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Home > Topics > Emerging Issues > Transmission of HIV through Breast Milk
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Use of Antiretrovirals to Prevent Transmission of HIV through Breast Milk

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Introduction

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Breast-feeding by HIV-infected mothers confers known risks of HIV transmission to infants. However, it also confers important benefits, and the absence of breast-feeding poses a variety of risks and challenges to infants of HIV-infected mothers. The risks of not breast-feeding range from higher mortality in settings with unpredictable water supply or unsafe sanitation to compromise of confidentiality regarding maternal HIV status. Thus, there is a continued need for new ways to decrease risk of HIV transmission via breast milk while retaining the benefits of breast-feeding. Extending highly active antiretroviral therapy (ART) for the mother or providing ARV prophylaxis for the infant are potentially attractive solutions to that dilemma. In this article, the term "maternal ART" refers to use of maternal highly active ART; it is important to note that this is different from the use of maternal short-course ARV regimens.

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Maternal ART

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In the absence of interventions, the overall risk of mother-to-child transmission of HIV (in utero, peripartum, and via breast-feeding) among HIV-infected mothers who breast-feed is 30-45%, with transmission through breast milk accounting for a substantial proportion (30-50%) of these infant HIV infections. The combination of potent combination ART for the mother during pregnancy and replacement feeding for the infant prevents almost all HIV transmission from mother to infant in developed countries. In resource-limited settings, early studies of short-course ARV regimens (2-4 weeks perinatal, and intrapartum zidovudine [ZDV] or single-dose nevirapine [sdNVP] to the mother, with sdNVP to the infant) demonstrated significant reduction in mother-to-child HIV transmission risk (from 30-45% to approximately 20%).( 1,2,3 ) More intensive ART regimens result in even lower transmission risk. For instance, interventions that include ART for women with advanced immunosuppression, and short-course regimens (ZDV plus sdNVP) for women who are not eligible to receive ART, result in about 6% transmission risk when breast-feeding is stopped near 6 months.( 4 )

Approximate Risk of MTCT for Selected Interventions

 Graph Showing Approximate MTCT for Selected Interventions
*Infant prophylaxis studies measured HIV transmission after birth, in contrast to other estimates in the graph that show overall mother-to-child-transmission risk

Another approach used both in programs and research studies is provision of maternal ART for all women, rather than only immunosuppressed women, continuing during 6 months of breast-feeding. Administering maternal ART until 6 months postpartum has been associated with persistent decreases in levels of HIV RNA in breast milk and was associated with an HIV transmission risk similar to that of replacement feeding (<3%) in a large programmatic observational study in Mozambique.( 5-8 ) However, the range for risk of HIV transmission via breast milk in studies of maternal ART during breast-feeding has been quite variable (~2 to 8%),( 9 ) and there have been concerns that maternal ART for prevention of infant HIV may pose toxicity risks or compromise later treatment efforts as a result of the treatment interruption or development of resistance.( 9 ) Reassuringly, studies of women taking ART for 6-9 months during pregnancy/postpartum in developed or resource-limited countries suggest that levels of safety and adherence are high.( 7 ) In developed countries, women who received ART during pregnancy, after which they stopped ART if it was not indicated for their own health, do not appear to have compromised long-term outcomes.( 10 ) Pending data that confirm the superior safety and efficacy of maternal ART for PMTCT in low-resource settings, programmatic efforts should focus on improving the evaluation of pregnant women's clinical indication for therapy, in order to ensure that all pregnant women who require ART for their own health are receiving and adhering to treatment.

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Infant ARV Prophylaxis

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Published data on infant NVP prophylaxis are limited to studies involving <14 weeks of postpartum infant NVP. Prophylaxis for infants using NVP has been shown to decrease risk of transmission via breast milk,( 11,12 ) without an increase in adverse events (compared with placebo) making prophylaxis an attractive option for protecting infants.( 11,12 ) Kumwenda et al demonstrated that 9-month-old infants who were given extended-dose NVP had a 5.2% rate of HIV infection compared with a 10.6% rate in the control group (p < .001).( 12 )

Graph Demonstrating Infant Prophylaxis while Breast-Feeding

Kaplan Meyer graph of HIV transmission for cohorts receiving infant prophylaxis vs. control
Kaplan Meyer curves of postnatal MTCT risk for infants in PEPI-Malawi. ( 12 )

Infants who become infected with HIV despite prophylaxis may be at risk of developing resistance to NVP; however, the overall benefit to the majority of infants of not acquiring HIV infection likely outweighs that concern. The potential for infant ARV prophylaxis to select resistant strains of HIV in the infant and to compromise later treatment also may apply to maternal ART.( 13 ) Maternal ART may have the additional, though minimal, risk of selecting resistant strains in the mother.
It is difficult to make valid comparisons between maternal ART and infant ARV prophylaxis studies for prevention of late postnatal transmission because of major differences in study designs, duration of interventions, disparate approaches to management of immunosuppressed women and peripartum PMTCT interventions, and age differences among the infants at the time the assessment of HIV transmission is made.

