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Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
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Hiv transmission thru breastfeeding

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  • 1. This publication is an update of the review of current knowledge on HIV transmission throughbreastfeeding, with a focus on information made available between 2001 and 2007. It re- HIV Transmission Throughviews scientific evidence on the risk of HIV transmission through breastfeeding, the impactof different feeding options on child health outcomes, and conceivable strategies to reduceHIV transmission through breastfeeding with an emphasis on the developing world. Breastfeeding For further information, please contact: World Health Organization Department of Child and Adolescent Health and Development (cah@who.int) or Department of HIV/AIDS (hiv-aids@who.int) or Department of Nutrition for Health and Development (nutrition@who.int) 20 Avenue Appia, 1211 Geneva 27, Switzerland website: http://www.who.int UNICEF Nutrition Section – Programme Division 3 United Nations Plaza A REVIEW OF AVAILABLE EVIDENCE New York, New York 10017, United States of America 2007 Update Tel +1 212 326 7000 ISBN 978 92 4 159659 6
  • 2. HIV TransmissionThrough Breastfeeding A Review of Available Evidence 2007 Update
  • 3. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007WHO Library Cataloguing-in-Publication DataHIV transmission through breastfeeding : a review of available evidence : 2007 update.1.HIV infections - transmission. 2.Acquired immunodeficiency syndrome - Transmission. 3.Breastfeeding - adverse effects. 4.Disease transmission, Vertical - prevention and control 5.Review litera-ture. I.World Health Organization.ISBN 978 92 4 159659 6 (NLM classification: WC 503.3)© World Health Organization 2008All rights reserved. Publications of the World Health Organization can be obtained from WHO Press,World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 7913264; fax: +41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce ortranslate WHO publications - whether for sale or for noncommercial distribution - should be ad-dressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int).The designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the World Health Organization or of the UnitedNations Childrens Fund concerning the legal status of any country, territory, city or area or of itsauthorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps repre-sent approximate border lines for which there may not yet be full agreement.The mention of specific companies or of certain manufacturers products does not imply that they areendorsed or recommended by the World Health Organization or the United Nations Childrens Fundin preference to others of a similar nature that are not mentioned. Errors and omissions excepted, thenames of proprietary products are distinguished by initial capital letters.All reasonable precautions have been taken by the World Health Organization and the United Na-tions Childrens Fund to verify the information contained in this publication. However, the publishedmaterial is being distributed without warranty of any kind, either expressed or implied. The respon-sibility for the interpretation and use of the material lies with the reader. In no event shall the WorldHealth Organization or the United Nations Childrens Fund be liable for damages arising from itsuse.Printed in France. ii
  • 4. Table of contentsPreface vAcknowledgements viiAcronyms viiiGlossary ixExecutive summary 1Introduction 3Mother-to-child transmission of HIV 5 HIV infection in women 5 Rates of, and risk factors for, overall mother-to-child transmission 5 Prevention of mother-to-child transmission of HIV 6HIV transmission through breastfeeding 9 Pathogenesis and mechanisms of breastfeeding transmission 9 Risk of postnatal transmission through breastfeeding 10 Timing of postnatal transmission through breastfeeding 10 Early postnatal transmission through breastfeeding 10 Late postnatal transmission through breastfeeding 11 Factors associated with risk of transmission through breastfeeding 12 Maternal factors 12 Infant factors 16Benefits of breastfeeding 19 Health benefits of breastfeeding in the general population 19 Maternal health benefits 19 Child health benefits 19 Health benefits of breastfeeding in children born to HIV-infected mothers 21 HIV-exposed children, regardless of HIV status 21 HIV-infected children 21 Global breastfeeding practices 22Strategies to reduce HIV transmission through breastfeeding 23 Primary prevention of HIV in women of childbearing age 23 Framework to assess interventions to prevent postnatal transmission 24 iii
  • 5. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007 Modifying infant feeding options for HIV-infected women: replacement feeding 24 Adverse outcomes of alternatives to breastfeeding practices 25 Social acceptability of feeding practices 25 HIV-infection 32 HIV-free survival 32 Discussion 32 Strategies for HIV-infected women who breastfed 33 Exclusive breastfeeding 33 Early cessation of breastfeeding 35 Heat treatment or pasteurization of expressed breast milk. 36 Microbicide treatment of expressed breast milk 36 Antiretroviral therapy during breastfeeding 37 Immunization of breastfed newborns 39 From research to public health recommendations on infant feeding: consequences for practice 39Ongoing or planned research addressing the breastfeeding period 41Conclusion 43References 44 iv
  • 6. PrefaceT his Review was originally prepared as a back ground paper for the Technical Consulta-tion on HIV and Infant Feeding that took place acquisition without gains for survival. It remains important to identify means of making breastfee- ding safer for HIV-infected women who have noin Geneva in October 2006. It was updated dur- choice other than to continue breastfeeding.ing 2007 to include relevant new information. In a study on mastitis in Zambia (abstractAs the Review was going to print at the begin- #650), breast milk samples were collected fromning of 2008, several trials were underway to 38 women who had clinical symptoms of masti-assess use of extended maternal or infant tis. The study found that during mastitis, eleva-antiretrovirals to reduce transmission among tions of breast milk viral load are restricted toHIV-exposed breastfed infants. Relevant find- the mastitic breast and eventually return to base-ings were presented at the 15th Conference on line levels, supporting current recommendationsRetroviruses and Opportunistic Infections for women with mastitis to breastfeed from the(CROI) held from 3 to 5 February 2008 and are unaffected breast.summarized here.1 Maternal outcomes and infant feedingPostnatal HIV transmission, infant practicesoutcomes and infant feeding practices In the Ditrame-Plus cohort study in AbidjanIn a pooled analysis of individual data from (abstract #73), the risk of pregnancy before 12a South African and a West African cohort months post-partum was comparable in replace-study (abstract #46), the overall risk of post- ment feeding and breastfeeding groups: 4%. Be-natal HIV infection was 3.9% among children tween 12 and 24 months post-partum, the riskbreastfed for <6 months and 8.7% among chil- of pregnancy was significantly lower among re-dren breastfed for >6 months (adjusted hazard placement feeders than breastfeeders. Replace-ratio: 1.8). Breastfeeding duration, as well as ment feeding was not responsible for a greatermaternal immune status, appear to be major incidence of pregnancies in this West Africandeterminants of HIV transmission. The risk did urban context, probably due to the systematicnot differ between exclusively and predominantly offer and the frequent use of contraceptive serv-breastfed children. Exposure to breastfeeding ices.mixed with solids during the first 2 months in-creased the postnatal risk of acquisition of HIV Antiretrovirals in breastfeeding women(adjusted hazard ratio: 2.9). The Kisumu Breastfeeding Study in Kenya (abstract #45LB) was an observational prospec-In the Vertical Transmission Study in South tive cohort of children of lactating women tak-Africa (abstract #636), 18-month HIV-free sur- ing antiretroviral treatment (ART) to preventvival of children of HIV-infected women shows mother-to-child transmission (MTCT). Overallthat breastfeeding of HIV-uninfected infants transmission rates were 3.9% at 6 weeks, 5% atbeyond 6 months of age increases the risk of HIV 6 months, 5.9% at 12 months and 6.7% at 181 CROI abstracts are available at http:/www.retroconference. org, accessed February 15, 2008. v
  • 7. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007months. There was no difference in HIV trans- well below levels required for treatment, suggest-mission by baseline maternal CD4 count. For ing minimal risk for drug toxicity. Lamivudinethose infants who became infected during the (3TC) and nelfinavir exposure in infants wouldfirst 6 weeks of life, resistance was initially not suggest minimal risk for resistance in HIV-in-detected (abstract #84LB), but emerged during fected children; however, low-level nevirapinethe breastfeeding period. (NVP) exposure via breast milk may predispose HIV-infected infants to resistance.In the MASHI trial in Botswana (abstract#637), the MTCT rate at one month was 1.2% Antiretrovirals in breastfed childrenamong breastfeeders and 1.1% among formula The PEPI-Malawi Study (abstract #42LB)feeders. The authors concluded that evaluated in a randomized controlled trial if 14breastfeeding was not a risk for MTCT within weeks of extended daily infant antiretroviralthe first month of life for children exposed to prophylaxis with NVP (group 2) or NVP+ZDVmaternal ART and receiving infant antiretroviral (group 3) with breastfeeding cessation from ageprophylaxis. 4-6 months would reduce postnatal transmission of HIV compared to controls receiving single doseThe preliminar y results of the non- (sd) NVP and one week ZDV (group 1). At agerandomized part of the Kesho-Bora study 9 months, the risk of HIV infection was 10.6%being conducted in five African sites (ab- in group 1, 5.2% in group 2 and 6.4% in groupstract #638) showed that the HIV transmis- 3. However, at 18 months, the HIV rate reachsion rate at 12 months was 7.6% in women with 13.9% in group 1, 10.1% in group 2 and 10.2%<200 CD4 with no significant difference accord- in group 3. Postnatal transmission occurred af-ing to infant feeding pattern; the rate was 5.8% ter NVP cessation among breastfed children.among women with >500 CD4 count, respec- Post-exposure prophylaxis in breastfed childrentively 7.5% and 0% in ever and never breastfed could reduce postnatal transmission but shouldinfants. be maintained over the entire breastfeeding du- ration.In the Dream cohort in Mozambique (ab-stract #369), 341 mother-infant pairs were fol- In the SWEN randomized controlled Triallowed from pregnancy until 12 months post conducted in Ethiopia, India and Ugandapartum; mothers breastfed while receiving ART (abstract #43), an extended infant post-expo-until 6 months post delivery. ART continued sure prophylaxis with daily NVP for 6 weeks inbeyond 6 months in women who initiated it for breastfed infants of HIV-infected mothers wastheir own health. The HIV MTCT rates were: assessed. The 6-week HIV transmission rate in1.2% (4) at birth, 1.9% (6) at 6 months, and the extended-NVP arm was 2.5% versus 5.3%2.8% (8) at 12 months. Four late post-natal HIV- in the sd NVP arm (p=0.009), but the 6-month1 infections (>1 month of age) were observed in HIV rate was 6.9% in the extended-NVP armthis cohort; 15% were lost to follow-up. versus 9.0% in the sd NVP arm (p=0.16). The extended-NVP arm was safe, but postnatal trans-The Breastfeeding, Antiretroviral and Nutri- mission occurred after stopping NVP in breastfedtion (BAN) Study in Malawi (abstract #648) children with a reduction of long term efficacy.reports on antiretroviral concentrations. Infants Occurrence of resistance to NVP in infected chil-plasma concentrations for all antiretrovirals were dren was very high (11/12). vi
  • 8. AcknowledgementsT his review was updated by Valériane Leroy (INSERM U593, Institut de SantéPublique, Epidémiologie et Développement, useful information on synthesis of the technical consultation. We would like to especially thank Rajiv Bahl, Renaud Becquet, André Briend,Université Victor Segalen, Bordeaux, France). It Anirban Chatterjee, Anna Coutsoudis, Françoisis based on an original review on HIV transmis- Dabis, Mary Glenn Fowler, Peggy Henderson,sion through breastfeeding prepared by Marie- Lida Lhotska, Jose Martines, Ellen Piwoz, Felic-Louise Newell (Institute of Child Health, ity Savage, Constanza Vallenas and Isabelle deLondon) for WHO in 2003. The 2003 review Vincenzi for reviewing the report and giving help-was updated in 2005 by the WHO Department ful comments. Finally, we would like to acknowl-of Nutrition for Health and Development as a edge the contributions of Coralie Thore,background paper for a consultation on Nutri- Christian Weller and Evelyne Mouillet from thetion and HIV. ISPED library in Bordeaux for their help in re- We are very grateful to Marie-Louise Newell searching papers.for helping in structuring the early draft of this Kai Lashley performed the final copy-edit ofreview and to Lynne Mofenson for providing the text. vii
  • 9. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007 Acronyms3TC lamivudineAIDS acquired immunodeficiency syndromeANRS Agence Nationale de Recherches sur le SIDA (France)ARV antiretroviralART antiretroviral therapyAZT azidothymidineBF breastfeedingCI confidence intervalD4T stavudineddI didanosineDNA deoxyribonucleic acidEBF exclusive breastfeedingFF formula feedingHIVIGLOB HIV hyperimmune globulinHIV human immunodeficiency virusHR hazard ratioMF mixed feedingMTCT mother-to-child transmission of HIVNVP nevirapineOR odds ratioPCR polymerase chain reactionPMTCT prevention of mother-to-child transmission of HIVRF replacement feedingRNA ribonucleic acidSLPI secretory leukocyte protease inhibitorSDS sodium dodecyl sulfateUN United NationsUNAIDS Joint United Nations Programme on HIV/AIDSUNGASS/AIDS United Nations General Assembly Special Session on HIV/AIDSUNICEF United Nations Children’s FundWHO World Health OrganizationZDV zidovudine viii
  • 10. GlossaryART, an abbreviation for antiretroviral therapy, Complementary food means any food, wheth- is a combination of three or more different er manufactured or locally prepared, used as a antiretroviral drugs used in the treatment of complement to breast milk or to a breast-milk those infected with HIV to reduce viral load. substitute, when either becomes insufficient to satisfy the nutritional requirements of theBreast-milk substitute refers to any food be- infant. ing marketed or otherwise represented as a partial or total replacement for breast milk, DNA, an abbreviation for deoxyribonucleic acid, whether or not suitable for that purpose. is the carrier of genetic information found in cell nuclei.CD4 cells (also known as T4 or helper T cells) are lymphocytes (a type of white blood cell), Exclusive breastfeeding means an infant re- which are key in both humoral and cell-medi- ceives no other food or drink, not even water, ated immune responses. These are the main other than breast milk (which can include ex- target cells for HIV. Their numbers decrease pressed breast milk), with the exception of during HIV infection, and their level is used drops or syrups consisting of vitamins, miner- as a marker of progression of the infection. al supplements or medicines. CD8 cells are a subtype of T lymphocytes, Formula feeding involves the use of commer- which also play an important role in fighting cial infant formula that is formulated indus- infections. Their numbers may be increased trially in accordance with applicable Codex during HIV infection. Alimentarius standards to satisfy the nutri-Cell-associated virus refers to HIV which lives tional requirements of infants during the first inside the cell, measured as HIV-DNA. months of life up to the introduction of com- plementary foods.Cell-free virus refers to parts of the virus (viri- ons) not associated with a cell, measured as Human immunodeficiency virus (HIV) refers HIV-RNA. to HIV-1 in this review. Cases of mother-to- child transmission of HIV-2 are rare.Cessation of breastfeeding means completely stopping breastfeeding, which includes no Immunoglobulins are any of the five distinct more suckling at the breast. antibodies present in the serum and external secretions of the body (IgA, IgD, IgE, IgG andColostrum is the thick yellow milk secreted by IgM). the breasts during the first few days after de- livery, which gradually evolves into mature Incidence density means the incidence rate of milk at 3–14 days postpartum. It contains an event, i.e. HIV infection or death per per- more antibodies and white blood cells than son-time (months or years). mature breast milk. Infant refers to a child from birth to 12 monthsCommercial infant formula means a breast- of age. milk substitute formulated industrially in ac- Intrapartum means the period during labour cordance with applicable Codex Alimentarius and delivery. standards to satisfy the nutritional require- ments of infants during the first months of life. ix
  • 11. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007Lamivudine, or 3TC, is an antiretroviral drug Peripartum transmission is mother-to-child often used in combination with zidovudine, transmission of HIV occurring around the time ZDV also known as azidothymidine, AZT. , of delivery (i.e. late in pregnancy, during or immediately after delivery).Late postnatal HIV transmission means trans- mission that takes place after about six weeks Postnatal transmission is mother-to-child of life, the earliest time at which it is possible transmission of HIV after delivery, during the to determine that transmission did not take breastfeeding period. place during delivery. Predominant breastfeeding means breastfeed-Lipid means any one of a widely varying group ing is the main source of nourishment, but an of fats and fat-like organic substances. infant is also given small amounts of non-nu- tritious drinks, such as tea, water and water-Macrophage is a large ‘wandering’ phagocytic based drinks. white blood cell that ingests foreign matter, and plays an important role in resisting infec- Replacement feeding means the process of feed- tion. ing a child who is not receiving any breast milk with a diet that provides all the nutrients theMature breast milk is milk produced from about child needs until the child is fully fed on fam- 14 days postpartum until the cessation of ily foods. breastfeeding. RNA, an abbreviation for ribonucleic acid, is aMixed feeding refers to breastfeeding with the substance found in the nucleus of all living addition of fluids, solid foods and/or non-hu- cells and in many viruses. An intermediate of man milks such as formula. DNA, it is the medium by which genetic in-Mother-to-child transmission (MTCT) indi- structions from the nucleus are transmitted cates instances of transmission of HIV to a to the rest of the cell. RNA viral load, ex- child from an HIV-infected woman during pressed as copies of RNA per ml of plasma or pregnancy, delivery or breastfeeding. The term other body fluid, reflects the amount of ac- is used in this document because the immedi- tively replicating virus in the body. High viral ate source of the child’s HIV infection is the RNA levels occur (temporarily) immediately mother. Use of the term mother-to-child trans- after acquisition of infection and later with mission implies no blame, whether or not a progression of disease, and are associated with woman is aware of her own infection status. higher rates of transmission.Neonatal describes the period immediately fol- Virion refers to those parts of the virus that are lowing birth through the first 28 days of life. able to replicate HIV.Nevirapine, or NVP, is an antiretroviral drug Wet-nurse refers to the breastfeeding of an infant commonly used as a treatment regimen, ei- by someone other than the infant’s mother. ther alone or in combination with other drugs, Zidovudine, or ZDV is an antiretroviral drug , to prevent MTCT. which inhibits HIV replication. It was the firstPartial breastfeeding means giving a baby some drug licensed to treat HIV infection. Today it breastfeeds and some artificial feeds, either is frequently used in combination with other milk or cereal, or other food. antiretroviral drugs and, alone or in combina-PCR means polymerase chain reaction, a labo- tion, it is used in the prevention of mother- ratory method in which the genetic material to-child transmission of HIV (It is also known . (DNA or RNA) of the virus is detected and as retrovir or azidothymidine, AZT.) amplified. It can be both qualitative and quan- titative. x
