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.
1. Centers for Disease Control and Prevention. Unexplained immunodeficiency and opportunistic infections in infants—New York, New Jersey, California. MMWR Morb Mortal Wkly Rep. 1982;31:665–667.
2. Mofenson LM. Prevention in neglected subpopulations: prevention of mother-to-child transmission
of HIV infection. Clin Infect Dis. 2010;50(suppl 3):S130–S148.
3. Fowler MG, Kourtis AP, Aizire J, et al.. Breastfeeding and transmission of HIV-1: epidemiology and global magnitude. Adv Exp Med Biol. 2012;743:3–25.
4. Abrams EJ. Prevention of mother-to-child transmission
of HIV—successes, controversies and critical questions. AIDS Rev. 2004;6:131–143.
5. Whitmore SK, Taylor AW, Espinoza L, et al.. Correlates of mother-to-child transmission
of HIV in the United States and Puerto Rico. Pediatrics. 2012;129:e74–81–e–81.
6. Townsend CL, Cortina-Borja M, Peckham CS, et al.. Low rates of mother-to-child transmission
of HIV following effective pregnancy interventions in the United Kingdom and Ireland, 2000-2006. AIDS. 2008;22:973–981.
7. Matida LH, da Silva MH, Tayra A, et al.. Prevention of mother-to-child transmission
of HIV in Sao Paulo State, Brazil: an update. AIDS. 2005;19(suppl 4):S37–S41.
8. Johnson N, Palmer P, Samuels LA, et al.. Evolving care of HIV-infected pregnant women in Jamaica–from nevirapine to HAART. West Indian Med J. 2008;57:216–222.
9. World Health Organization. Global HIV/AIDS response: epidemic update and health sector progress towards universal access. Geneva, Switzerland: World Health Organization; 2011.
10. UNAIDS. World AIDS Day Report. Geneva, Switzerland: UNAIDS; 2012.
12. Connor EM, Sperling RS, Gelber R, et al.. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331:1173–1180.
13. World Health Organization. Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infections in Infants: Recommendations for a Public Health Approach. Geneva, Switzerland: World Health Organization; 2010.
14. 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;354:795–802.
15. Spensley A, Sripipatana T, Turner AN, et al.. Preventing mother-to-child transmission
of HIV in resource-limited settings: the Elizabeth Glaser Pediatric AIDS Foundation experience. Am J Public Health. 2009;99:631–637.
16. Kourtis AP, Lee FK, Abrams EJ, et al.. Mother-to-child transmission
of HIV-1: timing and implications for prevention. Lancet Infect Dis. 2006;6:726–732.
17. Garcia PM, Kalish LA, Pitt J, et al.. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. Women and Infants Transmission Study Group. N Engl J Med. 1999;341:394–402.
18. Katzenstein DA, Mbizvo M, Zijenah L, et al.. Serum level of maternal human immunodeficiency virus (HIV) RNA, infant mortality, and vertical transmission of HIV in Zimbabwe. J Infect Dis. 1999;179:1382–1387.
19. 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.
20. Taha TE, Hoover DR, Chen S, et al.. Effects of cessation of breastfeeding in HIV-1-exposed, uninfected children in Malawi. Clin Infect Dis. 2011;53:388–395.
21. Taha TE, Li Q, Hoover DR, 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;57:319–325.
22. Chasela CS, Hudgens MG, Jamieson DJ, et al.. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med. 2010;362:2271–2281.
23. 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.
24. Kesho Bora Study Group, de Vincenzi I. Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission
of HIV-1 (Kesho Bora study): a randomised controlled trial. Lancet Infect Dis. 2011;11:171–180.
25. Coovadia HM, Brown ER, Fowler MG, et al.. Efficacy and safety of an extended nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled trial. Lancet. 2012;379:221–228.
27. Ruton H, Mugwaneza P, Shema N, et al.. HIV-free survival among nine- to 24-month-old children born to HIV-positive mothers in the Rwandan national PMTCT
programme: a community-based household survey. J Int AIDS Soc. 2012;15:4.
28. SAPMTCTE Study Group. Evaluation of effectiveness of the national prevention of mother-to-child transmission
) programme on intfant HIV measured at six weeks postpartum in South Africa. 2012. Available at: http://doh.gov.za/docs/reports/2012/pmtcteffectiveness.pdf
. Accessed May 19, 2013.
