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1
HIV and Infant Feeding: Knowledge, Gaps and
Challenges for the FutureJay Ross
&
Ellen G. Piwoz
Academy for Educational
Development
WH
O/P
. V
irot
2
Outline of the Presentation
• Overview
• Review of evidence on risk factors
• HIV and infant feeding risk analysis
• Research planned and underway
• Challenges for the future
4
Timing of Mother-to-Child Timing of Mother-to-Child TransmissionTransmission
Early Antenatal(<36 wks)
Late Antenatal(36 wks to labor)
Late Postpartum(6-24 months)
Early Postpartum(0-6 months)
Adapted from N Shaffer, CDC
5-10% 10-20% 10-20%
Labor and Delivery BreastfeedingPregnancy
5
MTCT in 100 HIV+ Mothers by Timing of Transmission
0
20
40
60
80
100
Uninfected: 63
Breastfeeding: 15
Delivery: 15
Pregnancy: 7
Diarrhoea12%
Other29%
Perinatal22% HIV/AIDS
4%
Measles5%
Malaria8%
Pneumonia20%
Major Causes of Death among
Children around the World
Deaths associated with undernutrition
60%
Sources:EIP/WHO, Caulfield LE, Black RE.Year 2000
7
Proportion of all < 5 yrs deaths that could be prevented with infant
feeding interventions
13
2
0
5
10
15
Breastfeeding Nevirapine & Formula
Jones et al, 2003, Lancet
9
Risk Factors For Postnatal Transmission
Mother• Immune/health
status
• Plasma viral load
• Breast milk virus
• Breast inflammation (mastitis, abscess, nipple lesions)
• New HIV infection
• Viral Characteristics
Infant• Breastfeeding
duration
• Non-exclusive BF
• Age (first months)
• Lesions in mouth, intestine
• Prematurity
• Infant immune response
10
How does HIV transmission during breastfeeding occur? -
1
• Exact mechanisms unknown
• HIV virus in blood passes to breast milk– cell-associated, cell-free virus observed
– virus shed intermittently (undetectable ~ 25-35%)
– levels vary between breasts in samples taken at same time (Willumsen et al, 2001)
• Virus may also come directly from infected cells in mammary gland – produced locally in mammary macrophages,
lymphocytes, epithelial cells (Becquart et al, 2002)
11
How does HIV transmission during breastfeeding occur? -
2
• Infant consumes HIV– HIV enters/infects infant through permeable mucosal
surfaces, lymphoid tissues, and/or lesions in mouth, intestines
• Although BF infant may consume >500,000 virons, >25,000 infected cells per day, majority do NOT become HIV infected (Lewis et al, 2001)
• Why? Immune factors in BM, saliva play a role (Miller et al, 2002; Sabbaj et al, 2002; Farquhar et al, 2002; Van der Perre et al, 1999; 1993; 1988)
12
Risk factors for postnatal transmission: Maternal immune
statusHI V transmission from 6 w - 24 mo in
West Africa by maternal baseline CD4
21.8
2
05
10152025
CD4 < 500 CD4 >= 500
Transmission
(%)
Leroy et al 2003
13
Risk factors for postnatal transmission: Maternal immune
statusHazard ratio for postnatal HI V transmission
8
3.7
1
0
5
10
CD4 < 200 CD4 200- 499 CD4 >= 500
BHITS meta-analysis, Read et al (CROI 2003)
14
Risk factor: Maternal viral load
• Viral load is an important predictor of intra-partum MTCT (Leroy et al, 2001; Semba et al, 1999)
• Plasma viral load is also a risk factor during breastfeeding– Mothers newly infected during lactation temporary
“pulse” in circulating virus 29% transmission risk (Dunn et al, 1992)
– Plasma viral load associated with increased risk of PN transmission in studies in:
Kenya (John et al, 2001; Richardson et al, 2003)Tanzania (Fawzi et al, 2002) West Africa (Leroy et al, 2003)
15
Risk Factor: Maternal Viral Load
Risk of HIV transmission per
day of BF (%)
0.011
0.044
0
0.01
0.02
0.03
0.04
0.05
Low Viral Load High Viral Load
Richardson et al, 2003
16
Risk factor: Maternal viral load
1.15
2.653.14
0
1
2
3
4
ZDV Plasma log10 viral load CD4 < 500
Adj.
