PMTCT: A REVIEW OF THE PAST TWO YEARS AND THE WAY ...

PMTCT: A REVIEW OF THE PAST
TWO YEARS AND THE WAY
FORWARD.
HOOSEN COOVADIA
Victor Daitz Professor of HIV/AIDS Research
University of KwaZulu-Natal, South Africa
THE TERESA GROUP SYMPOSIUM. CHILDREN AND
HIV/AIDS: “ACTION NOW,ACTION HOW” SYMPOSIUM.
AUGUST 1 ST 2008. 2.55-3.25 pm.HOTEL NIKKO

MOTHER TO CHILD TRANSMISSION
OF HIV:
GENETIC FACTORS
• Higher infant CCL3L1 gene copies =
reduced transmission of HIV in
absence of NVP
• Reduction in CCL3L1 production
with NVP exposure.
• Therefore NVP has contradictory
roles modifying the CCr5 ligand
CCL3 in MTCT
Kuhn L et al AIDS 2007; 21: 1753-1761

A FRAMEWORK FOR ACTION
TO PREVENT HIV INFECTION IN
INFANTS
Prevention of
HIV in women
(by 1.25%)
Prevention of
unintended
pregnancies in
HIV-infected
women
(by 16%)
Prevention of
transmission
from an HIVinfected
woman to her
infant
Care and support for HIV-infected women, their
infants and their families
Data from 8 African countries: Sweat MD et al.AIDS 2004;18:1661

COMPREHENSIVE PMTCT
PROGRAMME- WHO
Programme Costs [average,annual]
$4.8m
Infant HIV infections averted [average] 1898
Costs; per HIV infection averted $2517
per Daly averted $84
Equivalents to total HIV infections averted:
*lowering female HIV prevalence by 1.25%
*reducing unintended pregnancies
in HIV infected women by 16%
Data from 8 African countries: Sweat MD et al.AIDS 2004;18:1661

DECLINING MATERNAL HIV PREVALENCE
RATHER THAN PMTCT DECREASES MTCT
OF HIV IN ZIMBABWE.
MTCT of HIV decreased from 8.2% in 2000 to 6.2% in 2005,
predominantly attributable to declining maternal HIV
prevalence rather than to the PMTCT program.
Between 2002 and 2005, the single-dose NVP PMTCT
program may have averted 4600.
In 2005, 32% and 4.0% of infections were attributable to
breast-feeding and maternal seroconversion
Twice as many infections could have been averted had a
more efficacious but logistically more complex NVP +
zidovudine regimen been implemented with similar
coverage (50%) and acceptance (42%).
Dube, Sabada MPH et al. JAIDS 48(1):72-81, May 1, 2008.

MTCT and Integration of Services
Integrating antenatal clinic services with
ARV treatment facilities
MTCT
• In facilities with ARV therapy 4.3%
• In facilities for only sdNVP 10.7%
Coovadia Ashraf et al. Coronation Hospital,SA. JAIDS
2006;43;5

Summary from 3 Ongoing Trials Re
Serious GE Events following BF
Cessation among HIV Uninfected Infants
The trials in Blantyre Malawi, Kisumu Kenya, and
Kampala Uganda all include counselling to stop breast
feeding by 6 months of age as part of the study design
In each of these studies, a rise in serious GE adverse
events has been documented during the period
immediately following early Breastfeeding cessation
Each of these trials was able to compare data to
earlier studies at the site where there was not an
emphasis on early cessation of BF
The findings raise concerns that early BF cessation is
associated with significant morbidity/mortality for HIV
exposed uninfected infants

14.2
13.2
13.2
10.9
11.3
10.2
9.8
HVG
7.4
8
O12
6.4
6.7
2.9
2 2.1
2.1
2.1
2.2 2.2 2.2
2.1
1.4
0
0
0
1 2 3 4 5 6 7 8 9 10 11 12
Months
Monthly Rates of Serious GE Events for HIVIGLOB and HIVNET 012

