Comprehensive package of care for infants and young children exposed to HIV: policy brief

POLICY BRIEF COMPREHENSIVE PACKAGE OF CARE FOR INFANTS AND YOUNG CHILDREN EXPOSED TO HIV 2021 © UNICEF UNI221734 / Gonzalez Farran POLICY BRIEF COMPREHENSIVE PACKAGE OF CARE FOR INFANTS AND YOUNG CHILDREN EXPOSED TO HIV 2021 Comprehensive package of care for infants and young children exposed to HIV: policy brief ISBN 978-92-4-004023-6 (electronic version) ISBN 978-92-4-004024-3 (print version) © World Health Organization 2021 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. 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Layout by ACW. 13TC lamivudine ART antiretroviral therapy ARV antiretroviral AZT zidovudine CTX Co-trimoxazole LPV/r lopinavir/ritonavir NAT Nucleic acid testing NNRTI non-nucleoside reverse-transcriptase inhibitor NVP nevirapine PNP postnatal prophylaxis RAL raltegravir UNICEF United Nations Children’s Fund ABBREVIATIONS This policy brief was developed by Ivy Kasirye (Consultant, WHO) and Catherine Wedderburn (Consultant, WHO), with technical oversight by Martina Penazzato and Morkor Newman Owiredu of the Department of Global HIV, Hepatitis and Sexually Transmitted Infections Programmes of WHO, in collaboration with UNICEF, Elizabeth Glaser Pediatric AIDS Foundation and ICAP at Columbia University. WHO gratefully acknowledges the technical input of the external peer reviewers: Elaine Abrams and Nandita Sugandhi (ICAP at Columbia University, USA), George Alemji, Chelsea Solmo, Michelle Zavila, Michelle Chevalier, Hilary Wolf (United States Centers for Disease Control and Prevention and United States President’s Emergency Plan for AIDS Relief), Cathrien Alons and Judith Kose (Elizabeth Glaser Pediatric AIDS Foundation), Geoffrey Chipungu, Shaffiq Essajee and Laurie Gulaid (UNICEF), Stuart Keane (Consultant), Andy Prendergast (Queen Mary University of London, United Kingdom of Great Britain and Northern Ireland), Amy Slogrove (Stellenbosch University, South Africa). ACKNOWLEDGEMENTS 2Despite global progress to eliminate the vertical transmission of HIV, the targets for maternal antiretroviral therapy (ART) coverage and new vertical transmission have yet to be achieved (1). Globally, an estimated 85% of pregnant women living with HIV were receiving lifelong ART, and 150 000 infants acquired HIV through vertical transmission in 2020. Although more than 84% of vertical tranmissions occur in sub-Saharan Africa, it is encouraging that eastern and southern Africa (the epicentre of the HIV pandemic) has sustained maternal antiretroviral (ARV) coverage rates of ≥90% since 2014 (1). Nevertheless, persisting challenges remain in preventing infants and young children from acquiring HIV during pregnancy and the breastfeeding period. Viral suppression among mothers living with HIV, achieved with optimized ART and adherence, is critical for preventing the vertical transmission of HIV. ARV drug prophylaxis provided to infants exposed to HIV further reduces the risk of acquiring HIV. About half of all vertical transmission occurs during breastfeeding (2). Vertical transmission occurring postnatally primarily results from maternal seroconversion during breastfeeding and breastfeeding mothers not initiating or retained on ART. Nevertheless, considering the significant health benefits of breastfeeding in the context of HIV in preventing infant morbidity and mortality and the reduced risk of HIV transmission if mothers are receiving ART and have suppressed viral loads, WHO recommends that mothers living with HIV who are receiving ART and have suppressed viral loads may breastfeed their infants for up to two years, with the infants being exclusively breastfed in the initial six months to prevent vertical transmission in the postpartum period and optimize infant survival (2). Evidence suggests that even among infants who are not HIV-infected, HIV exposure results in greater morbidity and mortality than in unexposed infants. These effects on morbidity and mortality extend well beyond the period of HIV exposure and include low birth weight, prematurity, growth impairment and neurodevelopmental delays, increased risk of mortality, increased morbidity (congenital and acquired infections including TB, herpes simplex virus, syphylis, hepatitis B, cytomegalovirus and severe forms of infectious morbidity such as diarrhoeal disease, bacterial sepsis and pneumonia), potential for haematologic abnormalities as well as social and environmental factors (orphanhood, stigma, discrimination, household poverty, family illness and disruptions) (3–12). Following up infants and young children exposed to HIV throughout and beyond the exposure period is therefore critical to minimize the risk of HIV transmission and to intensify efforts to improve child survival, promote child growth and development in order to obtain holistic health and well-being outcomes. Justification for the comprehensive package of care for infants and young children exposed to HIV A systematic review revealed that 49% of women living with HIV in sub-Saharan Africa are lost between antenatal care registration and delivery, 34% of infants exposed to HIV are lost to follow-up by three months and a further 45% of infants exposed to HIV are lost after their first HIV test and before definitive diagnosis (13). This highlights significant attrition along the continuum between identifying HIV among pregnant women, initiating treatment to prevent vertical transmission and improve maternal health, initiating prophylaxis among infants and testing infants early for HIV. Several factors are associated with poor postnatal continuity of care, including fragmentation of services. During the first two years of life, infants are expected to access routine well- child services. In addition to these services, infants and young children exposed to HIV also need to access HIV preventive or treatment services. Furthermore, their mothers need to access services for their own health, including postnatal care, family planning and ART. These encounters often entail multiple clinic visits, multiple service delivery points, multiple service providers, service delivery on specific days and referral within or outside the facility, which serve as barriers to care and a full range of services for mothers and their infants (14). Integrating child health and HIV services has the potential to improve health outcomes by addressing multiple family health-care needs simultaneously and reducing missed opportunities to reach infants and children with all the health services they require (15). Integration is also associated with improved access to care, efficiency and cost-effectiveness of service delivery and patient BACKGROUND 3satisfaction (16). Integrating HIV testing services into child health platforms has been shown to: increase the identification of infants and children living with HIV; increase the uptake of postnatal services; improve TB treatment completion rates when integrated into TB programmes; and result in either increased or unchanged immunization uptake rates (17–21). Reproductive, maternal, newborn, child and adolescent health platforms and settings with high diagnostic yield for children living with HIV at primary care facilities including inpatient wards and nutrition centres (22) may also be strategic platforms for integrated service delivery for infants and children exposed to HIV. The purpose of this brief is to provide an integrated approach that combines effective interventions along the continuum of care in a harmonized package that simplifies implementation in decentralized settings, minimizes missed opportunities, eases navigation by mothers and their children and increases access to services aimed at HIV-free survival and optimal development for infants and young children exposed to HIV. Overview of the interventions along the continuum of care Children younger than two years typically receive well- child visits for routine services, including immunization, monitoring growth and development, micronutrient supplementation, deworming, preventing and managing common childhood conditions as well as infant feeding counselling and support. In addition to these routine services, infants and young children exposed to HIV should receive specific services in a comprehensive package as outlined below. Components of the comprehensive package of care for infants and young children exposed to HIV The comprehensive package of care brings together interventions across the continuum of care that collectively aim to reduce the risk of vertical transmission of HIV and improve the health and well-being of infants and young children exposed to HIV. The package includes both maternal and infant components (Fig. 1): • maternal HIV testing and retesting: other prevention interventions for HIV-negative mothers are highly relevant (2): • maternal ART, adherence counselling and monitoring; • infant diagnosis; • infant ARV prophylaxis; • co-trimoxazole prophylaxis; • postnatal care and infant feeding in the context of HIV; and • promoting nurturing care. Scope Although the comprehensive package of care includes maternal, infant and young child interventions, this policy brief focuses mainly on the service package for infants and young children up to two years of age who are exposed to HIV. It emphasizes the maternal interventions that directly affect decision-making for interventions