The Joint United Nations Programme on HIV/AIDS ‘Global Plan Towards the Elimination of New HIV Infections among Children and Keeping their Mothers Alive’ (i.e., The Global Plan) has set ambitious targets of a 90% reduction in vertical transmission of mother-to-child HIV infection (MTCT) by 2015, and to reduce AIDS-related deaths in infants by 50% . In the absence of any intervention, the MTCT risk can be as high as 40% , but with appropriate prevention of mother-to-child transmission interventions (PMTCT), including antiretroviral therapy (ART) for pregnant women living with HIV, MTCT rates can be reduced to 5% or less . Inherent in these goals is the assurance that appropriate mechanisms and strategies exist for diagnosing HIV in infants, children, and teenagers, and retaining mothers and their children in lifelong care and treatment.
Efforts to scale up PMTCT access for HIV-infected pregnant women have yielded encouraging results, with over 60% of pregnant women in sub-Saharan Africa accessing some level of PMCT before delivery. However, efforts to identify HIV-infected children have been less laudable . Among reporting countries, only one-third of infants born to HIV-infected mothers received an HIV test in 2012, with some countries reporting infant testing rates below 10%, leaving millions of HIV-exposed infants without an initial or definitive diagnosis . More importantly, an estimated 2.5 million HIV-infected children currently are in need of ART remain at risk for severe illness and death, and nearly 75% of them are not currently enrolled into HIV care and treatment . Despite improving PMTCT interventions and the efforts and resources allocated to meet the ‘Global Plan’ targets, 210 000 new pediatric infections occurred in the 21 Global Plan priority countries in 2012 . This suggests that current efforts to optimize PMTCT interventions will not independently eliminate pediatric HIV/AIDS. New strategies for early infant diagnosis (EID) and linkage of HIV-infected children to care are critical to achieve the Global Plan goals.
Redefining early infant diagnosis
Contrary to adults, the disease progression in HIV-infected infants is rapid, and without treatment 20% of perinatally infected infants will die by 3 months of age, and half will not survive beyond their second birthday [5,6]. The risk of mortality for HIV-infected infants during the early period of life can be up to 12 times higher than among uninfected infants. For infected infants who survive beyond 2 years of age, poor health outcomes are often irreversible, with increased occurrence of malnutrition, opportunistic infections, and permanent developmental challenges [5,7]. However, recent studies show that early ART can significantly reduce infant mortality. For example, the CHER study documented a 76% reduction in infant mortality among infants initiated on ART within the first 3 months of life . Given the extraordinary success of ART in reducing morbidity and mortality in infants, the early identification of HIV-infected infants must be prioritized [9,10].
The diagnosis of HIV in infants is complicated by the passage of maternal HIV antibodies across the placenta resulting in high proportions of false positives with serological testing (i.e. antibody testing). Serological testing is reliable in young children after the age of 18 months, although some country-specific guidelines recommend serological testing from 9, 12, or 15 months of age . In young infants serologic tests can be used as a screening tool to determine exposure to HIV in infants and children less than 18 months when maternal status is unknown . Only a virological assay such as DNA-PCR or Gag p24 antigen, which directly detects viral particles, can provide a definitive diagnosis of HIV infection . Thus, virological testing using a PCR test is recommended at 4–6 weeks of age and represents the first step of an HIV testing algorithm that should form part of the routine follow-up and care of all HIV-exposed infants throughout the period of exposure until weaning is complete  (Fig. 1).
The WHO recommendation that initial virological testing for all HIV-exposed infants take place 4–6 weeks after birth will capture infants infected in utero or intrapartum; however, infants with a negative test at 6 weeks are still at risk for acquiring the disease throughout the breastfeeding period. Strategies to prevent HIV transmission during the prenatal period have, as a result of their success, reduced the overall proportion of exposed infants infected during this period, with recent data suggesting that over 50% of new pediatric infections now occur in the postnatal period . Infants born to mothers who test negative in antenatal care (ANC), but acquire the disease later in pregnancy or seroconvert after delivery, are also at risk for infection. In high-incidence settings, more aggressive algorithms calling for maternal repeat testing during pregnancy and breastfeeding when infants are at risk for exposure could prevent additional future infections . Although the 2013 Consolidated WHO guidelines now advise a follow-up test at 9 months of age (Fig. 1), Global Plan core indicators for infant testing still only report coverage on testing at 2 months of age . Although PMTCT programs have been able to document low rates of transmission at 6 weeks , the current emphasis on the initial 6-week PCR test ignores the continued risk of infection for exposed infants , which has resulted in millions of HIV-exposed infants without a definitive HIV status and thousands of HIV-positive infants without treatment.