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Other Methods

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Other means of decreasing the risk of transmission through breast milk include treatment of breast milk with inactivation or filtration methods. Inactivation of HIV in breast milk is possible using flash-heat methods.( 14,15 ) These methods preserve the benefits of breast milk but decrease infectivity and do not require the use of ARVs. However, implementation is labor intensive and it requires a sustainable source of fuel; both these factors may be barriers to uptake. Pilot studies are under way to determine feasibility, and subsequent efficacy studies will be needed. A nipple shield intended to inactivate HIV without heat also has been described. Such a filtration method may be more feasible than flash-heat inactivation; however, development of the technology is still in process. Although these approaches do not require the use of ARVs, feasibility is major limiting factor.

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Breast-Feeding Duration

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Exclusive Breast-Feeding

Image of woman breastfeeding her baby from the Testing and Counseling for Prevention of Mother-to-Child Transmission Tools
Image from TC for PMTCT Support Tools

Given the many protective benefits of breast-feeding, preserving these benefits for as long as possible is attractive, if the risk of HIV transmission via breast milk can be reduced. Cessation of breast-feeding at or before 6 months has not been associated with increased mortality risk in some settings in Africa (eg, Ivory Coast, Botswana, and Kenya).( 4,16,17 ) However, studies in other settings have shown that early cessation of breast-feeding is associated with increased morbidity and growth compromise during the period after breast-feeding cessation at 6 months.( 18 ) A recent study in Zambia noted comparable risk of HIV-free survival among infants who underwent abrupt early breast-feeding cessation at 6 months and those who breast-fed for indefinite duration (typically longer than 1 year), but increased mortality rates among HIV-infected infants who stopped breast-feeding early.( 19 )

Potential interventions to reduce the risk of HIV transmission through breast milk while continuing breast-feeding beyond 6 months include extended maternal ART or extended infant ARV prophylaxis. However, data on these interventions after 6 months postpartum are limited. It is plausible that transitioning to stop breast-feeding around 6 months may be more safely facilitated by using heat-inactivated breast milk. Use of this fairly cumbersome technique may be feasible for a limited, short-term period.

Confidentiality is another potential consideration for mothers as they decide whether to breast-feed and for how long. For the many women who do not inform their communities or even their partners of their HIV status, avoiding breast-feeding might reveal their HIV status and subject them to violence or stigma.

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What Now?

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For health care providers and policy makers, the evidence for new interventions to preserve the option of breast-feeding by HIV-infected women is expanding, but it remains insufficient for recommending infant prophylaxis or maternal ART throughout extended lactation beyond 6 months. Research on preventing HIV transmission through breast milk has focused on the first 6 months postpartum, and in this period it is not clear whether maternal ART is more effective than tiered treatment that includes ART to immunosuppressed women and combined short-course ZDV/NVP to ART-ineligible women. Ongoing studies should soon provide data to help resolve these issues.

For women who do not meet the criteria of having acceptable, feasible, affordable, safe, and sustainable (AFASS) alternatives to breast-feeding, extending maternal ART or infant prophylaxis is an attractive option given increasing availability of ARVs and the relatively time-limited period of interventions (18-24 months), particularly if research data can be extrapolated to estimate risk vs benefit. Modeling studies using data from previous trials may provide such information more quickly than new trials of extended duration. At the same time, it is important to note that several studies in Africa have demonstrated minimal HIV transmission or infant mortality when breast-feeding is stopped at 6 months. Better implementation of AFASS guidelines and support for mothers between 6 and 24 months postpartum may allow women to safely stop breast-feeding, which would require neither prolonged maternal ART nor infant prophylaxis.

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Conclusions

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With tiered combined interventions (ART for women who meet criteria for treatment, breast-feeding cessation at 6 months, and combined short-course ZDV/NVP for women who are not ART eligible), mother-to-child transmission risk is approximately 6%.( 4 ) Current evidence suggests minimal or no benefit of replacement feeding compared with this combined approach during the first 6 months of breast-feeding.( 7,16 ) Ongoing and planned studies have been designed to determine whether 6-month maternal ART during pregnancy and during breast-feeding for all women incrementally reduces the risk of HIV transmission via breast milk when compared with the tiered combined short-course ARV regimen, and to compare the efficacy of maternal ART with infant ARV prophylaxis. Notably, several of these studies do not address breast-feeding risk beyond 6 months. At 6 months, careful consideration of AFASS criteria for ending breast-feeding should be combined with a more aggressive programmatic approach (including growth monitoring, nutrition and hygiene counseling, and infection prevention) to optimize infant survival rates between 6 and 24 months. For situations in which AFASS criteria are not met, ongoing and planned studies to determine the efficacy of extended infant or maternal ART will be important and may help to identify additional interventions to reduce mother-to-child-transmission in resource-limited settings.