Haz
ard R
atio
Leroy et al 2003
Adjusted HR for Postnatal Transmission in West Africa Combined Analysis
17
Risk Factor: Breast Pathology
Prevalence of breast pathologies in HIV+ women in Africa
• Mastitis (clinical or sub-clinical):– Clinical exam: 7-11% (Embree, 2000; John et al, 2001)– Na+/K > 1.0: 11-12% at 6, 14 wk (Willumsen et al, 2000)– Na+ > 12 mmol/L: 16.4% at 6 wk (Semba et al, 1999)
• Nipple lesions:– Clinical exam: 11-13% (Embree, 2000; John et al, 2001)– Clinical exam: 10% (Ekpini et al, 1997)– Hospitalized infants: 11% (Kambarami et al, 1997)
• Breast abscesses:– Clinical exam: 12% (John et al, 2001)– Clinical exam: 3% (Ekpini et al, 1997)
18
Risk factor: Breast Pathology
• Breast inflammation & mastitis increased risk of postnatal transmission (Embree et al; John et al; Semba et
al)
• Nipple lesions, breast abscesses increased transmission (Fawzi et al, 2002; Embree et al, 2000; Ekpini et al, 1997)
• Sub-clinical mastitis higher viral load in BM (Willumsen et al, 2000; Semba et al, 1999, Hoffman, 2003)
Estimated f raction of MTCT
due to breast infection
1820
0
5
10
15
20
25
Malawi Kenya
%
19
Association between breast inflammation and breast milk
virus
5.25
2.29
0
1
2
3
4
5
6
Viral Load
Breastinflammation
No breastinflammation
Hoffman et al, 2003
94
38
0
10
20
30
40
50
60
70
80
90
100
Sensitivity
Log10 copies/mL%
20
Impact of lactation counseling on sub-clinical mastitis:
BangladeshI ndicators of inflammation are significantly
lower (p<0.05) in the counseled group
73
16
9
0
5
10
15
20
Na/K ratio 0.6-
1.0
Na/K ratio > 1.0
%
Counseled
Not Counseled
(mild elevation)
(severe elevation)
Flores & Filteau 2002
21
Risk factor: First months
• Higher in the first months of life (Nduati et al, 2000; John et al, 2001)
• Why? Maybe:
– higher prevalence of mastitis, breastfeeding problems
– infant gut more immature, permeable
– greater exposure (higher concentration of cells)
22
Risk Factor: First month
4.5
1.9
2.9
1.8
0.9
0
1
2
3
4
5
Kenya Durban SAINT PETRA > 1 m
(Read)
Study
Tra
smis
sion
Ris
k (%
per
mon
th)
Estimated postnatal transmission during the first month of life
23
Risk Factor: Duration of breastfeeding
BHITS meta-analysis
0
5
10
15
20
0 6 12 18
Age (months)
%
Cumulative rates of late postnatal HIV infection (> 4 wks)
(Read et al, 2002)
24
Risk Factor:Duration of Breastfeeding
Nairobi, Kenya: Randomized trial of formula vs breastfeeding
• Statistical model developed (n=358 infants with 75 infections, 52 possibly through breastmilk)
• Overall probability of HIV transmission per day of BF = 0.00028/day (=0.85% per month)
• Risk continues as long as breastfeeding continues
• Median duration of breastfeeding: 17 months Richardson et al, 2003
25
Proportion of postnatal HIV transmission occurring after 6
months in selected studies (excludes first 4-6 weeks)
7666 63 62
52
01020304050607080
WestAfrica Malawi South
Africa
Tanzania Kenya
Estimated from Leroy et al, 2002; Miotti et al, 1999; Coutsoudis et al, 2001; Fawzi et al, 2002; Nduati et al, 2000
26
Risk Factor: Early Mixed breastfeeding
7
1619
25
7
2426
36
0
5
10
15
20
25
30
35
40
Birth 3 mo 6 mo 15 mo
%EBF to 3 mo
Partial BF
Coutsoudis et al, 1999; 2001
Cumulative HIV transmission Durban, SA
27
Feeding mode and Morbidity of children born to Women with HIV
26
40
20
3
0
10
20
30
40
50
I llness Hospitalization
%Ever BF
Never BF
Coutsoudis et al, 2003
Percent of children ill or hospitalized in the first two months
28
Bacterial Contamination and Improper Preparation of Commercial Infant Formula
in a PMTCT Program in Durban, South Africa
Characteristics of mothers (n=94) 54% completed high school or greater 66% had indoor piped water 70% flush toilet
Contamination of milk samples 64% E Coli 26% Enterococci
Over dilution of milk samples 22% for infants <= 12 months 78% for children > 12 months
Bergström, 2003
29
Higher Rates of Hospitalization for Non-Breastfed Infants of HIV+
Mothers in a PMTCT Program in Pune, India
Phadke et al, 2003
BF Non-BF
sample 62 86
hospitalizations 0 27*
deaths 0 4
*p<0.0001, no significant differences between BF and non-BF for any other infant or maternal characteristics
30
Breastfeeding Saves Lives
5.8
4.1
2.6
1.81.4
0
1
2
3
4
5
6
7
<2 2-3 4-5 6-8 9-11
Age (months)
Rel
ativ
e R
isk
Relative risk of infectious disease mortality from not breastfeeding
Source: WHO, 2000
32
Age
0
AdditionalRisk ofDeath
0
Breastfed
Not Breastfed
Timing the Introduction of Replacement Feeding
optimum
33
HIV and infant feeding risk model
4 feeding strategies compared:
B24 no postnatal intervention: BF “as usual” for 24 months
B0 no BF by HIV+ women: commercial infant formula provided
B6 BF initiation and early breastfeeding cessation at 6 months for HIV+ mothers
SB6 BF initiation and early cessation at 6 months for HIV+ mothers but intervention reduces BF transmission by 50%
34
Cumulative HIV-free Survival Among Infants of HIV-infected Mothers IMR=91 (average for sub-Saharan Africa)
Safer BF for 6 months by HIV+ mothers gives the best outcome. Continued BF by HIV+ mothers gives the worst result. At 6 months, No BF gives worst outcome. (Ross and Labbok, in press)
600
700
800
900
1000
0 6 12 18 24
Age (months)
HIV
-fr
ee s
urvi
val/
1000
SB6
B6
B0
B24
35
Cumulative HIV-free Survival Among Infants of HIV-infected Mothers
INDIA: IMR=66 (SRS, 2001)
600
700
800
900
1000
0 6 12 18 24
Age (months)
HIV
-fr
ee s
urvi
val/
1000
SB6
B6
B0
B24
37
Interventions to Prevent Postnatal Transmission
MotherAvoid breastfeeding
Wet nursing
Early cessation
Maternal ARV
Preventing and treating breast conditions
Exclusive Breastfeeding
Heat treatment
Nutrition?
