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Discussion

Overview

In resource-limited settings, HIV-infected mothers of HIV-uninfected infants often confront a difficult dilemma with regard to infant feeding: breastfeeding risks transmitting HIV to their infants, but formula feeding may not be a viable option due to high cost, lack of clean water, or stigma associated with not breastfeeding. Fortunately, recent clinical studies have established that HIV-infected mothers can breastfeed with minimal risk of HIV transmission to their infants, as long as the mother and the infant receive appropriate antiretroviral prophylaxis.

Epidemiology of HIV Acquisition from Breastfeeding

In the absence of any antiretroviral prophylaxis for either the mother or the infant, the risk of HIV transmission from mother to infant is 30 to 45% for breastfeeding infants and 15 to 30% for infants who are not breastfed (Figure 1)[1]. Globally, up to 40% of HIV infections in infants have resulted from breastfeeding[2]. The risk of HIV transmission is highest in the first few months of breastfeeding[3,4,5], but risk continues throughout the breastfeeding period; infants who are breastfed the longest have the highest risk of acquiring HIV[6,7]. Both maternal factors (high HIV viral load, mastitis, or maternal illness) and infant factors, such as oral candidiasis, can increase the infant's risk of acquiring HIV from breastfeeding[1,8].

Mortality and Morbidity in Non-breastfed Infants in Resource-limited Settings

Formula feeding, as a replacement for breastfeeding, reduces the risk of HIV transmission to infants of HIV-infected mothers, but it is associated with high morbidity and mortality rates in resource-limited settings[9,10,11,12,13,14]. The increased mortality associated with formula feeding in these settings is likely due to the absence of key breast milk-associated antibodies that provide protection against infectious diseases. In addition, the water used for formula preparation may be contaminated, resulting in severe gastrointestinal infections. Furthermore, infant formula may not be affordable, and formula feeding in some settings may carry a social stigma and imply that the mother is infected with HIV. For these reasons, the WHO guidelines endorse formula feeding over breastfeeding only in situations where six specific conditions are met (Figure 2)[15].

Extended Daily Infant Nevirapine to Prevent HIV Transmission via Breastfeeding

Although single-dose nevirapine given to the infant is effective in preventing peripartum and early breastmilk transmission of HIV, its effect does not extend beyond the first few weeks of life[16]. Several studies have evaluated longer-term daily nevirapine prophylaxis given to the infant, and all show that extended nevirapine prophylaxis for breastfeeding infants is more effective than single-dose nevirapine in reducing both HIV infection and infant mortality, particularly for those infants whose mothers are not receiving antiretroviral therapy. Extended infant nevirapine has been studied for 6 weeks (Figure 3)[17], 14 weeks (Figure 4Study Title and SourceInfection During 1st YearsDeath During 1st YearsInfection or Death)[18], and 6 months (Figure 5Study Title and SourceProbability of InfectionProbability of Infection or Death)[19]; the benefit to the infants continued for as long as nevirapine was given. Extended zidovudine, alone or in combination with nevirapine, is also effective at reducing HIV transmission, but has been associated with high rates of infant anemia and neutropenia[11,18]. For breastfeeding infants of HIV-infected mothers not receiving a triple antiretroviral drug regimen, the WHO therefore recommends the use of daily nevirapine from birth and until 1 week after all exposure to breast milk has ended (or for a minimum of 4 to 6 weeks if breastfeeding ceases prior to 6 weeks)[20]. Antiretroviral prophylaxis recommendations for infants of mothers receiving a triple-drug antiretroviral regimen are discussed below.

Maternal Antiretroviral Drugs to Prevent HIV Transmission via Breastfeeding

Multiple studies have established that administration of a triple-drug antiretroviral regimen to HIV-infected pregnant women who breastfeed reduces the risk of HIV transmission to their infants[19,21,22,23,24,25,26]. This finding applies to women who meet antiretroviral therapy eligibility criteria based on low CD4 count and/or advanced HIV disease, as well as to women with less advanced HIV disease who do not meet antiretroviral therapy eligibility criteria. The success of this approach derives from the effectiveness of triple-drug antiretroviral regimen in reducing maternal serum and breast milk HIV viral load, the strongest determinants of HIV transmission via breast milk[9]. Rates of transmission are lowest when women initiate drugs early in pregnancy[27], underscoring the importance of promoting early antenatal care and prompt HIV diagnosis and management during pregnancy. The most impressive results were seen in the Mma Bana ("mother of the baby") study (Figure 6), where prophylaxis began as early as the second trimester and the overall rate of HIV transmission was 1.1%[24]. The HIV transmission rates in most other studies of triple-drug antiretroviral prophylaxis, where antenatal prophylaxis was not initiated until mid-to-late third trimester, have ranged from 5 to 8% (Figure 7). If the HIV-infected mother is breastfeeding and receiving a triple-drug antiretroviral regimen only for prophylaxis (e.g., she doesn't require treatment for her own health) and plans to stop the regimen after breastfeeding cessation, she should continue the antiretroviral drugs until 1 week after all infant exposure to breastmilk has ended.