29. Singh S, Sedgh G, Hussain R. Unintended pregnancy: worldwide levels, trends, and outcomes. Stud Fam Plann. 2010;41:241–250.
30. UNICEF. State of the World's Children 2012: Children in an Urban World. New York, NY: UNICEF; 2012.
31. Stringer EM, Ekouevi DK, Coetzee D, et al.. Coverage of nevirapine-based services to prevent mother-to-child HIV transmission in 4 African countries. JAMA. 2010;304:293–302.
32. Stinson K, Boulle A, Coetzee D, et al.. Initiation of highly active antiretroviral therapy among pregnant women in Cape Town, South Africa. Trop Med Int Health. 2010;15:825–832.
33. Moodley D, Esterhuizen TM, Pather T, et al.. High HIV incidence during pregnancy: compelling reason for repeat HIV testing. AIDS. 2009;23:1255–1259.
34. Bernasconi D, Tavoschi L, Regine V, et al.. Identification of recent HIV infections and of factors associated with virus acquisition among pregnant women in 2004 and 2006 in Swaziland. J Clin Virol. 2010;48:180–183.
35. Kharsany AB, Hancock N, Frohlich JA, et al.. Screening for “window-period” acute HIV infection among pregnant women in rural South Africa. HIV Med. 2010;11:661–665.
36. Moodley D, Esterhuizen T, Reddy L, et al.. Incident HIV infection in pregnant and lactating women and its effect on mother-to-child transmission
in South Africa. J Infect Dis. 2011;203:1231–1234.
37. Johnson LF, Stinson K, Newell ML, et al.. The contribution of maternal HIV seroconversion during late pregnancy and breastfeeding to mother-to-child transmission
of HIV. J Acquir Immune Defic Syndr. 2012;59:417–425.
38. McNairy ML, El-Sadr WM. The HIV care continuum: no partial credit given. AIDS. 2012;26:1735–1738.
39. Rosen S, Fox MP. Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review. PLoS Med. 2011;8:e1001056.
41. Carter RJ, Dugan K, El-Sadr WM, et al.. CD4+ cell count testing more effective than HIV disease clinical staging in identifying pregnant and postpartum women eligible for antiretroviral therapy in resource-limited settings. J Acquir Immune Defic Syndr. 2010;55:404–410.
42. ICAP. ICAP Unified Reporting System (URS) Website. New York, NY: Columbia University; 2013. Available at: https://urs2.icap.columbia.edu/
. Accessed June 1, 2013.
43. Jani IV, Sitoe NE, Alfai ER, et al.. Effect of point-of-care CD4 cell count tests on retention of patients and rates of antiretroviral therapy initiation in primary health clinics: an observational cohort study. Lancet. 2011;378:1572–1579.
44. Shumbusho F, van Griensven J, Lowrance D, et al.. Task shifting for scale-up of HIV care: evaluation of nurse-centered antiretroviral treatment at rural health centers in Rwanda. PLoS Med. 2009;6:e1000163.
45. Sanne I, Orrell C, Fox MP, et al.. Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet. 2010;376:33–40.
46. Schouten EJ, Jahn A, Midiani D, et al.. Prevention of mother-to-child transmission
of HIV and the health-related Millennium Development Goals: time for a public health approach. Lancet. 2011;378:282–284.
48. World Health Organization. Anitretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants: Recommendations for a Public Health Approach. Geneva, Switzerland: World Health Organization; 2010.
49. World Health Organization. Guidance on Couples HIV Testing and Counselling—Including Antiretroviral Therapy for Treatment and Prevention in Serodiscordant Couples. Geneva, Switzerland: World Health Organization; 2012. Available at: http://www.who.int/hiv/pub/guidelines/9789241501972/en/
. Accessed May 19, 2013.
50. Mahy M, Stover J, Kiragu K, et al.. What will it take to achieve virtual elimination of mother-to-child transmission
of HIV? An assessment of current progress and future needs. Sex Transm Infect. 2010;86(suppl 2):ii48–ii55.
51. Lozano R, Gomez-Dantes H, Castro MV, et al.. Progress on the millenium development goals 4 and 5 in Mesoamerica [in Spanish]. Salud Publica Mex. 2011;53(suppl 3):S295–S302.