JAIDS Journal of Acquired Immune Deficiency Syndromes:
Decreasing HIV Transmission Through Breastfeeding: Moving From Evidence to Practice
Guay, Laura MD
From the Department of Epidemiology and Biostatistics, George Washington University School of Public Health and Health Services, Washington, DC.
The author have no funding or conflicts of interest to disclose.
Correspondence to: Laura Guay, MD, Department of Epidemiology and Biostatistics, George Washington University School of Public Health and Health Services, 2100W Pennsylvania Ave NW, 8th Floor, Washington, DC 20037 (e-mail: email@example.com).
The scientific and medical advancements in the field of prevention of mother-to-child HIV transmission (PMTCT) have been extraordinary. Scientifically, we have learned how to prevent transmission of HIV from mothers to their infants as evidenced by the dramatic decreases seen in the number of HIV-infected infants in well-resourced countries. However, less progress has been made in much of the developing world, where reaching all pregnant women with PMTCT services and addressing the issue of HIV transmission through breastfeeding have been challenging. Although early studies demonstrated the efficacy of antiretroviral (ARV) prophylaxis for the prevention of in utero and peripartum HIV transmission, recent clinical trial results demonstrate the efficacy of extending maternal and/or infant ARV use for the prevention of HIV transmission through breast milk.1-7
The most recent analysis of the PEPI study, “Post-Exposure Prophylaxis of Breastfeeding HIV-Exposed Infants with Antiretroviral Drugs to Age 14 Weeks: Updated Efficacy Results of the PEPI-Malawi Trial” by Taha et al,8 is published in this issue of J Acquir Immune Defic Syndr. This report updates the previously reported results of the PEPI trial2,9 and includes final safety and HIV transmission data at 24 months of age in the full cohort of 3126 infants who were uninfected at birth and randomized to the 3 study arms [control, extended infant nevirapine (ExtNVP) for 14 weeks, and extended NVP plus zidovudine (ExtNVP/ZDV) for 14 weeks]. Looking at the transmission rates reported at the 14-week time point (when the intervention ended), HIV infection had occurred in 2.6% of the ExtNVP and 2.5% of the ExtNVP/ZDV arm infants, significantly lower than the 8.5% of control arm infants. By age 24 months, there were an additional approximately 7%-8% of infants with HIV infection in each study arm, but the rates in the intervention arms were still significantly lower than in the control arm (10.8% and 11.2% in ExtNVP and ExtNVP/ZDV arms, respectively, compared with 15.6% in control). Although a difference between the intervention arms and the control arm persisted at 24 months, it was substantially diminished in the face of ongoing HIV exposure and transmission via breastfeeding. The estimated protective efficacy of ExtNVP and ExtNVP/ZDV at the end of the intervention period was approximately 70% compared to the control, but this decreased to 31% in ExtNVP and 20% in ExtNVP/ZDV group by 24 months of age despite early weaning and low rates of breastfeeding reported after 6 months of age.
The study by Taha et al adds strength to the evidence that infant prophylaxis with NVP is safe and effective in decreasing HIV acquisition for the duration of prophylaxis (duration in studies included single dose, 6 weeks, 14 weeks, and 6 months).2,3,5,7 However, once prophylaxis ends, the risk of transmission resumes at rates similar to those seen without prophylaxis as long as breastfeeding continues.
In addition to the prophylaxis regimen, Taha et al found that maternal CD4 cell count was also strongly associated with the risk of transmission to the infant. The extended infant prophylaxis regimens were effective in decreasing transmission even in the PEPI setting where many women with low CD4 cell counts did not have access to antiretroviral therapy (ART).2,9 Recently released results from the Kisumu Breastfeeding Study and the HIV Prevention Trials Network 046 study support the safety and efficacy of either maternal or infant prophylaxis for increasing duration during breastfeeding for PMTCT.6,7 Similar to the Taha study, both of these studies show ongoing risk of HIV infection after cessation of the intervention and increased infection among infants born to women with low CD4 counts, especially those who were not receiving ART. In previously reported results from the PEPI study, the rate of HIV transmission after 14 weeks of age (in cases per 100 person-years) for women who were ART eligible (by CD4 < 250 cells/μL criteria used at time of the study) but not on ART was 10.6, for the ART-eligible women on ART was 1.8, and ART-ineligible women was 3.7.9 This is consistent with the HIV Prevention Trials Network 046 study, which showed the highest risk of transmission (with or without prophylaxis) in women with CD4 counts <350 cells per microliter who were not on ART and the greatest benefit of the infant prophylaxis in women with CD4 cell counts >350 cells per microliter who were not eligible for ART.7
Given the increased rates of gastroenteritis, growth failure, hospitalizations, and mortality associated with early and rapid cessation of breastfeeding by 6 months of age,10-13 the World Health Organization (WHO) revised the infant feeding recommendations for settings where breastfeeding increases the likelihood of infant survival to encourage HIV-infected women to continue to breastfeed and receive either infant or maternal prophylaxis to minimize HIV transmission and maximize infant survival.14 Despite trial data investigating the use of prophylaxis for up to 6 months only, considerations for the current recommendations to use ARV for PMTCT for the duration of breastfeeding included ExtNVP dosing up to 6 months postpartum has been shown to be safe; NVP dosage for treatment of HIV infection in infants is considerably higher than the dosage used for prophylaxis and the period considerably longer; the risk of NVP toxicity seems to be greatest early in use; the risk of transmission persists for as long as there is exposure to breast milk; and as the PEPI study demonstrates, the benefit of prophylaxis is linked to the duration of use. This suggests that the infant (or maternal) prophylaxis will be effective as long as it is continued for the duration of breastfeeding. Evaluation of program outcomes as the revised WHO guidelines are implemented will be critical to determine the feasibility and the effectiveness of each of the prophylaxis regimens in the field.