Antiretroviral Prophylaxis for Infants of Mothers Receiving Triple-Drug Regimens

Administration of daily nevirapine or twice-daily zidovudine to the infant is recommended for the first 4 to 6 weeks of life, even if the mother is receiving a triple-drug antiretroviral regimen for treatment or prophylaxis. Infant antiretroviral prophylaxis is particularly important in infants of mothers who either received no antepartum antiretroviral drugs or started drugs late in pregnancy: nevirapine or zidovudine given directly to the infant provides prophylaxis against HIV that might persist in the mother's breast milk due to insufficient maternal exposure to antiretroviral drugs prior to delivery. Continuing the infant prophylaxis beyond 6 weeks when the mother is receiving a triple-drug antiretroviral regimen does not appear to provide any additional benefit[28].

Importance of Exclusive Breastfeeding

Exclusive breastfeeding, in which the infant receives no supplemental fluids or foods apart from breast milk during the first 6 months of life, is associated with a lower risk of HIV transmission from breast milk when compared with mixed feedings[29,30]. It is hypothesized that mixed feedings disrupt the integrity of the gut endothelium, and facilitate HIV entry via the gastrointestinal tract[31]. Current WHO Guidelines therefore recommend that HIV-infected mothers of infants who are not HIV-infected (or whose HIV status is unknown) should avoid mixed feedings. Mothers should instead exclusively breastfeed for the first 6 months of life, gradually introducing mixed feedings thereafter, while continuing to breastfeed for the first 12 months of life "or until a nutritionally adequate and safe diet without breast milk can be provided"[14].

Importance of Breastfeeding for at Least 1 Year

Previous guidelines endorsed weaning infants from breast milk by 6 months of age in order to reduce the risk of HIV transmission, but clinical studies (Figure 8) and (Figure 9) have subsequently established that, in resource-limited settings, weaning infants at 4 to 6 months of age is associated with marked increases in mortality, hospitalizations, and growth compromise [11,32,33]. The WHO breastfeeding guidelines therefore recommend that after exclusively breastfeeding for 6 months, infants should continue to breastfeed for the first 12 months of life. Since rapid weaning has also been associated with HIV transmission and mastitis[35], weaning should take place gradually over 1 month. For infants and mothers who are on antiretroviral prophylaxis to prevent HIV transmission, the antiretroviral drugs should continue for 1 week following complete weaning[15]. Mothers who are receiving antiretroviral therapy for maternal health (antiretroviral treatment is indicated) should continue to do so for life.

Use of Heat-treated, Expressed Breast Milk

The WHO has endorsed heat-treated, expressed breast milk as an interim feeding strategy that may enable women to continue breastfeeding under certain conditions. Heat treatment of breast milk inactivates HIV, but does not adversely affect the nutritional quality of breast milk[36]. The use of heat-treated expressed breast milk as a temporary strategy to continue breastfeeding without putting the infant at risk may be considered under certain circumstances, such as low birthweight newborns who cannot breastfeed, women with conditions that may temporarily interrupt breastfeeding (such as mastitis), women whose supply of antiretroviral therapy or prophylaxis is interrupted, or as an adjunct to weaning practices[15]. Under these circumstances, infants should continue nevirapine prophylaxis since they will be consuming breastmilk.

Current WHO Recommendation for Breastfeeding HIV-Infected Mothers

The WHO has issued recommendations for feeding of infants born to HIV-infected mothers[14] and for the use of maternal and infant antiretroviral prophylaxis to prevent HIV transmission from HIV-infected mothers to their infants who are breastfeeding[20]. The key points of these recommendations are summarized as follows:

