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UNCCDC Collaborative Study to Decrease MTCT of HIV during Breastfeeding in Malawi

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Title: UNCCDC Collaborative Study to Decrease MTCT of HIV during Breastfeeding in Malawi


1
UNC-CDC Collaborative Studyto Decrease MTCT of
HIV during Breastfeeding in Malawi
  • van der Horst, Kazembe, Duerr, Piwoz, Fiscus,
    Ahmed, Shugars, Kashuba, Bentley, Adair,
    Cornelli, Cross, Cohen, Hoffman, Jones, Moses,
    Martinson, Heilig, Kourtis, Thomas, Hurst, Bayer,
    Guay, Barry, Ryan, Merry

2
With heavy whitening wings, and a heart fallen
cold   I kiss my wailing child and press it to
my breast,           And hear the narrow graves
calling my child and me William Butler
Yeats The Wind Among the Reeds
3
Study Objectives
  • Decrease MTCT among breastfeeding HIV mothers
  • Decrease maternal morbidity and mortality during
    breastfeeding
  • Enhance nutritional status of HIV mothers and
    infants through feasible nutrition counseling and
    maternal supplementation

4
Lit review of infant HIV in BF studies
5
Monthly Risk of MTCT during Early Breastfeeding
(Nduati R, 2000 283 1167-74Coutsoudis A, AIDS
2001, 15379-387D Moodley Global Strategies
Conference, September 2001 Petra Study Team.
Lancet 2002 359 1178-86
6
Mortality of Breastfeeding HIVMothers in
KenyaNduati Lancet 20013571651
N425 Cox Regression control for VL/CD4 4.7
(1.8-12.0p0.001)
7
Patterns and Determinents of Maternal Nutritional
Status during Lactation in MalawiJ. Ross and J-P
Habicht Dec 1995
  • 923 women followed ap and for 12 mos pp
  • 6.1 kg wt gain during pregnancy
  • Lowest wgt Sept-Feb prior to harvest (-2 kg)
  • Maternal arm circum 22.2 cm (10th Percentile)
    with infant growing median rate 0.97 kg lighter
    if exclus BF
  • BMI best predictor of malnutrition
  • 47 of infants wt 2 SD below US norm at 12 mos

8
Arm Circumference J. Ross and J-P Habicht Dec
1995HIV Test Not Done, Pop25 Pos
9
Infants who do not breastfeed have an increased
risk of dying in the first year of life
Pooled Odds Ratios
WHO Collaborative Study Team, 2000
10
J. Ross and J-P Habicht Dec 1995 HIV Test Not
Done, Pop25 Pos
Median Duration of breastfeeding 21 mos (Haggerty
P, Rutstein S)
11
Risks of Breastfeeding CessationMillard and
Graham 1985
  • For Infants
  • Dehydration
  • Refusal to eat
  • Weight loss and malnutrition
  • Loss of special bond with mother
  • Loss of sucking
  • Increased risk of neglect
  • For Mothers
  • Engorgement (750 ml/day)
  • Mastitis
  • Increased risk of pregnancy
  • Depression
  • Stigmatization

12
EBF rates at 6 weeks - over time and after the
introduction of an education and counseling
program on safer breastfeeding practices in
Harare, Zimbabwe (n9,931)
Education and counseling intervention began
ZVITAMBO data
13
What do we know about the feasibility of early
breastfeeding cessation? Barcelona AIDS
Conference
  • Early, rapid cessation is possible (Uganda,
    Zambia, Botswana)
  • Problems encountered
  • breast engorgement mastitis babies crying,
    trouble sleeping, appetite loss, diarrhea
    financial constraints with replacement feeding
    family objections
  • more problems when cessation (Botswana)
  • Trained counselors were able to help mothers
    overcome problems
  • Provision of replacement feeds, family support
    facilitated process
  • Impact on HIV transmission, survival not yet known