  • 12. Executive summaryB reastfeeding is best for infants, and is an effective method of reducing the riskof common childhood morbidity, particularly their infants during pregnancy or delivery in about 15-25% of cases; and an additional 5-20% of infants may become infected postnatally dur-gastrointestinal and respiratory infections, and ing breastfeeding, for an overall risk of 30-45%.of promoting child survival and maternal health Breastfeeding may thus be responsible for onethrough child spacing. In 2001, the World Health third to one half of HIV infections in infantsAssembly endorsed the recommendation that when interventions are not available.infants should be exclusively breastfed for the HIV has been detected in breast milk in cell-first six months of life to achieve optimal growth, free and cell-associated compartments and theredevelopment and health. Thereafter, infants is now evidence that both compartments are in-should receive nutritionally adequate and safe volved in transmission of HIV through breastcomplementary foods while breastfeeding con- milk. Following ingestion of HIV infected breasttinues to 24 months or beyond. milk, infant gut mucosal surfaces are the most While breastfeeding carries significant health likely site at which transmission occurs.benefits to infants and young children, HIV can The rate of late postnatal transmission (thatbe transmitted during breastfeeding from an is, after six weeks of age) can be better quanti-HIV-infected mother to her infant. Reducing this fied in 2007 than previously. Data from a meta-transmission while ensuring improved HIV-free analysis show that the cumulative probability ofsurvival1 is one of the most pressing public health late postnatal transmission at 18 months is 9.3%dilemmas confronting researchers, health-care (95% confidence interval, CI, 3.8-14.8%). Lateprofessionals, health policy-makers and HIV-in- postnatal transmission, therefore, could contrib-fected women in many areas of the world, espe- ute as much as 42% to the overall rate of MTCT.cially in developing countries. Analysis indicates that late postnatal transmis- In 2007, 2.5 million children aged less than sion risk is around 1% per month of breastfeeding15 years worldwide were living with HIV and an and is constant over time from between four andestimated 420 000 children aged less than 15 six weeks to 18 months. Transmission can takeyears were newly infected with HIV in 2007 place at any point during breastfeeding, and thealone, nearly always through mother-to-child longer the duration of breastfeeding, the greatertransmission (MTCT). HIV/AIDS is an increas- the cumulative risk.ingly important cause of mortality in those aged The risk of postnatal transmission throughless than five years in Africa. Before the breastfeeding is associated with clinical, immu-antiretroviral therapy (ART) era, child mortal- nological and virological maternal factors andity due to HIV was estimated to be 35.2% by infant feeding patterns. Maternal seroconversionage one year and 52.5% by two years of age. during breastfeeding, low maternal CD4 cell Mother-to-child transmission of HIV can oc- count, increased maternal RNA viral load incur during pregnancy, labour or delivery, or plasma and breast milk and a lack of persistencethrough breastfeeding. Without specific interven- of HIV-specific IgM in breast-milk at 18 monthstions, HIV-infected women will pass the virus to are strongly associated with increased risk of1 HIV-free survival refers to young children who are both alive and HIV-uninfected at a given point in time, usually 18 months. 1
  • 13. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007transmission through breastfeeding. Breast low-up with repeated growth measurements ispathologies such as clinical and subclinical mas- also crucial to this support, as is nutritional coun-titis, nipple bleeding, and abscesses, fissures or selling, particularly around the period oflesions are also associated with a higher risk of breastfeeding cessation.transmission through breastfeeding. Exclusive Early cessation of breastfeeding could alsobreastfeeding for up to six months, however, is prevent a sizable proportion of postnatal HIVassociated with a three to fourfold decreased risk infections but several studies in Africa have re-of transmission of HIV compared to non-exclu- ported that it was associated with an increasedsive breastfeeding; mixed feeding, therefore, ap- risk of infant morbidity (especially diarrhoea)pears to be a clear risk factor for postnatal and mortality in HIV-exposed children. Recenttransmission. One study found that about 4% data from Zambia and Botswana show that pro-of exclusively breastfed infants became infected longed breastfeeding of children already infectedthrough exclusive breastfeeding from six weeks with HIV is associated with improved survivalto six months. compared to early cessation of breastfeeding. The incidence of HIV infection among women It is also important to identify approaches toduring the postpartum period is high in Africa. treating expressed breast milk to eliminate theThe overall risk of MTCT is increased in recently- risk of transmission while preserving the milksinfected lactating women and estimated to be nutritional content and protective qualities. With29% (95% Cl, 16–42%), illustrating the impor- this aim, expressed heat-treated breast milk andtance of prevention of primary infection through- microbicides to treat HIV-infected breast milkout the breastfeeding period. may have a role to play in shortening the dura- The most appropriate infant feeding option tion of breastfeeding and allowing for a safe tran-for an HIV-infected mother depends on her in- sition period to other types of foods.dividual circumstances, including her health sta- More research is required to provide practicaltus and the local situation. The health services tools that can be used routinely – especiallyavailable and the counselling and support she is around the time of early breastfeeding cessationlikely to receive should be considered. The World – to contribute to the assessment of the nutri-Health Organization (WHO) recommends HIV- tional adequacy of complementary feeding andinfected women breastfeed their infants exclu- guide efficiently the nutritional counselling ofsively for the first six months of life, unless children exposed to HIV.replacement feeding is acceptable, feasible, af- Other possibilities for preventing HIV fromfordable, sustainable and safe for them and their being transmitted through breast milk are emerg-infants before that time. When those conditions ing. These include giving ART to women duringare met, WHO recommends avoidance of all breastfeeding (whether or not necessary for thebreastfeeding by HIV-infected women. mothers health) and post-exposure prophylaxis To help HIV-positive mothers make the best to the infant. Recent studies have sought to de-choice, they should receive appropriate counsel- termine the effects of the former, and severalling that includes information about the risks studies on the latter are ongoing; both are dis-and benefits of various infant feeding options cussed in this review. Finally, passive and activebased on local assessments, and guidance in se- immunization strategies of breastfed newbornslecting the most suitable option for their own are increasingly being studied. Further researchsituation. Counselling, information provision and on their potential role in reducing MTCT of HIVsupport during the antenatal period is key for is needed and ongoing.women to make informed choices. Postnatal fol- 2
  • 14. IntroductionD espite substantial progress in reducing child morbidity and mortality and promotingfamily health in recent decades, there are still timated 420 000 children aged less than 15 years were newly infected in 2007 (UNAIDS 2006). There were also an estimated 380 000 deathsunacceptable disparities in maternal and child due to AIDS among children. Africa has the high-health worldwide (Black et al. 2003; WHO est prevalence: 90% of both new infections and2005). While child mortality has declined in the AIDS-related deaths among children occur there,past decades in many regions, progress on key particularly in southern Africa (UNAIDS 2007).indicators has begun to slow down. In parts of MTCT is the most significant source of HIVsub-Saharan Africa, child mortality is on the rise infection in young children. The virus may be trans-(Black et al. 2003). About 9.7 million children mitted during pregnancy, labour or delivery, orunder five die each year (WHO mortality data through breastfeeding (De Cock et al. 2000). With-bank, access on request), mainly from prevent- out specific interventions, HIV-infected women willable causes and almost all in poor countries. In pass the virus to their infants during pregnancy orthe period between 2000 and 2003, four causes delivery in about 15–25% of cases; and an addi-accounted for over 80% of the then estimated tional 5–20% of infants may become infected post-10.6 million yearly deaths in children aged less natally during breastfeeding (De Cock et al. 2000;than five years: pneumonia (19%), diarrhoea Nduati et al. 2000). About two thirds of infants(17%), malaria (8%), and neonatal conditions born to HIV-infected mothers will not be infected.(37%). Among neonatal deaths, 36% were due Breastfeeding may thus be responsible for one thirdto infections including sepsis, pneumonia, teta- to one half of HIV infections in infants and youngnus and diarrhoea, 28% were due to being pre- children in African settings (De Cock et al. 2000).term and 23% were due to asphyxia (Bryce et HIV/AIDS is an increasingly important cause ofal. 2005). Undernutrition is an underlying cause mortality in children aged less than five years inof more than half of all deaths in children aged Africa (Dabis & Ekpini 2002; Walker et al. 2002).less than five years, and is associated with infec- Before the antiretroviral therapy (ART) era, childtious diseases (Bryce et al. 2005). It is also the mortality due to HIV was estimated to be 35.2%leading underlying cause of disability and illness by age one year and 52.5% by two years of ageworldwide, particularly so in countries with high among HIV-infected children in a meta-analysis,infant mortality, where suboptimal feeding prac- which pooled information from the African clini-tices are a major cause of underweight (Bryce et cal trials that aimed to assess the efficacy of inter-al. 2005). Promotion of breastfeeding has played ventions to reduce MTCT. Mortality varied byan important role in protecting infants and young geographical region, and was associated with ma-children, since breastfeeding provides optimal nu- ternal death, maternal CD4 cell counts <200μl,trition, protects against common childhood in- and infant HIV infection and its timing. In HIV-fections, reduces mortality significantly, and has infected children, mortality was significantly lowerchild-spacing effects (Nicoll et al. 2000a; WHO for those with late infection than those with earlyCollaborative Study Team 2000). Exclusive infection (Newell et al. 2004). These findings high-breastfeeding is therefore recommended until six light the need for effective prevention of MTCT,months of age (WHO 2001). early paediatric HIV diagnosis and antiretroviral In 2007, 2.5 million children aged less than care and support for HIV-infected children and all15 years worldwide were living with HIV. An es- members of affected families. 3
  • 15. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007 Prevention of MTCT of HIV using available priate care and highlights missed sexual and re-antiretroviral interventions can be achieved, even productive health opportunities (UNAIDSin breastfeeding populations. Considerable effort 2006). To meet international goals for reductionsis ongoing to scale-up these interventions to in child mortality, efforts must continue to focusreach a wider population (WHO 2006). How- on preventing MTCT, but must also prevent un-ever, in settings where breastfeeding beyond one dernutrition and strengthen health systems andyear is the norm, postnatal transmission through programmes that can deliver available interven-breastfeeding reduces the impact of perinatal tions for the other major diseases killing chil-antiretroviral interventions (Leroy et al. 2002). dren in the developing world (Bryce et al. 2006a).While breastfeeding carries the risk of HIV trans- The fourth Millennium Development Goalmission, not breastfeeding carries other signifi- (MDG) calls for a two thirds reduction betweencant health risks to infants and young children, 1990 and 2015 in deaths of children aged lesssuch as an increased risk of diarrhoea and pneu- than five years (http://www.un.org/millenniumgoals).monia morbidity and mortality (Nicoll et al. Achieving this goal will require widespread use2000a; WHO Collaborative Study Team 2000; of effective interventions for preventing deaths,Thior et al. 2006). and is also linked to MDG5 on maternal mor- The prevention of HIV transmission should tality, as infant health and survival is closelybe balanced against the risk of other morbidity linked to maternal health (Bryce & Victoraand mortality risks, including malnutrition. The 2005; Costello & Osrin 2005; Mason 2005;reduction of HIV transmission through the Bryce et al. 2006b).breastfeeding period is one of the most pressing This report is an update of the review of currentpublic health dilemmas confronting researchers, knowledge on HIV transmission throughhealth-care professionals, health policy-makers breastfeeding (WHO/UNICEF/UNFPA/UNAIDSand HIV-infected women in many areas of the 2004) with a focus on information made availableworld, especially in developing countries. Preven- between 2001 and 2007. It reviews recent scien-tion of HIV transmission during breastfeeding tific evidence on the risk of HIV transmissionshould be considered in a broad context that through breastfeeding, the impact of different feed-takes into account the need to promote ing options on child health outcomes, and con-breastfeeding of infants and young children ceivable strategies to reduce HIV transmissionwithin the general population. Countries need through breastfeeding with a specific emphasis onto develop (or revise) comprehensive national the developing world. This review further informsfeeding policies of infants and young children to guidance on HIV prevention and infant feedingconsider the risks of HIV transmission during strategies (WHO 2006).infant feeding, while continuing to protect, pro- To update this review, published and unpub-mote and support breastfeeding for infants of lished literature contributing to recent evidenceHIV-negative women and women whose HIV about children affected and infected by HIV/infection status is unknown. AIDS and infant feeding patterns since 2001 was The Declaration of Commitment endorsed at consulted. Medline, one of the main biblio-the United Nations General Assembly Special graphic scientific databases, was used, facilitat-Session on HIV (UNGASS) in 2001 set the goal ing a wide variety of studies to be selected,of reducing the proportion of infants infected ranging from randomized clinical trials to epide-with HIV by 20% by 2005 and 50% by 2010 miological cohort studies (investigating HIV/(Harwood & Planetwire.org 2001; UN 2001). AIDS-related morbidity and mortality amongA further goal was ensuring that 80% of preg- children, MTCT and infant feeding patterns),nant women who receive antenatal care have to demographic and national surveillance surveysaccess to HIV prevention services. However, the (infant feeding indicators). The most relevantJoint United Nations Programme on HIV/AIDS references have been included in this review, in-(UNAIDS) reports that less than 10% of HIV- cluding other systematic reviews.infected pregnant women have access to appro- 4
  • 16. Mother-to-child transmission of HIVHIV infection in women Rates of, and risk factors for overallS exual contact continues to be the major mode of HIV transmission, leading to high preva-lence of HIV infection in women making access mother-to-child transmission of HIV In HIV-infected pregnant women, MTCT can occur before, during or after delivery, but trans-to sexual and reproductive health services essen- mission in early pregnancy is rare (Rouzioux ettial (Schmid et al. 2004). al. 1993). Without specific interventions aimed The prevalence of HIV infection varies con- at reducing the risk of transmission, estimatedsiderably from region to region. Children in sub- rates of MTCT range from 15% to 25% in Eu-Saharan Africa are disproportionately affected, rope and the United States of America and fromwith nearly nine in every 10 newly-infected chil- 25% to 45% in developing countries (The Work-dren worldwide living in this region (UNAIDS ing Group on Mother-to-Child Transmission of2007). In West and Central Africa, HIV preva- HIV 1995). The additional risk posed bylence in pregnant women currently reaches up breastfeeding as commonly practised in devel-to about 7% in some urban areas, with generally oping countries ranges from 5% to 20%, withlower rates in rural areas. Prevalence in East Af- an attributable risk of 40% (Table 1) (De Cockrica is up to about 9% in urban areas, while in et al. 2000). These breastfeeding practices ac-Southern Africa antenatal seroprevalences of count for a large part of the estimated differencesabout 16-39% have been reported. In the Carib- in the risks of MTCT between developing andbean, Central America and South America, rates developed countries (where breastfeeding is lessamong pregnant women are generally below 1%. common). The overall risk of MTCT is increasedIn Asia, seroprevalence rates in some cities or immediately after HIV is acquired, due to theprovinces of Cambodia, India, Indonesia and initially high levels of maternal viral load. There-Thailand range from less than 1% up to about fore, when a woman contracts HIV during preg-5%. In Eastern Europe, where there has been an nancy or the breastfeeding period, the risk ofexceptionally rapid increase in the number of virus transmission is increased. There is someHIV-infections, the estimated antenatal preva- evidence of an increased risk of acquisition oflence is still less than 1% (UNAIDS 2007). HIV during pregnancy (Gray et al. 2005). The incidence of HIV among women during The overall risk of MTCT is associated withthe postpartum period is also high in Africa. The factors related to the virus, the mother and theHIV incidence rate was 3.5/100 women-years infant (Newell 2001). Maternal RNA viral load(95% confidence interval, CI, 1.9–5.0) in early in plasma has been strongly associated with the1990 in Rwanda (Leroy et al. 1994). In Zimba- risk of MTCT (European Collaborative Studybwe in late 1990, among the 9562 women who 1996; European Collaborative Study 1997;were HIV-negative at the time of giving birth, Mayaux et al. 1997; Simonds et al. 1998; Shaffer3.4% (95% CI 3.0–3.8) and 6.5% (95% CI 5.7– et al. 1999b; Leroy et al. 2001). However, al-7.4) acquired HIV infection over 12 and 24 though the risk of transmission increases sub-months postpartum, respectively (Humphrey et stantially with increasing viral load, transmissional. 2006). As 85% of women still breastfeed at of the virus to the fetus or infant can occur, al-15 months and 30% at 21 months in this popu- beit rarely, even with very low, or undetectable,lation, new postpartum infections subsequently viral load levels. Similarly, at very high levels ofincrease the number of children exposed to HIV. HIV RNA, transmission does not always occur. 5
  • 17. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007TABLE 1. Estimated absolute rates of MTCT of HIV by timing of transmission, without interventions HIV transmission rate (%)Timing of HIV transmission No breastfeeding Breastfeeding through Breastfeeding through 18 six months to 24 monthsDuring pregnancy 5 to 10 5 to 10 5 to 10During labour 10 to 15 10 to 15 10 to 15During breastfeeding 0 5 to 10 15 to 20Overall 15 to 25 20 to 35 30 to 45Nevertheless, women with a low CD4 cell count gest that a highly-active combinationnear the time of delivery (below 200 cells per antiretroviral treatment regimen, given duringmm3) and those who have been diagnosed with and after pregnancy, is able to significantly re-severe clinical disease are more likely to trans- duce HIV RNA viral load in both plasma andmit the virus than those who are less severely breast milk. This suggests there may be a roleaffected by HIV infection (European Collabora- for ART prophylaxis in mothers as a means totive Study 2001; Leroy et al. 2002). HIV has reduce breastfeeding-associated transmissionbeen recovered from vaginal and cervical secre- (Giuliano et al. 2007).tions of pregnant women (Nielsen et al. 1996;John et al. 1997; Kovacs et al. 2001) and from Prevention of mother-to-childgastric secretions of infants born to HIV-serop- transmission of HIVositive women (Mandelbrot et al. 1999), consti- The United Nations strategy to prevent thetuting independent risk factors for MTCT. There transmission of HIV to infants and young chil-is also evidence that malaria could increase the dren involves: 1) prevention of HIV infection inrisk of MTCT (Ayouba et al. 2003; Mwapasa et general, especially in women and young people;al. 2004), although the interaction between pla- 2) prevention of unwanted pregnancies amongcental malaria and MTCT appears to be vari- HIV-infected women; 3) prevention of HIVable and complex (Ayisi et al. 2004). Delivery transmission from HIV-infected women to theirfactors such as vaginal delivery and duration of infants; and 4) provision of care, treatment anddelivery, which increase contact between the in- support to HIV-infected women, their infantsfant and HIV-infected maternal body fluids and family. Guidance for implementing pro-(cervico-vaginal secretions and blood) have been grammes at national scale is available (WHO/linked with increased risk of MTCT (European UNICEF, 2007).Collaborative Study 1996; European Collabora- In developed countries, the rate of MTCT hastive Study 1997). declined substantially in the past ten years. With The increasing use of ART in pregnancy in the use of antiretroviral combinations, electivedeveloped countries has resulted in a growing caesarean section delivery and avoidance ofproportion of women achieving undetectable lev- breastfeeding, rates below 2% have been reportedels of the virus by the time of delivery, which in American and European populations (Euro-has had a substantial impact on vertical trans- pean Collaborative Study 2001; Dorenbaum etmission. Several studies are currently under way al. 2002; Newell 2006). In developing countries,in breastfeeding populations in resource-poor shorter, simpler peripartum antiretroviralsettings to evaluate the use of ART for mothers prophylaxis interventions have been shown toduring pregnancy and postnatally, and for be effective in reducing transmission risk, butuninfected infants during the breastfeeding pe- their application in populations whereriod. (Thorne & Newell 2007). Results from the breastfeeding is commonly practised poses con-DREAM study carried out in Mozambique sug- siderable challenges (Dabis et al. 2000). 6
