HIV diagnosis and ARV use in HIV-exposed infants: a programmatic update

HIV DIAGNOSIS AND ARV USE IN HIV-EXPOSED INFANTS: A PROGRAMMATIC UPDATE JULY 2018 TECHNICAL REPORT 2© World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/ licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non- commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). 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The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Layout: 400.co.uk Printed in Switzerland 31.1 EXECUTIVE SUMMARY New HIV infections in children continue to occur globally and timely diagnosis and treatment of infants and children living with HIV remain critically important. The 2016 WHO ARV Consolidated Guidelines presented some innovative approaches, such as the use of nucleic acid testing (NAT) at or around birth for earlier diagnosis of HIV in infants, the introduction of point-of-care (POC) NAT for more rapid and decentralized diagnosis to enable prompt antiretroviral therapy (ART) initiation, and the use of enhanced postnatal prophylaxis (ePNP) to improve HIV prevention among infants exposed to HIV. To date, however, only a few countries have introduced these innovations and early lessons from the field have identified a number of implementation challenges that require careful review. Drawing on findings from a regional workshop held in Johannesburg, South Africa in 2017 and a follow-up expert meeting in Geneva, Switzerland in 2018, this programmatic update aims to describe changes in strategies for the identification, prevention and treatment of HIV in infants. This update will also highlight new information on the implementation of a postnatal package of care for HIV- exposed infants. ABBREVIATIONS 3TC lamivudine ART antiretroviral therapy ARV antiretroviral drugs AZT azidothymidine (zidovudine) CTX co-trimoxazole EID early infant diagnosis ePNP enhanced postnatal prophylaxis FDC fixed-dose combination HCW health-care worker HIV human immunodeficiency virus HIVDR HIV drug resistance LPV/r lopinavir/ritonavir MCH mother and child health MTCT mother-to-child transmission PMTCT prevention of mother-to-child transmission NAT nucleic acid test NVP nevirapine PCR polymerase chain reaction POC point-of-care RAL raltegravir RDT rapid diagnostics test SOP standard operating procedure VL viral load 42.1 BACKGROUND 2.1.1 Current status quo regarding pediatric HIV The Global Plan Towards the Elimination of New HIV Infections among Children by 2015 and Keeping their Mothers Alive initiative has had a substantial impact, leading to a 60% reduction in new pediatric HIV infections in 21 high-burden countries in sub-Saharan Africa.1,2 Nevertheless, the burden of new HIV infections in children remains significant: in 2017, there were 180 000 new infections in children globally, and 70% of these children were in the same 21 priority countries. The Start Free, Stay Free, AIDS Free framework3 was developed to build on the progress of the Global Plan and to provide a roadmap to achieve fast- track targets towards ending the AIDS epidemic by 2030. Following the adoption of the Option B+ policy4, the number of pregnant women on antiretroviral therapy (ART) has increased considerably across countries. This in turn has led to lower rates of vertical HIV transmission, now estimated to be less than 2% in non-breastfeeding populations, and less than 5% in breastfeeding populations.5,6 Despite the overall decrease in mother-to-child transmission (MTCT) of HIV, new pediatric infections continue to occur and transmission dynamics have now shifted towards a proportional increase in transmission during the postnatal period (Figure 1).3,7 Roughly half of all new infections among children occurs during breastfeeding. Although countries continue to make progress, challenges remain in retaining HIV-infected women in health- care services and on effective ART throughout pregnancy and the breastfeeding period, as well as in detecting and preventing new HIV infections in women during pregnancy and breastfeeding. This shift in transmission dynamics has also raised issues concerning optimal testing in infants, with the identification of HIV-exposed and HIV-infected children continuing to present a significant bottleneck in several settings. Early infant diagnosis (EID) coverage globally still remains low: in 2016 only 43% of infants exposed to HIV received an HIV test within the first 2 months of life.8 Figure 1 MTCT transmission rates in the priority countries of the Start Free, Stay Free, AIDS Free framework in 2017 (Source: UNAIDS 2018 estimates) 0 10 20 30 Indonesia 19% 7% 26% 26% 26% 21% 20% 19% 18% 16% 15% 14% 14% 12% 11% 11% 10% 9% 8% 8% 7% 6% 5% 5% Angola 15% 11% Nigeria 14% 14% Ethiopia 11% 10% Democratic Republic of Congo 12% 8% Ghana 10% 9% Chad Côte d’Ivoire Cameroon Mozambique Burundi United Republic of Tanzania Lesotho Kenya Zambia Malawi Uganda Eswatini Zimbabwe Namibia South Africa Botswana 10% 8% 8% 8% 9% 6% 7% 7% 6% 8% 6% 6% 5% 6% 6% 5% 4% 6% 3% 6% 4% 4% 3% 5% 2% 5% 2% 4% 2% 3% 3% 2% 6 week transmission rate Post 6 week transmission rate 5Furthermore, although pediatric ART coverage has notably improved since 2010, only 51% of the estimated 1.8 million children living with HIV were receiving ART by the end of 2017.3 HIV-infected infants and younger children have an exceptionally high mortality without treatment, approximately 30% by the first year and 50% by their second year of life.9 Many HIV-related deaths in infants can be avoided by early identification of HIV and rapid ART initiation. Limited availability of optimal antiretroviral (ARV) formulations for preventing and treating HIV infection in newborn and young infants remains, however, an ongoing challenge in many countries. 2.1.2 Rationale for this technical update The 2016 WHO Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection10 presented innovative approaches to diagnosis and treatment; however, to date only a few countries have started to implement these innovations. In addition, evidence from early adopter countries has raised a number of issues that require careful consideration and have generated lessons learned that may be useful for countries planning to adopt these interventions. • Reduction in MTCT rates has led to a decrease in the positive predictive value of nucleic acid testing (NAT), resulting in higher proportions of false-positive test results. There is currently no specific recommendation on what level of viremia should be considered a true- positive result in infants and whether there is benefit in defining an indeterminate range for NAT. • Significant drug exposure due to implementation of the Treat All policy and enhanced postnatal prophylaxis (ePNP) could cause delays in antibody development in infants with HIV infection. These dynamics may complicate the use of rrapid diagnostic tests (RDTs) in infants to determine exposure and/or infection and affect how RDTs are used and interpreted in infants under 18 months of age. • Addition of NAT at birth to the national infant testing algorithm has been considered by a number of countries. Several operational challenges have emerged and a critical review of these will be important to support the strategic introduction of birth testing where feasible and most appropriate. • ePNP for high-risk infants is being implemented in a number of countries but challenges persist with identifying infants at high-risk and providing ePNP with existing formulations. This has led to simplified approaches, currently being considered by a number of countries, that may have an impact on infant testing. • Greater emphasis should be placed on strengthening the postnatal package of care for HIV-exposed infants and their mothers. There are opportunities to consider combining successful interventions into packages in order to support service delivery, and placing greater importance on promoting the integration of services to ensure that infants are retained in care until final diagnosis. Following the WHO regional workshop in Johannesburg, South Africa (June 2017)11, an expert meeting was convened in April 2018 to provide insight and promote discussion on these matters. This programmatic update aims to detail important changes and new implementation considerations arising since the publication of the 2016 WHO ARV Consolidated Guidelines.10 3.0 KEY CONSIDERATIONS 3.1 Infant diagnosis The complexity of EID testing is now growing due to significant scale up of Treat All (including pregnant and breastfeeding women), implementation of ePNP, reduced MTCT rates and the increased relative contribution of postnatal transmission. EID can no longer be considered primarily a one-test process, since it now requires additional testing over the duration of exposure. Accordingly, several additional key considerations will be necessary to strengthen the EID testing cascade through the entire exposure period. This includes ensuring that ART initiation is not delayed in those infants found to have HIV infection. 3.1.1 Minimising false-positive results by introducing an indeterminate range for EID Although infant diagnosis is being scaled up globally, with increased access to Treat all, declining MTCT rates12 and low viremia observed in infants found to be infected with HIV13 mean that false-positive test results are increasingly being reported in programs. Some infants may therefore be incorrectly diagnosed as having HIV infection and started on lifelong ART unnecessarily. There is currently no specific recommendation on what level of viremia should be considered a true-positive result in infants and whether there is benefit to adding an indeterminate range to minimize false-positive test results (see Box 1). 6A systematic review of 32 studies using an indeterminate range found 14 753 non-negative test results of which 2 436 (16.5% [95% CI 15.9–17.1%]) were indeterminate (data unpublished); one study14 that reported the final diagnoses of indeterminate cases found that 76% of infants with an initial indeterminate test result were negative on repeat testing, suggesting these infants were not HIV-infected despite the initial non-negative test result. These data indicate that in countries not implementing an indeterminate range for NAT and where MCTC rates are low (<5%), 12.5% (76% of 16.5%) of non-negative results could be false-positive on initial testing with affected infants being potentially started on lifelong treatment unnecessarily. Typically, EID assays detect the presence of HIV using real-time NAT technologies that often report cycle thresholds. Reported cycle thresholds represent the PCR cycle at which amplification is first observed and are inversely correlated to the amount of virus in the sample. The approximate equivalent of a cycle threshold of 33 on the Roche COBAS® Ampliprep/COBAS® TaqMan® HIV-1 Qualitative Test v2.0 assay was selected as the optimal indeterminate range for further testing. This represented a balance between the proportion of infants living with HIV that would be incorrectly identified as indeterminate (about 8-13%) and the proportion of HIV-uninfected infants that would potentially start treatment unnecessarily (about 2–7%). South Africa has already implemented an indeterminate range and developed a standard operating procedure (SOP) for managing positive and indeterminate test results.15 Similarly, WHO technical consultation developed a new SOP that will help to ensure higher quality infant testing (Annex 1). Current evidence suggests that no specific requirements are necessary with regard to the type of assay (conventional or point-of-care (POC)) used to retest specimens with indeterminate test results. Most countries already apply a national SOP when testing errors are encountered (for example, device malfunction, insufficient or rejected specimen, etc.). In most countries the health-care facility concerned is contacted and asked to ensure that the infant returns to the facility in order to provide a new specimen for testing. Due to the delay caused by the testing error, these samples are generally considered urgent and prioritized for testing once received by the laboratory. A new study suggests that repeating an indeterminate test result using the same sample, if available, will resolve the majority (>95%) of indeterminate results.14 Therefore, prior to contacting the health- care facility to request the infant return to the facility for collection of a new sample, a repeat test should be conducted on the same sample using additional available dried blood spots or remaining whole blood. 3.1.2 Confirmatory testing of positive test results A cost-effectiveness analysis undertaken to assess the value of confirmatory testing in different scenarios highlighted that confirmatory testing is indeed cost- effective.16 Without confirmatory testing, this analysis showed that in settings with MTCT rates similar to those of South Africa, more than 10% of infants initiated on ART may in fact be HIV-uninfected. Confirmatory testing of positive test results using a new sample, as per WHO guidelines, may avoid this occurrence, although this policy is not consistently implemented (Box 2). It remains critical that programs ensure all HIV-exposed infants are retained and tested appropriately throughout the entire exposure Box 1. Definition of terms for diagnostic results • Indeterminate range: a range of viral copy equivalents that would be too low to accurately diagnose as positive. • False-positive result: HIV-uninfected infants incorrectly identified as HIV-infected and potentially started unnecessarily on ART. • False-negative result: HIV-infected infants incorrectly identified as HIV-uninfected. • Non-negative result: any positive or indeterminate result. Polmyerase chain reaction (PCR) instrument reports a detectable result, which may be subsequently classified as “indeterminate” based on other data (e.g. assay-reported cycle threshold). May also be referred to as “not confirmed”, “equivocal” or “irreproducible positive”. • Discordant result: positive/detectable first test; negative second test. • Cycle threshold: the point at which virus amplification is first observed during the course of repeated PCR cycles. The cycle threshold is inversely correlated to the amount of virus in the sample. 7period and all infants with a positive result receive a confirmatory test. Furthermore, those with repeatedly indeterminate test results should be actively tracked, retained, retested and their status resolved. Finally, POC EID testing is being implemented in several countries and settings (see 3.1.3). Previously there was limited evidence on how to conduct confirmatory testing of POC EID positive test results, but since publication of the 2016 WHO ARV Consolidated Guidelines10 several studies have been published on its performance. Two POC EID technologies are now included on the WHO list of prequalified in vitro diagnostic products.17 Results from both laboratory and field studies have shown performance comparable to that of laboratory-based technologies.18 Furthermore, two patient impact studies have been published which highlight the significantly improved patient outcomes when using POC EID technologies.19,20 Based on this updated evidence, POC EID testing can be used to confirm positive test results. 3.1.2 Managing discordant results and treatment interruption Since 2010, WHO has recommended initiating infants on ART after an initial positive NAT, while simultaneously collecting a confirmatory sample. The 2016 WHO ARV Consolidated Guidelines10 suggest that if the second (confirmatory) NAT is negative, a third NAT, either EID (qualitative) or viral load (VL), should be performed before considering ART interruption. The introduction of an indeterminate range should potentially reduce the number and proportion of infants with discordant test results (different NAT results on separate samples); however, guidance on how to conduct treatment interruptions is needed. Several factors should be considered when assessing patients for ART interruption after discordant test results (positive then a negative result) are followed by a third test with a negative result: • the infant ought to have no clinical signs or symptoms suggestive of HIV infection;21 • a follow-up plan should be agreed upon with family, caregiver(s) and health-care staff; • tracking information (phone, address, etc.) of the family/caregiver(s) should be collected and confirmed. The following factors should be considered when following up any infant undergoing treatment interruption: • there is a need for active follow-up to ensure that a potentially infected infant is retained and re-initiated on treatment if virological rebound occurs; • virological rebound in HIV-infected infants starting treatment early is expected to happen within 8 months of interruption in >99% of HIV-infected infants;22 • infants who develop signs and symptoms indicative of HIV infection should undergo immediate testing; • breastfeeding and continued risk of transmission require follow-up and appropriate testing throughout the period of risk until final diagnosis; • there is value in minimizing follow-up testing by leveraging existing opportunities for infant testing (based on the national infant testing schedule and immunization or well-child appointment schedules), until final diagnosis is ascertained. Few countries have existing policies on how to conduct treatment interruptions in infants with discordant test results. South Africa, for one, has implemented policies with intensive laboratory and clinical follow-up of these infants for 18 months.15 Both EID (qualitative) and VL (quantitative) tests are performed at 4 weeks, 3 months, and every 3 months after treatment interruption. However, since the likelihood of these infants being HIV-infected is low, a less aggressive 8 month approach is also reasonable in order to simplify the follow-up procedure: this is supported by emerging evidence on the timing of viral rebound in HIV-infected infants treated early.22 In this case both EID (qualitative) and VL (quantitative) tests could be performed at 4 weeks, 4 months and 8 months after treatment interruption (Annex 2). Infants who test positive on any follow-up test in either protocol should be re-initiated on treatment as per current guidelines,10 and a confirmatory sample taken. Any SOP for interruption should be implemented considering the continuous risk of transmission resulting from breastfeeding and, once the intensive follow up is completed (8 months after treatment interruption), the national infant testing schedule for HIV-exposed infants should be applied in order to ensure an appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post cessation of breastfeeding, as indicated in Annex 2 Scenario b. Box 2. Prioritizing confirmatory testing of positive and indeterminate tests • Decreasing MTCT rates globally have led to concerns about false-positive and indeterminate tests. • Patients with indeterminate results need immediate repeat testing and the patient should be managed according to the SOP presented in Annex 1. • Patients with repeated indeterminate results need a multidisciplinary team of health-care providers to support retention, tracking and status resolution. • In ART programs, there is a need to prioritize confirmatory testing of all positive test results using a new sample. • Clinical monitoring and further testing based on the national infant testing schedule need to be done until a definitive HIV status is established. 83.1.3 Implementation of POC EID testing The 2016 WHO ARV Consolidated Guidelines10 recommend the use of NAT technologies for early infant HIV testing that have been developed and validated for use at or near the point-of-care. POC EID provides the opportunity to reduce test turnaround times, limit patient loss along the HIV testing cascade, reduce infant mortality and facilitate task shifting to lower cadres of health workers at health- care facilities with decentralized services. Sufficient evidence has been generated on the performance of these assays in their intended field settings to support rapid national regulatory approval and initiation of scale-up (Box 3). A number of countries are currently implementing POC EID technologies.18 Implementation studies in Malawi20 and Mozambique19 have shown that using POC EID leads to significantly reduced test turnaround times, with a higher yield of results being returned to the health-care facility and caregivers, and earlier and higher rates of ART initiation among HIV-infected infants. Key lessons learned during pilot implementation projects include: • optimizing the use of POC EID through product and site selection; • selecting health facilities with high prevalence and high volumes to maximize device utilization; • considering placement within or in-facility referral from high-yield entry points (e.g. nutrition and pediatric wards); • ensuring service continuity by establishing a service and maintenance strategy with suppliers and provide service engineer back-up; • integrating services within health facilities by assessing the need for additional training and continuous mentoring of health-care workers (HCW); • strengthening the linkage between services to ensure prompt linkage to care for identified HIV-infected infants; • ensuring the availability of pediatric ARV formulations for neonates to guarantee earlier ART initiation. 3.1.4 Introduction of NAT at birth to facilitate earlier treatment initiation Adding NAT at birth to the existing national infant testing schedule may result in earlier identification of HIV-infected newborns and consequently lead to earlier treatment initiation and lower mortality among infants. Data suggest that infants testing positive at birth start ART approximately 2 months earlier than non-birth- tested infants (6 weeks vs 15 weeks).23 However, cost- effectiveness analyses have shown that the survival gains from adding NAT at birth to the standard 6-week test are lost if the loss-to-follow-up after a negative birth result exceeds 37%, underscoring the fact that a high-functioning 6-week program needs to already be in place. A number of countries have already started implementation of NAT at birth, and country experiences are outlined in Box 4. It should be noted, however, that strengthening existing EID systems remains the priority while programs consider adding birth testing. Several implementation considerations can be summarized from these experiences. • Countries that are considering birth testing should critically review current performance and opportunities for strengthening their 6-week EID program and consider other indicators, (e.g. PENTA1 immunization visit coverage and attended delivery rate), so that the potential gains provided by birth testing can be investigated more fully. For example, in settings where the attended delivery rate is much lower than PENTA1 immunization visit coverage the added value of birth testing as a means of expanding EID is limited. • Pilot projects are a good way to start gaining national experience on this innovative testing approach, but in order to measure impact fully programs need to collect data on the feasibility and impact of birth testing and linkage to ART initiation. • Targeted approaches which provide birth testing only for high-risk infants are expected to have a higher yield compared to routine birth testing. This approach may be potentially less resource intensive and present a lower burden for HCW. • Active tracking of infants with negative NAT results at birth is critical to ensure that they return at 6 weeks to be retested and start co-trimoxazole (CTX); establishing unique patient identifiers or other innovative mechanisms (e.g. bar codes) to track babies can be considered. • It is crucial that the turnaround time for reporting test results to health facilities and caregivers be rapid in order to optimize the benefit from NAT at birth, and POC assays should be used where they are available. Box 3. New POC EID technologies • Two technologies have received WHO prequalification. • National regulatory agencies are encouraged not to delay adoption by conducting further evaluations but instead to adopt a rapid and streamlined registration and national approval process for immediate implementation. 9• Birth testing is acceptable to mothers, but challenges arise from the increased human resources needed, the difficulty of collecting blood samples in newborns, the need to ensure sample collection outside of standard working hours and deliver results, linkage to ART and the nature of the EID system as a whole (stock-outs, referral mechanisms, delayed results). Box 4. Implementation of birth testing: country experiences South Africa South Africa introduced NAT at birth in 2015 with specific nurse training at postnatal and delivery services and health register updates to enable data acquisition. Implementation challenges met by South Africa include weak linkage of the identified HIV-infected infants to care with consequent delay in ART initiation, and a low return rate for future testing among infants with negative results at birth. A qualitative sub-study found that birth testing had a high acceptability. Refusals were rare and mothers did not indicate that birth testing affected their subsequent acceptance of infant testing or postnatal clinic attendance. Weak follow-up systems were detected for mothers who had home deliveries, and concerns were raised by laboratory staff about increased workloads associated with additional testing requirements. Kenya Kenya started a NAT at birth pilot project in 2015 (defined as testing within 72 hours of birth) and its results formed the basis of a revised EID algorithm in 2016 and national scale-up plan, due to start in mid-2018. Prior to implementation, a central point was designated within the health-care facility for birth testing, an innovative dispatch register was developed, mothers were offered mentoring to assist with linkage between hospitals and communities and a prevention of mother-to-child transmission (PMTCT) psychosocial support group was formed. Good leadership and coordination was identified as being important for seeing patients through service provision. Challenges included issues related to referral, demand creation, turnaround time for test results and mothers who failed to collect test results. In addition, ART formulations were lacking for neonates who tested positive during the initial implementation phase. Zimbabwe Zimbabwe started a POC NAT birth pilot in April 2017 in ten health facilities for high-risk HIV-exposed infants (< 48 hours after birth). Ninety-seven per cent of the results were transmitted to caregivers, and all HIV-infected infants started ART within 5 days of testing. This project is likely to provide critical experience on a different approach to tracking children after birth testing and will generate further information on the value of targeting birth testing for high-risk infants rather than all HIV-exposed infants. Democratic Republic of Congo NAT at birth was first implemented in December 2016, with samples sent to central laboratories for processing. Laboratory personnel were trained to prioritize birth samples and ensure prompt return of results to the health facility. Challenges included long turnaround times between specimen collection and receipt of results (8–12 weeks from the national laboratory), stock-outs due to limitations in supply chain management, and difficulties in specimen transportation. Uptake of birth testing was good, but yield was low with numerous missed opportunities due to early discharge of women from maternity wards. As a result, birth testing remains limited to this pilot project (now terminated) and efforts are being made to strengthen the existing 6-week EID program. Eswatini (Swaziland) Eswatini introduced two pilot projects to explore universal NAT at birth across five maternity sites in August 2017 using POC EID technologies in three sites (in partnership with EGPAF) and conventional testing in two sites (in partnership with ICAP). In the conventional test pilot, 93% of HIV-exposed newborns were tested before discharge from the maternity unit and six of the 1 548 tested were HIV-infected. In the POC testing pilot, 68% of HIV-exposed newborns were tested and 12 of the 1 314 tested were HIV-infected. Furthermore, 98% of results were returned to the caregiver. Of those HIV-infected, nine in the POC test pilot and four in the conventional test pilot were put on treatment. Both pilots confirmed that health-care facility staff face a heavier work burden when NAT at birth was added. Nurses often felt overwhelmed and failed to prioritize NAT at birth because many births occurred at night or on weekends when staffing was limited. Furthermore, although most mothers found birth testing to be acceptable, several were discharged or left the facility before getting tested, while others provided incorrect tracking information. Ensuring patient tracking and linkage proved to be a challenge. • The key to effective implementation is to ensure that newborns who have been identified as HIV-infected are linked to treatment and that age-appropriate formulations are available to start them on treatment. • Good leadership and coordination are needed to oversee service provision, support supervision, mentorship and the quality improvement cycle. 10 11 3.1.5 Ensuring accurate interpretation of the 9-month test and simplifying the testing algorithm The 2016 WHO ARV Consolidated Guidelines recommend that RDTs should be used to assess HIV exposure among infants younger than 4 months, while HIV exposure among infants 4–18 months old should be ascertained by testing the mother. When testing of the mother is not possible, current guidelines emphasize the importance of not considering a negative RDT result from an infant between 4–18 months as a definitive test of exposure. Implementation issues are highlighted in Box 5. Based on the 2016 WHO ARV Consolidated Guidelines10, RDTs are serological assays that can also be used to exclude established infection among healthy, HIV-exposed infants aged 9 months old and above. However, changes in transmission dynamics as well as in policy and practice have complicated RDT use for determining infection status. Substantial drug exposure for infants with implementation of the Treat All policy for mothers and enhanced postnatal prophylaxis of HIV-exposed infants may have resulted in viral load reduction and delayed antibody development in HIV-infected infants. Finally, the occurrence of maternal infection in late pregnancy or during the postnatal period may be responsible for a lack of passive HIV antibody transfer to the HIV-exposed infant. These factors increasingly jeopardize RDT accuracy at 9 months of age as a means of correctly ruling out established infection in HIV- exposed infants. These concerns are supported by findings from Uganda and Kenya,24, 25 where 15–40% of children under two years of age and identified as HIV-infected had a positive NAT but negative RDT. RDT at 9 months was initially recommended in the 2010 WHO recommendations on the diagnosis of HIV infection in infants and children21 with the goal of targeting NAT for those HIV-exposed infants most likely to be infected (e.g. those with a positive RDT) as a cost-saving measure. However, due to decreasing MTCT rates, increasing availability and lower costs of NAT, changing transmission and drug exposure dynamics, and the fact that RDTs are less effective at determining the need for NAT testing, such a targeted approach may be less compelling. Furthermore, the added programmatic complexity and potential for inappropriate interpretation of test results have additional unintended consequences. In light of the challenges and data outlined above, consideration can now be given to replacing RDT at 9 months with NAT in the interests of minimizing the challenges of interpretation and simplifying the infant testing algorithm. Annex 3 summarizes the new simplified algorithm, which is underscored by a number of key considerations: • assessing HIV exposure status by performing RDT on the mother; • at 9 months performing NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative; • ensuring indeterminate test results are repeat tested immediately and prioritized for rapid resolution; • ensuring confirmatory testing is undertaken following any positive result; and • ensuring all HIV-exposed infants are regularly followed up until final diagnosis, with the provision of CTX prophylaxis and clinical/nutritional assessment. Finally, it remains critical that infant retention be continued until the end of the exposure period. More effort should be given to establishing a final diagnosis at 18 months of age or 3 months after cessation of breastfeeding, whichever occurs later. Although there is increasing coverage of the traditional 6-week infant test and more consideration is given to earlier time-points, the changing dynamics of transmission and increased drug exposure mean that increased efforts are needed to maintain follow-up throughout the entire exposure period. The aim is to ensure that all HIV-infected infants, including those infected in the postnatal period, are identified and receive treatment. Box 5. Use of RDT: implementation considerations • Priority should continue to be given to the testing of mothers at all entry points to determine exposure status for infants and children less than 18 months. • If the mother is absent or unable to be tested, an RDT should be undertaken of the infant, but negative results of infants older than 4 months should not be considered as definitive exclusion of exposure and follow-up testing is required. • If the mother is absent or unable to be tested and the infant presents with signs and symptoms of HIV infection, a NAT should be undertaken. • NAT should be undertaken following any positive RDT in the mother or the infant and a confirmatory NAT undertaken following any positive NAT result. 12 3.2. ARV use for prevention and treatment of HIV in infants 3.2.1 Implementation challenges to providing ePNP for high-risk infants The 2016 WHO ARV Consolidated Guidelines recommend a dual regimen of AZT and NVP which can be extended for up to 12 weeks in breastfeeding infants deemed to be at high risk of MTCT. A high-risk infant is defined as an infant whose mother was first identified as HIV-infected at delivery or in the postpartum, infected during pregnancy or breastfeeding, started ART late in pregnancy, or did not achieve viral suppression by the time of delivery (Annex 4). All high-risk infants should receive dual drug prophylaxis (AZT plus NVP) for the first 6 weeks. In breastfeeding infants, this should be followed by either an extra 6 weeks of AZT plus NVP or an extra 6 weeks of NVP alone (see Box 6). This recommendation is based on evidence from randomized clinical trials26 and takes into account the risk- benefit ratio of ePNP: potential for increased drug toxicity versus additional protection from HIV transmission. The rationale for the use of extended ePNP especially in high- risk breastfeeding infants rests on the assumption that mothers started promptly on ART achieve viral suppression within 12 weeks, thereby greatly reducing the risk of breast milk transmission and the need for ongoing infant prophylaxis. Countries have adopted ePNP using a variety of different approaches. In Kenya, Eswatini (Swaziland), and Mozambique, ePNP has been adopted for all breastfeeding HIV-exposed infants, while nine countries (Botswana, Ghana, Namibia, Nigeria, South Africa, Tanzania, Uganda, Zambia and Zimbabwe) have adopted ePNP for high- risk infants identified primarily on the basis of maternal ART duration and, when available, maternal VL close to delivery. Most countries opted for at least 12 weeks of prophylaxis, usually AZT/NVP for the first 6 weeks followed by NVP alone. Three countries (Kenya, Namibia and South Africa) link the duration of ePNP to the maternal VL, and extend ePNP over the entire breastfeeding period when viral suppression is not achieved. Finally, in three countries (Botswana, Zambia and Tanzania), triple prophylaxis with a fixed-dose combination (FDC) of AZT/3TC/NVP has been adopted to address the challenges of procuring syrups. Recent guidelines on infant feeding27 in relation to HIV re-affirm the position of WHO that the best way to prevent MTCT in the postpartum period and optimize infant survival is to ensure that mothers living with HIV are well controlled on ART and able to breastfeed their infants for up to two years, with the infant being exclusively breastfed in the first six months of life. If a mother on ART is virologically suppressed, the risk of breast milk transmission of HIV is very low and infant prophylaxis confers minimal additional benefit beyond 4–6 weeks of life. Some program have adopted ePNP for all HIV-exposed infants. While this may simplify decision-making, it increases costs and exposes a large number of infants who may not need ePNP to added toxicity. This type of approach ought to be reserved for selected situations where a majority of mothers are at high risk of transmitting HIV. Data on the average duration of ART at delivery and, where available, the proportion of pregnant women with VL>1000 at the end of the third trimester might help policymakers to determine whether added costs and toxicity are outweighed by potential benefit. Even then, it should only be an interim measure while strategies to increase the coverage of maternal testing, early treatment and improved adherence are being implemented. However, there are several situations where viral suppression throughout the breastfeeding period cannot be ensured in the mother, for example: • if a mother refuses or is unable to start or continue ART and intends to breastfeed her infant; • if the provider knows the mother is poorly adherent to ART while breastfeeding; • if maternal VL is known to be high when the infant prophylaxis regimen is about to be stopped. There is no formal recommendation for these types of situations and no evidence to guide the best course of action. It is reasonable, however, to assume that infant prophylaxis serves as a “back-up” solution for preventing postnatal transmission of HIV, and national programs could consider the merits of giving clinical providers the option of continuing infant prophylaxis beyond the recommended 6- or 12-week period. If this option is introduced in the national guidelines, there ought to be clearly defined scenarios in which continuing prophylaxis is warranted. National guidelines should also emphasize that the best way to prevent breast milk transmission of HIV is by optimal maternal treatment for the entire duration of exposure. Continuing prophylaxis should therefore be seen as an interim measure while efforts are made to support and improve maternal treatment adherence. Deciding to continue prophylaxis should take into consideration the factors that led to poor maternal adherence as they may have an impact on adherence to infant prophylaxis. Once stopped, infant prophylaxis should not be re-started if there are new concerns about maternal adherence. There is no evidence to support such an approach; instead the focus should be on determining why the mother was unable to remain adherent. If the decision has been made to continue infant prophylaxis, mothers and infants should be evaluated at regular intervals to assess the need for ongoing infant prophylaxis. 13 As more effective treatments increasingly come to be used in pregnant women, we can expect decreasing MTCT rates. However, some women will still be diagnosed late or have incident infections and this group is likely to drive most new cases of HIV transmission to infants, owing to the high level of maternal virus in the absence of treatment. One possibility would be to provide “presumptive treatment” as postnatal ePNP, by administering a triple-drug regimen at therapeutic doses to this selected group of infants with the goal of minimizing transmission and drug-resistant HIV (HIVDR) selection in the event of established infection despite prophylaxis. Such approaches need to be paired with careful review of infant testing practices in order to determine the potential impact of triple ePNP on virological assay performance for infant diagnosis (i.e. at least one specimen must be collected prior to initiating any presumptive treatment so that a NAT can be performed as soon as possible). 