InfantPost-exposure ARV prophylaxis
Preventing and treating lesions in mouth, intestine
Immunization ?
38
Overview of Trials Planned or Underway
32 intervention field trials on MTCT reviewed
18 related to some aspect of infant feeding:– Post-exposure prophylaxis (PEP) during BF (8)
– PEP + immunization (1)
– Early cessation (3)
– Vitamin A + EBF (1)
– EBF (1)
– Highly Active Antiretroviral Therapy (HAART) (3)
– Chloroquin (1)
14 on perinatal transmission:
– ARVs (12)
– Immunization (2)
Sources: Ghent PMTCT working group, 2003; Gaillard, 2003
39
SIMBA Study – Uganda and Rwanda -1
Design:
• 405 HIV+ women received ZDV+DDI (from 36 wks+ 1 wk pp)
• All counseled to EBF and wean from 3-6 months
• 397 infants randomized to daily NVP or 3TC from 1 wk to 1 month after BF stopped
Findings: Overall rate HIV transmission (KM): 8% – 6% in-utero; 1% from birth-4 wks; 1% 4 wks-6 mo
40
SIMBA Study – Uganda and Rwanda -2
Conclusions/Concerns:
• Infant prophylaxis a promising strategy for reducing PN transmission
• Concerns:– Widely cited comparison with 15% transmission rate
in other studies is misleading
– lack of control arm
– asymptomatic population so risk of transmission was low to begin with
– What was the intervention? Dual treatment of mother, infant prophylaxis, EBF (88%), early cessation (3.3 months)
Vyankandondera et al, 2003
42
1.Focus on maternal health & nutrition
• Keeping HIV+ mothers well may be among the most important things we can do to prevent P/N transmission
• BF transmission was ~2% between 6 w-24 months in women with CD4 >500 (Leroy et al, 2003)
• Nutrition depletion, weight loss during BF may increase risk of maternal mortality, especially in immune compromised mothers (Nduati et al, 2001)
• Keeping mothers alive will improve child’s chances for survival (Nduati et al, 2001; Nakiyingi et al, 2003)
43
2. Expanding Use of ARVs• Lower prices, wider variety of available regimens,
easier logistics, trial results spurring demand (including HAART PMTCT trials) expanding postnatal use and availability of ARVs
• increasing concerns about long term effects on infant (toxicity and resistance) – studies looking at this now
• Legitimate demand for a single standard of care regardless of socioeconomic conditions currently HAART for mother, perinatal ARV therapy, and replacement feeding from birth (with all necessary support)
44
3. Strengthen approaches for making breastfeeding safer for
ALL women• Provide adequate lactation counseling and support,
involving families/communities
– increase adherence to exclusive breastfeeding
– promote good breastfeeding techniques
– prevent cracked nipples, maintain breast health
• Immediate treatment for mastitis, other systemic infections that could affect viral load in BM
– could prevent a sizeable fraction of BF transmission
– may be most important in early month(s)
• Safe sex/condom use for prevention
45
4. Make breastfeeding safer for HIV+ women
• Assist families with decisions about early breastfeeding cessation
– assess health status of mother and infant
– prepare for the process so that the transition is safe (cup-feeding, safe preparation/hygiene, stigma)
– heat treat breast milk if weaning is gradual
– could prevent ½ to ¾ of BF transmission
• Provide adequate infant nutrition after breastfeeding ends
– appropriate breast milk substitutes and/or multi-nutrient supplements should be provided to prevent malnutrition
46
5. Make replacement feeding safer for HIV+ women
• Provide safe water & environmental conditions
– rural and urban areas may vary
• Family support, community understanding
• Postnatal follow-up and enhanced care
– essential child health interventions
• Screen mothers, target use to those most at risk
• Take measures to prevent unnecessary use of RF
– need to strengthen efforts to support optimal infant feeding for all