for the infants and young children exposed to HIV. For the detailed interventions for preventing vertical transmission, including combination HIV prevention for pregnant and breastfeeding women at risk of acquiring HIV, see the 2021 WHO consolidated guidelines (2). Since some children younger than two years both within the vertical transmission cascade and among those who have not had access to services to prevent vertical transmission may acquire HIV, the recommendations and service considerations in relation to the comprehensive package that remain relevant to infants and young children living with HIV will also be highlighted to demonstrate the continuity of care. This policy, however, will not articulate a comprehensive service package for infants and children living with HIV. 4Fig. 1. Components of the comprehensive package of care for infants and young children exposed to HIV Infant diagnosis Timely identification of infants living with HIV by testing multiple times and ensuring infant diagnosis Postnatal care Routine postnatal care, including immunization, growth and development monitoring, infant feeding counselling and support Maternal testing, treatment and monitoring Identifying mothers through antenatal care and maternal, newborn and child health services, ensuring that they start ART and remain virally suppressed Postnatal prophylaxis Timely provision of ARV drugs to prevent HIV acquisition for all infants exposed, with particular attention to those at high risk Co-trimoxazole Timely provision of co-trimoxazole to prevent Pneumocystis jirovecii pneumonia and mortality among infants and children living with HIV Nurturing care Implementing simple interventions to promote early childhood development at the facility and in the community Box 1. Infants and young children living with HIV If an infant or young child is confirmed to be living with HIV during the period of follow- up, the early infant diagnosis cascade will have reached a final endpoint. If the infant is still on ARV drug prophylaxis, this should be stopped, and ART initiated with the recommended triple ARV drug first-line ART regimen (Fig. 3). WHO recommends early or same-day initiation of ART with an age-appropriate ART regimen once the HIV diagnosis is made and while awaiting confirmation. Co-trimoxazole prophylaxis and nurturing care interventions should be continued based on the recommendations discussed in Sections 4 and 5. Further guidance on WHO recommendations for ART for infants and children living with HIV is available (2). The initiation and duration of the components occur at different times during the period of risk. The scheduling of several interventions coincides or is near the times for childhood immunization, although this may vary depending on national immunization schedules (Fig. 2). © UNICEF UN0422241 Dejongh 5Fig. 2. Package of care service tim es R esponsive caregiving, prom ote early learning, integrated caregiving and nutrition interventions, support m aternal m ental hea lth E xtended postnatal prophylaxis if risk rem ains high: breastfeeding w ith m aternal viraem ia Infants and young children exposed to HIV Mother living with HIV Viral load tests IDPNP CTXNC S M ay start at 4 – 6 w eeks N HIV-negative and high-risk mother HIV tests H igh -risk infant Low -risk infant C onduct viral load tests three m onths after initiating A R T if the m other started A R T during pregnancy B irth 12 w eeks N N 34–36 w eeks gestation 6 w eeks 6 m onths 9 m onths 15 m onths 18 m onths 21 m onths 24 m onths 14 w eeks Routine C ountry -specific routine and booster im m unizations, vitam in A supplem entation, dew orm ing, grow th and developm ental m onitoring H IV infection excluded w ith appropriate test 3 m onths after stopping breastfeeding C o -trim oxazole and extended P N P m ay be stopped any tim e after H IV infection is excluded w ith an age - appropriate test at the end of at-risk period (w hich m ay occur before 18 m onths) Low -risk settings: discontinue once H IV infection is ruled out R etest m others w ith ongoing risks, key populations or m others w ith H IV -positive partners w ith unsuppressed viral load at 14 w eeks or six or nine m onths postpartum H igh-risk settings: discontinue co-trim oxazole w hen the at-risk period ends and once H IV infection is ruled out ID : Infant diagnosis; C TX: C o-trim oxazole; PN P: postnatal prophylaxis; N C : N urturing care; N : N ucleic acid test; S: Serology test 6Fi g. 3. M od ifi ca tio ns to th e co m po ne nt s o f t he c om pr eh en siv e pa ck ag e of c ar e af te r c hi ld re n ac qu ire H IV In te gr at ed c ar eg iv in g an d nu tr iti on in te rv en tio ns S up po rt m at er na l m en ta l h ea lth R es po ns iv e ca re gi vi ng , P ro m ot e ea rly le ar ni ng In te gr at ed c ar eg iv in g an d nu tr iti on in te rv en tio ns S up po rt m at er na l m en ta l h ea lth PNPID NCCTX HIV-POSITIVE DIAGNOSIS 5 years of age ART A ll in fa nt s an d ch ild re n re ga rd le ss of c lin ic al o r im m un e co nd iti on s A ll ch ild re n in s et tin gs w ith a h ig h pr ev al en ce of m al ar ia a nd s ev er e ba ct er ia l i nf ec tio ns 8 ye ar s of a ge 3 ye ar s of a ge R ea ss es sm en t in a du lth oo d Li fe lo ng Routine 2 ye ar s of a ge M ay b e di sc on tin ue d if on A R T, s ta bl e an d v ira l l oa d su pp re ss io n in lo w -p re va le nc e m al ar ia an d se ve re b ac te ria l i nf ec tio n se tti ng s ID : I nf an t d iag no sis ; C TX : C o- tri m ox az ol e; P N P: p os tn at al pr op hy lax is; N C : N ur tu rin g ca re ; N : N uc lei c ac id te st ; S : S er ol og y t es t 7Maternal viraemia during pregnancy and the breastfeeding period significantly increases the risk of vertical HIV transmission (23,24). Evidence shows that perinatal HIV-1 transmission is virtually zero in mothers who start ART before conception, maintain viral load suppression through pregnancy and have viral load <50 copies/mL at delivery (25). Preventing the vertical transmission of HIV during pregnancy and breastfeeding therefore depends on timely identification of HIV infection and achieving and sustaining maternal viral suppression with ART before conception and throughout the period of risk. Most infants who acquire HIV do so because their mothers were not diagnosed as living with HIV, did not receive ART during pregnancy or breastfeeding, faced ART adherence challenges or discontinued ART or acquired HIV during pregnancy or breastfeeding (Fig. 4). Only an estimated 80% of women are retained on ART at the time of delivery, whether ART was initiated before or during pregnancy (1). Programmes aimed at eliminating vertical transmission should concentrate efforts towards: • preventing primary HIV infection among women of reproductive age; • diagnosing maternal HIV infection before or early during pregnancy; • achieving early initiation of optimal ART regimens before conception or during pregnancy and breastfeeding for mothers living with HIV; • testing during pregnancy and breastfeeding for the timely detection of incident HIV infection; • monitoring maternal viral load during the pregnancy and breastfeeding period; and • implementing interventions that promote adherence to ART, continuity of care and proper care and management of infants and young children exposed to HIV. 1. MATERNAL HIV TESTING, TREATMENT AND MONITORING Fig. 4. Infants acquiring HIV vertically by cause of transmission, global, 2020 Source: UNAIDS epidemiological estimates, 2021 (1). Mother acquired HIV during pregnancy of breastfeeding Mother did not receive antiretroviral therapy during pregnancy or breastfeeding Mother did not continue with treatment during pregnancy or breastfeeding Mother was on antiretroviral therapy but not virally suppressed 160 000 140 000 120 000 100 000 80 000 60 000 40 000 20 000 0 14 000 38 000 65 000 35 000 2020 81.1 Maternal HIV testing and retesting Preventing unplanned pregnancy and HIV acquisition, confirming HIV status before pregnancy, early identification of HIV infection during pregnancy and breastfeeding and timely initiation of ART are critical for minimizing vertical HIV transmission. All pregnant women should be offered HIV testing at the earliest opportunity during pregnancy and, if HIV positive, same- day initiation of ART. HIV re-testing and partner testing are important for women who initially test HIV negative, since seroconversion during pregnancy and breastfeeding is increasingly becoming an important source of HIV exposure for infants. Women should be retested for HIV during pregnancy and breastfeeding to identify previously HIV-negative mothers who seroconvert during the period of HIV transmission risk to initiate ART as early as possible. Women who test negative for HIV but continue to be at high risk of acquiring HIV should be linked to prevention interventions, including pre-exposure prophylaxis. HIV retesting during the third trimester is recommended for all women with unknown or HIV-negative status in settings with a high burden of HIV infection; in low-burden settings, retesting should be based on risk, emphasizing the need for ongoing risk screening (Box 2). An additional retest at 14 weeks, six months or nine months postpartum may be considered for HIV-negative women at elevated risk of acquiring HIV in settings with a high or low burden of HIV infection. The suggested times for postpartum retesting consider the opportunity provided