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References

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  1. Wiktor SZ, Ekpini E, Karon JM, et al. Short-course oral zidovudine for prevention of mother-to-child transmission of HIV-1 in Abidjan, Côte d'Ivoire: a randomised trial. Lancet. 1999 Mar 6;353(9155):781-5.
  2. Shaffer N, Chuachoowong R, Mock PA, et al. Short-course zidovudine for perinatal HIV-1 transmission in Bangkok, Thailand: a randomised controlled trial. Bangkok Collaborative Perinatal HIV Transmission Study Group. Lancet. 1999 Mar 6;353(9155):773-80.
  3. Guay LA, Musoke P, Fleming T, et al. Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: HIVNET 012 randomised trial. Lancet. 1999 Sep 4;354(9181):795-802.
  4. Tonwe-Gold B, Ekouevi DK, Viho I, et al. Antiretroviral treatment and prevention of peripartum and postnatal HIV transmission in West Africa: evaluation of a two-tiered approach. PLoS Med. 2007 Aug;4(8):e257.
  5. Chung MH, Kiarie JN, Richardson BA, et al. Highly active antiretroviral therapy versus zidovudine/nevirapine effects on early breast milk HIV type-1 Rna: a phase II randomized clinical trial. Antivir Ther. 2008;13(6):799-807.
  6. Lehman DA, Chung MH, John-Stewart GC, et al. HIV-1 persists in breast milk cells despite antiretroviral treatment to prevent mother-to-child transmission. AIDS. 2008 Jul 31;22(12):1475-85.
  7. Palombi L, Marazzi MC, Voetberg A, et al. Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV. AIDS. 2007 Jul;21 Suppl 4:S65-71.
  8. Shapiro RL, Ndung'u T, Lockman S, et al. Highly active antiretroviral therapy started during pregnancy or postpartum suppresses HIV-1 RNA, but not DNA, in breast milk. J Infect Dis. 2005 Sep 1;192(5):713-9.
  9. Mofenson LM. Antiretroviral prophylaxis to reduce breast milk transmission of HIV type 1: new data but still questions. J Acquir Immune Defic Syndr. 2008 Jul 1;48(3):237-40. Review.
  10. Watts D, Mofenson L, Lu M, et al; Women and Infants Transmission Study. Treatment interruption after pregnancy and disease progression: A Report from the Women and Infants Transmission Study. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 751.
  11. Bedri A, Gudetta B, Isehak A, et al. Six Week Extended-Dose Nevirapine (SWEN) Study Team. 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 Jul 26;372(9635):300-13.
  12. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med. 2008 Jul 10;359(2):119-29.
  13. Stringer JS, Chi BH. Extended nevirapine prophylaxis to prevent HIV transmission. Lancet. 2008 Jul 26;372(9635):267-9.
  14. Chantry CJ, Morrison P, Panchula J, et al. Effects of lipolysis or heat treatment on HIV-1 provirus in breast milk. J Acquir Immune Defic Syndr. 2000 Aug 1;24(4):325-9.
  15. Israel-Ballard K, Donovan R, Chantry C, et al. Flash-heat inactivation of HIV-1 in human milk: a potential method to reduce postnatal transmission in developing countries. J Acquir Immune Defic Syndr. 2007 Jul 1;45(3):318-23.
  16. Thior I, Lockman S, Smeaton LM, et al; Mashi Study Team. 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 Aug 16;296(7):794-805.
  17. Nduati R, Richardson BA, John G, et al. Effect of breastfeeding on mortality among HIV-1 infected women: a randomised trial. Lancet. 2001 May 26;357(9269):1651-5.
  18. Thomas T, Masaba R, van Eijk A, et al. Rates of diarrhea associated with early weaning among infants in Kisumu, Kenya. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 774. Available at: http://www.retroconference.org/2007/Abstracts/29105.htm
  19. Kuhn L, Aldrovandi GM, Sinkala M, et al; Zambia Exclusive Breastfeeding Study. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med. 2008 Jul 10;359(2):130-41.
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For further reading on ARV toxicity in infants, breast health, and ARV concentrations and viral load suppression in breast milk see the previous Emerging Issues topic: Antiretroviral Treatment, Breast-Feeding, and Mother-to-Child Transmission of HIV

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