14
Breast milk contributes 50 of the nutrient
intake of children 6 months in developing
countries and wont be easy to replace
Adapted from WHO, 1998 Dewey and Brown, 2002
using data from Bangladesh, Ghana, Guatemala, Peru
15
17,920 Pregnant Women   25 refuse
VCT 13,440 Pregnant Women Tested for
HIV 20 positive 2,688 HIV Positive
10 CD4 Referred to Lighthouse Clinic 2,420 HIV
Positive All
receive HIVNET 012 Regimen
UNC-CDC Safe MotherBaby Project
16
2,420 HIV Positive mothersbabies
available   8 of Babies HIV pos at 2
weeks 2,225 Eligible 1,113 supplement
1,112 No supplement

371
371 371 371
371 371 Std Care Mom
Baby Std Care Mom Baby ART
NVP ART NVP
UNC-CDC Safe MotherBaby Project
17
UNC-CDC Safe MotherBaby Project
371
371 371
371 371 371
ART 28 weeks
weaning project
10 LFU at 28 weeks
3 7 3 3 7 3 10 
23 10 HIV Pos Babies
10 23 10

18
Infant NVP Dose to reach 100 ng/ml serum level
for 28 weeks (for tox, switch to 3TC)
19
Maternal Intervention
  • Combivir (AZT 3TC) plus Nevirapine
  • For anemia, switch to D4T
  • For hepatitis/rash switch to nelfinavir

20
Nutrient Requirements during Lactation (RDA
healthy women, first 6 mo)
  • Energy 500-650 kcal /d
  • Protein 15-20 g/d
  • Iron 15 mg/d
  • Zinc 19 mg/d
  • Selenium 75 microgram/d
  • Vitamin A 1300 RE/d
  • Vitamin B6 2.1 mg/d
  • Vitamin B12 2.6 microgram/d
  • Vitamin C 95 mg/d
  • Vitamin E 65 mg/d

National Academy of Sciences. 1989. Recommended
Dietary Allowances. Washington DC National
Academy Press.
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Breastmilk Substitute 28 wks
  • The food is a spread (meant to be sucked from a
    spoon by children)
  • made from peanut butter (about 25), full cream
    powdered milk, oil and sugar with multivitamins
  • The energy density is 540 kcal/100g
  • The cost is about 1.50/kg.
  • The product is packaged in 250 g bottles.
  • Mark Manary, Dept Pediatrics Wash Univ St. Louis
    May Society for Pediatric Research

23
Safety Measures
  • Women CD4
  • 5 wt loss/month after 4 weeks pp get nutrition
  • 5 kg maize per family per week (3,500 kcal/kg)
  • Standard antenatal and post partum care
  • OI prophylaxis,
  • dx and rx TB, malaria

24
  • Total number of women enrolled in study
  • 2 x 3 factorial design
  • Two sided test
  • .

25
Risk Factor for HIV Transmission via BM and
Strength of Evidence (UNICEF 1998)
26
Proposed Laboratory Studies Virology
  • Cellular Compartments of HIV Replication in BM
    and plasma (Butera)
  • CD26-lymphocyte, CD14 or 36-macrophage,
    HLA-DR-activation
  • Mucosal tissue tropism-capacity to infect BM
    derived vs blood derived macrophages
  • HTA of V1-V3 Envelope (Shugars)
  • variants transmitted, influence of mastitis and
    evolution of variants
  • Virologic Factors (Fiscus)
  • Blood VL, BM Na, VL
  • Resistance (Fiscus)
  • Assoc with transmission, evolution in Blood and
    BM, correl with VL and PK

27
Immunological parameters of HIV transmission
through breastfeeding
28
Proposed Laboratory Studies Immunology
  • Mucosal Immune Activation Markers (Kourtis)
  • CD103 (alphaEbeta7Integrin) intestinal lymphocyte
    interaction with epithelial cells
  • alpha4beta7Integrinlymphocyte homing to mucosa
  • Cells without CCR7 (CD45RA-CCR7-) home to
    peripheral sites
  • Isolate Specific Neutralizing Antibodies in Blood
    and BM (Kourtis)
  • Soluble Immune Factors in BM (Shugars)
  • Anti-HIV factors (SLPI, lactoferin, RANTES,
    IFN-?),
  • Pro-inflammatory (IL-8, IL-6, IL-1ß and TNF-?)