when the mother has contact with the health system, especially when the child is brought in for immunization (2). Box 2. Suggested optimal retesting frequency for pregnant and breastfeeding women Settings with a high burden of HIV infection Retest all pregnant women with unknown or HIV-negative status in late pregnancy, at the third-trimester visit. If either the first test or retest is missed or delayed, catch-up testing is needed. An additional postpartum retest for women of unknown or HIV-negative status can be considered. Countries could consider an additional postpartum test in specific districts or provinces with a high burden or incidence of HIV and among women from a key population or who have partners with HIV who do not have suppressed viral loads. Settings with a low burden of HIV infection Retest pregnant women with unknown or HIV-negative status who are in serodiscordant relationships, whose partner does not have suppressed viral loads on ART or who have other known ongoing HIV risk in late pregnancy – at a third-trimester visit. If either the first test or retest is missed or delayed, catch-up testing is needed. An additional postpartum retest for women of unknown or HIV-negative status can be considered for women from key populations or women who have partners with HIV who do not have suppressed viral loads. Countries could also consider an additional postpartum test in specific districts or provinces. Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). 9Implementation considerations Strategies to improve early identification of maternal HIV infection should include activities that promote early initiation of antenatal services, attending all recommended antenatal visits and promoting facility deliveries. Health system interventions to improve the utilization and quality of antenatal care include: • woman-held case notes to improve the continuity and quality of care and pregnancy experience; • midwife-led continuity-of-care models that support women throughout the antenatal to postnatal continuum; • group antenatal care; • community-based interventions to improve communication and support; • task shifting components of antenatal care delivery, including promoting health-related behaviour for maternal and newborn health and distributing recommended nutritional supplements and intermittent preventive treatment in pregnancy for preventing malaria; and • recruiting and retaining personnel in rural and remote areas (26). Other interventions include behavioural interventions (birth planning, reminders and incentives) (27) and interventions that increase facility delivery, including maternity waiting homes, demand-side financing schemes, education programmes and participatory women’s groups (28). National programmes should heighten efforts to fully integrate services for preventing vertical transmission and optimize facility-based HIV testing at antenatal clinics at all levels in public and private facilities, especially in settings with a high burden of HIV infection. HIV testing services for pregnant and breastfeeding women should be incorporated into other service delivery approaches that provide antenatal services or linkage to antenatal care enrolment, including community outreaches and targeted community interventions for adolescent mothers and key populations. Programmes, especially in low-risk settings, should consider risk assessment tailored to the specific context for targeted HIV retesting of pregnant and breastfeeding women with ongoing risk for acquiring HIV. Targeted retesting in these settings may also be implemented for specific populations and geographical regions with known high HIV prevalence (Table 1). If either the first test or retest is missed or delayed, catch-up testing should be provided. In South Africa, universal retesting in the postpartum period has been adopted because of the high HIV prevalence. Countries with high HIV prevalence may consider routine repeat testing for all women during the postnatal period, especially if risk-based testing is not feasible. Selecting the right time points for postpartum retesting should be based on local context. Table 1. Recommended times for HIV retesting for pregnant and postpartum women Source: WHO consolidated guidelines on HIV testing services, 2019 (29). Further guidance on HIV testing during pregnancy and postpartum is available (2). Time points Setting Early in pregnancy (first antenatal care visit) Late in pregnancy (third-trimester antenatal care visit) One additional postpartum retest (14 weeks, 6 months or 9 months postpartum) Settings with a high HIV burden All All Can be considered for those with ongoing high risk Settings with a low HIV burden All pregnant women as part of eliminating vertical transmission, otherwise focused on those with high ongoing risk Can be considered for those with high ongoing risk Can be considered for those with high ongoing risk Among key population groups and their partners All settings All settings All settings 10 1.2 Viral load monitoring Viral load monitoring during pregnancy and the breastfeeding period is recommended to identify women who already have suppressed viral loads and to offer timely intervention to achieve viral suppression in women who are viraemic during the period of HIV transmission risk. The 2021 WHO consolidated guidelines (2) recommend routine viral load monitoring at six and 12 months after initiating ART and every 12 months thereafter for all people living with HIV (Annex 1). In addition to the routine viral load monitoring tests recommended for nonpregnant adults, additional viral load assessments during pregnancy and the breastfeeding period are advisable to determine whether viral suppression is sustained or to detect viraemia during the high-risk period for vertical transmission of HIV. An unsuppressed viral load while receiving ART may be the result of poor adherence to treatment or underlying HIV drug resistance. If a mother receiving an NNRTI- based regimen has an unsuppressed viral load, the ART regimen should be switched immediately. Otherwise, for non-NNRTI-based regimens, interventions to support adherence to ART (enhanced adherence counselling and peer support) should precede treatment modifications. Viraemia that persists after enhanced adherence counselling despite improved adherence warrants adjusting the ART regimen. Table 2 summarizes the additional viral load testing points and the early infant diagnosis recommendations for maternal viraemia. Table 2. Monitoring treatment for pregnant and breastfeeding women Category Timing of viral load monitoring Action Pregnant women receiving ART before conception First antenatal care visit (or when first presenting) • If viral load >1000 copies/mL, follow the treatment monitoring algorithm (Fig.5) and consider infant nucleic acid testing at birth if available Pregnant women starting ART during pregnancy Three months after initiating ART • If viral load >1000 copies/mL, follow the treatment monitoring algorithm (Fig. 5) • Regardless of maternal viral load, infants born to women starting ART at any time during pregnancy could be considered for birth testing if available All pregnant women, regardless of ART initiation timing 34–36 weeks of gestation (or at the latest at delivery) • If viral load >1000 copies/mL, follow the treatment monitoring algorithm (Fig. 5) and provide enhanced postnatal prophylaxis for the infant All breastfeeding women, regardless of when ART was initiated Three months after delivery and every six months thereafter • If viral load >1000 copies/mL, follow the treatment monitoring algorithm (Fig.5), conduct infant HIV testing immediately and consider reinitiating enhanced postnatal prophylaxis for the infant Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). 11 Point-of-care viral load testing Evidence suggests that point-of-care viral load testing has the capacity to improve access to viral load testing, reduce turnaround time for results to the clinician, increase the probability of same-day results, improve the timeliness of clinical action to address elevated viral load and increase continuity of treatment and viral suppression (30–32). Point-of-care testing should be considered especially for pregnant and breastfeeding mothers for whom rapid test results are critical for decision-making. Integrating point-of-care viral load technologies to complement laboratory capacity in the health system to address access and turnaround time for results should be considered. Point-of-care viral load technologies are often already available at reproductive, maternal, newborn, child and adolescent platforms that have early infant diagnosis infrastructure in place. Where they are not available and depending on the availability of resources, a phased introduction and scale-up of point-of-care viral load technologies with strategic placement within the laboratory system network may be preferred. Setting priorities for the placement may be based on contextual factors, including demand, client concentration, geographical location, coverage of laboratory services and integration with other diagnostic needs. Low- and middle- inclome countries may consider implementing a Diagnostics Network Optimization (DNO) exercise, which aligns testing demand and capacity in the most cost-effective way by defining the optimal instrument combination, identifying the most appropriate locations where