  • 18. MOTHER-TO-CHILD TRANSMISSION OF HIV Early randomized clinical trials from 1998 in six to eight weeks, in comparison with NVP, onlyAfrica and Thailand demonstrated the short- the longest combination of ZDV and 3TC is sig-term efficacy of several antiretroviral regimens nificantly more effective, leading to a 61% ad-administered around the time of deliver y justed reduction (p=<0.0005). These results(peripartum) to prevent transmission (Dabis et suggest that there exists an equivalence of choiceal. 1999; Guay et al. 1999; Saba 1999; Shaffer between single-dose NVP and short-course ZDV .et al. 1999a; Wiktor 1999). This short-term ef- They confirm that a combination of ZDV andficacy was measured by comparing infant HIV 3TC from 36 weeks of gestation has a greaterinfection status at six and eight weeks of age efficacy in reducing early transmission than thebetween groups receiving different antiretroviral same combination starting during labour andinterventions or a placebo. These regimens in- delivery or than any single antiretroviral prophy-volved three different ARV drugs, used alone or laxis (short-course ZDV or single-dose NVP).in combination: zidovudine (ZDV), lamivudine There is no doubt that even lower peripartum(3TC) and nevirapine (NVP). transmission rates, comparable to those obtained The NVP prophylactic regimen is particularly in developed countries, could be achievedeasy to use with one single dose given to the through enhanced short-course antiretroviralwoman at the onset of labour, and one dose of regimens. In the ANRS 1201/1202 Ditrame Plussyrup administered to the baby within 72 hours cohort in Abidjan, Côte d’Ivoire, transmissionof delivery, reducing transmission by around rates at six to eight weeks postpartum were 6.5%40%, from a rate of 20% to 12% at six to eight (95% CI 3.9–9.1%) with ZDV plus single-doseweeks postpartum (Guay et al. 1999). Transmis- NVP, a relative 72% reduction compared withsion rates at six to eight weeks of 15% have been ZDV alone (95% CI 52–88%, p=0.0002 ad-reported when ZDV is given to the mother from justed on maternal CD4 cell count, clinical stageweek 36 of gestation (Dabis et al. 1999; Wiktor of infection and breastfeeding status) (Dabis et1999). Peripartum ZDV efficacy has been re- al. 2005). The overall rate was 4.7% (95% CIported as greater in women with higher CD4 cell 2.4–7.0%) when mothers were given both ZDVcounts, even at six weeks postpartum (Leroy et and 3TC from week 32 of gestation, continuedal. 2002). In another regimen, ZDV given in for one week postpartum (for both mother andcombination with 3TC to the mother from weeks child), in addition to single-dose NVP to mother28–36 of gestation until one week postpartum, and infant. Despite these considerable advances,while the newborn receives ZDV prophylaxis several problems remain to be addressed, whichduring one week, reduced transmission to be- are detailed elsewhere (WHO 2006).tween 6% and 9% (Saba et al. 2002). Single-dose NVP given to women and infants The respective efficacy of these different reduces mother-to-child HIV transmission andantiretroviral regimens was compared in a recent is easy to use, but NVP resistance develops in apooled analysis using a standardized definition large percentage of women, raising concerns forof peripartum HIV infection (Leroy et al. 2005). future maternal treatment (Eshleman et al.This study included 4125 singleton live births 2004a; Eshleman et al. 2004b; Jourdain et al.from six African trials, which adjusted MTCT 2004; Eshleman et al. 2005). Alternatives torates at six to eight weeks for other maternal NVP are being considered, but this problem canand child determinants. In comparison with pla- be avoided to a considerable extent by a post-cebo, the adjusted relative reduction in MTCT partum three-day to one week regimen of AZTreached 77% for the combination of ZDV and and 3TC.3TC administered antepartum, intrapartum and Residual MTCT rates remain high in mothersseven days postpartum; 51% for the combina- who have advanced HIV disease (Leroy et al.tion of ZDV and 3TC during the intrapartum 2002). Antiretroviral therapy is now recom-and postpartum periods only; 45% for ZDV only, mended for these women (WHO 2006). Moreadministered antepartum, intrapartum and post- recent cohort studies in Côte d’Ivoire and Mo-partum; and 40% for single-dose NVP. Thus, at zambique indicate that when three-drug combi- 7
  • 19. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007nation antiretroviral therapy (i.e. ART) is given where prolonged breastfeeding is the norm (Leroyto HIV-infected pregnant women either univer- et al. 2003). In the West African trials, the 24-sally – irrespective of CD4 cell count (Giuliano month efficacy of short-course ZDV to motherset al. 2007) – or only to those who require it for was still significant, giving a 26% reduction, withtheir own health (Tonwe-Gold 2007), MTCT a residual MTCT rate of 22.5% in the ZDV armrates below 5% can be achieved at four weeks compared to 30.2% in the placebo arm (Leroypostpartum. et al. 2002). In the NVP trial, the 18-month Women presenting late for delivery without efficacy was sustained with a residual MTCT rateknowing their HIV status, which frequently hap- of 15.7% in the NVP arm, a 41% significant re-pens in resource-constrained settings, do not re- duction (Jackson et al. 2003). In the PETRA trial,ceive the ante and intrapartum components of although the six-week efficacy of the combinedthese regimens. In this context, the efficacy of a ZDV+3TC long-course (ante, intra and postpar-simple neonatal-only antiretroviral post-exposure tum/postnatal) regimen and the ZDV+3TCprophylactic regimen has been demonstrated in medium-course (intra- and postpartum/postna-Malawi. The overall MTCT rate at six to eight tal) regimen was significantly effective, the 18-weeks was 15.3% in 484 babies who received month long-term efficacy was lost mainlyNVP and ZDV and 20.9% in 468 babies who because of postnatal transmission (Saba et al.received NVP only in the NVAZ trial conducted 2002). However, this trial lacked statistical powerin Malawi (p=0.03) (Taha et al. 2003). In South to address differences at 18 months.Africa, single-dose NVP given to newborns ex- Given the considerable advances that haveposed to HIV tended to reduce MTCT. The rate been made in the past ten years, peripartum HIVat 12 weeks was 14.3% in 518 babies who re- transmission rates below 5% can be achieved,ceived NVP, and 18.1% in 533 babies who re- even in African breastfeeding populations, withceived ZDV during six weeks postnatally relatively inexpensive, easy-to-use and feasible(p=0.4). Among newborns who were not in- short-term antiretroviral combinations (WHOfected at birth, the 12-week MTCT rate was 2006). The introduction of short-course7.9% in the NVP arm and 13.1% in the ZDV antiretroviral regimens to prevent MTCT in less-arm (p=0.06) (Gray et al. 2005). developed countries should be accompanied by All these short-course peripartum antiretro- interventions to minimize the risk of subsequentviral regimens have lower field efficacy when tak- transmission through breastfeeding (Leroy et al.ing into account the subsequent risk of postnatal 2003). Postnatal transmission will be detailedtransmission of HIV in African populations in the next section. 8
  • 20. HIV transmission through breastfeedingT ransmission of HIV through breastfeeding has been well documented since 1985. Thefirst reports indicating the possibility of HIV not be predicted from the analysis of circulating viral populations (Becquart et al. 2002). The origin of HIV in breast milk is still nottransmission through breast milk were in well understood. There is now evidence that bothbreastfed infants of women who had acquired cell-free and cell-associated HIV in breast milkinfection postnatally through blood transfusions are responsible for breast-milk transmissionor through heterosexual exposure (Ziegler et al. (Koulinska et al. 2006). Studies have demon-1985; Hira et al. 1990; Van de Perre et al. 1991; strated the presence of cell-free virus and latentPalasanthiran et al. 1993). There were also re- (non-productive) infected cells, but not produc-ports of infants – with no other known exposure tive HIV infective cells. Cells, includingto HIV – who were infected through being wet- macrophages and lymphocytes, and cell-free vi-nursed and through pooled breast milk (Nduati rus may migrate from the systemic compartmentet al. 1994). There is a theoretical risk of oral to breast milk. Recently, it has been reported thattransmission from infant to wet-nurse, with cases infected CD4 cells demonstrate a greater capac-having been reported (Visco-Comandini et al. ity to enter into a viral replication cycle in the2005). breast-milk compartment compared with blood (Petitjean et al. 2006).Pathogenesis and mechanisms of Following ingestion of HIV infected breastbreastfeeding transmission milk, infant gut mucosal surfaces are the most likely site at which transmission occurs. Cell-freeHIV has been detected in breast milk in cell-free or cellular HIV may penetrate to the submucosaand cell-associated compartments. To date most through mucosal breaches or lesions, viastudies have used DNA or RNA polymerase transcytosis through M cells or enterocytes ex-chain reaction assays to evaluate breast milk for pressing galactosyl ceramide (Gal Cer) or FcHIV. In an early study from Kenya, breast milk receptors. In vitro models suggest that secretoryHIV RNA was detected in 39% of 75 specimens IgA or IgM may inhibit transcytosis of HIV(Lewis et al. 1998). In this study viral levels in across enterocytes (Bomsel 1997; Bomsel et al.breast milk were about one log lower than in 1998). Breast-milk HIV immunoglobins mayplasma. However, there were some cases that play a role in protection from transmission bysuggested compartmentalization of virus to coating infant mucosal surfaces: in a cohort ofbreast milk with higher levels in breast milk than lactating women infected with HIV in Rwanda,plasma. Viral variants in blood and breast milk anti-HIV antibodies of the IgG isotype were morewere found to be distinct, with some major vari- frequently detected in breast milk followed byants in breast milk not detected in blood. This secretory IgM (Van de Perre et al. 1993). Tonsilsfinding would suggest that some virus in breast may also be a portal of entry for HIV in breast-milk replicates independently, in the mammary milk transmission. Tonsils include M cells in closecompartment. The observation of a compart- proximity to lymphocytes and dendritic cells, andmentalization of HIV between peripheral blood tonsillar M cells are capable of HIV replicationand breast milk highlights that postnatal trans- (Frankel et al. 1997).mission of HIV can occur with variants that may 9
  • 21. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007Risk of postnatal transmission through sion beyond four to six weeks ranging from 4%breastfeeding to 12% was reported from these trials (Ekpini et al. 1997; Saba et al. 2002; Jackson et al. 2003;The risk attributable to transmission of HIV Leroy et al. 2003). Differences need to be inter-through breastfeeding has been difficult to meas- preted according to the risk factors for postnatalure because of the difficulty in distinguishing transmission. However, there is strong evidenceintrapartum transmission from early transmis- of a continued increase in cumulative transmis-sion through breastfeeding. sion risk as long as the child is breastfed (Leroy Based on an assessment of the limited data et al. 1998; Miotti et al. 1999; Leroy et al. 2003;available in the early 1990s, the additional risk The Breastfeeding and HIV International Trans-of transmission from breast milk – above that mission Study Group (BHITS) 2004; Iliff et al.occurring during pregnancy and delivery – among 2005).women with established HIV infection was esti-mated to be approximately 15% whenbreastfeeding continued for two years or more. Timing of postnatal transmissionWhen the mother acquires HIV postnatally, the through breastfeedingestimated risk of transmission is estimated to be Transmission of HIV through breastfeeding can29% (95% Cl: 16–42%) (Dunn et al. 1992). take place at any time during lactation. There is Subsequent data, including the results of a insufficient information available to estimate therandomized clinical trial, confirm these initial exact association between duration of breast-findings in HIV-infected pregnant women. In the feeding and the timing of transmission. How-clinical trial in Nairobi, HIV-infected pregnant ever, there is some evidence that there is anwomen were randomly allocated to either breast increased early postnatal risk within the first six(n=212) or formula (n=213) feeding groups in to eight weeks. This still remains uncertain, how-the absence of any preventive antiretroviral in- ever; a late postnatal risk beyond six to eighttervention (Nduati et al. 2000). Compliance with weeks has been better characterized recentlyassigned feeding modality was 96% in the (The Breastfeeding and HIV International Trans-breastfeeding arm and 70% in the formula arm. mission Study Group (BHITS) 2004).Median duration of breastfeeding was 17months. The cumulative probability of HIV in- Early postnatal transmission throughfection at 24 months of age was 36.7% in the breastfeedingbreastfeeding arm and 20.5% in the formula- Data suggest that the first six to eight weeks offeeding arm, with 44% of HIV infection in the breastfeeding could be a high risk period forbreastfeeding arm attributable to breastfeeding. transmission of HIV. However, it is difficult toMost breastfeeding transmission occurred early, investigate for technical reasons, and thus diffi-although transmission continued throughout the cult to draw any conclusions about the relativeduration of exposure (Nduati et al. 2000). Al- risk of transmission through colostrum and ma-though exclusive breastfeeding was recom- ture breast milk (Van de Perre et al. 1993; Ruffmended in this trial it was likely not always et al. 1994; Lewis et al. 1998). First, colostrumexclusive in this population. Furthermore, infor- and mature breast milk contain different typesmation on the mode of breastfeeding was not of cells and varying levels of immune-modulat-collected. ing components (e.g. vitamin A, immunoglobu- Other estimations of the rate of transmission lins and lactoferrin). Second, the total volumethrough breastfeeding can be inferred from the of colostrum ingested by the infant is muchresults of trials in which a peripartum interven- smaller than that of mature breast milk. Third,tion to reduce MTCT risk was evaluated both in the infant’s immune system is less well-devel-the short-term (four to six weeks) and in the long- oped during the first few days of lactation thanterm, after the end of breastfeeding exposure at in later lactation, while younger infants have an18–24 months. Additional postnatal transmis- increased blood concentration of maternal anti- 10
  • 22. HIV TRANSMISSION THROUGH BREASTFEEDINGbodies. There is no evidence to suggest that load in plasma. Of note, the probability of infec-avoidance of colostrum would reduce the risk of tion through breastfeeding per day of exposurebreastfeeding transmission to the infant. was not significantly different for children aged Based on statistical modelling using data from less than four months versus those older thanstudies with a limited duration of breastfeeding, this (0.00015 versus 0.00031, p=0.4).it appears that the highest risk period for trans- In the SAINT trial in South Africa, althoughmission is within the first four to eight weeks of not randomized on infant feeding modalities, thelife, and that infectivity may vary in populations proportion of new infections having occurredat different stages of the disease (Dunn 1998). between birth and six to eight weeks increasedEvidence remains weak to detail the percentage to 5.6% when comparing breastfed infants toof transmission occurring early. In the rando- formula-fed infants (Moodley et al. 2003).mized clinical trial of breast milk versus formulacarried out in Nairobi, Kenya, 10% of the total Late postnatal transmission through16% cumulative difference in infection rates be- breastfeedingtween infants in the breastfed and formula-fed Late postnatal risk of HIV transmissionarms apparently occurred by week six of age. The through breastfeeding can be reliably estimatedcumulative rate of HIV infection in the formula- among children born to infected mothers whofeeding arm was approximately half that of the tested negative at four to six weeks postpar-breastfeeding arm at birth (3.1% versus 7.0%, tum. These children are followed until afterp=0.35). Although not statistically significant, they cease breastfeeding to determine their ratethis differential between arms raised concern of acquisition of HIV infection throughabout the true comparability of the two arms at breastfeeding. The time at which the exposurebirth, with women in the breastfeeding arm hav- starts is determined by the age at which in-ing more advanced disease than in the formula- fants are tested. This is now usually aroundfeeding arm (Bulterys 2000). four to six weeks of age, but in earlier studies Additionally, the breastfeeding women were was between three and six months of age. Theselikely more ill as evidenced by the much higher different ‘starting points’ may explain differ-than expected mortality in this group compared ent estimates of rates of late postnatal trans-to the women giving formula to their children mission between studies (Table 2).(Nduati et al. 2001). In the Kenya trial, the pro- The best evidence on the risk of late postna-portion of new HIV infections between birth and tal transmission comes from a meta-analysis ofsix to eight weeks was 6.3% (from 3.1% to 9.7% a large number of data relating to breastfeedingin formula-fed versus 7.0% vs19.9% in breastfed and postnatal transmission of HIV frombabies, p=0.005) (Nduati et al. 2000). Seventy- randomized controlled trials of peripartum in-five per cent of the risk difference between the terventions conducted in sub-Saharan Africa.two arms occurred by six months of age, although Early transmission was defined as a positive HIVtransmission continued throughout the duration test before four weeks, and late postnatal trans-of exposure (Nduati et al. 2000). In a subsequent mission as a negative diagnostic test at or afteranalysis of this data, 75% of the risk difference four weeks of age, followed by a subsequent posi-between the two arms occurred by six months of tive test result (The Breastfeeding and HIV In-age, although transmission continued through- ternational Transmission Study Group (BHITS)out the duration of exposure (Nduati et al. 2000). 2004). Of 4085 children (breastfed singletonsIn a subsequent analysis of this trial data, the for whom HIV testing was performed) from nineprobability of transmission through breastfeeding eligible trials, 993 (24%) were definitively in-was estimated to be 0.00064 per litre of breast fected (placebo arms, 25.9%; treatment arms,milk ingested and 0.00028 per day of 23.4%, p=0.08). The time of infection was un-breastfeeding (Richardson et al. 2003). Breast- known for 454 children. Of 539 children wheremilk infectivity was significantly higher for moth- the time of infection was known, 225 (42%) wereers with low CD4 cell counts and high RNA viral infected during the late postnatal period. Late 11
