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

3

Introduction: The Context

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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

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Overview of HIV Transmission during

Breastfeeding

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

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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)

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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

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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)

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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)

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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

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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

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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)

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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

%

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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%

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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

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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)

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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

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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)

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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

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Proportion of postnatal HIV transmission occurring after 6

months in selected studies (excludes first 4-6 weeks)

7666 63 62

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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

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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

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Feeding mode and Morbidity of children born to Women with HIV

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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

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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

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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

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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

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Quantifying theBalance of Risks

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Age

0

AdditionalRisk ofDeath

0

Breastfed

Not Breastfed

Timing the Introduction of Replacement Feeding

optimum

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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%

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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

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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

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Intervention Research on Postnatal Transmission

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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 ?

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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

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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

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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

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Challenges for the Future

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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)

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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)

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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

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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

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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

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Thank You!