JAIDS Journal of Acquired Immune Deficiency Syndromes:
Antiretroviral Prophylaxis to Reduce Breast Milk Transmission of HIV Type 1: New Data but Still Questions
Mofenson, Lynne M MD
From the 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, Rockville, MD.
Received for publication April 23, 2008; accepted April 24, 2008.
The opinions in this manuscript are those of the author and do not necessarily represent the views of the National Institutes of Health or US Department of Health and Human Services.
Reprints: Lynne M. Mofenson, MD, 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, 6100 Executive Boulevard, Room 4B11 Rockville, MD 20852 (e-mail: LM65D@nih.gov).
Over the past 2 decades, considerable strides have been made in the prevention of mother-to-child HIV-1 transmission. Effective interventions are now available that can reduce in utero and intrapartum mother-to-child HIV-1 transmission even in resource-limited settings.1-3 However, a significant challenge in such settings is transmission of HIV-1 through breast-feeding. In sub-Saharan Africa, where 90% of HIV-1-infected children live, acquisition of HIV-1 through breast milk accounts for as much as 40% of new infections-more than 150,000 new infections annually.4,5
The only method to eliminate the risk of breast-feeding-associated HIV-1 transmission is not to breast-feed; this is recommended in settings in which infant replacement feeding is affordable and sustainable, clean water is widely available, hygiene and sanitation conditions are good, and deaths due to diarrhea and other infectious diseases are relatively uncommon. However, this approach is not feasible or safe in many resource-limited countries because of cost, inadequate replacement foods to meet the nutritional needs of the infant, unsafe water supply, and/or low acceptability due to stigma associated with no breast-feeding.6 In such resource-limited settings, infants of HIV-1-infected mothers who are not breast-fed are at high risk for mortality and morbidity, which can outweigh the risk associated with HIV-1 infection itself.7-10
Thus, there has been a critical need to identify strategies to prevent HIV-1 transmission by breast-feeding. Exclusive breast-feeding has been shown to lower the risk of postnatal HIV-1 transmission compared with mixed feeding but does not eliminate risk.11,12 Two potential prevention strategies under study in resource-limited settings are provision of antiretroviral drugs to infants exposed to HIV-1 during breast-feeding and provision of combination antiretroviral therapy to lactating women.13,14
Several open-label observational studies have provided important suggestive evidence that infant prophylaxis is safe and may reduce breast milk HIV-1 transmission. The Mitra study in Tanzania, published in this issue of Journal of Acquired Immune Deficiency Syndromes, evaluated the provision of a short regimen of zidovudine (AZT) and lamivudine (3TC) regimen to the mother from 36 weeks gestation to 1 week postpartum, combined with 1 week AZT/3TC to the infant, followed by administration of daily 3TC to the infant during breast-feeding for a maximum of 6 months.15 The cumulative infection rate was 3.8% at 6 weeks and 4.9% at 6 months of age. The authors note that the infection rate at age 6 months in the Mitra infants was significantly lower than that observed in breast-feeding infants enrolled in an earlier perinatal trial, the Petra study, in which the same AZT/3TC regimen was given to mother and infant but without extended infant 3TC prophylaxis (overall transmission was 11.9% at age 6 months in Petra).16 However, the populations are not completely comparable as the median duration of breast-feeding in infants in Mitra was only 18 weeks, whereas the median duration of breast-feeding in the Petra study was 28 weeks.15,16 Most women in Mitra reportedly exclusively breast-fed, whereas mixed feeding was more likely in Petra. Because the rate of transmission at birth was not assessed in Mitra, only late postnatal transmission between 6 weeks and 6 months (1.2%) can be extrapolated from the data provided.
The SIMBA study, presented only in abstract form, evaluated a similar short maternal regimen of AZT combined with didanosine (ddI), with infants randomized to receive either daily nevirapine (NVP) or daily 3TC during breast-feeding for up to 6 months.17 This study reported an overall rate of transmission of 6.9% at 1 month and 7.7% at 6 months. Although these overall rates are higher than reported in Mitra, the postnatal transmission rate in infants uninfected at birth was 1.6% between birth and 1 month and the late postnatal transmission between 1 and 6 months of age was 0.8%, similar to the 1.2% in Mitra. No significant differences in postnatal transmission were observed between infant nevirapine or 3TC regimens. Like the Mitra study, the median duration of breast-feeding in SIMBA was relatively short, 14 weeks, and most women (87%) reported exclusive breast-feeding.
