Prevention of human immunodeficiency virus-1 transmission to the infant through breastfeeding: new developments

Article Outline

• Abstract
• Biology of breastfeeding transmission of HIV to the infant
  • Virology
  • Immunology
  • Role of mucosal factors
• General feeding recommendations in resource-limited settings
• Approaches to decrease mother-to-child HIV transmission during breastfeeding
• Current clinical trials
• Antiretroviral intervention studies
• Immune strategies to reduce the risk of transmission during breastfeeding
• Other studies on exclusive breastfeeding
• The Future
• References
• Copyright

Breastfeeding accounts for up to half of all infant human immunodeficiency virus (HIV) infections worldwide and carries an estimated transmission risk of about 15% when continued into the second year of life. Because replacement feeding is not safely available, culturally acceptable, or affordable in many parts of the world and because breastfeeding provides protection against other causes of infant mortality, approaches that reduce breastfeeding mother-to child transmission of HIV are being explored. These include exclusive breastfeeding for the infant’s first few months of life followed by rapid weaning, treatments of expressed milk to inactivate the virus, and antiretroviral prophylaxis taken by the infant or mother during breastfeeding, which are strategies currently being tested in clinical trials. Passive (antibodies) and active (vaccine) immunoprophylaxis will also soon begin to be tested. This paper focuses on current and planned research on strategies to prevent breastfeeding transmission of HIV.

Key words: breast milk, human immunodeficiency virus, infant, prevention, transmission

Currently about 800,000 children become infected with human immunodeficiency virus type 1 (HIV) every year through mother-to-child transmission (MTCT); 90% of these children live in resource-limited countries.¹ Breastfeeding transmission accounts for about one third to one half of all HIV transmission from mothers to their infants in resource-limited settings in which breastfeeding into the second year of life is the norm.², ³, ⁴, ⁵

A number of studies have documented the risk of transmission per month of breastfeeding and cumulative risk after the first 1-2 months of age. Data from Malawi², ⁶ found a risk of 0.6-0.7% per month in the first year of life from months 1 to 12 and 0.3% per month in the second year of lactation. Some studies suggested that the highest risk of breast milk transmission of HIV is in the immediate neonatal period.⁷, ⁸ A more recent metaanalysis suggested a more constant risk of about 0.9% per month after the first month of life.⁹ There is limited information on risk of transmission during the early weeks of life, due in part to the difficulty in differentiating early breast milk transmission from intrapartum transmission.

Two studies have been able to estimate postpartum transmission based on differences in transmission between mothers who breast fed and those who used formula from birth.¹⁰, ¹¹ Both studies demonstrated a very high risk of transmission for the breastfed, compared with the formula-fed infant in the early weeks of life: 6.3% difference in the risk of transmission in the randomized trial in Nairobi from birth to 6 weeks (or about 1% per week) and about 5.6% difference in the South African study over an 8-week period (or about 0.7% per week).¹⁰, ¹¹ In contrast, in the Mashi trial, in which infant prophylactic zidovudine was used during breastfeeding, no difference in the risk of HIV transmission to the infant at 1 month was detected in the formula-fed (5.0%) and breastfed infants (4.6%).¹²

Risk factors for postnatal transmission include higher deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) viral load in milk and plasma⁸, ¹³, ¹⁴; decreased maternal CD4 cell count; increased maternal illness severity, mastitis and breast milk stasis¹⁵, ¹⁶, ¹⁷; thrush and other infant coinfections; type of infant feeding (exclusive breastfeeding [EBF] versus mixed feeding [MF])¹⁸, ¹⁹; longer duration of breastfeeding⁹; and maternal seroconversion or HIV-1 superinfection during lactation.²⁰, ²¹

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Biology of breastfeeding transmission of HIV to the infant 

Virology 

HIV is detected in both the liquid phase of breast milk and in breast milk cells.¹⁵, ²² Free virus can be derived from blood, or it can be produced by local replication in macrophages and in ductal and alveolar mammary epithelial cells.²³ Evidence of HIV compartmentalization between blood and breast milk has been conflicting.²⁴, ²⁵ HIV is detected in the breast milk of HIV-infected mothers at varying frequencies across studies (39-89%)⁷, ⁸; intermittent shedding and differences in viral load between the 2 breasts have been noted by several investigators.²⁶, ²⁷ The concentration of HIV in cell-free breast milk is generally lower than that in plasma by 1-2 logs.⁷ Studies have shown that breast milk viral load is highest immediately after birth⁸ and that both clinical and subclinical mastitis are associated with increased viral loads in breast milk.¹⁶, ²⁶, ²⁷, ²⁸

