This publication is an update of the review of current knowledge on HIV transmission throughbreastfeeding, with a focus on...
HIV TransmissionThrough Breastfeeding  A Review of Available Evidence         2007 Update
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007WHO Library Cataloguin...
Table of contentsPreface                                                                             vAcknowledgements    ...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007     Modifying infant ...
PrefaceT    his Review was originally prepared as a back     ground paper for the Technical Consulta-tion on HIV and Infan...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007months. There was no d...
AcknowledgementsT    his review was updated by Valériane Leroy     (INSERM U593, Institut de SantéPublique, Epidémiologie ...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007                      ...
GlossaryART, an abbreviation for antiretroviral therapy,           Complementary food means any food, wheth-  is a combina...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007Lamivudine, or 3TC, is...
Executive summaryB      reastfeeding is best for infants, and      is an effective method of reducing the riskof common ch...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007transmission through b...
IntroductionD      espite substantial progress in reducing child       morbidity and mortality and promotingfamily health ...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007   Prevention of MTCT ...
Mother-to-child transmission of HIVHIV infection in women                                   Rates of, and risk factors for...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007TABLE 1. Estimated abs...
MOTHER-TO-CHILD TRANSMISSION OF HIV   Early randomized clinical trials from 1998 in        six to eight weeks, in comparis...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007nation antiretroviral ...
HIV transmission through                        breastfeedingT     ransmission of HIV through breastfeeding      has been ...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007Risk of postnatal tran...
HIV TRANSMISSION THROUGH BREASTFEEDINGbodies. There is no evidence to suggest that               load in plasma. Of note, ...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007TABLE 2. Estimated rat...
HIV TRANSMISSION THROUGH BREASTFEEDING  In conclusion, the rate of late postnatal trans-               HIV infection, when...
HIV TRANSMISSION THROUGH BREASTFEEDING: A REVIEW OF AVAILABLE EVIDENCE - AN UPDATE FROM 2001 TO 2007of CD4 cell count abov...
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
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Hiv transmission thru breastfeeding
Hiv transmission thru breastfeeding
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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
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Hiv transmission thru breastfeeding
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Hiv transmission thru breastfeeding

  1. 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. 2. HIV TransmissionThrough Breastfeeding A Review of Available Evidence 2007 Update
  3. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
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