Finally, the Mashi study in Botswana compared infants who were formula fed and received 1 month of daily AZT with infants who were breast-fed and received 6 months of daily AZT (all mothers received AZT starting at 28 weeks gestation with or without single-dose NVP).7 Overall infection rates at age 7 months were 5.6% in the formula-fed and 9.0% in the breast-fed infants. In breast-fed infants who were uninfected at birth, the early postnatal infection rate between birth and 1 month was 1.3% but the later postnatal infection rate between age 1 month and 7 months was 4.4%, higher than observed in the Mitra and SIMBA infant prophylaxis studies. The median duration of breast-feeding was not reported in the paper, but mothers were instructed to wean at age 5 months (20 weeks); mixed feeding was more common in Mashi (49% of mothers at 3 months were mixed feeding). All 3 of these studies lacked a concurrent control group of infants who were breast-feeding but not receiving the intervention.
Two randomized, controlled clinical trials were recently reported that definitively demonstrate the safety and efficacy of infant prophylaxis to reduce postnatal HIV-1 transmission. The Six-Week Extended Nevirapine (SWEN) study, a combined analysis of similar studies in Ethiopia, Uganda, and India, compared single-dose maternal/infant NVP with single-dose NVP plus extended daily infant NVP from age 1 through 6 weeks.18 In contrast to the observational studies previously discussed, no maternal antenatal therapy was received. Among infants who were uninfected at birth, there was a 46% decrease in the relative risk of postnatal infection at age 6 weeks (transmission rate 2.5% in the extended NVP vs 5.3% in the single-dose NVP arm); however, by age 6 months, diminished efficacy (only a 20% decrease in the relative risk of postnatal infection) was observed (6.9% vs 9.0% in extended vs single-dose NVP arm). Mixed feeding was common (51% of women reported mixed feeding at week 14); most infants weaned between 14 weeks and 6 months of age. The Post-Exposure Prophylaxis to the Infant (PEPI) trial in Malawi evaluated a somewhat longer regimen of infant prophylaxis, comparing a control regimen of single-dose maternal/infant NVP combined with 1 week of infant AZT to two experimental regimens which combined the control regimen with either 14 weeks of extended daily infant NVP or extended NVP/AZT19; similar to SWEN, no antepartum maternal antiretroviral drugs were received. Among infants who were uninfected at birth, there was a 66% decrease in postnatal infection in both extended arms at age 14 weeks (transmission rate 2.8% in both extended arms vs 8.4% in control arm) and at age 6 months, efficacy remained 60% in the extended NVP arm and 40% in the extended NVP/AZT arm (4.0% and 5.2% in extended NVP and NVP/AZT arms vs 10.1% in control arm). Significant efficacy persisted through age 18 months in the extended NVP arm. Most infants weaned between 6 and 9 months of age. Adverse events were similar in control and experimental arms in both studies.
Direct comparison of the Mitra, SIMBA, Mashi, SWEN, and PEPI-Malawi studies is difficult; in addition to geographic differences, there were differences in maternal treatment (Mitra and SWEN having 4 weeks of maternal antepartum, intrapartum, and 1 week postpartum dual therapy and Mashi having 12 weeks of maternal AZT, whereas only maternal single-dose NVP was given in SWEN and PEPI-Malawi), duration of breast-feeding (shortest in the Mitra and SIMBA studies and longest in PEPI-Malawi), the extent of exclusive breast-feeding, and duration of infant prophylaxis. However, together, they provide definitive evidence through both observational studies and randomized clinical trial that infant prophylaxis can reduce postnatal transmission. It should be noted that maternal antenatal therapy, in addition to reducing in utero and intrapartum transmission, may reduce the extent of early postnatal transmission in the first month of life, as the early postnatal infection rates (between birth and age 4-6 weeks) in SWEN and PEPI-Malawi, where mothers did not receive antepartum drugs, are almost twice that in the SIMBA and Mashi studies.
