS - Lusaka, Zambia
• ZVITAMBO - Harare, Zimbabwe
• DITRAME Plus - Abidjan, Côte dIvoire
• MASHI - Botswana

4
Conclusions from Infant Feeding Studies

• Possible to get high rates EBF first 4 months but
  requires intensive counseling/follow-up.
• EBF in first 4 months significantly reduces but
  does not eliminate postnatal HIV transmission.
• In studies in Botswana, Zimbabwe, Zambia and S
  Africa, formula feeding or breastfeeding with
  early weaning did not result in long-term
  increased HIV-free survival and was particularly
  bad for HIV-infected infants.
• Abrupt weaning (over 24-48 hours) results in
  increased risk of mastitis compared and increased
  milk viral load.

5
Exclusive BreastfeedingUptake
6
High Uptake of Exclusive Breastfeeding Among 958
HIV-Infected Women in Lusaka, Zambia Kuhn L et
al. 4th IAS Conf, Sydney, Australia
Cumulative 84 still EBF by 4 months
Non-EBF giving any non-breast milk liquid or
solid (except medicines) in past 24 hours or at
least once per week
7
ZEBS Intensive Interventions to
PromoteExclusive Breastfeeding Kuhn L et al.
4th IAS Conf, Sydney, Australia

• One-to-one counseling
• Antenatal (at least 2 sessions)
• Postnatal
• Clinic-based (monthly)
• Home visits (interspersed)
• Support for breastfeeding initiation at delivery
• Community outreach and education
• Mothers support groups

8
Rates of Exclusive Breastfeeding in HIV-Infected
Women are Low in Resource-Poor Countries Even in
Setting of a Clinical Trial
9
Exclusive Breastfeedingand Postnatal MTCT
10
HIV Infection Rate at Age 26 Weeksby Mode of
Infant Feeding at 26 WeeksCoovadia H et al.
Lancet 20073691107-16
11
Exclusive Breastfeeding Associated
with Significantly Lower Postnatal Transmission
Zambia Kuhn L et al. 4th IAS Conf, Sydney,
Australia
12
How Safe is Early Weaning?
Many of PMTCT Interventions Presume Early
Weaning of the Infant to Avoid Continued HIV
Exposure Post Prophylaxis
13
Mashi Cumulative Rate of HIV Infection by
Infant Feeding Thior I et al. JAMA
2006296794-805
Significantly More HIV Infections With
Breastfeeding AZT
p0.02
Breastfeeding AZT
Formula
14
Mashi Cumulative Rate of Death by Infant
Feeding Thior I et al. JAMA 2006296794-805
Significantly More Early Deaths With Formula
Feeding
overall p0.21
7 month difference
p0.003
Formula
Breastfeeding AZT
15
Cumulative Rate of HIV Infection or Death by
Infant Feeding Thior I et al. JAMA
2006296794-805
Resulting in No Difference in HIV-Free Survival
P0.48
Breastfeeding AZT
Formula
16
No Overall Benefit in HIV-Free Survival to Early
Cessation vs. Continued Breastfeeding Thea D et
al. 14th CROI, 2007, Los Angeles, CA Abs. LB
Stopped breastfeeding
Continued breastfeeding
Overall HIV-free Survival among Children without
HIV Still Breastfeeding at Age 4 Months of Age
by Group Assignment (Abrupt vs Standard Weaning)
p 0.21
17
Early Cessation of Breastfeeding Was
Particularly Harmful for Children Who Became
HIV-Infected Thea D et al. 14th CROI, 2007, Los
Angeles, CA Abs. LB
Survival of HIV-infected Children with Positive
Results before Age 4 Months by Group Assignment
(Abrupt vs Standard Weaning)
Continued Breastfeeding
Stopped Breastfeeding
p 0.01
18
No Difference in Risk Diarrhea/LRTI/Malnutrition
in Breast- vs Formula-Fed Infants, Cote dIvoire
Becquet R et al. PLos Med 20074e17
No significant difference overall (p0.45) or for
HIV-uninfected (p0.34) or HIV-infected children
(p0.81)
ANRS 1201/2 Short course AZT or AZT/3TC SD
NVP Self-choice mode infant feeding
Breastfed (N295) Formula-fed (N262)
19
No Difference in Risk of Hospitalization or Death
in Breast- vs Formula-Fed Infants, Cote dIvoire
Becquet R et al. PLos Med 20074e17
No significant difference overall (p0.62) or for
HIV-uninfected (p0.81) or HIV-infected children
(p0.66)
ANRS 1201/2 Short course AZT or AZT/3TC SD
NVP Self-choice mode infant feeding
Breastfed (N295) Formula-fed (N262)
20
Infant Morbidity/Mortality by Feeding Mode in
AMATA Maternal HAART Prophylaxis, Rwanda Gitega
HC. 4th IAS Conf 2007 Sydney, Australia Abs
TuAS102