29
Proposed Laboratory Studies Immunology Part Deux
  • Detection of HIV Specific CD4/CD8 in infants
    (Kourtis)
  • Immune Activation First two days of life
    (Kourtis)
  • Soluble L-selectin shed by naïve lymphocytes upon
    activation, correlate with presence or absence of
    pos PCR first 2 days

30
Proposed Laboratory Studies
  • Intestinal Permeability (Kourtis)
  • Lactulose/mannitol assay mannitol passes through
    transcellular route so is measure of absorptive
    surface, lactulose is not absorbed by healthy
    enterocytes
  • Role of Coinfections
  • CMV, HHV-6, oral candida
  • Nutrients
  • Transferrin receptors, Vit A, B12, E, selenium
  • Host genetics (HLA)
  • PK-Intensive and Trough (Kashuba)

31
Three investigations will be performed
  • in the HAART arm
  • all mothers will have timed (in relation to drug
    dose) blood plasma (3 mL) and whole breast milk
    samples (5 mL) collected at 1, 4, and 6 months
  • all infants will have times blood plasma (0.5mL)
    at 1, 4, and 6 months
  • pharmacologic testing will occur on a subset of
    30 women babies who agree to extensive (4
    sample) PK analyses at 1, 4, and 6 months (for
    population PK model development)
  • in the HAART arm
  • pharmacologic testing will be performed on
    samples from a subset of 15 women who transmitted
    HIV to their babies, and 15 who did not
  • in the Nevirapine arm
  • pharmacologic testing will be performed on
    samples from a subset of 15 babies who acquired
    HIV and 15 who did not

Drug concentrations in blood plasma and breast
milk HPLC-UV detection Concentration data will
be analyzed by noncompartmental and compartmental
analyses WinNonlinPro Antiretroviral drug
exposure will be assessed using AUC0-12h data,
and will be compared using parametric methods
(SAS JMP)
32
Two investigations will be performed
  • In the HAART arm, pharmacokinetic-pharmacodynamic
    analyses will be performed on zidovudine,
    lamivudine, and nelfinavir for women with and
    without drug-related toxicities
  • In the Nevirapine arm, pharmacokinetic-pharmacodyn
    amic analyses will be performed on nevirapine for
    babies with and without toxicities

Drug concentrations in blood plasma and breast
milk will be determined using validated HPLC-UV
detection methods Concentration data will be
analyzed by noncompartmental and compartmental
analyses using WinNonlin Pro software Antiretrovir
al drug exposure will be assessed using AUC0-12h
data, and will be compared using parametric
methods (SAS JMP)
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Luanda
ANGOLA
MALAWI
ZAMBIA
Lusaka
Harare
MOZAMBIQUE
ZIMBABWE
NAMIBIA
Windhoek
BOTSWANA
Gaborone
Maputo
Johannesburg
SWAZILAND
LESOTHO
SOUTH AFRICA
Cape Town
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Background on Malawi
  • Population - 10 million, size of Pennsylvania
  • Per capita GNP
  • Antenatal HIV prevalence
  • 26 urban areas
  • 18 outside urban areas
  • 497,000 live births/year
  • 20,000 babies born HIV (50/day)
  • Total Fertility Rate 6.4
  • 49 children
  • 37 in Lilongwe
  • 20,000 delivers per year in Lilongwe

UNAIDS, 2000 DHS, 2001 SC, 2001
43
Hurdles
  • No money
  • Personnel
  • Doctors, nurses, pharmacists, laboratory
    technicians
  • Training of staff
  • Access to consultation
  • Health of staff
  • Roll out to rural areas
  • Government Issues
  • Corruption
  • Nongovernmental Organization Issues (NGOs)
  • Lack of cooperation
  • Inaction through assessment and training
  • If its not sustainable we cant do it.
  • Neocolonialism of NGOs
  • Infrastructure
  • Clinic rooms/hospital rooms/labs/pharmacies
  • Roads
  • Electricity
  • Clean Water
  • Food
  • Medication issues
  • Security
  • Sharing of drugs
  • Storage conditions
  • Monitoring labs
  • CD4, viral load, resistance testing
  • Toxicity monitoring
  • Role of women in society
  • Burden of disease
  • Endemic Diseases (TB, Malaria)
  • AIDS
  • Orphans