  • Mothers known to be HIV infected should exclusively breastfeed their infants for the first 6 months of life, introducing complementary food thereafter, and continue breastfeeding for the first 12 months of life. Breastfeeding should then only stop once a nutritionally adequate and safe diet without breast milk can be provided.
  • Mothers known to be HIV infected that decide to stop breastfeeding at any time should stop gradually over a 1-month period.  Abrupt weaning is not advisable.  Mothers or infants who have been receiving antiretroviral prophylaxis should continue prophylaxis for 1 week after breastfeeding has completely stopped. Mothers receiving antiretroviral therapy for their own health should continue their antiretroviral therapy regimen.
  • When an HIV-infected mother decides to stop breastfeeding, the infant should be provided with safe and adequate replacement feeds to enable normal growth and development. For infants less than 6 months of age, commercial infant formula (if WHO safe formula feeding criteria are met) or expressed heat-treated breast milk are considered acceptable. Animal milk is not recommended as a replacement food in the first 6 months of life. For children older than 6 months of age, commercial infant formula or boiled animal milk are acceptable. Meals should include complementary foods and should be provided 4 to 5 times per day.
  • If infants are known to be HIV infected, mothers are strongly encouraged to exclusively breastfeed for the first 6 months of life and continue breastfeeding as per the recommendations for the general population, that is, up to 2 years or beyond.
  • If antiretroviral prophylaxis is not available (for example, in an emergency situation), or health services are unavailable, women with HIV or unknown status are strongly encouraged to breastfeed their children.
  • The infant prophylaxis will depend on whether the mother is eligible to receive antiretroviral therapy for her own health, or, if the mother does not need treatment for her own health, the mother’s antiretroviral regimen used to prevent mother-to-child transmission—WHO Option A or Option B (Figure 10Title Slide and SourceMother Eligible for TreatmentMother does not Need Treatment: Option AMother does not Need Treatment: Option B[20]:
    • Mother eligible for treatment for her own health: If the mother received antiretroviral therapy for her own health during the pregnancy and delivery (and will continue on antiretroviral therapy), the infant should receive daily nevirapine or twice daily zidovudine from birth until 4 to 6 weeks of age, irrespective of the mode of feeding.
    • Mother does not need treatment for her own health—Option A: If the mother received zidovudine monotherapy antepartum for preventing mother-to-child transmission, the breastfeeding infant should receive daily nevirapine for a minimum of 4 to 6 weeks and until 1 week after all exposure to breast milk has ended. Infants receiving replacement feeding only should receive daily nevirapine or single dose-nevirapine plus twice-daily zidovudine from birth until 4 to 6 weeks of age.  
    • Mother does not need treatment for her own health—Option B: If the mother received a triple-drug antiretroviral regimen during pregnancy (and continues this regimen post-partum if she breastfeeds), the infant should receive daily nevirapine or twice daily zidovudine from birth until 4 to 6 weeks of age, irrespective of the mode of feeding.
  • The nevirapine (Figure 11) and zidovudine (Figure 12) dosing for the infant is based on the birth weight and age of the infant.

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  • The following link will open in a new window.
    Figure 1. Risks and Timing of HIV Transmission in Breastfeeding versus Non-breastfeeding Infants

    This figure shows the timing and absolute rates for mother-to-child HIV-1 transmission among breastfeeding and non-breastfeeding HIV-1 infected mothers. The superscript numerals in the figure denote the following: (1) Detection of HIV-1 RNA or DNA in infant blood less than 48 hours after delivery diagnostic of in utero transmission; (2) Detection of HIV-1 RNA or DNA in infant blood 48 hours–14 days after birth consistent with in utero, intrapartum, or early breast milk transmission; (3) Detection of HIV-1 RNA or DNA in infant blood 14 days–1 month after birth most consistent with intrapartum or breast milk transmission; (4) Infants with negative HIV-1 RNA assays at 1 month of age who subsequently have positive assays most likely to be infected via breast milk; (5) Infants with negative HIV-1 RNA assays at 14 days of age who subsequently have positive assays most likely to be infected intrapartum.

    Source: Lehman DA, Farquhar C. Biological mechanisms of vertical human immunodeficiency virus (HIV-1) transmission. Rev Med Virol. 2007;17:381-403.
    This figure reproduced with permission from John Wiley & Sons Copyright © 2007.


    Figure 1
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    Figure 2. WHO Safe Formula Feeding Criteria (formerly known as the <em>AFASS</em> criteria).

    Source: World Health Organization. Guidelines on HIV and infant feeding. 2010. Principles and recommendations for infant feeding in the context of HIV and a summary of evidence. WHO, Geneva, 2010.


    Figure 2
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    Figure 3. SWEN Study: Risk of HIV Infection or Death at 6 weeks, 14 weeks, and 6 Months of Life

    The SWEN study in Ethiopia, India, and Uganda compared extended infant nevirapine prophylaxis for 6 weeks with single-dose nevirapine and found significant improvement in HIV-free survival at multiple time points among infants receiving 6 weeks of nevirapine. At each of three time points assessed (6 weeks, 14 weeks, and 6 months of age), there was a lower cumulative probability of death or HIV transmission in the infants receiving extended-dose nevirapine when compared to infants receiving only single-dose nevirapine.