• Mortality (9 months?)
• 24 children died (4)
• Breastfed 6 children (3)
• Formula-fed 18 children (6) p0.15

21
Growth by Infant Feeding Mode in AMATA Gitega
HC. 4th IAS Conf 2007 Sydney, Australia Abs
TuAS102
Height Weight
No significant difference
22
Comment on Formula/Early Weaning Data

• Different results in different sites
• Data from Malawi, Uganda, Botswana , Zambia
  Excess morbidity and mortality with formula
  feeding and early weaning
• Data from Ivory Coast, Rwanda Do not see excess
  morbidity or mortality with formula feeding or
  early weaning
• What makes formula feeding and early weaning safe
  in some settings and not others?

23
Peri-Weaning as Risk Period
24
Early Rapid Breastfeeding Cessation (at 4 Mos
PP) Increases Risk of Breast Health Problems -
Zambia Thea D et al. AIDS 2006201539-47
25
BM Viral Load Increases After Early Rapid Weaning
Infants at Increased Risk MTCT if Resume BF?
Thea D et al. AIDS 2006201539-47
Longitudinal analysis among 29 women who abruptly
weaned samples from 2 weeks post stopping
breastfeeding Median VL copies Before 353 2
wk after 15,822
26
Passive/ActiveImmunization
27
Immune Prophylaxis of Postnatal Transmission

• Passive immune prophylaxis
• HIV1GLOB/NVP study - Kampala, Uganda
• Mother NVP at onset labour
• Child NVP at birth
• Study arms1) Child 6 wks infant NVP
• vs 2) HIV1GLOB Mother 37-38
  weeks pregnancy Child lt24 hrs old
• vs 3) No added treatment
• Monoclonal antibodies Phase I pharmacokinetic
  and safety study - Durban, S. Africa (RO1,
  Coovadia)
• Active immune prophylaxis
• HIVNET 027 canarypox HIV vaccine in neonates
• P1067 Merck adenovector HIV vaccine neonates

28
Conclusions Immune Prophylaxis

• HIVIG in the U.S. and HIVIGLOB in Uganda did not
  appear to significantly reduce in utero,
  intrapartum or postnatal MTCT.
• Monoclonal antibody studies on hold due to
  concerns regarding anti-cardiolipin antibodies,
  potential for autoimmune reactions/cardiac
  toxicity, and issues of clade coverage.
• HIVNET 027 has shown ALVAC vaccine in neonates is
  safe.
• Merck HIV adenovirus study on hold due to lack of
  protection in adult phase 2 study.

29
Antiretroviral Prophylaxisof Postnatal
Transmission
30
Maternal Antiretroviral Prophylaxis ofBreast
Milk HIV Transmission

• Some uncontrolled studies have suggested maternal
  HAART during lactation may reduce transmission.
  However
• While HAART decreases free virus in breast milk,
  cell-associated virus is not decreased and
  persists (Shapiro R et al. J Infect Dis
  2005192713-9)
• Breast milk CD4 cells expressing CCR5 and CXCR4
  as well as activation markers are preserved in
  milk of women on HAART with undetectable viral
  load. (Kourtis A et al. J Infect Dis
  2007195965-72)
• Controlled clinical trials are ongoing.