instruments should be placed and designing referral network linkages across the revised network (for example hub vs spokes). In addition, programmes should ensure that point-of-care viral load placement favours accessibility on maternal, newborn and child health platforms at all levels and that systems for transporting samples and returning results are streamlined and optimized. Scale-up will also require training, mentorship and support supervision of appropriate human resources (including for executing tests and accurately interpreting point-of-care viral load results), quality assurance and having supply chain and maintenance systems in place. Further guidance on monitoring treatment among pregnant and breastfeeding mothers is available (17). Implementation considerations Viral load testing capacity and coverage should be expanded by scaling up laboratory viral load testing infrastructure; strengthening the efficiency of sample processing and transport systems; supporting community viral load sample collection and testing using dried blood spot or plasma separation card and establishing networks for point-of-care viral load testing to improve access on the maternal; newborn and child health platform and enable monitoring of pregnant and breastfeeding women receiving ART. It will also be important to establish and disseminate clear protocols for viral load testing and to strengthen data collection and laboratory information systems to accurately and reliably capture viral load data. In settings with highly performing viral load testing systems and high coverage, viral load testing at delivery may be done as this is a clearly defined time point and may help identify the appropriate postnatal prophylaxis intervention. Box 3. WHO recommendations on point-of- care viral load testing The WHO 2021 consolidated guidelines (2) recommend same-day point-of-care viral load testing to monitor treatment among pregnant and breastfeeding women to expedite result return and clinical decision-making. If this is not available, viral load specimens and results for pregnant and breastfeeding women should be given priority across the laboratory referral process. © UNICEF UN0481130 Satu 12 Mortality in the first year of life among untreated infants living with HIV is very high. The mortality of untreated, perinatally infected children peaks at two to three months of age, with about 35% dying by 12 months of age and 52% by 24 months of age (33–35). An estimated 40% of children living with HIV remain undiagnosed (1). Early HIV testing, prompt return of results and rapid initiation of treatment are essential to decrease risk of morbidity and mortality (9,36). Since maternal HIV antibody may persist among children up to 18 months of age, HIV infection among children younger than 18 months can only be definitively confirmed with virological testing using nucleic acid testing technologies (37,38), and serological assays can be used to definitively diagnose children older than 18 months. WHO recommends multiple nucleic acid testing, including at birth (in settings with high-functioning six- week early infant diagnosis programmes and high continuity of care for infants at six weeks), 4–6 weeks, nine months, at any time infants exposed to HIV present sick, as soon as infants are newly identified as exposed during breastfeeding, followed by serology testing at 18 months (Annex 3). For breastfeeding infants, HIV is definitively excluded three months after breastfeeding ends. Early infant diagnosis for high-risk infants Nucleic acid testing at birth may be considered for high- risk infants. In addition, infants who are first identified as HIV-exposed postpartum have a high cumulative risk of already having acquired HIV by the time prophylaxis is initiated. Under these circumstances, HIV nucleic acid testing should be performed and presumptive treatment started to avoid extended prophylaxis among infants who are already HIV infected (see infant ARV prophylaxis). Point-of-care infant diagnosis Access to early infant diagnosis remains low, with only 60% of infants exposed to HIV globally tested by the second month of age in 2020 (39). Even when infants are tested, delays in receiving test results and weak linkage to ART contribute to attrition along the testing- to-treatment cascade. Evidence suggests that point-of- care nucleic acid testing enables more rapid testing with return of results to caregivers and clinicians; increased continuity in the testing-to-treatment cascade; fewer health facility visits for caregivers to receive results; more reliability in the timing of results and possibly more likelihood for test documentation; increased access to ART with more rapid initiation; and improved quality of services (40). The overall global proportion of infants living with HIV initiating treatment within 60 days was 90% when tested at the point of care versus 54% when tested using the standard of care (41). Point-of-care infant diagnosis has also been shown to be cost-effective compared with laboratory-based testing (42). Updated evidence also suggests that point-of-care infant testing can be used to conduct confirmatory tests. Implementation considerations Improving continuity along the infant diagnosis cascade to final diagnosis requires several interventions, including concerted efforts to optimize existing early infant testing systems and to scale up access to both laboratory nucleic acid testing and point-of-care nucleic acid testing technologies. Same-day linkage between infant diagnosis and ART initiation will be critical. In addition, programmes may need to consider aligning infant diagnosis within various service delivery models and contexts, including community-based service delivery and differentiated service delivery modalities, to promote continuity along the testing-to-final diagnosis cascade. Efforts should be made to ensure that guidelines to follow up HIV-exposed infants during the exposure period are consistently implemented, including actively tracking mother–baby pairs using a digital register of positive results. 2. INFANT DIAGNOSIS Box 4. WHO recommendation on point-of- care infant diagnosis Point-of-care nucleic acid testing should be used to diagnose HIV among infants and children younger than 18 months of age (strong recommendation; high-certainty evidence). Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). 13 Point-of-care infant diagnosis technologies should be integrated within the existing infant diagnosis networks, with introduction and scale-up tailored to the available resources and local contexts and with the aim of achieving equitable access and broader coverage. Programmes may consider specific factors, such as demand, client volume and concentration, infant diagnosis coverage, geographical location and integration with other diagnostics in setting priorities for strategic positioning of point-of-care infant diagnosis and subsequent expansion. Alongside scaling up point- of-care infant diagnosis, laboratory nucleic acid testing networks should be strengthened, especially systems for sample collection and transport, efficiency of sample processing, communication and returning results. Scale- up will also require training, mentorship and support supervision of appropriate human resources (including accurately executing the tests and interpreting the point-of-care infant diagnosis results), quality assurance and having supply chain and maintenance systems adequately in place. Further guidance on infant diagnosis is available in the WHO Consolidated Guidelines (2). Other resources include: Key considerations for introducing new HIV point-of-care diagnostic technologies (http:// childrenandaids.org/node/995) and the POC Toolkit (http://childrenandaids.org/poc-toolkit-page). © UNICEF UN0536256 Wenga 14 Infant ARV prophylaxis is provided as an adjunct to maternal ART to reduce the risk of vertical transmission of HIV. The period of exposure extends until breastfeeding completely ends. WHO infant feeding guidelines recommend that mothers who are living with HIV, receiving ART and have suppressed viral loads can breastfeed their infants up to two years of age, with exclusive breastfeeding in the first six months (43). 3. INFANT ANTIRETROVIRAL PROPHYLAXIS Box 5. WHO good practice statement ART should be initiated before pregnancy and urgently among all pregnant and breastfeeding women living with HIV, even if they are identified late in pregnancy or postpartum, because the most effective way to reduce the risk of HIV vertical transmission is to suppress maternal viral load. Whenever possible, all efforts should be made to identify HIV-infected pregnant women early enough to avoid the need for enhanced prophylaxis. Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). Risk assessment of infants exposed to HIV Risk assessment is based on prevailing maternal factors that affect the probability of HIV vertical transmission and is essential for selecting appropriate preventive interventions for infants exposed to HIV. Infants exposed to HIV are considered to have low risk for vertical transmission if their mothers are receiving ART and have suppressed viral loads during pregnancy and delivery and throughout breastfeeding. WHO defines high-risk infants as those (Fig. 5): • born to women with established HIV infection who have received less than four weeks of ART at the time of delivery; or • born to women with established HIV infection and viral load >1000 copies/mL in the four weeks before delivery, if viral load is available; or • born to women acquiring HIV during pregnancy or breastfeeding; or • born to women identified for the first time during the postpartum period with or without a negative HIV test prenatally. © UNICEF UN0481138 Satu 15 Fig. 5. Algorithm for risk assessment at the time of delivery to help identify infants at high and low risk of infection Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). Antiretroviral prophylaxis Infants at low risk of vertical transmission should receive a single ARV drug as postnatal prophylaxis for 4–6 weeks (Box 6). Enhanced postnatal prophylaxis Infants at high risk for vertical transmission should receive dual ARV drugs for six weeks followed by dual or single ARV drugs for another six weeks for a total of 12 weeks (Box 6). When the recommended regimen is not available or feasible, alternative options such as RAL, 3TC, LPV/r solid formulations or triple-drug fixed-dose combinations containing AZT, NVP and 3TC may be considered (see Annex 1 for the dosing recommendations of ARV drugs currently used for infant prophylaxis). Assess mother AT DELIVERY YES: VL >1,000 YES: VL ≤1,000 HIGH RISK HIGH RISK HIGH RISK LOW RISK Known HIV+ mother on ART Is a VL result available from no more than <4 weeks before delivery? YES LOW RISK NO HIGH RISK NO Has mother been on ART for >4 weeks prior to delivery? Known HIV+ mother not on ART Mother newly identified as HIV+within 72 hours of delivery © UNICEF UN0422226 Dejongh 16 Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). Box 6. WHO recommendations on infant ARV prophylaxis Infants of mothers who are receiving ART and are breastfeeding should receive six weeks of infant prophylaxis with daily NVP. If infants are receiving replacement feeding, they should be given four to six weeks of infant prophylaxis with daily NVP (or twice-daily AZT) (strong recommendation, moderate-certainty evidence for breastfeeding infants; strong recommendation, low-certainty evidence for infants receiving only replacement feeding). Infants born to mothers living with HIV who are at high risk of acquiring HIV should receive dual prophylaxis with daily AZT (twice daily) and NVP (once daily) for the first six weeks of life, whether they are breastfed or formula fed (strong recommendation, moderate-certainty evidence). Breastfed infants who are at high risk of acquiring HIV should continue infant prophylaxis for an additional six weeks (total of 12 weeks of infant prophylaxis) using either AZT (twice daily) and NVP (once daily) or NVP (once daily) alone (conditional recommendation, low-certainty evidence). Implementation considerations Various countries have adopted enhanced postnatal prophylaxis using a variety of approaches to adapt to the country context. A policy review conducted in 18 AIDS Free priority countries revealed that seven countries adopted enhanced postnatal prophylaxis for all breastfeeding infants exposed to HIV and 11 countries for only high-risk infants. Risk was determined primarily based on the timing of maternal HIV diagnosis, whether the mother was on ART, duration on ART before delivery, maternal viral load at delivery and viral load during the breastfeeding period. Five countries link the duration of enhanced postnatal prophylaxis to infant feeding practice and maternal viral load during the breastfeeding period, extending enhanced postnatal prophylaxis over the breastfeeding period when viral suppression is not achieved. Most countries opted for at least 12 weeks of prophylaxis, usually AZT + NVP for the first six weeks followed by NVP alone. Three countries adopted three drugs in a fixed-dose dispersible tablet formulation (AZT + 3TC + NVP) to address the challenges of accessing appropriate formulations. Country programmes may consider a contextual approach to implement a feasible postnatal prophylaxis regimen as they strengthen systems to be able to implement risk-based postnatal prophylaxis. Infant ARV prophylaxis should be provided in the same setting as maternal ART to improve uptake and continuity of treatment. Providing enhanced postnatal prophylaxis to all infants exposed to HIV This may be considered in settings in which most mothers are at high risk of transmitting HIV because of poor maternal ART coverage, high rates of loss to follow-up, poor maternal viral load testing coverage and poor maternal viral suppression rates. It should serve as an interim measure as strategies to improve maternal ART coverage, maternal viral load testing coverage and maternal viral suppression rates are put in place. Although this approach offers a safety net, it may lead to increased costs and strained ARV drug stocks and may unnecessarily expose infants who do not need enhanced prophylaxis to ARV drug toxicity. Extended or prolonged postnatal prophylaxis beyond 12 weeks Although limited evidence suggests additional benefit of combination or prolonged regimens in the context of maternal ART (44), infants and young children who remain at high risk for HIV transmission during the breastfeeding period may receive extended prophylaxis until the risk is considered limited or has ended. Circumstances that present persistent risk to breastfeeding infants beyond the recommended 12 weeks of prophylaxis include: maternal unwillingness or inability to start or continue ART, poor maternal adherence, documented maternal viraemia when the infant prophylaxis is about to be stopped, poor continuity of treatment and viral load monitoring. In these cases, the priority should be attaining maternal viral suppression as quickly as possible by increasing 17 access to viral load testing and supporting continuity of treatment. In addition, although supportive evidence is limited, breastfeeding infants whose mothers are viraemic may receive prolonged postnatal prophylaxis (beyond the recommended 12 weeks of prophylaxis) as a provisional back-up until maternal ART is established, adherence improves and viral suppression is achieved. However, once infant prophylaxis is stopped, it should not be restarted even with new concerns about maternal adherence. Instead, efforts should focus on timely interventions to promote maternal adherence to ART. Presumptive treatment Infants may be identified as exposed to HIV late when they present for health services outside the prevention- of-vertical-transmission cascade. Their mothers may be diagnosed with HIV late or may have acquired HIV during the breastfeeding period. These infants are at high risk of vertical transmission because of high levels of maternal viraemia and the absence of maternal ART. Under these circumstances, nucleic acid testing should be performed at the earliest opportunity and presumptive treatment with a triple-ARV drug regimen at therapeutic doses initiated. This approach will reduce the risk of morbidity and mortality if the infant has already acquired HIV or minimize the risk of transmission if the infant has not. The triple ARV drug regimen will also reduce the risk of drug-resistant HIV selection if infection has already occurred. Maternal ART should also be started. If the nucleic acid test results are negative, the presumptive treatment may be stopped and appropriate ARV drug prophylaxis for high-risk infants continued for a minimum of 12 weeks, when it is presumed maternal viral suppression will have been achieved. If the nucleic acid test results are positive, the presumptive treatment should be adjusted to the recommended first- line ART regimen (45). Further guidance on infant ARV drug prophylaxis is available (2). © UNICEF UN0527099 Cus 18 4. CO-TRIMOXAZOLE PROPHYLAXIS Co-trimoxazole prophylaxis was first introduced in the WHO guidelines in 2006 as a component of standard HIV care, primarily as prophylaxis for Pneumocystis jirovecii pneumonia and toxoplasmosis for people living with HIV and infants exposed to HIV until it could be reliably established that they were HIV-uninfected (46). In subsequent years, the use of co-trimoxazole prophylaxis was extended to preventing malaria and severe bacterial infections among people living with HIV in settings with a high prevalence of these conditions. Evidence has shown significant decrease in morbidity and mortality, supporting the continuous use of co-trimoxazole prophylaxis for people living with HIV regardless of ART status, age, CD4 cell count or WHO clinical stage in settings with a high prevalence of malaria and/or severe bacterial infections (47–50). Co-trimoxazole prophylaxis also continues to be recommended for infants exposed to HIV because it benefits infants with HIV infection, who may not be diagnosed in a timely manner. However, emerging evidence examining the use of co-trimoxazole prophylaxis among infants who are HIV-exposed and uninfected suggests a lack of clinical benefit and potential harm to these infants, and implementation considerations have therefore been made for this group. a Parameter for immune recovery in children older than five years: CD4 cell count >350 cells/mm3, with suppressed viral loads. b In settings with low vertical transmission rates, high HIV infant diagnosis coverage and strong retention in the testing-to-treatment cascade, country programmes may consider stopping providing routine co-trimoxazole as soon as HIV infection is ruled out by age-appropriate HIV testing. Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). Population Criteria for initiating co-trimoxazole prophylaxis Criteria for discontinuing co-trimoxazole prophylaxis Children and adolescents living with HIV • Initiate for everyone regardless of WHO clinical stage or CD4 cell count • As a priority: – Initiate for everyone younger than five years regardless of WHO clinical stage or CD4 cell count – Initiate for everyone five years and older with severe or advanced HIV disease (WHO clinical stage 3 or 4) or CD4 cell count ≤350 cells/mm3 • In settings with high prevalence of malaria and/or severe bacterial infections: should not be discontinued until adulthood • In settings with low prevalence of both malaria and severe bacterial infections: may be discontinued for those older than five years who are clinically stable, with evidence of immune recoverya and/or suppression of viral loads on ART HIV-exposed infants Initiate for everyone starting at 4–6 weeks after birth Until the risk of HIV transmission ends and HIV infection is excluded with age-appropriate testb Table 3. Criteria for initiating and discontinuing co-trimoxazole prophylaxis among children 19 Implementation considerations Infants exposed to HIV and uninfected A systematic review was conducted to assess the effect of co-trimoxazole prophylaxis on the morbidity and mortality of infants who are HIV exposed and uninfected (51). Two trials were identified that addressed the research question. A randomized placebo-controlled trial in Botswana (52) that started co-trimoxazole at 14–34 days and continued it until 15 months of age showed no evidence of benefit of co-trimoxazole for children who are HIV exposed and uninfected for cumulative mortality to 18 months, hospitalization, diarrhoea or pneumonia; neutropenia was more frequent in the co-trimoxazole group. A randomized controlled non-inferiority trial in South Africa (53) gave co-trimoxazole from six weeks until infants were confirmed HIV uninfected at the end of the at-risk HIV period and showed that no co-trimoxazole prophylaxis was not inferior to giving co-trimoxazole to children who are HIV exposed and uninfected on combined grade 3 and 4 pneumonia, diarrhoea or all-cause mortality until 12 months of age. Sub studies of these trials investigated the effect of co- trimoxazole prophylaxis on antibiotic resistance and the infant microbiome. Co-trimoxazole was not associated with major dysbiosis of the gut microbiota but was associated with acquisition of co-trimoxazole-resistant gut bacteria. Some evidence indicated that resistance to other antibiotics such as amoxicillin may increase among children receiving co-trimoxazole (54,55). Collectively, the available data suggest no benefit of co-trimoxazole to infants exposed to HIV but uninfected; however, the generalizability of these trial findings to epidemic settings with higher infant mortality, burden of malaria and other severe bacterial infections remains unclear. Three further studies from Uganda found that co-trimoxazole prophylaxis protected against malaria when continued after breastfeeding ended but did not affect mortality or other morbidity (Table 4) (56–58). Table 4. Summary table of evidence from the systematic review examining the effect of co-trimoxazole on the morbidity and mortality of infants who are HIV-exposed and uninfected Study Country Co- trimoxazole n No co- trimoxazole n Mortality Hospitaladmission Diarrhoea Pneumonia Combined outcome* Malaria Neutropenia Anaemia Main studies: key outcomes Daniels et al. (53) South Africa 611 609 N/A N/A Lockman et al. (52) Botswana 1423 1425 N/A Substudies: antibiotic resistance and microbiome D’Souza et al. (55) South Africa 34 29 Decreased gut microbiome β-diversity and increased antibiotic resistance gene α-diversity and prevalence in the co-trimoxazole group compared with no co-trimoxazole Powis et al. (54) Botswana 105 115 Increased co-trimoxazole-resistant commensal gastrointestinal bacteria in the co-trimoxazole group compared with placebo Studies from malarial countries: outcomes (examined continuation of co-trimoxazole prophylaxis after cessation of breastfeeding) Sandison et al. (56) Uganda 98 87 N/A Homsy et al. (57) Uganda 45 46 N/A Kamya et al. (58) Uganda 47 46 N/A N/A No significant difference between co-trimoxazole or placebo / no co-trimoxazole. Negative effects of co-trimoxazole prophylaxis. Positive effects of co-trimoxazole prophylaxis. N/A: not applicable * Combined outcome: grade 3 or 4 pneumonia or diarrhoea or all-cause mortality (53); death, admission to hospital or grade 3 or 4 clinical adverse events (52). ‡ On analysis of safety outcomes, incidence of grade 3 or 4 anaemia was significantly lower in the co-trimoxazole group than in the control group. ‡ Source: PROSPERO 21 CRD42021215059 20 A modelling study was undertaken to investigate the potential reduction in mortality that would arise by providing co-trimoxazole to children with undiagnosed HIV aged six weeks to two years using different context- tailored approaches to co-trimoxazole provision across epidemic settings (59). Assuming full co-trimoxazole uptake, changing current guidelines to reduce co- trimoxazole duration was predicted to increase mortality in all settings. However, the benefits of the current policy are expected to be greatest in settings with substantial vertical transmission and poor infant testing coverage, in contrast to settings with low vertical transmission and very good infant testing, in which a strategy of shorter co-trimoxazole administration may be a reasonable alternative. Of note, this model did not include potential harm associated with disrupting the microbiome and selecting antibiotic resistance because of the lack of clear clinical correlates. It was therefore concluded that how policy change affects mortality depends on the country setting (vertical transmission rates, infant diagnosis uptake and awareness of infant HIV-exposure status) and exploring a context-tailored approach to co-trimoxazole provision may be of value. Alternative strategies to reduce co-trimoxazole duration may be a reasonable approach in low-risk contexts. The findings support operational research to investigate the real-world impact of strategies involving shorter co-trimoxazole use in settings with well- performing programmes. WHO convened a technical expert group in March 2021 to review the guidance for co-trimoxazole prophylaxis among infants with HIV exposure. Given the rationale of providing co-trimoxazole prophylaxis to infants who could potentially become infected, country implementation of measures to prevent vertical tranmission of HIV and infant diagnosis were reviewed. Overall, despite progress in preventing vertical transmission, gaps persist in timely identification and continuity of care of infants in the testing-to-treatment cascade. Maternal ART and early infant diagnosis coverage differ across settings, and in some countries vertical transmission is still considerable and increasing postnatally, with limited capacity to identify infants with HIV early. The guidelines for co-trimoxazole prophylaxis need to protect the children at high risk of becoming infected but may not reach children who are lost to follow-up or provide additional benefit to children who are HIV exposed and uninfected. The group concluded that fully revising the existing recommendations would be of value but might be premature considering the gaps that remain in services for preventing vertical transmission and early infant diagnosis. Implementation guidance should consider the different country contexts, including maternal ART and early infant diagnosis coverage and mortality rates. Current co-trimoxazole prophylaxis guidelines provide protection for infants at high risk of acquiring HIV who may become infected and be missed by infant testing services. However, as suggested by the systematic review findings, if HIV infection can be excluded, co-trimoxazole does not provide clinical benefit to infants who are HIV exposed and uninfected and may disrupt the microbiome and increase antibiotic resistance to co-trimoxazole and other widely used antibiotics. The guidelines therefore continue the previous recommendations with the addition of implementation considerations (Box 7). Box 7: Implementation considerations for co-trimoxazole prophylaxis Co-trimoxazole prophylaxis may be discontinued at the end of the at-risk period for HIV transmission (after breastfeeding ends and once HIV infection is ruled out by age-appropriate HIV testing), which may occur before 18 months of age. In settings with low vertical transmission rates, high HIV infant diagnosis coverage and strong retention in the testing-to-treatment cascade, country programmes may consider stopping providing routine co-trimoxazole as soon as HIV infection is ruled out by age-appropriate HIV testing. 