Point-of-care tests for diagnosing HIV infection among children younger than 18 months, 03 April 2020

TARGET PRODUCT PROFILE HIV TREATMENT AND CARE TEAM 03 APRIL 2020 POINT-OF-CARE TESTS FOR DIAGNOSING HIV INFECTION AMONG CHILDREN YOUNGER THAN 18 MONTHS Background Programmes aimed at eliminating mother-to- child transmission of HIV have substantially reduced the number of children acquiring HIV infection through routine HIV testing of pregnant women and providing antiretroviral therapy to mothers living with HIV (1). In 2018, 82% of mothers living with HIV globally received antiretroviral therapy, up from 44% in 2010. However, preventing mother-to- child transmission requires sustained viral This target product profile describes the optimal and minimal product characteristics of an ideally device- free point-of-care test that enables health-care providers to diagnose HIV infection among children younger than 18 months. suppression throughout pregnancy, delivery and breastfeeding, and even low-level viraemia is associated with mother-to-child transmission (2,3). For this reason, since 2010, WHO has recommended routine HIV testing for all HIV-exposed infants regardless of maternal antiretroviral therapy status (4). HIV disease progresses much more rapidly among children than among adults. In sub- Saharan Africa, 50% of perinatally infected infants and 25% of infants infected during breastfeeding die before two years of age without antiretroviral therapy (5); testing HIV- exposed infants and linkage to antiretroviral therapy for those with HIV infection are therefore imperative and time-sensitive interventions that substantially affect morbidity and mortality. To account for transmission risks in utero, at delivery and during breastfeeding, WHO recommends that HIV-exposed infants be tested at age six weeks, nine months, after breastfeeding ends and any time there are signs or symptoms suggesting HIV infection (Fig. 1). Testing HIV-exposed infants at birth for earlier detection of in utero infection may also be considered (6). Despite longstanding WHO recommendations and significant investments in building testing capacity, in 2018 only 59% of HIV-exposed infants had been tested by two months of age, and testing coverage is even lower later (such as nine months) for HIV-exposed infants who are still breastfeeding (1). The presence of maternal antibodies precludes the use of antibody-based HIV rapid tests to diagnose children younger than 18 months, necessitating virological testing. Because laboratory-based virological tests require sophisticated infrastructure and highly trained personnel, most virological tests for Fig.1 Revised WHO early infant diagnosis algorithm, 2018 Conduct NATd (at 4–6 weeks or at the earliest opportunity thereafter) HIV-exposed newborn (0–2 days) HIV-exposed infant or child (4–6 weeks to 18 months) Negative Positive Negative Infant/child is infected Immediately start ARTc Repeat NAT to confirm HIV infection not detected but if infant/child is breastfed the risk of acquiring HIV infection remains until complete cessation of breastfeedingd Consider NATa,b Conduct NATd (at 9 months) Regular clinical monitoring Negative Positive HIV unlikely unless still breastfeedinge Antibody testing at 18 months of age or 3 months after cessation of breastfeeding, whichever is laterf Infant/child is infected Immediately start ARTg Repeat NAT to confirm infection 1 Based on 2016 WHO Consolidated ARV Guidelines, addition of NAT at birth to the existing testing algorithm can be considered. 2 POC NAT can be used to diagnose HIV infection as well as to confirm positive results. 3 Start ART without delay. At the same time, retest to confirm infection. As maternal treatment is scaled up and mother to child 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. 4 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. 5 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. 