Key challenges for early infant diagnosis programs
Virological testing by PCR has measurably improved in recent years in terms of sensitivity, specificity and ease of implementation, but requires significant investments in specialized laboratory equipment, and highly skilled personnel. Initial access to PCR testing for EID in resource-limited countries used blood obtained by venipuncture, and was performed on complicated, multiplatform, manual laboratory equipment housed in centrally located laboratories. The use of ‘dried blood spot’ (DBS) technology for sample collection, in which capillary blood from a heel puncture is dropped on filter paper, dried and transported to the laboratory, has allowed countries to significantly scale up EID testing by decentralizing sample collection to even the most rural areas . DBS does not require centrifuges or freezers at the sample collection site, and remains viable for weeks at room temperatures. Once delivered to the laboratory, sample processing has been simplified with the use of automated PCR platforms .
Despite the use of DBS and the automated laboratory systems, testing coverage of HIV-exposed infants remains poor. In 2012, over 1 million PCR tests for EID were performed globally, but this still only represents one-third of HIV-exposed infants in need . Uptake of PCR testing in the first 2 months of life, as recommended by the WHO, is much lower. Although the volume of PCR tests for EID is growing, many patients still lack access to this test . Sample transportation over long distances or difficult terrains often leads to loss of samples and delays in the return of results. The turn-around time (TAT) – from sample being taken to the result being shared with the patient – can be several months . The long TAT contributes to high loss to follow-up (LTFU); thus, infected infants subsequently are not identified and do not receive the treatment they need (Fig. 1). In recent studies conducted in some of the highest HIV burden settings, up to 85% of exposed infants were LTFU . Some of the key challenges affecting EID testing programs are listed below.
Access to EID testing is further constrained when stock-outs or delayed access to commodities occur . Collecting a DBS specimen from an HIV-exposed infant requires multiple items, and the stock-out of a single component may preclude sample collection entirely. In resource-limited settings, it is not uncommon for shortages of gloves or swabs to prevent healthcare workers from collecting DBS samples. In the laboratories, similar challenges are seen in the stocking of consumables. For example, EID test reagents have approximately 6–9 months of shelf life once they arrive in country. Because of the short shelf life, reagent batches are made to order, and manufacturers do not maintain back stock. In cases wherein countries are facing stock shortages, this may hamper testing programs for months. Challenges in data management and sample transportation often make it complex to predict the needs for EID commodities; therefore, regular monitoring of stock levels and accurate forecasting are critical .
The introduction of ‘bundled’ EID commodities has improved commodity management for EID testing by ensuring that all the items needed for a single test are bundled together into individual, cost-effective packages for healthcare workers and laboratory technicians. Optimization of EID commodities through bundling has streamlined the supply chain and reduced the likelihood of stock-outs and reappropriations, and further use of such bundled products should be encouraged.
Sample transport networks and result delivery
Sample transportation and the long TAT of samples and test results are key bottlenecks to timely EID . A sample referral network that reliably transports samples, commodities, and results between collection sites and laboratories is needed to link facilities at different levels of the healthcare system and provide access to PCR testing. However, many countries have not invested in such networks , resulting in nonstandardized sample transport, with anecdotal reports of health workers personally transporting samples. This frequently results in samples being lost or mishandled in a way that compromises specimen integrity. When deliveries finally arrive at the laboratory, backlogs in processing, loss of samples, and other errors add to the delays in performing accurate testing and providing timely results .