21 Early child development refers to the physical, cognitive, linguistic, motor and socio-emotional development that occurs in the first eight years of life. Studies have shown that children born to mothers living with HIV are more likely to have motor and neurocognitive delays than their unexposed counterparts (61,62). Providing nurturing care, including adequate and quality HIV prevention and care, nutrition, security and safety, responsive caregiving and opportunities for early learning (Fig. 6), directly affects child development, supporting children to reach their full developmental potential. Fig. 6. Components of nurturing care 5. PROMOTING NURTURING CARE Developmental assessments by direct measurement and observation are used to assess various aspects of a child’s functioning and abilities (motor, sensory, cognition, communication, behaviour, social interaction and adaptive skills). Systematic and structured developmental assessments using standardized validated tools are advised. Several age-dependent tools are used for formal developmental assessment, including norm-referenced tests (comparing with peers) and criterion-reference tests (comparing with prespecified criteria). Assessment should assess the child’s family environment. Nurturing care interventions should be provided to infants and young children exposed to or living with HIV as well as to caregivers, during contacts with the health facilities and in the communities. Supporting caregivers and providing them with the knowledge, skills, time and material resources to give appropriate childcare is essential. Box 8. WHO recommendations for nurturing care Responsive caregiving All infants and children should receive responsive care during the first three years of life; parents and other caregivers should be supported to provide responsive care (strong recommendation; moderate- quality evidence). Promote early learning All infants and children should have early learning activities with their parents and other caregivers during the first three years of life; parents and other caregivers should be supported to engage in early learning with their infants and children (strong recommendation; moderate-quality evidence). Integrate caregiving and nutrition interventions Support for responsive care and early learning should be included as part of interventions for optimal nutrition of infants and young children (strong recommendation; moderate-quality evidence). Support maternal mental health Psychosocial interventions to support maternal mental health should be integrated into early childhood health and development services (strong recommendation; moderate-quality evidence). Source: Improving early childhood development (60). Implementation considerations Multistakeholder engagement and multisectoral approaches at the national and community levels to ensure local contexts and available supportive systems to implement nurturing care interventions are considered critical to comprehensive service delivery, uptake and sustainability. Programmes should select validated tools that are appropriate for implementation in the local context to identify infants and young children exposed to HIV with developmental delay or at risk for it for timely intervention. Training appropriate cadres to implement nurturing care activities at facilities and within communities and establishing referral and linkage systems to facilitate seamless service delivery will be crucial for successful implementation. Further guidance on nurturing care is available (60,63). 22 Country programmes are encouraged to tailor the package to their specific contexts based on the level of implementation and capacities for the individual components, nevertheless endeavouring to ensure that all the components of care are optimally delivered jointly in a comprehensive approach. National level The comprehensive integrated package of care for infants and young children exposed to HIV should be strategically positioned on reproductive, maternal, newborn, child and adolescent health platforms. Contextual assessment and inclusive multistakeholder engagement for operationalizing this package of care will be critical. It will be important for programme leadership to ensure that the care package is aligned with the relevant reproductive, maternal, newborn, child and adolescent health guidelines, policies and service delivery models and that there are adequate commodities, funding and coordination of implementation at all levels. Human resources The potential challenges of introducing a new care package within contexts of limited human resources and capacity at the different levels of care need to be carefully considered. Existing networks, including lay and peer providers and community health workers at facilities and in communities, provide opportunities for task sharing and linking the package with other service delivery components, including psychosocial and adherence support, community follow-up, sample collection, sample transport and drug distribution. This will entail capacity building for the cadres engaged in the various components of the care package and, if possible, innovative technologies, tools and aids to facilitate its implementation. Service delivery The comprehensive care package should be strategically integrated on reproductive, maternal, newborn and child health platforms, including at primary health facilities. Facility protocols and standard operating procedures for clinical and laboratory services should be put in place. Clinic appointments for the mother–infant pairs should be synchronized and, as much as possible, services provided in the same clinic and room. Child-friendly service provision that is judgement and stigma free, especially for adolescent and young mothers and their children, is fundamental. Dedicated areas for developmental assessments and nurturing care activities are desirable. Robust appointment systems and mobile text message reminders to enhance adherence and the continuity of treatment and care will be useful. Programmes should provide structured psychosocial and adherence support for mothers, especially adolescent and young mothers or those experiencing vulnerability, to promote adherence to medication and continuity of treatment. Psychosocial support may be provided at both facilities and in the community by trained clinical and lay providers, including peers if feasible. Improving stock management for commodities, including ARV drugs for treatment and prophylaxis, co-trimoxazole and reagents for laboratory tests, is also important to avoid stock-outs and ensure continuity of service delivery and treatment. Infants and young children exposed to HIV who may not have been identified within programmes for preventing vertical transmission need to be sought out and identified through other channels: facility-based testing (children attending malnutrition wards, TB wards and inpatient wards); targeted testing (sick children and determining the exposure status of children who present to outpatient and immunization clinics); index and family testing, especially establishing the mothers’ status; and screening and testing in programmes for orphans and vulnerable children. Infants and young children exposed to HIV identified outside the platform for preventing vertical transmission should still receive the comprehensive package of care: however, the HIV status of the infant should be rapidly determined and, in the interim, presumptive treatment initiated. This is to avoid giving dual or single ARV drug prophylaxis that may adversely affect eventual treatment regimens if HIV has already been acquired. The presence within families of infants and young children exposed to HIV who need more frequent clinical visits and extra maternal treatment monitoring tests may POLICY IMPLEMENTATION CONSIDERATIONS FOR THE COMPREHENSIVE PACKAGE OF CARE 23 have implications for the family-centred care and the differentiated care other family members are receiving in specific community models. Pregnant and breastfeeding mothers may need to change differentiated service delivery models or modify their differentiated service delivery arrangements to cater for their increased needs and the needs of their babies. This may be poorly synchronized with other family members in care. Options and protocols for the changes that may need to occur to maintain the two unique clients (mother and child) at the centre of the model as the service delivery transforms while minimizing the disruption of care for other family members should be carefully considered. The comprehensive care package has components that may be integrated with community-based child health activities or that may be strengthened by other community-based interventions, such as home-based testing, adherence and psychosocial counselling. Community outreach should also integarate the package of care to increase access for infants and young children exposed to HIV who dropped out or never received prevention of vertical transmission services. There should be strong community engagement of key influencers for creating demand, reducing stigma, improving community literacy with strong emphasis on support and guidance to mothers and caregivers (such as treatment literacy for the significance of viral load, preventing vertical transmission and the need for following up infants and young children exposed to HIV to final diagnosis and beyond) and promoting sustainability. Specific community service delivery strategies should be developed that consider special circumstances that restrict access, such as natural disasters and pandemics, to ensure continuity of care and to promote continuity of treatment and care. Monitoring, evaluation and learning Determining priorities for monitoring and evaluating the comprehensive package of care and identifying programme indicators are important for programmes. Priorities for monitoring will include: • antenatal initiation and attendance; • postnatal