3.2.2 Early infant treatment: limited options and complex administration Early infant ART improves survival and reduces long-term morbidity but mortality remains substantial in the first months of life. Introducing NAT at birth could enable ART to be started before 2 weeks of age. However the only regimen available for this age group has for many years been one containing AZT, 3TC and NVP. This regimen could be continued with close clinical monitoring until 3 months of age and then switched to a LPV/r-based regimen, using LPV/r pellets, or LPV/r could be introduced at the end of the second week of life as syrup and then switched to a solid formulation at 3 months of age. Raltegravir (RAL) granules have recently been approved by the US Food and Drug Administration for use in neonates at full term, except for low birthweight or premature babies. This is a considerable advance in increasing treatment options for neonates. Feasibility and acceptability of this formulation are currently being assessed in a study in South Africa. The 2016 WHO ARV Consolidated Guidelines10 already recommend the use of RAL as an alternative first- line treatment for children younger than 3 months where LPV/r pellets cannot be used. At present, RAL suitable for administration in the neonatal period is only available as a granule for oral suspension, but improved formulations are being developed for future use. Countries considering whether to introduce birth testing will need to consider their ability to decentralize newborn treatment by strengthening HCW capacity, ensuring commodities are available at peripheral health facilities and/or extending the referral system to nearby facilities, as well as ensuring that HCW are fully trained and equipped to start newborn infants on treatment. Box 6. ARV Formulations for ePNP: implementation considerations There are three available formulations that can be used for dosing ePNP: • NVP and AZT syrups; • pediatric dispersible NVP tablets and; • pediatric fixed-dose combinations (FDCs). Each formulation has its own benefits and risks (see Annex 5). A pediatric FDC of AZT/3TC/NVP has some appeal as ePNP because it is widely available and well established in a child-friendly formulation. However, there are several challenges to using this triple-drug FDC option that programs should consider: • NVP is administered as a once-daily dose for prophylaxis, whereas AZT is a twice-daily dose, so using an FDC compromises one or other of the drug regimens. Either AZT should be administered once daily or NVP twice daily. • The AZT:NVP ratio within the FDC is appropriate for the first 6 weeks of ePNP but it cannot be used for weeks 6 to 12 when the AZT dose increases fourfold while the NVP dose increases by only one third. • This pediatric FDC contains 3TC in addition to AZT and NVP. Although 3TC is very well tolerated, and has been used as a single drug for ePNP in clinical trials, WHO does not currently recommend this drug for infant prophylaxis. Administration of the FDC would inevitably expose the infant to 3TC. • In order to use an FDC as ePNP in the first 6 weeks of life, a single tablet would have to be divided into quarters. Tablets are scored but only into halves. Despite these challenges, FDCs are readily available, easy to use and have been proposed as a mean to simplifying administration in high-risk infant prophylaxis. Benefits and risks of the different dosing options are outlined in Annex 5. 14 provide opportunities to strengthen service delivery for HIV-exposed infants. Integration within a well established maternal, neonatal, and child services platform, which traditionally provides services closest to clients, facilitates mother-infant pair follow-up and reduces the cost and time-visit burden on clients. The integrated information systems that link mother and infant information improve client tracking and facilitate continuity of care provision. Examples include longitudinal follow-up registers and cohort analysis as well as linkage with information on communit-based services. Programs should however take into consideration the increasing burden on the MCH platform within the context of existing human resources and the challenges of changing services. Community engagement and community-based services play an important role in supporting HIV-exposed infant care. These clear and highly context specific services play a “boosting” role in supporting facility-focused services and include community-based HIV testing. The engagement of networks of women living with HIV has been effective in several countries and has been used to improve community HIV literacy to create demand, form support groups at the facility and community levels, strengthen linkage to care by escorting newly diagnosed clients to treatment clinics, conduct defaulter tracking and provide active follow-up of mother-infant pairs. In several settings, these interventions led to reduced loss to follow-up among mother-infant pairs. Ensuring provision of a comprehensive integrated postnatal package of HIV services will promote the delivery of a set of interventions that contributes not only to improved HIV outcomes but better early childhood development overall. 3.3. Improving service delivery and implementing a postnatal package of care There are several barriers to the uptake of effective infant HIV services, and no single intervention can address all the barriers facing women and their infants at different times and places. Socio-economic and traditional factors that keep mother-infant pairs together are among the enabling circumstances that improve service uptake. Programs could benefit from combining effective interventions into “service packages” to support service provision and focus on the community engagement that supports uptake. Interventions which have been proven to improve provision and uptake of infant HIV services and the retention of mother-infant pairs include: • client-focused interventions that provide support to individual clients using reminder text messaging, conditional cash incentives and male partner involvement; • and health system-focused interventions, including measures to enhance the program (POC testing technologies, provider training and support, enhanced counselling services and peer support), to strengthen the health system (quality improvement initiatives and mother and child health (MCH)/HIV service integration) and to support community-based services and HCWs. Promoting integration to reduce fragmentation of care for mothers and infants and ensure that infants remain in the testing cascade until final diagnosis should be a priority. Strong antenatal and well-baby care systems 15 Box 7: Key research questions Infant diagnosis • Assess the impact of implementing an indeterminate range, particularly at different testing time points, sample types, and technologies. • Acquire impact data to assess the added value of birth testing within the EID program. • Assess the value of providing birth testing to high-risk infants only. • Measure the impact of tracking tools (ie, bar codes) to ensure effective tracking and repeat testing at 6 weeks among infants testing negative at birth. • Determine if there is added value in integrating birth testing with BCG vaccination. • Assess the optimal timing and frequency of VL testing of pregnant and breastfeeding women. • Assess the impact of maternal treatment and infant prophylaxis on infant diagnoses. • Determine and evaluate the most effective approaches to retaining infants throughout the EID cascade until final definite diagnosis. Infant prophylaxis and treatment • Determine dosing and safety of new ARVs for the purpose of prophylaxis or treatment in neonates and infants. • Develop optimal formulations and ensure timely uptake of newly recommended ARVs for newborns and infants. • Document country experiences with ePNP. • Understand the clinical relevance of maternal viremic episodes and their relative contribution to the overall transmission rate. • Conduct studies to explore the additional benefit of ePNP in the context of well implemented effective maternal ART regimens. • Assess adherence to ePNP and how to improve retention and support for mothers. • Determine the feasibility of using triple therapy as prophylaxis for infants whose mothers are first identified as HIV-infected in the post-partum period. Service delivery and post-natal package of care • Consider combining interventions together into packages to support service delivery. • Promote integration to ensure that infants remain in the testing cascade until final diagnosis. 4. SUMMARY AND WAY FORWARD Several novel innovations implemented by countries and partners have shown promise. While successful interventions are being scaled up, it remains imperative to focus on strengthening existing systems that support infant testing and early treatment initiation. Moreover, changing dynamics in transmission and treatment standards are adding to the complexity and interdependency of testing, prophylaxis and treatment. This will require an increasing need to tailor strategies to the epidemic and policy context. Finally, more programmatic evidence-driven experiences are needed to support and inform national policies, programmatic planning and implementation. 16 ACKNOWLEDGEMENTS Meeting participants Adolfo Vubil (INS Mozambique), Ahmed Haeri Mazanderai (University of Pretoria), Andrea Ciaranello (Harvard Medical School), Angela Mushavi (MOH Zimbabwe), Anna Laura Ross (Unitaid), Archawin Rojanawiwat (Chulalongkorn University), Arne Kroidl (University of Munich), Charles Kiyaga (MOH Uganda), David Sullivan (USAID), Debbie Boras (London School of Hygiene and Tropical Medicine), Deborah Persaud (Johns Hopkins University), Elaine Abrams (ICAP), George Siberry (OGAC), Heather Alexander (CDC), Helen Dale (US CDC), Jean Maritz (University of Stellenbosch), Jilian Sacks (CHAI), Landon Myer (University of Cape Town), Laura Broyles (CDC), Laura Onyengo (MOH Kenya), Laura Thuo (ICW Kenya), Lynne Mofenson (EGPAF), Marc Cotton (University of Stellenbosch), Marie-Claude Bottineau (MSF), Nicholas Furtado (Global Fund), Nobuhle Mthethwa (MOH Swaziland), Philip Goulder (University of Oxford), Roger Shapiro (Harvard T.H. Chan School of Public Health, Botswana), Sally Hargreaves (Imperial College London), Shaffiq Essajee (UNICEF), Smiljka de Lussigny (Unitaid), Timothy Cressey (Harvard T.H. Chan School of Public Health, Thailand), Trevor Peter (CHAI Botswana). WHO Staff Meg Doherty, Martina Penazzato, Lara Vojnov, Anisa Ghadrshenas, Serena Brusamento, Morkor Newman, Mercedes Perez, Fatim Jallow. 17 15. Mazanderani AH, Technau K-G, Hsiao N-Y, Maritz J, Carmona S, Sherman GG. Recommendations for the management of indeterminate HIV PCR results within South Africa’s early infant diagnosis programme. Southern African Journal of HIV Medicine. 2016;17(1):1-5. 16. Dunning L, Francke JA, Mallampati D, MacLean RL, Penazzato M, Hou T, et al. The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis. PLoS Medicine. 2017;14(11):e1002446. 17. WHO. WHO list of prequalified in vitro diagnostic products. Geneva: World Health Organisation; 2018 25 June. 18. WHO. Novel point-of-care tools for early infant diagnosis of HIV. Geneva: WHO; 2017. 19. Jani IV, Meggi B, Loquiha O, Tobaiwa O, Mudenyanga C, Zitha A, et al. Effect of point-of-care early infant diagnosis on antiretroviral therapy initiation and retention of patients. AIDS. 2018;32(11):1453-63. 20. Mwenda R, Fong Y, Magombo T, Saka E, Midian D, Mwase C, et al. Significant Patient Impact Observed Upon Implementation of Point-Of-Care Early Infant Diagnosis Technologies in an Observational Study in Malawi. Clinical Infectious Diseases. 27 Feb 2018. 21. WHO. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. Geneva: WHO; 2010. 22. Avy Violari; Man Chan; Kennedy Otwombe; Ravindre Panchia; Patrick J-PD, Gibb; Mark, Cotton; Abdel, Babiker;. Time to viral rebound after stopping ART in children treated from infancy in CHER. Abstract #137, CROI; March 4-7, 2018; Boston, Massachusetts. 23. Gill MM, Hoffman HJ, Mokone M, Tukei VJ, Nchephe M, Phalatse M, et al. Assessing Very Early Infant Diagnosis Turnaround Times: Findings from a Birth Testing Pilot in Lesotho. AIDS Research and Treatment. 2017: 2572594. 24. Urick B, Fong Y, Okiira C, Nabukeera-Barungi N, Nansera D, Ochola E, et al. Rapid Serological Tests Ineffectively Screen for HIV Exposure in HIV-Positive Infants. JAIDS. 2018;77(3):331-6. 25. Wagner AD, Njuguna IN, Andere RA, Cranmer LM, Okinyi HM, Benki-Nugent S, et al. Infant/child rapid serology tests fail to reliably assess HIV exposure among sick hospitalized infants. AIDS. 2017;31(11):F1-F7. 26. Beste S, Essajee S, Siberry G, Hannaford A, Dara J, Sugandhi N, et al. Optimal Antiretroviral Prophylaxis in Infants at High Risk of Acquiring HIV: A Systematic Review. Pediatr Infect Dis J. 2018;37(2):169-75. 27. WHO. Updates on HIV and infant feeding. Geneva: WHO; 2016. REFERENCES 1. UNAIDS. On the Fast-track to an AIDS-Free Generation. Geneva: UNAIDS; 2016. 2. UNAIDS. Global Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva: UNAIDS; 2016. 3. UNAIDS. Start free Stay Free AIDS free: 2017 progress report. UNAIDS; 2017. 4. WHO. WHO Consolidated ARV Guidelines on the use of antiretroviral Geneva: WHO; 2013. 5. Townsend CL, Byrne L, Cortina-Borja M, Thorne C, de Ruiter A, Lyall H, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049-57. 6. Sherman GG, Mazanderani AH, Barron P, Bhardwaj S, Niit R, Okobi M, et al. Toward elimination of mother– to–child transmission of HIV in South Africa: how best to monitor early infant infections within the Prevention of Mother–to–Child Transmission Program. Journal of Global Health. 2017;7(1). 7. Penazzato M, Lule F, Essajee S. Paediatric HIV: the unfinished business. Lancet HIV. 2017;4(10):e425-e7. 8. UNAIDS. Ending AIDS: progress towards the 90-90-90 targets. Geneva: UNAIDS; 2017. 9. Newell M, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Ghent International AIDS Society (IAS) Working Group on HIV Infection in Women and Children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):1236-43. 10. WHO. Consolidated ARV Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd ed. Geneva: WHO; 2016. 11. WHO. Innovating and strengthening the postnatal package of care for HIV-exposed infants: ensuring comprehensive services for the first two years of life. Johannesburg, South Africa, 20-23 June 2017 Meeting report. Geneva: WHO; 2017. 12. UNAIDS. AIDS info 2017. Geneva: UNAIDS; 2017. 13. Mazanderani AH, Moyo F, Kufa T, Sherman GG. Brief Report: Declining Baseline Viremia and Escalating Discordant HIV-1 Confirmatory Results Within South Africa’s Early Infant Diagnosis Program, 2010–2016. JAIDS. 2018;77(2):212-6. 14. Mazanderani AH, Moyo F, Kufa T, Maritz J, Sherman GG. Differentiating clearly positive from indeterminate results: A review of irreproducible HIV-1 PCR positive samples from South Africa’s Early Infant Diagnosis Program, 2010–2015. Diagnostic Microbiology and Infectious Disease. 2018;91:248-255. 18 EID sample no. 1 test no. 1 EID sample no. 1 test no. 2 NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE2 Request a new sample within 4 weeks3,4 Further review by a clinical and laboratory team4 ANNEXES Annex 1: Managing indeterminate test results: standard operating procedure 1. Refer to 2016 WHO ARV Consolidated guidelines. 2. Do not report as positive nor initiate ART, but maintain prophylaxis per current guidance. 3. Repeat samples should be prioritized in the laboratory. 4. Repeated indeterminate results in two separate samples should, together with clinical information, be reviewed by a team of laboratories, clinicians pediatricians, complex case experts (if possible), and caregivers. Infants should be actively tracked to ensure follow-up and retention. 19 Annex 2: Managing discordant results and treatment interruption This option provides follow-up care to the infant for a minimum of 8 months after interruption of ART. Where possible, both EID (qualitative) and VL (quantitative) tests should be performed at 4 weeks, 4 months, and 8 months after treatment interruption. EID and viral load at 4 weeks, 4 months, and 8 months after interruption Scenario a: Cessation of breastfeeding occurs after completion of the follow up post ART interruption. Scenario b: When cessation of breastfeeding occurs before completion of the follow up post ART interruption. 8 months NAT 1: + Start ART Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 2: - Stay on ART NAT 3: - Stop ARTNAT 3 Cessation of breastfeeding RDT 3 months after cessation of breastfeeding Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 3 Cessation of breastfeeding 8 months NAT 1: + Start ART NAT 2: - Stay on ART NAT 3: - Stop ART Further follow-up is needed to consider the exposure to breastfeeding and carry out the national infant testing schedule for HIV-exposed infants to ensure appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post- cessation of breastfeeding. 20 Annex 3: Simplified EID algorithm HIV-exposed newborn (0-2 days) Consider NATa,b Negative Negative Immediately start ARTc Repeat NAT to confirm infection Infant/child is infected HIV-exposed infant or child (4-6 weeks to 18 months) Conduct NATb (at 4-6 weeks or at the earliest opportunity thereafter) Positive Positive Immediately start ARTc Repeat NAT to confirm infection HIV infection not detected but if infant/child is breastfed the risk of acquiring HIV infection remains until complete cessation of breastfeedingd Regular clinical monitoring Conduct NATb (at 9 months) Antibody testing at 18 months of age or 3 months after cessation of breastfeeding, whichever is laterf Infant/child is infected HIV unlikely unless still breastfedinge Negative The key principles for establishing whether HIV-exposed infants and children younger than 18 months are infected with HIV in low- and middle-income countries are as follows: • Assess HIV exposure status by antibody testing the mother. • Perform NAT test for any HIV exposed child that presents outside of national infant testing algorithm with clinical symptoms irrespective of previous NAT results • At 9 months perform NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative. • Ensure that indeterminate test results are repeat tested immediately and given priority for rapid resolution. • Ensure that confirmatory testing is undertaken following any positive result. • Ensure regular follow-up for all HIV-exposed infants until final diagnosis, including providing co-trimoxazole prophylaxis and clinical and nutritional assessment. Notes: a. Based on 2016 WHO Consolidated ARV Guidelines10, addition of NAT at birth to the existing testing algorithm can be considered. b. POC NAT can be used to diagnose HIV infection as well as to confirm positive results. c. Start ART without delay. At the same time, retest to confirm infection. As maternal treatment is scaled up and MTCT transmission rates decrease, false-positive results are expected to increase: retesting after a first positive NAT is hence important to avoid unnecessary treatment, particularly in settings with lower transmission rates. If the second test is negative, a third NAT should be performed before interrupting ART. d. For children who were never breastfed, additional testing following a negative NAT at 4–6 weeks is included in this algorithm to account for potential false-negative NAT results. e. The risk of HIV transmission remains as long as breastfeeding continues. If the 9-month test is conducted earlier than 3 months after cessation of breastfeeding, infection acquired in the last days of breastfeeding may be missed. Retesting at 18 months or 3 months after cessation of breastfeeding (whichever is later) should be carried out for final assessment of HIV status. f. If breastfeeding extends beyond 18 months, the final diagnosis of HIV status can only be assessed at the end of breastfeeding. If breastfeeding ends before 18 months, the final diagnosis of HIV status with antibody testing can only be assessed at 18 months. Antibody testing should be undertaken at least 3 months after cessation of breastfeeding (to allow for development of HIV antibodies). For infants younger than 18 months of age NAT should be performed to confirm infection. If the infant is older than 18 months, negative antibody testing confirms that the infant is uninfected; positive antibody testing confirms infant is infected. 21 Annex 4: Algorithm for risk assessment This algorithm was developed to support risk assessment at the time of delivery and to help identify infants at high and low risk: Infants at low risk should be given standard prophylaxis (NVP or AZT alone for 4–6 weeks) while those at high risk should be given ePNP. In order to navigate this algorithm successfully, clinicians will need to know a number of parameters from the mother’s antenatal chart: • HIV status and date of last HIV test (to identify status and need for testing or retesting at delivery); • if known to be positive, and ART started, date of ART initiation; • if VL collected, date of sample collection relative to delivery and VL result. Programs should consider incorporating a VL test at or around 36 weeks’ gestation, ensuring that the turnaround time is short enough to have a result available by the expected delivery date. Mother newly identified as HIV+ within 72 hours of delivery NO Known HIV+ mother not on ART Known HIV+ mother on ART HIGH RISK HIGH RISK HIGH RISK HIGH RISKLOW RISK LOW RISK NOYES Has mother been on ART for > 4 weeks prior to delivery? YES: VL < 1,000 YES: VL > 1,000 Assess mother AT DELIVERY Is a VL result available from no more than < 4 weeks before delivery? 22 Annex 5: Dosing and formulation options for infant prophylaxis Dosage forms Dose 0-6 weeks AZT plus NVP Dose 6-12 weeks AZT plus NVP Dose 6-12 weeks NVP only Comments Syrups AZT 10mg/ml NVP 10mg/ml AZT dose 1.5ml (15mg) twice daily AZT dose 6ml (60mg) twice daily NVP dose 2ml (20mg) once daily - Accurate dosing for all drugs (included for low birth weight newborns) and one type of formulation for the whole 12-week period - Costly to procure and transport syrups - Difficult to hide in the home - Supplier availability may be limited - Might be acceptable where most women of childbearing age are well controlled on ART and numbers of high-risk infants is low, but would not be the best option for a program that chooses to treat all infants as high risk NVP dose 1.5ml (15mg) once daily NVP dose 2ml (20mg) once daily Syrups and single drug tablets AZT 60mg NVP 50mg AZT dose 1.5ml (15mg) twice daily AZT dose 1 tab (60mg) twice daily NVP dose ½ tab (25mg) once daily - Combines accuracy of syrup dosing in the first 6 weeks and the ease of tablets from 6 to 12 weeks - Challenges of syrups as before - ½ a tab of NVP represents a slight overdose of NVP (25mg vs 20mg) NVP dose 1.5ml (15mg) once daily NVP dose ½ tab (25mg) once daily FDC ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily Unsuitable Not applicable - Difficult to quarter a FDC accurately: caregivers should use the first quarter in the morning and the second quar- ter in the evening in order to keep daily dose accurate - 3TC not part of the recommended prophylaxis regimen - Cannot use FDC during weeks 6 to 12 without giving 5 times more than the recommended daily NVP dose FDCs and single drug tablets ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily AZT dose 1 tab (60mg) twice daily NVP: ½ a 50mg tablet once daily - Combines ease of FDC with single drug tablet for the second - Challenges of FDC as above NVP dose ½ tab (25mg) once daily Remarks: • It should be noted that unlike for NVP, there is no specific prophylaxis dose for AZT. The recommended dose is the same as that used for treatment - 15 mg twice daily for term infants in the first six weeks of life, increasing to 60mg twice daily from week 6 to week 12. • When presumptive treatment is administered, age-appropriate regimens and dosing should be used as illustrated in current WHO treatment guidelines10. 23 24 For more information, contact: World Health Organization Department of HIV/AIDS 20, avenue Appia 1211 Geneva 27 Switzerland WHO/CDS/HIV/18.17 E-mail: hiv-aids@who.int www.who.int/hiv

HIV DIAGNOSIS AND ARV USE IN HIV-EXPOSED INFANTS: A PROGRAMMATIC UPDATE JULY 2018 TECHNICAL REPORT 2WHO/CDS/HIV/18.17 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/ licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non- commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. HIV diagnosis and ARV use in HIV-exposed infants: a programmatic update. Geneva, Switzerland: World Health Organization; 2018 (WHO/CDS/HIV/18.17). Licence: CC BY-NC- SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/ bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Layout: 400.co.uk Printed in Switzerland 31.1 EXECUTIVE SUMMARY New HIV infections in children continue to occur globally and timely diagnosis and treatment of infants and children living with HIV remain critically important. The 2016 WHO ARV Consolidated Guidelines presented some innovative approaches, such as the use of nucleic acid testing (NAT) at or around birth for earlier diagnosis of HIV in infants, the introduction of point-of-care (POC) NAT for more rapid and decentralized diagnosis to enable prompt antiretroviral therapy (ART) initiation, and the use of enhanced postnatal prophylaxis (ePNP) to improve HIV prevention among infants exposed to HIV. To date, however, only a few countries have introduced these innovations and early lessons from the field have identified a number of implementation challenges that require careful review. Drawing on findings from a regional workshop held in Johannesburg, South Africa in 2017 and a follow-up expert meeting in Geneva, Switzerland in 2018, this programmatic update aims to describe changes in strategies for the identification, prevention and treatment of HIV in infants. This update will also highlight new information on the implementation of a postnatal package of care for HIV- exposed infants. ABBREVIATIONS 3TC lamivudine ART antiretroviral therapy ARV antiretroviral drugs AZT azidothymidine (zidovudine) CTX co-trimoxazole EID early infant diagnosis ePNP enhanced postnatal prophylaxis FDC fixed-dose combination HCW health-care worker HIV human immunodeficiency virus HIVDR HIV drug resistance LPV/r lopinavir/ritonavir MCH mother and child health MTCT mother-to-child transmission PMTCT prevention of mother-to-child transmission NAT nucleic acid test NVP nevirapine PCR polymerase chain reaction POC point-of-care RAL raltegravir RDT rapid diagnostics test SOP standard operating procedure VL viral load 42.1 BACKGROUND 2.1.1 Current status quo regarding pediatric HIV The Global Plan Towards the Elimination of New HIV Infections among Children by 2015 and Keeping their Mothers Alive initiative has had a substantial impact, leading to a 60% reduction in new pediatric HIV infections in 21 high-burden countries in sub-Saharan Africa.1,2 Nevertheless, the burden of new HIV infections in children remains significant: in 2017, there were 180 000 new infections in children globally, and 70% of these children were in the same 21 priority countries. The Start Free, Stay Free, AIDS Free framework3 was developed to build on the progress of the Global Plan and to provide a roadmap to achieve fast- track targets towards ending the AIDS epidemic by 2030. Following the adoption of the Option B+ policy4, the number of pregnant women on antiretroviral therapy (ART) has increased considerably across countries. This in turn has led to lower rates of vertical HIV transmission, now estimated to be less than 2% in non-breastfeeding populations, and less than 5% in breastfeeding populations.5,6 Despite the overall decrease in mother-to-child transmission (MTCT) of HIV, new pediatric infections continue to occur and transmission dynamics have now shifted towards a proportional increase in transmission during the postnatal period (Figure 1).3,7 Roughly half of all new infections among children occurs during breastfeeding. Although countries continue to make progress, challenges remain in retaining HIV-infected women in health- care services and on effective ART throughout pregnancy and the breastfeeding period, as well as in detecting and preventing new HIV infections in women during pregnancy and breastfeeding. This shift in transmission dynamics has also raised issues concerning optimal testing in infants, with the identification of HIV-exposed and HIV-infected children continuing to present a significant bottleneck in several settings. Early infant diagnosis (EID) coverage globally still remains low: in 2016 only 43% of infants exposed to HIV received an HIV test within the first 2 months of life.8 Figure 1 MTCT transmission rates in the priority countries of the Start Free, Stay Free, AIDS Free framework in 2017 (Source: UNAIDS 2018 estimates) 0 10 20 30 Indonesia 19% 7% 26% 26% 26% 21% 20% 19% 18% 16% 15% 14% 14% 12% 11% 11% 10% 9% 8% 8% 7% 6% 5% 5% Angola 15% 11% Nigeria 14% 14% Ethiopia 11% 10% Democratic Republic of Congo 12% 8% Ghana 10% 9% Chad Côte d’Ivoire Cameroon Mozambique Burundi United Republic of Tanzania Lesotho Kenya Zambia Malawi Uganda Eswatini Zimbabwe Namibia South Africa Botswana 10% 8% 8% 8% 9% 6% 7% 7% 6% 8% 6% 6% 5% 6% 6% 5% 4% 6% 3% 6% 4% 4% 3% 5% 2% 5% 2% 4% 2% 3% 3% 2% 6 week transmission rate Post 6 week transmission rate 5Furthermore, although pediatric ART coverage has notably improved since 2010, only 51% of the estimated 1.8 million children living with HIV were receiving ART by the end of 2017.3 HIV-infected infants and younger children have an exceptionally high mortality without treatment, approximately 30% by the first year and 50% by their second year of life.9 Many HIV-related deaths in infants can be avoided by early identification of HIV and rapid ART initiation. Limited availability of optimal antiretroviral (ARV) formulations for preventing and treating HIV infection in newborn and young infants remains, however, an ongoing challenge in many countries. 2.1.2 Rationale for this technical update The 2016 WHO Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection10 presented innovative approaches to diagnosis and treatment; however, to date only a few countries have started to implement these innovations. In addition, evidence from early adopter countries has raised a number of issues that require careful consideration and have generated lessons learned that may be useful for countries planning to adopt these interventions. • Reduction in MTCT rates has led to a decrease in the positive predictive value of nucleic acid testing (NAT), resulting in higher proportions of false-positive test results. There is currently no specific recommendation on what level of viremia should be considered a true- positive result in infants and whether there is benefit in defining an indeterminate range for NAT. • Significant drug exposure due to implementation of the Treat All policy and enhanced postnatal prophylaxis (ePNP) could cause delays in antibody development in infants with HIV infection. These dynamics may complicate the use of rrapid diagnostic tests (RDTs) in infants to determine exposure and/or infection and affect how RDTs are used and interpreted in infants under 18 months of age. • Addition of NAT at birth to the national infant testing algorithm has been considered by a number of countries. Several operational challenges have emerged and a critical review of these will be important to support the strategic introduction of birth testing where feasible and most appropriate. • ePNP for high-risk infants is being implemented in a number of countries but challenges persist with identifying infants at high-risk and providing ePNP with existing formulations. This has led to simplified approaches, currently being considered by a number of countries, that may have an impact on infant testing. • Greater emphasis should be placed on strengthening the postnatal package of care for HIV-exposed infants and their mothers. There are opportunities to consider combining successful interventions into packages in order to support service delivery, and placing greater importance on promoting the integration of services to ensure that infants are retained in care until final diagnosis. Following the WHO regional workshop in Johannesburg, South Africa (June 2017)11, an expert meeting was convened in April 2018 to provide insight and promote discussion on these matters. This programmatic update aims to detail important changes and new implementation considerations arising since the publication of the 2016 WHO ARV Consolidated Guidelines.10 3.0 KEY CONSIDERATIONS 3.1 Infant diagnosis The complexity of EID testing is now growing due to significant scale up of Treat All (including pregnant and breastfeeding women), implementation of ePNP, reduced MTCT rates and the increased relative contribution of postnatal transmission. EID can no longer be considered primarily a one-test process, since it now requires additional testing over the duration of exposure. Accordingly, several additional key considerations will be necessary to strengthen the EID testing cascade through the entire exposure period. This includes ensuring that ART initiation is not delayed in those infants found to have HIV infection. 3.1.1 Minimising false-positive results by introducing an indeterminate range for EID Although infant diagnosis is being scaled up globally, with increased access to Treat all, declining MTCT rates12 and low viremia observed in infants found to be infected with HIV13 mean that false-positive test results are increasingly being reported in programs. Some infants may therefore be incorrectly diagnosed as having HIV infection and started on lifelong ART unnecessarily. There is currently no specific recommendation on what level of viremia should be considered a true-positive result in infants and whether there is benefit to adding an indeterminate range to minimize false-positive test results (see Box 1). 6A systematic review of 32 studies using an indeterminate range found 14 753 non-negative test results of which 2 436 (16.5% [95% CI 15.9–17.1%]) were indeterminate (data unpublished); one study14 that reported the final diagnoses of indeterminate cases found that 76% of infants with an initial indeterminate test result were negative on repeat testing, suggesting these infants were not HIV-infected despite the initial non-negative test result. These data indicate that in countries not implementing an indeterminate range for NAT and where MCTC rates are low (<5%), 12.5% (76% of 16.5%) of non-negative results could be false-positive on initial testing with affected infants being potentially started on lifelong treatment unnecessarily. Typically, EID assays detect the presence of HIV using real-time NAT technologies that often report cycle thresholds. Reported cycle thresholds represent the PCR cycle at which amplification is first observed and are inversely correlated to the amount of virus in the sample. The approximate equivalent of a cycle threshold of 33 on the Roche COBAS® Ampliprep/COBAS® TaqMan® HIV-1 Qualitative Test v2.0 assay was selected as the optimal indeterminate range for further testing. This represented a balance between the proportion of infants living with HIV that would be incorrectly identified as indeterminate (about 8-13%) and the proportion of HIV-uninfected infants that would potentially start treatment unnecessarily (about 2–7%). South Africa has already implemented an indeterminate range and developed a standard operating procedure (SOP) for managing positive and indeterminate test results.15 Similarly, WHO technical consultation developed a new SOP that will help to ensure higher quality infant testing (Annex 1). Current evidence suggests that no specific requirements are necessary with regard to the type of assay (conventional or point-of-care (POC)) used to retest specimens with indeterminate test results. Most countries already apply a national SOP when testing errors are encountered (for example, device malfunction, insufficient or rejected specimen, etc.). In most countries the health-care facility concerned is contacted and asked to ensure that the infant returns to the facility in order to provide a new specimen for testing. Due to the delay caused by the testing error, these samples are generally considered urgent and prioritized for testing once received by the laboratory. A new study suggests that repeating an indeterminate test result using the same sample, if available, will resolve the majority (>95%) of indeterminate results.14 Therefore, prior to contacting the health- care facility to request the infant return to the facility for collection of a new sample, a repeat test should be conducted on the same sample using additional available dried blood spots or remaining whole blood. 3.1.2 Confirmatory testing of positive test results A cost-effectiveness analysis undertaken to assess the value of confirmatory testing in different scenarios highlighted that confirmatory testing is indeed cost- effective.16 Without confirmatory testing, this analysis showed that in settings with MTCT rates similar to those of South Africa, more than 10% of infants initiated on ART may in fact be HIV-uninfected. Confirmatory testing of positive test results using a new sample, as per WHO guidelines, may avoid this occurrence, although this policy is not consistently implemented (Box 2). It remains critical that programs ensure all HIV-exposed infants are retained and tested appropriately throughout the entire exposure Box 1. Definition of terms for diagnostic results • Indeterminate range: a range of viral copy equivalents that would be too low to accurately diagnose as positive. • False-positive result: HIV-uninfected infants incorrectly identified as HIV-infected and potentially started unnecessarily on ART. • False-negative result: HIV-infected infants incorrectly identified as HIV-uninfected. • Non-negative result: any positive or indeterminate result. Polmyerase chain reaction (PCR) instrument reports a detectable result, which may be subsequently classified as “indeterminate” based on other data (e.g. assay-reported cycle threshold). May also be referred to as “not confirmed”, “equivocal” or “irreproducible positive”. • Discordant result: positive/detectable first test; negative second test. • Cycle threshold: the point at which virus amplification is first observed during the course of repeated PCR cycles. The cycle threshold is inversely correlated to the amount of virus in the sample. 7period and all infants with a positive result receive a confirmatory test. Furthermore, those with repeatedly indeterminate test results should be actively tracked, retained, retested and their status resolved. Finally, POC EID testing is being implemented in several countries and settings (see 3.1.3). Previously there was limited evidence on how to conduct confirmatory testing of POC EID positive test results, but since publication of the 2016 WHO ARV Consolidated Guidelines10 several studies have been published on its performance. Two POC EID technologies are now included on the WHO list of prequalified in vitro diagnostic products.17 Results from both laboratory and field studies have shown performance comparable to that of laboratory-based technologies.18 Furthermore, two patient impact studies have been published which highlight the significantly improved patient outcomes when using POC EID technologies.19,20 Based on this updated evidence, POC EID testing can be used to confirm positive test results. 3.1.2 Managing discordant results and treatment interruption Since 2010, WHO has recommended initiating infants on ART after an initial positive NAT, while simultaneously collecting a confirmatory sample. The 2016 WHO ARV Consolidated Guidelines10 suggest that if the second (confirmatory) NAT is negative, a third NAT, either EID (qualitative) or viral load (VL), should be performed before considering ART interruption. The introduction of an indeterminate range should potentially reduce the number and proportion of infants with discordant test results (different NAT results on separate samples); however, guidance on how to conduct treatment interruptions is needed. Several factors should be considered when assessing patients for ART interruption after discordant test results (positive then a negative result) are followed by a third test with a negative result: • the infant ought to have no clinical signs or symptoms suggestive of HIV infection;21 • a follow-up plan should be agreed upon with family, caregiver(s) and health-care staff; • tracking information (phone, address, etc.) of the family/caregiver(s) should be collected and confirmed. The following factors should be considered when following up any infant undergoing treatment interruption: • there is a need for active follow-up to ensure that a potentially infected infant is retained and re-initiated on treatment if virological rebound occurs; • virological rebound in HIV-infected infants starting treatment early is expected to happen within 8 months of interruption in >99% of HIV-infected infants;22 • infants who develop signs and symptoms indicative of HIV infection should undergo immediate testing; • breastfeeding and continued risk of transmission require follow-up and appropriate testing throughout the period of risk until final diagnosis; • there is value in minimizing follow-up testing by leveraging existing opportunities for infant testing (based on the national infant testing schedule and immunization or well-child appointment schedules), until final diagnosis is ascertained. Few countries have existing policies on how to conduct treatment interruptions in infants with discordant test results. South Africa, for one, has implemented policies with intensive laboratory and clinical follow-up of these infants for 18 months.15 Both EID (qualitative) and VL (quantitative) tests are performed at 4 weeks, 3 months, and every 3 months after treatment interruption. However, since the likelihood of these infants being HIV-infected is low, a less aggressive 8 month approach is also reasonable in order to simplify the follow-up procedure: this is supported by emerging evidence on the timing of viral rebound in HIV-infected infants treated early.22 In this case both EID (qualitative) and VL (quantitative) tests could be performed at 4 weeks, 4 months and 8 months after treatment interruption (Annex 2). Infants who test positive on any follow-up test in either protocol should be re-initiated on treatment as per current guidelines,10 and a confirmatory sample taken. Any SOP for interruption should be implemented considering the continuous risk of transmission resulting from breastfeeding and, once the intensive follow up is completed (8 months after treatment interruption), the national infant testing schedule for HIV-exposed infants should be applied in order to ensure an appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post cessation of breastfeeding, as indicated in Annex 2 Scenario b. Box 2. Prioritizing confirmatory testing of positive and indeterminate tests • Decreasing MTCT rates globally have led to concerns about false-positive and indeterminate tests. • Patients with indeterminate results need immediate repeat testing and the patient should be managed according to the SOP presented in Annex 1. • Patients with repeated indeterminate results need a multidisciplinary team of health-care providers to support retention, tracking and status resolution. • In ART programs, there is a need to prioritize confirmatory testing of all positive test results using a new sample. • Clinical monitoring and further testing based on the national infant testing schedule need to be done until a definitive HIV status is established. 