Mofenson, Lynne M.
Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, Maryland, USA
Correspondence to Lynne M. Mofenson, Chief, Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Boulevard, Room 4B11, Rockville, MD 20852, USA. Tel: +1 301 435 6870; e-mail: LM65D@nih.gov
One of the greatest public health success stories has been the development and implementation of interventions to prevent mother-to-child HIV transmission (PMTCT). In the USA and other high-resource countries, mother-to-child HIV transmission (MTCT) has been nearly eliminated. From a global perspective, UNAIDS has set a goal of ‘virtual elimination’ of MTCT worldwide by 2015 . This series of papers considers the current status of PMTCT in both high and low-resource settings and critically examines what will be needed to reach this elimination goal.
Dr Nesheim et al. discuss the success in preventing – and nearly eliminating – MTCT in the USA. Prior to 1994, approximately one in every four HIV-infected mothers in the USA transmitted HIV to their infant. It was recognized that most pediatric HIV infections occurred through MTCT, although the exact timing of transmission was unclear, and there were no specific preventive interventions other than for a woman to know her HIV status and not get pregnant. In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) 076 clinical trial demonstrated that an antiretroviral (ARV) drug, zidovudine (AZT), given during pregnancy, intravenously during labor and to the newborn for 6 weeks, significantly reduced in-utero and intrapartum HIV transmission . This regimen was rapidly adopted as standard of care for HIV-infected pregnant women and their infants in the USA, with a subsequent precipitous decline in overall MTCT rates [4–6]. As new ARV drugs became available, treatment with combination ARV regimens (initially dual and then triple regimens) became the standard of care, including for treatment of pregnant women. Although there were no randomized clinical trials, observational data suggested that use of combination regimens during pregnancy further reduced MTCT compared to AZT alone . Thus, in resource-rich countries, combination regimens including at least three ARV drugs are currently given during pregnancy to HIV-infected women . Despite an increasing number of HIV-infected pregnant women delivering annually in the USA, current transmission rates are below 2%, and most new infections are attributable to ‘missed opportunities’ – failure to implement known effective interventions [8,9]. The authors discuss the remaining challenges in elimination of MTCT in the USA, noting that elimination is not a single event, but is an ongoing process that requires sustained provision of prevention and care to changing populations of HIV-infected women and continued examination of prophylaxis ‘failures’ to determine the most effective interventions to prevent residual infections.
After the PACTG 076 results in 1994, as interventions for PMTCT began to be implemented in high-resource countries, attention turned to the developing world, where most pediatric HIV infections were occurring. By 1994, 1 million infected infants were estimated to have been born and by 1999, more than 500 000 infected infants were born in this one year alone, mostly in sub-Saharan Africa. In June 1994, the WHO held a meeting of scientists and ministries of health to discuss implications of PACTG 076 for the developing world; the group concluded that the PACTG 076 AZT regimen was not applicable to developing countries because of cost and operational issues, and that rapid conduct of placebo-controlled trials offered the best opportunity to obtain rapid and scientifically valid results and identify regimens capable of being implemented in the developing world . Although the conduct of placebo-controlled trials in developing countries became contentious, several critical placebo-controlled trials were developed and conducted [11–13]. Trials then built sequentially on each other to enable evolving and improving PMTCT standards for the developing world, with global WHO PMTCT recommendations evolving as results from clinical trials have become available . Results from more recent clinical trials demonstrating that ARV prophylaxis of the lactating woman or her breastfeeding infant is a well tolerated and effective way to reduce breast milk transmission, coupled with the increasing availability of ARV treatment in the developing world, have led to the possibility of extending the success of PMTCT in high-resource countries to the developing world . In 2011, the Joint United Nations Programme on HIV/AIDS (UNAIDS) called for the virtual elimination of MTCT of HIV globally by 2015 (i.e. to <40 000 new infections annually and transmission rate <5%), promoting a comprehensive approach including primary prevention of HIV infection among women of childbearing age; preventing unintended pregnancies among women living with HIV; preventing transmission from an HIV-positive woman to her infant; and providing appropriate treatment, care, and support to mothers living with HIV, and their children and families .
Given the new call for global elimination of MTCT, Drs Doherty and Ciaranello  discuss results from their computer simulation model-based analyses that evaluate what is actually needed to achieve the elimination objective. They note that modeling provides an important implementation science tool, allowing integration of data from multiple sources on PMTCT cascade uptake and permitting projection of long-term clinical and economic outcomes; identification of important influential parameters and uptake of services required to reach elimination goals; and provision of cost-effectiveness evaluations. These and other models suggest that to achieve virtual elimination, PMTCT programs must do more than just provide ARV drugs . High levels of coverage and retention are required at each step of the PMTCT cascade. In addition, a comprehensive approach including meeting unmet family planning needs and reducing new HIV infections among reproductive-age women will be required to meet the elimination goal .