Several other key points emerge from this article. Although the new WHO recommendations based on this and other studies have led to much discussion about option A (infant prophylaxis) versus option B (maternal prophylaxis) for breastfeeding prophylaxis,15 the most critical component for maintaining the health of the mother and for eliminating the highest risk of transmitting HIV infection to infants remains, ensuring that all women who require ART for their own health access ART. Priority must be given to establishing the infrastructure necessary to provide ART to all women who need it, within the maternal child health (MCH) setting if possible or with strong linkage and referral systems to ART services otherwise.
Also, although clinical trials have provided the scientific evidence that elimination of pediatric HIV is possible, the translation of results obtained in clinical trials into routine health services in the field has met with considerable barriers. The UNAIDS 2010 report on the global AIDS epidemic reflects significant progress in increasing access to PMTCT services, but there were still an estimated 370,000 new pediatric HIV infections in 2009.16 Of particular concern is the widening of the gap between the percentage of HIV-infected women accessing ARV for PMTCT (53%) and the percentage of HIV-exposed infants who receive ARV for prophylaxis (35%). Transmission rates in the absence of ARV treatment or prophylaxis in women not accessing PMTCT services will remain the driver of the epidemic of HIV in infants. In addition, to realize the benefits of both reducing transmission during breastfeeding and identifying HIV-infected infants for early access to ARV, HIV-infected women and their HIV-exposed infants must be identified early and followed consistently. Implementing the new postnatal regimens, reaching and retaining all exposed infants in care, and providing the daily prophylaxis of either type are considerably more complex, requiring considerable improvements in the postnatal infrastructure and health system. With lost to follow-up rates at 24 months of 23% in the PEPI study and 20% for the Kisumu Breastfeeding Study at 24 months under very strictly controlled clinical trial settings, the loss to follow-up within routine PMTCT services is likely to be substantially higher. Mechanisms for maintaining mother-infant pairs within PMTCT services are critical and will likely be best accomplished by integrating PMTCT programs within improved routine MCH services. When we put the knowledge gained through trials such as PEPI into practice and learn how to provide comprehensive PMTCT and MCH services to all HIV-positive women and their infants from the first visit to ANC through to the end of breastfeeding and beyond with strong linkages to HIV care and treatment programs, we will get closer to the goal of eliminating pediatric HIV/AIDS and improving maternal-child survival.
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6. Thomas TK, Masaba R, Borkowf CB, et al. Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding—The Kisumu Breastfeeding Study, Kenya: a clinical trial. PLoS Med. 2011;8:e1001015. doi:10.1371/journal.pmed.1001015.
7. Coovadia H, Maldonado Y, Mofenson L, et al. HPTN 046: Efficacy of extended daily infant NVP through age 6 months compared to 6 weeks for postnatal PMTCT of HIV through breastfeeding. Presented at: 18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27, to March 2, 2011; Boston, MA. Paper 123LB.
8. Taha T, Li Q, Hoover D, et al. Postexposure prophylaxis of breastfeeding HIV-exposed infants with antiretroviral drugs to age 14 weeks: updated efficacy results of the PEPI-Malawi Trial. J Acquir Immune Defic Syndr. 2011;54:319-325.
9. Taha TE, Kumwenda J, Cole SR, et al. Postnatal HIV-1 transmission after cessation of extended infant antiretroviral prophylaxis and effect of maternal HAART. J Infect Dis. 2009;200:1490-1497.
10. Kafulafula G, Hoover DR, Taha TE, et al. Frequency of gastroenteritis and gastroenteritis-associated mortality with early weaning in HIV-1-uninfected children born to HIV-infected women in Malawi. J Acquir Immune Defic Syndr. 2010;53:6-13.
11. Onyango-Makumbi C, Bagenda D, Mwatha A, et al. Early weaning of HIV-exposed uninfected infants and risk of serious gastroenteritis: findings from two perinatal HIV prevention trials in Kampala, Uganda. J Acquir Immune Defic Syndr. 2010;53:20-27.
12. Homsy J, Moore D, Barasa A, et al. Breastfeeding, mother-to-child transmission, and mortality among infants born to HIV-infected women on highly active antiretroviral therapy in rural Uganda. J Acquir Immune Defic Syndr. 2010;53:28-35.
13. Kuhn L, Aldrovandi GM, Sinkala M, et al. Effects of early, abrupt weaning on HIV-free survival of children in Zambia. N Engl J Med. 2008;359:130-141.
14. HIV and Infant Feeding: Revised Principles and Recommendations: Rapid Advice. Geneva, Switzerland: World Health Organization; 2009.
15. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Recommendations for a Public Health Approach, 2010 Version. Geneva, Switzerland: World Health Organization, 2010.
16. WHO, UNAIDS, UNICEF Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector. Progress Report 2010. Geneva, Switzerland: World Health Organization, 2011.
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