83.1.3 Implementation of POC EID testing The 2016 WHO ARV Consolidated Guidelines10 recommend the use of NAT technologies for early infant HIV testing that have been developed and validated for use at or near the point-of-care. POC EID provides the opportunity to reduce test turnaround times, limit patient loss along the HIV testing cascade, reduce infant mortality and facilitate task shifting to lower cadres of health workers at health- care facilities with decentralized services. Sufficient evidence has been generated on the performance of these assays in their intended field settings to support rapid national regulatory approval and initiation of scale-up (Box 3). A number of countries are currently implementing POC EID technologies.18 Implementation studies in Malawi20 and Mozambique19 have shown that using POC EID leads to significantly reduced test turnaround times, with a higher yield of results being returned to the health-care facility and caregivers, and earlier and higher rates of ART initiation among HIV-infected infants. Key lessons learned during pilot implementation projects include: • optimizing the use of POC EID through product and site selection; • selecting health facilities with high prevalence and high volumes to maximize device utilization; • considering placement within or in-facility referral from high-yield entry points (e.g. nutrition and pediatric wards); • ensuring service continuity by establishing a service and maintenance strategy with suppliers and provide service engineer back-up; • integrating services within health facilities by assessing the need for additional training and continuous mentoring of health-care workers (HCW); • strengthening the linkage between services to ensure prompt linkage to care for identified HIV-infected infants; • ensuring the availability of pediatric ARV formulations for neonates to guarantee earlier ART initiation. 3.1.4 Introduction of NAT at birth to facilitate earlier treatment initiation Adding NAT at birth to the existing national infant testing schedule may result in earlier identification of HIV-infected newborns and consequently lead to earlier treatment initiation and lower mortality among infants. Data suggest that infants testing positive at birth start ART approximately 2 months earlier than non-birth- tested infants (6 weeks vs 15 weeks).23 However, cost- effectiveness analyses have shown that the survival gains from adding NAT at birth to the standard 6-week test are lost if the loss-to-follow-up after a negative birth result exceeds 37%, underscoring the fact that a high-functioning 6-week program needs to already be in place. A number of countries have already started implementation of NAT at birth, and country experiences are outlined in Box 4. It should be noted, however, that strengthening existing EID systems remains the priority while programs consider adding birth testing. Several implementation considerations can be summarized from these experiences. • Countries that are considering birth testing should critically review current performance and opportunities for strengthening their 6-week EID program and consider other indicators, (e.g. PENTA1 immunization visit coverage and attended delivery rate), so that the potential gains provided by birth testing can be investigated more fully. For example, in settings where the attended delivery rate is much lower than PENTA1 immunization visit coverage the added value of birth testing as a means of expanding EID is limited. • Pilot projects are a good way to start gaining national experience on this innovative testing approach, but in order to measure impact fully programs need to collect data on the feasibility and impact of birth testing and linkage to ART initiation. • Targeted approaches which provide birth testing only for high-risk infants are expected to have a higher yield compared to routine birth testing. This approach may be potentially less resource intensive and present a lower burden for HCW. • Active tracking of infants with negative NAT results at birth is critical to ensure that they return at 6 weeks to be retested and start co-trimoxazole (CTX); establishing unique patient identifiers or other innovative mechanisms (e.g. bar codes) to track babies can be considered. • It is crucial that the turnaround time for reporting test results to health facilities and caregivers be rapid in order to optimize the benefit from NAT at birth, and POC assays should be used where they are available. Box 3. New POC EID technologies • Two technologies have received WHO prequalification. • National regulatory agencies are encouraged not to delay adoption by conducting further evaluations but instead to adopt a rapid and streamlined registration and national approval process for immediate implementation. 9• Birth testing is acceptable to mothers, but challenges arise from the increased human resources needed, the difficulty of collecting blood samples in newborns, the need to ensure sample collection outside of standard working hours and deliver results, linkage to ART and the nature of the EID system as a whole (stock-outs, referral mechanisms, delayed results). Box 4. Implementation of birth testing: country experiences South Africa South Africa introduced NAT at birth in 2015 with specific nurse training at postnatal and delivery services and health register updates to enable data acquisition. Implementation challenges met by South Africa include weak linkage of the identified HIV-infected infants to care with consequent delay in ART initiation, and a low return rate for future testing among infants with negative results at birth. A qualitative sub-study found that birth testing had a high acceptability. Refusals were rare and mothers did not indicate that birth testing affected their subsequent acceptance of infant testing or postnatal clinic attendance. Weak follow-up systems were detected for mothers who had home deliveries, and concerns were raised by laboratory staff about increased workloads associated with additional testing requirements. Kenya Kenya started a NAT at birth pilot project in 2015 (defined as testing within 72 hours of birth) and its results formed the basis of a revised EID algorithm in 2016 and national scale-up plan, due to start in mid-2018. Prior to implementation, a central point was designated within the health-care facility for birth testing, an innovative dispatch register was developed, mothers were offered mentoring to assist with linkage between hospitals and communities and a prevention of mother-to-child transmission (PMTCT) psychosocial support group was formed. Good leadership and coordination was identified as being important for seeing patients through service provision. Challenges included issues related to referral, demand creation, turnaround time for test results and mothers who failed to collect test results. In addition, ART formulations were lacking for neonates who tested positive during the initial implementation phase. Zimbabwe Zimbabwe started a POC NAT birth pilot in April 2017 in ten health facilities for high-risk HIV-exposed infants (< 48 hours after birth). Ninety-seven per cent of the results were transmitted to caregivers, and all HIV-infected infants started ART within 5 days of testing. This project is likely to provide critical experience on a different approach to tracking children after birth testing and will generate further information on the value of targeting birth testing for high-risk infants rather than all HIV-exposed infants. Democratic Republic of Congo NAT at birth was first implemented in December 2016, with samples sent to central laboratories for processing. Laboratory personnel were trained to prioritize birth samples and ensure prompt return of results to the health facility. Challenges included long turnaround times between specimen collection and receipt of results (8–12 weeks from the national laboratory), stock-outs due to limitations in supply chain management, and difficulties in specimen transportation. Uptake of birth testing was good, but yield was low with numerous missed opportunities due to early discharge of women from maternity wards. As a result, birth testing remains limited to this pilot project (now terminated) and efforts are being made to strengthen the existing 6-week EID program. Eswatini (Swaziland) Eswatini introduced two pilot projects to explore universal NAT at birth across five maternity sites in August 2017 using POC EID technologies in three sites (in partnership with EGPAF) and conventional testing in two sites (in partnership with ICAP). In the conventional test pilot, 93% of HIV-exposed newborns were tested before discharge from the maternity unit and six of the 1 548 tested were HIV-infected. In the POC testing pilot, 68% of HIV-exposed newborns were tested and 12 of the 1 314 tested were HIV-infected. Furthermore, 98% of results were returned to the caregiver. Of those HIV-infected, nine in the POC test pilot and four in the conventional test pilot were put on treatment. Both pilots confirmed that health-care facility staff face a heavier work burden when NAT at birth was added. Nurses often felt overwhelmed and failed to prioritize NAT at birth because many births occurred at night or on weekends when staffing was limited. Furthermore, although most mothers found birth testing to be acceptable, several were discharged or left the facility before getting tested, while others provided incorrect tracking information. Ensuring patient tracking and linkage proved to be a challenge. • The key to effective implementation is to ensure that newborns who have been identified as HIV-infected are linked to treatment and that age-appropriate formulations are available to start them on treatment. • Good leadership and coordination are needed to oversee service provision, support supervision, mentorship and the quality improvement cycle. 10 11 3.1.5 Ensuring accurate interpretation of the 9-month test and simplifying the testing algorithm The 2016 WHO ARV Consolidated Guidelines recommend that RDTs should be used to assess HIV exposure among infants younger than 4 months, while HIV exposure among infants 4–18 months old should be ascertained by testing the mother. When testing of the mother is not possible, current guidelines emphasize the importance of not considering a negative RDT result from an infant between 4–18 months as a definitive test of exposure. Implementation issues are highlighted in Box 5. Based on the 2016 WHO ARV Consolidated Guidelines10, RDTs are serological assays that can also be used to exclude established infection among healthy, HIV-exposed infants aged 9 months old and above. However, changes in transmission dynamics as well as in policy and practice have complicated RDT use for determining infection status. Substantial drug exposure for infants with implementation of the Treat All policy for mothers and enhanced postnatal prophylaxis of HIV-exposed infants may have resulted in viral load reduction and delayed antibody development in HIV-infected infants. Finally, the occurrence of maternal infection in late pregnancy or during the postnatal period may be responsible for a lack of passive HIV antibody transfer to the HIV-exposed infant. These factors increasingly jeopardize RDT accuracy at 9 months of age as a means of correctly ruling out established infection in HIV- exposed infants. These concerns are supported by findings from Uganda and Kenya,24, 25 where 15–40% of children under two years of age and identified as HIV-infected had a positive NAT but negative RDT. RDT at 9 months was initially recommended in the 2010 WHO recommendations on the diagnosis of HIV infection in infants and children21 with the goal of targeting NAT for those HIV-exposed infants most likely to be infected (e.g. those with a positive RDT) as a cost-saving measure. However, due to decreasing MTCT rates, increasing availability and lower costs of NAT, changing transmission and drug exposure dynamics, and the fact that RDTs are less effective at determining the need for NAT testing, such a targeted approach may be less compelling. Furthermore, the added programmatic complexity and potential for inappropriate interpretation of test results have additional unintended consequences. In light of the challenges and data outlined above, consideration can now be given to replacing RDT at 9 months with NAT in the interests of minimizing the challenges of interpretation and simplifying the infant testing algorithm. Annex 3 summarizes the new simplified algorithm, which is underscored by a number of key considerations: • assessing HIV exposure status by performing RDT on the mother; • at 9 months performing NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative; • ensuring indeterminate test results are repeat tested immediately and prioritized for rapid resolution; • ensuring confirmatory testing is undertaken following any positive result; and • ensuring all HIV-exposed infants are regularly followed up until final diagnosis, with the provision of CTX prophylaxis and clinical/nutritional assessment. Finally, it remains critical that infant retention be continued until the end of the exposure period. More effort should be given to establishing a final diagnosis at 18 months of age or 3 months after cessation of breastfeeding, whichever occurs later. Although there is increasing coverage of the traditional 6-week infant test and more consideration is given to earlier time-points, the changing dynamics of transmission and increased drug exposure mean that increased efforts are needed to maintain follow-up throughout the entire exposure period. The aim is to ensure that all HIV-infected infants, including those infected in the postnatal period, are identified and receive treatment. Box 5. Use of RDT: implementation considerations • Priority should continue to be given to the testing of mothers at all entry points to determine exposure status for infants and children less than 18 months. • If the mother is absent or unable to be tested, an RDT should be undertaken of the infant, but negative results of infants older than 4 months should not be considered as definitive exclusion of exposure and follow-up testing is required. • If the mother is absent or unable to be tested and the infant presents with signs and symptoms of HIV infection, a NAT should be undertaken. • NAT should be undertaken following any positive RDT in the mother or the infant and a confirmatory NAT undertaken following any positive NAT result. 12 3.2. ARV use for prevention and treatment of HIV in infants 3.2.1 Implementation challenges to providing ePNP for high-risk infants The 2016 WHO ARV Consolidated Guidelines recommend a dual regimen of AZT and NVP which can be extended for up to 12 weeks in breastfeeding infants deemed to be at high risk of MTCT. A high-risk infant is defined as an infant whose mother was first identified as HIV-infected at delivery or in the postpartum, infected during pregnancy or breastfeeding, started ART late in pregnancy, or did not achieve viral suppression by the time of delivery (Annex 4). All high-risk infants should receive dual drug prophylaxis (AZT plus NVP) for the first 6 weeks. In breastfeeding infants, this should be followed by either an extra 6 weeks of AZT plus NVP or an extra 6 weeks of NVP alone (see Box 6). This recommendation is based on evidence from randomized clinical trials26 and takes into account the risk- benefit ratio of ePNP: potential for increased drug toxicity versus additional protection from HIV transmission. The rationale for the use of extended ePNP especially in high- risk breastfeeding infants rests on the assumption that mothers started promptly on ART achieve viral suppression within 12 weeks, thereby greatly reducing the risk of breast milk transmission and the need for ongoing infant prophylaxis. Countries have adopted ePNP using a variety of different approaches. In Kenya, Eswatini (Swaziland), and Mozambique, ePNP has been adopted for all breastfeeding HIV-exposed infants, while nine countries (Botswana, Ghana, Namibia, Nigeria, South Africa, Tanzania, Uganda, Zambia and Zimbabwe) have adopted ePNP for high- risk infants identified primarily on the basis of maternal ART duration and, when available, maternal VL close to delivery. Most countries opted for at least 12 weeks of prophylaxis, usually AZT/NVP for the first 6 weeks followed by NVP alone. Three countries (Kenya, Namibia and South Africa) link the duration of ePNP to the maternal VL, and extend ePNP over the entire breastfeeding period when viral suppression is not achieved. Finally, in three countries (Botswana, Zambia and Tanzania), triple prophylaxis with a fixed-dose combination (FDC) of AZT/3TC/NVP has been adopted to address the challenges of procuring syrups. Recent guidelines on infant feeding27 in relation to HIV re-affirm the position of WHO that the best way to prevent MTCT in the postpartum period and optimize infant survival is to ensure that mothers living with HIV are well controlled on ART and able to breastfeed their infants for up to two years, with the infant being exclusively breastfed in the first six months of life. If a mother on ART is virologically suppressed, the risk of breast milk transmission of HIV is very low and infant prophylaxis confers minimal additional benefit beyond 4–6 weeks of life. Some program have adopted ePNP for all HIV-exposed infants. While this may simplify decision-making, it increases costs and exposes a large number of infants who may not need ePNP to added toxicity. This type of approach ought to be reserved for selected situations where a majority of mothers are at high risk of transmitting HIV. Data on the average duration of ART at delivery and, where available, the proportion of pregnant women with VL>1000 at the end of the third trimester might help policymakers to determine whether added costs and toxicity are outweighed by potential benefit. Even then, it should only be an interim measure while strategies to increase the coverage of maternal testing, early treatment and improved adherence are being implemented. However, there are several situations where viral suppression throughout the breastfeeding period cannot be ensured in the mother, for example: • if a mother refuses or is unable to start or continue ART and intends to breastfeed her infant; • if the provider knows the mother is poorly adherent to ART while breastfeeding; • if maternal VL is known to be high when the infant prophylaxis regimen is about to be stopped. There is no formal recommendation for these types of situations and no evidence to guide the best course of action. It is reasonable, however, to assume that infant prophylaxis serves as a “back-up” solution for preventing postnatal transmission of HIV, and national programs could consider the merits of giving clinical providers the option of continuing infant prophylaxis beyond the recommended 6- or 12-week period. If this option is introduced in the national guidelines, there ought to be clearly defined scenarios in which continuing prophylaxis is warranted. National guidelines should also emphasize that the best way to prevent breast milk transmission of HIV is by optimal maternal treatment for the entire duration of exposure. Continuing prophylaxis should therefore be seen as an interim measure while efforts are made to support and improve maternal treatment adherence. Deciding to continue prophylaxis should take into consideration the factors that led to poor maternal adherence as they may have an impact on adherence to infant prophylaxis. Once stopped, infant prophylaxis should not be re-started if there are new concerns about maternal adherence. There is no evidence to support such an approach; instead the focus should be on determining why the mother was unable to remain adherent. If the decision has been made to continue infant prophylaxis, mothers and infants should be evaluated at regular intervals to assess the need for ongoing infant prophylaxis. 13 As more effective treatments increasingly come to be used in pregnant women, we can expect decreasing MTCT rates. However, some women will still be diagnosed late or have incident infections and this group is likely to drive most new cases of HIV transmission to infants, owing to the high level of maternal virus in the absence of treatment. One possibility would be to provide “presumptive treatment” as postnatal ePNP, by administering a triple-drug regimen at therapeutic doses to this selected group of infants with the goal of minimizing transmission and drug-resistant HIV (HIVDR) selection in the event of established infection despite prophylaxis. Such approaches need to be paired with careful review of infant testing practices in order to determine the potential impact of triple ePNP on virological assay performance for infant diagnosis (i.e. at least one specimen must be collected prior to initiating any presumptive treatment so that a NAT can be performed as soon as possible). 3.2.2 Early infant treatment: limited options and complex administration Early infant ART improves survival and reduces long-term morbidity but mortality remains substantial in the first months of life. Introducing NAT at birth could enable ART to be started before 2 weeks of age. However the only regimen available for this age group has for many years been one containing AZT, 3TC and NVP. This regimen could be continued with close clinical monitoring until 3 months of age and then switched to a LPV/r-based regimen, using LPV/r pellets, or LPV/r could be introduced at the end of the second week of life as syrup and then switched to a solid formulation at 3 months of age. Raltegravir (RAL) granules have recently been approved by the US Food and Drug Administration for use in neonates at full term, except for low birthweight or premature babies. This is a considerable advance in increasing treatment options for neonates. Feasibility and acceptability of this formulation are currently being assessed in a study in South Africa. The 2016 WHO ARV Consolidated Guidelines10 already recommend the use of RAL as an alternative first- line treatment for children younger than 3 months where LPV/r pellets cannot be used. At present, RAL suitable for administration in the neonatal period is only available as a granule for oral suspension, but improved formulations are being developed for future use. Countries considering whether to introduce birth testing will need to consider their ability to decentralize newborn treatment by strengthening HCW capacity, ensuring commodities are available at peripheral health facilities and/or extending the referral system to nearby facilities, as well as ensuring that HCW are fully trained and equipped to start newborn infants on treatment. Box 6. ARV Formulations for ePNP: implementation considerations There are three available formulations that can be used for dosing ePNP: • NVP and AZT syrups; • pediatric dispersible NVP tablets and; • pediatric fixed-dose combinations (FDCs). Each formulation has its own benefits and risks (see Annex 5). A pediatric FDC of AZT/3TC/NVP has some appeal as ePNP because it is widely available and well established in a child-friendly formulation. However, there are several challenges to using this triple-drug FDC option that programs should consider: • NVP is administered as a once-daily dose for prophylaxis, whereas AZT is a twice-daily dose, so using an FDC compromises one or other of the drug regimens. Either AZT should be administered once daily or NVP twice daily. • The AZT:NVP ratio within the FDC is appropriate for the first 6 weeks of ePNP but it cannot be used for weeks 6 to 12 when the AZT dose increases fourfold while the NVP dose increases by only one third. • This pediatric FDC contains 3TC in addition to AZT and NVP. Although 3TC is very well tolerated, and has been used as a single drug for ePNP in clinical trials, WHO does not currently recommend this drug for infant prophylaxis. Administration of the FDC would inevitably expose the infant to 3TC. • In order to use an FDC as ePNP in the first 6 weeks of life, a single tablet would have to be divided into quarters. Tablets are scored but only into halves. Despite these challenges, FDCs are readily available, easy to use and have been proposed as a mean to simplifying administration in high-risk infant prophylaxis. Benefits and risks of the different dosing options are outlined in Annex 5. 14 provide opportunities to strengthen service delivery for HIV-exposed infants. Integration within a well established maternal, neonatal, and child services platform, which traditionally provides services closest to clients, facilitates mother-infant pair follow-up and reduces the cost and time-visit burden on clients. The integrated information systems that link mother and infant information improve client tracking and facilitate continuity of care provision. Examples include longitudinal follow-up registers and cohort analysis as well as linkage with information on communit-based services. Programs should however take into consideration the increasing burden on the MCH platform within the context of existing human resources and the challenges of changing services. Community engagement and community-based services play an important role in supporting HIV-exposed infant care. These clear and highly context specific services play a “boosting” role in supporting facility-focused services and include community-based HIV testing. The engagement of networks of women living with HIV has been effective in several countries and has been used to improve community HIV literacy to create demand, form support groups at the facility and community levels, strengthen linkage to care by escorting newly diagnosed clients to treatment clinics, conduct defaulter tracking and provide active follow-up of mother-infant pairs. In several settings, these interventions led to reduced loss to follow-up among mother-infant pairs. Ensuring provision of a comprehensive integrated postnatal package of HIV services will promote the delivery of a set of interventions that contributes not only to improved HIV outcomes but better early childhood development overall. 3.3. Improving service delivery and implementing a postnatal package of care There are several barriers to the uptake of effective infant HIV services, and no single intervention can address all the barriers facing women and their infants at different times and places. Socio-economic and traditional factors that keep mother-infant pairs together are among the enabling circumstances that improve service uptake. Programs could benefit from combining effective interventions into “service packages” to support service provision and focus on the community engagement that supports uptake. Interventions which have been proven to improve provision and uptake of infant HIV services and the retention of mother-infant pairs include: • client-focused interventions that provide support to individual clients using reminder text messaging, conditional cash incentives and male partner involvement; • and health system-focused interventions, including measures to enhance the program (POC testing technologies, provider training and support, enhanced counselling services and peer support), to strengthen the health system (quality improvement initiatives and mother and child health (MCH)/HIV service integration) and to support community-based services and HCWs. Promoting integration to reduce fragmentation of care for mothers and infants and ensure that infants remain in the testing cascade until final diagnosis should be a priority. Strong antenatal and well-baby care systems 15 Box 7: Key research questions Infant diagnosis • Assess the impact of implementing an indeterminate range, particularly at different testing time points, sample types, and technologies. • Acquire impact data to assess the added value of birth testing within the EID program. • Assess the value of providing birth testing to high-risk infants only. • Measure the impact of tracking tools (ie, bar codes) to ensure effective tracking and repeat testing at 6 weeks among infants testing negative at birth. • Determine if there is added value in integrating birth testing with BCG vaccination. • Assess the optimal timing and frequency of VL testing of pregnant and breastfeeding women. • Assess the impact of maternal treatment and infant prophylaxis on infant diagnoses. • Determine and evaluate the most effective approaches to retaining infants throughout the EID cascade until final definite diagnosis. Infant prophylaxis and treatment • Determine dosing and safety of new ARVs for the purpose of prophylaxis or treatment in neonates and infants. • Develop optimal formulations and ensure timely uptake of newly recommended ARVs for newborns and infants. • Document country experiences with ePNP. • Understand the clinical relevance of maternal viremic episodes and their relative contribution to the overall transmission rate. • Conduct studies to explore the additional benefit of ePNP in the context of well implemented effective maternal ART regimens. • Assess adherence to ePNP and how to improve retention and support for mothers. • Determine the feasibility of using triple therapy as prophylaxis for infants whose mothers are first identified as HIV-infected in the post-partum period. Service delivery and post-natal package of care • Consider combining interventions together into packages to support service delivery. • Promote integration to ensure that infants remain in the testing cascade until final diagnosis. 4. SUMMARY AND WAY FORWARD Several novel innovations implemented by countries and partners have shown promise. While successful interventions are being scaled up, it remains imperative to focus on strengthening existing systems that support infant testing and early treatment initiation. Moreover, changing dynamics in transmission and treatment standards are adding to the complexity and interdependency of testing, prophylaxis and treatment. This will require an increasing need to tailor strategies to the epidemic and policy context. Finally, more programmatic evidence-driven experiences are needed to support and inform national policies, programmatic planning and implementation. 16 ACKNOWLEDGEMENTS Meeting participants Adolfo Vubil (INS Mozambique), Ahmed Haeri Mazanderai (University of Pretoria), Andrea Ciaranello (Harvard Medical School), Angela Mushavi (MOH Zimbabwe), Anna Laura Ross (Unitaid), Archawin Rojanawiwat (Chulalongkorn University), Arne Kroidl (University of Munich), Charles Kiyaga (MOH Uganda), David Sullivan (USAID), Debbie Boras (London School of Hygiene and Tropical Medicine), Deborah Persaud (Johns Hopkins University), Elaine Abrams (ICAP), George Siberry (OGAC), Heather Alexander (CDC), Helen Dale (US CDC), Jean Maritz (University of Stellenbosch), Jilian Sacks (CHAI), Landon Myer (University of Cape Town), Laura Broyles (CDC), Laura Onyengo (MOH Kenya), Laura Thuo (ICW Kenya), Lynne Mofenson (EGPAF), Marc Cotton (University of Stellenbosch), Marie-Claude Bottineau (MSF), Nicholas Furtado (Global Fund), Nobuhle Mthethwa (MOH Swaziland), Philip Goulder (University of Oxford), Roger Shapiro (Harvard T.H. Chan School of Public Health, Botswana), Sally Hargreaves (Imperial College London), Shaffiq Essajee (UNICEF), Smiljka de Lussigny (Unitaid), Timothy Cressey (Harvard T.H. Chan School of Public Health, Thailand), Trevor Peter (CHAI Botswana). WHO Staff Meg Doherty, Martina Penazzato, Lara Vojnov, Anisa Ghadrshenas, Serena Brusamento, Morkor Newman, Mercedes Perez, Fatim Jallow. 17 15. Mazanderani AH, Technau K-G, Hsiao N-Y, Maritz J, Carmona S, Sherman GG. Recommendations for the management of indeterminate HIV PCR results within South Africa’s early infant diagnosis programme. Southern African Journal of HIV Medicine. 2016;17(1):1-5. 16. Dunning L, Francke JA, Mallampati D, MacLean RL, Penazzato M, Hou T, et al. The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis. PLoS Medicine. 2017;14(11):e1002446. 17. WHO. WHO list of prequalified in vitro diagnostic products. Geneva: World Health Organisation; 2018 25 June. 18. WHO. Novel point-of-care tools for early infant diagnosis of HIV. Geneva: WHO; 2017. 19. Jani IV, Meggi B, Loquiha O, Tobaiwa O, Mudenyanga C, Zitha A, et al. Effect of point-of-care early infant diagnosis on antiretroviral therapy initiation and retention of patients. AIDS. 2018;32(11):1453-63. 20. Mwenda R, Fong Y, Magombo T, Saka E, Midian D, Mwase C, et al. Significant Patient Impact Observed Upon Implementation of Point-Of-Care Early Infant Diagnosis Technologies in an Observational Study in Malawi. Clinical Infectious Diseases. 27 Feb 2018. 21. WHO. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. Geneva: WHO; 2010. 22. Avy Violari; Man Chan; Kennedy Otwombe; Ravindre Panchia; Patrick J-PD, Gibb; Mark, Cotton; Abdel, Babiker;. Time to viral rebound after stopping ART in children treated from infancy in CHER. Abstract #137, CROI; March 4-7, 2018; Boston, Massachusetts. 23. Gill MM, Hoffman HJ, Mokone M, Tukei VJ, Nchephe M, Phalatse M, et al. Assessing Very Early Infant Diagnosis Turnaround Times: Findings from a Birth Testing Pilot in Lesotho. AIDS Research and Treatment. 2017: 2572594. 24. Urick B, Fong Y, Okiira C, Nabukeera-Barungi N, Nansera D, Ochola E, et al. Rapid Serological Tests Ineffectively Screen for HIV Exposure in HIV-Positive Infants. JAIDS. 2018;77(3):331-6. 25. Wagner AD, Njuguna IN, Andere RA, Cranmer LM, Okinyi HM, Benki-Nugent S, et al. Infant/child rapid serology tests fail to reliably assess HIV exposure among sick hospitalized infants. AIDS. 2017;31(11):F1-F7. 26. Beste S, Essajee S, Siberry G, Hannaford A, Dara J, Sugandhi N, et al. Optimal Antiretroviral Prophylaxis in Infants at High Risk of Acquiring HIV: A Systematic Review. Pediatr Infect Dis J. 2018;37(2):169-75. 27. WHO. Updates on HIV and infant feeding. Geneva: WHO; 2016. REFERENCES 1. UNAIDS. On the Fast-track to an AIDS-Free Generation. Geneva: UNAIDS; 2016. 2. UNAIDS. Global Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva: UNAIDS; 2016. 3. UNAIDS. Start free Stay Free AIDS free: 2017 progress report. UNAIDS; 2017. 4. WHO. WHO Consolidated ARV Guidelines on the use of antiretroviral Geneva: WHO; 2013. 5. Townsend CL, Byrne L, Cortina-Borja M, Thorne C, de Ruiter A, Lyall H, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049-57. 6. Sherman GG, Mazanderani AH, Barron P, Bhardwaj S, Niit R, Okobi M, et al. Toward elimination of mother– to–child transmission of HIV in South Africa: how best to monitor early infant infections within the Prevention of Mother–to–Child Transmission Program. Journal of Global Health. 2017;7(1). 7. Penazzato M, Lule F, Essajee S. Paediatric HIV: the unfinished business. Lancet HIV. 2017;4(10):e425-e7. 8. UNAIDS. Ending AIDS: progress towards the 90-90-90 targets. Geneva: UNAIDS; 2017. 9. Newell M, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Ghent International AIDS Society (IAS) Working Group on HIV Infection in Women and Children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):1236-43. 10. WHO. Consolidated ARV Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd ed. Geneva: WHO; 2016. 11. WHO. Innovating and strengthening the postnatal package of care for HIV-exposed infants: ensuring comprehensive services for the first two years of life. Johannesburg, South Africa, 20-23 June 2017 Meeting report. Geneva: WHO; 2017. 12. UNAIDS. AIDS info 2017. Geneva: UNAIDS; 2017. 13. Mazanderani AH, Moyo F, Kufa T, Sherman GG. Brief Report: Declining Baseline Viremia and Escalating Discordant HIV-1 Confirmatory Results Within South Africa’s Early Infant Diagnosis Program, 2010–2016. JAIDS. 2018;77(2):212-6. 14. Mazanderani AH, Moyo F, Kufa T, Maritz J, Sherman GG. Differentiating clearly positive from indeterminate results: A review of irreproducible HIV-1 PCR positive samples from South Africa’s Early Infant Diagnosis Program, 2010–2015. Diagnostic Microbiology and Infectious Disease. 2018;91:248-255. 18 EID sample no. 1 test no. 1 EID sample no. 1 test no. 2 NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE2 Request a new sample within 4 weeks3,4 Further review by a clinical and laboratory team4 ANNEXES Annex 1: Managing indeterminate test results: standard operating procedure 1. Refer to 2016 WHO ARV Consolidated guidelines. 2. Do not report as positive nor initiate ART, but maintain prophylaxis per current guidance. 3. Repeat samples should be prioritized in the laboratory. 4. Repeated indeterminate results in two separate samples should, together with clinical information, be reviewed by a team of laboratories, clinicians pediatricians, complex case experts (if possible), and caregivers. Infants should be actively tracked to ensure follow-up and retention. 19 Annex 2: Managing discordant results and treatment interruption This option provides follow-up care to the infant for a minimum of 8 months after interruption of ART. Where possible, both EID (qualitative) and VL (quantitative) tests should be performed at 4 weeks, 4 months, and 8 months after treatment interruption. EID and viral load at 4 weeks, 4 months, and 8 months after interruption Scenario a: Cessation of breastfeeding occurs after completion of the follow up post ART interruption. Scenario b: When cessation of breastfeeding occurs before completion of the follow up post ART interruption. 8 months NAT 1: + Start ART Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 2: - Stay on ART NAT 3: - Stop ARTNAT 3 Cessation of breastfeeding RDT 3 months after cessation of breastfeeding Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 3 Cessation of breastfeeding 8 months NAT 1: + Start ART NAT 2: - Stay on ART NAT 3: - Stop ART Further follow-up is needed to consider the exposure to breastfeeding and carry out the national infant testing schedule for HIV-exposed infants to ensure appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post- cessation of breastfeeding. 20 Annex 3: Simplified EID algorithm HIV-exposed newborn (0-2 days) Consider NATa,b Negative Negative Immediately start ARTc Repeat NAT to confirm infection Infant/child is infected HIV-exposed infant or child (4-6 weeks to 18 months) Conduct NATb (at 4-6 weeks or at the earliest opportunity thereafter) Positive Positive Immediately start ARTc Repeat NAT to confirm infection HIV infection not detected but if infant/child is breastfed the risk of acquiring HIV infection remains until complete cessation of breastfeedingd Regular clinical monitoring Conduct NATb (at 9 months) Antibody testing at 18 months of age or 3 months after cessation of breastfeeding, whichever is laterf Infant/child is infected HIV unlikely unless still breastfedinge Negative The key principles for establishing whether HIV-exposed infants and children younger than 18 months are infected with HIV in low- and middle-income countries are as follows: • Assess HIV exposure status by antibody testing the mother. • Perform NAT test for any HIV exposed child that presents outside of national infant testing algorithm with clinical symptoms irrespective of previous NAT results • At 9 months perform NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative. • Ensure that indeterminate test results are repeat tested immediately and given priority for rapid resolution. • Ensure that confirmatory testing is undertaken following any positive result. • Ensure regular follow-up for all HIV-exposed infants until final diagnosis, including providing co-trimoxazole prophylaxis and clinical and nutritional assessment. Notes: a. Based on 2016 WHO Consolidated ARV Guidelines10, addition of NAT at birth to the existing testing algorithm can be considered. b. POC NAT can be used to diagnose HIV infection as well as to confirm positive results. c. Start ART without delay. At the same time, retest to confirm infection. As maternal treatment is scaled up and MTCT transmission rates decrease, false-positive results are expected to increase: retesting after a first positive NAT is hence important to avoid unnecessary treatment, particularly in settings with lower transmission rates. If the second test is negative, a third NAT should be performed before interrupting ART. d. For children who were never breastfed, additional testing following a negative NAT at 4–6 weeks is included in this algorithm to account for potential false-negative NAT results. e. The risk of HIV transmission remains as long as breastfeeding continues. If the 9-month test is conducted earlier than 3 months after cessation of breastfeeding, infection acquired in the last days of breastfeeding may be missed. Retesting at 18 months or 3 months after cessation of breastfeeding (whichever is later) should be carried out for final assessment of HIV status. f. If breastfeeding extends beyond 18 months, the final diagnosis of HIV status can only be assessed at the end of breastfeeding. If breastfeeding ends before 18 months, the final diagnosis of HIV status with antibody testing can only be assessed at 18 months. Antibody testing should be undertaken at least 3 months after cessation of breastfeeding (to allow for development of HIV antibodies). For infants younger than 18 months of age NAT should be performed to confirm infection. If the infant is older than 18 months, negative antibody testing confirms that the infant is uninfected; positive antibody testing confirms infant is infected. 21 Annex 4: Algorithm for risk assessment This algorithm was developed to support risk assessment at the time of delivery and to help identify infants at high and low risk: Infants at low risk should be given standard prophylaxis (NVP or AZT alone for 4–6 weeks) while those at high risk should be given ePNP. In order to navigate this algorithm successfully, clinicians will need to know a number of parameters from the mother’s antenatal chart: • HIV status and date of last HIV test (to identify status and need for testing or retesting at delivery); • if known to be positive, and ART started, date of ART initiation; • if VL collected, date of sample collection relative to delivery and VL result. Programs should consider incorporating a VL test at or around 36 weeks’ gestation, ensuring that the turnaround time is short enough to have a result available by the expected delivery date. Mother newly identified as HIV+ within 72 hours of delivery NO Known HIV+ mother not on ART Known HIV+ mother on ART HIGH RISK HIGH RISK HIGH RISK HIGH RISKLOW RISK LOW RISK NOYES Has mother been on ART for > 4 weeks prior to delivery? YES: VL < 1,000 YES: VL > 1,000 Assess mother AT DELIVERY Is a VL result available from no more than < 4 weeks before delivery? 22 Annex 5: Dosing and formulation options for infant prophylaxis Dosage forms Dose 0-6 weeks AZT plus NVP Dose 6-12 weeks AZT plus NVP Dose 6-12 weeks NVP only Comments Syrups AZT 10mg/ml NVP 10mg/ml AZT dose 1.5ml (15mg) twice daily AZT dose 6ml (60mg) twice daily NVP dose 2ml (20mg) once daily - Accurate dosing for all drugs (included for low birth weight newborns) and one type of formulation for the whole 12-week period - Costly to procure and transport syrups - Difficult to hide in the home - Supplier availability may be limited - Might be acceptable where most women of childbearing age are well controlled on ART and numbers of high-risk infants is low, but would not be the best option for a program that chooses to treat all infants as high risk NVP dose 1.5ml (15mg) once daily NVP dose 2ml (20mg) once daily Syrups and single drug tablets AZT 60mg NVP 50mg AZT dose 1.5ml (15mg) twice daily AZT dose 1 tab (60mg) twice daily NVP dose ½ tab (25mg) once daily - Combines accuracy of syrup dosing in the first 6 weeks and the ease of tablets from 6 to 12 weeks - Challenges of syrups as before - ½ a tab of NVP represents a slight overdose of NVP (25mg vs 20mg) NVP dose 1.5ml (15mg) once daily NVP dose ½ tab (25mg) once daily FDC ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily Unsuitable Not applicable - Difficult to quarter a FDC accurately: caregivers should use the first quarter in the morning and the second quar- ter in the evening in order to keep daily dose accurate - 3TC not part of the recommended prophylaxis regimen - Cannot use FDC during weeks 6 to 12 without giving 5 times more than the recommended daily NVP dose FDCs and single drug tablets ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily AZT dose 1 tab (60mg) twice daily NVP: ½ a 50mg tablet once daily - Combines ease of FDC with single drug tablet for the second - Challenges of FDC as above NVP dose ½ tab (25mg) once daily Remarks: • It should be noted that unlike for NVP, there is no specific prophylaxis dose for AZT. The recommended dose is the same as that used for treatment - 15 mg twice daily for term infants in the first six weeks of life, increasing to 60mg twice daily from week 6 to week 12. • When presumptive treatment is administered, age-appropriate regimens and dosing should be used as illustrated in current WHO treatment guidelines10. 23 24 For more information, contact: World Health Organization Department of HIV/AIDS 20, avenue Appia 1211 Geneva 27 Switzerland WHO/CDS/HIV/18.17 E-mail: hiv-aids@who.int www.who.int/hiv