44
Infrastructure in Place
  • 40 ANC rooms 5 group counseling rooms 2 on
    site laboratories
  • PCR facility
  • Cell separation and storage facility
  • New 10,000 sq foot bldg at LCH

45
VCT and HIVNET 012 6/1-11/30/02
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Sample for the Formative Research (target
numbers)
  • 60 in-depth interviews w/ HIV women
  • infant feeding
  • maternal nutrition
  • study participation
  • 6 focus group discussions
  • fathers
  • pregnant women
  • grandmothers
  • 90 home visits
  • 30 households, 3x each
  • food availability
  • modified 24 h food recalls
  • testing new products, practices
  • 20 key informant interviews
  • health providers
  • community leaders
  • TBAs

52
Study Design and Enrollment Issues and
Recommendations - 1
  • Process of informed consent needs careful
    planning/testing
  • lack of comprehension of medical research such as
    prevention versus cure, treatment versus
    research, and the purpose of randomization
    women may assume that they are assigned to a
    group because of their health condition, not
    because of study design/allocation
  • women will need to consult with husbands before
    agreeing to enroll
  • multiple contacts to recruit, consent, enroll
    needed

53
Study Design and Enrollment Issues and
Recommendations - 2
  • There is blind faith in the medical
    establishment - with implications at several
    levels, both favorable and challenging - but not
    to be violated
  • Positive aspects relate to compliance with drug
    regimen and stopping when instructed, confidence
    in the medical community/advice being given
  • Negative aspects relate to failure to fully
    understand the potential risks of participation.
  • Assumption that the drugs are known to be
    beneficial and safe, not the subject of further
    research. As stated by one participant There is
    no danger - if the hospitals are using the
    medicines it means they are not dangerous.
  • Safety assumption particularly with the NVP arm

54
Taking Specimens and Follow-up
  • Breast milk sample no problem
  • Urine sample - long time to wait, but okay
  • Maternal blood - some worried that it is too
    much. Most would agree to give but will be likely
    to complain. Best to minimize amount. Need to
    guard against rumors!
  • Infant blood - some concerned about depleting the
    babys blood, but most would give blood to learn
    the condition of the baby
  • Follow-up visit schedule no problem
  • Home visits - no problem if done with discretion

55
ART for Mothers - 1
  • Dosing instructions easy to follow
  • If side effects observed, mothers say they would
    discuss with research nurses and get an
    alternative
  • Expectation that drugs will also be available for
    husband. As stated by one participant
  • There are two people who are positive - husband
    and wife - I dont think it makes sense to give
    medicine to the wife alone.
  • Perception that drugs cure the disease
  • need to stress that drugs are given to reduce BF
    transmission not for treating maternal HIV

56
ART for Mothers -2
  • Stopping drugs at 6 months - some concerns
  • women will be disappointed
  • women concerned about that their health will
    deteriorate, life expectancy will decrease when
    drugs stop
  • women will worry that baby will become infected
    after the drugs stop
  • women also very concerned about how they will
    feed their babies when they stop breastfeeding
  • a few women felt that stopping would be okay
    since women would be told at the outset that the
    drugs would stop

57
NVP for Babies
  • Assumption that drugs designed for babies, tested
    and safe
  • if there are side effects, assumption is that
    another drug will be available/given to the
    babies
  • Giving NVP to babies for 6 months may cause
    confusion with CTA (single dose)
  • heard from the community advisory board
  • some wondering if CTA regimen is not adequate

58
Maternal Nutrition Supplement
  • Four different products were tested for
    acceptability and preference
  • maize soy blend (cooked porridge)
  • groundnut biscuit
  • sweet biscuit
  • micronutrient sprinkles
  • Maize and the sweet biscuit were preferred by
    mothers
  • Sharing will be a problem. As stated by one
    participant Its very disappointing because in
    our culture you cant eat other food in the house
    while others are watching you eating.