Concerns have been expressed regarding the potential development of antiretroviral drug resistance among infants who become infected despite postnatal infant prophylaxis. Preliminary data from the Mitra study found resistance mutations to 3TC in 4 of 4 infected infants tested.15 In the SWEN study, infants who became infected during the period of infant prophylaxis almost universally had virus with NVP resistance mutations; however, infants who became infected after the period of infant prophylaxis was completed were more frequently infected with wild-type virus.20 Whether the extended NVP plus AZT regimen in the PEPI-Malawi study will reduce NVP resistance in infants infected despite prophylaxis is not yet known but under study.
The use of maternal highly active antiretroviral therapy (HAART) during lactation has also been discussed as an approach to reduce postnatal HIV-1 transmission. Although the use of maternal HAART is clearly warranted in women who require therapy for their own health, the benefits and safety of HAART used solely for prevention of postnatal transmission in healthy HIV-1-infected women have not yet been demonstrated in clinical trials. Similar to infant prophylaxis, a number of observational studies have suggested that maternal HAART can reduce postnatal transmission.21-24 In the Kisumu Breastfeeding Study in Kenya, mothers were given HAART starting at 34 weeks gestation through 6 months postpartum; the cumulative rate of postnatal infection in infants uninfected at birth was 1.5% and 2.6% at age 6 weeks and 6 months, respectively (overall infection rates of 3.9% and 5.0%, respectively).21 The Mitra-Plus study was conducted at the same clinics in Tanzania as the Mitra study; mothers were given HAART starting at 34 weeks gestation through 6 months postpartum; overall infant infection rates were 4.1% and 5.0% at 6 weeks and 6 months, respectively.22 The 0.9% postnatal transmission rate between 6 weeks and 6 months with maternal HAART in Mitra-Plus is comparable to the 1.2% rate reported in Mitra with infant prophylaxis.15,22 There are 2 ongoing, controlled, randomized clinical trials evaluating 6 months of maternal HAART for prevention of postnatal transmission in women who do not require therapy for their own health compared with standard short-course regimens, the BAN study in Malawi and the multicountry Kesho Bora study13; results may be available by the end of 2008.
The risk of resistance in infants infected despite prophylaxis is present with maternal HAART and infant prophylaxis. Drug-resistant virus was identified in 67% of the 24 infants infected postnatally in the Kisumu Breastfeeding Study.25 Interestingly, resistant virus was identified in only 16% of infants on their initial viral isolate but rather emerged at weeks 14-24 as the infant continued to breast-feed while awaiting test results. This is likely due to the infants ingesting subtherapeutic levels of antiretroviral drugs in breast milk of mothers receiving HAART.26-28 Another concern with the use of maternal HAART solely for prophylaxis is the impact of interruption of therapy after prolonged use of HAART on long-term maternal health. Some studies have demonstrated an increased risk of disease progression and death among HIV-1-infected adults with high CD4 counts who interrupt treatment compared with continuous therapy.29,30
Both maternal and infant antiretroviral interventions evaluated to date are predicated upon early weaning of the infant, generally at or before age 6 months. However, increasing data, including that from the infant and maternal prophylaxis trials, suggest that shortening the duration of breast-feeding may be associated with increased risk of malnutrition and infant mortality due to infectious diseases.31-34 In the PEPI-Malawi infant prophylaxis study, where weaning at 6 months of age was recommended, there was a significantly higher incidence of gastroenteritis and infant mortality in the period immediately following breast-feeding cessation when compared with an historical control with continued breast-feeding.32 In the Kisumu Breastfeeding open-label study of maternal HAART prophylaxis, an increase in serious gastroenteritis events, hospitalizations, and growth faltering was observed after early breast-feeding cessation around 6 months of age.33 Additionally, in the Mashi study, discontinuation of breast-feeding was the primary risk factor for serious infant morbidity.9