HIV DIAGNOSIS AND ARV USE IN HIV-EXPOSED INFANTS: A PROGRAMMATIC UPDATE JULY 2018 TECHNICAL REPORT 2WHO/CDS/HIV/18.17 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/ licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non- commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. HIV diagnosis and ARV use in HIV-exposed infants: a programmatic update. Geneva, Switzerland: World Health Organization; 2018 (WHO/CDS/HIV/18.17). Licence: CC BY-NC- SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/ bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Layout: 400.co.uk Printed in Switzerland 31.1 EXECUTIVE SUMMARY New HIV infections in children continue to occur globally and timely diagnosis and treatment of infants and children living with HIV remain critically important. The 2016 WHO ARV Consolidated Guidelines presented some innovative approaches, such as the use of nucleic acid testing (NAT) at or around birth for earlier diagnosis of HIV in infants, the introduction of point-of-care (POC) NAT for more rapid and decentralized diagnosis to enable prompt antiretroviral therapy (ART) initiation, and the use of enhanced postnatal prophylaxis (ePNP) to improve HIV prevention among infants exposed to HIV. To date, however, only a few countries have introduced these innovations and early lessons from the field have identified a number of implementation challenges that require careful review. Drawing on findings from a regional workshop held in Johannesburg, South Africa in 2017 and a follow-up expert meeting in Geneva, Switzerland in 2018, this programmatic update aims to describe changes in strategies for the identification, prevention and treatment of HIV in infants. This update will also highlight new information on the implementation of a postnatal package of care for HIV- exposed infants. ABBREVIATIONS 3TC lamivudine ART antiretroviral therapy ARV antiretroviral drugs AZT azidothymidine (zidovudine) CTX co-trimoxazole EID early infant diagnosis ePNP enhanced postnatal prophylaxis FDC fixed-dose combination HCW health-care worker HIV human immunodeficiency virus HIVDR HIV drug resistance LPV/r lopinavir/ritonavir MCH mother and child health MTCT mother-to-child transmission PMTCT prevention of mother-to-child transmission NAT nucleic acid test NVP nevirapine PCR polymerase chain reaction POC point-of-care RAL raltegravir RDT rapid diagnostics test SOP standard operating procedure VL viral load 42.1 BACKGROUND 2.1.1 Current status quo regarding pediatric HIV The Global Plan Towards the Elimination of New HIV Infections among Children by 2015 and Keeping their Mothers Alive initiative has had a substantial impact, leading to a 60% reduction in new pediatric HIV infections in 21 high-burden countries in sub-Saharan Africa.1,2 Nevertheless, the burden of new HIV infections in children remains significant: in 2017, there were 180 000 new infections in children globally, and 70% of these children were in the same 21 priority countries. The Start Free, Stay Free, AIDS Free framework3 was developed to build on the progress of the Global Plan and to provide a roadmap to achieve fast- track targets towards ending the AIDS epidemic by 2030. Following the adoption of the Option B+ policy4, the number of pregnant women on antiretroviral therapy (ART) has increased considerably across countries. This in turn has led to lower rates of vertical HIV transmission, now estimated to be less than 2% in non-breastfeeding populations, and less than 5% in breastfeeding populations.5,6 Despite the overall decrease in mother-to-child transmission (MTCT) of HIV, new pediatric infections continue to occur and transmission dynamics have now shifted towards a proportional increase in transmission during the postnatal period (Figure 1).3,7 Roughly half of all new infections among children occurs during breastfeeding. Although countries continue to make progress, challenges remain in retaining HIV-infected women in health- care services and on effective ART throughout pregnancy and the breastfeeding period, as well as in detecting and preventing new HIV infections in women during pregnancy and breastfeeding. This shift in transmission dynamics has also raised issues concerning optimal testing in infants, with the identification of HIV-exposed and HIV-infected children continuing to present a significant bottleneck in several settings. Early infant diagnosis (EID) coverage globally still remains low: in 2016 only 43% of infants exposed to HIV received an HIV test within the first 2 months of life.8 Figure 1 MTCT transmission rates in the priority countries of the Start Free, Stay Free, AIDS Free framework in 2017 (Source: UNAIDS 2018 estimates) 0 10 20 30 Indonesia 19% 7% 26% 26% 26% 21% 20% 19% 18% 16% 15% 14% 14% 12% 11% 11% 10% 9% 8% 8% 7% 6% 5% 5% Angola 15% 11% Nigeria 14% 14% Ethiopia 11% 10% Democratic Republic of Congo 12% 8% Ghana 10% 9% Chad Côte d’Ivoire Cameroon Mozambique Burundi United Republic of Tanzania Lesotho Kenya Zambia Malawi Uganda Eswatini Zimbabwe Namibia South Africa Botswana 10% 8% 8% 8% 9% 6% 7% 7% 6% 8% 6% 6% 5% 6% 6% 5% 4% 6% 3% 6% 4% 4% 3% 5% 2% 5% 2% 4% 2% 3% 3% 2% 6 week transmission rate Post 6 week transmission rate 5Furthermore, although pediatric ART coverage has notably improved since 2010, only 51% of the estimated 1.8 million children living with HIV were receiving ART by the end of 2017.3 HIV-infected infants and younger children have an exceptionally high mortality without treatment, approximately 30% by the first year and 50% by their second year of life.9 Many HIV-related deaths in infants can be avoided by early identification of HIV and rapid ART initiation. Limited availability of optimal antiretroviral (ARV) formulations for preventing and treating HIV infection in newborn and young infants remains, however, an ongoing challenge in many countries. 2.1.2 Rationale for this technical update The 2016 WHO Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection10 presented innovative approaches to diagnosis and treatment; however, to date only a few countries have started to implement these innovations. In addition, evidence from early adopter countries has raised a number of issues that require careful consideration and have generated lessons learned that may be useful for countries planning to adopt these interventions. • Reduction in MTCT rates has led to a decrease in the positive predictive value of nucleic acid testing (NAT), resulting in higher proportions of false-positive test results. There is currently no specific recommendation on what level of viremia should be considered a true- positive result in infants and whether there is benefit in defining an indeterminate range for NAT. • Significant drug exposure due to implementation of the Treat All policy and enhanced postnatal prophylaxis (ePNP) could cause delays in antibody development in infants with HIV infection. These dynamics may complicate the use of rrapid diagnostic tests (RDTs) in infants to determine exposure and/or infection and affect how RDTs are used and interpreted in infants under 18 months of age. • Addition of NAT at birth to the national infant testing algorithm has been considered by a number of countries. Several operational challenges have emerged and a critical review of these will be important to support the strategic introduction of birth testing where feasible and most appropriate. • ePNP for high-risk infants is being implemented in a number of countries but challenges persist with identifying infants at high-risk and providing ePNP with existing formulations. This has led to simplified approaches, currently being considered by a number of countries, that may have an impact on infant testing. • Greater emphasis should be placed on strengthening the postnatal package of care for HIV-exposed infants and their mothers. There are opportunities to consider combining successful interventions into packages in order to support service delivery, and placing greater importance on promoting the integration of services to ensure that infants are retained in care until final diagnosis. Following the WHO regional workshop in Johannesburg, South Africa (June 2017)11, an expert meeting was convened in April 2018 to provide insight and promote discussion on these matters. This programmatic update aims to detail important changes and new implementation considerations arising since the publication of the 2016 WHO ARV Consolidated Guidelines.10 3.0 KEY CONSIDERATIONS 3.1 Infant diagnosis The complexity of EID testing is now growing due to significant scale up of Treat All (including pregnant and breastfeeding women), implementation of ePNP, reduced MTCT rates and the increased relative contribution of postnatal transmission. EID can no longer be considered primarily a one-test process, since it now requires additional testing over the duration of exposure. Accordingly, several additional key considerations will be necessary to strengthen the EID testing cascade through the entire exposure period. This includes ensuring that ART initiation is not delayed in those infants found to have HIV infection. 3.1.1 Minimising false-positive results by introducing an indeterminate range for EID Although infant diagnosis is being scaled up globally, with increased access to Treat all, declining MTCT rates12 and low viremia observed in infants found to be infected with HIV13 mean that false-positive test results are increasingly being reported in programs. Some infants may therefore be incorrectly diagnosed as having HIV infection and started on lifelong ART unnecessarily. There is currently no specific recommendation on what level of viremia should be considered a true-positive result in infants and whether there is benefit to adding an indeterminate range to minimize false-positive test results (see Box 1). 6A systematic review of 32 studies using an indeterminate range found 14 753 non-negative test results of which 2 436 (16.5% [95% CI 15.9–17.1%]) were indeterminate (data unpublished); one study14 that reported the final diagnoses of indeterminate cases found that 76% of infants with an initial indeterminate test result were negative on repeat testing, suggesting these infants were not HIV-infected despite the initial non-negative test result. These data indicate that in countries not implementing an indeterminate range for NAT and where MCTC rates are low (<5%), 12.5% (76% of 16.5%) of non-negative results could be false-positive on initial testing with affected infants being potentially started on lifelong treatment unnecessarily. Typically, EID assays detect the presence of HIV using real-time NAT technologies that often report cycle thresholds. Reported cycle thresholds represent the PCR cycle at which amplification is first observed and are inversely correlated to the amount of virus in the sample. The approximate equivalent of a cycle threshold of 33 on the Roche COBAS® Ampliprep/COBAS® TaqMan® HIV-1 Qualitative Test v2.0 assay was selected as the optimal indeterminate range for further testing. This represented a balance between the proportion of infants living with HIV that would be incorrectly identified as indeterminate (about 8-13%) and the proportion of HIV-uninfected infants that would potentially start treatment unnecessarily (about 2–7%). South Africa has already implemented an indeterminate range and developed a standard operating procedure (SOP) for managing positive and indeterminate test results.15 Similarly, WHO technical consultation developed a new SOP that will help to ensure higher quality infant testing (Annex 1). Current evidence suggests that no specific requirements are necessary with regard to the type of assay (conventional or point-of-care (POC)) used to retest specimens with indeterminate test results. Most countries already apply a national SOP when testing errors are encountered (for example, device malfunction, insufficient or rejected specimen, etc.). In most countries the health-care facility concerned is contacted and asked to ensure that the infant returns to the facility in order to provide a new specimen for testing. Due to the delay caused by the testing error, these samples are generally considered urgent and prioritized for testing once received by the laboratory. A new study suggests that repeating an indeterminate test result using the same sample, if available, will resolve the majority (>95%) of indeterminate results.14 Therefore, prior to contacting the health- care facility to request the infant return to the facility for collection of a new sample, a repeat test should be conducted on the same sample using additional available dried blood spots or remaining whole blood. 3.1.2 Confirmatory testing of positive test results A cost-effectiveness analysis undertaken to assess the value of confirmatory testing in different scenarios highlighted that confirmatory testing is indeed cost- effective.16 Without confirmatory testing, this analysis showed that in settings with MTCT rates similar to those of South Africa, more than 10% of infants initiated on ART may in fact be HIV-uninfected. Confirmatory testing of positive test results using a new sample, as per WHO guidelines, may avoid this occurrence, although this policy is not consistently implemented (Box 2). It remains critical that programs ensure all HIV-exposed infants are retained and tested appropriately throughout the entire exposure Box 1. Definition of terms for diagnostic results • Indeterminate range: a range of viral copy equivalents that would be too low to accurately diagnose as positive. • False-positive result: HIV-uninfected infants incorrectly identified as HIV-infected and potentially started unnecessarily on ART. • False-negative result: HIV-infected infants incorrectly identified as HIV-uninfected. • Non-negative result: any positive or indeterminate result. Polmyerase chain reaction (PCR) instrument reports a detectable result, which may be subsequently classified as “indeterminate” based on other data (e.g. assay-reported cycle threshold). May also be referred to as “not confirmed”, “equivocal” or “irreproducible positive”. • Discordant result: positive/detectable first test; negative second test. • Cycle threshold: the point at which virus amplification is first observed during the course of repeated PCR cycles. The cycle threshold is inversely correlated to the amount of virus in the sample. 7period and all infants with a positive result receive a confirmatory test. Furthermore, those with repeatedly indeterminate test results should be actively tracked, retained, retested and their status resolved. Finally, POC EID testing is being implemented in several countries and settings (see 3.1.3). Previously there was limited evidence on how to conduct confirmatory testing of POC EID positive test results, but since publication of the 2016 WHO ARV Consolidated Guidelines10 several studies have been published on its performance. Two POC EID technologies are now included on the WHO list of prequalified in vitro diagnostic products.17 Results from both laboratory and field studies have shown performance comparable to that of laboratory-based technologies.18 Furthermore, two patient impact studies have been published which highlight the significantly improved patient outcomes when using POC EID technologies.19,20 Based on this updated evidence, POC EID testing can be used to confirm positive test results. 3.1.2 Managing discordant results and treatment interruption Since 2010, WHO has recommended initiating infants on ART after an initial positive NAT, while simultaneously collecting a confirmatory sample. The 2016 WHO ARV Consolidated Guidelines10 suggest that if the second (confirmatory) NAT is negative, a third NAT, either EID (qualitative) or viral load (VL), should be performed before considering ART interruption. The introduction of an indeterminate range should potentially reduce the number and proportion of infants with discordant test results (different NAT results on separate samples); however, guidance on how to conduct treatment interruptions is needed. Several factors should be considered when assessing patients for ART interruption after discordant test results (positive then a negative result) are followed by a third test with a negative result: • the infant ought to have no clinical signs or symptoms suggestive of HIV infection;21 • a follow-up plan should be agreed upon with family, caregiver(s) and health-care staff; • tracking information (phone, address, etc.) of the family/caregiver(s) should be collected and confirmed. The following factors should be considered when following up any infant undergoing treatment interruption: • there is a need for active follow-up to ensure that a potentially infected infant is retained and re-initiated on treatment if virological rebound occurs; • virological rebound in HIV-infected infants starting treatment early is expected to happen within 8 months of interruption in >99% of HIV-infected infants;22 • infants who develop signs and symptoms indicative of HIV infection should undergo immediate testing; • breastfeeding and continued risk of transmission require follow-up and appropriate testing throughout the period of risk until final diagnosis; • there is value in minimizing follow-up testing by leveraging existing opportunities for infant testing (based on the national infant testing schedule and immunization or well-child appointment schedules), until final diagnosis is ascertained. Few countries have existing policies on how to conduct treatment interruptions in infants with discordant test results. South Africa, for one, has implemented policies with intensive laboratory and clinical follow-up of these infants for 18 months.15 Both EID (qualitative) and VL (quantitative) tests are performed at 4 weeks, 3 months, and every 3 months after treatment interruption. However, since the likelihood of these infants being HIV-infected is low, a less aggressive 8 month approach is also reasonable in order to simplify the follow-up procedure: this is supported by emerging evidence on the timing of viral rebound in HIV-infected infants treated early.22 In this case both EID (qualitative) and VL (quantitative) tests could be performed at 4 weeks, 4 months and 8 months after treatment interruption (Annex 2). Infants who test positive on any follow-up test in either protocol should be re-initiated on treatment as per current guidelines,10 and a confirmatory sample taken. Any SOP for interruption should be implemented considering the continuous risk of transmission resulting from breastfeeding and, once the intensive follow up is completed (8 months after treatment interruption), the national infant testing schedule for HIV-exposed infants should be applied in order to ensure an appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post cessation of breastfeeding, as indicated in Annex 2 Scenario b. Box 2. Prioritizing confirmatory testing of positive and indeterminate tests • Decreasing MTCT rates globally have led to concerns about false-positive and indeterminate tests. • Patients with indeterminate results need immediate repeat testing and the patient should be managed according to the SOP presented in Annex 1. • Patients with repeated indeterminate results need a multidisciplinary team of health-care providers to support retention, tracking and status resolution. • In ART programs, there is a need to prioritize confirmatory testing of all positive test results using a new sample. • Clinical monitoring and further testing based on the national infant testing schedule need to be done until a definitive HIV status is established. 83.1.3 Implementation of POC EID testing The 2016 WHO ARV Consolidated Guidelines10 recommend the use of NAT technologies for early infant HIV testing that have been developed and validated for use at or near the point-of-care. POC EID provides the opportunity to reduce test turnaround times, limit patient loss along the HIV testing cascade, reduce infant mortality and facilitate task shifting to lower cadres of health workers at health- care facilities with decentralized services. Sufficient evidence has been generated on the performance of these assays in their intended field settings to support rapid national regulatory approval and initiation of scale-up (Box 3). A number of countries are currently implementing POC EID technologies.18 Implementation studies in Malawi20 and Mozambique19 have shown that using POC EID leads to significantly reduced test turnaround times, with a higher yield of results being returned to the health-care facility and caregivers, and earlier and higher rates of ART initiation among HIV-infected infants. Key lessons learned during pilot implementation projects include: • optimizing the use of POC EID through product and site selection; • selecting health facilities with high prevalence and high volumes to maximize device utilization; • considering placement within or in-facility referral from high-yield entry points (e.g. nutrition and pediatric wards); • ensuring service continuity by establishing a service and maintenance strategy with suppliers and provide service engineer back-up; • integrating services within health facilities by assessing the need for additional training and continuous mentoring of health-care workers (HCW); • strengthening the linkage between services to ensure prompt linkage to care for identified HIV-infected infants; • ensuring the availability of pediatric ARV formulations for neonates to guarantee earlier ART initiation. 3.1.4 Introduction of NAT at birth to facilitate earlier treatment initiation Adding NAT at birth to the existing national infant testing schedule may result in earlier identification of HIV-infected newborns and consequently lead to earlier treatment initiation and lower mortality among infants. Data suggest that infants testing positive at birth start ART approximately 2 months earlier than non-birth- tested infants (6 weeks vs 15 weeks).23 However, cost- effectiveness analyses have shown that the survival gains from adding NAT at birth to the standard 6-week test are lost if the loss-to-follow-up after a negative birth result exceeds 37%, underscoring the fact that a high-functioning 6-week program needs to already be in place. A number of countries have already started implementation of NAT at birth, and country experiences are outlined in Box 4. It should be noted, however, that strengthening existing EID systems remains the priority while programs consider adding birth testing. Several implementation considerations can be summarized from these experiences. • Countries that are considering birth testing should critically review current performance and opportunities for strengthening their 6-week EID program and consider other indicators, (e.g. PENTA1 immunization visit coverage and attended delivery rate), so that the potential gains provided by birth testing can be investigated more fully. For example, in settings where the attended delivery rate is much lower than PENTA1 immunization visit coverage the added value of birth testing as a means of expanding EID is limited. • Pilot projects are a good way to start gaining national experience on this innovative testing approach, but in order to measure impact fully programs need to collect data on the feasibility and impact of birth testing and linkage to ART initiation. • Targeted approaches which provide birth testing only for high-risk infants are expected to have a higher yield compared to routine birth testing. This approach may be potentially less resource intensive and present a lower burden for HCW. • Active tracking of infants with negative NAT results at birth is critical to ensure that they return at 6 weeks to be retested and start co-trimoxazole (CTX); establishing unique patient identifiers or other innovative mechanisms (e.g. bar codes) to track babies can be considered. • It is crucial that the turnaround time for reporting test results to health facilities and caregivers be rapid in order to optimize the benefit from NAT at birth, and POC assays should be used where they are available. Box 3. New POC EID technologies • Two technologies have received WHO prequalification. • National regulatory agencies are encouraged not to delay adoption by conducting further evaluations but instead to adopt a rapid and streamlined registration and national approval process for immediate implementation. 9• Birth testing is acceptable to mothers, but challenges arise from the increased human resources needed, the difficulty of collecting blood samples in newborns, the need to ensure sample collection outside of standard working hours and deliver results, linkage to ART and the nature of the EID system as a whole (stock-outs, referral mechanisms, delayed results). Box 4. Implementation of birth testing: country experiences South Africa South Africa introduced NAT at birth in 2015 with specific nurse training at postnatal and delivery services and health register updates to enable data acquisition. Implementation challenges met by South Africa include weak linkage of the identified HIV-infected infants to care with consequent delay in ART initiation, and a low return rate for future testing among infants with negative results at birth. A qualitative sub-study found that birth testing had a high acceptability. Refusals were rare and mothers did not indicate that birth testing affected their subsequent acceptance of infant testing or postnatal clinic attendance. Weak follow-up systems were detected for mothers who had home deliveries, and concerns were raised by laboratory staff about increased workloads associated with additional testing requirements. Kenya Kenya started a NAT at birth pilot project in 2015 (defined as testing within 72 hours of birth) and its results formed the basis of a revised EID algorithm in 2016 and national scale-up plan, due to start in mid-2018. Prior to implementation, a central point was designated within the health-care facility for birth testing, an innovative dispatch register was developed, mothers were offered mentoring to assist with linkage between hospitals and communities and a prevention of mother-to-child transmission (PMTCT) psychosocial support group was formed. Good leadership and coordination was identified as being important for seeing patients through service provision. Challenges included issues related to referral, demand creation, turnaround time for test results and mothers who failed to collect test results. In addition, ART formulations were lacking for neonates who tested positive during the initial implementation phase. Zimbabwe Zimbabwe started a POC NAT birth pilot in April 2017 in ten health facilities for high-risk HIV-exposed infants (< 48 hours after birth). Ninety-seven per cent of the results were transmitted to caregivers, and all HIV-infected infants started ART within 5 days of testing. This project is likely to provide critical experience on a different approach to tracking children after birth testing and will generate further information on the value of targeting birth testing for high-risk infants rather than all HIV-exposed infants. Democratic Republic of Congo NAT at birth was first implemented in December 2016, with samples sent to central laboratories for processing. Laboratory personnel were trained to prioritize birth samples and ensure prompt return of results to the health facility. Challenges included long turnaround times between specimen collection and receipt of results (8–12 weeks from the national laboratory), stock-outs due to limitations in supply chain management, and difficulties in specimen transportation. Uptake of birth testing was good, but yield was low with numerous missed opportunities due to early discharge of women from maternity wards. As a result, birth testing remains limited to this pilot project (now terminated) and efforts are being made to strengthen the existing 6-week EID program. Eswatini (Swaziland) Eswatini introduced two pilot projects to explore universal NAT at birth across five maternity sites in August 2017 using POC EID technologies in three sites (in partnership with EGPAF) and conventional testing in two sites (in partnership with ICAP). In the conventional test pilot, 93% of HIV-exposed newborns were tested before discharge from the maternity unit and six of the 1 548 tested were HIV-infected. In the POC testing pilot, 68% of HIV-exposed newborns were tested and 12 of the 1 314 tested were HIV-infected. Furthermore, 98% of results were returned to the caregiver. Of those HIV-infected, nine in the POC test pilot and four in the conventional test pilot were put on treatment. Both pilots confirmed that health-care facility staff face a heavier work burden when NAT at birth was added. Nurses often felt overwhelmed and failed to prioritize NAT at birth because many births occurred at night or on weekends when staffing was limited. Furthermore, although most mothers found birth testing to be acceptable, several were discharged or left the facility before getting tested, while others provided incorrect tracking information. Ensuring patient tracking and linkage proved to be a challenge. • The key to effective implementation is to ensure that newborns who have been identified as HIV-infected are linked to treatment and that age-appropriate formulations are available to start them on treatment. • Good leadership and coordination are needed to oversee service provision, support supervision, mentorship and the quality improvement cycle. 10 11 3.1.5 Ensuring accurate interpretation of the 9-month test and simplifying the testing algorithm The 2016 WHO ARV Consolidated Guidelines recommend that RDTs should be used to assess HIV exposure among infants younger than 4 months, while HIV exposure among infants 4–18 months old should be ascertained by testing the mother. When testing of the mother is not possible, current guidelines emphasize the importance of not considering a negative RDT result from an infant between 4–18 months as a definitive test of exposure. Implementation issues are highlighted in Box 5. Based on the 2016 WHO ARV Consolidated Guidelines10, RDTs are serological assays that can also be used to exclude established infection among healthy, HIV-exposed infants aged 9 months old and above. However, changes in transmission dynamics as well as in policy and practice have complicated RDT use for determining infection status. Substantial drug exposure for infants with implementation of the Treat All policy for mothers and enhanced postnatal prophylaxis of HIV-exposed infants may have resulted in viral load reduction and delayed antibody development in HIV-infected infants. Finally, the occurrence of maternal infection in late pregnancy or during the postnatal period may be responsible for a lack of passive HIV antibody transfer to the HIV-exposed infant. These factors increasingly jeopardize RDT accuracy at 9 months of age as a means of correctly ruling out established infection in HIV- exposed infants. These concerns are supported by findings from Uganda and Kenya,24, 25 where 15–40% of children under two years of age and identified as HIV-infected had a positive NAT but negative RDT. RDT at 9 months was initially recommended in the 2010 WHO recommendations on the diagnosis of HIV infection in infants and children21 with the goal of targeting NAT for those HIV-exposed infants most likely to be infected (e.g. those with a positive RDT) as a cost-saving measure. However, due to decreasing MTCT rates, increasing availability and lower costs of NAT, changing transmission and drug exposure dynamics, and the fact that RDTs are less effective at determining the need for NAT testing, such a targeted approach may be less compelling. Furthermore, the added programmatic complexity and potential for inappropriate interpretation of test results have additional unintended consequences. In light of the challenges and data outlined above, consideration can now be given to replacing RDT at 9 months with NAT in the interests of minimizing the challenges of interpretation and simplifying the infant testing algorithm. Annex 3 summarizes the new simplified algorithm, which is underscored by a number of key considerations: • assessing HIV exposure status by performing RDT on the mother; • at 9 months performing NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative; • ensuring indeterminate test results are repeat tested immediately and prioritized for rapid resolution; • ensuring confirmatory testing is undertaken following any positive result; and • ensuring all HIV-exposed infants are regularly followed up until final diagnosis, with the provision of CTX prophylaxis and clinical/nutritional assessment. Finally, it remains critical that infant retention be continued until the end of the exposure period. More effort should be given to establishing a final diagnosis at 18 months of age or 3 months after cessation of breastfeeding, whichever occurs later. Although there is increasing coverage of the traditional 6-week infant test and more consideration is given to earlier time-points, the changing dynamics of transmission and increased drug exposure mean that increased efforts are needed to maintain follow-up throughout the entire exposure period. The aim is to ensure that all HIV-infected infants, including those infected in the postnatal period, are identified and receive treatment. Box 5. Use of RDT: implementation considerations • Priority should continue to be given to the testing of mothers at all entry points to determine exposure status for infants and children less than 18 months. • If the mother is absent or unable to be tested, an RDT should be undertaken of the infant, but negative results of infants older than 4 months should not be considered as definitive exclusion of exposure and follow-up testing is required. • If the mother is absent or unable to be tested and the infant presents with signs and symptoms of HIV infection, a NAT should be undertaken. • NAT should be undertaken following any positive RDT in the mother or the infant and a confirmatory NAT undertaken following any positive NAT result. 12 3.2. ARV use for prevention and treatment of HIV in infants 3.2.1 Implementation challenges to providing ePNP for high-risk infants The 2016 WHO ARV Consolidated Guidelines recommend a dual regimen of AZT and NVP which can be extended for up to 12 weeks in breastfeeding infants deemed to be at high risk of MTCT. A high-risk infant is defined as an infant whose mother was first identified as HIV-infected at delivery or in the postpartum, infected during pregnancy or breastfeeding, started ART late in pregnancy, or did not achieve viral suppression by the time of delivery (Annex 4). All high-risk infants should receive dual drug prophylaxis (AZT plus NVP) for the first 6 weeks. In breastfeeding infants, this should be followed by either an extra 6 weeks of AZT plus NVP or an extra 6 weeks of NVP alone (see Box 6). This recommendation is based on evidence from randomized clinical trials26 and takes into account the risk- benefit ratio of ePNP: potential for increased drug toxicity versus additional protection from HIV transmission. The rationale for the use of extended ePNP especially in high- risk breastfeeding infants rests on the assumption that mothers started promptly on ART achieve viral suppression within 12 weeks, thereby greatly reducing the risk of breast milk transmission and the need for ongoing infant prophylaxis. Countries have adopted ePNP using a variety of different approaches. In Kenya, Eswatini (Swaziland), and Mozambique, ePNP has been adopted for all breastfeeding HIV-exposed infants, while nine countries (Botswana, Ghana, Namibia, Nigeria, South Africa, Tanzania, Uganda, Zambia and Zimbabwe) have adopted ePNP for high- risk infants identified primarily on the basis of maternal ART duration and, when available, maternal VL close to delivery. Most countries opted for at least 12 weeks of prophylaxis, usually AZT/NVP for the first 6 weeks followed by NVP alone. Three countries (Kenya, Namibia and South Africa) link the duration of ePNP to the maternal VL, and extend ePNP over the entire breastfeeding period when viral suppression is not achieved. Finally, in three countries (Botswana, Zambia and Tanzania), triple prophylaxis with a fixed-dose combination (FDC) of AZT/3TC/NVP has been adopted to address the challenges of procuring syrups. Recent guidelines on infant feeding27 in relation to HIV re-affirm the position of WHO that the best way to prevent MTCT in the postpartum period and optimize infant survival is to ensure that mothers living with HIV are well controlled on ART and able to breastfeed their infants for up to two years, with the infant being exclusively breastfed in the first six months of life. If a mother on ART is virologically suppressed, the risk of breast milk transmission of HIV is very low and infant prophylaxis confers minimal additional benefit beyond 4–6 weeks of life. Some program have adopted ePNP for all HIV-exposed infants. While this may simplify decision-making, it increases costs and exposes a large number of infants who may not need ePNP to added toxicity. This type of approach ought to be reserved for selected situations where a majority of mothers are at high risk of transmitting HIV. Data on the average duration of ART at delivery and, where available, the proportion of pregnant women with VL>1000 at the end of the third trimester might help policymakers to determine whether added costs and toxicity are outweighed by potential benefit. Even then, it should only be an interim measure while strategies to increase the coverage of maternal testing, early treatment and improved adherence are being implemented. However, there are several situations where viral suppression throughout the breastfeeding period cannot be ensured in the mother, for example: • if a mother refuses or is unable to start or continue ART and intends to breastfeed her infant; • if the provider knows the mother is poorly adherent to ART while breastfeeding; • if maternal VL is known to be high when the infant prophylaxis regimen is about to be stopped. There is no formal recommendation for these types of situations and no evidence to guide the best course of action. It is reasonable, however, to assume that infant prophylaxis serves as a “back-up” solution for preventing postnatal transmission of HIV, and national programs could consider the merits of giving clinical providers the option of continuing infant prophylaxis beyond the recommended 6- or 12-week period. If this option is introduced in the national guidelines, there ought to be clearly defined scenarios in which continuing prophylaxis is warranted. National guidelines should also emphasize that the best way to prevent breast milk transmission of HIV is by optimal maternal treatment for the entire duration of exposure. Continuing prophylaxis should therefore be seen as an interim measure while efforts are made to support and improve maternal treatment adherence. Deciding to continue prophylaxis should take into consideration the factors that led to poor maternal adherence as they may have an impact on adherence to infant prophylaxis. Once stopped, infant prophylaxis should not be re-started if there are new concerns about maternal adherence. There is no evidence to support such an approach; instead the focus should be on determining why the mother was unable to remain adherent. If the decision has been made to continue infant prophylaxis, mothers and infants should be evaluated at regular intervals to assess the need for ongoing infant prophylaxis. 