  • 23. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007TABLE 2. Estimated rates of late postnatal transmission of HIV in African cohortsStudy location Age at nega- Median Infection inci- Cumulative Cumulative(citation) tive test duration of dence per 100 percentage of percentage of (determining breastfeeding child-years of infants in- infants in- denominator) breastfeeding fected by 12 fected at last (%) months follow-upMalawi (Miotti et al. 1999) 1 month >12 months 6.9 8.9 10.3 (18 months)Africa (Leroy et al. 1998) 3 months 16 months 3 2.5 9.2 (36 months)West Africa(Leroy et al. 4 weeks 12 months 8.6 9.5 13.1 (182003) months); 13.1 (24 months)Africa BHITS (The 4 weeks 10 months 8.9 7 9.3 (18 months)Breastfeeding and HIVInternational TransmissionStudy Group (BHITS)2004)Zvitambo, Zimbabwe (Iliff 6 weeks >18 months 9.2 7.7 12.1 (18 months)et al. 2005) EBF: 3.42 EBF: 6.94 PBF: 7.29 PBF: 8.56 MF: 8.41 MF: 13.92South Africa, the Vertical 4-8 weeks 6 months 10.7 (EBF only) NA EBF: 4.04 (6Transmission Study months)(Coovadia et al. 2007)Côte d’Ivoire, the ANRS 4 weeks 5 months 3.8 NA NA1201/1202 Ditrame Plus EBF: 5.9study (Leroy et al. 2004) PBF: 11.3 MF: 31.6NA, not available; EBF, exclusive breastfeeding; PBF, predominant breastfeeding; MF, mixed feeding (breast milk and otherfluids, foods and/or formula).postnatal transmission occurred throughout sion Study Group (BHITS) 2004). Analysis ofbreastfeeding. The cumulative probability of late how transmission rates vary with time from birthpostnatal transmission at 18 months was 9.3% indicated that late postnatal transmission risk is(95% CI 3.8-14.8%). The overall risk of late around 1% per month of breastfeeding and ispostnatal transmission was 8.9 transmissions per constant over time from four to six weeks and100 child-years of breastfeeding (95% CI 7.8- 18 months, i.e. between 0.8 and 1.2 per 10010.2 per 100 child-years) follow-up (Table 2). child-months of breastfeeding. The longer theLate postnatal transmission could contribute as duration of breastfeeding, the higher the cumu-much as 42% to the overall rate of MTCT (The lative risk of postnatal transmission of HIV.Breastfeeding and HIV International Transmis- 12
  • 24. HIV TRANSMISSION THROUGH BREASTFEEDING In conclusion, the rate of late postnatal trans- HIV infection, when the rate of postnatal trans-mission is now better characterized than previ- mission has been estimated to be nearly 30%ously and is estimated to be around 1% per (Dunn et al. 1992). In a study in Kenya, themonth of breastfeeding and constant over time. relative risk of MTCT was increased about six-When breastfeeding is prolonged to 18-24 fold during primary infection of the mothermonths or beyond, the additional cumulative (Embree et al. 2000).postnatal risk of transmission throughbreastfeeding varies from 4% to 16% according HIV-related immune statusto the study (Miotti et al. 1999; Nduati et al. More data are now available on the association2000; Jackson et al. 2003; Leroy et al. 2003). between maternal immune status (CD4 cell counts) and MTCT through breastfeeding. Ma-Factors associated with risk of ternal immunosuppression defined by low CD4transmission of HIV through cell count, although strongly correlated with plasma RNA viral load, is an independent riskbreastfeeding factor for breastfeeding transmission in all stud-There is reliable quantification of the effect of ies with available information. In an analysis ofrisk factors associated with an increased or de- pooled data from two West African ZDV trialscreased likelihood of transmission of the virus (Leroy et al. 2002; Leroy et al. 2003), maternalthrough breastfeeding. Clinical, immunological CD4 cell counts below 500 cells per mm3 inand virological factors in mothers, as well as in- plasma close to time of delivery was associatedfant feeding patterns, affect postnatal transmis- with a threefold increase in risk of late postnatalsion (Table 3). transmission compared to women with CD4 cell counts equal to or greater than 500 per mm3Maternal factors (Leroy et al. 2003). In the BHITS meta-analysisMaternal seroconversion during breastfeeding of data from nine intervention trials in sub-Sa-HIV maternal seroconversion during breastfee- haran Africa, the risk of late postnatal acquisi-ding constitutes a high risk factor for postnatal tion of infection after four weeks of age wasHIV transmission; it is higher than among strongly associated with maternal CD4 cellwomen who have been infected previous to count. Transmission increased eightfold whenbreastfeeding (Van de Perre et al. 1991; Dunn et CD4 cell counts were below 200 per ml, and 3.7-al. 1992). High levels of virus in plasma, and fold where CD4 cell counts were between 200probably also in breast milk, are seen in primary and 500 per ml, compared to the reference groupTable 3. Factors associated with transmission of HIV through breastfeedingMaternal InfantYounger maternal age, lower parity Factors associated with the immune systemMaternal seroconversion during lactation Pattern of infant feeding (exclusive breastfeeding versusClinical and/or immunological (CD4 cell count) disease mixed)progression Morbidity leading to less vigorous suckling, milk stasis andRNA viral load in plasma increased leakage of virus across milk ducts (oral thrush)RNA viral load in breast milkLocal immune factors in breast milkBreast health (subclinical or clinical mastitis, abscess,cracked nipples) (indirect factor)Maternal nutritional statusDuration of breastfeedingSource: Adapted from John-Stewart et al. (2004). 13
  • 25. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007of CD4 cell count above 500 per ml (The understood. In particular, viral load rebound (i.e.Breastfeeding and HIV International Transmis- increased levels of the virus after cessation ofsion Study Group (BHITS) 2004). In the Verti- antiretrovirals) in breast milk after discontinua-cal Transmission Study in South Africa, infants tion of peripartum antiretrovirals is of concernborn to mothers with CD4 cell counts less than (Van de Perre et al. 1997). An increase in the200 cells per mm3 were almost four times more levels of HIV RNA in breast milk from day eightlikely to acquire HIV or die than were those born to day 45 after delivery was associated withto mothers with CD4 cell counts greater than maternal short-course ZDV prophylaxis com-500 cells per mm3; and those born to mothers pared to the placebo group in the Ditrame Pluswith CD4 cell counts between 200 and 500 cells ANRS 049a trial (Manigart et al. 2004). In thisper mm3 were 2.2 times more likely to acquire West African trial, breast-milk HIV-RNA fromHIV or die (Coovadia et al. 2007). 28 women who transmitted HIV postnatally and from 130 women who did not transmit HIV wasRNA viral load in plasma and breast milk compared. Levels of HIV RNA in breast milk atIncreased maternal RNA viral load in plasma and day eight after delivery and its increase from daybreast milk are both strongly associated with eight to days 45-90 postpartum were both inde-increased risk of transmission through pendently associated with postnatal transmissionbreastfeeding. In West Africa, the rate of late (Manigart et al. 2004). Although HIV transmis-postnatal transmission increased 2.6-fold for sion continues after cessation of peripartumevery one log10 increase in plasma RNA viral antiretroviral therapy, there is no clinical evidenceload (measured in late pregnancy) (Leroy et al. to suggest that stopping antiretroviral therapy2001; Leroy et al. 2003). Breast-milk HIV RNA in this early period is associated with an increasedlevels cor relate with systemic viral load rate of breastfeeding transmission due to viral(Willumsen 2003), and are likely to be associ- rebound after cessation of antiretrovirals. Indeed,ated with risk of breast-milk HIV transmission in the pooled analysis of the West African trials(Semba et al. 1999a; Willumsen 2003). In Ma- using short-course perinatal ZDV prophylaxis,lawi, the risk of transmission increased fivefold the cumulative postnatal transmission risks werewhen RNA virus had been detected in breast- similar in the ZDV (9.8%, n=254) and placebomilk samples taken at six weeks postpartum groups (9.1%, n=225) at age 24 months (Leroy(Semba et al. 1999a). In Nairobi, breast-milk et al. 2003). The long-term overall efficacy ofRNA levels were assessed in serial samples up to this peripartum ZDV regimen was reduced intwo years after delivery (John et al. 2001). In both groups. Global recommendations onanalyses comparing 92 infected infants with 187 antiretrovirals during pregnancy are availableinfants who were uninfected at two years, ma- (WHO, 2006).ternal plasma RNA, mastitis and breast abscesswere associated with late transmission (occur- Anti-infective properties of breast milk in HIV-ring after two months postpartum). Median RNA infected womenload in colostrum and early milk was higher than Breast milk contains maternal antibodies, within mature milk collected more than 14 days af- all basic forms of immunoglobulins IgG, IgM,ter delivery. Breast-milk RNA load was signifi- IgA, IgD, and IgE present. The most abundantcantly associated with transmission through is usually secretory IgA (Lawrence & Lawrencebreastfeeding. In a study conducted in Durban, 2004). The role of breast-milk HIV-specific an-South African women with detectable RNA vi- tibodies in inhibiting HIV transmission throughral load in breast milk at any time during the breastfeeding has been investigated ( Van de Perrefirst six months postpartum were more likely to et al. 1993, Kuhn et al. 2006). The breast milktransmit than those with undetectable RNA vi- of women with established HIV infection hasral load (Pillay et al. 2000). been found to have HIV-specific IgG, with its The evolution of HIV RNA in breast milk af- wide spectrum of activity against HIV proteins,ter peripartum antiretrovirals needs to be better comparable to HIV-specific IgG in serum. The 14
  • 26. HIV TRANSMISSION THROUGH BREASTFEEDINGspectrum of activity of serum IgA against HIV elsewhere, defined as having elevated levels ofhas been found to be similar to that of serum sodium and/or potassium in breast milk, in stud-IgG, but the spectrum of activity of HIV-spe- ies of HIV-infected mothers six to 14 weeks af-cific secretory IgA (sIgA) in breast milk is di- ter delivery ranged from 11 to 16% (Semba etrected against only a limited number of viral al. 1999b; Willumsen 2001; Willumsen 2003).proteins (envelope protein, glycoprotein 160, Nipple lesions have been detected in 10-13% ofcore proteins). In Zambia, HIV-specific sIgA was HIV-infected mothers in several cohort studiesdetected more often in breast milk of transmit- (Embree et al. 2000; John et al. 2001; Ekpini etting mothers (76.9%) than in breast milk of non- al. 2002). Breast abscess on clinical exam wastransmitting mothers (46.9%, p=.009). The detected at least once in 12% of breastfeedingauthors concluded that HIV-specific sIgA in mothers over a two-year follow-up period in onebreast milk did not appear to be a protective fac- study and in 3% of mothers in another studytor against HIV transmission among breastfed with a shorter follow-up period. Mastitis, abscess,infants (Kuhn et al. 2006). and nipple lesions have all been associated with In another study in Zambia, the concentra- a relative increase in the risk of transmissiontion of alpha-defensins in breast milk was sig- through breastfeeding (Semba et al. 1999a;nificantly associated with reduced transmission Embree et al. 2000; Willumsen 2000; John etthrough breastfeeding (Kuhn et al. 2005). This al. 2001; Willumsen 2003).is consistent with earlier work in Rwanda (Vande Perre et al. 1993), where the most frequently Nutritional statusidentified HIV-specific antibody in breast milk Maternal nutritional status may influence riskwas IgG (in >95% of samples), the next was IgM of transmission overall, as well as breastfeeding(in 41-78% of samples) and the least frequent transmission. In a randomized trial investigat-was IgA (in 23-41% of samples). Low levels of ing the effect of multivitamins and vitamin A onHIV-specific IgM in breast milk collected at 18 the risk of transmission, multivitamins (exclud-months were associated with a high risk of trans- ing A) given to the mother had no effect on themission of HIV. overall risk of transmission. However, vitamin A Other components of breast milk are protec- alone was associated with a slight increase intive against viral infections. Human lactoferrin MTCT, and an increased risk of transmissionhas been shown in vitro to have an inhibitory during breastfeeding (Fawzi et al. 2002b).activity against HIV (Van de Perre 1999), and Multivitamins were associated with a non-sig-lipid-dependent antiviral activity, specifically di- nificant reduction in breastfeeding transmissionrected at HIV. Data suggest the presence of HIV- and mortality of the infant in the first two yearsspecific major HIV CD8(+) cytotoxic T of life. In a further analysis of these data, chil-lymphocytes in breast milk of HIV-infected dren of women who were randomized to receivewomen could play a role in limiting transmis- multivitamins during pregnancy and lactationsion and provide a rationale for vaccine strate- had a significantly lower risk of diarrhoeagies to enhance these responses (Sabbaj et al. (p=0.03) and a substantially higher mean CD42002). cell count (p=0.006) than those in the arm with no multivitamins. The benefit for HIV-infectedBreast health children was similar to that for uninfected chil-Breast health has also been associated with the dren.risk of transmission through breastfeeding, with Vitamin A supplementation given to mothersbreast pathologies such as clinical and subclini- reduced the risk of respiratory infections in thecal mastitis, nipple bleeding, abscess or fissures child (p=0.03) but was not associated with arelatively common in HIV-infected populations. reduction in diarrhoea. It has been speculatedIn Kenya, clinical mastitis was detected in 7-11% that antioxidant micronutrient (e.g. vitamin E,of HIV infected mothers (John et al. 2001), while selenium, vitamin A and B-carotene) deficien-the estimated prevalence of subclinical mastitis cies may increase the risk of mastitis and there- 15
  • 27. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007fore the risk of MTCT (Semba et al. 1994; Semba cretory leukocyte protease inhibitor (SLPI). In-& Neville 1999). Finally, in Zimbabwe, the fant salivary SLPI has been associated with de-Zvitambo trial did not report a significant role creased risk of late breast-milk HIV transmissionof vitamin A supplementation on the risk of post- (Farquhar & John-Stewart 2003). However, in anatal transmission (Iliff et al. 2005). However, study of 43 unselected HIV-infected breastfeed-the investigators reported that severe anaemia ing mothers in Bangui, with breast-milk samples(<70g/l) and low maternal arm circumference obtained at one week, four weeks and six monthsrelated to nutritional maternal health, were in- after delivery, the mean levels of SLPI in breastdependent risk factors for HIV transmission post- milk of mothers who transmitted HIV did notnatally (Iliff et al. 2005). These findings highlight significantly differ from those of mothers whothe importance of nutritional support for HIV- did not transmit HIV (Becquart et al. 1999).infected breastfeeding women, but more clarity Further controlled studies are needed to confirmis needed about which interventions would best the role of maternal and infant SLPI in trans-decrease postnatal transmission of HIV. mission, either alone or in combination with other innate and specific immune factors. InInfant factors addition, HIV-specific cellular immune responsesIntegrity of mucous membranes to HIV envelope peptides detected in HIV-ex-Factors resulting in disruption of the integrity of posed infants are associated with reduced trans-infants mucous membranes, such as oral thrush, mission through breastfeeding (Kuhn et al.may be associated with an increased risk of trans- 2001).mission through breastfeeding. However, the di-rection of any causality is difficult to establish Patterns of infant feeding: mode and durationsince early HIV infection may also be associated Of greater importance than other factors, thewith thrush (Ekpini et al. 1997; Embree et al. mode of infant feeding is now clearly associated2000). Infant oral thrush can also lead to ma- with HIV transmission through breast milk. Internal nipple thrush and fissures. Feeding with most populations worldwide, breastfeeding iscows milk, allergic reactions to complementary usually initiated, but supplemented with water,foods and infectious illness can all result in in- other drinks or foods at an early age (Nicoll ettestinal damage, which could also be a risk fac- al. 2000a). Exclusive breastfeeding for the rec-tor for transmission. It has also been ommended six months is uncommon, althoughhypothesized that the intestinal permeability of globally rates are increasing (UNICEF 2005).the young infant may be affected by mode of There is observational evidence from three largefeeding, with infants who receive only breast milk studies that exclusive breastfeeding is associatedhaving a less permeable and therefore healthier with a lower risk of postnatal transmission oflining of the gut than those who also receive other HIV compared to non-exclusive breastfeeding,foods. However, in the one study carried out to that is, breastfeeding with formula, other fluidsinvestigate this further, feeding mode was not (water, fruit juice) or solids (Table 2). In a studyassociated with infant intestinal permeability in Durban, South Africa, 551 HIV-infected(measured with lactulose-mannitol ratios, i.e. women self-selected to breastfeed or formula feeddual sugars), although infants who had been di- after being counselled (Coutsoudis et al. 2001).agnosed with HIV infection at 14 weeks had Breastfeeding women were encouraged to prac-higher permeability at six and 14 weeks than tise exclusive breastfeeding for three to sixdid uninfected children (Rollins et al. 2001). months. A total of 157 women formula-fed their infants from birth and never breastfed, 118 ex-Immune factors clusively breastfed for three months or more andA well-characterized innate factor that has been 276 women mixed fed. The three feeding groupsconsidered for protection against mucosal trans- did not differ in any of the significant risk fac-mission of HIV, including by breast milk, is se- tors for transmission, and at birth the rate of 16
  • 28. HIV TRANSMISSION THROUGH BREASTFEEDINGinfection in their infants was similar at about (6.9%) (Iliff et al. 2005). In Côte dIvoire, mixed7%. Children who received both breast milk and breastfed children tended to have a higher post-other foods before three months were signifi- natal transmission risk than exclusively breastfedcantly more likely to be infected by 15 months children, although the difference was not signifi-of age (36%) than those who were exclusively cant (Leroy et al. 2004). These data support thebreastfed until at least three months (25%) or hypothesis that exclusive breastfeeding carries athose who had been formula-fed (19%). Exclu- lower risk than mixed feeding. This phenomenonsive breastfeeding was associated with a signifi- could be explained by the effect of enteric infec-cantly lower risk of HIV infection than mixed tion caused by the early introduction of foodsbreastfeeding (hazard ratio, HR, 0.56, 95% CI on the integrity of the infant intestinal gut (Goto0.32-0.98) and had a similar risk to children who et al. 1999). It has been hypothesized that in-were never breastfed (HR 1.19, 95% CI 0.63- creased risk of transmission with mixed feeding2.22). early in life could be associated with increased In the Vertical Transmission Study in South gut permeability or levels of local inflammation.Africa, 1132 of 1372 (83%) infants born to HIV- Another potential mechanism is that mixed feed-infected mothers initiated exclusive breastfeeding ing may be associated with suboptimalfrom birth. Of 1276 infants with complete feed- breastfeeding practices and with subclinical mas-ing data, median duration of cumulative exclu- titis, or it could be due to confounding betweensive breastfeeding was 159 days (first quartile to mixed feeding and susceptibility to infection.third quartile, 122-174 days). Further, 14.1% Duration of breastfeeding is confirmed to be(95% CI 12.0-16.4) of exclusively breastfed in- one of the main risk factors for HIV transmis-fants were infected with HIV by age six weeks sion through breastfeeding. In Zimbabwe, amongand 19.5% (95% CI 17.0-22.4) by six months; the 2060 children exposed to breastfeeding, therisk was significantly associated with maternal risk of postnatal transmission was 12%; 68% ofCD4 cell counts below 200 per mm3 (adjusted transmission events occurred after six monthsHR 3.79, 95% CI 2.35-6.12), and birth weight (Iliff et al. 2005). This is consistent with studiesless than 2500 g (adjusted HR 1.81, 95% CI in West Africa (Leroy et al. 2003), South Africa1.07-3.06). Kaplan-Meier estimated risk of ac- (Coutsoudis et al. 2001) and the United Repub-quisition of infection at age six months was lic of Tanzania (Fawzi et al. 2002a). The authors4.04% (95% CI 2.29-5.76) (Coovadia et al. in Zimbabwe concluded that early cessation of2007). Breastfed infants who also received sol- breastfeeding could prevent a sizable proportionids were significantly more likely to acquire in- of postnatal HIV infections, but that this canfection than were exclusively breastfed children only be done when women are socially supported(HR 10.87, 95% CI 1.51-78.00, p=0.018), as to do so, and when safe, nutritionally adequatewere infants who at 12 weeks received both alternatives are available.breast milk and formula milk (HR 1.82, 95%CI 0.98-3.36, p=0.057). Cumulative three- Sexmonth mortality in exclusively breastfed infants In the international meta-analysis of late post-was 6.1% (95% CI 4.74-7.92) versus 15.1% natal transmission (The Breastfeeding and HIV(95% CI 7.63-28.73) in infants given replace- International Transmission Study Groupment foods (HR 2.06, 95% CI 1.00-4.27, (BHITS) 2004), covariates potentially affectingp=0.051) (Coovadia et al. 2007). the relationship between breastfeeding and late In Zimbabwe, children who received both postnatal transmission of HIV were evaluated,breast milk and other foods or were predomi- including both maternal variables (age, parity,nantly breastfed during the first three months CD4 cell count) and child variables (birth weight,of life were significantly more likely to be infected sex). Neither maternal age, parity nor birthby 18 months of age (13.9% and 8.6% respec- weight were significantly associated with latetively) than those who were exclusively breastfed postnatal transmission, but maternal CD4 cell 17