Recently a 3-fold increase in transmission was demonstrated for every 10-fold increase in cell-free or cell-associated viral load in breast milk⁸, ²⁹; however, no lower threshold for transmission could be determined. Cell-associated virus was found to be a stronger predictor for HIV transmission to the infant than cell-free virus.²⁹, ³⁰ Recent evidence also indicates that highly active antiretroviral therapy (HAART), started during pregnancy or postpartum, suppresses HIV RNA,³⁰, ³¹ but not DNA, in breast milk.³⁰ In fact, part of the efficacy of the peripartum single-dose nevirapine (sdNVP) regimen may be attributable to its effects in lowering breast milk viral loads early during lactation.³²

Emerging data on the pharmacokinetics of antiretroviral agents in breastfeeding mothers indicate that nevirapine (NVP), zidovudine (ZDV), and lamivudine (3TC) achieve HIV inhibitory concentrations in the breast milk (similar or higher than those of serum) and that NVP in addition achieves inhibitory concentrations in the serum of breastfed infants.³³ These data suggest that a maternal regimen may be sufficient to provide prophylaxis from breastfeeding transmission to the infant but also that adverse effects of antiretroviral (ARV) therapy (toxicities, development of resistance) could theoretically be seen among breastfed infants exposed to them.

Immunology 

Breast milk contains a multitude of antimicrobial and immunomodulatory factors, including lactoferrin, lysozyme, fibronectin, mucin, lipids, epidermal growth factor, interleukin (IL)-1β, IL-6, IL-8, and IL-10, transforming growth factor (TGF)-β, secretory leukocyte protease inhibitor (SLPI), defensins, adhesion molecules, selectins, and chemokines.³⁴, ³⁵, ³⁶, ³⁷, ³⁸ These soluble factors have diverse effects on HIV; some have in vitro anti-HIV activity (SLPI, lactoferrin, regulated upon activation, normal T cell expressed, and secreted, interferon-γ, α- and β-defensins) and others have proinflammatory activity that might promote local HIV replication (IL-6, IL-8, IL-1β, tumor necrosis factor-α). HIV-specific antibodies have been detected in the breast milk of HIV-infected mothers, predominantly of the immunoglobulin (Ig) G isotype.³⁹ Often the specificity of IgG and IgA HIV antibodies in the breast milk differs from that of antibodies in the serum of the same person.²⁴

Breast milk also contains a large number of lymphocytes, macrophages, and other mononuclear cells (ranging from 10⁵ to 10⁷/mL in colostrum and declining up to 10-fold during the subsequent 2-3 months of lactation). The breast milk lymphocytes have an activated phenotype⁴⁰, ⁴¹, ⁴² and express chemokine receptors and mucosal homing markers such as CD103 in high frequency. They thus seem to bear a mucosal phenotype and are thought to migrate to the breast from distant mucosal sites such as the gastrointestinal or genital tract. The macrophages in the breast milk are distinct in their phenotypic characteristics.⁴³ IL-4–stimulated breast milk macrophages express DC-SIGN, a dendritic cell receptor for HIV. Recent findings indicate that HIV virions captured by dendritic cell-specific ICAM-3 grabbing nonintegrin (DC-SIGN) may be transmitted more efficiently through the gastrointestinal tract,⁴⁴ suggesting a role in transmission to the infant.

Role of mucosal factors 

Two nonrandomized studies from southern Africa have suggested that type of infant feeding has a substantial effect on the risk of postnatal HIV transmission from mothers to their infants. Both studies presented observational data suggesting that exclusive breastfeeding is associated with a lower risk of transmission than mixed feeding (breastfeeding and other liquids or solids) among HIV-infected mothers. First, Coutsoudis et al¹⁷ in South Africa found that at 6 months of age, there was a substantially lower risk of transmission among infants who had been exclusively breastfed during the first 3 months, compared with infants who had received mixed feeding. Recent data from the Zvitambo trial in Zimbabwe found that exclusive breastfeeding in the first 3 months of life was associated with only a 1.3% risk of transmission from 6 weeks to 6 months, which is significantly lower than the transmission risk of 4.4% associated with mixed feeding.⁴⁵