GASTRO-ENTERITIS RATES IN EARLY WEANING GROUP
COMPARED WITH CONTINUED BREASTFEEDING GROUP
Gastro Enteritis rate per 100 infants
7
6
5
4
3
2
1
Continued Breastfeeding Group
Early Weaning Group
CDC HAART Trial
Gastro-enteritis
Hospitalizations
KiBS and Vertical
Transmission
Study
Kisumu Kenya
0
0 1 2 3 4 5 6 7 8 9 10 11 12
Age of Weaning
Age in months
Mary Glenn Fowler, CROI 2007

GE Related Mortality Among HIV
UNINFECTED Babies in PEPI versus NVAZ

Reduced Mortality Associated With
Breastfeeding-Acquired HIV Infection in
Zambia.
.
Children with intrauterine [IU] or intrapartum/early
postpartum [IP/EPP] transmission had higher
mortality over the first 12 months after infection than
children with postpartum transmission (P = 0.001
and P = 0.006, respectively)
Nearly 20% of the IU and IP/EPP groups vs 10% of the
PP group died by 100 days after infection.
Children infected postpartum had one quarter the
mortality rate (HR = 0.27) of those infected IU.
Stopping breast-feeding increased mortality in
infected children (HR = 3.1, 95% CI: 1.8 to 5.3).
Fox, Matthew P DSc, MPH et al. JAIDS Journal of Acquired Immune Deficiency
Syndromes. 48(1):90-96, May 1, 2008

Net HARM of early breastfeeding
cessation if maternal CD4 count is
higher >350
Continued BF
Stopped BF < 4 m
P = 0.03
Gp A: not yet needing ARVs
i.e. CD4 >350 & asymptomatic

EARLY MORTALITY IS HIGHER IN FORMULA-
FED THAN BREASTFED [+ AZT] INFANTS:
BOTSWANA
20%
Formula
Breast [+ AZT]
% Mortality
10%
4.3%
9.3%
4.9%
10.9% 9.5%
1.5%
0%
1 Month 7 Months 12 Months
Infant age Thior I et al, JAMA 2006

25
20
15
10
5
DIARRHOEA; MALNUTRITION; CHILD
MORTALITY
Francistown, Botswana, Nov 2005-April 2006

BOTSWANA.
EMERGENCY ROOM FINDINGS: CDC
CHARACTERISTIC
AOR*(95% CI)
• Not breastfeeding 50.0[4.5-100]
• Storing drinking water 3.7[1.5-9.1]
• Overflowing latrines 3.0[1.1-8.6]
• Stagnant water near home 2.6[1.1-6.3]
• Unwashed hands: caregivers 2.5[1.1-5.0]
*adjusted for socio-economic status, age, mothers HIV status
Tracey Creek, CDC 2006

SUMMARY:
PREVENTING BREASTFEEDING
ASSOCIATED HIV TRANSMISSION
Primary Prevention
Infant Feeding Options
Immunisation
Chemoprophylaxis
Policy Options

LOW CD4 CONSISTENTLY SHOWN TO BE
AN IMPORTANT RISK FACTOR
Vertical Transmission Study [VTS]– South Africa
6-month Transmission in Exclusively
Breastfed Infants
Maternal CD4 count
200 17.0%
Zvitambo Study Transmission 5 times higher in CD4500 cells
Coovadia HM et al, In Press Lancet 2007

DETECTABLE%
D
e
t
e
c
t
a
b
l
e
%
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
HAART SUPPRESSES
BREASTMILK HIV RNA BUT
HAART
NOT DNA
NO HAART
Plas.RNA
Breast. RNA
Breast.DNA
Shapiro RL et al.JID.2005;192:713-19

HOW EFFICACIOUS ARE SHORT-COURSE
ARVs IN MOTHER-TO-CHILD-TRANSMISSION
AT ABOUT 6 WEEKS IN BREASTFEEDING
AFRICAN WOMEN. 1995-2005?
(%) Transmission Rate
25
20
15
10
5
0
22
13
12
9.3
6.5
4.7
2
none Sc ZDV NVPsd
ScZDV+3TC Sc ZDV +NVPsd Sc ZDV+3TC + NVPsd
HAART
LeRoy V, WHO 2006