  • 29. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007count and childs sex were, with girls being 40% infection than boys were (Thorne & Newellless likely to become infected after four weeks of 2004). Duration of breastfeeding was similarage during breastfeeding than boys (HR 0.6, 95% among boys and girls, but no information wasCI 0.4-0.9, p=0.014). The risk of late postnatal available on the age at which, and what type oftransmission was highest for boys breastfed by other foods were introduced. This difference maymothers with CD4 cell counts below 200 per be due to boys receiving complementary foodsmm3, followed by boys breastfed by mothers with at an earlier age, which thus put them at higherCD4 cell counts between 200 and 499 per mm3 risk of becoming infected. Further research isand then girls breastfed by mothers with CD4 ongoing to confirm this finding, although a re-cell counts below 200 per mm3. It was previously cent study did not confirm these differences inreported in the European Collaborative Study, transmission rates between boys and girls dur-which studied the effect of sex among newborns ing exclusive breastfeeding (Coovadia et al.delivered by elective caesarean section, that girls 2007).were more at risk of antepartum and peripartum 18
  • 30. Benefits of breastfeedingHealth benefits of breastfeeding in the died of diarrhoea, while none that were breastfedgeneral population did. Details are provided in section 5.3.5. In a substudy of the Botswana outbreak, 93% of 153 babies with diarrhoea were not breastfedMaternal health benefitsE (about 75% were fed infant formula and the re- xclusive breastfeeding helps a mother space mainder were fed cow’s milk). Sixty-five per cent her pregnancies. Healthy birth spacing is as- of their mothers were HIV-positive, and amongsociated with improved birth outcomes and ma- the infants, 18% were HIV-infected at the timeternal recovery following birth. A woman who of the study. Kwashiorkor was the only signifi-exclusively, or almost exclusively, breastfeeds her cant predictor of death, not maternal or infantinfant during the first six months of life, and has HIV status. In the United States of America, anot resumed menstruation, has a less than 2% nationally representative cross-sectional homerisk of becoming pregnant during that time survey conducted from 1988 to 1994 docu-(WHO et al. 1995). mented an increased risk of respiratory tract in- fections, including pneumonia and recurrentChild health benefits otitis media, in children who were fully breastfedCurrent evidence that breastfeeding is beneficial for four versus six months (Chantry et al. 2006).for infant health is mainly based on observational There are earlier studies showing the benefits ofstudies. Potential sources of bias in such studies breastfeeding (Habicht et al. 1986; Victora ethave led to doubts about the magnitude of these al. 1987; Victora et al. 2000; WHO Collabora-health benefits in developed countries. However, tive Study Team 2000). In a study in Brazil, theseveral randomized clinical trials show that risk of hospital admissions for pneumonia wasbreastfeeding is the best nutrition during the first increased 17-fold in infants who were not beingmonths of life (Nicoll & Williams 2002). breastfed (odds ratio, OR, 16.7, 95% CI 7.7– One of the most important benefits of breast 36.0) compared to those being breastfed (Cesarmilk is its ability to protect against common et al. 1999).childhood infections such as diarrhoea, pneumo- Results from a pooled analysis of six case–con-nia, neonatal sepsis and acute otitis media. In a trol studies carried out from 1983 to 1991 con-recent outbreak of diarrhoea in Botswana, not firm that breastfed infants have a reducedbeing breastfed was the most significant risk fac- mortality risk compared to non-breastfed chil-tor for diarrhoea and death among children dren (WHO Collaborative Study Team 2000).(Creek 2006). Following a period of unusually In the three studies in non-African settings whereheavy rainfall cases of diarrhoea quadrupled, outcomes for breastfed infants could be comparedfrom about 8500 in 2004 to more than 35 000, to that of non-breastfed infants, mortality rateswhile deaths increased more than 20-fold, from were significantly higher for non-breastfed in-24 to about 530. An epidemiological investiga- fants through the first eight months of life. Thistion of the outbreak revealed that a large pro- finding was particularly striking in the first fewportion of the infants who experienced diarrhoea months of life with a pooled odds ratio of 5.8were not breastfed. In a multivariate analysis, (95% CI 3.4–9.8) for infants less than twolack of breastfeeding was the strongest predictor months of age, indicating a nearly sixfold in-of infant diarrhoea, increasing the risk 50-fold. creased risk of mortality for these young non-In one village, one third of formula-fed babies 19
  • 31. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007breastfed infants. The protective effect of and that this is accompanied by significant healthbreastfeeding is most marked in the first six gains during an infant’s first year of life. It alsomonths of life and gradually diminishes as the demonstrates that implementing exclusiveinfant grows older. breastfeeding on a population basis is feasible More recently, the Promotion of Breastfeeding with adequate support and training of health-Inter vention Trial (PROBIT), a cluster- care professionals (Kramer et al. 2001).randomized trial, has produced convincing evi- In a secondary analysis of a large randomizeddence of benefit for term infants (Kramer et al. clinical trial on immunization and Vitamin A,2001). Maternity hospitals were randomly allo- infant feeding patterns (exclusive breastfeeding,cated to receive an evidence-based intervention predominant breastfeeding, partial breastfeedingdesigned to increase the uptake and duration of and no breastfeeding) were studied in relationbreastfeeding according to the principles of the to mortality and hospital admissions over sixBaby-friendly Hospital Initiative sponsored by months. Altogether, 9424 infants and theirthe World Health Organization (WHO) and the mothers in Ghana, India and Peru were enrolledUnited Nations Children’s Fund (UNICEF). when infants were in the neonatal period. TheAmong the 16 491 mother-baby pairs followed main outcome measures were all-cause mortal-for 12 months, those born in intervention hos- ity, diarrhoea-specific mortality, mortality causedpitals were significantly more likely to be exclu- by acute lower respiratory infections and hospi-sively breastfed at three and six months of age. tal admissions. There was no significant differ-Moreover these children had approximately half ence in the risk of death between children whothe risk of experiencing gastrointestinal infection were exclusively breastfed and those who were(OR 0.60, 95% CI 0.40–0.91) and atopic eczema predominantly breastfed (adjusted HR 1.46,(OR 0.54, 95% CI 0.31–0.95). 95% CI 0.75–2.86). Non-breastfed infants had The optimum duration of exclusive a higher risk of dying when compared with thosebreastfeeding in terms of health benefit has long who had been predominantly breastfed (adjustedbeen a subject of debate. In the PROBIT trial, HR 10.5, 95% CI 5.0–22.0, p<0.001) as didthe effects on infant growth and health compar- partially breastfed infants (adjusted HR 2.46,ing 2862 infants exclusively breastfed for three 95% CI 1.44–4.18, p=0.001). These findingsmonths with 621 infants who were exclusively highlight that the risks of death are high in non-breastfed at least six months were reported breastfed children, but are significatly lower and(Kramer et al. 2003). Weight and length gain similar for infants who are predominantlywere slightly greater in the three-month group breastfed and those who are exclusively breastfed.but the six-month group had a faster length gain The authors suggested that in settings wherefrom nine to 12 months and a larger head cir- rates of predominant breastfeeding are alreadycumference at 12 months. A significant reduc- high, promotion efforts should focus on sustain-tion in the incidence of gastrointestinal infections ing these high rates rather than on attemptingwas observed during the period from three to six to achieve a shift from predominant breastfeedingmonths in the six-month group (adjusted inci- to exclusive breastfeeding (Bahl et al. 2005).dence density ratio: 0.35 [0.13, 0.96]), but there In 2001, the World Health Assembly endorsedwere no significant differences in risk of respira- the recommendation that infants should be ex-tory infectious outcomes or atopic eczema. Ex- clusively breastfed for the first six months of lifeclusive breastfeeding for six months was to achieve optimal growth, development andassociated with a lower risk of gastrointestinal health. Thereafter, infants should receive nutri-infection and no demonstrable adverse health tionally adequate and safe complementary foodseffects in the first year of life in a general popu- while breastfeeding continues to 24 months orlation with low HIV prevalence (Kramer et al. beyond (WHO 2001). This recommendation has2003). This trial shows both that exclusive considered the benefits of breastfeeding, as wellbreastfeeding prevalence can be increased by a as the adverse effects associated with formulahospital intervention promoting breastfeeding, feeding at an early age in the general population 20
  • 32. BENEFITS OF BREASTFEEDINGwith low HIV-prevalence (Kramer & Kakuma movement between arms, and many in the for-2004). mula arm left the study before follow-up. On the other hand, in the Mashi trial in Bot-Health benefits of breastfeeding in swana, results were slightly different from thechildren born to HIV-infected mothers Kenya trial (Thior et al. 2006). The Mashi trial evaluated the efficacy and safety of breastfeedingThere is little information regarding whether the and ZDV prophylaxis in infants for six monthsbreast milk from HIV-infected women confers compared to formula feeding from birth and oneimmune properties for both their uninfected and month of ZDV prophylaxis of the infant for re-infected children. HIV-infected women may have ducing postnatal transmission of HIV There were .immune dysfunction and produce lower levels significantly higher rates of mortality (mainlyof protective antibody and cell-associated immu- related to diarrhoeal disease and pneumonia) innity against diarrhoeal and respiratory infections; formula-fed than in breastfed children in the firsthence their milk would have lower levels of pro- six months of life. The cumulative incidence oftective antibodies, than women without HIV infant death was significantly higher in the for-infection. The findings from these two studies mula-fed group than in the breastfed plus ZDVindicate that breastfeeding does confer protec- group at age seven months (9.3% versus 4.9%,tive benefits on HIV-exposed infants. p=0.003); however, this difference diminished beyond seven months, such that the mortalityHIV-exposed children, regardless of HIV status through 18 months of age was not significantlyOnly two trials randomized on infant feeding different (10.7% in the formula-fed arm versuspractices have been conducted among HIV-in- 8.5% in the breastfed arm, p=0.21).fected pregnant women and these have providedinformation on the health benefits of breastfee-ding among HIV-exposed children. HIV-infected children There is more reliable information relating to the In a secondary analysis from a randomized benefits of breastfeeding for HIV-infected chil-trial aimed at evaluating mode of infant feeding dren issued from observational cohort studieson the risk of MTCT of HIV in Nairobi, Kenya (with available data from highly selective sam-(Nduati et al. 2000), the two-year mortality rate ples). In a small study from Durban, South Af-among infants in the formula-feeding group was rica, HIV-infected infants who were never20%, not significantly different from the 24% breastfed had a poorer outcome than breastfedfigure in the breastfeeding group (HR 0.8, 95% HIV-infected children: 60% of 15 never-breastfedCI 0.5–1.3), even after adjusting for HIV infec- infected infants had three or more morbiditytion status (HR 1.1, 95% CI: 0.7–1.7). The in- episodes in the first 18 months of life comparedcidence of diarrhoea during the first two years of to 32% of 47 breastfed HIV-infected infantslife was also similar in both groups: 155 and 149 (Coutsoudis et al. 2003). During the first twoper 100 child-years of follow-up in the formula months of life, never-breastfed infants, regard-and breastfeeding groups respectively, while the less of their HIV status, were nearly twice asincidence of pneumonia was identical at 62 per likely to have had an illness episode as compared100 child-years of follow-up (Mbori-Ngacha et to breastfed infants (OR 1.91, p=0.006). Twoal. 2001). Infants in the breastfeeding arm earlier studies from South Africa compared 90 par-tended to have better nutritional status than tially breastfed and exclusively formula-fed HIV-those in the formula arm (p=0.06 overall), sig- infected infants (Bobat et al. 1997); both groupsnificantly so during the first six months of life had similar frequencies of failure to thrive, episodes(p=0.003). After adjusting for HIV infection of diarrhoea and pneumonia, as did 43 uninfectedstatus, infants in the breastfeeding arm had sig- infants born to HIV-positive mothers.nificantly better nutritional status than those in More recently, preliminary data presentedthe formula arm over the two-year period from Zambia in the ZEBS trial (Thea et al.(p=0.04). In this trial, there was substantial 21
  • 33. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 20072004), showed that breastfeeding of HIV-in- 94% of infants in the world were breastfed forfected infants beyond four months was associ- some time, 79% of infants continuedated with improved sur vival compared to breastfeeding at age one year and 52% at twostopping breastfeeding at four months (Kuhn et years of age (WHO Global Databank onal. 2007). These studies indicate that HIV-in- Breastfeeding and Complementar y Feedingfected infants fare better when breastfed rather 2006).than formula fed. Non-exclusive breastfeeding is common, and giving fluids and foods in addition to breast milkGlobal breastfeeding practices is frequent (Becquet et al. 2005a). The practiceNearly all infants in developing countries are of exclusive breastfeeding at age one month var-initially breastfed from the first week of life ies according to geographic region and is mainly(WHO Global Databank on Breastfeeding and observed in East Africa and Nepal, while it re-Complementary Feeding 2006), and most chil- mains low (less than 30%) in other regions (Fig-dren continue to be breastfed until at least six ure 1) (Nicoll et al. 2000b). Between 1990 andmonths of age, frequently into the second year 2000, the data suggest that exclusive breastfeed-of life (Nicoll et al. 2000a; WHO Collaborative ing levels in the developing world increased 15%Study Team 2000). Continued breastfeeding overall among infants aged less than four months(beyond 12 months) is common in sub-Saharan (from 46% to 53%) and aged less than sixAfrica and Asia, but less so elsewhere (Nicoll & months (from 34% to 39%) (Labbok et al. 2006;Williams 2002). In 2005, it was estimated that UNICEF Global Breastfeeding Databank 2005).FIGURE 1. Prevalence of exclusive breastfeeding at four weeks of age in African and Asian children100 90 80 70 60 50 40 30 20 10 0 Central African Republic 1994-5 United Republic of Tanzania 1991-2 Cameroon 1991 Malawi 1992 Burkina Faso 1993 Ghana 1993 Senegal 1992-3 Kenya 1993 Philippines 1993 Bangladesh 1993-4 Niger 1992 Zambia 1992 Mali 1995 Namibia 1992 Rwanda 1992 Nigeria 1990 Zimbabwe 1994 Madagascar 1992 Uganda 1995 Pakistan 1990-1 Indonesia 1994 Nepal 1996 India 1992-3 Cote d’Ivoire 1994 AFRICA ASIASource: Adapted from Nicoll et al. (2000b) 22
  • 34. Strategies to reduce HIV transmission through breastfeedingB ecause guidance on prevention of HIV trans- mission in the peripartum period is relativelynon-controversial, research on the prevention of provide education about safer sex, condoms, and diagnosis and treatment of sexually transmitted infections, and that ensure the safety of medicalmother-to-child transmission of HIV now con- procedures. HIV prevention should be empha-centrates mostly on the breastfeeding period, sized for women who test seronegative in preg-including the primary prevention of HIV in lac- nancy (a considerable percentage of whom maytating women, antiretroviral prophylaxis to acquire infection in the two years after deliverymothers or their infants and other interventions while still breastfeeding) because of the particu-relating to infant feeding practices (Dabis et al. larly high risk of MTCT if mothers are infected2004; Kourtis et al. 2006). These interventions with HIV during breastfeeding. In poorer set-need to be tailored according to different con- tings, some of the benefits of breastfeeding re-texts. sult from its physiological contraceptive effect, which helps to maintain an advantageous birthPrimary prevention of HIV in women of interval; lactational amenorrhoea is 98% effec-childbearing age tive as a contraceptive method (Vekemans 1997). Additionally, in some cultures there is a reduc-The best approach to preventing HIV infection tion in coitus associated with breastfeeding,in infants and young children, including trans- which may enhance this effect. Hence, the issuemission through breast milk, is to prevent HIV of contraception should be addressed, given thatinfection of young girls and women of childbear- interventions for the prevention of MTCT in-ing age (De Cock et al. 2002). In sub-Saharan clude replacement feeding and may include modi-Africa, Asia and the Caribbean, the main mode fications to breastfeeding, such as early cessationof HIV transmission is heterosexual contact as an option. Antenatal testing and counselling(Buve et al. 2002). In developed countries, al- (including infant feeding options) for HIV-in-though most women with HIV have a history of fected pregnant women are part of the strategyinjecting drug use, or sexual partners with a his- to reduce HIV transmission during breastfeeding.tory of injecting drug use or bi-sexuality, hetero- Such strategies must include high rates of ante-sexual transmission has become an increasingly natal testing and use of interventions to reduceimportant route of infection (European Collabo- HIV transmission; ensuring continued contactrative Study 2001). The risk of HIV infection in between health-care professionals and motherswomen is increased by such factors as immatu- and infants from 18 to 24 months postpartumrity of the genital tract, cervical ectopy, sexually is also vital (Temmerman et al. 2003).transmitted infections and poor nutritional sta- HIV prevention interventions directed at preg-tus (Mostad et al. 1999). Cultural, social and nant and lactating women could contribute toeconomic factors also contribute to HIV trans- reducing MTCT in several settings, but this cur-mission by increasing the vulnerability of girls rently does not attract much research or program-and women (Buve et al. 2002; De Cock et al. matic effort (Rollins et al. 2007).2002). Strategies to prevent all MTCT should belinked to primary prevention programmes that 23