A significant point of patients’ LTFU appears to occur after the initial PCR test (Fig. 1). Lack of communication between facilities and the laboratory is another major obstacle for EID programs . The inability of healthcare workers to communicate with laboratories to follow-up on outstanding test results could lead to unnecessary repeat DBS collection. Likewise, a laboratory can face challenges if they are unable to communicate with facilities to correct issues around unsuitable sample collection or to advise immediately if a repeat sample is required. Although the use of technologies to expedite test result delivery through text messaging or remote data printing has successfully shown to reduce TAT of test results , the success of these solutions depends as much on their effective use by EID programs, as on the technologies themselves. Stronger communication and coordination between clinics and laboratories, coupled with formal systems and tools for tracking patients who do not return, could significantly reduce the number of infants who are LTFU [21,25].
Data management tools
Standardized data management tools and adequate training in their use will help EID programs run more efficiently by enabling healthcare workers to collect accurate and consistent data . Capturing EID data requires coordination across all levels of an EID program, to improve both the quality of HIV-exposed infant follow-up programs and the early identification of HIV-infected infants and referral for early ART. DBS samples should be accompanied by specimen tracking logs to ensure accurate and timely turnaround. PCR laboratories will function more efficiently if sample requisition forms and other associated documents are standardized across all collection sites.
At the facility level, the use of child health cards for all HIV-exposed infants, which can be readily accessed during follow-up visits and carried with the patient if they move to a different facility, can serve as a tool to enhance retention in care . Assigning HIV-infected mothers and their HIV-exposed infants with a unique ‘mother–infant’ pair identifier, for example, has helped healthcare workers to follow-up on infants whose mothers are HIV-infected, but for whom no HIV test results are available .
National databases linking information between the facilities and the laboratories would facilitate follow-up on delays, sample integrity, and supply stock-outs. Data from facilities, such as the number of infants tested, age at testing, and number of results delivered to the patients, are important to evaluate the performance of the EID testing sites as well as to inform forecasting of EID commodities.
As improved PMTCT services continue to reduce HIV transmission during the antepartum and intrapartum period, the proportion of transmission events during breastfeeding is expected to increase . In many settings, over 80% of mothers breastfeed their children ; therefore, appropriate follow-up of HIV-exposed infants until weaning is critical. Given the dramatic rates of infant attrition  and rapid disease progression in HIV-infected infants , one can expect that most LFTU infants will not survive. Furthermore, as there is very little information about testing performed beyond the 6-week PCR, it becomes difficult to understand the true vertical HIV transmission rate and monitor the progress of PMTCT programs. Access to EID virological testing presents an opportunity to improve the follow-up of HIV-exposed children, and to ensure HIV-infected children are linked to ART care swiftly .
Conducting an initial PCR test provides an opportunity for healthcare workers to reinforce infant feeding guidance and provide counsel and support to families. Tools for improved client tracking and record keeping can help healthcare workers follow children who were missed at their 4–6 week visit, or who may be at continued risk for HIV exposure . Many of the interventions described in the previous sections are proven, cost-effective methods to optimize service delivery , but distribution, training, and nonstandardization of these tools at various levels of the health system have limited their effectiveness . Busy facilities, human resource constraints, and long delays in receiving results all hinder health facilities from providing quality follow-up care for HIV-exposed infants . This attrition during the postnatal phase is unacceptable. Despite the best efforts of national programs to provide follow-up, the retention of infants through the EID testing cascade remains a huge task and the expectation that PMTCT programs could carry the burden for the follow-up of exposed infants alone may be unrealistic.
Linkage to antiretroviral therapy
Coverage rates for ART treatment suggest that only a fraction of the children diagnosed as HIV-infected are successfully enrolled into treatment programs, and significant delays occur between testing and initiation . Approximately 3.4 million children are living with HIV, but only 28% of those eligible for treatment were receiving it in 2011, compared with 58% of adults . This is unacceptable for HIV-infected infants whose risk of mortality is highest within the first few months of life . The ultimate benefit of an EID testing program is to ensure that shortly after diagnosis an HIV-infected infant will be linked and retained in pediatric-friendly HIV clinical services. Countries must expand their routine follow-up and care of HIV-exposed infants to integrate initiation of ART for infants found to be infected  – regularly reviewing the number of HIV-infected infants identified from each testing site and comparing this to how many are enrolled at associated ART centers. Several countries have developed electronic EID dashboards that report EID results in real time . These databases should be used to follow initiation of ART for the identified infected infants.