31
Transmission Cell-Associated vs Cell-Free
Breast Milk Virus?
32
Breast Milk Cell-Associated HIV DNA Associated
with Postnatal MTCT Regardless of Age but with
Cell-Free HIV RNA Only gt9 Months of Age
Tanzania Koulinska IN et al. JAIDS 20064193-99
Adjusted for maternal CD4 count at delivery and
HIV disease stage at baseline.
Evaluated milk nearest to time of infection from
61 women with postnatal MTCT and milk sample
within 1 week of case sample from 61 women
without MTCT
33
HAART Reduces Breast Milk HIV-1 Cell-Free (RNA)
But Not HIV-1 Cell-Associated (DNA) Viral Load
Shapiro R et al. J Infect Dis 2005192713-9
p0.39
34
Breast Milk CD4 and CD8 Cells Expressing
Activation Markers CCR5 Preserved in HIV Women
on HAART Kourtis A et al. J Infect Dis
2007195965-72

median viral load 386 copies/mL
significantly different HIV uninfected vs
infected
35
Comparison of Blood and Milk Distributions of
CD4, HIV DNA Copies, and HIV Antigen-Secreting
Cells (Median, 25 and 75th ile Values)
Becquart P et al. AIDS 2006201453-62
Measured by ELISPOT plt0.01 for comparison of
HIV Ag-secreting cells in blood vs milk Milk
cells 17 times more productive when
activated than cells in blood
36
Maternal HAART ProphylaxisObservational
Studies
37
DREAM PMTCT with HAART in AfricaPalombi L et
al. AIDS 200721(Suppl 4)S65-71

• DREAM Program provides HAART to all pregnant
  women
• Cohort 1 Jan 2004-Dec 2006 (Mozambique, Malawi,
  Tanzania) - follow-up data on 809 children (91
  of 879 enrolled)
• provided formula and water filters
• Cohort 2 Aug 2005-July 2006 (Mozambique) 341
  infants born follow-up available 251 infants
  (74) at age 6 month
• Provided HAART through 6 months PP while
  breastfeeding
• No breakdown by maternal CD4, RNA, no duration of
  breastfeeding given, cant interpret.

38
MTCT in DREAM Cohorts Palombi L et al. AIDS
200721(Suppl 4)S65-71
Not clear what these data represent (eg, does 6
month data represent incidence between 1 and 6
months? or total infection at that age? If so,
why cumulative data provided?)
39
AMATA Study, Rwanda Maternal HAARTGitega HC.
4th IAS Conference 2007 Sydney, Australia Abs
TuAS102

• Mothers eligible for ARV (CD4 lt350 or WHO Stage
  4) d4T 3TC NVP choice infant feeding.
• Mothers not eligible for ARV (WHO Stage 1, 2, or
  3 and CD4 gt350), choice infant feeding
• AZT 3TC EFV from 26 weeks of gestation
• stop at birth if FF
• stop at 7 months if BF
• Dual NRTI therapy for 7 days after HAART stops
• Baby NVP single dose AZT for 7 days

40
AMATA Patient Population and Infant Infection

• 573 women enrolled data on 554 delivered
• 316 Formula fed ( 57)
• 238 Breastfed ART ( 43) (note duration not
  stated)
• Infection status on 431 (77) infants at 7 months
  (255 (81) formula, 176 (74) BF)
• Transmission
• 7/431 children infected so far ( 1.6 )
• 6 infected at birth (no info mode feeding)
• 1/176 btn 1-7 mos through breastfeeding
• (postnatal MTCT 0.6, 95 CI, 0-3)

41
Issues to Consider re AMATA

• Unclear numbers who received ART for treatment
  vs prophylaxis and transmission rates in these
  groups.
• Unclear duration of breastfeeding in those who
  breastfed.
• Found low transmission rates using ART
  antepartum postpartum transmission rates low but
  contribution of postpartum ART unclear, given low
  viral load at birth (52 undetectable, 90 lt1,000
  c/mL at delivery).