Possible explanations for this finding include damage to the intestinal mucosa from early introduction of other foods, leading to the delayed closure of the enterocyte junctions in the intestinal mucosal barrier or intestinal immune activation from early introduction of foreign antigens or pathogens, both mechanisms that can enhance transmission of HIV to the infant.⁴⁶ Similar to the structure of intestinal epithelia, tight junctions form barriers between adjacent epithelial and endothelial cells in the mammary gland that restrict passage of serum components into milk.⁴⁷ Mammary epithelial permeability is increased during the immediate postpartum period and during weaning⁴⁸ as well as during periods of inflammation such as mastitis, when pericellular sodium and albumin can move into breast milk, resulting in elevated levels of these compounds in breast milk.⁴⁷, ⁴⁸ Infrequent breast emptying, such as might occur with nonexclusive breastfeeding, may increase the risk of ductal inflammation and mammary permeability and may also lead to subclinical mastitis and a higher risk of HIV transmission to the infant.

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General feeding recommendations in resource-limited settings 

Prevention of HIV transmission through breastfeeding should be considered against a backdrop of promoting appropriate feeding for all infants and young children. According to current World Health Organization recommendations, infants should be exclusively breastfed for the first 6 months of life to achieve optimal growth, development, and health. Thereafter infants should receive nutritionally adequate and safe complementary foods while breastfeeding continues up to 24 months or beyond.⁴⁹

However, given the need to reduce the risk of HIV transmission to infants and minimizing the risk of other causes of morbidity and mortality, the guidelines also state that “when replacement feeding is acceptable, feasible, affordable, sustainable, and safe, avoidance of all breastfeeding by HIV-infected mothers is recommended. Otherwise, exclusive breastfeeding is recommended during the first months of life” and should then be discontinued as soon as it is feasible. This would normally imply the same conditions as for replacement feeding from birth, that is, acceptable, feasible, affordable, sustainable, and safe.⁴⁹

For most HIV-infected mothers in resource-limited settings, breastfeeding remains the only feasible and sustainable option, given a societal context of unsafe water and unsanitary or nutritionally deficient home-modified animal milk substitutes, cultural norms for mothers to breastfeed with the risk of stigmatization if not breastfeeding, and prohibitive costs of breast milk substitutes.

For an individual HIV-infected mother, balancing risks and benefits is complex. Mothers should receive counseling that includes information about both the risks and benefits of various infant feeding options based on local assessment and guidance in selecting the most suitable option for their situation. The above recommendations on infant feeding and HIV are the same, whether or not the women receive ARV regimens for their own health. Women receiving ARV drugs for their own health who are breastfeeding should continue their ARV regimen. Currently World Health Organization–recommended ARV prophylactic regimens for women who do not need HAART for their own health are based on a short antepartum, intrapartum, postpartum, and postnatal component. The short postpartum and postnatal components are mainly designed to reduce the risk of developing maternal resistance to sdNVP and as a postexposure prophylaxis regimen for the child.

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Approaches to decrease mother-to-child HIV transmission during breastfeeding 

Exclusive replacement (formula) feeding is the most widely used and effective method to prevent MTCT of HIV-1 through breastfeeding in resource-rich settings²⁷ and is recommended in situations in which this is acceptable, feasible, affordable, sustainable, and safe.⁴⁹ In the United States, obstetricians/gynecologists counsel their HIV-infected patients not to breastfeed and to use formula feeding instead. However, in many resource-constrained settings, the above conditions are rarely all met. Based on findings from the studies mentioned above, exclusive breastfeeding for a few (3-6) months with rapid weaning has been advocated as a strategy that balances optimal nutritional source for the infant’s first few months of life with lessening the risk of MTCT of HIV. This approach is currently being evaluated in a number of clinical trials.

Recently concerns have arisen that early weaning of HIV-exposed infants may increase infant morbidity and mortality. For example, two studies from Malawi and Kenya have noted spikes in gastroenteritis in the 2-3 months following weaning at around 6 months of age, and the Kenya study has also noted increased rates of failure to thrive and growth faltering of infants following weaning.⁵⁰, ⁵¹ Results from the MASHI study demonstrated a near doubling of infant mortality at 7 months in infants who were formula fed from birth when compared with those who were breastfed and received ZDV prophylaxis for 6 months; at 12 months, overall HIV-free survival was comparable between the 2 infant-feeding strategies.⁵² If these findings concerning the deleterious effects of early weaning are further substantiated, alternative strategies including the need for an effective perinatal vaccine or other strategies that would allow breastfeeding safely throughout the first year of life will be emphasized.

