Abrams, Elaine J. MD*,†; Myer, Landon MBChB, PhD*,‡
Over the last 30 years, since the first cases of pediatric AIDS were reported, the field of perinatal HIV has met with remarkable successes and considerable challenges.1 Global efforts by scientists and clinicians have resulted in a nuanced understanding of the mechanisms of mother-to-child HIV transmission (MTCT) and optimal approaches for its prevention.2–4 In the United States, Europe, and a handful of other countries, scientific advances have been rapidly translated into policy, antiretroviral (ARV) therapy for prevention of mother-to-child transmission (PMTCT) is routine, and new pediatric infections are increasingly rare.5–8
By comparison, in less well-resourced parts of the world, efforts to prevent new pediatric infections have been far less effective. It is estimated that there are more than 900 new infections daily in children less than 15 years of age, 90% attributable to MTCT and 90% occurring in sub-Saharan Africa.9 In 2011, there were approximately 330,000 new pediatric HIV infections, bringing the total number to more than 3.3 million children worldwide since the beginning of the epidemic.10 In response to these global challenges, there is a renewed global dialog around PMTCT and new exciting expectations that successes achieved in wealthy countries can be extended to sub-Saharan Africa. A global plan toward elimination of new HIV infections among children, developed by a task team convened by UNAIDS and the President's Emergency Plan For AIDS Relief (PEPFAR), has been set in motion resulting in multilateral efforts to accelerate perinatal prevention efforts.11 This article will consider what it will take to reach an end to the pediatric HIV epidemic and what we can hope for in the context of resurgent global interest.
THE SCIENCE OF PREVENTING PEDIATRIC HIV INFECTION
The findings of the Pediatric AIDS Clinical Trials Group 076 Trial, published in 1994, heralded the first major breakthrough in the field of perinatal prevention.12 The study demonstrated that zidovudine, the only approved ARV medication at the time the study was designed, when given to the woman during pregnancy, labor and delivery, and to the infant during the first 6 weeks of life, was safe and provided substantial protection to the baby, lowering MTCT risk by almost two thirds. Over the next 2 decades, multiple studies were conducted examining a variety of drug regimens, building on the lessons of 076, and seeking to identify optimal strategies to safely reduce transmission risk.13 Early trials in sub-Saharan Africa focused on identifying short-course simplified regimens that were inexpensive and easy to implement in low-resource settings. The HIV Prevention Trials Network 012 trial demonstrated a 48% reduction in early MTCT by giving a single dose of nevirapine to both the laboring mother and to infant at birth.14 This was another landmark study that led to the establishment of the first programs using ARVs for PMTCT in sub-Saharan Africa and many other parts of the world.15
Clinical trials in tandem with cohort and laboratory studies have also elucidated the mechanisms of HIV-1 transmission. Understanding the timing and risks of MTCT has informed new interventions while failure to fully consider these issues has contributed to the limited impact of many PMTCT programs in high HIV prevalence settings. Three critical considerations are apparent. First, transmission can occur at any point during pregnancy, labor and delivery, and breastfeeding, highlighting the need for ARV protection throughout the long period of exposure.16 Second, women with advanced HIV disease and high viral loads are at highest risk for MTCT and disease progression. Effective treatment for antiretroviral therapy (ART)-eligible pregnant and lactating women will improve maternal health and prevent the vast majority of infant infections.17,18 Third, avoidance of breastfeeding, one of the key components of PMTCT in high-resource countries, can result in substantial morbidity and mortality in settings where breastfeeding is a key child survival intervention.19,20 A series of clinical trials have now demonstrated the efficacy of providing ARVs to the mother and/or infant during breastfeeding to prevent HIV transmission while preserving overall child health.21–25
THE PRACTICE OF PREVENTING PEDIATRIC HIV INFECTION
It is estimated that more than 100,000 pediatric infections were averted through PMTCT programs between 2003 and 20109 and a number of countries in sub-Saharan Africa have demonstrated substantial success. Botswana, Rwanda, and South Africa report good access to and uptake of PMTCT services and low rates of early MTCT.26–28 In a national survey conducted at 580 facilities in 9 South African provinces, caregiver–infant pairs were tested for HIV at the first immunization visit.28 The prevalence of HIV exposure among infants was 32.3% (95% CI: 30.7% to 33.6%) and the national perinatal MTCT rate at 4–8 weeks postpartum was 2.7% (85% CI: 2.1% to 3.2%).28 Similar population-wide data from other African countries do not exist, however, and it is likely that the majority of high HIV prevalence countries have less effective PMTCT programs.