13 As more effective treatments increasingly come to be used in pregnant women, we can expect decreasing MTCT rates. However, some women will still be diagnosed late or have incident infections and this group is likely to drive most new cases of HIV transmission to infants, owing to the high level of maternal virus in the absence of treatment. One possibility would be to provide “presumptive treatment” as postnatal ePNP, by administering a triple-drug regimen at therapeutic doses to this selected group of infants with the goal of minimizing transmission and drug-resistant HIV (HIVDR) selection in the event of established infection despite prophylaxis. Such approaches need to be paired with careful review of infant testing practices in order to determine the potential impact of triple ePNP on virological assay performance for infant diagnosis (i.e. at least one specimen must be collected prior to initiating any presumptive treatment so that a NAT can be performed as soon as possible). 3.2.2 Early infant treatment: limited options and complex administration Early infant ART improves survival and reduces long-term morbidity but mortality remains substantial in the first months of life. Introducing NAT at birth could enable ART to be started before 2 weeks of age. However the only regimen available for this age group has for many years been one containing AZT, 3TC and NVP. This regimen could be continued with close clinical monitoring until 3 months of age and then switched to a LPV/r-based regimen, using LPV/r pellets, or LPV/r could be introduced at the end of the second week of life as syrup and then switched to a solid formulation at 3 months of age. Raltegravir (RAL) granules have recently been approved by the US Food and Drug Administration for use in neonates at full term, except for low birthweight or premature babies. This is a considerable advance in increasing treatment options for neonates. Feasibility and acceptability of this formulation are currently being assessed in a study in South Africa. The 2016 WHO ARV Consolidated Guidelines10 already recommend the use of RAL as an alternative first- line treatment for children younger than 3 months where LPV/r pellets cannot be used. At present, RAL suitable for administration in the neonatal period is only available as a granule for oral suspension, but improved formulations are being developed for future use. Countries considering whether to introduce birth testing will need to consider their ability to decentralize newborn treatment by strengthening HCW capacity, ensuring commodities are available at peripheral health facilities and/or extending the referral system to nearby facilities, as well as ensuring that HCW are fully trained and equipped to start newborn infants on treatment. Box 6. ARV Formulations for ePNP: implementation considerations There are three available formulations that can be used for dosing ePNP: • NVP and AZT syrups; • pediatric dispersible NVP tablets and; • pediatric fixed-dose combinations (FDCs). Each formulation has its own benefits and risks (see Annex 5). A pediatric FDC of AZT/3TC/NVP has some appeal as ePNP because it is widely available and well established in a child-friendly formulation. However, there are several challenges to using this triple-drug FDC option that programs should consider: • NVP is administered as a once-daily dose for prophylaxis, whereas AZT is a twice-daily dose, so using an FDC compromises one or other of the drug regimens. Either AZT should be administered once daily or NVP twice daily. • The AZT:NVP ratio within the FDC is appropriate for the first 6 weeks of ePNP but it cannot be used for weeks 6 to 12 when the AZT dose increases fourfold while the NVP dose increases by only one third. • This pediatric FDC contains 3TC in addition to AZT and NVP. Although 3TC is very well tolerated, and has been used as a single drug for ePNP in clinical trials, WHO does not currently recommend this drug for infant prophylaxis. Administration of the FDC would inevitably expose the infant to 3TC. • In order to use an FDC as ePNP in the first 6 weeks of life, a single tablet would have to be divided into quarters. Tablets are scored but only into halves. Despite these challenges, FDCs are readily available, easy to use and have been proposed as a mean to simplifying administration in high-risk infant prophylaxis. Benefits and risks of the different dosing options are outlined in Annex 5. 14 provide opportunities to strengthen service delivery for HIV-exposed infants. Integration within a well established maternal, neonatal, and child services platform, which traditionally provides services closest to clients, facilitates mother-infant pair follow-up and reduces the cost and time-visit burden on clients. The integrated information systems that link mother and infant information improve client tracking and facilitate continuity of care provision. Examples include longitudinal follow-up registers and cohort analysis as well as linkage with information on communit-based services. Programs should however take into consideration the increasing burden on the MCH platform within the context of existing human resources and the challenges of changing services. Community engagement and community-based services play an important role in supporting HIV-exposed infant care. These clear and highly context specific services play a “boosting” role in supporting facility-focused services and include community-based HIV testing. The engagement of networks of women living with HIV has been effective in several countries and has been used to improve community HIV literacy to create demand, form support groups at the facility and community levels, strengthen linkage to care by escorting newly diagnosed clients to treatment clinics, conduct defaulter tracking and provide active follow-up of mother-infant pairs. In several settings, these interventions led to reduced loss to follow-up among mother-infant pairs. Ensuring provision of a comprehensive integrated postnatal package of HIV services will promote the delivery of a set of interventions that contributes not only to improved HIV outcomes but better early childhood development overall. 3.3. Improving service delivery and implementing a postnatal package of care There are several barriers to the uptake of effective infant HIV services, and no single intervention can address all the barriers facing women and their infants at different times and places. Socio-economic and traditional factors that keep mother-infant pairs together are among the enabling circumstances that improve service uptake. Programs could benefit from combining effective interventions into “service packages” to support service provision and focus on the community engagement that supports uptake. Interventions which have been proven to improve provision and uptake of infant HIV services and the retention of mother-infant pairs include: • client-focused interventions that provide support to individual clients using reminder text messaging, conditional cash incentives and male partner involvement; • and health system-focused interventions, including measures to enhance the program (POC testing technologies, provider training and support, enhanced counselling services and peer support), to strengthen the health system (quality improvement initiatives and mother and child health (MCH)/HIV service integration) and to support community-based services and HCWs. Promoting integration to reduce fragmentation of care for mothers and infants and ensure that infants remain in the testing cascade until final diagnosis should be a priority. Strong antenatal and well-baby care systems 15 Box 7: Key research questions Infant diagnosis • Assess the impact of implementing an indeterminate range, particularly at different testing time points, sample types, and technologies. • Acquire impact data to assess the added value of birth testing within the EID program. • Assess the value of providing birth testing to high-risk infants only. • Measure the impact of tracking tools (ie, bar codes) to ensure effective tracking and repeat testing at 6 weeks among infants testing negative at birth. • Determine if there is added value in integrating birth testing with BCG vaccination. • Assess the optimal timing and frequency of VL testing of pregnant and breastfeeding women. • Assess the impact of maternal treatment and infant prophylaxis on infant diagnoses. • Determine and evaluate the most effective approaches to retaining infants throughout the EID cascade until final definite diagnosis. Infant prophylaxis and treatment • Determine dosing and safety of new ARVs for the purpose of prophylaxis or treatment in neonates and infants. • Develop optimal formulations and ensure timely uptake of newly recommended ARVs for newborns and infants. • Document country experiences with ePNP. • Understand the clinical relevance of maternal viremic episodes and their relative contribution to the overall transmission rate. • Conduct studies to explore the additional benefit of ePNP in the context of well implemented effective maternal ART regimens. • Assess adherence to ePNP and how to improve retention and support for mothers. • Determine the feasibility of using triple therapy as prophylaxis for infants whose mothers are first identified as HIV-infected in the post-partum period. Service delivery and post-natal package of care • Consider combining interventions together into packages to support service delivery. • Promote integration to ensure that infants remain in the testing cascade until final diagnosis. 4. SUMMARY AND WAY FORWARD Several novel innovations implemented by countries and partners have shown promise. While successful interventions are being scaled up, it remains imperative to focus on strengthening existing systems that support infant testing and early treatment initiation. Moreover, changing dynamics in transmission and treatment standards are adding to the complexity and interdependency of testing, prophylaxis and treatment. This will require an increasing need to tailor strategies to the epidemic and policy context. Finally, more programmatic evidence-driven experiences are needed to support and inform national policies, programmatic planning and implementation. 16 ACKNOWLEDGEMENTS Meeting participants Adolfo Vubil (INS Mozambique), Ahmed Haeri Mazanderai (University of Pretoria), Andrea Ciaranello (Harvard Medical School), Angela Mushavi (MOH Zimbabwe), Anna Laura Ross (Unitaid), Archawin Rojanawiwat (Chulalongkorn University), Arne Kroidl (University of Munich), Charles Kiyaga (MOH Uganda), David Sullivan (USAID), Debbie Boras (London School of Hygiene and Tropical Medicine), Deborah Persaud (Johns Hopkins University), Elaine Abrams (ICAP), George Siberry (OGAC), Heather Alexander (CDC), Helen Dale (US CDC), Jean Maritz (University of Stellenbosch), Jilian Sacks (CHAI), Landon Myer (University of Cape Town), Laura Broyles (CDC), Laura Onyengo (MOH Kenya), Laura Thuo (ICW Kenya), Lynne Mofenson (EGPAF), Marc Cotton (University of Stellenbosch), Marie-Claude Bottineau (MSF), Nicholas Furtado (Global Fund), Nobuhle Mthethwa (MOH Swaziland), Philip Goulder (University of Oxford), Roger Shapiro (Harvard T.H. Chan School of Public Health, Botswana), Sally Hargreaves (Imperial College London), Shaffiq Essajee (UNICEF), Smiljka de Lussigny (Unitaid), Timothy Cressey (Harvard T.H. Chan School of Public Health, Thailand), Trevor Peter (CHAI Botswana). WHO Staff Meg Doherty, Martina Penazzato, Lara Vojnov, Anisa Ghadrshenas, Serena Brusamento, Morkor Newman, Mercedes Perez, Fatim Jallow. 17 15. Mazanderani AH, Technau K-G, Hsiao N-Y, Maritz J, Carmona S, Sherman GG. Recommendations for the management of indeterminate HIV PCR results within South Africa’s early infant diagnosis programme. Southern African Journal of HIV Medicine. 2016;17(1):1-5. 16. Dunning L, Francke JA, Mallampati D, MacLean RL, Penazzato M, Hou T, et al. The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis. PLoS Medicine. 2017;14(11):e1002446. 17. WHO. WHO list of prequalified in vitro diagnostic products. Geneva: World Health Organisation; 2018 25 June. 18. WHO. Novel point-of-care tools for early infant diagnosis of HIV. Geneva: WHO; 2017. 19. Jani IV, Meggi B, Loquiha O, Tobaiwa O, Mudenyanga C, Zitha A, et al. Effect of point-of-care early infant diagnosis on antiretroviral therapy initiation and retention of patients. AIDS. 2018;32(11):1453-63. 20. Mwenda R, Fong Y, Magombo T, Saka E, Midian D, Mwase C, et al. Significant Patient Impact Observed Upon Implementation of Point-Of-Care Early Infant Diagnosis Technologies in an Observational Study in Malawi. Clinical Infectious Diseases. 27 Feb 2018. 21. WHO. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. Geneva: WHO; 2010. 22. Avy Violari; Man Chan; Kennedy Otwombe; Ravindre Panchia; Patrick J-PD, Gibb; Mark, Cotton; Abdel, Babiker;. Time to viral rebound after stopping ART in children treated from infancy in CHER. Abstract #137, CROI; March 4-7, 2018; Boston, Massachusetts. 23. Gill MM, Hoffman HJ, Mokone M, Tukei VJ, Nchephe M, Phalatse M, et al. Assessing Very Early Infant Diagnosis Turnaround Times: Findings from a Birth Testing Pilot in Lesotho. AIDS Research and Treatment. 2017: 2572594. 24. Urick B, Fong Y, Okiira C, Nabukeera-Barungi N, Nansera D, Ochola E, et al. Rapid Serological Tests Ineffectively Screen for HIV Exposure in HIV-Positive Infants. JAIDS. 2018;77(3):331-6. 25. Wagner AD, Njuguna IN, Andere RA, Cranmer LM, Okinyi HM, Benki-Nugent S, et al. Infant/child rapid serology tests fail to reliably assess HIV exposure among sick hospitalized infants. AIDS. 2017;31(11):F1-F7. 26. Beste S, Essajee S, Siberry G, Hannaford A, Dara J, Sugandhi N, et al. Optimal Antiretroviral Prophylaxis in Infants at High Risk of Acquiring HIV: A Systematic Review. Pediatr Infect Dis J. 2018;37(2):169-75. 27. WHO. Updates on HIV and infant feeding. Geneva: WHO; 2016. REFERENCES 1. UNAIDS. On the Fast-track to an AIDS-Free Generation. Geneva: UNAIDS; 2016. 2. UNAIDS. Global Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva: UNAIDS; 2016. 3. UNAIDS. Start free Stay Free AIDS free: 2017 progress report. UNAIDS; 2017. 4. WHO. WHO Consolidated ARV Guidelines on the use of antiretroviral Geneva: WHO; 2013. 5. Townsend CL, Byrne L, Cortina-Borja M, Thorne C, de Ruiter A, Lyall H, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049-57. 6. Sherman GG, Mazanderani AH, Barron P, Bhardwaj S, Niit R, Okobi M, et al. Toward elimination of mother– to–child transmission of HIV in South Africa: how best to monitor early infant infections within the Prevention of Mother–to–Child Transmission Program. Journal of Global Health. 2017;7(1). 7. Penazzato M, Lule F, Essajee S. Paediatric HIV: the unfinished business. Lancet HIV. 2017;4(10):e425-e7. 8. UNAIDS. Ending AIDS: progress towards the 90-90-90 targets. Geneva: UNAIDS; 2017. 9. Newell M, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Ghent International AIDS Society (IAS) Working Group on HIV Infection in Women and Children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):1236-43. 10. WHO. Consolidated ARV Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd ed. Geneva: WHO; 2016. 11. WHO. Innovating and strengthening the postnatal package of care for HIV-exposed infants: ensuring comprehensive services for the first two years of life. Johannesburg, South Africa, 20-23 June 2017 Meeting report. Geneva: WHO; 2017. 12. UNAIDS. AIDS info 2017. Geneva: UNAIDS; 2017. 13. Mazanderani AH, Moyo F, Kufa T, Sherman GG. Brief Report: Declining Baseline Viremia and Escalating Discordant HIV-1 Confirmatory Results Within South Africa’s Early Infant Diagnosis Program, 2010–2016. JAIDS. 2018;77(2):212-6. 14. Mazanderani AH, Moyo F, Kufa T, Maritz J, Sherman GG. Differentiating clearly positive from indeterminate results: A review of irreproducible HIV-1 PCR positive samples from South Africa’s Early Infant Diagnosis Program, 2010–2015. Diagnostic Microbiology and Infectious Disease. 2018;91:248-255. 18 EID sample no. 1 test no. 1 EID sample no. 1 test no. 2 NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE2 Request a new sample within 4 weeks3,4 Further review by a clinical and laboratory team4 ANNEXES Annex 1: Managing indeterminate test results: standard operating procedure 1. Refer to 2016 WHO ARV Consolidated guidelines. 2. Do not report as positive nor initiate ART, but maintain prophylaxis per current guidance. 3. Repeat samples should be prioritized in the laboratory. 4. Repeated indeterminate results in two separate samples should, together with clinical information, be reviewed by a team of laboratories, clinicians pediatricians, complex case experts (if possible), and caregivers. Infants should be actively tracked to ensure follow-up and retention. 19 Annex 2: Managing discordant results and treatment interruption This option provides follow-up care to the infant for a minimum of 8 months after interruption of ART. Where possible, both EID (qualitative) and VL (quantitative) tests should be performed at 4 weeks, 4 months, and 8 months after treatment interruption. EID and viral load at 4 weeks, 4 months, and 8 months after interruption Scenario a: Cessation of breastfeeding occurs after completion of the follow up post ART interruption. Scenario b: When cessation of breastfeeding occurs before completion of the follow up post ART interruption. 8 months NAT 1: + Start ART Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 2: - Stay on ART NAT 3: - Stop ARTNAT 3 Cessation of breastfeeding RDT 3 months after cessation of breastfeeding Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 3 Cessation of breastfeeding 8 months NAT 1: + Start ART NAT 2: - Stay on ART NAT 3: - Stop ART Further follow-up is needed to consider the exposure to breastfeeding and carry out the national infant testing schedule for HIV-exposed infants to ensure appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post- cessation of breastfeeding. 20 Annex 3: Simplified EID algorithm HIV-exposed newborn (0-2 days) Consider NATa,b Negative Negative Immediately start ARTc Repeat NAT to confirm infection Infant/child is infected HIV-exposed infant or child (4-6 weeks to 18 months) Conduct NATb (at 4-6 weeks or at the earliest opportunity thereafter) Positive Positive Immediately start ARTc Repeat NAT to confirm infection HIV infection not detected but if infant/child is breastfed the risk of acquiring HIV infection remains until complete cessation of breastfeedingd Regular clinical monitoring Conduct NATb (at 9 months) Antibody testing at 18 months of age or 3 months after cessation of breastfeeding, whichever is laterf Infant/child is infected HIV unlikely unless still breastfedinge Negative The key principles for establishing whether HIV-exposed infants and children younger than 18 months are infected with HIV in low- and middle-income countries are as follows: • Assess HIV exposure status by antibody testing the mother. • Perform NAT test for any HIV exposed child that presents outside of national infant testing algorithm with clinical symptoms irrespective of previous NAT results • At 9 months perform NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative. • Ensure that indeterminate test results are repeat tested immediately and given priority for rapid resolution. • Ensure that confirmatory testing is undertaken following any positive result. • Ensure regular follow-up for all HIV-exposed infants until final diagnosis, including providing co-trimoxazole prophylaxis and clinical and nutritional assessment. Notes: a. Based on 2016 WHO Consolidated ARV Guidelines10, addition of NAT at birth to the existing testing algorithm can be considered. b. POC NAT can be used to diagnose HIV infection as well as to confirm positive results. c. Start ART without delay. At the same time, retest to confirm infection. As maternal treatment is scaled up and MTCT transmission rates decrease, false-positive results are expected to increase: retesting after a first positive NAT is hence important to avoid unnecessary treatment, particularly in settings with lower transmission rates. If the second test is negative, a third NAT should be performed before interrupting ART. d. For children who were never breastfed, additional testing following a negative NAT at 4–6 weeks is included in this algorithm to account for potential false-negative NAT results. e. The risk of HIV transmission remains as long as breastfeeding continues. If the 9-month test is conducted earlier than 3 months after cessation of breastfeeding, infection acquired in the last days of breastfeeding may be missed. Retesting at 18 months or 3 months after cessation of breastfeeding (whichever is later) should be carried out for final assessment of HIV status. f. If breastfeeding extends beyond 18 months, the final diagnosis of HIV status can only be assessed at the end of breastfeeding. If breastfeeding ends before 18 months, the final diagnosis of HIV status with antibody testing can only be assessed at 18 months. Antibody testing should be undertaken at least 3 months after cessation of breastfeeding (to allow for development of HIV antibodies). For infants younger than 18 months of age NAT should be performed to confirm infection. If the infant is older than 18 months, negative antibody testing confirms that the infant is uninfected; positive antibody testing confirms infant is infected. 21 Annex 4: Algorithm for risk assessment This algorithm was developed to support risk assessment at the time of delivery and to help identify infants at high and low risk: Infants at low risk should be given standard prophylaxis (NVP or AZT alone for 4–6 weeks) while those at high risk should be given ePNP. In order to navigate this algorithm successfully, clinicians will need to know a number of parameters from the mother’s antenatal chart: • HIV status and date of last HIV test (to identify status and need for testing or retesting at delivery); • if known to be positive, and ART started, date of ART initiation; • if VL collected, date of sample collection relative to delivery and VL result. Programs should consider incorporating a VL test at or around 36 weeks’ gestation, ensuring that the turnaround time is short enough to have a result available by the expected delivery date. Mother newly identified as HIV+ within 72 hours of delivery NO Known HIV+ mother not on ART Known HIV+ mother on ART HIGH RISK HIGH RISK HIGH RISK HIGH RISKLOW RISK LOW RISK NOYES Has mother been on ART for > 4 weeks prior to delivery? YES: VL < 1,000 YES: VL > 1,000 Assess mother AT DELIVERY Is a VL result available from no more than < 4 weeks before delivery? 22 Annex 5: Dosing and formulation options for infant prophylaxis Dosage forms Dose 0-6 weeks AZT plus NVP Dose 6-12 weeks AZT plus NVP Dose 6-12 weeks NVP only Comments Syrups AZT 10mg/ml NVP 10mg/ml AZT dose 1.5ml (15mg) twice daily AZT dose 6ml (60mg) twice daily NVP dose 2ml (20mg) once daily - Accurate dosing for all drugs (included for low birth weight newborns) and one type of formulation for the whole 12-week period - Costly to procure and transport syrups - Difficult to hide in the home - Supplier availability may be limited - Might be acceptable where most women of childbearing age are well controlled on ART and numbers of high-risk infants is low, but would not be the best option for a program that chooses to treat all infants as high risk NVP dose 1.5ml (15mg) once daily NVP dose 2ml (20mg) once daily Syrups and single drug tablets AZT 60mg NVP 50mg AZT dose 1.5ml (15mg) twice daily AZT dose 1 tab (60mg) twice daily NVP dose ½ tab (25mg) once daily - Combines accuracy of syrup dosing in the first 6 weeks and the ease of tablets from 6 to 12 weeks - Challenges of syrups as before - ½ a tab of NVP represents a slight overdose of NVP (25mg vs 20mg) NVP dose 1.5ml (15mg) once daily NVP dose ½ tab (25mg) once daily FDC ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily Unsuitable Not applicable - Difficult to quarter a FDC accurately: caregivers should use the first quarter in the morning and the second quar- ter in the evening in order to keep daily dose accurate - 3TC not part of the recommended prophylaxis regimen - Cannot use FDC during weeks 6 to 12 without giving 5 times more than the recommended daily NVP dose FDCs and single drug tablets ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily AZT dose 1 tab (60mg) twice daily NVP: ½ a 50mg tablet once daily - Combines ease of FDC with single drug tablet for the second - Challenges of FDC as above NVP dose ½ tab (25mg) once daily Remarks: • It should be noted that unlike for NVP, there is no specific prophylaxis dose for AZT. The recommended dose is the same as that used for treatment - 15 mg twice daily for term infants in the first six weeks of life, increasing to 60mg twice daily from week 6 to week 12. • When presumptive treatment is administered, age-appropriate regimens and dosing should be used as illustrated in current WHO treatment guidelines10. 23 24 For more information, contact: World Health Organization Department of HIV/AIDS 20, avenue Appia 1211 Geneva 27 Switzerland WHO/CDS/HIV/18.17 E-mail: hiv-aids@who.int www.who.int/hiv

HIV DIAGNOSIS AND ARV USE IN HIV-EXPOSED INFANTS: A PROGRAMMATIC UPDATE JULY 2018 TECHNICAL REPORT 2WHO/CDS/HIV/18.17 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/ licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non- commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. HIV diagnosis and ARV use in HIV-exposed infants: a programmatic update. Geneva, Switzerland: World Health Organization; 2018 (WHO/CDS/HIV/18.17). Licence: CC BY-NC- SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at http://apps.who.int/iris. Sales, rights and licensing. To purchase WHO publications, see http://apps.who.int/ bookorders. To submit requests for commercial use and queries on rights and licensing, see http://www.who.int/about/licensing. Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by WHO to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. Layout: 400.co.uk Printed in Switzerland 31.1 EXECUTIVE SUMMARY New HIV infections in children continue to occur globally and timely diagnosis and treatment of infants and children living with HIV remain critically important. The 2016 WHO ARV Consolidated Guidelines presented some innovative approaches, such as the use of nucleic acid testing (NAT) at or around birth for earlier diagnosis of HIV in infants, the introduction of point-of-care (POC) NAT for more rapid and decentralized diagnosis to enable prompt antiretroviral therapy (ART) initiation, and the use of enhanced postnatal prophylaxis (ePNP) to improve HIV prevention among infants exposed to HIV. To date, however, only a few countries have introduced these innovations and early lessons from the field have identified a number of implementation challenges that require careful review. Drawing on findings from a regional workshop held in Johannesburg, South Africa in 2017 and a follow-up expert meeting in Geneva, Switzerland in 2018, this programmatic update aims to describe changes in strategies for the identification, prevention and treatment of HIV in infants. This update will also highlight new information on the implementation of a postnatal package of care for HIV- exposed infants. ABBREVIATIONS 3TC lamivudine ART antiretroviral therapy ARV antiretroviral drugs AZT azidothymidine (zidovudine) CTX co-trimoxazole EID early infant diagnosis ePNP enhanced postnatal prophylaxis FDC fixed-dose combination HCW health-care worker HIV human immunodeficiency virus HIVDR HIV drug resistance LPV/r lopinavir/ritonavir MCH mother and child health MTCT mother-to-child transmission PMTCT prevention of mother-to-child transmission NAT nucleic acid test NVP nevirapine PCR polymerase chain reaction POC point-of-care RAL raltegravir RDT rapid diagnostics test SOP standard operating procedure VL viral load 42.1 BACKGROUND 2.1.1 Current status quo regarding pediatric HIV The Global Plan Towards the Elimination of New HIV Infections among Children by 2015 and Keeping their Mothers Alive initiative has had a substantial impact, leading to a 60% reduction in new pediatric HIV infections in 21 high-burden countries in sub-Saharan Africa.1,2 Nevertheless, the burden of new HIV infections in children remains significant: in 2017, there were 180 000 new infections in children globally, and 70% of these children were in the same 21 priority countries. The Start Free, Stay Free, AIDS Free framework3 was developed to build on the progress of the Global Plan and to provide a roadmap to achieve fast- track targets towards ending the AIDS epidemic by 2030. Following the adoption of the Option B+ policy4, the number of pregnant women on antiretroviral therapy (ART) has increased considerably across countries. This in turn has led to lower rates of vertical HIV transmission, now estimated to be less than 2% in non-breastfeeding populations, and less than 5% in breastfeeding populations.5,6 Despite the overall decrease in mother-to-child transmission (MTCT) of HIV, new pediatric infections continue to occur and transmission dynamics have now shifted towards a proportional increase in transmission during the postnatal period (Figure 1).3,7 Roughly half of all new infections among children occurs during breastfeeding. Although countries continue to make progress, challenges remain in retaining HIV-infected women in health- care services and on effective ART throughout pregnancy and the breastfeeding period, as well as in detecting and preventing new HIV infections in women during pregnancy and breastfeeding. This shift in transmission dynamics has also raised issues concerning optimal testing in infants, with the identification of HIV-exposed and HIV-infected children continuing to present a significant bottleneck in several settings. Early infant diagnosis (EID) coverage globally still remains low: in 2016 only 43% of infants exposed to HIV received an HIV test within the first 2 months of life.8 Figure 1 MTCT transmission rates in the priority countries of the Start Free, Stay Free, AIDS Free framework in 2017 (Source: UNAIDS 2018 estimates) 0 10 20 30 Indonesia 19% 7% 26% 26% 26% 21% 20% 19% 18% 16% 15% 14% 14% 12% 11% 11% 10% 9% 8% 8% 7% 6% 5% 5% Angola 15% 11% Nigeria 14% 14% Ethiopia 11% 10% Democratic Republic of Congo 12% 8% Ghana 10% 9% Chad Côte d’Ivoire Cameroon Mozambique Burundi United Republic of Tanzania Lesotho Kenya Zambia Malawi Uganda Eswatini Zimbabwe Namibia South Africa Botswana 10% 8% 8% 8% 9% 6% 7% 7% 6% 8% 6% 6% 5% 6% 6% 5% 4% 6% 3% 6% 4% 4% 3% 5% 2% 5% 2% 4% 2% 3% 3% 2% 6 week transmission rate Post 6 week transmission rate 5Furthermore, although pediatric ART coverage has notably improved since 2010, only 51% of the estimated 1.8 million children living with HIV were receiving ART by the end of 2017.3 HIV-infected infants and younger children have an exceptionally high mortality without treatment, approximately 30% by the first year and 50% by their second year of life.9 Many HIV-related deaths in infants can be avoided by early identification of HIV and rapid ART initiation. Limited availability of optimal antiretroviral (ARV) formulations for preventing and treating HIV infection in newborn and young infants remains, however, an ongoing challenge in many countries. 2.1.2 Rationale for this technical update The 2016 WHO Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection10 presented innovative approaches to diagnosis and treatment; however, to date only a few countries have started to implement these innovations. In addition, evidence from early adopter countries has raised a number of issues that require careful consideration and have generated lessons learned that may be useful for countries planning to adopt these interventions. • Reduction in MTCT rates has led to a decrease in the positive predictive value of nucleic acid testing (NAT), resulting in higher proportions of false-positive test results. There is currently no specific recommendation on what level of viremia should be considered a true- positive result in infants and whether there is benefit in defining an indeterminate range for NAT. • Significant drug exposure due to implementation of the Treat All policy and enhanced postnatal prophylaxis (ePNP) could cause delays in antibody development in infants with HIV infection. These dynamics may complicate the use of rrapid diagnostic tests (RDTs) in infants to determine exposure and/or infection and affect how RDTs are used and interpreted in infants under 18 months of age. • Addition of NAT at birth to the national infant testing algorithm has been considered by a number of countries. Several operational challenges have emerged and a critical review of these will be important to support the strategic introduction of birth testing where feasible and most appropriate. • ePNP for high-risk infants is being implemented in a number of countries but challenges persist with identifying infants at high-risk and providing ePNP with existing formulations. This has led to simplified approaches, currently being considered by a number of countries, that may have an impact on infant testing. • Greater emphasis should be placed on strengthening the postnatal package of care for HIV-exposed infants and their mothers. There are opportunities to consider combining successful interventions into packages in order to support service delivery, and placing greater importance on promoting the integration of services to ensure that infants are retained in care until final diagnosis. Following the WHO regional workshop in Johannesburg, South Africa (June 2017)11, an expert meeting was convened in April 2018 to provide insight and promote discussion on these matters. This programmatic update aims to detail important changes and new implementation considerations arising since the publication of the 2016 WHO ARV Consolidated Guidelines.10 3.0 KEY CONSIDERATIONS 3.1 Infant diagnosis The complexity of EID testing is now growing due to significant scale up of Treat All (including pregnant and breastfeeding women), implementation of ePNP, reduced MTCT rates and the increased relative contribution of postnatal transmission. EID can no longer be considered primarily a one-test process, since it now requires additional testing over the duration of exposure. Accordingly, several additional key considerations will be necessary to strengthen the EID testing cascade through the entire exposure period. This includes ensuring that ART initiation is not delayed in those infants found to have HIV infection. 3.1.1 Minimising false-positive results by introducing an indeterminate range for EID Although infant diagnosis is being scaled up globally, with increased access to Treat all, declining MTCT rates12 and low viremia observed in infants found to be infected with HIV13 mean that false-positive test results are increasingly being reported in programs. Some infants may therefore be incorrectly diagnosed as having HIV infection and started on lifelong ART unnecessarily. There is currently no specific recommendation on what level of viremia should be considered a true-positive result in infants and whether there is benefit to adding an indeterminate range to minimize false-positive test results (see Box 1). 6A systematic review of 32 studies using an indeterminate range found 14 753 non-negative test results of which 2 436 (16.5% [95% CI 15.9–17.1%]) were indeterminate (data unpublished); one study14 that reported the final diagnoses of indeterminate cases found that 76% of infants with an initial indeterminate test result were negative on repeat testing, suggesting these infants were not HIV-infected despite the initial non-negative test result. These data indicate that in countries not implementing an indeterminate range for NAT and where MCTC rates are low (<5%), 12.5% (76% of 16.5%) of non-negative results could be false-positive on initial testing with affected infants being potentially started on lifelong treatment unnecessarily. Typically, EID assays detect the presence of HIV using real-time NAT technologies that often report cycle thresholds. Reported cycle thresholds represent the PCR cycle at which amplification is first observed and are inversely correlated to the amount of virus in the sample. The approximate equivalent of a cycle threshold of 33 on the Roche COBAS® Ampliprep/COBAS® TaqMan® HIV-1 Qualitative Test v2.0 assay was selected as the optimal indeterminate range for further testing. This represented a balance between the proportion of infants living with HIV that would be incorrectly identified as indeterminate (about 8-13%) and the proportion of HIV-uninfected infants that would potentially start treatment unnecessarily (about 2–7%). South Africa has already implemented an indeterminate range and developed a standard operating procedure (SOP) for managing positive and indeterminate test results.15 Similarly, WHO technical consultation developed a new SOP that will help to ensure higher quality infant testing (Annex 1). Current evidence suggests that no specific requirements are necessary with regard to the type of assay (conventional or point-of-care (POC)) used to retest specimens with indeterminate test results. Most countries already apply a national SOP when testing errors are encountered (for example, device malfunction, insufficient or rejected specimen, etc.). In most countries the health-care facility concerned is contacted and asked to ensure that the infant returns to the facility in order to provide a new specimen for testing. Due to the delay caused by the testing error, these samples are generally considered urgent and prioritized for testing once received by the laboratory. A new study suggests that repeating an indeterminate test result using the same sample, if available, will resolve the majority (>95%) of indeterminate results.14 Therefore, prior to contacting the health- care facility to request the infant return to the facility for collection of a new sample, a repeat test should be conducted on the same sample using additional available dried blood spots or remaining whole blood. 3.1.2 Confirmatory testing of positive test results A cost-effectiveness analysis undertaken to assess the value of confirmatory testing in different scenarios highlighted that confirmatory testing is indeed cost- effective.16 Without confirmatory testing, this analysis showed that in settings with MTCT rates similar to those of South Africa, more than 10% of infants initiated on ART may in fact be HIV-uninfected. Confirmatory testing of positive test results using a new sample, as per WHO guidelines, may avoid this occurrence, although this policy is not consistently implemented (Box 2). It remains critical that programs ensure all HIV-exposed infants are retained and tested appropriately throughout the entire exposure Box 1. Definition of terms for diagnostic results • Indeterminate range: a range of viral copy equivalents that would be too low to accurately diagnose as positive. • False-positive result: HIV-uninfected infants incorrectly identified as HIV-infected and potentially started unnecessarily on ART. • False-negative result: HIV-infected infants incorrectly identified as HIV-uninfected. • Non-negative result: any positive or indeterminate result. Polmyerase chain reaction (PCR) instrument reports a detectable result, which may be subsequently classified as “indeterminate” based on other data (e.g. assay-reported cycle threshold). May also be referred to as “not confirmed”, “equivocal” or “irreproducible positive”. • Discordant result: positive/detectable first test; negative second test. • Cycle threshold: the point at which virus amplification is first observed during the course of repeated PCR cycles. The cycle threshold is inversely correlated to the amount of virus in the sample. 