Subclinical mastitis is associated with higher breast milk HIV viral copy number and MTCT of HIV.¹⁵, ¹⁶, ¹⁷ This condition has been shown to be common among HIV-infected, breastfeeding women in Malawi,⁵³ Zambia,²⁸ and Zimbabwe.⁵⁴ It has been hypothesized that mastitis might contribute to transmission in such populations and that empiric treatment for the condition might play a role in the prevention of MTCT. A recent study in Zimbabwe, however, demonstrated that empiric treatment of HIV-infected, breastfeeding women with amoxicillin/clavulanate did reduce breast milk leukocyte counts but was accompanied by only a small reduction in breast milk viral load at 4-12 weeks.⁵⁵

Health care providers should counsel breastfeeding, HIV-infected women about the proper breastfeeding technique, treat clinical mastitis with antibiotics, and expressing and discarding breast milk from the affected breast while also continuing feeding from the unaffected breast, and treating infant oral thrush or nipple candidiasis with nystatin. The efficacy of these methods in reducing MTCT, however, has not been formally assessed.

Poor maternal nutritional status has been shown in observational studies to be associated with the increased risk of HIV disease progression and MTCT of HIV.⁵⁶ Low maternal serum vitamin A levels have been associated with increased breast milk viral load²¹ and MTCT of HIV.⁵⁷, ⁵⁸, ⁵⁹ However, clinical trials of prenatal vitamin A supplementation have shown no effect on MTCT of HIV,¹⁷, ⁶⁰ with at least 1 study showing an increase in transmission.⁶¹ Similarly, a singe large dose of vitamin A postpartum was shown to have no effect on HIV transmission and in fact may increase mortality in infants who remained HIV negative at 6 weeks.⁶² An ongoing study in Malawi (the Breastfeeding Antiretrovirals Nutrition [BAN] trial) is currently assessing the value of maternal calorie, protein, and micronutrient supplementation during breastfeeding in preventing maternal wasting and the postnatal transmission of HIV to the infant.

Inactivation of HIV in breast milk by either chemical means or heat has also been proposed as a means of preventing breastfeeding MTCT of HIV. A preclinical study of treating breast milk with sodium dodecyl sulphate has shown some promise.⁶³ Boiling or pasteurization of breast milk appears to decrease HIV infectivity of milk.⁶⁴, ⁶⁵ Pretoria pasteurization, in which breast milk in a glass jar is placed in boiling water for 12-15 minutes, is a simple method for maintaining breast milk at 56-62.5°C by heat transfer.⁶⁶ This method, which can be done in the home has been shown to reduce bacterial contamination of unrefrigerated breast milk for up to 12 hours.⁶⁷

There is also some evidence that Pretoria pasteurization can inactivate HIV in breast milk.⁶⁵, ⁶⁸ In a small study in Cote d’Ivoire,⁶⁹ 76% of women felt breast milk pasteurization would be an acceptable way to reduce transmission of an infectious disease to the infant if a convenient method could be found for pasteurization. The effects of such pasteurization on MTCT and on other biological components of breast milk and the feasibility of the method’s widespread uptake in real-world settings is unknown but faces obvious obstacles, given cultural norms and logistical barriers.

The antimalarial agent chloroquine and its hydroxyl analogue have in vitro activity against HIV-1 replication and against several acquired immunodeficiency syndrome (AIDS)-related opportunistic microorganisms.⁷⁰, ⁷¹ Chloroquine also tends to concentrate in breast milk, with the highest concentration appearing in breast milk cells.⁷² Given that this drug is inexpensive, widely available, and has a low toxicity profile in prophylactic doses, it might have potential as a means of reducing HIV transmission to the breastfeeding infant. However, preliminary work has not shown a significant effect of chloroquine on breast milk virus loads⁷³ in the dosage used.