The development of ARV interventions to reduce the risk of breast milk HIV transmission was the key component in turning the tide of the pediatric HIV epidemic in the developing world. In low-resource countries, breastfeeding is the cornerstone of infant survival, and several studies have clearly demonstrated that shortening the duration of breastfeeding by HIV-infected women, while reducing HIV transmission, results in decreased infant survival . HIV-infected mothers in these settings were faced with an agonizing choice: to breastfeed but risk transmitting HIV to their infant or to not breastfed and risk their infant dying of malnutrition or infectious diseases. Whereas exclusive breastfeeding can lower the risk of postnatal HIV transmission compared to mixed feeding, it does not eliminate risk . Thus, there was a critical need for interventions to allow safer and more prolonged breastfeeding; research proving that ARV drugs given either to the infant or the mother reduce postnatal infection has transformed the landscape of prevention. Drs Rollins and Coovadia  discuss the history of breastfeeding and HIV transmission, and the ARV interventions now available to prevent postnatal transmission. The authors note that in low-resource countries with high rates of infant morbidity and mortality due to infectious diseases and malnutrition, prolonged breastfeeding with maternal or infant ARV prophylaxis will provide the greatest likelihood of HIV-free survival for infants born to HIV-infected mothers. They also note that even with current ARV interventions, there remains low-level residual breast milk transmission, and research – particularly to identify interventions that do not rely on prolonged daily adherence to drugs, such as active/passive immunoprophylaxis – continues to be needed.
A new public health approach to PMTCT – provision of life-long ARV therapy with a fixed-dose, once-daily efavirenz-based regimen, also called ‘Option B+’ – has been initiated in Malawi and endorsed as a potential strategy for countries to consider by WHO [22,23]. Dr Ahmed et al. give an elegant analysis of the benefits as well as potential risks of this approach for the mother and the child. They distinguish the individual health issues for mother and child from programmatic and public health issues of the approach, as well as provide research priorities. They continue the theme of other papers in this series – that provision of ARV drugs alone is not adequate for elimination of MTCT – and emphasize that addressing challenges with identification, uptake, adherence, and retention of mothers and their infants in care will be critical to the success of this approach. They also note that surveillance systems to evaluate potential toxicities from drug exposure will be critical to ensure the safety of this approach, as discussed by Drs Newell and Bunders  later in this series.
Dr Wilcher et al. discuss the essential ‘prong 2’ of PMTCT – prevention of unintended pregnancy among HIV-infected women. Modeling has demonstrated that virtual elimination of MTCT will not be possible without ensuring unmet family planning needs are addressed . The use of modern contraceptive methods in women aged 15–29 years who are married or have a partner is only 22% in Africa overall and 16% in sub-Saharan Africa; rates are 58% in Southern Africa, but rates were under 10% in Western and Central Africa . The authors note that whereas the importance of family planning to achieve elimination goals is often discussed in policy statements, in reality, few PMTCT programs have increased access to modern contraception for HIV-infected women and couples who do not want to become pregnant. They note that a shift in PMTCT programs to integrate family planning and HIV services will be critical to meet elimination goals, and should be a public health priority.
Dr Chi et al. discuss ‘on the ground’ implementation of PMTCT programs within the continuum of maternal, newborn, and child services. The authors note that global efforts for PMTCT have been hampered by poor delivery of effective services along the PMTCT cascade. High levels of performance across each step of the PMTCT pathway, including presentation to antenatal care, HIV testing and return of result, availability and patient acceptance of ARV drugs, retention in care and adherence to ARV regimens throughout pregnancy and breastfeeding (and beyond with Option B+), and infant testing to determine infection status after cessation of breastfeeding, are required for prevention. Failure to access services or lack of retention in care significantly diminishes program impact at both individual and population levels. They cogently argue for integrated service delivery, with integration of HIV and PMTCT services into maternal, newborn, and child health services, and discuss how this may be achieved.
In the last paper in this series, Drs Newell and Bunders  discuss the critical issue of safety of ARV drugs for both mother and child. Whereas the benefits of ARV therapy for PMTCT and maternal health are without dispute, they note that extended duration of ARV therapy through pregnancy and breastfeeding, and potentially from the time of conception onward, is not without potential risks. They discuss the published data related to ARV therapy and pregnancy outcome as well as long-term effects on uninfected but HIV and ARV-exposed infants. They point out with the rapid expansion of ARV use for PMTCT by pregnant and breastfeeding women, it will be critical to ensure surveillance for potential adverse effects of exposure and to determine the safest regimens and best standard of care.
Finally, we should not lose this unique opportunity to build on the PMTCT platform and infrastructure to address other health threats, and maternal and child mortality [29–32]. As this series of papers has demonstrated, true elimination of new pediatric HIV infections will require fundamental changes in health systems for women and children. We need to dramatically improve maternal healthcare and family planning to address the pediatric HIV epidemic. By wisely using our resources to strengthen maternal and child health services, we can not only address HIV, but the major causes of maternal and infant mortality overall worldwide.
Conflicts of interest
The findings and conclusions in this article are those of the author and do not necessarily represent the views of the National Institutes of Health or Department of Health and Human Services.
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