attendance; • the number of pregnant and breastfeeding women living with HIV disaggregated for timing of HIV diagnosis, maternal ART coverage, maternal ART timing, maternal viral load coverage and maternal viral suppression rates; • the number of identified infants and young children exposed to HIV disaggregated for risk and time of identification; • early infant diagnosis coverage; • continuity along the early infant diagnosis cascade to final diagnosis; • postnatal ARV drug and co-trimoxazole prophylaxis coverage; and • timing and duration and the number of infants acquiring HIV through vertical transmission disaggregated for the timing of transmission and coverage of nurturing care service delivery. The results framework should be integrated into existing reproductive, maternal, newborn, child and adolescent health frameworks, and the reporting schedules should be aligned with existing reproductive, maternal, newborn, child and adolescent health schedules. Developing and strengthening data systems will be critical, including laboratory information systems to produce timely and real-time data, timely data collation and dissemination using preferably digitalized systems and electronic medical records. In settings in which digitalization is not immediately feasible, strengthening existing data collection and management systems to improve efficiency with phased introduction and scaling up of computerized systems will be key. Programmes’ monitoring and evaluation systems should link information on mothers and infants to support client tracking and community follow-up such as longitudinal follow-up registries, cohort analysis and linkage with information on community services. Evaluation plans should include continuous and periodic data collection and assessments. Evaluating the performance of the package of care on the care platforms and the linked services will be critical to ensure no negative effects on linked services, such as immunization service delivery and coverage. The learning agenda on contextual variation in policy implementation and documentation of various implementation strategies will be necessary to further inform phased roll-outs, programme improvement and implementation considerations. Programmes should dedicate adequate funding and plan the capacity building of both programme and designated monitoring and evaluation staff to ensure the uptake and utilization of the monitoring and evaluation systems. 24 Quality improvement To ensure a safe, effective, patient-centred comprehensive package of care for infants and young children who are HIV exposed, quality improvement can be used to address gaps along the continuum of care. Quality can be assessed to ensure that the standards of care are met and to minimize missed opportunities. Key to this will be identifying quality indicators. Quality improvement teams and/or health-care providers can implement quality improvement projects to systematically address gaps in the package, especially access to services and optimal patient outcomes. Using a quality improvement approach, mothers and other stakeholders should be engaged in client-led improvement initiatives that further improve the efficiency of implementing a harmonized package and provide critical feedback in improving the uptake of the package in decentralized, resource-constrained settings. Research gaps ARV drug prophylaxis The additional benefit of combination or prolonged infant prophylaxis with maternal ART remains uncertain. In addition, limited evidence supports infant prophylaxis for infants with HIV exposure identified during the postpartum period or the mother acquiring HIV during pregnancy and the breastfeeding period. Research is needed, including clinical and pharmacological studies, to inform the development of improved ARV drug formulations and to identify alternative drugs for prophylaxis that are well tolerated and that may have greater efficacy for infant prophylaxis in case of prolonged use. Studies are also needed to evaluate the clinical relevance of viraemic episodes among breastfeeding mothers and whether enhanced prophylaxis adds additional benefit in a population with a well-implemented effective maternal ART programme but known difficulty with adherence and viraemia in the postpartum period. It will also be important to determine the optimal definition of high risk in the context of universal maternal ART in different settings and how various service delivery models affect adherence to enhanced postnatal prophylaxis and continuity of treatment. Co-trimoxazole prophylaxis WHO anticipates fully reviewing the co-trimoxazole prophylaxis recommendation as further evidence is gathered and increasing progress is made, to rapidly identify infants living with HIV and retaining those exposed to HIV in the testing cascade until final diagnosis is ascertained. Research gaps remain about how to optimize the use of co-trimoxazole prophylaxis, and well-conducted operational research will be critical to innovate and better inform co-trimoxazole prophylaxis for children in the future, including: • the optimal timing of initiation; • the clinical and programmatic impact of shorter duration of co-trimoxazole in different epidemic contexts and programmatic realities; • the added value of potential differentiated approaches to co-trimoxazole prophylaxis delivery; • the potential impact of shorter co-trimoxazole strategies on continuity in the testing-to-treatment cascade; • alternative antibiotic prophylactic regimens (other antibiotics); • the clinical relevance of the selection of antibiotic resistance associated with co-trimoxazole prophylaxis; • and the short- and long-term clinical relevance of the microbiome disruption resulting from co-trimoxazole prophylaxis. 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WHO, UNICEF. Nurturing care framework for children affected by HIV: early childhood development and children affected by HIV. Geneva: World Health Organization; 2020 (https://apps.who.int/iris/handle/10665/332904, accessed 27 September 2021). 28 ANNEX 1. SIMPLIFIED AGE-BASED ANTIRETROVIRAL DRUG DOSING FOR ADMINISTERING ENHANCED AND PROLONGED POSTNATAL PROPHYLAXISa a In special circumstances with stock-outs of NVP and/or AZT, alternative ARV drugs could be used: RAL with treatment dosing, 3TC or LPV/r based on evidence gathered through the PROMISE trial (3TC was administered as follows: 7.5 mg once daily for neonates weighing 2 to <4 kg, 25 mg once daily for infants weighing 4 to <8 kg and 50 mg once daily for children weighing more than 8 kg; LPV/r was administered twice daily after the first week of life according to the following dosing scheme: 40/10 mg once daily for neonates weighing 2 to <4 kg and 80/20 mg once daily for infants weighing more than 4 kg. b This simplified dosing was developed with a WHO generic tool based on previously established NVP prophylactic targets. For weight-based dosing of AZT and NVP, see the 2021 WHO consolidated guidelines (2). Drug Strength 0–6 weeks 6–12 weeks 12 weeks– 6 months 6–9 months 9–24 months AM PM AM PM AM PM AM PM AM PM NVPb 50-mg scored dispersible tablets 0.5 – 0.5 – 0.5 – 0.5 – 1 – NVP 10 mg/mL 1.5 mL – 2 mL – 2 mL – 3 mL 4 mL – AZT 10 mg/mL 1.5 mL 1.5 mL 6 mL 6 mL – – – – – – AZT = zidovudine, LPV/r = lopinavir/ritonavir, NVP = nevirapine 29 Drug Strength of tablet or oral liquid for children Number of tablets or mL by weight band once daily Strength of tablet for adults Number of tablets by weight band 3–5.9 kg 6–9.9 kg 10–13.9 kg 14–19.9 kg 20–24.9 kg 25–34.9 kg Co-trimoxazole Suspension 200 mg/40 mg per 5 ml 2.5 ml 5 ml 5 ml 10 ml 10 ml – – Tablets (dispersible) 100 mg/20 mg 1 2 2 4 4 – – Tablets (scored) 400 mg/80 mg – 0.5 0.5 1 1 400 mg/ 80 mg 2 Tablets (scored) 800 mg/160 mg – – – 0.5 0.5 800 mg/ 160 mg 1 Source: Consolidated guidelineson HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update (2). ANNEX 2. SIMPLIFIED DOSING OF CO- TRIMOXAZOLE PROPHYLAXIS FOR INFANTS AND CHILDREN AT LEAST FOUR WEEKS OLD 30 ANNEX 3. INFANT DIAGNOSIS ALGORITHM Source: Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach, 2021 update. Geneva: World Health Organization; 2021 update (https://apps.who.int/iris/handle/10665/342899, accessed 27 September 2021). Notes: a. Based on 2016 WHO Consolidated ARV Guidelines, 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 vertical 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. HIV-exposed infant or child (4-6 weeks to 18 months)HIV-exposed newborn (0-2 days) Consider NATa,b Conduct NATb (at 4-6 weeks or at the earliest opportunity thereafter) Infant/child is infected HIV unlikely unless still breastfeedinge Immediately start ARTc Repeat NAT to confirm infection 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 HIV infection not detected but if infant/child is breastfed the risk of acquiring HIV infection remains until complete cessation of breastfeedingd Infant/child is infected Immediately start ARTc Repeat NAT to confirm infection PositiveNegative Positive Negative Negative For more information, contact: World Health Organization Department of Global HIV, Hepatitis and STIs Programmes World Health Organization 20, avenue Appia 1211 Geneva 27 Switzerland E-mail: hiv-aids@who.int www.who.int/hiv ISBN 978-92-4-004023-6 (electronic version) ISBN 978-92-4-004024-3 (print version) © World Health Organization 2021. 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