7period and all infants with a positive result receive a confirmatory test. Furthermore, those with repeatedly indeterminate test results should be actively tracked, retained, retested and their status resolved. Finally, POC EID testing is being implemented in several countries and settings (see 3.1.3). Previously there was limited evidence on how to conduct confirmatory testing of POC EID positive test results, but since publication of the 2016 WHO ARV Consolidated Guidelines10 several studies have been published on its performance. Two POC EID technologies are now included on the WHO list of prequalified in vitro diagnostic products.17 Results from both laboratory and field studies have shown performance comparable to that of laboratory-based technologies.18 Furthermore, two patient impact studies have been published which highlight the significantly improved patient outcomes when using POC EID technologies.19,20 Based on this updated evidence, POC EID testing can be used to confirm positive test results. 3.1.2 Managing discordant results and treatment interruption Since 2010, WHO has recommended initiating infants on ART after an initial positive NAT, while simultaneously collecting a confirmatory sample. The 2016 WHO ARV Consolidated Guidelines10 suggest that if the second (confirmatory) NAT is negative, a third NAT, either EID (qualitative) or viral load (VL), should be performed before considering ART interruption. The introduction of an indeterminate range should potentially reduce the number and proportion of infants with discordant test results (different NAT results on separate samples); however, guidance on how to conduct treatment interruptions is needed. Several factors should be considered when assessing patients for ART interruption after discordant test results (positive then a negative result) are followed by a third test with a negative result: • the infant ought to have no clinical signs or symptoms suggestive of HIV infection;21 • a follow-up plan should be agreed upon with family, caregiver(s) and health-care staff; • tracking information (phone, address, etc.) of the family/caregiver(s) should be collected and confirmed. The following factors should be considered when following up any infant undergoing treatment interruption: • there is a need for active follow-up to ensure that a potentially infected infant is retained and re-initiated on treatment if virological rebound occurs; • virological rebound in HIV-infected infants starting treatment early is expected to happen within 8 months of interruption in >99% of HIV-infected infants;22 • infants who develop signs and symptoms indicative of HIV infection should undergo immediate testing; • breastfeeding and continued risk of transmission require follow-up and appropriate testing throughout the period of risk until final diagnosis; • there is value in minimizing follow-up testing by leveraging existing opportunities for infant testing (based on the national infant testing schedule and immunization or well-child appointment schedules), until final diagnosis is ascertained. Few countries have existing policies on how to conduct treatment interruptions in infants with discordant test results. South Africa, for one, has implemented policies with intensive laboratory and clinical follow-up of these infants for 18 months.15 Both EID (qualitative) and VL (quantitative) tests are performed at 4 weeks, 3 months, and every 3 months after treatment interruption. However, since the likelihood of these infants being HIV-infected is low, a less aggressive 8 month approach is also reasonable in order to simplify the follow-up procedure: this is supported by emerging evidence on the timing of viral rebound in HIV-infected infants treated early.22 In this case both EID (qualitative) and VL (quantitative) tests could be performed at 4 weeks, 4 months and 8 months after treatment interruption (Annex 2). Infants who test positive on any follow-up test in either protocol should be re-initiated on treatment as per current guidelines,10 and a confirmatory sample taken. Any SOP for interruption should be implemented considering the continuous risk of transmission resulting from breastfeeding and, once the intensive follow up is completed (8 months after treatment interruption), the national infant testing schedule for HIV-exposed infants should be applied in order to ensure an appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post cessation of breastfeeding, as indicated in Annex 2 Scenario b. Box 2. Prioritizing confirmatory testing of positive and indeterminate tests • Decreasing MTCT rates globally have led to concerns about false-positive and indeterminate tests. • Patients with indeterminate results need immediate repeat testing and the patient should be managed according to the SOP presented in Annex 1. • Patients with repeated indeterminate results need a multidisciplinary team of health-care providers to support retention, tracking and status resolution. • In ART programs, there is a need to prioritize confirmatory testing of all positive test results using a new sample. • Clinical monitoring and further testing based on the national infant testing schedule need to be done until a definitive HIV status is established. 83.1.3 Implementation of POC EID testing The 2016 WHO ARV Consolidated Guidelines10 recommend the use of NAT technologies for early infant HIV testing that have been developed and validated for use at or near the point-of-care. POC EID provides the opportunity to reduce test turnaround times, limit patient loss along the HIV testing cascade, reduce infant mortality and facilitate task shifting to lower cadres of health workers at health- care facilities with decentralized services. Sufficient evidence has been generated on the performance of these assays in their intended field settings to support rapid national regulatory approval and initiation of scale-up (Box 3). A number of countries are currently implementing POC EID technologies.18 Implementation studies in Malawi20 and Mozambique19 have shown that using POC EID leads to significantly reduced test turnaround times, with a higher yield of results being returned to the health-care facility and caregivers, and earlier and higher rates of ART initiation among HIV-infected infants. Key lessons learned during pilot implementation projects include: • optimizing the use of POC EID through product and site selection; • selecting health facilities with high prevalence and high volumes to maximize device utilization; • considering placement within or in-facility referral from high-yield entry points (e.g. nutrition and pediatric wards); • ensuring service continuity by establishing a service and maintenance strategy with suppliers and provide service engineer back-up; • integrating services within health facilities by assessing the need for additional training and continuous mentoring of health-care workers (HCW); • strengthening the linkage between services to ensure prompt linkage to care for identified HIV-infected infants; • ensuring the availability of pediatric ARV formulations for neonates to guarantee earlier ART initiation. 3.1.4 Introduction of NAT at birth to facilitate earlier treatment initiation Adding NAT at birth to the existing national infant testing schedule may result in earlier identification of HIV-infected newborns and consequently lead to earlier treatment initiation and lower mortality among infants. Data suggest that infants testing positive at birth start ART approximately 2 months earlier than non-birth- tested infants (6 weeks vs 15 weeks).23 However, cost- effectiveness analyses have shown that the survival gains from adding NAT at birth to the standard 6-week test are lost if the loss-to-follow-up after a negative birth result exceeds 37%, underscoring the fact that a high-functioning 6-week program needs to already be in place. A number of countries have already started implementation of NAT at birth, and country experiences are outlined in Box 4. It should be noted, however, that strengthening existing EID systems remains the priority while programs consider adding birth testing. Several implementation considerations can be summarized from these experiences. • Countries that are considering birth testing should critically review current performance and opportunities for strengthening their 6-week EID program and consider other indicators, (e.g. PENTA1 immunization visit coverage and attended delivery rate), so that the potential gains provided by birth testing can be investigated more fully. For example, in settings where the attended delivery rate is much lower than PENTA1 immunization visit coverage the added value of birth testing as a means of expanding EID is limited. • Pilot projects are a good way to start gaining national experience on this innovative testing approach, but in order to measure impact fully programs need to collect data on the feasibility and impact of birth testing and linkage to ART initiation. • Targeted approaches which provide birth testing only for high-risk infants are expected to have a higher yield compared to routine birth testing. This approach may be potentially less resource intensive and present a lower burden for HCW. • Active tracking of infants with negative NAT results at birth is critical to ensure that they return at 6 weeks to be retested and start co-trimoxazole (CTX); establishing unique patient identifiers or other innovative mechanisms (e.g. bar codes) to track babies can be considered. • It is crucial that the turnaround time for reporting test results to health facilities and caregivers be rapid in order to optimize the benefit from NAT at birth, and POC assays should be used where they are available. Box 3. New POC EID technologies • Two technologies have received WHO prequalification. • National regulatory agencies are encouraged not to delay adoption by conducting further evaluations but instead to adopt a rapid and streamlined registration and national approval process for immediate implementation. 9• Birth testing is acceptable to mothers, but challenges arise from the increased human resources needed, the difficulty of collecting blood samples in newborns, the need to ensure sample collection outside of standard working hours and deliver results, linkage to ART and the nature of the EID system as a whole (stock-outs, referral mechanisms, delayed results). Box 4. Implementation of birth testing: country experiences South Africa South Africa introduced NAT at birth in 2015 with specific nurse training at postnatal and delivery services and health register updates to enable data acquisition. Implementation challenges met by South Africa include weak linkage of the identified HIV-infected infants to care with consequent delay in ART initiation, and a low return rate for future testing among infants with negative results at birth. A qualitative sub-study found that birth testing had a high acceptability. Refusals were rare and mothers did not indicate that birth testing affected their subsequent acceptance of infant testing or postnatal clinic attendance. Weak follow-up systems were detected for mothers who had home deliveries, and concerns were raised by laboratory staff about increased workloads associated with additional testing requirements. Kenya Kenya started a NAT at birth pilot project in 2015 (defined as testing within 72 hours of birth) and its results formed the basis of a revised EID algorithm in 2016 and national scale-up plan, due to start in mid-2018. Prior to implementation, a central point was designated within the health-care facility for birth testing, an innovative dispatch register was developed, mothers were offered mentoring to assist with linkage between hospitals and communities and a prevention of mother-to-child transmission (PMTCT) psychosocial support group was formed. Good leadership and coordination was identified as being important for seeing patients through service provision. Challenges included issues related to referral, demand creation, turnaround time for test results and mothers who failed to collect test results. In addition, ART formulations were lacking for neonates who tested positive during the initial implementation phase. Zimbabwe Zimbabwe started a POC NAT birth pilot in April 2017 in ten health facilities for high-risk HIV-exposed infants (< 48 hours after birth). Ninety-seven per cent of the results were transmitted to caregivers, and all HIV-infected infants started ART within 5 days of testing. This project is likely to provide critical experience on a different approach to tracking children after birth testing and will generate further information on the value of targeting birth testing for high-risk infants rather than all HIV-exposed infants. Democratic Republic of Congo NAT at birth was first implemented in December 2016, with samples sent to central laboratories for processing. Laboratory personnel were trained to prioritize birth samples and ensure prompt return of results to the health facility. Challenges included long turnaround times between specimen collection and receipt of results (8–12 weeks from the national laboratory), stock-outs due to limitations in supply chain management, and difficulties in specimen transportation. Uptake of birth testing was good, but yield was low with numerous missed opportunities due to early discharge of women from maternity wards. As a result, birth testing remains limited to this pilot project (now terminated) and efforts are being made to strengthen the existing 6-week EID program. Eswatini (Swaziland) Eswatini introduced two pilot projects to explore universal NAT at birth across five maternity sites in August 2017 using POC EID technologies in three sites (in partnership with EGPAF) and conventional testing in two sites (in partnership with ICAP). In the conventional test pilot, 93% of HIV-exposed newborns were tested before discharge from the maternity unit and six of the 1 548 tested were HIV-infected. In the POC testing pilot, 68% of HIV-exposed newborns were tested and 12 of the 1 314 tested were HIV-infected. Furthermore, 98% of results were returned to the caregiver. Of those HIV-infected, nine in the POC test pilot and four in the conventional test pilot were put on treatment. Both pilots confirmed that health-care facility staff face a heavier work burden when NAT at birth was added. Nurses often felt overwhelmed and failed to prioritize NAT at birth because many births occurred at night or on weekends when staffing was limited. Furthermore, although most mothers found birth testing to be acceptable, several were discharged or left the facility before getting tested, while others provided incorrect tracking information. Ensuring patient tracking and linkage proved to be a challenge. • The key to effective implementation is to ensure that newborns who have been identified as HIV-infected are linked to treatment and that age-appropriate formulations are available to start them on treatment. • Good leadership and coordination are needed to oversee service provision, support supervision, mentorship and the quality improvement cycle. 10 11 3.1.5 Ensuring accurate interpretation of the 9-month test and simplifying the testing algorithm The 2016 WHO ARV Consolidated Guidelines recommend that RDTs should be used to assess HIV exposure among infants younger than 4 months, while HIV exposure among infants 4–18 months old should be ascertained by testing the mother. When testing of the mother is not possible, current guidelines emphasize the importance of not considering a negative RDT result from an infant between 4–18 months as a definitive test of exposure. Implementation issues are highlighted in Box 5. Based on the 2016 WHO ARV Consolidated Guidelines10, RDTs are serological assays that can also be used to exclude established infection among healthy, HIV-exposed infants aged 9 months old and above. However, changes in transmission dynamics as well as in policy and practice have complicated RDT use for determining infection status. Substantial drug exposure for infants with implementation of the Treat All policy for mothers and enhanced postnatal prophylaxis of HIV-exposed infants may have resulted in viral load reduction and delayed antibody development in HIV-infected infants. Finally, the occurrence of maternal infection in late pregnancy or during the postnatal period may be responsible for a lack of passive HIV antibody transfer to the HIV-exposed infant. These factors increasingly jeopardize RDT accuracy at 9 months of age as a means of correctly ruling out established infection in HIV- exposed infants. These concerns are supported by findings from Uganda and Kenya,24, 25 where 15–40% of children under two years of age and identified as HIV-infected had a positive NAT but negative RDT. RDT at 9 months was initially recommended in the 2010 WHO recommendations on the diagnosis of HIV infection in infants and children21 with the goal of targeting NAT for those HIV-exposed infants most likely to be infected (e.g. those with a positive RDT) as a cost-saving measure. However, due to decreasing MTCT rates, increasing availability and lower costs of NAT, changing transmission and drug exposure dynamics, and the fact that RDTs are less effective at determining the need for NAT testing, such a targeted approach may be less compelling. Furthermore, the added programmatic complexity and potential for inappropriate interpretation of test results have additional unintended consequences. In light of the challenges and data outlined above, consideration can now be given to replacing RDT at 9 months with NAT in the interests of minimizing the challenges of interpretation and simplifying the infant testing algorithm. Annex 3 summarizes the new simplified algorithm, which is underscored by a number of key considerations: • assessing HIV exposure status by performing RDT on the mother; • at 9 months performing NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative; • ensuring indeterminate test results are repeat tested immediately and prioritized for rapid resolution; • ensuring confirmatory testing is undertaken following any positive result; and • ensuring all HIV-exposed infants are regularly followed up until final diagnosis, with the provision of CTX prophylaxis and clinical/nutritional assessment. Finally, it remains critical that infant retention be continued until the end of the exposure period. More effort should be given to establishing a final diagnosis at 18 months of age or 3 months after cessation of breastfeeding, whichever occurs later. Although there is increasing coverage of the traditional 6-week infant test and more consideration is given to earlier time-points, the changing dynamics of transmission and increased drug exposure mean that increased efforts are needed to maintain follow-up throughout the entire exposure period. The aim is to ensure that all HIV-infected infants, including those infected in the postnatal period, are identified and receive treatment. Box 5. Use of RDT: implementation considerations • Priority should continue to be given to the testing of mothers at all entry points to determine exposure status for infants and children less than 18 months. • If the mother is absent or unable to be tested, an RDT should be undertaken of the infant, but negative results of infants older than 4 months should not be considered as definitive exclusion of exposure and follow-up testing is required. • If the mother is absent or unable to be tested and the infant presents with signs and symptoms of HIV infection, a NAT should be undertaken. • NAT should be undertaken following any positive RDT in the mother or the infant and a confirmatory NAT undertaken following any positive NAT result. 12 3.2. ARV use for prevention and treatment of HIV in infants 3.2.1 Implementation challenges to providing ePNP for high-risk infants The 2016 WHO ARV Consolidated Guidelines recommend a dual regimen of AZT and NVP which can be extended for up to 12 weeks in breastfeeding infants deemed to be at high risk of MTCT. A high-risk infant is defined as an infant whose mother was first identified as HIV-infected at delivery or in the postpartum, infected during pregnancy or breastfeeding, started ART late in pregnancy, or did not achieve viral suppression by the time of delivery (Annex 4). All high-risk infants should receive dual drug prophylaxis (AZT plus NVP) for the first 6 weeks. In breastfeeding infants, this should be followed by either an extra 6 weeks of AZT plus NVP or an extra 6 weeks of NVP alone (see Box 6). This recommendation is based on evidence from randomized clinical trials26 and takes into account the risk- benefit ratio of ePNP: potential for increased drug toxicity versus additional protection from HIV transmission. The rationale for the use of extended ePNP especially in high- risk breastfeeding infants rests on the assumption that mothers started promptly on ART achieve viral suppression within 12 weeks, thereby greatly reducing the risk of breast milk transmission and the need for ongoing infant prophylaxis. Countries have adopted ePNP using a variety of different approaches. In Kenya, Eswatini (Swaziland), and Mozambique, ePNP has been adopted for all breastfeeding HIV-exposed infants, while nine countries (Botswana, Ghana, Namibia, Nigeria, South Africa, Tanzania, Uganda, Zambia and Zimbabwe) have adopted ePNP for high- risk infants identified primarily on the basis of maternal ART duration and, when available, maternal VL close to delivery. Most countries opted for at least 12 weeks of prophylaxis, usually AZT/NVP for the first 6 weeks followed by NVP alone. Three countries (Kenya, Namibia and South Africa) link the duration of ePNP to the maternal VL, and extend ePNP over the entire breastfeeding period when viral suppression is not achieved. Finally, in three countries (Botswana, Zambia and Tanzania), triple prophylaxis with a fixed-dose combination (FDC) of AZT/3TC/NVP has been adopted to address the challenges of procuring syrups. Recent guidelines on infant feeding27 in relation to HIV re-affirm the position of WHO that the best way to prevent MTCT in the postpartum period and optimize infant survival is to ensure that mothers living with HIV are well controlled on ART and able to breastfeed their infants for up to two years, with the infant being exclusively breastfed in the first six months of life. If a mother on ART is virologically suppressed, the risk of breast milk transmission of HIV is very low and infant prophylaxis confers minimal additional benefit beyond 4–6 weeks of life. Some program have adopted ePNP for all HIV-exposed infants. While this may simplify decision-making, it increases costs and exposes a large number of infants who may not need ePNP to added toxicity. This type of approach ought to be reserved for selected situations where a majority of mothers are at high risk of transmitting HIV. Data on the average duration of ART at delivery and, where available, the proportion of pregnant women with VL>1000 at the end of the third trimester might help policymakers to determine whether added costs and toxicity are outweighed by potential benefit. Even then, it should only be an interim measure while strategies to increase the coverage of maternal testing, early treatment and improved adherence are being implemented. However, there are several situations where viral suppression throughout the breastfeeding period cannot be ensured in the mother, for example: • if a mother refuses or is unable to start or continue ART and intends to breastfeed her infant; • if the provider knows the mother is poorly adherent to ART while breastfeeding; • if maternal VL is known to be high when the infant prophylaxis regimen is about to be stopped. There is no formal recommendation for these types of situations and no evidence to guide the best course of action. It is reasonable, however, to assume that infant prophylaxis serves as a “back-up” solution for preventing postnatal transmission of HIV, and national programs could consider the merits of giving clinical providers the option of continuing infant prophylaxis beyond the recommended 6- or 12-week period. If this option is introduced in the national guidelines, there ought to be clearly defined scenarios in which continuing prophylaxis is warranted. National guidelines should also emphasize that the best way to prevent breast milk transmission of HIV is by optimal maternal treatment for the entire duration of exposure. Continuing prophylaxis should therefore be seen as an interim measure while efforts are made to support and improve maternal treatment adherence. Deciding to continue prophylaxis should take into consideration the factors that led to poor maternal adherence as they may have an impact on adherence to infant prophylaxis. Once stopped, infant prophylaxis should not be re-started if there are new concerns about maternal adherence. There is no evidence to support such an approach; instead the focus should be on determining why the mother was unable to remain adherent. If the decision has been made to continue infant prophylaxis, mothers and infants should be evaluated at regular intervals to assess the need for ongoing infant prophylaxis. 13 As more effective treatments increasingly come to be used in pregnant women, we can expect decreasing MTCT rates. However, some women will still be diagnosed late or have incident infections and this group is likely to drive most new cases of HIV transmission to infants, owing to the high level of maternal virus in the absence of treatment. One possibility would be to provide “presumptive treatment” as postnatal ePNP, by administering a triple-drug regimen at therapeutic doses to this selected group of infants with the goal of minimizing transmission and drug-resistant HIV (HIVDR) selection in the event of established infection despite prophylaxis. Such approaches need to be paired with careful review of infant testing practices in order to determine the potential impact of triple ePNP on virological assay performance for infant diagnosis (i.e. at least one specimen must be collected prior to initiating any presumptive treatment so that a NAT can be performed as soon as possible). 3.2.2 Early infant treatment: limited options and complex administration Early infant ART improves survival and reduces long-term morbidity but mortality remains substantial in the first months of life. Introducing NAT at birth could enable ART to be started before 2 weeks of age. However the only regimen available for this age group has for many years been one containing AZT, 3TC and NVP. This regimen could be continued with close clinical monitoring until 3 months of age and then switched to a LPV/r-based regimen, using LPV/r pellets, or LPV/r could be introduced at the end of the second week of life as syrup and then switched to a solid formulation at 3 months of age. Raltegravir (RAL) granules have recently been approved by the US Food and Drug Administration for use in neonates at full term, except for low birthweight or premature babies. This is a considerable advance in increasing treatment options for neonates. Feasibility and acceptability of this formulation are currently being assessed in a study in South Africa. The 2016 WHO ARV Consolidated Guidelines10 already recommend the use of RAL as an alternative first- line treatment for children younger than 3 months where LPV/r pellets cannot be used. At present, RAL suitable for administration in the neonatal period is only available as a granule for oral suspension, but improved formulations are being developed for future use. Countries considering whether to introduce birth testing will need to consider their ability to decentralize newborn treatment by strengthening HCW capacity, ensuring commodities are available at peripheral health facilities and/or extending the referral system to nearby facilities, as well as ensuring that HCW are fully trained and equipped to start newborn infants on treatment. Box 6. ARV Formulations for ePNP: implementation considerations There are three available formulations that can be used for dosing ePNP: • NVP and AZT syrups; • pediatric dispersible NVP tablets and; • pediatric fixed-dose combinations (FDCs). Each formulation has its own benefits and risks (see Annex 5). A pediatric FDC of AZT/3TC/NVP has some appeal as ePNP because it is widely available and well established in a child-friendly formulation. However, there are several challenges to using this triple-drug FDC option that programs should consider: • NVP is administered as a once-daily dose for prophylaxis, whereas AZT is a twice-daily dose, so using an FDC compromises one or other of the drug regimens. Either AZT should be administered once daily or NVP twice daily. • The AZT:NVP ratio within the FDC is appropriate for the first 6 weeks of ePNP but it cannot be used for weeks 6 to 12 when the AZT dose increases fourfold while the NVP dose increases by only one third. • This pediatric FDC contains 3TC in addition to AZT and NVP. Although 3TC is very well tolerated, and has been used as a single drug for ePNP in clinical trials, WHO does not currently recommend this drug for infant prophylaxis. Administration of the FDC would inevitably expose the infant to 3TC. • In order to use an FDC as ePNP in the first 6 weeks of life, a single tablet would have to be divided into quarters. Tablets are scored but only into halves. Despite these challenges, FDCs are readily available, easy to use and have been proposed as a mean to simplifying administration in high-risk infant prophylaxis. Benefits and risks of the different dosing options are outlined in Annex 5. 14 provide opportunities to strengthen service delivery for HIV-exposed infants. Integration within a well established maternal, neonatal, and child services platform, which traditionally provides services closest to clients, facilitates mother-infant pair follow-up and reduces the cost and time-visit burden on clients. The integrated information systems that link mother and infant information improve client tracking and facilitate continuity of care provision. Examples include longitudinal follow-up registers and cohort analysis as well as linkage with information on communit-based services. Programs should however take into consideration the increasing burden on the MCH platform within the context of existing human resources and the challenges of changing services. Community engagement and community-based services play an important role in supporting HIV-exposed infant care. These clear and highly context specific services play a “boosting” role in supporting facility-focused services and include community-based HIV testing. The engagement of networks of women living with HIV has been effective in several countries and has been used to improve community HIV literacy to create demand, form support groups at the facility and community levels, strengthen linkage to care by escorting newly diagnosed clients to treatment clinics, conduct defaulter tracking and provide active follow-up of mother-infant pairs. In several settings, these interventions led to reduced loss to follow-up among mother-infant pairs. Ensuring provision of a comprehensive integrated postnatal package of HIV services will promote the delivery of a set of interventions that contributes not only to improved HIV outcomes but better early childhood development overall. 3.3. Improving service delivery and implementing a postnatal package of care There are several barriers to the uptake of effective infant HIV services, and no single intervention can address all the barriers facing women and their infants at different times and places. Socio-economic and traditional factors that keep mother-infant pairs together are among the enabling circumstances that improve service uptake. Programs could benefit from combining effective interventions into “service packages” to support service provision and focus on the community engagement that supports uptake. Interventions which have been proven to improve provision and uptake of infant HIV services and the retention of mother-infant pairs include: • client-focused interventions that provide support to individual clients using reminder text messaging, conditional cash incentives and male partner involvement; • and health system-focused interventions, including measures to enhance the program (POC testing technologies, provider training and support, enhanced counselling services and peer support), to strengthen the health system (quality improvement initiatives and mother and child health (MCH)/HIV service integration) and to support community-based services and HCWs. Promoting integration to reduce fragmentation of care for mothers and infants and ensure that infants remain in the testing cascade until final diagnosis should be a priority. Strong antenatal and well-baby care systems 15 Box 7: Key research questions Infant diagnosis • Assess the impact of implementing an indeterminate range, particularly at different testing time points, sample types, and technologies. • Acquire impact data to assess the added value of birth testing within the EID program. • Assess the value of providing birth testing to high-risk infants only. • Measure the impact of tracking tools (ie, bar codes) to ensure effective tracking and repeat testing at 6 weeks among infants testing negative at birth. • Determine if there is added value in integrating birth testing with BCG vaccination. • Assess the optimal timing and frequency of VL testing of pregnant and breastfeeding women. • Assess the impact of maternal treatment and infant prophylaxis on infant diagnoses. • Determine and evaluate the most effective approaches to retaining infants throughout the EID cascade until final definite diagnosis. Infant prophylaxis and treatment • Determine dosing and safety of new ARVs for the purpose of prophylaxis or treatment in neonates and infants. • Develop optimal formulations and ensure timely uptake of newly recommended ARVs for newborns and infants. • Document country experiences with ePNP. • Understand the clinical relevance of maternal viremic episodes and their relative contribution to the overall transmission rate. • Conduct studies to explore the additional benefit of ePNP in the context of well implemented effective maternal ART regimens. • Assess adherence to ePNP and how to improve retention and support for mothers. • Determine the feasibility of using triple therapy as prophylaxis for infants whose mothers are first identified as HIV-infected in the post-partum period. Service delivery and post-natal package of care • Consider combining interventions together into packages to support service delivery. • Promote integration to ensure that infants remain in the testing cascade until final diagnosis. 4. SUMMARY AND WAY FORWARD Several novel innovations implemented by countries and partners have shown promise. While successful interventions are being scaled up, it remains imperative to focus on strengthening existing systems that support infant testing and early treatment initiation. Moreover, changing dynamics in transmission and treatment standards are adding to the complexity and interdependency of testing, prophylaxis and treatment. This will require an increasing need to tailor strategies to the epidemic and policy context. Finally, more programmatic evidence-driven experiences are needed to support and inform national policies, programmatic planning and implementation. 16 ACKNOWLEDGEMENTS Meeting participants Adolfo Vubil (INS Mozambique), Ahmed Haeri Mazanderai (University of Pretoria), Andrea Ciaranello (Harvard Medical School), Angela Mushavi (MOH Zimbabwe), Anna Laura Ross (Unitaid), Archawin Rojanawiwat (Chulalongkorn University), Arne Kroidl (University of Munich), Charles Kiyaga (MOH Uganda), David Sullivan (USAID), Debbie Boras (London School of Hygiene and Tropical Medicine), Deborah Persaud (Johns Hopkins University), Elaine Abrams (ICAP), George Siberry (OGAC), Heather Alexander (CDC), Helen Dale (US CDC), Jean Maritz (University of Stellenbosch), Jilian Sacks (CHAI), Landon Myer (University of Cape Town), Laura Broyles (CDC), Laura Onyengo (MOH Kenya), Laura Thuo (ICW Kenya), Lynne Mofenson (EGPAF), Marc Cotton (University of Stellenbosch), Marie-Claude Bottineau (MSF), Nicholas Furtado (Global Fund), Nobuhle Mthethwa (MOH Swaziland), Philip Goulder (University of Oxford), Roger Shapiro (Harvard T.H. Chan School of Public Health, Botswana), Sally Hargreaves (Imperial College London), Shaffiq Essajee (UNICEF), Smiljka de Lussigny (Unitaid), Timothy Cressey (Harvard T.H. Chan School of Public Health, Thailand), Trevor Peter (CHAI Botswana). WHO Staff Meg Doherty, Martina Penazzato, Lara Vojnov, Anisa Ghadrshenas, Serena Brusamento, Morkor Newman, Mercedes Perez, Fatim Jallow. 17 15. Mazanderani AH, Technau K-G, Hsiao N-Y, Maritz J, Carmona S, Sherman GG. Recommendations for the management of indeterminate HIV PCR results within South Africa’s early infant diagnosis programme. Southern African Journal of HIV Medicine. 2016;17(1):1-5. 16. Dunning L, Francke JA, Mallampati D, MacLean RL, Penazzato M, Hou T, et al. The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis. PLoS Medicine. 2017;14(11):e1002446. 17. WHO. WHO list of prequalified in vitro diagnostic products. Geneva: World Health Organisation; 2018 25 June. 18. WHO. Novel point-of-care tools for early infant diagnosis of HIV. Geneva: WHO; 2017. 19. Jani IV, Meggi B, Loquiha O, Tobaiwa O, Mudenyanga C, Zitha A, et al. Effect of point-of-care early infant diagnosis on antiretroviral therapy initiation and retention of patients. AIDS. 2018;32(11):1453-63. 20. Mwenda R, Fong Y, Magombo T, Saka E, Midian D, Mwase C, et al. Significant Patient Impact Observed Upon Implementation of Point-Of-Care Early Infant Diagnosis Technologies in an Observational Study in Malawi. Clinical Infectious Diseases. 27 Feb 2018. 21. WHO. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. Geneva: WHO; 2010. 22. Avy Violari; Man Chan; Kennedy Otwombe; Ravindre Panchia; Patrick J-PD, Gibb; Mark, Cotton; Abdel, Babiker;. Time to viral rebound after stopping ART in children treated from infancy in CHER. Abstract #137, CROI; March 4-7, 2018; Boston, Massachusetts. 23. Gill MM, Hoffman HJ, Mokone M, Tukei VJ, Nchephe M, Phalatse M, et al. Assessing Very Early Infant Diagnosis Turnaround Times: Findings from a Birth Testing Pilot in Lesotho. AIDS Research and Treatment. 2017: 2572594. 24. Urick B, Fong Y, Okiira C, Nabukeera-Barungi N, Nansera D, Ochola E, et al. Rapid Serological Tests Ineffectively Screen for HIV Exposure in HIV-Positive Infants. JAIDS. 2018;77(3):331-6. 25. Wagner AD, Njuguna IN, Andere RA, Cranmer LM, Okinyi HM, Benki-Nugent S, et al. Infant/child rapid serology tests fail to reliably assess HIV exposure among sick hospitalized infants. AIDS. 2017;31(11):F1-F7. 26. Beste S, Essajee S, Siberry G, Hannaford A, Dara J, Sugandhi N, et al. Optimal Antiretroviral Prophylaxis in Infants at High Risk of Acquiring HIV: A Systematic Review. Pediatr Infect Dis J. 2018;37(2):169-75. 27. WHO. Updates on HIV and infant feeding. Geneva: WHO; 2016. REFERENCES 1. UNAIDS. On the Fast-track to an AIDS-Free Generation. Geneva: UNAIDS; 2016. 2. UNAIDS. Global Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva: UNAIDS; 2016. 3. UNAIDS. Start free Stay Free AIDS free: 2017 progress report. UNAIDS; 2017. 4. WHO. WHO Consolidated ARV Guidelines on the use of antiretroviral Geneva: WHO; 2013. 5. Townsend CL, Byrne L, Cortina-Borja M, Thorne C, de Ruiter A, Lyall H, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049-57. 6. Sherman GG, Mazanderani AH, Barron P, Bhardwaj S, Niit R, Okobi M, et al. Toward elimination of mother– to–child transmission of HIV in South Africa: how best to monitor early infant infections within the Prevention of Mother–to–Child Transmission Program. Journal of Global Health. 2017;7(1). 7. Penazzato M, Lule F, Essajee S. Paediatric HIV: the unfinished business. Lancet HIV. 2017;4(10):e425-e7. 8. UNAIDS. Ending AIDS: progress towards the 90-90-90 targets. Geneva: UNAIDS; 2017. 9. Newell M, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Ghent International AIDS Society (IAS) Working Group on HIV Infection in Women and Children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):1236-43. 10. WHO. Consolidated ARV Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd ed. Geneva: WHO; 2016. 11. WHO. Innovating and strengthening the postnatal package of care for HIV-exposed infants: ensuring comprehensive services for the first two years of life. Johannesburg, South Africa, 20-23 June 2017 Meeting report. Geneva: WHO; 2017. 12. UNAIDS. AIDS info 2017. Geneva: UNAIDS; 2017. 13. Mazanderani AH, Moyo F, Kufa T, Sherman GG. Brief Report: Declining Baseline Viremia and Escalating Discordant HIV-1 Confirmatory Results Within South Africa’s Early Infant Diagnosis Program, 2010–2016. JAIDS. 