Shortcomings in current approaches to PMTCT exist on multiple fronts. There is a high burden of unintended pregnancy among HIV-infected women in many countries29,30 and an urgent need for access to family planning services as a basic part of PMTCT programs. Availability of PMTCT services remains a concern because only 4 countries in sub-Saharan Africa report greater than 90% coverage of PMTCT services.9 Many countries continue to rely on less efficacious ARV short-course regimens and face major challenges in identifying and adequately treating pregnant and lactating women eligible for ART for their own health who are also at highest risk for MTCT.31,32 Moreover, few programs, even those in countries reporting successful outcomes, retain mothers and their infants in long-term follow-up to ensure ARV coverage throughout the duration of breastfeeding, final determination of infant infection status at weaning, and transfer of the HIV-positive mother into HIV care and treatment services. And with evidence that women's risk of HIV acquisition may increase during pregnancy,33–35 there is growing concern around incident HIV infection during pregnancy or breastfeeding as an important cause of vertical HIV transmission.36,37
These issues facing PMTCT services are rooted in broader challenges facing maternal and child health (MCH) services. In most countries, PMTCT programs have been built on the fragile infrastructure of MCH services that generally provide only the most basic pediatric and reproductive health services and are ill-prepared to deliver the more complex continuous care, and therapies required for successful perinatal prevention. Although there is an increasing awareness within ART programs that retention in care is critical to ensure good long-term health outcomes,38,39 PMTCT has been implemented as a short-term health intervention with limited focus on long-term engagement.
REACHING ELIMINATION TARGETS—WHAT WILL IT TAKE?
There are ambitious international aims to reduce the number of new HIV infections among children by 90% and the number of maternal AIDS-related deaths by 50% by 2015.11 These goals are both inspirational and daunting, aiming to see fewer than 40,000 new pediatric infections, which represent an 88% reduction compared with 2011. To achieve these targets, a rapid expansion of the breadth and depth of PMTCT services will be needed to reach significantly more women in countries where HIV is prevalent and to provide them with effective ARV interventions to prevent infant infections and protect maternal health.
Availability of and access to PMTCT services is the necessary first step to prevent new pediatric HIV infections. If HIV testing during pregnancy can be used as a proxy for access to PMTCT, in 2010, only 35% of pregnant women in low- and middle-income countries received an HIV test.10 Nine of the 22 countries with the highest number of new pediatric infections reported testing rates of less than 50% including the Democratic Republic of Congo (11%) and Nigeria (14%). The challenge of increasing access is considerable if PMTCT services are to reach women where they obtain antenatal care that, in most settings, is often decentralized to rural and distant communities. Although several countries have expanded PMTCT services, effective scale-up has been elusive in many lower prevalence settings where the diagnosis and treatment of HIV infection during pregnancy are less common.9 As a more fundamental barrier, some of the most affected countries are challenged by low rates of attendance in antenatal care. For instance, in Ethiopia, the majority of pregnant women do not access MCH services during pregnancy thwarting traditional PMTCT efforts.40 Novel approaches are urgently needed to reach beyond health facilities to identify HIV-positive pregnant women in their communities and engage them in both PMTCT and MCH services.
To reach international elimination targets, the depth of PMTCT services will also need to be “scaled-up.” Effective PMTCT requires, at a minimum, therapeutic treatment for ART-eligible women, estimated to be approximately 40% of those entering care.41 Historically, PMTCT programs have provided ARV prophylaxis but have had limited ability to identify, engage, and treat ART-eligible women. In 2011, only 57% of all HIV-positive pregnant women received efficacious ARV regimens (other than single-dose nevirapine) and of among women receiving any prophylaxis, only 45% were assessed for ART eligibility. Availability of infant testing is limited but is critical for identifying HIV-infected infants and linking them to early treatment; in 2011, only 28% of HIV-exposed babies had early infant diagnostic testing within the first 2 months of life.10
Access to timely CD4 testing is critical to distinguish ART-eligible pregnant women but is often poor in the MCH setting. And despite the vast scale-up of ART services in sub-Saharan Africa access to treatment is generally restricted to ART centers where it is prescribed by physicians and specially trained nurses. For example, in the Kagera region of Tanzania, ICAP, a PEPFAR implementing partner, works with the Ministry of Health to implement HIV services. Between 2008 and 2011, there was an expansion of both PMTCT and ART services: PMTCT services sites increased from 22 to 228 health care facilities and ART service site increased from 9 to 59 facilities.42 At the 59 ART facilities, PMTCT services were also available and PMTCT clients could access on-site ART. By comparison, the vast majority of facilities offering PMTCT were unable to provide ART for eligible women. In this case, scaling up effective PMTCT would require expansion of ART services to as many as 169 additional facilities in the region.