  • 35. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007Framework to assess interventions to The full assessment of strategies aimed at pre-prevent postnatal transmission venting postnatal transmission of HIV through breastfeeding should balance benefits and risksThere are several conceivable interventions to of each infant feeding option in its specific con-prevent mother-to-child transmission of HIV text. An intervention should be recommendedthat are applicable to different settings. These only if its positive effects outweigh its negativeinterventions need to be assessed as complex effects after balancing benefit and risk. The nega-public health interventions using several evalu- tive effects of the intervention, therefore, mustation criteria. The basic principle is to provide always be judged on whether risks can be mini-decision-makers (including women) with all rel- mized to an acceptable level, given the effective-evant information needed to make interventions ness. With this aim, HIV-free survival2 is a usefulavailable to solve this public health issue in their index with which to assess both effectiveness andspecific context. Safety is a key issue which ad- safety; indeed, it is now the most reliable anddresses negative adverse effects of interventions easy measurement to assess the long-term effectaimed at preventing postnatal transmission. It of postnatal interventions (Alioum et al. 2001).could be assessed in various groups using differ-ent criteria: for the infant (morbidity, mortality,growth), for the woman (mortality, fertility), for Modifying infant feeding options for HIV-the general population (the spillover effect).1 infected women: replacement feeding Acceptability is a key issue in assessing inter- Modifying infant feeding practices could play anventions aimed at reducing postnatal transmis- important role in preventing postnatal risk andsion of HIV. It should be assessed at three needs to be assessed according to the local con-different population levels: the target population text. The first alternative to prolonged breastfee-(in terms of social acceptability), the health sys- ding consists of the complete avoidance oftem and decision-makers. Alternatives to pro- breastfeeding, which is then usually replaced bylonged breastfeeding are often considered as commercial infant formula. Support for adequateunusual infant feeding practices in some parts replacement feeding is needed throughout theof the world. It is therefore essential to evaluate period for which breast milk is normally recom-mothers’ acceptance and use of these interven- mended and during which the child is at great-tions, and their compliance with them in the long est risk of malnutrition; that is, the first two yearsterm. of life. Effectiveness is the level to which the inter- Table 4 presents data on replacement feedingvention meets its objectives when used in real- options from various recent studies. The studieslife conditions after the evidence of its efficacy include the Kenya trial conducted in an urbanis assessed in ideal conditions. Documentation site and published in early 2000 (Nduati et al.of effectiveness in preventing postnatal transmis- 2000; Mbori-Ngacha et al. 2001); the MASHIsion could be assessed using both the residual randomized clinical trial conducted in a semi-overall MTCT rate after the complete cessation rural setting in Botswana (Thior et al. 2006);of breastfeeding and the postnatal rate of trans- and the ANRS 1201/1202 Ditrame Plus cohortmission in conditions close to those of the con- study conducted in an urban setting in Abidjan,text where implementation of the intervention Côte d’Ivoire (Becquet et al. 2007; Leroy et al.is considered. 2007).1 Spillover is a term used to designate the feeding behaviour of new mothers who either know that they are HIV-negative or are unaware of their HIV status – they do not breastfeed, or they breastfeed for a short time only, or they mix-feed, because of unfounded fears about HIV or of misinformation or of the ready availability of breast-milk substitutes.2 HIV-free survival refers to young children who are both alive and HIV-uninfected at a given point in time, usually 18 months. 24
  • 36. STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDINGAdverse outcomes of alternatives to the relatively high morbidity and mortality ratesbreastfeeding practices associated with the feeding of formula, and theCompared to unrestricted breastfeeding, replace- need to carefully assess the local management ofment feeding was shown to be safe in the clini- childhood illnesses before the implementationcal trial in Kenya, which allocated infant feeding of a formula-feeding strategy in a given context.practices at random: morbidity and mortality In the ANRS 1201/1202 Ditrame Plus studyrates were similar over two years in breastfed and conducted in Côte d’Ivoire, the two-year occur-formula-fed children (Mbori-Ngacha et al. rence of adverse health events defined as hospi-2001). The incidence of diarrhoea and pneumo- talization or death was similar amongnia during the two years of follow-up was simi- early-weaned breastfed and formula-fed childrenlar in the formula and breastfeeding arms, and (15% and 14%, respectively) (Becquet et al.there were no significant differences in incidence 2007). To assess whether these two modifiedof other recorded illnesses. Infants in the infant-feeding practices were safe as opposed tobreastfeeding arm tended to have better nutri- a longer breastfeeding period, the 18-monthtional status, significantly so during the first six mortality among these children was comparedmonths of life. However, the population studied with the mortality obser ved in long-termin this trial was urban with access to a relatively breastfed children within an historical cohortgood water supply, and it is crucial to determine followed in the same population. No differenceswhether formula feeding could be a safe inter- in mortality were observed in the children givenvention in a more resource-poor population (Ta- alternative foods over the same period as thoseble 4). breastfed, when taking into account HIV status: In the Mashi trial in Botswana, all of the an overall 18-month probability of survival ofmothers received ZDV from week 34 of gesta- 96% was observed among HIV-uninfected earlytion and during labour. Mothers and infants were weaned infants and formula-fed children, whichfirst randomized to receive single-dose NVP or a was similar to the 95% probability observed inplacebo. Infants were then randomized to groups the long-term breastfed children. Given appro-provided with six months of breastfeeding and priate nutritional counselling and care, access toprophylactic ZDV (breastfed plus ZDV), or six clean water and a supply of breast-milk substi-months of formula feeding and one month of tutes, replacement feeding could be a safe inter-ZDV prophylaxis (Shapiro et al. 2005b; Thior vention to prevent MTCT of HIV in urbanet al. 2006). The median duration of African settings.breastfeeding was six months, and self-reportedcompliance with formula feeding high (93%). Social acceptability of feeding practicesHowever, compliance with exclusive breastfeed- As the infant feeding option was allocated ating was poor. The cumulative incidence of in- random in the Kenyan and the Botswana trials,fant death by month seven was significantly the social acceptability of the intervention can-higher in the formula-fed group than in the not be fully studied. In the Kenya trial, compli-breastfed plus ZDV group (9.3% versus 4.9%, ance for women in the formula-feeding group wasp=0.003), but this difference diminished beyond estimated to be 70%, compared to 96% in themonth seven, such that the time-to-mortality breastfeeding group (Nduati et al. 2000). Indistributions through 18 months of age were not Mashi, full adherence to formula feeding was self-significantly different (10.7% versus 8.5%, reported as 93% (Thior et al. 2006). However,p=0.21). Formula feeding was more commonly three infants of 245 in the formula-fed groupassociated with severe diarrhoea and pneumo- were infected between four weeks and sevennia (17.6%), which were also the leading causes months, presumably because they were exposedof death in this group, compared to breastfed to breast milk.children (13.1%, p=.03). These results highlight 25
  • 37. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007 The ANRS 1201/1202 Ditrame Plus cohort socially acceptable than breastfeeding. This so-study of women attending community-run health cial acceptability must be balanced with long-facilities was conducted in poor areas in Abidjan, term health outcomes of the mother and childCôte d’Ivoire (Becquet et al. 2005c; Leroy et al. in order to guide safe recommendations on in-2007). Two nutritional interventions were sys- fant feeding among HIV-infected women in ur-tematically proposed to the women during ante- ban African settings.natal visits, and the staff was trained to support In contrast, Bland and colleagues (2007)individual women’s choices (Table 4). The first found that exclusive breastfeeding was more so-option consisted of the complete avoidance of cially acceptable than replacement feeding in abreastfeeding: replacement feeding from birth to study near Durban, South Africa. The purposenine months of age with free provision of infant of the study was to examine the intentions offormula, facilitated by the use of a single oral HIV-infected and uninfected women with regarddose of cabergoline for inhibiting lactation. The to feeding their infants. This involved assessingsecond option consisted of practising exclusive the appropriateness of their choices according tobreastfeeding for the first few months with the their local resources, as well as determining theaim of stopping after a short period (not exceed- mothers’ adherence to those choices during theing two weeks) and obtaining complete cessa- first week postpartum. The intentions of preg-tion of breastfeeding by four months of age. nant women were studied within the context ofReplacement feeding from cessation of four resources that facilitate replacement feed-breastfeeding until nine months of age as well as ing: clean water, adequate fuel, access to a re-the materials needed were provided free of charge, frigerator and regular maternal income.while cup feeding was encouraged from three First-week feeding practices were documented.months of age. Overall, 53% of women initiated The antenatal feeding intentions of 1253 HIV-formula feeding. Of those, only 15% were non- infected women were: exclusive breastfeedingcompliant to this intervention at age one year 73%; replacement feeding 9%; undecided 18%.(i.e. they had breastfed their child at least once), Significantly more HIV-infected women intend-of whom 41% mixed-breastfed temporarily at ing to exclusively breastfeed adhered to their in-day two, mainly because of the pressure of their tention in week one (exclusive breastfeedingenvironment or because of low birth-weight 78%; replacement feeding 42%; p<0.001). Of(Leroy et al. 2007). 1238 HIV-negative women, 82% intended to Among the breastfeeding mothers, the prob- exclusively breastfeed; 2% to replacement feed;ability of practising exclusive breastfeeding from and 16% were undecided. Seventy-five per centbirth was extremely low: only 10% at three who intended to exclusively breastfeed adheredmonths of age (Becquet et al. 2005c). The dura- to this intention postnatally, and only 11 infantstion of breastfeeding was considerably reduced (<1%) received no breast milk. The number ofin this population: breastfeeding cessation oc- antenatal home visits during the study signifi-curred at approximately four months of age, af- cantly influenced adherence to feeding intention.ter a short (median: nine days) transition period The authors concluded that adherence to inten-of mixed feeding when breast milk and infant tion among HIV-infected women was higher informula were given simultaneously to the infant. those who chose to exclusively breastfeed thanProvided with the necessary support, women’s to replacement feed, and that with appropriateacceptance of, and compliance with, formula counselling and support, spillover of suboptimalfeeding and early cessation of breastfeeding were feeding practices to HIV-negative women washigh. Exclusive breastfeeding was not practised minimal.despite regular nutritional counselling given dur-ing antenatal and postnatal counselling to pro-mote it. In this setting, formula feeding was more 26
  • 38. Table 4. Assessment of various intervention strategies to prevent postnatal transmission of HIV through breastfeeding in studies conducted in Africa Study location Study design Peripartum ARV Postpartum ARV Sample Infant feeding Choice of Safety: morbid- Effectiveness: and name regimen regimen size options feeding ity and mortality HIV transmission (citation) method, and rate and HIV-free adherence to it survival Nairobi, Kenya Randomized None. None. 425 Randomization of Self-reported 24 month mortality: HIV: 20% in the FF (Nduati et al. clinical trial. infant feeding compliance: 71% 20.0% in the FF arm vs. 36.7% in 2000; Mbori- option: exclusive FF in FF arm. arm vs. 24.4% in the BF arm Ngacha et al. or BF. Median duration the BF arm (HR 0.8, (p=.001). 2001) of BF: 17 months. 95% CI 0.5-1.3). HIV-free survival: 58% in the FF arm vs. 70% in the BF arm (p=.02).27 Botswana, the Randomized 1st randomization: 2nd randomization: 1179 Randomization of Self-reported Death: at 7 months HIV: at 7 months MASHI trial clinical trial Initial ZDV from 34 BF + ZDV (infant) infant feeding compliance of BF 9.3% in the FF arm 5.6% in the FF arm (Shapiro et al. design: short- weeks of gestation for 6 months + option: FF or short- arm (50%): vs. 4.9% in the BF vs. 9.0% in the BF 2005a; Shapiro et course ZDV with/ + oral ZDV single-dose NVP term EBF recom- adherence to EBF: arm (p=.003); at arm (p=.04); at 18 al. 2005b; Shapiro without maternal intrapartum and (infant) mended; then early 57% at 4 weeks 18 months 10.7% months 6.0% in the et al. 2006; Thea and infant NVP and either single-dose vs. cessation between and 18% at 5 in the FF arm vs. FF arm vs. 9.5% in et al. 2006) BF/FF.Revised: NVP at onset of FF + ZDV (infant) months 5 and 6. months; compli- 8.5% in the BF arm the BF arm (p=.02). short-course ZDV labour or placebo. for 4 weeks + (Infant formula ance in FF arm (p=.21). HIV-free survival: at and infant NVP single-dose NVP provided at no cost (50%): 93% 7 months 12.5% in STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDING with/without (infant). for 12 months.) reported full the FF arm vs. maternal NVP and adherence. 12.9% in the BF BF/FF; if CD4 arm (p=.86); at 18 count <200: ART months 13.9% in given to mothers. the FF arm vs. 15.1% in the BF arm (p=.60). ARV, antiretroviral; ART, high activity antiretroviral therapy; BF, breastfeeding; EBF, exclusive breastfeeding; FF, formula feeding; RF, replacement feeding; NA, not available; HR, hazard ratio; CI, confidence interval; MF, mixed feeding (breast milk and other fluids, foods or formula); ddI, didanosine; D4T, stavudine
  • 39. Study location Study design Peripartum ARV Postpartum ARV Sample Infant feeding Choice of Safety: morbid- Effectiveness: and name regimen regimen size options feeding ity and mortality HIV transmission rate (citation) method, and and HIV-free survival adherence to it Abidjan, Côte Open label cohort: ZDV from 36 Mother: none; 373 Antenatal 53% of mothers Probability of a At 6 weeks: 6.5%; at 18 d’Ivoire,ANRS ZDV + single-dose weeks of gesta- infant: single-dose choice: RF or chose FF, of severe event months: FF: 9%; short- 1201/1202 NVP. tion; intrapartum NVP, and ZDV for short-term EBF whom 15% (morbidity) in 2 term BF: 16%. Ditrame Plus oral ZDV + single- seven days. then cessation breastfed at least years: FF infants: Historical control group study, (Becquet et dose NVP at onset between months once; 47% chose 14%; short-term BF given short-course ZDV al. 2005c; Dabis et of labour. 4 and 5. (Infant short-term EBF. children: 15% only, and were breastfed: al. 2005; Becquet formula EBF at 3 months: (adjusted HR 1.19, 6 weeks: 12.8%; 18 et al. 2006; Leroy provided at no 10%; median 95% CI 0.75-1.91, months: 22%. et al. 2008; cost for 9 duration: 4 p=0.44). 18 month HIV-free Becquet et al. months.) months. 18-month probabil- survival: 2007; Leroy et al. Complete ity of survival of FF : 15.8%28 2007) cessation of any 96% for both FF short-term BF: 18.4% BF: in 45% and and short-term BF long-term BF: 24.5% 63% of BF infants. (Similar to Abidjan, Côte Open label cohort: ZDV + 3TC from Mother: ZDV + 3TC 420 Antenatal women] by 4 and the 95% probability At 6 weeks: 4.7%; at 18 d’Ivoire, ANRS ZDV + 3TC + 32 weeks of for 3 days; infant: choice: RF or 6 months, observed in the months: FF: 6%; short- 1201/1202 single-dose NVP. gestation; single-dose NVP, short-term EBF respectively. long-term BF term BF: 7%. Ditrame Plus study intrapartum oral and ZDV for seven (4 months). children of the Historical control group (Becquet et al. ZDV + 3TC + days. historical ANRS exposed to short-course 2005c; Dabis et al. single-dose NVP at Ditrame trial.) ZDV only, and were 2005; Becquet et onset of labour. breastfed: 6 weeks: al. 2006; Leroy et 12.8%; 18 months: 22%. al. 2008; Becquet 18 month HIV-free et al. 2007; Leroy survival: et al. 2007) FF : 12.3% short-term BF: 10.4% HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007 long-term BF: 24.5%
  • 40. Study location Study design Peripartum ARV Postpartum ARV Sample Infant feeding Choice of Safety: morbid- Effectiveness: and name regimen regimen size options feeding ity and mortality HIV transmission rate (citation) method, and and HIV-free survival adherence to it South Africa, the Open label cohort. Single-dose NVP. None. 1372 Promotion of 82.5% of mothers RF was associated Overall contraction of Vertical Transmis- EBF. initiated EBF; with an increased HIV: at 4-8 weeks: 15%; sion Study median duration mortality compared at 6 months: 21.6%. (Coovadia et al. of EBF: 159 days; with EBF (15.12% HIV-free survival: at 6 2007) 40% of women vs. 6.13% at 3 months: 75%; among continued BF to 6 months). infants EBF: at 4-8 months. Mothers weeks: 15%; at 6 with CD4 count months: 16%. <200 were more (Early mixed feeding was likely to use RF. a risk factor.)29 Zvitambo, Zimba- Open label cohort. None. None. 14 110 Promotion of 100% of mothers NA Overall postnatal HIV bwe (Piwoz et al. EBF. initiated EBF. transmission: at 18 2004; Iliff et al. EBF at 3 months: months: 12.1%, 68% 2005; Piwoz et al. 7.6%. occurring after 6 months. 2005) (Early mixed feeding was a risk factor.) HIV-free survival: NA Rwanda and Randomized clinical ZDV + ddI from 36 ZDV + ddI for 7 358 Short-term EBF. Median duration NA HIV infection at 4 weeks: STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDING Uganda, the SIMBA trial: NVP vs. 3TC weeks of gesta- days (mother); NVP of BF: 3.5 months 6.9%; 7.8% at 6 months trials postnatally in tion; intrapartum once daily for 14 (interquartile (difference not statisti- (Vyankandondera breastfeeding oral ZDV + ddI. days then twice range 2.9-5.1 cally significant); et al. 2003) infants born to daily vs. 3TC twice months). transmission rate 2.4% women who daily while between day 3 and 6 received ZDV + ddI breastfeeding months. antenatally and 7 (infant). HIV-free survival: NA days postpartum.
  • 41. Study location Study design Peripartum ARV Postpartum ARV Sample Infant Choice of Safety: Effectiveness: and name regimen regimen size feeding feeding morbidity HIV transmission rate (citation) options method, and and mortal- and HIV-free survival adherence to it ity United Republic of Open label cohort: ZDV + 3TC from ZDV + 3TC (mother and NA BF. Median duration NA 3.4% infection at 6 weeks Tanzania, the Mitra ZDV + 3TC 36 weeks of infant, seven days); 3TC of BF: 20 weeks. and 5.1% at 3 months, trial (Kilewo 2005) (mothers), and 3TC gestation; for 6 months (infant among infants who were (infants). intrapartum oral only). HIV-uninfected at birth. ZDV + 3TC. HIV-free survival: NA Nairobi and Open label cohort and randomized clinical Mother CD4 count: 200- NA Promotion of Trial ongoing. NA NA 3 500/mm3: ZDV + 3TC + Mombasa, Kenya; trial: If CD4 count <200/mm : ART given to EBF. Bobo-Dioulasso, mothers (ZDV + 3TC + NVP); if CD4 count lopinavir & Burkina Faso, the >500/mm3: ARV prophylaxis (ZDV from 34– ritonavir regimen Kesho Bora Trial 36 weeks of gestation until delivery, and beginning at 34-36 weeks30 (Farley & Kesho intrapartum dose of NVP; if CD4 count 200– of gestation until 6 Bora Study Group 500/mm3: ZDV + 3TC + lopinavir & ritonavir months postpartum 2006) regimen, beginning at 34–36 weeks of vs. no regimen. gestation until 6 months postpartum vs. short-course ZDV + NVP regimen beginning at 34–36 weeks of gestation until delivery. Kenya, the Kisumu Phase II, open ART for mothers 6 months of ZDV + 3TC NA Early weaning Study ongoing. Peak of severe NA Study (KIBS) (vant label cohort. from 34 weeks of and NVP for women with from 5.5 event: Hoog et al. 2005; gestation. CD4 counts <250/mm3; months, with diarrhoea Thomas 2007) ZDV + 3TC and nelfinavir BF cessation at after weaning. for women with CD4 6 months. counts above 250. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007
  • 42. Study location Study design Peripartum ARV Postpartum ARV Sample Infant Choice of Safety: Effectiveness: and name regimen regimen size feeding feeding morbidity and HIV transmission (citation) options method, and mortality rate and HIV-free adherence to it survival Rwanda, the Open label cohort. AZT or D4T + 3TC Breastfeeding with ART or FF 425 Early 61% of mothers Study ongoing. HIV transmission at AMATA study and NVP. (formula given at no cost). weaning at 6 chose RF; 39% birth: 1.1%. (Peltier, 2007, months. chose EBF with personal communi- ART. cation) Malawi, the Open label cohort: 1) Single-dose NVP + 7 Mother: 3-drug ARV for 28 827 BF NA Peak of severe NA Breastfeeding three-drug ART for 28 days ZDV and 7 weeks; infant: daily NVP for 28 event: diarrhoea Antiretroviral weeks (mothers) or 2) days 3TC. weeks. after weaning Nutrition Study daily infant NVP for 28 (mainly during (BAN) weeks, or 3) PMTCT only. rainy season).31 (Bramson et al. Women are counseled to 2006; Corneli et al. breastfeed exclusively for 2007; Kourtis 28weeks, followed by 2007) rapid weaning. Mozambique, the Open label cohort: NVP- D4T or ZDV + 3TC Breastfeeding women: continued NA Primarily RF. NA NA HIV transmission DREAM cohort based ART, irrespective and NVP from 24 D4T or ZDV + 3TC & NVP rate 2.7% at 6 (Giuliano et al. of CD4 count. weeks of gestation; regimen until infant weaned, then months. 2007) continued orally stopped ART; single-dose NVP + STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDING intrapartum. 7 days of ZDV (infant). Zambia, the ZEBS Randomized clinical trial. Single-dose NVP. None. 958 Early NA Significantly NA trial (Thea et al. weaning at 4 lower survival 2004; Thea et al. months vs. among HIV- 2006; Kuhn et al. prolonged infected children 2007) breastfeeding weaned at 4 months.