42
MITRA-PLUS Maternal HAART to Prevent Postnatal
Transmission, TanzaniaKilewo et al. 4th IAS
Sydney Australia 2007 Abs. TuAX101

• Mitra AZT/3TC provided to mothers from 36
  weeks, labor and 1 week postpartum, plus
  provision of 6 months of 3TC to the breastfeeding
  infant
• Mitra-Plus Provided AZT/3TC/NVP from 34 weeks
  gestation, during labor, through 6 months
  postpartum, infant AZT/3TC x 1 week
• 501 enrolled At baseline
• 94 WHO Stage 1
• Median CD4 460 (16 CD4 lt200)
• Median HIV RNA 14,621 copies/mL

43
Overall Transmission Mitra-Plus vs Mitra
No significant difference in terms of
postnatal transmission between maternal or
infant prophylaxis strategies
44
Issues to Consider re Mitra-Plus

• Mitra-Plus enrolled a very healthy group of
  infected women over 90 asymptomatic with CD4
  460 and RNA 14,600.
• Unclear what risk of postnatal transmission would
  be in this group without PP HAART.
• No obvious difference between maternal and infant
  prophylaxis.
• BAN study (Malawi) will directly address this
  question
• Comparing postnatal 6 month maternal HAART vs 6
  month infant NVP to standard short-course
  treatment

45
Randomized Maternal HAART Prophylaxis Trial Design
AP
IP
PP
6 mos
34-36 wks
1 wk
Malawi (CDC/ UNC)
ZDV/3TC NVP x1
ZDV/3TC NVP x1
ZDV/3TC NVP x1
ZDV/3TC NVP x1
ZDV/3TC/LPV/r Mother
ZDV/3TC NVP x1
ZDV/3TC NVP x1
NVP Infant
Multisite Africa (WHO) Kesho Bora
ZDV
ZDV NVP x1
ZDV NVP x1
ZDV/3TC/LPV/r
ZDV/3TC/LPV/r
Mother ZDV/3TC/LPV/r Infant NVP x 1 ZDV x 1 wk
In randomized studies, CD4 lt200 all get HAART,
CD4 gt200 are randomized and stop ARV at 6 months
46
Mma Bana Study Botswana HAART Study in
Breastfeeding Mothers Shapiro R and Colleagues
R01 Grant
26 Weeks IP
PP
AZT/3TC/ABC
AZT/3TC/ABC
AZT/3TC/ABC
SD NVP 1 Mo AZT
AZT/3TC/LPV/r
AZT/3TC/LPV/r
AZT/3TC/LPV/r
SD NVP 1 Mo AZT
- Enrolling women who dont require ARV for own
health - Safety and efficacy of two different
HAART regimens to prevent breast milk HIV
transmission.
47
HAART and Short Course ARV Prophylaxis
48
Two-Tiered Approach to PMTCT Cote dIvorie
Tonwe-Gold B et al, PLoS Med 20074e257

• HAART per WHO recommendations (N107)
• Mom AZT (d4T) 3TC NVP continue PP
• Infant SD NVP AZT x 1 week
• Median CD4 189 start, 27 wks duration 74 d
• 96 infants tested (59 BF, 61, median 4.6 mo)
• For women not needing HAART (N143)
• Mom Short regimens (72 ZDV/3TC SD NVP)
• Infant SD NVP AZT x 1 week
• Median CD4 467 start, 32 wks duration 6 d
• 129 infants tested (109 BF, 84, median 5.8 mo)

49
HIV Transmission and HIV-Free Survival Cote
dIvorie ResultsTonwe-Gold B et al, PLoS Med
20074e257
50
HIV Transmission and HIV-Free Survival Cote
dIvorie ResultsTonwe-Gold B et al, PLoS Med
20074e257
51
HIV Transmission and HIV-Free Survival Cote
dIvorie ResultsTonwe-Gold B et al, PLoS Med
20074e257
52
Infant Antiretroviral Prophylaxis ofBreast Milk
HIV Transmission

• SWEN study has demonstrated that 6 weeks of NVP
  in breastfeeding infants results in improved
  HIV-free survival at 6 weeks and 6 months
  (although narrowing of infection difference
  between 6 weeks 6 months).
• Would extending NVP to 6 months be safe and offer
  enough incremental protection to make more
  complex extended prophylaxis cost-effective
  intervention?
• Would two drugs be better than one?