To improve linkage to ART, programs must ensure there are sufficient sites offering pediatric testing and treatment services. One current opportunity is to include EID and pediatric ART in all PMTCT sites that are expanding and decentralizing to accommodate Option B/B+. As these programs scale up ART services to pregnant women, simultaneous scale up of EID testing services as well as pediatric ART should follow.
Strengthening the link between the community and the facility is just as important as strengthening the services provided within the facility. For example in a pilot program in Malawi that used 16 community health workers to visit and monitor 1027 antenatal clients living with HIV, 98% of the infants received antiretroviral (ARV) prophylaxis and 77% were tested for HIV; of the 26 identified as positive, 92% were successfully enrolled into an ART clinic .
Expanding early infant diagnosis beyond PMTCT
The current approach to EID testing in PMTCT programs misses far too many children as almost 40% of pregnant women never access ANC during their pregnancy . In addition, current ANC attendance estimates document at least one visit, but no reliable estimates are available for infected women who complete the PMTCT cascade, with some studies showing up to 80% are lost 6 months postpartum [19,24]. It is safe to assume that the HIV-infected children of these women are also LTFU, and may only enter the health system much later, after they have begun to develop symptoms of advanced disease . Innovative and new approaches to EID testing are needed to ensure these children are identified earlier (see Case Finding paper in this series). One method is to utilize existing systems wherein infants have routine contact with the healthcare system. For example, immunization programs have achieved success in the uptake of routine vaccinations and can be used as a platform to schedule other routine health services . The 6-week EID test visit currently coincides with the first diphtheria, pertussis, and tetanus vaccination; however, subsequent visits at 10 weeks, 14 weeks, and 9 months provide additional opportunities for finding infants who have been missed . A study of such a program in Tanzania demonstrated the potential to improve early identification of HIV-infected infants through integration with immunization services if carefully managed .
Offering HIV testing in points of care wherein HIV-infected children are likely to present with symptoms of the disease (i.e., diarrhea, malnutrition, tuberculosis, respiratory infections) as well as providing continued routine care for an HIV-exposed infants will make case-finding more comprehensive . This approach led to increases in identification of previously undiagnosed infections . National-level data suggest that the prevalence of HIV-infected infants coming from other entry points, such as inpatient pediatric wards and malnutrition centers, is significant (see UNICEF paper in this series) . Achieving this goal requires a concerted effort on the part of child survival policy makers to advocate for a more comprehensive approach for this vulnerable population, and to establish clear and operational pathways between entry points and EID testing services.
Other strategies to improve early infant diagnosis
Strategies to retest mothers who were negative during their first antenatal visit are incorporated into many national guidelines as an additional intervention to identify new HIV infections; however, specific implementation plans and uptake have not been comprehensive . Retesting should be considered at various opportunities  – throughout gestation, at delivery, at the 6-week postnatal check, and every 3–6 months during breastfeeding, particularly in settings of high HIV incidence. With increasing PMTCT coverage, incident and untreated maternal infections have contributed to higher proportions of vertically infected infants . Checking the HIV status of women on their health cards, and offering regular routine testing to all women of childbearing age could improve the early identification of maternal infections.
Rapid testing for infants
Rapid diagnostic tests (RDTs) can be used to confirm HIV exposure for infants less than 18 months at about 85% sensitivity, with especially good correlation for infants less than 3 months  and 6 months of age . Both oral  and blood RDTs have good performance compared with conventional virological testing for excluding HIV infection [31,32].