6 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. WHO/UCN/HHS/19.57 2child transmission (such as malnutrition clinics, inpatient paediatric wards and TB clinics) to improve HIV case-finding among children as recommended by WHO (15). The requirement for multiple virological tests for HIV-exposed infants up to age 18 months as well as the recommendation for a confirmatory test for an initial positive test further underscores the need for a point-of-care virological test that provides immediate results for clinical management. Document objective The objective of a target product profile is to inform product developers of key test characteristics and performance specifications that are required to meet the needs of end-users for a defined use case. This target product profile describes the optimal and minimal product characteristics of a point-of-care test that enables health-care providers to diagnose HIV infection among children younger than 18 months. The intended audience is diagnostic technology developers, regulatory agencies, procurement agencies, donors and funders of diagnostic research. Methods This target product profile is the result of an ongoing consultative process among many stakeholders in the global health and scientific community. The WHO Global HIV, Hepatitis and STIs programme developed a draft version of the target product profile, which included a list of performance and operational characteristics. An iterative approach was taken to obtain inputs over several rounds of feedback and consultation from more than 100 experts and key stakeholders, including representatives of health ministries and national HIV programmes, implementers, diagnostics experts, donors, clinicians and manufacturers. WHO prequalification The WHO prequalification process acts as an international assurance of quality, safety, efficacy and suitability for low- and middle- income country programmes. WHO encourages manufacturers of diagnostic technologies to be aware of the WHO prequalification process, even at the early stages of development, and to discuss the product and the regulatory requirements with WHO. The Overview of the WHO prequalification of in vitro diagnostics assessment (16) describes the prequalification process in detail. Acknowledgements The Global HIV, Hepatitis, and STIs Programme at WHO prepared this document with input from key stakeholders. WHO gratefully acknowledges the many individuals and institutions that provided valuable contributions in the compilation and review of this target product profile, including the WHO Department of Essential Medicines and Health Products, WHO Regional Office for Africa, Clinton Health Access Initiative, Elizabeth Glazer Pediatric AIDS Foundation, Foundation for Innovative New Diagnostics, Médecins Sans Frontières, Office of the United States Global AIDS Coordinator, Global Fund to Fight AIDS, Tuberculosis and Malaria and UNICEF. This document was prepared following public consultations and consideration of all comments and suggestions by stakeholders. HIV-exposed infants in low- and middle- income countries involve transporting specimens from hundreds of clinics to a few centralized molecular testing sites. This cascade entails numerous steps between sample collection, sample transport, testing, return of results and linkage to care and treatment. As a result, adequate laboratory capacity and support for laboratory systems to perform centralized molecular testing for children younger than 18 months has not always translated into timely diagnostic results for caregivers and health-care providers (7). Delayed return of results is a critical problem given the poor clinical outcomes and high mortality for HIV- infected infants who are not identified and treated early (8,9). Since countries continue to face challenges with human resources shortages, sample transport and laboratory systems, recognition is growing that centralized testing networks are unlikely to meet all programmatic needs of HIV-exposed infants. Device-based point-of-care technologies recently introduced in clinics for HIV-exposed infants have been shown to substantially reduce the time until results are returned and to accelerate life-saving antiretroviral therapy initiation compared with laboratory-based approaches (10–13). A simple, accurate, device-free and rapid point-of-care test that is feasible even in primary health clinics in low- resource settings could further expand access to virological tests for HIV- exposed infants while providing similar improvements in returning results, antiretroviral therapy initiation times and retention of mother-infant pairs in services for HIV-exposed infants. As a result of these programmatic benefits, even rapid point-of-care tests with lower sensitivities could substantially affect the morbidity and mortality of HIV-exposed infants (14). A simple, ideally device-free, point-of-care early infant diagnosis test could also be used in other high-yield settings other than those intended to prevent mother-to- 3CHARACTERISTICS MINIMAL OPTIMAL INTENDED USE