2018;77(2):212-6. 14. Mazanderani AH, Moyo F, Kufa T, Maritz J, Sherman GG. Differentiating clearly positive from indeterminate results: A review of irreproducible HIV-1 PCR positive samples from South Africa’s Early Infant Diagnosis Program, 2010–2015. Diagnostic Microbiology and Infectious Disease. 2018;91:248-255. 18 EID sample no. 1 test no. 1 EID sample no. 1 test no. 2 NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE NEGATIVE Manage in accordance with current guidance1 POSITIVE Manage in accordance with current guidance1 INDETERMINATE2 Request a new sample within 4 weeks3,4 Further review by a clinical and laboratory team4 ANNEXES Annex 1: Managing indeterminate test results: standard operating procedure 1. Refer to 2016 WHO ARV Consolidated guidelines. 2. Do not report as positive nor initiate ART, but maintain prophylaxis per current guidance. 3. Repeat samples should be prioritized in the laboratory. 4. Repeated indeterminate results in two separate samples should, together with clinical information, be reviewed by a team of laboratories, clinicians pediatricians, complex case experts (if possible), and caregivers. Infants should be actively tracked to ensure follow-up and retention. 19 Annex 2: Managing discordant results and treatment interruption This option provides follow-up care to the infant for a minimum of 8 months after interruption of ART. Where possible, both EID (qualitative) and VL (quantitative) tests should be performed at 4 weeks, 4 months, and 8 months after treatment interruption. EID and viral load at 4 weeks, 4 months, and 8 months after interruption Scenario a: Cessation of breastfeeding occurs after completion of the follow up post ART interruption. Scenario b: When cessation of breastfeeding occurs before completion of the follow up post ART interruption. 8 months NAT 1: + Start ART Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 2: - Stay on ART NAT 3: - Stop ARTNAT 3 Cessation of breastfeeding RDT 3 months after cessation of breastfeeding Start treatment interruption NAT @ 4 weeks after interruption NAT @ 4 months after interruption NAT @ 8 months after interruption NAT 1 NAT 2 NAT 3 Cessation of breastfeeding 8 months NAT 1: + Start ART NAT 2: - Stay on ART NAT 3: - Stop ART Further follow-up is needed to consider the exposure to breastfeeding and carry out the national infant testing schedule for HIV-exposed infants to ensure appropriate final diagnosis. If breastfeeding has stopped prior to the end of the intensive follow up, final HIV status can be defined with NAT performed at least 6 weeks post- cessation of breastfeeding. 20 Annex 3: Simplified EID algorithm HIV-exposed newborn (0-2 days) Consider NATa,b Negative Negative Immediately start ARTc Repeat NAT to confirm infection Infant/child is infected HIV-exposed infant or child (4-6 weeks to 18 months) Conduct NATb (at 4-6 weeks or at the earliest opportunity thereafter) Positive Positive Immediately start ARTc Repeat NAT to confirm infection HIV infection not detected but if infant/child is breastfed the risk of acquiring HIV infection remains until complete cessation of breastfeedingd Regular clinical monitoring Conduct NATb (at 9 months) Antibody testing at 18 months of age or 3 months after cessation of breastfeeding, whichever is laterf Infant/child is infected HIV unlikely unless still breastfedinge Negative The key principles for establishing whether HIV-exposed infants and children younger than 18 months are infected with HIV in low- and middle-income countries are as follows: • Assess HIV exposure status by antibody testing the mother. • Perform NAT test for any HIV exposed child that presents outside of national infant testing algorithm with clinical symptoms irrespective of previous NAT results • At 9 months perform NAT for HIV-exposed infants, symptomatic and asymptomatic, and even where previous NAT results have been negative. • Ensure that indeterminate test results are repeat tested immediately and given priority for rapid resolution. • Ensure that confirmatory testing is undertaken following any positive result. • Ensure regular follow-up for all HIV-exposed infants until final diagnosis, including providing co-trimoxazole prophylaxis and clinical and nutritional assessment. Notes: a. Based on 2016 WHO Consolidated ARV Guidelines10, addition of NAT at birth to the existing testing algorithm can be considered. b. POC NAT can be used to diagnose HIV infection as well as to confirm positive results. c. Start ART without delay. At the same time, retest to confirm infection. As maternal treatment is scaled up and MTCT transmission rates decrease, false-positive results are expected to increase: retesting after a first positive NAT is hence important to avoid unnecessary treatment, particularly in settings with lower transmission rates. If the second test is negative, a third NAT should be performed before interrupting ART. d. For children who were never breastfed, additional testing following a negative NAT at 4–6 weeks is included in this algorithm to account for potential false-negative NAT results. e. The risk of HIV transmission remains as long as breastfeeding continues. If the 9-month test is conducted earlier than 3 months after cessation of breastfeeding, infection acquired in the last days of breastfeeding may be missed. Retesting at 18 months or 3 months after cessation of breastfeeding (whichever is later) should be carried out for final assessment of HIV status. f. If breastfeeding extends beyond 18 months, the final diagnosis of HIV status can only be assessed at the end of breastfeeding. If breastfeeding ends before 18 months, the final diagnosis of HIV status with antibody testing can only be assessed at 18 months. Antibody testing should be undertaken at least 3 months after cessation of breastfeeding (to allow for development of HIV antibodies). For infants younger than 18 months of age NAT should be performed to confirm infection. If the infant is older than 18 months, negative antibody testing confirms that the infant is uninfected; positive antibody testing confirms infant is infected. 21 Annex 4: Algorithm for risk assessment This algorithm was developed to support risk assessment at the time of delivery and to help identify infants at high and low risk: Infants at low risk should be given standard prophylaxis (NVP or AZT alone for 4–6 weeks) while those at high risk should be given ePNP. In order to navigate this algorithm successfully, clinicians will need to know a number of parameters from the mother’s antenatal chart: • HIV status and date of last HIV test (to identify status and need for testing or retesting at delivery); • if known to be positive, and ART started, date of ART initiation; • if VL collected, date of sample collection relative to delivery and VL result. Programs should consider incorporating a VL test at or around 36 weeks’ gestation, ensuring that the turnaround time is short enough to have a result available by the expected delivery date. Mother newly identified as HIV+ within 72 hours of delivery NO Known HIV+ mother not on ART Known HIV+ mother on ART HIGH RISK HIGH RISK HIGH RISK HIGH RISKLOW RISK LOW RISK NOYES Has mother been on ART for > 4 weeks prior to delivery? YES: VL < 1,000 YES: VL > 1,000 Assess mother AT DELIVERY Is a VL result available from no more than < 4 weeks before delivery? 22 Annex 5: Dosing and formulation options for infant prophylaxis Dosage forms Dose 0-6 weeks AZT plus NVP Dose 6-12 weeks AZT plus NVP Dose 6-12 weeks NVP only Comments Syrups AZT 10mg/ml NVP 10mg/ml AZT dose 1.5ml (15mg) twice daily AZT dose 6ml (60mg) twice daily NVP dose 2ml (20mg) once daily - Accurate dosing for all drugs (included for low birth weight newborns) and one type of formulation for the whole 12-week period - Costly to procure and transport syrups - Difficult to hide in the home - Supplier availability may be limited - Might be acceptable where most women of childbearing age are well controlled on ART and numbers of high-risk infants is low, but would not be the best option for a program that chooses to treat all infants as high risk NVP dose 1.5ml (15mg) once daily NVP dose 2ml (20mg) once daily Syrups and single drug tablets AZT 60mg NVP 50mg AZT dose 1.5ml (15mg) twice daily AZT dose 1 tab (60mg) twice daily NVP dose ½ tab (25mg) once daily - Combines accuracy of syrup dosing in the first 6 weeks and the ease of tablets from 6 to 12 weeks - Challenges of syrups as before - ½ a tab of NVP represents a slight overdose of NVP (25mg vs 20mg) NVP dose 1.5ml (15mg) once daily NVP dose ½ tab (25mg) once daily FDC ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily Unsuitable Not applicable - Difficult to quarter a FDC accurately: caregivers should use the first quarter in the morning and the second quar- ter in the evening in order to keep daily dose accurate - 3TC not part of the recommended prophylaxis regimen - Cannot use FDC during weeks 6 to 12 without giving 5 times more than the recommended daily NVP dose FDCs and single drug tablets ¼ tab (15mg AZT, 7.5mg 3TC, 12.5mg NVP) twice daily AZT dose 1 tab (60mg) twice daily NVP: ½ a 50mg tablet once daily - Combines ease of FDC with single drug tablet for the second - Challenges of FDC as above NVP dose ½ tab (25mg) once daily Remarks: • It should be noted that unlike for NVP, there is no specific prophylaxis dose for AZT. The recommended dose is the same as that used for treatment - 15 mg twice daily for term infants in the first six weeks of life, increasing to 60mg twice daily from week 6 to week 12. • When presumptive treatment is administered, age-appropriate regimens and dosing should be used as illustrated in current WHO treatment guidelines10. 23 24 For more information, contact: World Health Organization Department of HIV/AIDS 20, avenue Appia 1211 Geneva 27 Switzerland WHO/CDS/HIV/18.17 E-mail: hiv-aids@who.int www.who.int/hiv

DIAGNÓSTICO DO VIH E USO DE ARV EM CRIANÇAS EXPOSTAS AO VIH: ACTUALIZAÇÃO PROGRAMÁTICA JULHO DE 2018 RELATÓRIO TÉCNICO 2WHO/CDS/HIV/18.17 © Organização Mundial da Saúde 2018 Alguns direitos reservados. Este trabalho poderá ser disponibilizado através da licença da Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO (CC BY-NC-SA 3.0 IGO; https:// creativecommons.org/licenses/by-nc-sa/3.0/igo). Nos termos da referida licença, é possível copiar, redistribuir e adaptar este trabalho para fins não comerciais, desde que a ele seja feita a devida menção, como abaixo se indica. Em nenhuma utilização que seja dada a este trabalho poderá ser sugerido que a OMS aprova qualquer organização, produtos ou serviços específicos. Não é permitido o uso do logótipo da OMS. No caso de adaptação do trabalho, é obrigatório que a mesma seja autorizada nos termos da licença da Creative Commons acima mencionada ou equivalente. 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Arranjo gráfico: 400.co.uk Impresso na Suíça 31.1 RESUMO Em todo o mundo, continuam a ocorrer novas infecções de crianças pelo VIH e, por isso, continua a ser fundamental fazer rapidamente o diagnóstico e iniciar de imediato o tratamento dos bebés e crianças que vivem com o VIH. As Orientações Consolidadas da OMS para os ARV de 2016 apresentavam algumas abordagens inovadoras, tais como o uso do teste de ácido nucleico (NAT) à nascença ou logo a seguir, para um diagnóstico mais rápido do VIH nos bebés, e a introdução do NAT nos pontos de cuidados (PC), para um diagnóstico mais rápido e descentralizado, com vista a permitir o rápido início da terapia antirretroviral (TAR) e o uso de uma profilaxia pós-natal melhorada (PPNm), a fim de melhorar a prevenção nos bebés expostos ao VIH. No entanto, até à data, apenas alguns países introduziram estas inovações e as primeiras experiências no terreno identificaram alguns desafios na implementação, as quais requerem uma análise atenta. Com base nos resultados de um workshop regional realizado em Joanesburgo, na África do Sul, em 2017, e uma reunião de peritos para seguimento, que se realizou em Genebra, na Suíça, em 2018, a presente actualização programática destina-se a descrever as alterações a introduzir nas estratégias de identificação, prevenção e tratamento do VIH em bebés. Esta actualização incluirá igualmente nova informação sobre a implementação de um pacote pós-natal de cuidados a prestar aos recém- nascidos expostos ao VIH. SIGLAS E ACRÓNIMOS 3TC lamivudina ARV antirretrovirais AZT azidotimidina (zidovudina) CDF combinação de dose fixa CTX cotrimoxazole CV carga viral DPP diagnóstico pediátrico precoce HCW agente de cuidados de saúde HIVDR resistência aos medicamentos antiretrovirais LPV/r lopinavir/ritonavir NAT teste do ácido nucleico NVP nevirapina PC ponto de cuidados PCR reacção em cadeia da polimerase POP procedimento operacional padrão PPNm profilaxia pós-natal melhorada PTV prevenção da transmissão vertical RAL raltegravir SMC saúde da mãe e da criança TAR terapia antirretroviral TDR teste de diagnóstico rápido TV transmissão vertical VIH vírus da imunodeficiência humana 42.1 ANTECEDENTES 2.1.1 Situação actual relativamente ao VIH pediátrico O Plano Mundial para a Eliminação de Novas Infecções pelo VIH em Crianças até 2015 e a iniciativa Salvar a Vida das Mães tiveram um impacto considerável, conduzindo a uma redução de 60% das novas infecções pediátricas pelo VIH em 21 países de elevada incidência na África Subsariana.1,2 No entanto, o número de novas infecções pelo VIH nas crianças continua a ser significativo: em 2017, ocorreram 180 000 novas infecções em crianças de todo o mundo, vivendo 70% dessas crianças nos mesmos 21 países prioritários. O quadro Start Free, Stay Free, AIDS Free3 (Nascer e Viver Livre da SIDA) foi desenvolvido com base nos progressos do Plano Mundial, com vista a oferecer um roteiro para se atingirem rapidamente as metas destinadas a erradicar a epidemia da SIDA até 2030. Depois da adopção da política da Opção B+4, o número de mulheres grávidas em terapia antirretroviral (TAR) aumentou consideravelmente em todos os países. Isso, por sua vez, resultou em taxas mais baixas da transmissão vertical do VIH, actualmente estimadas em menos de 2% nas populações que não amamentam e menos de 5% nas populações que amamentam.5,6 Apesar da diminuição generalizada da transmissão vertical (TV) do VIH, continuam a ocorrer novas infecções pediátricas, tendo a dinâmica da transmissão mudado para um aumento proporcional da transmissão durante o período pós-natal (Figura 1).3,7 Aproximadamente, metade de todas as novas infecções em crianças ocorrem durante a amamentação. Embora os países continuem a fazer progressos, mantêm-se os desafios da retenção das mulheres infectadas pelo VIH nas unidades de saúde e de uma TAR eficaz durante a gravidez e o período de amamentação, assim como da detecção e prevenção de novas infecções pelo VIH durante a gravidez e a amamentação. Esta mudança na dinâmica da transmissão tem igualmente levantado dúvidas quanto aos melhores testes para as crianças, continuando a identificação de crianças expostas e infectadas pelo VIH a constituir uma enorme dificuldade em vários contextos. A cobertura do diagnóstico pediátrico precoce (DPP) a nível mundial continua a ser baixa: em 2016, apenas 43% dos bebés expostos ao VIH fizeram o teste nos primeiros dois meses de vida.8 Figura 1 Taxas de transmissão vertical do VIH nos países prioritários do quadro Start Free, Stay Free, AIDS Free em 2017 (Fonte: estimativas da ONUSIDA 2018) 0 10 20 30 Indonésia 19% 7% 26% 26% 26% 21% 20% 19% 18% 16% 15% 14% 14% 12% 11% 11% 10% 9% 8% 8% 7% 6% 5% 5% Angola 15% 11% Nigéria 14% 14% Etiópia 11% 10% República Democrática do Congo 12% 8% Gana 10% 9% Chade Côte d’Ivoire Camarões Moçambique Burundi República Unida da Tanzânia Lesoto Quénia Zâmbia Maláui Uganda Eswatini Zimbabué Namíbia África do Sul Botsuana 10% 8% 8% 8% 9% 6% 7% 7% 6% 8% 6% 6% 5% 6% 6% 5% 4% 6% 3% 6% 4% 4% 3% 5% 2% 5% 2% 4% 2% 3% 3% 2% Transmissão após 6 semanas rate Taxa de transmissão às 6 semanas 5Por outro lado, embora a cobertura da TAR pediátrica tenha melhorado consideravelmente desde 2010, apenas 51% dos 1,8 milhões de crianças que vivem com o VIH recebiam TAR no final de 20173.3 A mortalidade de bebés e crianças pequenas é excepcionalmente elevada quando não fazem tratamento, aproximadamente 30% no primeiro ano e 50% no segundo ano de vida.9 Muitas mortes de crianças relacionadas com o VIH podem ser evitadas pela identificação precoce do VIH e imediato início da TAR. Em muitos países, contudo, a limitada disponibilidade de melhores formulações de ARV para evitar e tratar a infecção pelo VIH em recém-nascidos e crianças pequenas continua a constituir um grande desafio. 2.1.2 Fundamentação para esta actualização técnica Em 2016, as Orientações Consolidadas da OMS sobre o uso de Medicamentos Antirretrovirais no Tratamento da Infecção pelo VIH10 apresentavam abordagens inovadoras para o diagnóstico e tratamento; contudo, até à data, apenas alguns países começaram a implementar essas inovações. Para além disso, as evidências de países que as adoptaram rapidamente colocaram algumas questões que requerem cuidadosa atenção e constituem lições que podem ser úteis para os países que planeiem adoptar essas intervenções. • Redução das taxas da TV levou também a uma diminuição do valor preditivo positivo dos testes de ácido nucleico (NAT), resultando numa maior percentagem de resultados falsos- positivos. Não existe actualmente qualquer recomendação específica sobre o nível de viremia que deve ser considerado um resultado verdadeiro-positivo em bebés, nem é conhecido se existe benefício em definir uma amplitude indeterminada para o NAT. • Uma exposição significativa ao medicamento devido implementação da política Tratar Todos e uma profilaxia pós-natal melhorada (PPNm) podem causar atraso no desenvolvimento de anticorpos em crianças infectados pelo VIH. Essas dinâmicas podem complicar o uso dos testes de diagnóstico rápido (TDR) nos bebés, para determinar a exposição e/ou a infecção e afectar o modo como os TDR são usados e interpretados em crianças menores de 18 meses. • A adição de NAT à nascença ao algoritmo nacional de testes pediátricos foi considerada por alguns países. Surgiram vários desafios operacionais, sendo fundamental a sua análise crítica para apoiar a introdução estratégica dos testes à nascença, quando isso for viável e o mais apropriado. • A PPNm para bebés de alto risco está a ser implementada em alguns países, mas continuam a existir problemas na identificação dos bebés de alto risco e na administração da PPNm com as formulações existentes. Isso conduziu a abordagens simplificadas, que actualmente estão a ser consideradas por alguns países e que podem ter impacto nos testes pediátricos. • É aconselhável prestar mais atenção ao reforço do pacote de cuidados pós-natais a prestar às crianças expostas ao VIH, assim como às suas mães. Existem oportunidades para considerar a integração de intervenções bem sucedidas nos pacotes, para sustentar a prestação de serviços e atribuir maior importância à promoção da integração dos serviços, para garantir que as crianças sejam retidas nas unidades de cuidados até ao diagnóstico final. Na sequência do workshop regional da OMS, em Joanesburgo, na África do Sul (Junho de 2017)11, realizou-se uma reunião de peritos, em Abril de 2018, para expor opiniões e promover o debate sobre estas questões. A presente actualização programática pretende informar sobre alterações importantes introduzidas e novas considerações de implementação que surgiram desde a publicação das Orientações Consolidadas da OMS sobre ARV de 2016.10 3.0 PRINCIPAIS CONSIDERAÇÕES 3.1 Diagnóstico em bebés A complexidade dos testes de DPP é agora maior, devido a um significativo reforço da iniciativa Tratar Todos (incluindo as mulheres grávidas e as lactantes), implementação da PPNm, menores taxas de TV e aumento da contribuição relativa da transmissão pós-natal. O DPP já não pode ser considerado sobretudo um processo de teste único, visto que agora requer outros testes durante toda a exposição. Do mesmo modo, serão necessárias várias outras considerações importantes para reforçar a panóplia de testes de DPP durante todo o período de exposição. Isso inclui assegurar que o início da TAR não sofre atrasos em crianças com infecção pelo VIH. 3.1.1 Minimizar resultados falsos-positivos introduzindo um intervalo indeterminado para o DPP Embora o diagnóstico pediátrico esteja a ser melhorado à escala mundial, com maior acesso à iniciativa Tratar Todos, as menores taxas de TV12 e a baixa viremia observada nos bebés infectados com VIH13 significa que existem cada vez mais resultados falsos-positivos a ser reportados nos programas. Alguns bebés podem, portanto, ser incorrectamente diagnosticados como estando infectados pelo VIH e ter iniciado desnecessariamente uma TAR vitalícia. Não existe actualmente qualquer recomendação específica sobre o nível de viremia que deve ser considerado um resultado verdadeiro- positivo em bebés, nem é conhecido se existe benefício em acrescentar uma amplitude indeterminada para minimizar os resultados falsos-positivos (ver Caixa 1). 6 Uma revisão sistemática de 32 estudos usando uma amplitude indeterminada encontrou 14 753 resultados não negativos dos quais 2 436 (16,5% [95% CI 15,9–17,1%]) foram indeterminados (dados não publicados); um estudo14 que registou os diagnósticos finais de casos indeterminados revelou que 76% dos bebés com um resultado inicial do teste indeterminado foram negativos na repetição do teste, sugerindo que esses bebés não estavam infectados pelo VIH, apesar do resultado inicial do teste ter sido não negativo. Estes dados indicam que nos países que não implementam uma amplitude indeterminada para o NAT e quando as taxas de TV são baixas (<5%), 12,5% (76% de 16,5%) dos resultados não negativos podem ser falsos-positivos no teste inicial, podendo os bebés afectados iniciarem desnecessariamente um tratamento vitalício. Normalmente, os testes de DPP detectam a presença do VIH usando tecnologias de NAT em tempo real que, muitas vezes, reportam limiares do ciclo. Os limiares do ciclo reportados representam o ciclo de PCR no qual se observa amplificação pela primeira vez e estão inversamente correlacionados com a quantidade de vírus na amostra. O equivalente aproximado de um limiar do 33º ciclo no teste qualitativo Roche COBAS® Ampliprep/COBAS® TaqMan® HIV-1 v2.0 foi seleccionado como o melhor limite indeterminado para novos testes. Isso representava um equilíbrio entre a proporção de bebés que vivem com o VIH e seriam incorrectamente identificados como indeterminados (cerca de 8-13%) e a proporção de bebés não infectados que poderiam iniciar desnecessariamente o tratamento (cerca de 2 –7%). A África do Sul já implementou uma amplitude indeterminada e desenvolveu um procedimento operacional padrão (POP) para gerir os resultados dos testes positivos e indeterminados.15 Do mesmo modo, uma reunião técnica da OMS desenvolveu um novo POP que ajudará a garantir testes pediátricos de melhor qualidade (Anexo 1). As evidências actuais sugerem que não são necessários requisitos específicos relativamente ao tipo de teste (convencional ou no ponto de cuidados (PC)) usado para analisar novamente as amostras com resultados indeterminados. A maioria dos países já aplica um POP nacional quando se encontram erros de teste (por exemplo, mau funcionamento do equipamento, amostra insuficiente ou rejeitada, etc.). Na maior parte dos países, a unidade de saúde em questão é contactada, sendo-lhe pedido que assegure o regresso do bebé à unidade, para que lhe seja colhida nova amostra para teste. Em virtude da demora causada pelos erros dos testes, essas amostras são geralmente consideradas urgentes, recebendo prioridade para análise, logo que são recebidas pelo laboratório. Um novo estudo sugere que a repetição de um determinado teste usando a mesma amostra, quando possível, resolve a maioria (>95%) dos resultados indeterminados.14 Por conseguinte, antes de se contactar a unidade de saúde, para que esta peça o regresso do bebé à unidade para a colheita de uma nova amostra, deverá realizar-se um novo teste com a mesma amostra usando gotas de sangue seco ou o sangue total restante. 3.1.2 Testes de confirmação dos resultados positivos Uma análise não dispendiosa, realizada para avaliar o valor dos testes de confirmação em diferentes cenários, revelou que os testes de confirmação têm, de facto, uma boa relação custo- benefício.16 Sem testes de confirmação, esta análise revelou que, em contextos com taxas de TV semelhantes àquelas que se observaram na África do Sul, mais de 10% dos bebés que iniciaram a TAR poderiam, na verdade, não estar infectados pelo VIH. Os testes de confirmação dos resultados positivos usando uma nova amostra, em conformidade com as orientações da OMS, poderão evitar essa ocorrência, embora esta política não seja consistentemente implementada (Caixa 2). Continua a ser essencial que os programas garantam que todos as crianças expostas ao VIH sejam retidas nas unidades de saúde e devidamente examinadas durante todo o período de exposição, devendo todas as crianças com resultados positivos fazer um teste de confirmação. Caixa 1. Definição dos termos dos resultados do diagnóstico • Amplitude indeterminada: limites de equivalentes de cópias do vírus que seriam demasiado baixos para se fazer um diagnóstico positivo rigoroso. • Resultado falso-positivo: bebés não infectados pelo VIH que foram incorrectamente identificados com infecção e podem ter iniciado a TAR desnecessariamente. • Resultado falso-negativo: bebés infectados pelo VIH que foram incorrectamente identificados como não infectados. • Resultado não negativo: um resultado positivo ou indeterminado. O instrumento de reacção em cadeia da polimerase (PCR) regista um resultado detectável, que pode ser posteriormente classificado como “indeterminado” com base noutros dados (e.g., limiar do ciclo notificado por ensaios). Pode também ser referido como “não confirmado”, “equívoco” ou “positivo irreprodutível”. • Resultado discordante: primeiro teste positivo/detectável; segundo teste negativo. • Limiar do ciclo: o ponto em que a amplificação do vírus é observada pela primeira vez no decurso de ciclos de PCR repetidos. O limiar do ciclo está inversamente correlacionado com a quantidade de vírus na amostra. 7Para além disso, as crianças que tiverem repetidamente resultados indeterminados devem ser activamente acompanhadas, retidas, reanalisadas e o seu estado decidido. Finalmente, o teste de DPP nos PC está a ser implementado em vários países e contextos (ver 3.1.3). Anteriormente, eram escassas as evidências sobre o modo de realizar um teste de confirmação do DPP nos PC com resultados positivos, mas desde a publicação das Orientações Consolidadas da OMS sobre ARV de 2016 10, foram publicados vários estudos sobre o seu desempenho. Actualmente, existem duas tecnologias de DPP nos PC que estão incluídas na lista da OMS de produtos de diagnóstico in vitro pré-qualificados.17 Os resultados dos estudos laboratoriais e no terreno revelaram um desempenho comparável ao das tecnologias laboratoriais.18 Por outro lado, foram publicados dois estudos de impacto sobre os doentes que salientam os resultados significativamente melhores, quando se usam as tecnologias de DPP nos PC.19,20 Com base nestas evidências actualizadas, pode usar-se o teste DPP nos PC para confirmar resultados positivos. 3.1.2 Gerir resultados discordantes e interrupção do tratamento Desde 2010, a OMS recomenda o início da TAR nos bebés depois de um NAT inicial positivo, em simultâneo com a colheita de uma amostra para confirmação. As Orientações Consolidadas da OMS sobre ARV de 201610 sugerem que, se o segundo NAT (de confirmação) for negativo, se deve fazer um terceiro NAT, quer seja um DPP (qualitativo) ou da carga viral (CV), antes da decisão de interromper a TAR. A introdução de uma amplitude indeterminada poderá reduzir o número e a proporção de crianças com resultados de teste discordantes (resultados de NAT diferentes em amostras separadas); todavia, são necessárias orientações sobre o modo de decidir a interrupção do tratamento. Há vários factores a considerar, quando se avalia os doentes para a interrupção da TAR, após a obtenção de resultados discordantes (resultado negativo após um resultado positivo) seguidos de um terceiro teste com resultado negativo: • a criança não deve ter sinais ou sintomas clínicos sugestivos de infecção por VIH;21 • deve ser estabelecido um plano de seguimento com a família, cuidadores e profissionais de saúde;; • a informação sobre contactos (telefone, morada, etc.) da família/cuidador(es) deve ser obtida e confirmada.. Quando se acompanha uma criança, cujo tratamento vai ser interrompido, devem considerar-se os seguintes factores: • é necessário fazer um seguimento activo para garantir que uma criança potencialmente infectada é retida e reiniciará o tratamento, se ocorrer uma recidiva do vírus; • a recidiva vírica em crianças infectadas pelo VIH que iniciaram rapidamente o tratamento deverá ocorrer nos 8 meses seguintes à interrupção em >99% das crianças infectadas pelo VIH;22 • As crianças que desenvolvam sinais ou sintomas indicativos de infecção pelo VIH devem ser imediatamente submetidos a testes; • a amamentação e o risco continuado de transmissão requerem seguimento e testes apropriados durante o período de risco, até ao diagnóstico final; • é importante minimizar os testes de seguimento, aproveitando as oportunidades existentes para os testes pediátricos (com base no calendário nacional de testes pediátricos e nos calendários de vacinação ou de consultas pediátricas de rotina), até que seja determinado o diagnóstico final. Poucos países têm políticas sobre o modo de realizar as interrupções dos tratamentos em crianças com resultados de testes discordantes. A África do Sul, por exemplo, implementou políticas com seguimento laboratorial e clínico intensivo destes bebés durante 18 meses15; tanto os testes de DPP (qualitativos) como os da CV (quantitativos) são realizados às 4 semanas, 3 meses e de 3 em 3 meses depois da interrupção do tratamento. No entanto, uma vez que é baixa a probabilidade de esses bebés estarem infectados pelo VIH, também é razoável uma abordagem menos agressiva de 8 meses para simplificar o procedimento de seguimento: isto tem o apoio das novas evidências sobre o momento da recidiva vírica em crianças infectadas pelo VIH e precocemente tratados.22 Neste caso, tanto o teste de DPP (qualitativo) como o teste da CV (quantitativo) podem ser realizados às 4 semanas, 4 meses e 8 meses após a interrupção do tratamento (Anexo 2). As crianças com resultados positivos num teste de seguimento por qualquer um dos protocolos devem reiniciar o tratamento de acordo com as actuais orientações,10 devendo ser colhida uma amostra para confirmação. Qualquer POP para interrupção deve ser implementado considerando o contínuo risco de transmissão que resulte da amamentação e, uma vez concluído o seguimento (8 meses após a interrupção do tratamento), deve aplicar-se o calendário nacional de testes pediátricos para crianças expostas ao VIH, a fim de garantir um diagnóstico final apropriado. Se a amamentação tiver parado antes do final do seguimento intensivo, pode ser definido o estado final em relação ao VIH, com realização do NAT, pelo menos, 6 semanas após a cessação da amamentação, conforme se indica no Anexo 2, Cenário b. Caixa 2. Priorizar os testes de confirmação de resultados positivos e indeterminados • A diminuição das taxas de TV à escala mundial levantaram dúvidas acerca dos testes falsos-positivos e indeterminados. • Os doentes com resultados indeterminados requerem uma imediata repetição do teste, devendo o doente ser tratado de acordo com o POP apresentado no Anexo 1. • Os doentes com resultados indeterminados repetidos exigem uma equipa multidisciplinar de prestadores de cuidados de saúde para apoiar a sua retenção, acompanhamento e uma decisão sobre o seu estado. • Nos programas de TAR, é necessário dar prioridade aos testes de confirmação de todos os resultados positivos usando uma nova amostra. • A monitorização clínica e a realização de novos testes, com base na calendário nacional de testes pediátricos, deverão ser feitas, até que seja estabelecido definitivamente o seu estado em relação ao VIH. 83.1.3 Implementação dos testes de DPP nos PC As Orientações Consolidadas da OMS sobre ARV de10 recomendam o uso das tecnologias NAT nos testes pediátricos precoces do VIH que foram desenvolvidos e validados para uso nos pontos de cuidados ou perto deles. O DPP nos PC constitui uma oportunidade para reduzir os tempos de entrega dos resultados dos testes, limitar a perda de doentes no decurso da panóplia de testes do VIH, reduzir a mortalidade infantil e facilitar a delegação de tarefas para quadros inferiores de agentes de saúde nas unidades de saúde que tenham serviços descentralizados. Foram geradas evidências suficientes sobre o desempenho desses testes nos respectivos contextos no terreno para apoiar uma aprovação rápida das autoridades reguladoras nacionais e o início do reforço (Caixa 3). Alguns países estão actualmente a implementar as tecnologias de DPP nos PC.18 Os estudos sobre a sua implementação no Maláui20 e em Moçambique19 revelaram que o uso do DPP nos PC proporciona uma redução significativa dos tempos de entrega dos resultados dos testes, com uma maior quantidade de resultados sendo entregues às unidades de saúde e aos cuidadores e taxas de início da TAR mais rápidas e mais elevadas entre as crianças infectadas pelo VIH. Os principais ensinamentos retirados dos projectos-piloto de implementação incluem: • optimizar o uso de DPP nos PC, através da selecção de produtos e locais; • seleccionar as unidades de saúde com maior prevalência e grandes volumes, para maximizar a utilização do equipamento; • considerar a colocação nas unidades ou a transferência no seio das unidades a partir de pontos de entrada de elevada produção (e.g., enfermarias de nutrição e pediátricas); • garantir a continuidade do serviço criando uma estratégia de serviço e manutenção com os fornecedores e disponibilizar o apoio de técnicos; • integrar os serviços nas unidades de saúde, avaliando a necessidade de formação adicional e de acompanhamento contínuo dos agentes de saúde; • reforçar a ligação entre os serviços para garantir uma rápida ligação aos cuidados para as crianças infectadas pelo VIH que tenham sido identificados; • garantir a disponibilidade de formulações pediátricas de ARV para recém-nascidos, para permitir o início precoce da TAR. 3.1.4 Introdução do NAT à nascença para facilitar o início mais rápido do tratamento Acrescentar o NAT à nascença ao calendário nacional de testes pediátricos poderá resultar na identificação precoce de recém-nascidos infectados pelo VIH e, assim, levar a um início mais rápido do tratamento e à redução da mortalidade infantil. Os dados sugerem que crianças com testes positivos à nascença iniciam a TAR aproximadamente 2 meses mais cedo do que as crianças não testados à nascença (6 semanas vs. 15 semanas).23 No entanto, as análises da relação custo- benefício revelaram que os ganhos de sobrevivência da adição do NAT à nascença ao teste normal realizado às 6 semanas se perdem, se a perda no seguimento depois de um resultado negativo do teste à nascença exceder 37%, sublinhando o facto de que é necessário que esteja já instituído um programa de alta eficácia de 6 semanas. Alguns países já iniciaram a implementação do NAT à nascença e as experiências dos países são apresentadas na Caixa 4. É de notar, contudo, que o reforço dos sistemas de DPP já existentes continua a ser a prioridade, enquanto os programas consideram adoptar o teste à nascença. Há várias considerações sobre a implementação que podem ser resumidas a partir dessas experiências. • Os países que estejam a considerar a introdução do teste à nascença devem rever criticamente o actual desempenho e oportunidades para reforçar o seu programa de DPP de 6 semanas e considerar outros indicadores (e.g., cobertura das consultas de vacinação PENTA1 e taxa de partos esperada), para que os potenciais ganhos obtidos pelo teste à nascença possam ser investigados em maior profundidade. Por exemplo, nos contextos em que a taxa de partos esperada é muito inferior à cobertura das consultas de vacinação PENTA1, o valor acrescentado do teste à nascença como meio de expandir o DPP é limitado. • Os projectos-piloto são um bom meio para começar a adquirir experiência nacional sobre esta abordagem inovadora de teste, mas, para medir integralmente o impacto, os programas terão de recolher dados sobre a viabilidade e o impacto do teste à nascença e sua ligação ao início da TAR. • Abordagens orientadas que apenas prevejam o teste à nascença para bebés de alto risco deverão apresentar uma maior produção, em comparação com os testes à nascença de rotina. Esta abordagem poderá exigir menos recursos e representar um fardo mais leve para os agentes de saúde. • O acompanhamento activo dos bebés que tenham resultados negativos do NAT à nascença é fundamental para garantir que eles regressarão às 6 semanas, para voltarem a fazer o teste e iniciar o tratamento com cotrimoxazole (CTX); pode considerar- se também a criação de identificadores exclusivos dos doentes ou outros mecanismos inovadores (e.g., códigos de barras) para acompanhar os bebés. • É essencial que o tempo de entrega dos resultados do teste às unidades de saúde e aos cuidadores seja curto, para optimizar o benefício do NAT à nascença, devendo os testes dos PC ser usados, quando estiverem disponíveis. Caixa 3. Novas tecnologias de DPP nos PC • Há duas tecnologias que receberam pré-qualificação da OMS. • As autoridades reguladoras nacionais são encorajadas a não retardarem a sua adopção fazendo mais avaliações mas, pelo contrário, deverão adoptar um registo e um processo nacional de aprovação rápidos e simplificados para implementação imediata. 9• O teste à nascença é aceitável para as mães, mas há problemas relacionados com a necessidade de mais recursos humanos, a dificuldade da colheita de amostras de sangue em recém- nascidos, a necessidade de garantir a colheita de amostras e entrega dos resultados fora das horas normais de expediente, a ligação à TAR e a natureza do sistema de DPP no geral (ruptura de stocks, mecanismos de referência e atraso na entrega nos resultados). Caixa 4. Implementação dos testes à nascença: experiências dos países África do Sul A África do Sul introduziu o NAT à nascença em 2015, com formação específica para os enfermeiros dos serviços de assistência aos partos e pós-natais e actualizações dos registos clínicos, a fim de permitir a obtenção de dados. Os desafios da implementação que a África do Sul teve de enfrentar incluem a insuficiente ligação entre os bebés identificados como infectados pelo VIH e os cuidados, com a consequente demora no início da TAR e uma baixa taxa de entrega de resultados para testes futuros nos bebés com resultados negativos à nascença. Um sub-estudo qualitativo revelou que o teste à nascença teve uma elevada aceitação. Foram raras as recusas e as mães não deram qualquer indicação de que o teste à nascença afectasse a sua subsequente aceitação do teste nos bebés ou o recurso a cuidados pós-natais. Foram detectados sistemas fracos de seguimento para as mães que fizeram o parto em casa e os técnicos de laboratório manifestaram preocupações relativamente ao maior volume de trabalho associado às exigências de testes adicionais. Quénia O Quénia iniciou um projecto-piloto de NAT à nascença em 2015 (definido como teste nas 72 horas seguintes ao nascimento) e os respectivos resultados constituíram a base para um algoritmo de DPP revisto em 2016 e um plano nacional de reforço, com início previsto para meados de 2018. Antes da implementação, foi designado na unidade de saúde um ponto central para os testes à nascença, tendo sido desenvolvido um registo inovador de expedição, as mães foram assistidas por mentores para a ligação entre os hospitais e as comunidades e foi constituído um grupo de apoio psicossocial para a prevenção da transmissão vertical (PTV) do VIH. Uma boa liderança e coordenação foram identificadas como importantes para atender os doentes através da prestação de serviços. Os desafios incluíam questões relacionadas com a transferência, geração de procura, tempo de entrega dos resultados dos testes e mães que não iam receber esses resultados. Por outro lado, não existiam formulações de TAR para os recém-nascidos com testes positivos durante a fase inicial de implementação. Zimbabué O Zimbabué iniciou um projecto-piloto de NAT à nascença nos PC, em Abril de 2017, em dez unidades de saúde, para bebés de alto risco expostos ao VIH (< 48 horas após o nascimento). Noventa e sete por cento dos resultados foram transmitidos aos cuidadores e todos os bebés infectados pelo VIH iniciaram a TAR nos 5 dias seguintes ao teste. Este projecto deverá fornecer experiência crítica sobre uma abordagem diferente ao acompanhamento de crianças depois do teste à nascença, devendo gerar novas informações sobre o valor de orientar o teste à nascença para bebés de alto risco e não para todos as crianças exposts ao VIH. República Democrática do Congo O NAT à nascença foi implementado pela primeira vez em Dezembro de 2016, tendo as amostras sido enviadas aos laboratórios centrais para processamento. O pessoal de laboratório recebeu formação no sentido de priorizar as amostras colhidas à nascença e assegurar a rápida entrega dos resultados à unidade de saúde. Os problemas eram o longo tempo de espera entre a colheita das amostras e o envio dos resultados (8–12 semanas a partir do laboratório nacional), rupturas de stocks devido a limitações na gestão da cadeia de abastecimento e dificuldades no transporte das amostras. A receptividade ao teste à nascença foi boa mas a produção foi baixa, com numerosas oportunidades perdidas devido à alta precoce das mulheres da maternidade. Por conseguinte, o teste à nascença continua limitado a este projecto-piloto (que já terminou), estando a ser envidados esforços para reforçar o actual programa de DPP de 6 semanas. Eswatini (Suazilândia) Eswatini introduziu dois projectos-piloto para implementar o NAT à nascença universal em cinco maternidades, em Agosto de 2017, usando as tecnologias de DPP nos PC em três dessas maternidades (em parceria com a EGPAF) e os testes convencionais nas outras duas (em parceria com o ICAP). No teste-piloto convencional, 93% dos recém-nascidos expostos ao VIH fizeram o teste antes da alta da maternidade e seis dos 1 548 testados estavam infectados pelo VIH. Nos testes-piloto realizados nos PC, 68% dos recém-nascidos expostos ao VIH fizeram o teste e 12 dos 1 314 testados estavam infectados. Para além disso, 98% dos resultados foram entregues ao cuidador. Dos infectados, nove do teste-piloto realizado nos PC e quatro do teste-piloto convencional foram colocados em tratamento. Ambos os estudos-piloto confirmaram que o pessoal das unidades de saúde sofre uma sobrecarga de trabalho quando se acrescenta o NAT à nascença. Os enfermeiros sentiam-se, muitas vezes, exaustos e não conseguiam dar prioridade ao NAT à nascença, porque muitos dos nascimentos ocorriam durante a noite ou aos fins-de-semana, quando o número de agentes de saúde é reduzido. Para além disso, embora a maioria das mães considerasse aceitável o teste à nascença, muitas recebiam alta ou abandonavam a maternidade antes de ser feito o teste e outras forneciam informação de contacto incorrecta. • A chave para uma implementação eficaz é garantir que os recém-nascidos que tenham sido identificados como infectados pelo VIH serão tratados e que existem formulações apropriadas à idade para iniciar o tratamento. • São necessárias uma boa liderança e coordenação para supervisionar a prestação dos serviços, apoiar a supervisão, a mentoria e o ciclo de melhoria da qualidade. 