ANTENATAL HAART FOR ALL HIV+ PREGNANT
WOMEN :BREASTFEEDING WITH HAART
COMPARED TO FORMULA FEEDING WITH
WATER FILTERS AND FREE FORMULA
THE DREAM STUDY
• All HIV+ pregnant women got HAART from 25 th
week.
• Formula + water filters for 6 months. Infant PEP.
n=809 evaluated at 6 months.[2004-2006]
• Breastfeeding option group, postnatal HAART.
251 infants evaluable at 6 months.[2005-2006]
Palombi L et al. AIDS 2007;21:[Supplement 4] S65-S71

THE DREAM STUDY
HIV transmission:@ 1 mth: b/f 1.2% ff 0.8%
@ 6 mths: b/f 0.8% ff 1.8%
Cumulative Incidence 6 mths: b/f 2.2% ff 2.7%
Mortality @ 6 mths: b/f 28.5/10 3 py
Growth
ff 27/10 3 py
[Mocambique] 101/10 3 py
weight[

HAART,BREASTFEEDING, AND MTCT
MITRA-PLUS TANZANIA
• Open-label, prospective, non-randomised study
• All HIV+ pregnant women enrolled, counselled on Exclusive
Breastfeeding, AZT+3TC+NVP during late pregnancy and
breastfeeding, stopped at 6 months except those who
required HAART for their own treatment.
• Infants: AZT+3TC for one week; n=441;
• Breastfeeding; median =24weeks
• MTCT @ 6 weeks= 4.1% [95%CI 2.1%-6.0%]
• MTCT @ 6 months= 5.0% [3.2%-7.0%]
• Breastfeeding Transmission = 0.9%
Kilewo C et al .Abs TUAX101.4 th IAS Conference on HIV Pathogenesis, Treatment
and Prevention., incorporating the 19 th ASHM
Conference.22-25 July,2007,Sydney,Australia. www.ias2007.org

Kaplan-Meier Estimated Transmission of HIV-1,
Mortality, and HIV-Free Survival in the Mitra Study
and in the Breast-Feeding Population in the Petra
Trial Arm A
HIV-1 infection %
(95% CI)
Mortality % (95%
CI)
HIV-1 infection or
death % (95% CI)
Mitra Petra Mitra Petra Mitra Petra
6
weeks
3.8 %
(2.0 -
5.6)
5.4 %
(2.7 –
8.1)
0.8 %
(0 – 1.6)
0.4 %
(0 – 1.1)
4.5 %
(2.4 –
6.5)
8.7 %
(5.4 –
11.9)
6
mnths
4.9 %
(2.7 –
7.1)
11.9 %
(7.9 –
15.8)
3.7 %
(1.9 –
5.6)
4.7 %
(2.1 –
7.3)
8.5 %
(5.7 –
11.4)
15.5 %
(11.1 –
19.9)
Kilewo C et al. JAIDS 2008; Vol 48, No. 3

HAART,BREASTFEEDING, AND
MTCT.AMATA STUDY, RWANDA
• All HIV+ pregnant women enrolled,NNRTI HAART after 2 nd
trimester for breastfeeders; choice of breast or
formula,HAART until one month after cessation of
breastfeeding.
• Results for 419 infants @ 6weeks,236 @7 months
• Only 6 HIV+[1.4%] at birth.
• Breastfeeding transmission @ 7months = 0
• No significant differences between FF and BF for
psychomotor development; morbidity [1.23 episodes in
FF vs 1.21 in BF], mortality [2.9% in FF vs 1.3% in BF]
Arendt V et al .Abs TUAX102.4 th IAS Conference on HIV Pathogenesis, Treatment
and Prevention., incorporating the 19 th ASHM
Conference.22-25 July,2007,Sydney,Australia. www.ias2007.org

ADJUVANT TRUVADA DOES
NOT REDUCE MTCT IN WOMEN
ON scAZT+sdNVP
• ZDV and NVP in all: intrapartum/early postpartum
transmission was 1.6% among infants whose mothers
received TDF/FTC , compared with 2.8% among those
who did not [p = 0.67).
• Mothers :no antenatal ZDV but confirmed NVP
ingestion, transmission similar (0 of 19 vs.1 of 26)
Chi, Benjamin et al. JAIDS. 2008;48:220-223

Cumulative
Probability of HIV-
Free Survival
among Uninfected
Children and of
Survival among
Infected Children,
According to
Study Group
Kuhn L et al. N Engl
J Med 2008;10.