To maximize prevention of HIV-1 transmission and maternal and infant survival, it is critical that care of both the mother and the infant is optimized.10 This begins with prevention of HIV-1 infection among women and provision of reproductive health services to avoid unintended pregnancy. HIV-1 screening during pregnancy is essential to enable women to know their infection status and make informed decisions regarding infant feeding. HIV-1-infected pregnant women need to be assessed to determine their need for therapy, and CD4+ count assays need to be readily available in the antenatal setting. Women with advanced disease are more likely to transmit HIV-1 to their infants (including during breast-feeding), develop resistance with use of single-dose nevirapine prophylaxis, and to have progression of disease and death; such women need to be started on HAART as soon as possible.35 Women who do not require treatment should receive an appropriate short-course antiretroviral intervention during pregnancy and intrapartum and neonatal prophylaxis to prevent in utero and peripartum transmission.35 For women who do not have safe, affordable, sustainable replacement feeding available to them, exclusive breast-feeding for at least 6 months is recommended.6 Infant antiretroviral prophylaxis, as demonstrated by observational studies, such as the Mitra study and the recent randomized clinical trials, has been identified as an important new intervention to allow HIV-infected mothers to safely breast-feed their infants. However, the optimal duration of prophylaxis remains to be determined. The available data suggest that early weaning in many resource-limited settings may result in excess morbidity and mortality among infants who escape infection, resulting in no advantage of the intervention in overall HIV-free survival.36 Thus, evaluation of the safety, additional efficacy, and cost-effectiveness of more extended infant prophylaxis to allow for more prolonged breast-feeding is warranted. Data should soon be available from ongoing randomized, controlled trials regarding the benefit and safety of maternal HAART used solely for prophylaxis of postnatal mother-to-child HIV-1 transmission. The comparative efficacy, safety (for mother and infant), and cost-effectiveness of extended maternal vs infant prophylaxis during prolonged breast-feeding will be an important question to evaluate.
1. Towne-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
2. Plipat T, Naiwatanakul T, Rattanasuporn N, et al. Reduction in mother to child transmission of HIV in Thailand, 2001-2003: results from population based surveillance in six provinces. AIDS
3. Fowler MG, Lampe MA, Jamieson DJ, et al. Reducing the risk of mother-to-child human immunodeficiency virus transmission: past successes, current progress and challenges, and future directions. Am J Obstet Gynecol
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5. Newell ML. Current issues in the prevention of mother to child transmission of HIV-1 infection. Trans R Soc Trop Med Hyg
6. World Health Organization. HIV and Infant Feeding: New Evidence and Programmatic Experience: Report of a Technical Consultation Held on Behalf of the Inter-Agency Task Team (IATT) on Prevention of HIV Infections in Pregnant Women, Mothers, and Their Infants, Geneva, Switzerland, 25-27 October 2006
. Geneva, Switzerland: World Health Organization; 2007. Available at: http://whqlibdoc.who.int/publications/2007/9789241595971_eng.pdf
. Accessed April 20, 2008.
7. 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
8. Sinkala M, Kuhn L, Kankasa C, et al. No benefit of early cessation of breastfeeding at 4 months on HIV-free survival of infants born to HIV-infected mothers in Zambia: the Zambia Exclusive Breastfeeding Study. 14th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 25-28 February 2007. Abstract 74LB.
9. Shapiro RL, Lockman S, Kim S, et al. Infant morbidity, mortality, and breast milk immunologic profiles among breastfeeding HIV-infected and uninfected women in Botswana. J Infect Dis
10. Wilfert CM, Fowler MG. Balancing maternal and infant benefits and the consequences of breast-feeding in the developing world during the era of HIV infection. J Infect Dis
11. Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. Lancet
12. Kuhn L, Aldrovandi G, Sinkala M, et al. High uptake of exclusive breastfeeding and reduce post-natal HIV transmission: prospective results from the Zambia exclusive breastfeeding study. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22-25 July 2007. Abstract TuAX103.
13. Kourtis AP, Jamieson DJ, de Vincenzi I, et al. Prevention of human immunodeficiency virus-1 transmission to the infant through breastfeeding: new developments. Am J Obstet Gynecol
. 2007;197(Suppl 3):S113-S122.
14. Becquet R, Newell M-L. Prevention of postnatal HIV infection: infant feeding and antiretroviral interventions. Curr Opin HIV AIDS
15. Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother to child transmission of HIV-1 through breastfeeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir Immune Defic Syndr
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16. The Petra Study Team. Efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of HIV-1 from mother to child in Tanzania, South Africa, and Uganda (Petra study): a randomized, double-blind, placebo-controlled trial. Lancet
17. Vyankandondera J, Luchters S, Hassink E, et al. Reducing risk of HIV-1 transmission from mother to infant through breastfeeding using antiretroviral prophylaxis in infants (SIMBA study). 2nd International AIDS Conference on HIV Pathogenesis and Treatment, Paris, France, 13-17 July 2003. Abstract LB7.