53
Six Week Extended Nevirapine (SWEN) Study
IP PP to 6 weeks

NVP x1
Infant NVP x1
Infant NVP 1-6 wks
Infant Placebo 1-6 wks
NVP x1
Infant NVP x1

• At 6 weeks, extended NVP had lower transmission
  and
• improved survival
• At 6 months, transmission difference narrowing
  but
• improved survival still significantly better with
  extended NVP

54
Revised HPTN 046 Safety and Comparative
Efficacy of 6 Weeks vs 6 Months Infant NVP
IP PP to 6 weeks 6 weeks
to 6 months

NVP x1
Infant NVP x1
NVP 6 wk 6 mos
Infant NVP 1- 6 wks
Placebo 6 wk 6 mos
Infant NVP 1- 6 wks
NVP x1
Infant NVP x1
55
Does Short-Term Combination Infant Prophylaxis of
Postnatal MTCT Increase Efficacy of Infant SD NVP
1 Week AZT (NVAZ Regimen) in Breastfeeding
Infants?
IP PP
NVP x1
Infant NVP x1
Infant AZT x1 wk
NVP x1
Infant NVP x1
Infant AZT x1 wk
Infant NVP x 16 wks
NVP x1
Infant NVP x1
Infant AZT x1 wk
Infant NVP AZT x 16 wks
If mom diagnosed in time for IP prophylaxis
56
ARV Prophylaxis 6 Month Transmission Rates in
Breastfeeding Populations
Short Course ARV only
Maternal PP HAART
Infant ARV
57
Additional Trials
58
PROMISE-PEP Planned Infant Prophylaxis Study
Promise for Exclusive Breastfeeding Research
ConsortiumBurkina Faso, Uganda, Zambia, S.
Africa (CDC sponsored?) Kourtis A et al. Am J
Obstet Gynecol 2007Suppl SeptS113-122
Baseline regimen
AZT/3TC x 7 days or mom HAART if needed
Same as AP SD NVP
ZDV or mom HAART if needed
Mom Infant
SD NVP AZT x 7 days
3TC for up to 9 months
Infant randomized to
EBF with weaning at 6-8 months
59
Thailand Perinatal HIV Prevention Trial Network
Lallemant M and PHPT-5 Colleagues R01 Grant
ARM 1
AZT 28 wk
oral
SD NVP
NVPx1
AZT 1 wk

ARM 2
AZT 28 wk
oral
Is maternal SD NVP needed?
PL
NVP birth 72h
AZT 1 wk

ARM 3
Safety and efficacy of PI-based short ARV?
AZT/LPV/r 28 wk
oral

AZT 1 wk
60
TD-2 Study Truvada to Reduce NVP
ResistanceStringer J et al. Lancet 2007 in press
Endpoint NVP resistance at 2 6 weeks
IP
PP
AP
NVP x1
81 AZT
Mother
Infant
NVP x1
Delivery RNA lt400 29
NVP x1
85 AZT
TFV 300 mg/ FTC 200 mg
Mother
Infant
NVP x1
Delivery RNA lt400 28
61
Prevention of Maternal NVP Resistance at 2 or 6
Weeks Post SD NVP TOPS and TD-2 McIntyre J et
al. IAS 2005 Stringer J et al. Lancet 2007 in
press
62
Perinatal Transmission at Age 6 Weeksin TOPS and
TD-2McIntyre J et al. IAS 2005 Stringer J et
al. Lancet 2007 in press