10 11 3.1.5 Garantir uma interpretação rigorosa do teste aos 9 meses e simplificar o algoritmo do teste As Orientações Consolidadas da OMS para os ARV de 2016 recomendam que se devem usar os TDR para avaliar a exposição ao VIH entre crianças com menos de 4 meses, enquanto a exposição ao VIH das crianças entre 4–18 meses deve ser determinada aplicando o teste às mães. Se não for possível fazer o teste às mães, as actuais orientações realçam a importância de não considerar como definitivo um resultado negativo de um TDR numa criança entre 4–18 meses. Os problemas da implementação são expostos na Caixa 5. Com base nas Orientações Consolidadas da OMS para os ARV de 201610, os TDR são ensaios serológicos que também podem ser usados para excluir uma infecção estabelecida entre crianças saudáveis expostas ao VIH com 9 meses ou mais. No entanto, as mudanças na dinâmica da transmissão, assim como nas políticas e práticas, complicaram o uso de TDR para determinar o estado da infecção. Uma exposição substancial das crianças a medicamentos, com implementação da política Tratar Todos para as mães e a profilaxia pós-natal melhorada ás crianças expostas ao VIH, pode ter resultado numa redução da carga viral e atraso no desenvolvimento de anticorpos em crianças infectadas pelo VIH. Por fim, a ocorrência de infecção materna no final da gravidez ou durante o período pós-natal pode ser responsável pela falta de transferência de anticorpos passivos do VIH para o bebé . Estes factores contribuem cada vez mais para colocar em risco o rigor do TDR aos 9 meses de idade como meio de excluir correctamente a infecção estabelecida em crianças expostos ao VIH. Estas preocupações são apoiadas pelos resultados obtidos no Uganda e Quénia24, 25, onde 15–40% das crianças menores de 2 anos e identificados como infectados pelo VIH tiveram um NAT positivo, mas um TDR negativo O TDR aos 9 meses era inicialmente preconizado nas Recomendações da OMS de 2010 sobre o diagnóstico da infecção pelo VIH em bebés e crianças pequenas21 com o objectivo de orientar o NAT para as crianças expostas ao VIH com maior probabilidade de estarem infectados (e.g., os que tiveram um TDR positivo) como uma medida de poupança. Contudo, devido à diminuição das taxas da TV, uma maior disponibilidade e custos mais baixos do NAT, mudanças na transmissão e na dinâmica da exposição aos medicamentos, assim como ao facto de os TDR serem menos eficazes na determinação da necessidade dos testes NAT, essa abordagem orientada poderá ser menos imperiosa. Para além disso, a maior complexidade e o potencial do programa para uma interpretação inapropriada dos resultados dos testes têm outras consequências não desejadas. À luz dos desafios e dados acima mencionados, pode agora considerar-se a substituição dos TDR aos 9 meses pelo NAT, com vista a minimizar os problemas de interpretação e simplificar o algoritmo dos testes para crianças. O Anexo 3 resume o novo algoritmo simplificado, que é reforçado por algumas importantes considerações: • avaliar o estado de exposição ao VIH, aplicando o TDR às mães; • realizar o NAT em crianças de 9 meses expostas ao VIH, quer sejam sintomáticos ou assintomáticos, e mesmo quando resultados anteriores do NAT tenham sido negativos; • garantir que os testes com resultados indeterminados serão repetidos imediatamente e priorizados, tendo em vista uma rápida resolução; • garantir a realização de testes de confirmação a seguir a um resultado positivo; e • garantir que todos as crianças expostas ao VIH serão regularmente seguidas até um diagnóstico final, com a administração da profilaxia CTX e avaliação clínica e nutricional. Finalmente, continua a ser essencial que a retenção da criança prossiga até ao fim do período de exposição. Devem ser feitos mais esforços para estabelecer um diagnóstico final aos 18 meses de idade ou 3 meses após a cessação da amamentação, conforme o que ocorrer mais tarde. Embora haja uma cobertura cada vez maior do teste tradicional às 6 semanas e seja dada mais atenção a tempos mais precoces, a mudança da dinâmica da transmissão e o aumento da exposição a medicamentos significam que são necessários mais esforços para manter o seguimento durante todo o período da exposição. A finalidade é garantir que todos os bebés infectados pelo VIH, incluindo os infectados no período pós-natal, sejam identificados e recebam tratamento. Caixa 5. Uso do TDR: considerações sobre a implementação • Deve continuar-se a dar prioridade ao teste das mães em todos os pontos de entrada, para determinar o estado da exposição nos bebés e crianças menores de 18 meses. • Se a mãe estiver ausente ou não puder fazer o teste, deve fazer-se um TDR à criança, mas os resultados negativos em crianças com mais de 4 meses não devem ser considerados como exclusão definitiva da exposição e é necessário fazer o seu seguimento. • Se a mãe estiver ausente ou não puder fazer o teste e o bebé apresentar sinais e sintomas de infecção pelo VIH, deve realizar-se um NAT. • O NAT deve realizar-se na sequência de um TDR positivo na mãe ou no bebé, devendo fazer-se um NAT de confirmação perante um resultado positivo de um NAT anterior. 12 3.2. Uso de ARV na prevenção e tratamento do VIH em bebés 3.2.1 Desafios da implementação da PPNm a bebés de alto risco As Orientações Consolidadas da OMS para os ARV de 2016 recomendam um regime duplo de AZT e NVP, que pode ser alargado até 12 semanas nos bebés amamentados que sejam considerados em alto risco de TV. Um bebé de alto risco é definido como um bebé cuja mãe tenha sido identificada como infectada pelo VIH durante o parto ou no período pós-parto, infectada durante a gravidez ou a amamentação, tenha iniciado a TAR tardiamente durante a gravidez ou não tenha atingido a supressão viral no momento do parto (Anexo 4). Todos os bebés de alto risco devem receber profilaxia medicamentosa dupla (AZT e NVP) durante as primeiras 6 semanas. Nos bebés amamentados, a isso devem seguir-se mais 6 semanas de AZT e NVP ou mais 6 semanas só de NVP (ver Caixa 6). Esta recomendação baseia-se em evidências de ensaios clínicos aleatórios26 e toma em consideração o rácio risco- benefício da PPNm: o potencial para uma maior toxicidade medicamentosa versus protecção adicional contra a transmissão do VIH. O fundamento para prolongar o uso da PPNm, especialmente em lactentes de alto risco, reside na assunção de que as mães que iniciaram precocemente a TAR conseguem a supressão viral em 12 semanas, reduzindo assim, em grande medida, o risco de transmissão pelo leite materno e a necessidade de continuar a profilaxia no bebé. Os países adoptaram a PPNm usando várias abordagens diferentes. No Quénia, Eswatini (Suazilândia) e Moçambique, a PPNm foi adoptada para todos os bebés amamentados expostos ao VIH, enquanto nove países (Botsuana, Gana, Namíbia, Nigéria, África do Sul, Tanzânia, Uganda, Zâmbia e Zimbabué) adoptaram a PPNm para bebés de alto risco identificados primariamente com base na duração da TAR materna e, quando disponível, na CV materna próxima do parto. A maioria dos países optou por, pelo menos, 12 semanas de profilaxia, normalmente AZT/NVP para as primeiras 6 semanas, seguida de NVP isolada. Três países (Quénia, Namíbia e África do Sul) ligam a duração da PPNm à CV materna e prolongam a PPNm por todo o período de amamentação, quando não é atingida a supressão viral. Finalmente, em três países (Botsuana, Zâmbia e Tanzânia), foi adoptada a profilaxia tripla com um combinação de dose fixa de AZT/3TC/NVP, para resolver o desafio da compra de xaropes. Orientações recentes para a alimentação infantil27 relacionada com o VIH reafirmam a posição da OMS de que a melhor forma de evitar a TV no período pós-parto e optimizar a sobrevivência infantil é garantir que as mães que vivem com o VIH são bem controladas através da TAR, conseguindo amamentar os seus bebés durante cerca de dois anos, sendo o bebé exclusivamente amamentado no primeiros seis meses de vida. Se a mãe submetida à TAR conseguir a supressão viral, o risco de transmissão do VIH pelo leite materno é muito baixo e a profilaxia infantil confere um benefício adicional mínimo para além das 4–6 semanas de vida. Alguns programas adoptaram a PPNm para todos os bebés expostos ao VIH. Embora isso possa simplificar a tomada de decisões, também aumenta os custos e expõe um grande número de bebés que poderão não precisar de PPNm a uma maior toxicidade. Este tipo de abordagem deveria ser reservada para determinadas situações em que existe uma maioria de mães em alto risco de transmitirem o VIH. Os dados sobre a duração média da TAR no parto e, se disponível, a percentagem de mulheres grávidas com CV >1000 no final do terceiro trimestre poderão ajudar os decisores políticos a determinar se os custos e a toxicidade adicionais são superados pelo potencial benefício. Mesmo assim, esta apenas deverá ser uma medida provisória, enquanto estão a ser implementadas estratégias para aumentar a cobertura dos testes maternos, o tratamento precoce e uma maior adesão. No entanto, há várias situações em que a supressão viral durante o período de amamentação não pode ser garantida na mulher, por exemplo: • Se a mãe recusar ou não conseguir iniciar ou continuar a TAR e pretende amamentar o seu bebé; • Se o prestador de cuidados souber que a mãe não está disposta a fazer a TAR durante a amamentação; • Se for conhecido que a CV é elevada quando o regime profilático do bebé está prestes a terminar. Não existe uma recomendação formal para estes tipos de situações, nem evidências que apontem o melhor procedimento. É, contudo, razoável presumir que a profilaxia infantil serve como solução de “salvaguarda” para evitar a transmissão pós-natal do VIH e os programas nacionais poderiam considerar o mérito de dar aos prestadores de cuidados médicos a opção de continuarem a profilaxia infantil para além do período recomendado de 6 ou 12 semanas. Se esta opção for introduzida nas orientações nacionais, deverão ser definidos claramente os cenários em que deve continuar a ser feita a profilaxia infantil. As orientações nacionais deverão igualmente referir se a forma mais indicada para evitar a transmissão do VIH pelo leite materno é o melhor tratamento possível da mãe durante todo o período de exposição. A continuação da profilaxia deverá, por isso, ser vista como uma medida provisória, enquanto se fazem esforços para apoiar e melhorar a adesão ao tratamento por parte das mães. A decisão de continuar a profilaxia deve ter em conta os factores que causam a fraca adesão materna, uma vez que eles poderão ter impacto na adesão à profilaxia infantil. Depois de terminar, a profilaxia infantil não deve ser retomada, se existirem novas preocupações acerca da adesão materna. Não existem evidências que apoiem essa abordagem; pelo contrário, o foco deve incidir sobre as razões que levam a mãe a não aderir. Se for tomada a decisão de continuar a profilaxia infantil, tanto as mães como os bebés devem ser avaliados a intervalos regulares, para determinar a necessidade de continuar essa profilaxia. Uma vez que há cada vez mais tratamentos eficazes a serem usados em mulheres grávidas, é de esperar que as taxas de TV diminuam. No entanto, algumas mulheres ainda poderão ser 13 diagnosticadas tardiamente ou ter infecções incidentais, pelo que é provável que este grupo seja responsável pela maioria da transmissão de novos casos de VIH aos bebés, devido ao elevado nível de vírus maternos, quando não se faz o tratamento. Uma possibilidade seria fazer-se um “tratamento inicial” como PPNm, administrando um regime de três medicamentos em doses terapêuticas a este grupo específico de bebés, com o objectivo de minimizar a transmissão e a selecção de VIH resistente aos medicamentos (HIVDR) no caso de infecção estabelecida, apesar da profilaxia. Essas abordagens terão de ser acompanhadas de uma atenta revisão das práticas de testes em crianças, para determinar o potencial impacto da PPNm sobre o desempenho do teste virológico de diagnóstico em crianças (i.e., pelo menos, uma amostra deve ser colhida antes de se iniciar qualquer tratamento, para se poder realizar um NAT o mais cedo possível). 3.2.2 Tratamento precoce do bebé: opções limitadas e administração complexa A TAR pediátrica precoce melhora a sobrevivência e reduz a morbilidade a longo prazo, mas a mortalidade continua a ser considerável nos primeiros meses de vida. A introdução do NAT à nascença poderá permitir o início da TAR antes das 2 semanas de idade. Contudo, o único regime disponível para este grupo etário é, há muitos anos, um regime que combina AZT, 3TC e NVP. Este regime pode continuar com uma monitorização clínica atenta até aos 3 meses de idade e depois mudar para um regime à base de LPV/r, usando granulado de LPV/r ou introduzindo o LPV/r no final da segunda semana de vida como xarope, passando depois para uma formulação sólida, aos 3 meses de idade. RO granulado de Raltegravir (RAL) foi recentemente aprovado pela Administração Americana dos Alimentos e Medicamentos para ser usado em recém-nascidos, excepto se tiverem baixo peso à nascença ou forem prematuros. Este é um avanço considerável no aumento de opções de tratamento em recém-nascidos. A viabilidade e a aceitabilidade desta formulação estão presentemente a ser avaliadas num estudo que se realiza na África do Sul. As Orientações Consolidadas da OMS sobre ARV de 201610 10 já recomendam o uso de RAL como tratamento de primeira linha alternativo para crianças menores de 3 meses, nas quais o granulado de LPV/r não pode ser usado. Presentemente, o RAL adequado para administração no período neonatal apenas está disponível como granulado para suspensão oral, mas estão a ser desenvolvidas formulações melhoradas para uso futuro. Os países que estão a considerar a introdução do teste à nascença terão de pensar na sua capacidade para descentralizar o tratamento dos recém-nascidos, reforçando as capacidades dos agentes de saúde, assegurando o abastecimento de produtos nas unidades de saúde do nível periférico e/ou alargando o sistema de referência para unidades próximas, assim como garantindo que os agentes de saúde têm formação adequada e o necessário equipamento para iniciar o tratamento em recém-nascidos. Caixa 6. Formulações de ARV para a PPNm: considerações sobre a implementação Existem três formulações que podem ser usadas para doseamento da PPNm: • Xaropes de NVP e AZT; • Comprimidos pediátricos dispersíveis de NVP e; • Combinações pediátricas de dose fixa (CDF). Cada formulação tem os seus próprios benefícios e riscos (ver Anexo 5). Uma CDF pediátrica de AZT/3TC/NVP tem as mesmas vantagens que a PPNm, visto que está facilmente disponível e bem estabelecida numa formulação pediátrica adequada às crianças. No entanto, existem alguns problemas no uso desta opção de CDF que os programas devem considerar: • A NVP é administrada numa dose única diária para a profilaxia, enquanto a AZT é usada duas vezes por dia e, portanto, usar uma CDF compromete um ou outro dos regimes de medicação. Ou se usa a AZT uma vez por dia ou a NVP duas vezes por dia. • O rácio AZT:NVP nas CDF é apropriado nas primeiras seis semanas de PPNm, mas não pode ser usado nas semanas 6 a 12, quando a dose de AZT aumenta quatro vezes, enquanto a dose de NVP apenas aumenta um terço. • Esta CDF pediátrica contém 3TC além da AZT e da NVP. Embora a 3TC seja muito bem tolerada e tenha sido usada como medicamento único para a PPNm em ensaio clínicos, a OMS não recomenda actualmente este medicamento para a profilaxia infantil. A administração da CDF iria expor inevitavelmente a criança à 3TC. • Para se usar uma CDF como a PPNm nas primeiras seis semanas de vida, um comprimido terá de ser dividido em quartos. Os comprimidos têm ranhuras que apenas os dividem em metades. Apesar destes desafios, existem CDF fáceis de usar e que têm sido propostas como meio de simplificar a administração na profilaxia de bebés de alto risco. Os benefícios e os riscos das diferentes opções de doses são apresentados no Anexo 5. 14 serviços às criançass expostas ao VIH. A integração numa plataforma materna, neonatal e infantil bem estabelecida, que tradicionalmente fornece serviços mais próximos dos utentes, facilita o seguimento do par mãe-filho e reduz o custo e o fardo tempo-visita para os utentes. Os sistemas de informação integrados que estabelecem uma ligação entre a informação sobre a mãe e o bebé melhoram o acompanhamento da utente e facilitam a continuação da prestação dos cuidados. Alguns exemplos são os registos de seguimento longitudinal e a análise de coortes, assim como a ligação com a informação sobre os serviços baseados na comunidade. Os programas deverão, no entanto, ter em consideração o fardo cada vez maior que impende sobre a plataforma da SMC no contexto dos recursos humanos existentes e dos desafios das mudanças nos serviços. O envolvimento da comunidade e os serviços baseados nas comunidades desempenham um importante papel no apoio aos cuidados prestados ás crianças expostas ao VIH. Estes serviços claros e altamente específicos do contexto desempenham um papel de “aceleração” no apoio aos serviços centrados nas unidades de saúde e incluem testes de VIH realizados nas comunidades. O envolvimento das redes de mulheres que vivem com o VIH tem-se revelado eficaz em vários países e tem sido usado para melhorar a literacia da comunidade sobre o VIH, com vista a gerar procura, constituir grupos de apoio ao nível das unidades de saúde e das comunidades, reforçar a ligação aos cuidados acompanhando as utentes recentemente diagnosticadas às clínicas de tratamento, localizar as desistentes e fazer o seguimento activo do par mãe-filho. Em vários cenários, estas intervenções conduziram a uma menor perda no seguimento dos pares mães-filhos. Assegurar a prestação de serviços de VIH num pacote pós- natal integrado e completo promove a prestação de um conjunto de intervenções que contribuem, não apenas para melhores resultados no âmbito do VIH, mas também para um melhor desenvolvimento geral na primeira infância. 3.3. Melhorar a prestação de serviços e implementar um pacote de cuidados pós-natais Há vários obstáculos que se colocam ao recurso a serviços eficazes para o VIH infantil, não existindo uma intervenção única que possa superar todos esses obstáculos que se colocam às mães e aos bebés em diferentes momentos e locais. Os factores socioeconómicos e tradicionais que mantêm as mães e os seus filhos juntos encontram-se entre as circunstâncias facilitadoras da melhoria da prestação de serviços. Os programas poderão beneficiar com a combinação de intervenções eficazes em “pacotes de cuidados” que apoiem a prestação de serviços e conquistem o envolvimento da comunidade para incrementar a adesão. As intervenções que comprovadamente melhoram a prestação e o recurso aos serviços de VIH infantil, assim como a retenção do par mãe-bebé incluem: • intervenções centradas na utente que prestem apoio a cada uma das utentes e usem mensagens de texto como lembretes, incentivos condicionais em dinheiro e o envolvimento do pai da criança; • intervenções centradas no sistema de saúde, incluindo medidas para aperfeiçoar os programas (tecnologias de teste nos PC, formação e apoio ao prestador de cuidados, melhores serviços de aconselhamento e apoio dos pares), para reforçar o sistema de saúde (iniciativas de melhoria da qualidade e integração dos serviços de saúde da mãe e da criança (SMC)/VIH) e para apoiar os serviços baseados na comunidade e os agentes de saúde. A prioridade deve ser dada à promoção da integração, para reduzir a fragmentação dos cuidados prestados às mães e aos bebés e garantir que estes continuam o ciclo de testes, até ao diagnóstico final. Sistemas de cuidados de qualidade e sistemas de cuidados para o bem-estar das crianças constituem oportunidades para melhorar a prestação de 15 Caixa 7: Principais questões da investigação Diagnóstico pediátrico • Avaliar o impacto de implementar uma amplitude indeterminada, particularmente em diferentes momentos dos testes, tipos de amostras e tecnologias. • Obter dados sobre o impacto, para determinar o valor acrescentado dos testes à nascença no âmbito dos programas de DPP. • Determinar o valor de fazer o teste à nascença apenas a bebés de alto risco. • Medir o impacto dos instrumentos de localização (i.e., códigos de barras), para garantir o acompanhamento eficaz e a repetição dos testes às 6 semanas nos bebés que tenham resultado negativo à nascença. • Determinar se existe valor acrescentado na integração dos testes à nascença com a vacina da BCG. • Determinar qual o melhor momento e frequência do teste da CV nas mulheres grávidas e lactantes. • Avaliar o impacto do tratamento materno e da profilaxia infantil no diagnóstico pediátrico. • Determinar e avaliar as abordagens mais eficazes para a retenção das crianças durante todo o ciclo do DPP até ao diagnóstico definitivo. Profilaxia e tratamento das crianças • Determinar o doseamento e a segurança dos novos ARV para efeitos de profilaxia ou tratamento de recém-nascidos e crianças pequenas. • Desenvolver formulações eficazes e garantir a administração rápida dos novos ARV recomendados para recém-nascidos e crianças pequenas. • Documentar as experiências dos países no domínio da PPNm. • Compreender a relevância clínica dos episódios virémicos maternos e a sua contribuição relativa para a taxa geral de transmissão. • Conduzir estudos destinados a explorar o benefício adicional da PPNm no contexto dos regimes de TAR materna eficazes e devidamente implementados. • Avaliar a adesão à PPNm e o modo de melhorar a retenção e o apoio às mães. • Determinar a viabilidade de usar a terapêutica tripla como profilaxia para os bebés cujas mães tenham sido identificadas como infectadas pelo VIH no período pós-parto Prestação de serviços e pacote de cuidados pós-natais • Considerar a combinação das intervenções em pacotes para apoiar a prestação de serviços. • Promover a integração para garantir que as crianças permaneçam no ciclo de testes até ao diagnóstico final. 4. RESUMO E PERSPECTIVAS Existem várias inovações prometedoras que estão a ser implementadas pelos países e parceiros. Embora as intervenções bem sucedidas estejam a ser melhoradas, continua a ser imperioso prestar atenção ao reforço dos sistemas existentes que sustentam os testes pediátricos e o início precoce do tratamento. Para além disso, as mudanças na dinâmica dos padrões de transmissão e tratamento agravam a complexidade e a interdependência dos testes, o que implica a necessidade crescente de adaptar as estratégias ao contexto das epidemias e políticas. Finalmente, são necessárias mais experiências programáticas motivadas pelas evidências para apoiar e informar as políticas nacionais, o planeamento e a implementação dos programas 16 AGRADECIMENTOS Participantes na reunião Adolfo Vubil (INS Moçambique), Ahmed Haeri Mazanderai (Universidade de Pretória), Andrea Ciaranello (Escola Médica de Harvard), Angela Mushavi (MS do Zimbabué),Anna Laura Ross (Unitaid), Archawin Rojanawiwat (Universidade de Chulalongkorn), Arne Kroidl (Universidade de Munique), Charles Kiyaga (MS do Uganda), David Sullivan (USAID), Debbie Boras (Escola de Higiene e Medicina Tropical de Londres), Deborah Persaud (Universidade Johns Hopkins), Elaine Abrams (ICAP), George Siberry (OGAC), Heather Alexander (CDC), Helen Dale (US CDC), Jean Maritz (Universidade de Stellenbosch), Jilian Sacks (CHAI), Landon Myer (Universidade do Cabo, Laura Broyles (CDC), Laura Onyengo (MS do Quénia), Laura Thuo (ICW Quénia), Lynne Mofenson (EGPAF), Marc Cotton (Universidade de Stellenbosch), Marie-Claude Bottineau (MSF), Nicholas Furtado (Fundo Mundial), Nobuhle Mthethwa (MS da Suazilândia), Philip Goulder (Universidade de Oxford), Roger Shapiro (Escola T.H. Chan de Saúde Pública, Botsuana), Sally Hargreaves (Colégio Imperial de Londres), Shaffiq Essajee (UNICEF), Smiljka de Lussigny (Unitaid), Timothy Cressey (Harvard T.H. Escola T. H. Chan de Saúde Pública, Tailândia), Trevor Peter (CHAI Botsuana). Funcionários da OMS Meg Doherty, Martina Penazzato, Lara Vojnov, Anisa Ghadrshenas, Serena Brusamento, Morkor Newman, Mercedes Perez, Fatim Jallow. 17 15. Mazanderani AH, Technau K-G, Hsiao N-Y, Maritz J, Carmona S, Sherman GG. Recommendations for the management of indeterminate HIV PCR results within South Africa’s early infant diagnosis programme. Southern African Journal of HIV Medicine. 2016;17(1):1-5. 16. Dunning L, Francke JA, Mallampati D, MacLean RL, Penazzato M, Hou T, et al. The value of confirmatory testing in early infant HIV diagnosis programmes in South Africa: A cost-effectiveness analysis. PLoS Medicine. 2017;14(11):e1002446. 17. WHO. WHO list of prequalified in vitro diagnostic products. Geneva: World Health Organisation; 2018 25 June. 18. WHO. Novel point-of-care tools for early infant diagnosis of HIV. Geneva: WHO; 2017. 19. Jani IV, Meggi B, Loquiha O, Tobaiwa O, Mudenyanga C, Zitha A, et al. Effect of point-of-care early infant diagnosis on antiretroviral therapy initiation and retention of patients. AIDS. 2018;32(11):1453-63. 20. Mwenda R, Fong Y, Magombo T, Saka E, Midian D, Mwase C, et al. Significant Patient Impact Observed Upon Implementation of Point-Of-Care Early Infant Diagnosis Technologies in an Observational Study in Malawi. Clinical Infectious Diseases. 27 Feb 2018. 21. WHO. Antiretroviral therapy for HIV infection in infants and children: towards universal access. Recommendations for a public health approach. Geneva: WHO; 2010. 22. Avy Violari; Man Chan; Kennedy Otwombe; Ravindre Panchia; Patrick J-PD, Gibb; Mark, Cotton; Abdel, Babiker;. Time to viral rebound after stopping ART in children treated from infancy in CHER. Abstract #137, CROI; March 4-7, 2018; Boston, Massachusetts. 23. Gill MM, Hoffman HJ, Mokone M, Tukei VJ, Nchephe M, Phalatse M, et al. Assessing Very Early Infant Diagnosis Turnaround Times: Findings from a Birth Testing Pilot in Lesotho. AIDS Research and Treatment. 2017: 2572594. 24. Urick B, Fong Y, Okiira C, Nabukeera-Barungi N, Nansera D, Ochola E, et al. Rapid Serological Tests Ineffectively Screen for HIV Exposure in HIV-Positive Infants. JAIDS. 2018;77(3):331-6. 25. Wagner AD, Njuguna IN, Andere RA, Cranmer LM, Okinyi HM, Benki-Nugent S, et al. Infant/child rapid serology tests fail to reliably assess HIV exposure among sick hospitalized infants. AIDS. 2017;31(11):F1-F7. 26. Beste S, Essajee S, Siberry G, Hannaford A, Dara J, Sugandhi N, et al. Optimal Antiretroviral Prophylaxis in Infants at High Risk of Acquiring HIV: A Systematic Review. Pediatr Infect Dis J. 2018;37(2):169-75. 27. WHO. Updates on HIV and infant feeding. Geneva: WHO; 2016. REFERÊNCIAS 1. UNAIDS. On the Fast-track to an AIDS-Free Generation. Geneva: UNAIDS; 2016. 2. UNAIDS. Global Plan towards the elimination of new HIV infections among children by 2015 and keeping their mothers alive. Geneva: UNAIDS; 2016. 3. UNAIDS. Start free Stay Free AIDS free: 2017 progress report. UNAIDS; 2017. 4. WHO. WHO Consolidated ARV Guidelines on the use of antiretroviral Geneva: WHO; 2013. 5. Townsend CL, Byrne L, Cortina-Borja M, Thorne C, de Ruiter A, Lyall H, et al. Earlier initiation of ART and further decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049-57. 6. Sherman GG, Mazanderani AH, Barron P, Bhardwaj S, Niit R, Okobi M, et al. Toward elimination of mother–to–child transmission of HIV in South Africa: how best to monitor early infant infections within the Prevention of Mother– to–Child Transmission Program. Journal of Global Health. 2017;7(1). 7. Penazzato M, Lule F, Essajee S. Paediatric HIV: the unfinished business. Lancet HIV. 2017;4(10):e425-e7. 8. UNAIDS. Ending AIDS: progress towards the 90-90-90 targets. Geneva: UNAIDS; 2017. 9. Newell M, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Ghent International AIDS Society (IAS) Working Group on HIV Infection in Women and Children. Mortality of infected and uninfected infants born to HIV-infected mothers in Africa: a pooled analysis. Lancet. 2004;364(9441):1236-43. 10. WHO. Consolidated ARV Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. 2nd ed. Geneva: WHO; 2016. 11. WHO. Innovating and strengthening the postnatal package of care for HIV-exposed infants: ensuring comprehensive services for the first two years of life. Johannesburg, South Africa, 20-23 June 2017 Meeting report. Geneva: WHO; 2017. 12. UNAIDS. AIDS info 2017. Geneva: UNAIDS; 2017. 13. Mazanderani AH, Moyo F, Kufa T, Sherman GG. Brief Report: Declining Baseline Viremia and Escalating Discordant HIV-1 Confirmatory Results Within South Africa’s Early Infant Diagnosis Program, 2010–2016. JAIDS. 2018;77(2):212-6. 14. Mazanderani AH, Moyo F, Kufa T, Maritz J, Sherman GG. Differentiating clearly positive from indeterminate results: A review of irreproducible HIV-1 PCR positive samples from South Africa’s Early Infant Diagnosis Program, 2010–2015. Diagnostic Microbiology and Infectious Disease. 2018;91:248-255. 18 Amostra n.º 1 para DPP Teste n.º 1 EID sample no. 1 test no. 2 NEGATIVO Gerir de acordo com as actuais orientações1 POSITIVO Gerir de acordo com as actuais orientações1 INDETERMINADO NEGATIVE Gerir de acordo com as actuais orientações1 POSITIVE Gerir de acordo com as actuais orientações1 INDETERMINADO2 Requisitar uma nova amostra dentro de 4 semanas3,4 Nova análise por uma equipa clínica e laboratorial4 ANEXOS Anexo 1: Gerir os resultados indeterminados dos testes: procedimentos operacionais padrão 1. Consultar as Orientações Consolidadas da OMS para os ARV de 2016. 2. Não notificar como positivo nem iniciar a TAR, mas manter a profilaxia segundo as actuais orientações. 3. A repetição de amostras deve receber prioridade nos laboratórios. 4. Resultados indeterminados repetidos em duas amostras separadas devem, juntamente com a informação clínica, ser revistos por uma equipa de laboratórios, pediatras clínicos, especialistas em casos complexos (se possível) e cuidadores. Os bebés devem ser activamente acompanhados para garantir o seu seguimento e retenção. 19 Anexo 2: Gerir resultados discordantes e interromper o tratamento Esta opção oferece cuidados de seguimento ao bebé durante o mínimo de 8 meses após a interrupção da TAR. Quando possível, tanto o teste de DPP (qualitativo) como o teste da CV (quantitativo) devem ser feitos às 4 semanas, 4 meses e 8 meses após a interrupção do tratamento. DPP e carga viral às 4 semanas, 4 meses e 8 meses após a interrupção Cenário a: A cessação da amamentação ocorre depois de concluído o seguimento, após a interrupção da TAR. Cenário b: Quando a cessação da amamentação ocorre antes de ter concluído o seguimento, após a interrupção da TAR. 8 meses NAT 1: + Iniciar TAR Iniciar a interrupção do tratamento NAT @ 4 semanas após interrupção NAT @ 4 meses após interrupção NAT @ 8 meses após interrupção NAT 1 NAT 2 NAT 2: - Continuar TAR NAT 3: - Para TARNAT 3 Cessação da amamentação TDR 3 meses após cessação da amamentação Iniciar interrupção do tratamento NAT @ 4 semanas após interrupção NAT @ 4 meses após interrupção NAT @ 8 meses após interrupção NAT 1 NAT 2 NAT 3 Cessação da amamentação 8 months NAT 1: + Iniciar TAR NAT 2: - Continuar a TAR NAT 3: - Para TAR É preciso continuar o seguimento considerando a exposição à amamentação e cumprir o calendário nacional de testes para crianças expostas ao VIH, de modo a garantir um diagnóstico final apropriado. Se a amamentação tiver cessado antes do final do seguimento intensivo, o estado final do VIH pode ser definido com o NAT realizado, pelo menos, 6 semanas após a cessação da amamentação. 20 Anexo 3: Algoritmo do DPP simplificado Recém-nascido exposto (0-2 dias) Considerar NATa,b Negativo Negativo Iniciar imediatamente a TARc Repetir o NAT para confirmar a infecção criança está infectada criança exposta ao VIH (4-6 semanas a 18 meses) Realizar NATb (às 4-6 semanas ou na primeira oportunidade seguinte) Positivo Positivo Iniciar imediatamente a TARc Repetir o NAT para confirmar a infecção Infecção pelo VIH não detectada, mas se a criança for amamentada, o risco de adquirir a infecção pelo VIH permanece até à completa cessação da amamentaçãod Monitorização clínica regular Realizar NATb (aos 9 meses) Teste de anticorpos aos 18 meses de idade ou 3 meses após a cessação da amamentação, consoante o que ocorrer mais tardef Bebé/criança está infectado VIH improvável, a não ser que ainda amamentadoe Negativo Os princípios-chave para estabelecer se os bebés e as crianças menores de 18 meses expostos ao VIH estão infectados nos países de baixos e médios rendimentos são os seguintes: • Avaliar o estado de exposição ao VIH através de um teste de anticorpos na mãe. • Realizar o teste NAT às crianças expostas ao VIH que se apresentem fora do algoritmo nacional de testes pediátricos com sintomas clínicos, independentemente dos resultados anteriores do NAT. • Aos 9 meses realizar o NAT nas crianças expostas ao VIH, quer sejam sintomáticos ou assintomáticos, e mesmo quando resultados anteriores do NAT tenham sido negativos. • Garantir que os testes com resultados indeterminados são imediatamente repetidos e têm prioridade para uma resolução rápida. • Garantir a realização dos testes de confirmação após um resultado positivo. • Garantir um seguimento regular de todos as crianças expostas ao VIH, até ao diagnóstico final, incluindo a administração de profilaxia com cotrimoxazole e avaliação clínica e nutricional. Notas: a. Com base nas Orientações Consolidadas da OMS sobre os ARV de 201610, pode considerar-se a adição do NAT à nascença ao algoritmo de teste existente. b. O NAT nos PC pode ser usado para diagnosticar a infecção pelo VIH, assim como para confirmar resultados positivos. c. Iniciar a TAR sem demora. Ao mesmo tempo, fazer novo teste para confirmar a infecção. À medida que o tratamento materno é reforçado e as taxas de transmissão vertical diminuem, é normal que os resultados falsos-positivos aumentem: por isso, é importante fazer novo teste após um primeiro NAT positivo, para evitar um tratamento desnecessário, particularmente em cenários com taxas de transmissão mais baixas. Se o segundo teste for negativo, deve realizar-se um terceiro NAT, antes da interrupção da TAR. d. Relativamente às crianças que nunca foram amamentadas, novo teste após um NAT negativo às 4–6 semanas está incluído neste algoritmo, para justificar os potenciais resultados falsos-negativos do NAT. e. O risco de transmissão do VIH permanece enquanto continuar a amamentação. Se o teste dos 9 meses for realizado antes dos 3 meses após a cessação da amamentação, poderá não ser detectada uma infecção adquirida nos últimos dias da amamentação. Para a avaliação final do estado de VIH, deve realizar-se novo teste aos 18 meses ou 3 meses após cessação da amamentação (consoante o que ocorrer mais tarde). f. Se a amamentação se prolongar para além dos 18 meses, o diagnóstico final do estado de VIH apenas poderá ser avaliado no final da amamentação. Se a amamentação terminar antes dos 18 meses, o diagnóstico final do estado de VIH com testes de anticorpos apenas poderá ser avaliado aos 18 meses. O teste de anticorpos deve ser realizado, pelo menos, 3 meses após a cessação da amamentação (para permitir o desenvolvimento de anticorpos do VIH). Para as crianças com menos de 18 meses de idade, deve realizar-se o NAT para confirmar a infecção. Se a criança tiver mais de 18 meses, o teste de anticorpos negativo confirma que a criança não está infectada; um teste da anticorpos positivo confirma que a criança está infectada. 21 Anexo 4: Algoritmo pra a avaliação do risco Este algoritmo foi desenvolvido para ajudar a avaliar o risco no momento do parto e ajudar a identificar os bebés de alto e baixo risco: Os bebés de risco baixo devem fazer profilaxia (NVP ou AZT isolados durante 4–6 semanas), enquanto os de risco alto devem fazer PPNm. Para utilizarem este algoritmo com êxito, os clínicos terão de conhecer alguns parâmetros da ficha pré-natal da mãe: • Estado de VIH e data do último teste de VIH (para identificar o estado e a necessidade de fazer um teste ou repetir o teste no parto); • Se o estado for positivo e tiver iniciado a TAR, data do início da TAR; • Se tiver sido determinada a CV, data de colheita da amostra relativa ao parto e resultado da CV. Os programas devem considerar a incorporação de um teste de CV aproximadamente às 36 semanas de gestação, garantindo que o tempo de entrega dos resultados é suficientemente curto para que o resultado esteja disponível na data prevista para o parto. Mãe identificada como VIH+ nas 72 horas seguintes ao parto NÃO Mãe positiva para VIH não em TAR Mãe positiva para VIH em TAR RISCO ALTO RISCO ALTO RISCO ALTO RISCO ALTORISCO BAIXO LOW RISK NÃOSIM A mãe fez TAR durante > 4 semanas antes do parto? SIM: CV > 1,000 SIM: CV > 1,000 Avaliar a mãe NO PARTO Existe um resultado da CV obtido < 4 semanas antes do parto? 22 Anexo 5: Opções de doseamento e formulação para a profilaxia infantil Dosagem Dose 0-6 semanas de AZT mais NVP Dose 6-12 semanas de AZT mais NVP Dose 6-12 semanas só de NVP Observações Xaropes AZT 10mg/ml NVP 10mg/ml AZT dose 1.5ml (15mg) duas vezes/dia Dose de AZT 6ml (60mg) duas vezes/dia Dose de NVP 2ml (20mg) uma vez/dia - Dose exacta de todos os medicamentos (inclusive, para recém-nascidos com baixo peso à nascença) e um tipo de formulação para todo o período de 12 semanas - Dispendioso comprar e transportar xaropes - Difícil de esconder em casa - A disponibilidade de fornecedores pode ser limitada - Pode ser aceitável quando a maioria das mulheres em idade fértil estão devidamente controladas pela TAR e o número de bebés de alto risco é baixo, mas não será a melhor opção para um programa que escolha tratar todos os bebés como sendo de alto risco Dose de NVP 1.5ml (15mg) uma vez/dia Dose de NVP 2ml (20mg) uma vez/dia Xaropes e comprimidos de medicamento único AZT 60mg NVP 50mg Dose de AZT 1.5ml (15mg) duas vezes/dia Dose de AZT 1 comp (60mg) duas vezes/dia Dose de NVP ½ comp (25mg) uma vez/dia - Combina o rigor da dose de xarope nas primeiras 6 semanas e a facilidade dos comprimidos das 6 às 12 semanas - Desafios dos xaropes acima mencionados - ½ comp de NVP representa uma ligeira sobredose de NVP (25mg vs 20mg) Dose de NVP 1.5ml (15mg) uma vez/dia Dose de NVP ½ comp (25mg) uma vez/dia CDF ¼ comp (15mg AZT, 7.5mg 3TC, 12.5mg NVP) duas vezes/dia Inadequado Não aplicável - Difícil dividir rigorosamente em quartos uma CDF: os cuidadores devem usar o primeiro quarto de manhã e o segundo quarto à noite, para manter a dose diária correcta - 3TC não é parte do regime profiláctico recomendado - Não se pode usar a CDF durante as semanas 6 a 12 sem dar 5 vezes mais do que a dose diária recomendada de NVP CDF e comprimidos de medicamento único ¼ comp (15mg AZT, 7.5mg 3TC, 12.5mg NVP) duas ve-zes/dia Dose de AZT 1comp (60mg) duas vezes/dia NVP: ½ comp 50mg uma vez/dia - Combina a facilidade da CDF com um comprimido de medicamento único para a segunda - Desafios da CDF acima mencionadosDose de NVP ½ comp (25mg) uma vez/dia Observações: • De notar que, ao contrário da NVP, não existe uma dose profiláctica específica para a AZT. A dose recomendada é a mesma que a usada no tratamento - 15 mg duas vezes/dia para bebés bem formados nas primeiras seis semanas de vida, aumentando para 60 mg duas vezes por dia, da semana 6 à semana 12. • Quando é administrado o tratamento inicial, devem usar-se regimes e doses apropriadas, como se ilustra nas actuais orientações de tratamento da OMS10. 23 24 Para mais informações, contactar: World Health Organization Department of HIV/AIDS 20, avenue Appia 1211 Geneva 27 Switzerland WHO/CDS/HIV/18.17 E-mail: hiv-aids@who.int www.who.int/hiv