59
Providing Maize Flour to Everyone - 5 kg/visit
  • Pros
  • addresses food insecurity (20 said facing food
    shortage now 100 lack food during months
    Jan-Mar)
  • may minimize sharing of maternal biscuit
  • may also help to make arm 6 more palatable
  • motivation for mothers in all arms for follow-up
    visits
  • can reduce visit remuneration from K 200 to K
    50-60
  • Cons
  • logistics (procurement, storage, distribution)
  • stigma (minimal since food often given out)
  • might cause community strife (among ineligible
    women)

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Exclusive Breastfeeding
  • Women know about EBF, but it is not practiced as
    recommended (to 6 months)
  • early introduction of solids/liquids common
  • DHS median - 2.0 months
  • Water is given early to quench thirst, perception
    that all humans need water
  • Traditional medicine widely given to speed
    closing of fontanelle

61
Early Cessation of Breastfeeding-1
  • Data clearly indicate that abrupt cessation at 6
    months is not acceptable
  • vulnerability of the infant at this age is a
    concern
  • As stated by some of the participants
  • the mother will be worried that the baby is
    young and will become malnourished
  • abrupt cessation is cruel
  • the baby will suffer and start losing weight
    because the food (breast milk) is taken away

62
Early Cessation of Breastfeeding -2
  • Data also suggest that early cessation at 6
    months is not acceptable for poor women
  • felt that this was good advice for women who
    could afford milk from shops but most of them
    could not afford and continued to breastfeed
  • mothers concerned about what they will feed their
    babies once breastfeeding stops
  • mothers less concerned about stigma associated
    with early cessation

63
Early Cessation of Breastfeeding -3
  • Preliminary analysis of 24-hour dietary recall
    data suggests that cessation at 6 months will
    lead to serious malnutrition without
    supplementation
  • breast milk is a major source of energy, protein,
    micronutrients
  • quality of weaning diet is poor - maize based, no
    consumption of animal milk (except in tea)

64
Latent Reservoir
65
Drugs
Plasma
66
Abacavir simplification trial
  • Excluded patients with 215 Y/F in PBMC DNA
  • PI-treated patients with plasma HIV-1 RNA c/mL for 6 months randomized to continue PI or
    change to ABC (N163)
  • Virologic failure 6 in continuation group vs 15
    in switch group (p0.08)
  • Prior NRTI mono- or dual therapy significant
    predictor of treatment failure on ABC

Opravil et al JID 2002
67
ABC switch study Time to failure
Opravil et al JID 2002
68
Mutations at failure on ABC
Opravil et al JID 2002
69
Thanks
  • UNC-Chapel Hill
  • Myron Cohen MD
  • Irving Hoffman PA
  • Susan Fiscus PhD
  • Frieda Behets PhD
  • Robin Ryder MD PhD
  • Steve Meshnick MD
  • Joe Eron MD
  • Annelies van Rie MD
  • Cheryl Marcus RN
  • Peggy Bentley PhD
  • Angela Kashuba PharmD
  • Diane Shugars, DDS, PhD
  • UNC Malawi
  • Francis Martinson MD
  • David Jones
  • Agnes Moses MBBS
  • Peter Kazembe MBBS
  • David Chilongozi, CO
  • CAB
  • Our patients

70
Thanks 2
  • CDC Reproductive Health Unit
  • Ann Duerr MD
  • Yusuf Ahmed MD
  • Beth Tohill PhD
  • Roshan Thomas MPH
  • Athena Kourtis MD
  • Sal Butera PhD
  • Denise Jamieson MD
  • Stacey Hurst MPH
  • Chad Heilig PhD
  • Elizabeth Glaser Pediatric AIDS Foundation
  • Cathy Wilfert MD
  • Dirk Buyse MD
  • Trish
  • Chuck Hoblitzelle

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