Several innovations are poised to address these implementation challenges, and if successful could lead to substantially more pregnant women initiating treatment. Point of care technology for CD4 testing is now increasingly available allowing on-site, same day determination of ART eligibility. Introduction of point of care CD4 testing has resulted in higher rates of ART initiation and retention in nonpregnant adults,43 but there are few evaluations from PMTCT settings. Furthermore, initiatives to train and certify nurses and midwives to prescribe ART have been highly effective in a number of countries and critical to efforts to decentralize ART services.44,45 Coupled with increased availability of CD4 testing, determination of ART eligibility and initiation of treatment can be accomplished by existing staff in antenatal clinics. However, it should be noted that MCH services are chronically underresourced and adding new skills and responsibilities to existing staff provides only a partial solution. More extensive efforts to address the human resource for health crisis in sub-Saharan Africa are urgently needed to reach the Millennium Development Goals (MDG) and these elimination targets.
Although these innovations are likely to lead to incremental improvements in PMTCT services, “Option B+,” which recommends initiation of lifelong treatment for all HIV-positive pregnant and lactating women, may be a game changer, transforming the framework of perinatal prevention and dramatically improving MCH outcomes.46,47 World Health Organization 2010 guidelines offer 2 options for PMTCT both of which prioritize the identification and treatment of ART-eligible pregnant women. For women not eligible for ART Option A provides zidovudine prophylaxis during pregnancy coupled with daily nevirapine to the infant during breastfeeding, whereas Option B offers triple drug prophylaxis to the mother during pregnancy and breastfeeding.48 In contrast to these approaches, Option B+ replaces “CD4 count” with “pregnancy status” to determine ART eligibility so that all pregnant and breastfeeding women are recommended to initiate lifelong ART. Option B+ shifts the paradigm of ART initiation from disease status to transmission risk, not dissimilar to the recommendation for discordant couples.49 This new approach, Option B+, recognizes that pregnancy is a critical entry point for HIV-positive women to engage in lifelong HIV care and treatment services.
The country of Malawi began implementing Option B+ more than a year ago and has seen a dramatic increase in the number of pregnant women initiating ART.47 Early reports of retention in care for women initiating ART during pregnancy are similar to rates reported among nonpregnant adults. Many critical questions remain to be answered to determine if this approach is safe for mother and child and acceptable to women and communities. It also remains to be determined whether this approach improves ARV adherence, retention of mothers and children across the PMTCT cascade, and whether it is effective at keeping mothers healthy and protecting infants from acquiring HIV infection. Option B+ has now been adopted by a number of other countries in sub-Saharan Africa. Coupled with other simplification strategies such as use of once-daily fixed dose combination ART regimens, Option B+, has the potential to jumpstart the elimination campaign and propel perinatal prevention efforts forward.
It should be noted, however, that although expansion of PMTCT and ART coverage among pregnant and postpartum women is at the core of the global elimination campaign, without ongoing prevention efforts treatment alone will be insufficient to achieve an AIDS-free generation. Prevention of new HIV infections among women and unwanted pregnancies among HIV-positive women are central components of PMTCT and are critical to achieving elimination targets.50 Not surprisingly, only by combining prevention and treatment efforts will substantial progress be made.
CAN WE ACHIEVE AN AIDS-FREE GENERATION?
The campaign to eliminate new pediatric infections and keep mothers alive is well under way: governments and communities are being engaged; financial resources are being mobilized; new strategies are being employed, and early reports suggest that increasing numbers of women and children are being reached with PMTCT services. These are important achievements that set the tone for a rapid and robust scale-up of PMTCT programs. However, it seems unlikely that elimination targets will be reached by 2015, which may be unsurprising given that similar accomplishments that took several decades to achieve in developed countries with well-resourced health systems. Experience with other health campaigns may further temper expectations. In a recent assessment of progress in developing countries toward MDG 4 and 5, to reduce under-5 mortality by two thirds and maternal mortality by three quarters, respectively, between 1990 and 2015, it was estimated that only 31 countries will achieve MDG 4, 13 MDG 5, and 9 countries will achieve both.51 Twenty-three countries in sub-Saharan Africa are not expected to reach MDG 4 before 2040.
Elimination targets may be out of reach by 2015, but expectations for the campaign should remain high. Renewed attention to the health of women and children, particularly those affected by HIV, is long overdue as is a shift in the PMTCT model of care from one that focuses on short-term prophylaxis to one that embraces PMTCT as an entry point into comprehensive HIV services able to address the health needs of the HIV-positive women, her infant and family. Furthermore, efforts to strengthen health systems and address the human resource for health crisis in sub-Saharan Africa and other parts of the world where children are highly vulnerable to a variety of severe health threats will likely do more than prevent new pediatric HIV infections. In synergy with other global health initiatives, the campaign to eliminate new pediatric infections and keep mothers alive should lead to substantial and measurable improvements in health outcomes for women and children worldwide. We can expect and demand nothing less.
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