  • 43. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007HIV-infection sulting in similar HIV-free survival in these twoThe clinical trial randomized on infant feeding groups by age 18 months (Thior et al. 2006).practices in Kenya showed that the cumulativeprobability of HIV infection at age two years was Discussion37% in breastfed children and 21% among the Available findings in 2006 on replacement feed-formula-fed arm (p=0.001) (Nduati et al. 2000). ing options show that formula feeding is highlyIn the Mashi trial, HIV infection at age 18 effective in reducing postnatal transmission, butmonths was higher in breastfed children than in its safety depends greatly on the local context informula-fed children despite six months of ZDV which it is implemented. In the Kenya trial andprophylaxis, 9.5% and 6.0%, respectively the ANRS 1201/1202 Ditrame Plus study, re-(p=0.02) (Thior et al. 2006). duction of postnatal transmission outweighed the In the ANRS 1201/1202 Ditrame Plus study risks of adverse events. In Mashi, benefits andin Côte d’Ivoire, the provision of peripartum risks are balanced between infant feeding optionsantiretroviral prophylaxis combined with the with a comparable HIV-free survival at 18promotion of alternatives to prolonged months.breastfeeding considerably reduced MTCT rates In these studies, infant formula was providedwith a long-term benefit sustained until age 18 at no cost for up to 12 months with demonstra-months (Becquet et al. 2007). HIV transmission tion of its safe preparation. The differences be-rates as low as 6.8% and 5.6% at 18 months tween the findings of the Kenya and thewere found in short-term breastfed and formula- Botswana trials have been explained by the factfed children, respectively, whose mothers had that the Kenyan women were urban and hadreceived a peripartum short-course regimen of better access to clean municipal water and prob-ZDV in addition to a single-dose of NVP. , ably a higher socioeconomic status. Other dif- In Kampala, Uganda, 306 children were en- ferences in these contexts could explain theserolled in a programme to prevent MTCT provid- discrepancies and need to be further explored:ing short-course ZDV prophylaxis and access to, and the content and quality of postna-replacement feeding to mothers (Magoni et al. tal follow-up, including nutritional counselling;2005). Transmission rates were 12.0% at month and the characteristics of formula delivery. Fi-six (3.7% in the exclusively formula-fed group, nally, the fact that in both these trials, the in-16.0% in the exclusively breastfed group, and fant feeding choice was allocated by20.4% in the mixed-fed group). No significant randomization is informative in terms of causal-risk difference was observed between the exclu- ity analysis, but this methodological choice raisessive breastfed and the mixed-fed groups. How- other problems that could interfere with infantever, there are no follow-up data to further health if women’s choices are not assessed basedmeasure the long-term outcome of this interven- on acceptability, feasibility, affordability,tion within this context, and there have been sustainability and safety.some methodological concerns. An outbreak of diarrhoeal disease in Botswana showed that replacement feeding is of concernHIV-free survival in such instances: a recent study of infant feed-HIV-free survival at two years was significantly ing practices showed that early weaning was fre-higher in the formula arm compared to the quent even in HIV-negative women and thisbreastfeeding arm in the Kenya trial and in the practice predisposed children to greater morbid-ANRS 1201/1202 Ditrame Plus study compared ity in this outbreak (Creek 2006). Governmentto the ANRS Ditrame historical cohort policy in Botswana is to provide free formula for(Valériane Leroy, personal communication, 25 the infants of all HIV-infected women whoOctober 2006). In the Mashi trial, transmission choose that option, and about 63% of theserates were significantly lower among formula-fed women formula feed. During the outbreak, thechildren, but infant mortality was also higher in number of reported cases of diarrhoea in chil-this group compared to breastfed children, re- dren aged less than five years increased fourfold 32
  • 44. STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDINGfrom between 2004 and 2005 to 2006; and Strategies for HIV-infected women whodeaths from diarrhoeal illnesses of those aged less breastfeedthan five years increased from 24 and 21 reported Several options could be considered to reducein 2004 and 2005, respectively, to at least 532 postnatal transmission in breastfeedingin 2006. These deaths were associated with di- populations. A potential intervention would bearrhoea and malnutrition and followed unusu- the promotion of exclusive breastfeeding duringally heavy rains, in which 25% of patients’ the first six months of life. Another alternativefamilies had overflowing latrines. Among chil- to prolonged breastfeeding consists of shorten-dren hospitalized for diarrhoea, 96% were aged ing the duration of breastfeeding. These two in-less than two years and 93% were not terventions can be combined and constitute anbreastfeeding. When reviewing the records of 20 alternative to prolonged breastfeeding: exclusiveinfants who died after being fed with formula, it breastfeeding with early cessation, which is ex-was found that their mothers reported receiving pected to reduce the cumulative risk of postna-only 51% of the formula they should have re- tal transmission of HIV while retaining theceived before their infant’s illness. In such con- benefits of exclusive breastfeeding during the firstditions, formula feeding may not save lives. months of life. This highlights the need to ensure that mini-mal conditions are in place for safe replacement Exclusive breastfeedingfeeding practices: inter alia, access to clean wa- Improving breastfeeding practices by promotingter; counselling and information on which exclusive breastfeeding and breastfeeding cessa-women can base sound choices during the ante- tion as soon as it is acceptable, feasible, afford-natal period; regular postnatal follow-up (with able, sustainable and safe, in conjunction withrepeated growth measurements) and nutritional lactation management to reduce (sub)clinicalcounselling; an uninterrupted supply of formula mastitis could be effective in reducing postnatal(whether formula is given at no cost or subsi- transmission of HIV (Piwoz et al. 2005).dized) as well as the materials to dispense it. Several studies are completed or currentlyThus, programmes that provide infant formula ongoing in Africa (Côte d’Ivoire, South Africa,on a large scale need to review management dif- Zambia and Zimbabwe) to evaluate the feasibil-ficulties. Further, health staff should be taught ity and acceptability of exclusive breastfeedingthat formula-fed infants are at high risk of mor- for up to six months in HIV-infected women,bidity. They should be shown the clinical signs and its efficacy to decrease postnatal transmis-of diseases and how to intervene in such cases to sion of HIV though breastfeeding. There is con-aid the child. Formula feeding should be proposed sistent evidence from four different studiesonly alongside regular postnatal follow-up to showing a lower postnatal risk in exclusively-adapt the formula to the nutritional requirements breastfed children and those predominantlyof the growing child. In settings where infant breastfed, compared to those who were mixedformula is used widely by HIV-negative women, fed (Tables 2 and 4).the promotion of breastfeeding needs strength- In Zimbabwe, the Zvitambo trial assessed theening in the general population. effect of postpartum vitamin A supplementation, These restrictive and selective conditions serve and provided education and counselling aboutto remind that formula feeding could be an op- infant feeding practices and HIV (Iliff et al.tion to replace breastfeeding but is far from be- 2005). Information on infant feeding practicesing applicable in all settings; thus, the need for and associated infant infections and deaths weremore studies on alternative strategies for prospectively collected. A total of 14 110breastfeeding (e.g. antiretroviral prophylaxis). mother-newborn pairs were enrolled, randomly assigned to a vitamin A-treatment group after delivery, and followed for two years. At baseline, six weeks and three months, mothers were asked 33
  • 45. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007whether they were still breastfeeding, and transmission by age six months in exclusivelywhether any of 22 liquids or foods offered in the breastfed infants who were HIV-negative at fourstudy had been given to the infant. Breastfed to eight weeks of age was about 4% (Coovadiainfants were classified as exclusively or predomi- et al. 2007). This risk was about 11 times highernantly breastfed, or mixed fed. However, one with the introduction of solids and two timeslapse in the exclusivity of breastfeeding at one higher with mixed feeding. Similarly, in theof the three time points was allowed if the non- ANRS 1201/1202 Ditrame Plus cohort, a trendbreast-milk item consumed was not a milk-based for a higher postnatal risk in mixed-fed childrenliquid (e.g. fruit juice). One lapse in predomi- compared to exclusively breastfed infants wasnant breastfeeding was allowed only if the reported (Leroy et al. 2004).mother reported exclusive breastfeeding for the These data support the recommendation,time period. A total of 4495 mothers tested HIV- originally based on other considerations, thatpositive at baseline, and 2060 HIV-exposed in- mixed feeding should be avoided to decrease thefants tested negative through polymerase chain risk of HIV transmission. They also show thatreaction (PCR) at age six weeks. All infants ini- exclusive breastfeeding is possible and acceptabletiated breastfeeding: 156 were exclusively among both HIV-infected and uninfectedbreastfed, 490 predominantly breastfed and women. However, frequent, good-quality coun-1414 received mixed feeding. Overall postnatal selling and support is necessary to achieve hightransmission (defined by a positive HIV test af- rates of exclusive breastfeeding. Among womenter a negative test at six weeks) was 12.1%, with who decide to breastfeed, exclusive breastfeeding68.2% of these transmissions occurring after six should be promoted until six months of age.months of age. Compared with exclusivebreastfeeding, early mixed feeding was associated Early cessation of breastfeedingwith a 4.03 (95% CI 0.98–16.61), 3.79 (95% Following the period of exclusive breastfeeding,CI 1.40–10.29) and 2.60 (95% CI 1.21–5.55) it has been suggested that HIV-infected womengreater risk of postnatal transmission at six, 12 should cease breastfeeding completely. Early ces-and 18 months, respectively. Predominant sation could substantially prevent breastfeeding-breastfeeding was associated with a 2.63 (95% associated HIV transmission, while still providingCI 0.59–11.67), 2.69 (95% CI 0.95–7.63) and the many benefits of breastfeeding in terms of1.61 (95% CI 0.72–3.64) trend towards greater morbidity and mortality prevention during thepostnatal transmission risk at six, 12, and 18 early months of an infant’s life. However, theremonths, respectively, compared with exclusive is little experience on how this early cessationbreastfeeding. can be achieved with a minimum of adverse ef- In the Vertical Transmission Study, high rates fects for the infant. There is also no evidence yetof exclusive breastfeeding were obtained in rural to inform the timing of this cessation. Never-South Africa (Bland et al. 2006). Women will- theless it would be appropriate for many womening to practise exclusive breastfeeding were sup- to do this as soon as replacement feeding be-ported at home by people trained in breastfeeding comes acceptable, feasible, affordable, sustain-counselling, but with no previous health back- able and safe, or at six months of age, whenground. In this context, the median duration of exclusive breastfeeding is no longer adequate toexclusive breastfeeding from birth was five meet an infant’s nutritional needs. As statedmonths, which is elevated in the African con- above, continued support is needed beyond thetext, and adherence to exclusive breastfeeding first six months to ensure adequate nutrition forwas higher than for formula feeding (Bland et the young child throughout the first years of life.al. 2007). Replacement feeding was practised by A clinical trial was conducted in Zambia to8% of the Vertical Transmission Study cohort test the safety and efficacy of exclusiveand was associated with increased mortality com- breastfeeding to four months of age to reducepared with exclusive breastfeeding (15.12% ver- HIV transmission and child mortality (the ZEBSsus 6.13% at three months). The risk of postnatal trial): half of the women were randomly selected 34
  • 46. STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDINGto cease breastfeeding at age four months (Thea could enhance morbidity compared to those chil-et al. 2004), although many women found it dif- dren who are breastfed for a longer period.ficult to stop and continued for longer. This study Indeed, early cessation of breastfeeding beforewas expected to assess the magnitude of reduc- six months was associated with an increased risktion of postnatal transmission associated with of infant morbidity (especially diarrhoea) andearly cessation at four months compared to pro- mortality in HIV-exposed children in preliminarylonged breastfeeding. Early results showed that results from three studies in Kenya, Malawi andbreast-milk viral load increased after early wean- Uganda. These studies included the phase IIIing in this trial. Breast milk was obtained at 22 infant prophylaxis Post-Exposure Prophylaxis forweeks from 222 women who had either stopped Infant (PEPI) trial in Blantyre, Malawior continued to breastfeed past four months. (Kafulafula 2007); the Kisumu Kenya KIBSBreast-milk viral load was measured at 20 and study (van’t Hoog et al. 2005) in which mothers22 weeks in 71 randomly selected women from received ART in the last month of pregnancy andboth groups: breast-milk viral load was detect- for six months postpartum; and the HIVIGLOBable in 68% of those who stopped breastfeeding trial in Kampala, Uganda, a phase II/III study,at four months vs. 42% of those who continued which compared either an infusion of HIVbeyond, p=0.03); median breast-milk viral load hyperimmune globulin (HIVIGLOB) to the(448 copies versus <50 copies HIV-RNA/ml, mother and newborn or six weeks of NVP dailyp=0.005) was significantly higher among those to the infant compared to the HIVNET 012 sin-who had stopped in comparison with those who gle-dose NVP regimen1 (Onyango 2007). In thewere still breastfeeding and was significantly Kenya and Malawi studies there was a signifi-higher in the same women after stopping com- cantly increased risk of diarrhoea-relatedpared with two weeks earlier (p=0.001). It is hospitalizations for the infants whose mothersunclear whether this increase was temporary. stopped breastfeeding by six months comparedBreast-milk viral load is substantially higher af- to historical data where mothers breastfed intoter rapid cessation, and this may pose an in- the second year of life (Kafulafula 2007; Tho-creased risk of HIV transmission if children mas 2007). In addition, in the Malawi PEPIresume breastfeeding after a period of cessation. study there was a significantly increased risk ofIncreases in breast-milk viral load with differing both overall and diarrhoea-related mortality com-degrees of mixed feeding needs to be assessed pared to historical data. In the HIVIGLOB study,(Thea et al. 2006), together with the long-term among 579 uninfected infants there was a dou-efficacy of such an intervention. bling of gastroenteritis hospitalizations in the To be assessed fully, the benefits of early ces- three months following cessation of breastfeedingsation in terms of reduction of postnatal HIV when compared to the three months beforetransmission have to be balanced with their po- breastfeeding stopped; and of the 15 infanttential risks for infant health. Complementary deaths that occurred among uninfected infants,feeding practices are often inadequate in devel- all occurred after cessation of breastfeedingoping countries, resulting in a significant nutri- (Onyango 2007). Early breastfeeding cessationtional decline between six and 18 months of age at four months was associated with reduced HIV(Bhandari et al. 2004). One of the potential ad- transmission but also with increased child mor-verse effects is that if complementary foods were tality from four to 24 months in preliminary datato displace breast milk it would not be nutri- presented from the randomized ZEBS trial intionally appropriate. International guidelines Zambia. Consequently, in this trial, early cessa-stress that from six months breastfeeding should tion of breastfeeding did not improve HIV-freebe coupled with the introduction of nutrition- survival (Kuhn et al. 2007).ally adequate and safe complementary foods(WHO 1998; WHO 2001). Early cessation of 1 One dose of NVP given to the mother at the onset ofbreastfeeding may induce undernutrition if an- labour and one dose of NVP given to the neonate <72other milk source is not available, which in turn hours postpartum. 35
  • 47. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007 The nutritional adequacy of complementary physical growth must be better understood tofeeding was recently assessed in Côte d’Ivoire plan more effective nutrition programmes.among breastfed children exposed tobreastfeeding for a median of four months Heat treatment or pasteurization of expressed(Becquet et al. 2006). After early cessation, breast milkbreastfeeding was replaced by food which met Heat-treated expressed breast milk is a methodnutritional requirements in terms of source of endorsed by WHO to reduce postnatal transmis-milk (e.g. infant formula, baby food), but the sion of HIV. Initial results show that methodsdiversity of diet was not appropriate for the nu- such as Pretoria Pasteurization or Flash Heattritional needs of babies aged six months (e.g. Treatment can effectively inactivate the virus inlacking sufficient protein). Inadequate comple- breast milk from HIV-infected mothers (Jefferymentary feeding at age six months was associ- & Mercer 2000; Israel-Ballard et al. 2006b; Is-ated with impaired growth during at least the rael-Ballard et al. 2007). These methods can alsonext 12 months. However, in this cohort study, eliminate potential contaminants and adequatelywhere regular nutritional counselling was pro- inhibit bacterial growth while retaining nutrientsvided, the nutritional adequacy of complemen- contained in breast milk (Jeffery et al. 2003; Is-tary feeding was then improved to cover the rael-Ballard et al. 2006a). It was recently re-nutritional needs of most of the children at ages ported that heat-treated human milk may be anine and 12 months. As a result, two-year mor- feasible infant-feeding option for HIV-positivebidity was not different in short-term breastfed mothers in Zimbabwe. Yet, its field feasibilityinfants compared to long-term breastfed children now needs to be assessed among HIV-infected(Becquet et al. 2007). women (Israel-Ballard et al. 2006b). It could be More research is needed in this area to pro- useful after a period of exclusive breastfeedingvide practical tools that can be used routinely, in children older than six months. Expressedespecially around the period of cessation, to con- heat-treated breast milk may also have a valu-tribute to the assessment of the nutritional ad- able role as an alternative to breastfeeding dur-equacy of complementary feeding. Such tools ing periods of increased risk, such as mastitis andcould help detect children who are at risk for cracked or bleeding nipples. Pasteurization ofmalnutrition and whose mothers need to receive breast milk seems difficult to implement on aappropriate and reinforced nutritional counsel- large scale, however, and shares some of the sameling. obstacles as replacement feeding – it requires In Burkina Faso, an ongoing study is assess- mothers have access to a developed infrastruc-ing a locally-produced fortified flour formulation ture and safe practices (such as sterilization ofdesigned to meet nutrient and energy needs of materials used in the process), which can be dif-infants among women practising early ficult to achieve in resource-poor settings.breastfeeding cessation in the Kesho Bora study(Cames et al. 2006). It is provided free of cost, Microbicide treatment of expressed breast milkwhile mothers have to pay for cow milk. The Microbicides to treat HIV-infected breast milkfirst results suggest high acceptability among could present an alternative to reduce transmis-mothers who choose either breastfeeding with sion of HIV through breast milk (Urdaneta etearly cessation or replacement feeding. The study al. 2005). It has been reported that alkyl sulfateson mothers’ perceptions of the product, and the (i.e. sodium dodecyl sulfate, SDS) are microbi-infants’ food consumption, growth and morbid- cidal against HIV at low concentrations, are bio-ity is ongoing. degradable, have little or no toxicity and are In addition, a randomized clinical trial in In- inexpensive. Therefore, they may be used fordia showed that improving complementary feed- treatment of HIV-infected breast milk. Humaning practices through an educational programme milk was infected artificially by adding HIV (cell-is feasible, but the effect on physical growth is free or cell-associated); it was then treated withlimited (Bhandari et al. 2004). Factors that limit an SDS dilution d”1% at 37 degrees Celsius or 36