The use of RDTs to screen infants has been proposed as a way to identify more exposed infants [20,29], as well as a means to facilitate rapid expansion of infant and young child HIV testing services across additional entry points . It should be noted that although this method of screening is viable, if a pregnant woman is infected late in pregnancy or during breastfeeding, the natural delay in developing and transferring HIV-specific antibodies from the infected mother may produce false-negative results in serological tests of the HIV-infected infant who do not, yet, produce his/her own HIV-specific antibodies. Newly available Ag–Ab combination tests, including one that detects and differentiates both P24Ag and HIV antibodies, raised high hopes for an RDT that would more effectively detect HIV infection in infants; however, the performance thus far has been poor [28,33]. The p24 antigen component of combination fourth-generation tests has poor sensitivity to detect infection, whereas the antibody component performs well to detect exposure. Ab–Ag RTD assays can therefore be used to detect exposure with good performance and sensitivity, but currently available tests are not effective for detecting infection in infants [28,33].
Until improvements are made in increasing sensitivity of the antigen portion, the use of these RDTs for infants will be limited to the detection of exposure. Continued investments in rapid virological testing for EID is needed to ensure quick and definitive diagnosis in infants.
Earlier infant testing
The evidence suggests that the risk of mortality for infants infected in utero is significantly greater in comparison to those with later infections . Earlier, ARV treatment reduces early mortality by 75% , but these results are less likely to be achieved without the swift diagnosis of HIV infection. An urban PMTCT program in South Africa recorded a median interval of 10 weeks between a PCR test and an ART initiation , and the ART initiation occurred at a median age of 16 weeks, which is after the documented peak of HIV-related mortality at 12 weeks of age . Thus, the initiation of treatment for infected infants comes very late for many of the infants who need it the most. Performing earlier EID will allow for earlier identification of HIV-infection in some infants, and may facilitate better outcomes. In fact, a high proportion of HIV-infected infants can be identified by 48 h of age: one study reported up to 76% of all perinatal infections detected at 6 weeks were also detectable at birth in some PMTCT settings . Earlier virological testing should be considered as part of a comprehensive EID testing algorithm that would catch all intrapartum and postpartum infections. The benefits of earlier testing must also be evaluated in terms of feasibility and in the context of different settings. Factors such as hospital delivery rates, LTFU of infants, and time between testing and ART initiation should lead to developing optimal strategies for earlier case finding and ART initiation, thereby reducing morbidity and mortality of perinatally infected infants.
Point of care early infant diagnosis
Point of care (POC) technologies present an opportunity to significantly improve access to EID, by bringing HIV testing out of the centralized laboratory and into settings where patients receive services. Utilizing POC technologies can positively impact patient outcomes and improve the national HIV program in several ways . First, shorter test TAT will allow results to be returned during the same visit, reducing LTFU and providing actionable results to clinicians immediately. Second, these technologies can reduce the burden of managing an extensive sample transportation network, particularly in difficult to reach places. Third, POC technologies can be performed by health workers lacking specialized laboratory skills. Finally, POC technologies can be placed at various entry points of healthcare facilities, such as maternity wards, for immediate testing of HIV-exposed infants at birth, or immunization and inpatient wards, facilitating a more rapid clinical response.
Several new POC diagnostic products will become available in the next several years for detecting viral RNA, DNA, and Gag p24 antigen . The new platforms will not have the high volume throughput of traditional laboratory-based technologies, and thus an appropriate balance of POC and conventional testing will need to be established in order for EID services to be most effective. Attention must be given to ensure that health workers are trained to follow standard operating procedures, that quality control and quality assurance measurements are in place, that commodities for EID POC and conventional laboratory testing are appropriately forecasted, and systems to integrate data collected from POC devices into national EID databases are developed. With appropriate deployment and integration of POC platforms into the existing EID laboratory network, the potential to improve access to EID testing for the millions of HIV-exposed infants in substantial.
Viral load and early infant diagnosis synergies
The Consolidated WHO ART guidelines recommend HIV viral load testing for ART monitoring of HIV-infected patients . As countries begin to scale up access to viral load testing, they may consider leveraging the existing PCR testing platforms that are currently being used for EID . It will be critical to monitor overall testing volumes for both EID and ART monitoring to ensure laboratory capacity is adequate to meet the increase in volumes and maintain high standards of quality. Clear guidelines for laboratories performing both tests should outline a workflow that ensures that the timely processing of EID samples is not compromised by the high volume of ART monitoring tests.