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Current clinical trials 

Several peripartum strategies including short-course ZDV,⁷⁴, ⁷⁵, ⁷⁶ short-course ZDV/3TC,⁷⁷ or the use of sdNVP⁷⁸, ⁷⁹ given to mothers at labor and to their newborns have demonstrated a substantial reduction in the risk of perinatal HIV transmission. The use of combination short-course antiretroviral drugs appears to have a synergistic effect in lowering the risk of transmission. Studies from Thailand and France, respectively, demonstrated that the combined use of either short-course ZDV from 28 weeks of gestation plus sdNVP⁸⁰ or ZDV plus 3TC from 32 weeks⁸¹ can reduce transmission to about 2% among non–breastfeeding women, which is similar to rates achieved in the United States and Europe with the use of HAART. In breastfeeding settings, however, the risk of transmission remained substantially higher.¹⁰, ⁴⁵, ⁷⁵, ⁷⁷, ⁷⁹

Reducing the risk of HIV transmission during lactation in a safe manner for HIV-infected women in resource-limited settings who opt to breastfeed remains 1 of the major challenges facing perinatal HIV researchers, policy makers, and HIV-infected mothers in resource-limited settings.

Several current or planned randomized trials are designed to test strategies aimed at reducing the risk of transmission during the breastfeeding period. These include using antiretroviral drugs given to either the mother or infant during lactation; using passive and/or active immune strategies given to mothers and/or their infants; or assessing various infant feeding and weaning methods. The trials are summarized in the Table and will be presented here.

TABLE. Summary of ongoing or planned trials for prevention of mother-to-child transmission of HIV through breastfeeding

For further information on some of these clinical trials, please see http://www.clinicaltrials.gov.

NFV, nelfinavir; LPV/rv, lopinavir/ritonavir; Trizivir, zidovudine/lamivudine/abacavir; sd, single dose; MVit, multivitamin supplement; MAbs, monoclonal antibodies; NRTI, nucleoside reverse transcriptase inhibitors; PI, protease inhibitors.

Depending on maternal CD4 count.

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Antiretroviral intervention studies 

Several clinical trials investigating the role of antiretroviral drugs during breastfeeding to mothers or infants to reduce MTCT of HIV are ongoing. The Breastfeeding Antiretrovirals Nutrition (BAN) study is a randomized, phase III, 2 × 3 factorial clinical trial of 2400 mother-infant pairs evaluating the effect of a maternal nutritional supplement and antiretroviral prophylaxis during 6 months of exclusive breastfeeding followed by rapid weaning. All mothers and infants receive the perinatal sdNVP regimen plus a week of postpartum/postnatal ZDV/3TC. The antiretroviral regimens tested include a combination maternal regimen (ZDV/3TC/lopinavir/ritonavir) or daily infant NVP during breastfeeding vs standard of care. Only mothers with a CD4+ T cell count greater than 200/mm³ are enrolled. Outcomes include infant HIV infection at 6 and 12 months, maternal weight loss during breastfeeding, infant survival at 12 months, and the feasibility of exclusive breastfeeding for 6 months followed by rapid weaning.

Second, the Kisumu Breastfeeding Study (KiBS) in Kisumu, Kenya, is a phase II single-arm, open-label clinical trial using ZDV, 3TC, and nelfinavir or NVP (depending on CD4+ count) beginning at 34 weeks of gestation and continuing until 6 months postpartum. In addition to safety, end points include cumulative infant HIV infection risk at 6 weeks, 9 months, and 18 months and infant HIV-free survival at 24 months. Target sample size is 520 mother-infant pairs.

Third, the Kesho-Bora study (Swahili for a better future) is a phase III, randomized, open-label clinical trial comparing ZDV, 3TC, and lopinavir/ritonavir beginning at 28 weeks of gestation through 6 months of breastfeeding to short-course ZDV (also beginning at 28 weeks) and sdNVP at labor among HIV-infected women with CD4 counts between 200 and 500 cells/mm³ at enrollment. The infant receives sdNVP and a week of ZDV. This multinational clinical trial is taking place in Burkina Faso, Kenya, and may also include a site in South Africa. End points include HIV-free infant survival at 6 weeks and 12 months, maternal AIDS-free survival, and incidence of serious adverse events in both mother and infant. The target sample size is 1000 mother-infant pairs.

Fourth, the Post-Exposure Prophylaxis for Infants (PEPI-Malawi) trial in Blantyre, Malawi, is a phase III, randomized clinical trial comparing 3 different regimens of antiretroviral drugs given to infants of HIV-infected breastfeeding mothers. The control arm receives sdNVP and 1 week of ZDV. The 2 intervention arms both receive the control regimen but then receive NVP alone or NVP/ZDV for 14 weeks thereafter. End points include infant HIV infection rates (at various points up to 24 months), HIV-free survival rates (at 6, 12, 18, and 24 months), safety, and tolerability. The target sample size is 3500 mother-infant pairs.