  • 48. STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDINGroom temperature for 10 minutes. SDS was viru- With regard to NVP this exposed infants to thecidal against cell-free and cell-associated HIV in potential for beneficial and adverse effects (e.g.breast milk. Viral load in artificially-infected milk hepatotoxicity) of the drug (Shapiro et al.was reduced to undetectable levels after treat- 2005a). These antiretrovirals suppressed cell-freement with 0.1% SDS. SDS could be removed HIV RNA in breast milk but had no apparentfrom breast milk if necessary, and milk was not effect on cell-associated HIV DNA loads in breastinfectious after SDS removal. The proposed treat- milk (Shapiro et al. 2005b). These facts high-ment concentrations are within reported safe lim- light the need for further research on this issueits for ingestion of SDS by children of 1 g per to fully assess the public health effectiveness andkg/day. This treatment could be helpful to pro- safety of antiretroviral treatment.tect infants from postnatal transmission after sixmonths, where heat treatment is not feasible. Maternal antiretroviral treatment duringThe feasibility, acceptability and safety of SDS breastfeedinghave not yet been studied. ART for pregnant or lactating women is of indis- putable benefit when the mother has a CD4 cellAntiretroviral therapy during breastfeeding count £200/mm 3 or HIV-related symptoms.In addition to replacement feeding, possibilities HIV-infected women who require antiretroviralfor preventing HIV from being transmitted therapy for their own health and arethrough breast milk include ART during breastfeeding should continue to receive it, asbreastfeeding (whether or not necessary for the the benefit to the health of the woman outweighsmother’s health) and post-exposure prophylaxis potential risks to the infant, with a beneficialto the infant. Antiretroviral regimens were re- expected outcome for infant health (Newell etcently designed to provide either maternal treat- al. 2004; WHO 2006).ment, reducing the maternal viral load, or ART to lactating women is expected to sub-post-exposure prophylaxis to the infant during stantially reduce the overall risk of transmissionthe period of breastfeeding, thus maximally re- to infants by lowering viral load in plasma andducing the risk of MTCT in settings where breast milk. Whether it will prevent all, most orbreastfeeding is common (Gaillard et al. 2004). part of postnatal transmission when breastfeeding exposure cannot be avoided mustMaternal antiretroviral prophylaxis be established: will breast-milk HIV viral loadPreliminary data are available from a trial con- be lowered as it is lowered in the blood compart-ducted in Rwanda and Uganda evaluating post- ment? Not only is it crucial to assess the effectexposure antiretroviral prophylaxis in children of these highly-active antiretroviral regimens onduring the breastfeeding period, combined with breast-milk HIV viral load, but also on antiviralthe promotion of early cessation of breastfeeding drug diffusion and pharmacokinetics in both(Vyankandondera et al. 2003). The trial breast milk and in breastfed infants, as well asrandomized newborns in Rwanda and Uganda on transmission of resistant mutations of theto receive either 3TC or NVP from birth until virus. Additional evidence is needed on the safetyone month after their mothers stopped of antiretroviral prophylaxis given to women orbreastfeeding. The duration of breastfeeding was the infant for preventing HIV transmission dur-around three months and the overall six-month ing breastfeeding.transmission rate was estimated to be 7.8% and The optimal duration of antiretroviral prophy-did not differ between these two groups. Long- laxis is unknown, and there are concerns thatterm outcome estimates are still awaited to fully viral rebound following cessation of prophylaxisunderstand the effect of this intervention. may lead to a high risk of MTCT among infants In the Mashi trial in Botswana, it was reported who continue to breastfeed after prophylaxis hasthat antiretrovirals given to breastfeeding moth- stopped; it may also be detrimental to theers (NVP, 3TC and ZDV) were measured in mother. There are limited data about the levelbreast milk in concentrations inhibiting HIV. of penetration of antiretroviral therapies into 37
  • 49. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007breast milk; some drugs may have high levels of ticipants received either: 1) three-dr ugpenetration while others may have low or antiretroviral therapy for 28 weeks (mothers),undetectable levels in breast milk. Therefore the or daily NVP for 28 weeks (infants), or 3) noth-detrimental effects on mother and child cannot ing more than the initial drugs to prevent peri-be established, and the link between drug pen- natal PMTCT. Women were counseled toetration into breast milk and risk of HIV trans- breastfeed exclusively for 28 weeks, followed bymission through breastfeeding has not yet been rapid weaning.established. Data from a study in Botswana in- In the ongoing Kisumu Kenya KIBS phase IIdicated that levels of NVP in breast milk of study, mothers are receiving ART in the lastwomen receiving NVP-based antiretroviral month of pregnancy and for six months postpar-therapy were lower than their plasma, while lev- tum. The DREAM study in Mozambique is alsoels of 3TC and AZT in breast milk were about considering this.threefold higher (Shapiro et al. 2005a). Moreresearch is needed, and is indeed ongoing to ad- Infant prophylaxis during breastfeedingdress these important issues and to guide the Post-exposure prophylaxis (PEP) to the infant isdefinition of comprehensive strategies for both an attractive intervention in breastfeedingthe care of women and prevention of MTCT, women which deserves attention. It has beenwhich are safe and adapted to different contexts. shown to prevent HIV infection after occupa- When a pregnant and/or lactating woman is tional exposure of health-care workers (Panlilionot eligible for ART, the benefit in terms of et al. 2005). The use of NVP perinatally, amount-prophylaxis for postnatal transmission has still ing to ‘peri-exposure’ prophylaxis, approachesto be demonstrated and balanced against the risk post-exposure prophylaxis. Post-exposureof maternal intolerance and/or emergence of prophylaxis can offer protection against HIVantiretroviral drug resistance and safety for the infection to babies of women who missed oppor-baby. It is hypothesized that antiretroviral drugs tunities to be tested and counselled before orgiven to breastfeeding women will reduce the risk during pregnancy. Recent studies in Malawi (Tahaof postnatal transmission of HIV. Several ongo- et al. 2003) showed that neonatal prophylaxising studies are evaluating the effect of single or with short-course NVP and/or ZDV reduced peri-combination antiretroviral regimens given to natal transmission of HIV even when mothersbreastfeeding women and/or the infant to pre- reached the health centre after delivery. Thevent early and/or late postnatal transmission SIMBA trial (Vyankandondera et al. 2003)during breastfeeding. The WHO-coordinated tested two peri-exposure prophylaxis regimensKesho Bora study randomized control trial com- (with no control arm) associated with a short-pared women with CD4 cell counts between ened duration of breastfeeding (three months).200–500/mm3 given a short-course ZDV/NVP Several studies are planned or ongoing in Brazil,regimen beginning at 34–36 weeks versus ART Ethiopia, India, South Africa and Uganda aimed(regimen of ZDV and 3TC + lopinavir/ritonavir at comparing single-dose NVP versus six weeksbeginning at 34–36 weeks) during six months of NVP as peri-exposure prophylaxis. Extendingbreastfeeding (Farley & Kesho Bora Study Group this perinatal PEP for the entire duration of2006). breastfeeding thus seems to be an attractive op- The Breastfeeding Antiretroviral Nutrition tion but its efficacy needs to be assessed. PEP(BAN) study is a prospective randomized con- has several advantages over ART. First,trolled clinical trial of antiretroviral and nutri- antiretroviral drug prophylaxis in an uninfectedtional interventions conducted in the postpartum child carries no risk that the virus will developperiod in Malawi (Bramson et al. 2006). At birth, resistance to antiretroviral drugs (although itmother-infant pairs with mothers whose CD4 would if the infant became infected); second, itcell counts were greater than 200 per ml received spares the mother from treatment when she doessingle-dose NVP and seven days ZDV and 3TC not need it for herself, avoiding the frequent side-to prevent perinatal PMTCT. Further, study par- effects such treatment entails; third, it may be 38
  • 50. STRATEGIES TO REDUCE HIV TRANSMISSION THROUGH BREASTFEEDINGapplicable in a great deal more settings; and fi- tal period are important determinants in mater-nally, it is cheaper. nal choices, and mothers’ adherence to thoseImmunization of breastfed newborns choices; further, improved education will helpAn infant vaccine regimen, begun at birth, would them avoid risky practices of mixed feeding duebe an attractive strategy and might also provide to social pressure. There is a need to train health-the basis for lifetime protection. Unique features care professionals on how to conduct timelyof MTCT and HIV-positive children could be counselling without any coercion (Becquet et al.helpful in understanding correlates of immune 2005b), and how to include antenatal home vis-protection and could facilitate rapid assessment its (Bland et al. 2007).of vaccine efficacy (Luzuriaga et al. 2006). A Mother and child pairs should also have ac-study on acceptability of paediatric vaccine was cess to follow-up care and support, including fam-performed in Kenya, which reported that con- ily planning and nutritional support WHOcerns about side-effects of such interventions are 2006). The longer-term health needs of bothpresent in the population (Farquhar et al. 2006). HIV-infected and uninfected children and theirResearch on this issue is ongoing and urgently mothers, the mortality of children living in fami-needed. The HIVIGLOB trial in Kampala, lies with HIV, and the plight of increasing num-Uganda is a phase II/III study comparing either bers of orphans should not be underestimated.an infusion of HIVIGLOB to the mother and These issues deserve further research and imple-newborn or six weeks of NVP daily to the infant mentation of effective interventions, includingcompared to the HIVNET 012 single-dose NVP monitoring and evaluation for better understand-regimen. ing the impact of those interventions (UNAIDS 2006).Translating research to public health National health services should make special efforts to support primary prevention for HIVrecommendations on infant feeding seronegative women in the antenatal andA key issue concerns the translation of research breastfeeding periods. In situations where moth-findings into practical recommendations: these ers are being screened and identified as HIV-in-depend on several criteria (acceptable, feasible, fected, provision will need to be made for theiraffordable, sustainable and safe) that need to be subsequent care and for that of their infectedcarefully defined according to the context before and uninfected children. Counselling on infantconsidering interventions to prevent postnatal feeding for women known to be HIV-infectedtransmission. The consideration of these crite- needs to be appropriate to their situations. Policy-ria needs to be adapted to each individual con- makers should also consider the effect such coun-text. Bland and colleagues (2007) explored the selling will have on uninfected women and thoserelationship of some of these criteria in provi- of unknown HIV status in the same setting; allsion of feeding options, and adherence by moth- these women should continue to be advised anders to that choice. supported to exclusively breastfeed for the first To help HIV-positive mothers make the best six months (WHO 2001; WHO 2006).choice, they should receive appropriate counsel- Early cessation of breastfeeding among HIV-ling that includes information about both the negative women in some settings seems common,risks and benefits of various infant feeding op- and in these settings breastfeeding promotiontions based on local assessments, and guidance needs strengthening. The Vertical Transmissionin selecting the most suitable option for their Study conducted in South Africa recently showedown situation. Individual women’s choice about it is possible for lay counsellors, with no healthinfant feeding options is highly influenced by background, to help both HIV-infected andsociodemographic factors, including both part- uninfected women make appropriate infant feed-ner or family environment and access to clean ing choices based on their socioeconomic condi-water (Becquet et al. 2005c; Leroy et al. 2007). tions (Bland et al. 2006). The counsellingCounselling and information during the antena- approach used was based on the set of tools de- 39
  • 51. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007veloped by WHO and was effective, in most ity counselling. In clinics offering HIV testingcases, in matching the intention of HIV-infected and counselling to pregnant women (and wherewomen with their resources: access to water, re- formula was furnished to HIV-infected women)frigerator, fuel and regular income. Another is- most HIV-negative women opted for breastfee-sue concerns the effect of providing formula at ding and <1% of infants born to HIV-uninfectedno cost to HIV-infected women in areas of high women received no breast milk at all in their firstHIV prevalence. This South African study week of life. It is therefore possible to put in prac-showed that the ‘spillover’ of suboptimal feed- tice international guidelines on infant feeding ifing practices to HIV-negative women is minimal investment is made in the training of lay coun-if investment is made in provision of high-qual- sellors involved in infant feeding counselling. 40
  • 52. Ongoing or planned research addressing the breastfeeding periodI n 2007 there were new key research priorities on HIV and infant feeding. They are listedbelow. ferent interventions to optimize nutrition, de- velopment and survival among older infants. Antiretroviral therapiesFactors affecting HIV transmission through Research includes: determining the effects of dif-breast milk ferent antiretroviral treatments on timing of HIVThese include: protective and risk factors, in both transmission among breastfeeding women; iden-the absence and presence of antiretroviral drugs; tifying the ways in which antiretroviral drugsfactors affecting early and late transmission; vi- affect the risk factors for HIV transmissionral factors affecting transmission including through breast milk; determining levels ofsubtypes; proportion of transmission occurring antiretroviral drugs in breast milk and in thevia cell-free versus cell-associated virus; evalua- breastfeeding infant; ensuring infant safetytion of immunologic quality of breast milk of through the course of their exposure toinfected women at different disease stages and antiretroviral drugs in breast milk; determiningCD4 cell counts, such as antibody content the efficacy of antiretroviral therapies in reduc-against common pathogens; quantification of risk ing postnatal MTCT, and the effects they haveof MTCT during the transition period from on cell-free and cell-associated viral load; identi-breastfeeding to replacement feeding; evaluation fying the mechanisms through which HIV de-of the risk of postnatal MTCT in women who velops resistance to antiretroviral treatments inseroconvert during lactation. breast-milk; and finally, determining how antiretroviral resistance develops amongEarly cessation of breastfeeding breastfeeding infants who become infected post-Research is ongoing to: determine the conse- natally.quences of cessation of breastfeeding the infantbefore six months of age in terms of morbidity Efficacy and safety for mothers and infantsand mortality; define the optimal time and du- Research is ongoing to: ascertain the efficacy andration of the transition period from breast milk safety of antiretroviral prophylaxis for mothersto replacement formula, as well as the optimal and infants during breastfeeding (currently be-length of breastfeeding; and determine effective ing evaluated in clinical trials); define the effi-interventions to optimize nutrition following cacy and optimal regimen and duration ofbreastfeeding cessation. antiretroviral prophylaxis for mothers and infants during the postnatal period; and to determineTransition from exclusive breastfeeding to the safety of ceasing antiretroviral treatments formixed feeding the mother, when they are being used solely forThese issues include: assessing the risks of prophylaxis.breastfeeding cessation after six months includ-ing postnatal MTCT of HIV, and infant morbid- Role of passive and active immunizationity/mortality during the transition from exclusive strategiesbreastfeeding to breastfeeding with complemen- This includes: researching the potential role oftary foods; determining the optimal time to cease passive and active immunization strategies forbreastfeeding for HIV-exposed uninfected in- HIV prevention; assessing the safety andfants; and the feasibility and effectiveness of dif- immunogenicity of HIV vaccine candidates (in- 41
  • 53. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007fants exposed to HIV, both those that remain or when used temporarily during the transitionuninfected and those who become infected de- period to mixed feeding or during periods ofspite prophylaxis); and determining the efficacy breast pathology, such as mastitis.and safety of passive, active or passive/activeimmunization for prevention of postnatal MTCT. Social factors More research is required on: counselling, pro-Alternatives to replacement feeding gramme implementation and monitoring of in-Alternatives to replacement feeding include strat- fant feeding practices; the social factorsegies to reduce infectivity of breast milk by use influencing maternal decision-making with re-of heat treatment, microbicides, etc. Further ef- gard to infant feeding practices, including part-forts are required to: study the effects of such ner involvement; the optimal level of counselling,interventions on cell-free and cell-associated vi- training, and the assessment of the quality ofrus and milk components; determine the safety, that counselling; the efficacy of community-feasibility, and effectiveness of such interventions based interventions.when used for prevention of postnatal MTCT, 42
  • 54. ConclusionT he most appropriate infant feeding option for an HIV-infected mother depends on herindividual circumstances, including her health tion. The family environment in which the mother lives plays a key role in her choice of feed- ing option.status and the local situation, and should also Early cessation of breastfeeding by HIV-in-consider the health services available and the fected women remains a challenge that needs tocounselling and support she is likely to receive. be addressed. The five criteria (acceptable, fea-Exclusive breastfeeding is recommended for HIV- sible, affordable, sustainable and safe) need toinfected women for the first six months of life be reassessed at the time of early HIV diagnosisunless replacement feeding meets five criteria - in infants and at other times when feeding prac-that it is acceptable, feasible, affordable, sustain- tices may be changing. Evidence now clearlyable and safe - before that time. When these shows that infants who are known to be HIV-conditions are met avoidance of all breastfeeding infected should continue breastfeeding.by HIV-infected women is recommended (WHO It is anticipated that new data will be avail-2006). able in 2008 to help clarify the issue of infant In considering replacement feeding, the fol- feeding in the context of HIV. Current recom-lowing conditions are critical: sustainable access mendations as contained in the Report from theto clean water; regular postnatal follow-up (with 2006 technical consultation (WHO et al. 2007)repeated growth monitoring); nutritional coun- provide the best guidance for preventing post-selling; and drugs and supplies at no cost or at a natal HIV infection and improving HIV-free sur-subsidized price, and with a controlled distribu- vival while awaiting the new data. 43
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  • 65. HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007 54
  • 66. This publication is an update of the review of current knowledge on HIV transmission throughbreastfeeding, with a focus on information made available between 2001 and 2007. It re- HIV Transmission Throughviews scientific evidence on the risk of HIV transmission through breastfeeding, the impactof different feeding options on child health outcomes, and conceivable strategies to reduceHIV transmission through breastfeeding with an emphasis on the developing world. Breastfeeding For further information, please contact: World Health Organization Department of Child and Adolescent Health and Development (cah@who.int) or Department of HIV/AIDS (hiv-aids@who.int) or Department of Nutrition for Health and Development (nutrition@who.int) 20 Avenue Appia, 1211 Geneva 27, Switzerland website: http://www.who.int UNICEF Nutrition Section – Programme Division 3 United Nations Plaza A REVIEW OF AVAILABLE EVIDENCE New York, New York 10017, United States of America 2007 Update Tel +1 212 326 7000 ISBN 978 92 4 159659 6

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