PEPI-Malawi Study Design
Taha TE et al. 15 th CROI, Boston, MA 2008 Abs 42LB
Intrapartum*
Post-partum
Birth 1 - 7 d 8 - 98 d
Control
Suspended
Aug 2007
NVP x1*
Infant
NVP x1
Infant
ZDV x1 wk
Extended
NVP x1*
NVP
Infant
NVP x1
Infant
ZDV x1 wk
Infant: NVP x 14 wks
Extended
NVP + AZT
NVP x1*
Infant
NVP x1
Infant
ZDV x1 wk
Infant: NVP + ZDV x 14 wks
Mothers counselled to exclusively
breastfeed and wean by 6 months
Kumwenda et al NEJM. 2008 June 4th. www.nejm.org

Probability of HIV-1 Infection in Infants
Uninfected at Birth by Treatment Arm: PEPI-Malawi
Probability of HIV-1 Infection
0.10 0.15 0.20 0.25 0.30
0.00 0.05
C ontro l
E xte nd ed NV P
E xte nd ed NV P +ZD V
Age
Estimates (%)
1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o
1
wk
6
wks
9
wks
14
wks
In fan t Ag e
6
mos
9
mos
12
mos
15
mos
18
mos
24
mos
Control 0.3 5.1 7.4 8.4 10.1 10.6 11.5 12.4 13.9 14.5
Extended NVP 0.1 1.7 2.6 2.8 4.0 5.2 7.0 7.8 10.1 11.2
Extended NVP+ZDV 0.2 1.6 2.4 2.8 5.2 6.4 8.1 8.7 10.2 12.3

Probability of HIV-1 Infection or Death in Infants
Uninfected at Birth by Treatment Arm: PEPI-Malawi
Probability of HIV-1 Infection or Death
0.10 0.15 0.20 0.25 0.30
0.00 0.05
C ontrol
E xtended NV P
E xtended NV P +ZD V
Age
Estimates (%)
1wk 9wk 6m o 9m o 12m o 15m o 18m o 24m o
1
wk
6
wks
9
wks
14
wks
6
mos
In fan t Ag e
9
mos
12
mos
15
mos
18
mos
24
mos
Control 0.6 6.7 9.3 10.7 13.2 16.8 18.1 20.5 22.6 24.1
Extended NVP 0.6 3.3 4.2 4.7 6.6 10.6 13.9 16.0 19.0 20.9
Extended
NVP+ZDV
0.5 2.8 4.1 5.1 8.2 11.2 15.0 16.5 18.6 22.0

Six-Week Extended Nevirapine
(SWEN) Study:
Ethiopia, India, Uganda: Separate but Coordinated Trials
IP Birth-72hr Day 8 to 42
Arm 1
SD NVP
NVP x1
Infant
NVP x1
Infant:
Multivitamin “placebo” 0.5 mL
BID from Day 8 to 42
Arm 2
6-Week
NVP
NVP x1
Infant
NVP x1
Infant:
NVP 0.5 mL QD +
Multivitamin 1 mL QD
from Day 8 to 42
Sastry J et al. 15th CROI, Boston, MA 2008 Abs 43

SWEN: 6-Week NVP Decreases Postnatal HIV MTCT
at Age 6 Wks but No Longer Significant at 6 Mos
12%
6-Week NVP
RR 0.54, p=0.009
SD NVP
RR 0.80, p=0.16
9.0%
% Postnatal MTCT
6%
2.5%
5.3%
6.9%
0%
6 Weeks 6 Months
Infant Age at HIV Test

SWEN:6-Week NVP Reduces Risk of
HIV Infection or Death at 6 Wks and 6 Mos
15%
10%
5%
6-Week NVP
RR 0.58, p=0.008
6.8%
3.7%
SD NVP
RR 0.73, p=0.028
11.6%
8.1%
0%
6 Weeks 6 Months