Fifth HIV Prevention Trials Network (HPTN) 046 is a multisite, phase III, blinded, randomized clinical trial in Uganda, Zimbabwe, Tanzania, and South Africa with a planned enrollment of 1576 mother-infant pairs. This trial will provide either daily NVP prophylaxis or placebo to infants during breastfeeding through their first 6 months of life. Mothers and newborns will receive the background standard prevention regimen used at each site, such as sdNVP or short-course ZDV, and some mothers will be receiving HAART for their own treatment.

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Immune strategies to reduce the risk of transmission during breastfeeding 

The first strategy, an ongoing trial in Uganda, which is a 3-arm phase II/III trial (HIV immune globulin [HIVIGLOB]), is assessing the possible protective effect of an HIV hyperimmmune globulin product given as an infusion to mothers at 36-37 weeks of gestation and to the newborn; in another arm NVP is given daily to the newborn for 6 weeks. Safety and HIV transmission rates in both arms will be compared with those for sdNVP. Data from the HIVIGLOB 6-week infant NVP prophylaxis arm will be pooled with data from trials in Ethiopia and India, which are also looking at the relative efficacy of 6 weeks of infant NVP prophylaxis, compared with sdNVP. The sample size enrolled across the 3 sites is 2222 (Table).

Second, a planned phase I/II trial in South Africa will assess the use of monoclonal antibodies for the prevention of postpartum mother-to-child HIV transmission.⁸², ⁸³, ⁸⁴

Third, in Uganda, a phase I trial (HPTN 027) with a sample size of 50 evaluable infants is an ongoing trial looking at the safety of a perinatal HIV vaccine candidate using a canary pox vector (ALVAC-HIV vCP1521), which is given to infants as 4 injections during the first 3 months of life. If the data suggest this product to be safe and immunogenic, then a phase II/III trial would be the next step to evaluate whether the vaccine could allow mothers to breastfeed safely through the first year of life.

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Other studies on exclusive breastfeeding 

All of the current trials described above are in the background of recommendations for EBF followed by early weaning at around 3-6 months postpartum. The PROMISE for Exclusive Breastfeeding (EBF) research consortium is running a randomized trial of the safety and efficacy of EBF promotion by peer-counselors among both HIV-uninfected and infected mothers in Burkina-Faso, Uganda, Zambia, and South Africa. The plan is to add, in a factorial design, the assessment of 3TC given to the child during the breastfeeding period. All HIV-infected mothers will have received 1 month of ZDV and sdNVP. ZEBS, an ongoing study in Zambia, is addressing whether abrupt vs gradual weaning has a lower risk of transmission.⁸⁵

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The Future 

There are still significant gaps in our understanding of how HIV is transmitted to the infant through breastfeeding, such as whether cell-free or cell-associated virus is the primary mode of transmission and characterizing the immunologic and other properties in breast milk, which help protect most breastfed infants from such transmission despite daily exposure. It is recommended that HIV-infected women should be advised not to breastfeed in parts of the world in which safe substitutes for breast milk exist, but the ideal strategy for the developing world is less clear.

Exclusive breastfeeding for 6 months, followed by rapid weaning, has been advocated as a measure to reduce breastfeeding transmission of HIV and is currently being evaluated in clinical trials. However, the balance of risk and benefit for the health, development and survival of the infant and the implementation of this strategy in many resource-limited settings needs to be carefully assessed, given social and cultural practices as well as the economic and logistic challenges. Furthermore, if the current or planned trials demonstrate efficacy of maternal combination antiretroviral treatment or infant antiretroviral prophylaxis during breastfeeding, operational challenges of implementing these programs widely in resource-limited settings will need to be addressed. If antiretroviral drugs for both maternal therapy and prevention of MTCT become more widely available and are demonstrated to be safe, efficacious, and cost effective, extended breastfeeding with antiretroviral prophylaxis could indeed be considered for as long as the mother wishes to breastfeed.

Pharmacokinetic and safety information of newer antiretroviral agents for nursing mothers and their infants that have less potential for resistance (such as tenofovir) should be encouraged. Finally, passive and ideally active immunization, alone or in combination with peripartum antiretroviral regimens, might be a good future approach to protect breastfed infants from HIV transmission. Support for and completion of the above described research needs to receive high priority if we are to conquer this remaining challenge in prevention of mother-to-child HIV transmission and reduce the number of pediatric HIV infections worldwide.

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