    Source: Six Week Extended-Dose Nevirapine (SWEN) Study Team, Bedri A, Gudetta B, et al. Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials. Lancet. 2008;372:300-13.
    This figure reproduced with permission from Elsevier (© 2008 Elsevier limited).


    Figure 3
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    Figure 4: Post-Exposure Infant Prophylaxis (PEPI-Malawi) Study. Image 1. Study Title and Source.<br />

The PEPI study in Malawi compared standard treatment with single-dose nevirapine and one week of zidovudine with extended nevirapine for 14 weeks or extended nevirapine plus zidovudine for 14 weeks. At 9 months of age, infants in the extended prophylaxis groups were half as likely to be HIV infected.
    Figure 4 (series)

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    Figure 5: Effectiveness of Maternal Postpartum HAART and Infant Nevirapine in Reducing HIV Transmission: the BAN Study. Image 1. Study Title and Source
    Figure 5 (series)
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    Figure 6. Mma Bana Study: Virologic Responses of Different Regimens at Birth and During Breast-Feeding Period

    Mma Bana Study in Botswana started HIV positive mothers on antiretroviral therapy from 26 to 34 weeks gestation and continued antiretroviral therapy during breastfeeding. This figure shows that greater than 90% of women on all antiretroviral therapy regimens had undetectable plasma HIV viral RNA levels throughout the 6 months of breastfeeding. This high level of maternal virologic suppression was associated with a very low overall HIV transmission rate to infants of 1.1%.

    Source: Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-feeding in Botswana. N Engl J Med. 2010;362:2282-94.
    This figure reproduced with permission from the Massachusetts Medical Society. Copyright © 2010 Massachusetts Medical Society. All rights reserved.


    Figure 6
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    Figure 7. Overall and postnatal transmission of HIV at 6 months across studies of infant and maternal ARV prophylaxis

    This figure shows overall HIV transmission rates at 6 months in infants in trials of 6-month infant nevirapine (green) or maternal triple drug (orange) prophylaxis regimens. Most residual transmission rates are in the 5% range. The highest transmission rate is in mothers receiving triple drugs in the BAN study, where no antenatal drugs were received. The lowest rate of 1% is in mothers receiving triple drugs started early in the second trimester. All of the other triple drug prophylaxis studies show rates between 5 to 8%. Looking solely at postnatal transmission after birth, the studies suggest a residual 2 to 3% risk of postnatal infection despite postnatal maternal or infant prophylaxis.

    Source: This figure is courtesy Lynne M. Mofenson, Chief, Pediatric, Adolescent and Maternal AIDS Branch, Center for Research for Mothers and Children, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health.


    Figure 7
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    Figure 8. The MASHI Study

    The MASHI study compared HIV transmission and survival among formula-fed infants with infants who were breastfeeding and receiving extended ziodvudine prophylaxis for 6 months. Breastfeeding with ziodvudine prophylaxis was less effective than formula feeding for preventing postnatal HIV transmission, but was associated with significantly lower early mortality (although 18 month mortality was comparable between the two study arms). Both strategies had comparable HIV-free survival at 18 months. The MASHI study underscored again that formula feeding may increase infant mortality in resource-limited settings.

    Source: Thior I, Lockman S, Smeaton LM, et al. Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study. JAMA. 2006;296:794-805.


    Figure 8
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    Figure 9. Mortality Associated with Early versus Delayed Weaning Among HIV-Exposed Infants

    In a secondary analysis of a randomized clinical trial of short-course v. extended infant prophylaxis, HIV-exposed, uninfected infants who were still breastfeeding at 6 months were compared to those who were weaned early. Excess mortality was associated with early weaning when compared with weaning at 15 months of age or older.

    Source: Taha TE, Hoover DR, Chen S,et al. Effects of cessation of breastfeeding in HIV-1-exposed, uninfected children in Malawi. Clin Infect Dis. 2011;53:388-95.
    Reproduced with permission from Oxford University Press.


    Figure 9
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    Figure 10: WHO-Recommended Maternal and Infant Antiretroviral Therapy Prophylaxis for HIV-Infected Pregnant Women in Resource-Limited Settings. Image 1. Title Slide and Source
    Figure 10 (series)

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    Figure 11. Infant Nevirapine Dosing

    Source: World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: recommendations for a public health approach. – 2010 version. WHO, Geneva, 2010.


    Figure 11
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    Figure 12. Infant Zidovudine Dosing

    Source: World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: recommendations for a public health approach. – 2010 version. WHO, Geneva, 2010.


    Figure 12