1. 1 HIV and Infant Feeding: Knowledge, Gaps and Challenges for the Future Jay Ross & Ellen G. Piwoz Academy for Educational Development WHO/P. Virot

2. 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. 3 Introduction: The Context

4. 4 Timing of Mother-to-Child Transmission 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% Labor and DeliveryBreastfeeding Pregnancy

5. 5 MTCT in 100 HIV+ Mothers by Timing of Transmission Uninfected: 63 Breastfeeding: 15 Delivery: 15 Pregnancy: 7

6. Major Causes of Death among Children around the World Deaths associated with undernutrition 60% Sources: EIP/WHO, Caulfield LE, Black RE. Year 2000

7. 7 Proportion of all < 5 yrs deaths that could be prevented with infant feeding interventions Jones et al, 2003, Lancet

8. 8 Overview of HIV Transmission during Breastfeeding

9. 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. 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. 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. 12 Risk factors for postnatal transmission: Maternal immune status Leroy et al 2003

13. 13 Risk factors for postnatal transmission: Maternal immune status BHITS meta-analysis, Read et al (CROI 2003)

14. 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. 15 Risk Factor: Maternal Viral Load Richardson et al, 2003

16. 16 Risk factor: Maternal viral load Leroy et al 2003 Adjusted HR for Postnatal Transmission in West Africa Combined Analysis

17. 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. 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)

19. 19 Association between breast inflammation and breast milk virus Hoffman et al, 2003 Log 10 copies/mL %

20. 20 Impact of lactation counseling on sub-clinical mastitis: Bangladesh (mild elevation) (severe elevation) Flores & Filteau 2002

21. 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. 22 Risk Factor: First month Estimated postnatal transmission during the first month of life

23. 23 Risk Factor: Duration of breastfeeding BHITS meta-analysis Cumulative rates of late postnatal HIV infection (> 4 wks) (Read et al, 2002)

24. 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. 25 Proportion of postnatal HIV transmission occurring after 6 months in selected studies (excludes first 4-6 weeks) Estimated from Leroy et al, 2002; Miotti et al, 1999; Coutsoudis et al, 2001; Fawzi et al, 2002; Nduati et al, 2000

26. 26 Risk Factor: Early Mixed breastfeeding Coutsoudis et al, 1999; 2001 Cumulative HIV transmission Durban, SA

27. 27 Feeding mode and Morbidity of children born to Women with HIV Coutsoudis et al, 2003 Percent of children ill or hospitalized in the first two months

28. 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. 29 Higher Rates of Hospitalization for Non- Breastfed Infants of HIV+ Mothers in a PMTCT Program in Pune, India Phadke et al, 2003 BFNon-BF sample6286 hospitalizations027* deaths04 *p<0.0001, no significant differences between BF and non-BF for any other infant or maternal characteristics

30. 30 Breastfeeding Saves Lives Relative risk of infectious disease mortality from not breastfeeding Source: WHO, 2000

31. 31 Quantifying the Balance of Risks

32. 32 Age 0 Additional Risk of Death 0 Breastfed Not Breastfed Timing the Introduction of Replacement Feeding optimum

33. 33 HIV and infant feeding risk model 4 feeding strategies compared: B 24 no postnatal intervention: BF “as usual” for 24 months B0B0 no BF by HIV+ women: commercial infant formula provided B6B6 BF initiation and early breastfeeding cessation at 6 months for HIV+ mothers SB 6 BF initiation and early cessation at 6 months for HIV+ mothers but intervention reduces BF transmission by 50%

34. 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)

35. 35 Cumulative HIV-free Survival Among Infants of HIV-infected Mothers INDIA: IMR=66 (SRS, 2001)

36. 36 Intervention Research on Postnatal Transmission

37. 37 Interventions to Prevent Postnatal Transmission Mother Avoid breastfeeding Wet nursing Early cessation Maternal ARV Preventing and treating breast conditions Exclusive Breastfeeding Heat treatment Nutrition? Infant Post-exposure ARV prophylaxis Preventing and treating lesions in mouth, intestine Immunization ?

38. 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. 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. 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

41. 41 Challenges for the Future

42. 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. 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. 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. 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. 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

47. 47 Thank You!