The current, relatively low global coverage of infant HIV testing services has created a small market for EID testing commodities, which has been challenging and unattractive for manufacturers. As a result, EID has been characterized by inefficiencies, including a paucity of suppliers and high reagent costs. The integration of processes common to EID and ART patient monitoring, such as sample transport systems and laboratory testing platforms, will be critical to programs looking to streamline supply chain, reduce costs, and improve sample processing at the laboratory. This integration may also provide a significant opportunity to provide EID and viral load as a single test – whether through a POC device, or potentially through a combined RNA-based PCR assay. Further research is required to understand the technical feasibility and any potential challenges that could come from a viral load and EID test synergy.
There are many opportunities to improve EID testing programs. First, expand the definition of EID within PMTCT to thoroughly encompass the entire risk period through the end of breastfeeding. Second, expand case-finding of exposed and infected infants and children beyond PMTCT to other child-oriented programs. This requires continued dialogue with child-survival program leaders and optimal strategies to find the children outside the traditional PMTCT cascade. Third, prioritize EID operational activities to improve weak sample transportation systems, delayed result delivery, poor data management, low uptake of optimized EID commodities, and other systemic concerns that will help to reduce the LTFU of infants in care. Fourth, develop and evaluate new and innovative testing strategies that would identify more HIV-exposed and infected infants, for their operational and technical feasibility. These should include, among others, systematic retesting of mothers who are negative at ANC; inclusion of PCR testing at birth as an additional option, but not a replacement, for subsequent PCR testing within a national infant and young child HIV testing algorithm; deployment of POC technologies in harmony with centralized laboratories; and potential synergies of viral load and EID testing.
Although we have highlighted some of the key challenges in implementing EID testing, we also outlined several potential interventions to improve access and service delivery. However, further research is required to guide the timing of optimal testing and the potential benefits and drawbacks of testing at birth, as well as the use of a combined EID/viral load assay. The introduction of POC should involve careful planning and evaluation of the existing laboratory network to determine appropriate operational deployment strategies, as well as the best balance between POC and conventional testing volumes. Programs should also evaluate which entry points would be most successful in improving case-finding of HIV-exposed and infected infants, and review the feasibility and opportunity of expanding EID testing into different settings.
PMTCT services have significantly expanded in recent years throughout high HIV burden, low-resource countries, but to achieve the ambitious goals of the Global Plan, programs must redefine their approach to be more child-centric. The strong investments in PMTCT programs have resulted in the scale-up of maternal ANC interventions with very few provisions for the effective follow-up of HIV-exposed infants. Efforts to prevent new infections through vertical transmission can only be successful if all HIV-exposed infants are followed through the entire testing cascade. The recent Global Plan progress report celebrates improved access to PMTCT services for pregnant women, and reports reduced rates of HIV transmission, but antenatal PMTCT coverage rates should not be the final measure of success, nor can the real impact of these interventions be interpreted from 6-week PCR test results alone, as infants continue to be at risk throughout the breastfeeding period. EID testing should and will remain a critical part of successful PMTCT programs. Identifying HIV-infected infants and initiating them on ART immediately will greatly impact the lives of those infants, whereas identifying and retaining all HIV-exposed infants through the end of the exposure period will highlight the success of PMTCT programs.
In the global response to HIV and AIDS, children have long been underserved. Improving access to EID presents an opportunity to increase the retention of exposed infants, and improve the outcome of those infected. In other words, give this vulnerable population a chance at survival.
Conflicts of interest
There are no conflicts of interest.
Disclaimer: The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the World Health Organization or the U.S. government including the U.S. Centers for Disease Control and Prevention and Agency for Toxic Substances Disease Registry and the United States Agency for International Development. The authors acknowledge the support of UNICEF and the Canadian International Development Agency (CIDA) whose financial assistance made this series possible and the U.S. President's Emergency Plan for AIDS Relief for support of contributing staff time.
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