18. Sastry J, and the SWEN Study Team. Extended dose nevirapine to 6 weeks of age for infants in Ethiopia, India and Uganda: a randomized trial for prevention of HIV transmission through breastfeeding. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 3-6 February 2008. Abstract 43.
19. Taha T, Thigpen M, Kumwenda N, et al. Extended infant post-exposure prophylaxis with antiretroviral drugs significantly reduces postnatal HIV transmission: the PEPI-Malawi study. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 3-6 February 2008. Abstract 42.
20. Moorthy A, Gupta A, Sastry J, et al. Timing of infection is critical for nevirapine resistance outcomes among breastfed subtype C HIV-1-infected infants exposed to extended vs single-dose nevirapine prophylaxis: the India SWEN Study. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 3-6 February 2008. Abstract 44.
21. Thomas T, Masaba R, Ndivo R, et al. PMTCT of HIV-1 among breastfeeding women using HAART: the Kisumu Breastfeeding Study, Kisumu, Kenya, 2003-2007. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 3-6 February 2008. Abstract 45aLB.
22. Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother to child transmission of HIV-1 through breastfeeding by treating mothers prophylactically with triple antiretroviral therapy in Dar es Salaam, Tanzania-the MITRA PLUS study. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22-25 July 2007. Abstract TuAX101.
23. Arendt V, Ndimubanzi P, Vyankandondera J, et al. AMATA study: effectiveness of antiretroviral therapy in breastfeeding mothers to prevent post-natal vertical transmission in Rwanda. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, Australia, 22-25 July 2007. Abstract TuAX102.
24. 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;21(Suppl 4):S65-S71.
25. Zeh C, Weidle P, Nafisa L, et al. Emergency of HIV-1 drug resistance among breastfeeding infants born to HIV-infected mothers taking antiretrovirals for prevention of mother to child transmission of HIV: the Kisumu Breastfeeding Study, Kenya. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 3-6 February 2008. Abstract 84LB.
26. Shapiro RL, Holland DT, Capparelli E, et al. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. J Infect Dis
27. Mirochnick M, Thomas T, Capparelli E, et al. Plasma ARV concentrations in breastfeeding infants whose mothers are receiving HAART. 14th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 25-28 February 2007. Abstract 72.
28. Corbett A, Kashuba A, Rezk N, et al. Antiretroviral drug concentrations in breast milk and breastfeeding infants. 15th Conference on Retroviruses and Opportunistic Infections, Boston, MA, 3-6 February 2008. Abstract 648.
29. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med
30. The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. Major clinical outcomes in antiretroviral naïve participants and those not receiving ART at baseline in the SMART study. J Infect Dis
31. Kourtis A, Fitzgerald D, Hyde L, et al. Diarrhea in uninfected infants of HIV-infected mothers who stop breastfeeding at 6 months: the BAN study experience. 14th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 25-28 February 2007. Abstract 772.
32. Kafulafula G, Thigpen M, Hoover D, et al. Post-weaning gastroenteritis and mortality among HIV-uninfected African infants receiving ARV prophylaxis to prevent MTCT of HIV-1. 14th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 25-28 February 2007. Abstract 773.
33. Thomas T, Masaba R, van Eijk A, et al. Rates of diarrhea associated with early weaning among infants in Kisumu, Kenya. 14th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 25-28 February 2007. Abstract 774.
34. Onyango C, Mmiro F, Bagenda D, et al. Early breastfeeding cessation among HIV-exposed negative infants and risk of serious gastroenteritis: findings from a perinatal prevention trial in Kampala, Uganda. 14th Conference on Retroviruses and Opportunistic Infections, San Francisco, CA, 25-28 February 2007. Abstract 775.
35. Dao H, Mofenson LM, Ekpini R, et al. International recommendations on antiretroviral drugs for treatment of HIV-infected women and prevention of mother-to-child HIV transmission in resource-limited settings: 2006 update. Am J Obstet Gynecol
. 2007;197(Suppl 3):S42-S55.
36. Coovadia HM, Coutsoudis A. HIV, infant feeding, and survival: old wine in new bottles, but brimming with promise. AIDS
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© 2008 Lippincott Williams & Wilkins, Inc.
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