Primary goal Easy to use and device-minimal diagnostic test that can be used at the point-of-care (POC) for same-day diagnosis of HIV in children <18 months of age Setting All HIV-burden countries with mother-to-child HIV transmission Health care level All levels including community-based testing, mobile testing, health centers, hospitals; centralized and decentralized; low- and high-volume settings Results Presence or absence of HIV nucleic acids and/or p24 antigen Operator Health care facility staff Lay counsellor, non-professional staff Target population Children < 18 months of age in the determination of HIV infection PERFORMANCE Equipment Minimal or ancillary–Small results reader None required–device free/disposable Result output Qualitative Result interpretation Visual manual or reader interpretation required No interpretation necessary Clinical sensitivity 80% 98% Clinical specificity 98% 98% Reference test Internationally approved nucleic acid technology Invalid/error rate 10% 5% OPERATIONAL CHARACTERISTICS Sample specimen Finger or heel-prick whole blood Sample volume < 200 µl < 100 µl Sample preparation No more than 5 steps No more than 3 steps Additional 3rd party consumables None required outside of what is provided in test and sample collection kits Cold chain None required Power requirements Battery or solar-power operated; > 6 hours rechargeable battery life None required Water requirements None required Test kit components All materials for test included All materials for test and sample preparation included Test kit stability 12 months at 10–30°C; 50% humidity 18 months at 2–35°C; 80% humidity Operating conditions 15–30°C; altitude up to 1000 meters 10–40°C; altitude up to 2000 meters Sample stability pre-testing 5 minutes 3 hours Result validity stability 1 hour 5 hours Safety precautions Self-contained system; only standard blood collection safety precautions needed and all materials are free of components with a GHS classification H (particularly H350, H340, H360)* Waste disposal requirements Biosafety trash for all materials QUALITY ASSURANCE Training required 2 days 1 day Routine service and maintenance None, swap out or replace ancillary device when needed None required as device-free Calibration None required Quality control Internal procedural control(s) Internal positive and negative controls, External quality assessment (EQA) material compatible Regulatory requirements Manufactured under ISO 13485:2003 certified; WHO prequalified; or authorized for use by a regulatory authority of the founding members of the Global Harmonization Task Force for in vitro diagnostic use Connectivity If device-based: Remote export of data possible If no device: Export could be available with separate 3rd party reader Test is compatible with readers and other data capture devices TARGET PROCUREMENT PRICE Target price for device ≤ US$ 2000 NA: no device required Target price for cartridge < US$ 12 per test < US$ 8 per test * Globally Harmonized System of Classification and Labelling of Chemicals; H350: may cause cancer; H340: may cause genetic defects; H360: may damage fertility of the unborn child TARGET PRODUCT PROFILE OBJECTIVE: TO DETECT HIV INFECTION AT THE POINT OF CARE AMONG CHILDREN YOUNGER THAN 18 MONTHS TARGET PRODUCT PROFILE WORLD HEALTH ORGANIZATION HIV TREATMENT AND CARE TEAM For more information, contact: World Health Organization Department of HIV/AIDS 20, Avenue Appia 1211 Geneva 27 Switzerland E-mail: hiv-aids@who.int www.who.int/hiv WHO/UCN/HHS/19.57 © World Health Organization 2020 Some rights reserved. Licence: CC BY-NC-SA 3.0 IGO 4 6. Updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of HIV. Geneva: World Health Organization; 2018 (https:// www.who.int/hiv/pub/guidelines/ ARV2018update/en, accessed 2 March 2020). 7. Sutcliffe CG, van Dijk JH, Hamangaba F, Mayani F, Moss WJ. Turnaround time for early infant HIV diagnosis in rural Zambia: a chart review. PLoS One. 2014;9:e87028. 8. Wagner A, Slyker J, Langat A, Inwani I, Adhiambo J, Benki- Nugent S et al. High mortality in HIV-infected children diagnosed in hospital underscores need for faster diagnostic turnaround time in prevention of mother-to-child transmission of HIV (PMTCT) programs. BMC Pediatr 2015;15:10. 9. Braun M, Kabue MM, McCollum ED, Ahmed S, Kim M, Aertker L et al. Inadequate coordination of maternal and infant HIV services detrimentally affects early infant diagnosis outcomes in Lilongwe, Malawi. 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