% MTCT 6 Months
10%
ARV Prophylaxis: Birth - 6 Month HIV
Transmission Rates (uninfected at birth)
8%
6%
4%
2%
All also AP maternal ARVs
(HAART, Dual or AZT)
2.6%
1.3% 1.1% 0.6%
0.9%
2.4%
NO AP maternal ARV
6.9%
5.7%
4.0%
0%
DREAM
(CROI
2008)
Mitra
Plus
Amata KIBS Mitra
(infant
3TC)
Mom
AZT/3TC
SIMBA
(infant
NVP)
Mom
AZT/ddI
Mashi
(infant
AZT)
Mom
AZT
SWEN
(infant
NVP)
PEPI-
Malawi
(infant
NVP)
Maternal PP HAART
Infant PP ARV

2. EXCLUSIVE
BREASTFEEDING

CUMULATIVE RISK OF POSTNATAL HIV
TRANSMISSION RATE BY EARLY FEEDING
PATTERN & AGE
20
6wks-6 mo
6-18 mo
% HIV TRANSMISSION
15
10
5
0
5.6
1.3
5.6
3
9.5
4.4
EXCLUSIVE
PREDOMINANT
PARTIAL
Iliff P et al, AIDS 2005

ESTIMATED KAPLAN-MEIER
CUMULATIVE HIV TRANSMISSION RISK.
VTS
4.5
4
3.5
3
2.5
2
1.5
1
After 1mth
After 2 mths
After 3 mths
After 4 mths
After 5 mths
0.5
0
EBF exposure
Estimated risk per 100 child years of EBF exposure = 10.72
**0.89 per month EBF exposure

MIXED- BREASTFEEDING IS ASSOCIATED
WITH A HIGHER RISK OF HIV
TRANSMISSION THAN EXCLUSIVE-
BREASTFEEDING. VTS
Breastfeeding Type Hazard Ratio
Exclusive Breastfeeding: 1.00
Breastmilk + Solids: 10.84*
Breastmilk + Formula : 1.80

IS THERE BENEFIT TO EARLY BREASTFEEDING
CESSATION[GR.A] vs CTD BREASTFEEDING[GR.B]
ZAMBIA
Group A Rapid Weaning
4months
Group B
Continued Breastfeeding
through 6 months
Kuhn L, CROI 2007, ZEBS

Duration and Pattern of Breastfeeding
and Postnatal Transmission
WEST AFRICA,COTE D`IVOIRE
SOUTH AFRICA,KWAZULU/NATAL
• Overall 18 month postnatal transmission was
higher in S. Africa study (longer BF):
– 5% (CI 3-8%) W. Africa vs 9% (CI 7-11%) S.
Africa, p=0.03.
• BF duration was major determinant of MTCT -
18 month postnatal transmission by duration:
Longer duration associated with 2.1-fold (CI
1.2-3.7) increased hazard postnatal MTCT.
Becquet R et al. 15 th CROI, Boston, MA, 2008, Abs 46

CAN WE CHANGE BREASTFEEDING BEHAVIOUR?
DURATION OF EXCLUSIVE BREASTFEEDING
81.90%
PREINTERVENTION
POSTINTERVENTION
66.50%
40.10%
10%
6%
6 weeks ≥ 3 months 6 months
Bland R et al, Acta Pediatr 2002 & Coovadia HM et al, VTS 2007

Low Birth Weight and ARV Regimen Used
During Pregnancy: Cote d’Ivorie
% Low Birth Weight
30%
15%
9.4%
12.3%
22.3%
0%
AZT+SD NVP
(N=96)
AZT/3TC+SD NVP
(N=65)
Type of Antenatal ARV Regimen
AZT/d4T+3TC+NVP
(N=139)
Ekouvei D et al. 15th CROI, Boston, MA, 2008 Abs. 641

PROMISE General Overview: Sequential Randomized 2x2 Factorial Trial
Women with CD4 >350
R
a
n
d
o
m
i
z
e
Late
presenters
AP 28-term
HAART
AZT
IP PP for Duration BF After Weaning
HAART
AZT +
SD NVP+
7d TRV
Maternal
AZT +
SD NVP+
TRV
No ARV
Infant uninfected
at birth
R
a
n
d
o
m
i
z
e
HAART
Infant SD NVP +
AZT x1 wk
Infant NVP
Infant SD NVP +
AZT x1 wk
Mother
Infant
(if HIV-
&