Table1_Paediatric medicine issues and gaps from healthcare workers point of view: survey results and a narrative review from the global accelerator for paediatric formulations project.XLSX

The WHO Model List of Essential Medicines for Children (EMLc) has not been systematically revised in the last few years. We conducted a survey addressed to healthcare professionals prescribing, preparing, or administering medicines to children and a narrative review to identify problematic paediatric formulations or missing medicines in all therapeutic fields to inform the review of the EMLc in 2023. A total of 285 physicians (63%), 28 nurses (6%) and 142 pharmacists (31%), mostly working in the hospital setting, reported at least one problematic medicine. 290 medicines were reported as missing (completely or the child-appropriate formulation). The top three most mentioned were ciprofloxacin together with phenobarbital and omeprazole. 387 medicines were reported as problematic (34% were oral liquid formulations, 34% tablets, 18% parenteral preparations. Mostly of the products were antibacterials (27%), cardiovascular medicines (11%) and antivirals (11%). The obtained responses show the perspective of healthcare workers working around the world, particularly in the European region (25%), in the African region (24%), and in the Region of the Americas (19%), with limited representation from Northern Africa and the Middle East. Our results need to be analysed with the outputs of other ongoing works before specific products can enter the WHO-hosted Global Accelerator for Paediatric formulations network prioritisation process. Efforts to develop appropriate formulations for children should be accelerated so that the uncertainties associated with off-label drug preparation and use are minimised, and therapeutic benefits are optimised.</p

DataSheet1_Paediatric medicine issues and gaps from healthcare workers point of view: survey results and a narrative review from the global accelerator for paediatric formulations project.docx

The WHO Model List of Essential Medicines for Children (EMLc) has not been systematically revised in the last few years. We conducted a survey addressed to healthcare professionals prescribing, preparing, or administering medicines to children and a narrative review to identify problematic paediatric formulations or missing medicines in all therapeutic fields to inform the review of the EMLc in 2023. A total of 285 physicians (63%), 28 nurses (6%) and 142 pharmacists (31%), mostly working in the hospital setting, reported at least one problematic medicine. 290 medicines were reported as missing (completely or the child-appropriate formulation). The top three most mentioned were ciprofloxacin together with phenobarbital and omeprazole. 387 medicines were reported as problematic (34% were oral liquid formulations, 34% tablets, 18% parenteral preparations. Mostly of the products were antibacterials (27%), cardiovascular medicines (11%) and antivirals (11%). The obtained responses show the perspective of healthcare workers working around the world, particularly in the European region (25%), in the African region (24%), and in the Region of the Americas (19%), with limited representation from Northern Africa and the Middle East. Our results need to be analysed with the outputs of other ongoing works before specific products can enter the WHO-hosted Global Accelerator for Paediatric formulations network prioritisation process. Efforts to develop appropriate formulations for children should be accelerated so that the uncertainties associated with off-label drug preparation and use are minimised, and therapeutic benefits are optimised.</p

Table3_Paediatric medicine issues and gaps from healthcare workers point of view: survey results and a narrative review from the global accelerator for paediatric formulations project.XLSX

The WHO Model List of Essential Medicines for Children (EMLc) has not been systematically revised in the last few years. We conducted a survey addressed to healthcare professionals prescribing, preparing, or administering medicines to children and a narrative review to identify problematic paediatric formulations or missing medicines in all therapeutic fields to inform the review of the EMLc in 2023. A total of 285 physicians (63%), 28 nurses (6%) and 142 pharmacists (31%), mostly working in the hospital setting, reported at least one problematic medicine. 290 medicines were reported as missing (completely or the child-appropriate formulation). The top three most mentioned were ciprofloxacin together with phenobarbital and omeprazole. 387 medicines were reported as problematic (34% were oral liquid formulations, 34% tablets, 18% parenteral preparations. Mostly of the products were antibacterials (27%), cardiovascular medicines (11%) and antivirals (11%). The obtained responses show the perspective of healthcare workers working around the world, particularly in the European region (25%), in the African region (24%), and in the Region of the Americas (19%), with limited representation from Northern Africa and the Middle East. Our results need to be analysed with the outputs of other ongoing works before specific products can enter the WHO-hosted Global Accelerator for Paediatric formulations network prioritisation process. Efforts to develop appropriate formulations for children should be accelerated so that the uncertainties associated with off-label drug preparation and use are minimised, and therapeutic benefits are optimised.</p

Table2_Paediatric medicine issues and gaps from healthcare workers point of view: survey results and a narrative review from the global accelerator for paediatric formulations project.XLSX

The WHO Model List of Essential Medicines for Children (EMLc) has not been systematically revised in the last few years. We conducted a survey addressed to healthcare professionals prescribing, preparing, or administering medicines to children and a narrative review to identify problematic paediatric formulations or missing medicines in all therapeutic fields to inform the review of the EMLc in 2023. A total of 285 physicians (63%), 28 nurses (6%) and 142 pharmacists (31%), mostly working in the hospital setting, reported at least one problematic medicine. 290 medicines were reported as missing (completely or the child-appropriate formulation). The top three most mentioned were ciprofloxacin together with phenobarbital and omeprazole. 387 medicines were reported as problematic (34% were oral liquid formulations, 34% tablets, 18% parenteral preparations. Mostly of the products were antibacterials (27%), cardiovascular medicines (11%) and antivirals (11%). The obtained responses show the perspective of healthcare workers working around the world, particularly in the European region (25%), in the African region (24%), and in the Region of the Americas (19%), with limited representation from Northern Africa and the Middle East. Our results need to be analysed with the outputs of other ongoing works before specific products can enter the WHO-hosted Global Accelerator for Paediatric formulations network prioritisation process. Efforts to develop appropriate formulations for children should be accelerated so that the uncertainties associated with off-label drug preparation and use are minimised, and therapeutic benefits are optimised.</p

Excess deaths per year by country under alternative cotrimoxazole strategies.

Columns represent additional deaths from each alternate strategy in comparison to the current WHO programmatic strategy of providing cotrimoxazole to all HIV-exposed infants. 12m = 12 months, 9m = 9 months, 6m = 6 months, 3m = 3 months.</p

TRIPOD Checklist: Prediction model development.

BackgroundWorld Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed.Methods and findingsUsing a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d’Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV.Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d’Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis.ConclusionsChanging current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings.</div

Comparison of predicted mortality, between ages 6 weeks to 2 years, with different programmatic cotrimoxazole strategies for children born to mothers with HIV.

For the current WHO strategy (base case) of providing cotrimoxazole (CTX) to all HIV-exposed children, mortality rate is expressed in percent (%). Alternative strategies explored were (1) initiating cotrimoxazole at 6 weeks and stopping at 12 months; (2) initiating cotrimoxazole at 6 weeks and stopping at 9 months; (3) initiating cotrimoxazole at 6 weeks and stopping at 6 months; (4) initiating cotrimoxazole at 6 weeks and stopping at 3 months; and (5) initiating cotrimoxazole prophylaxis only once a positive HIV test result is confirmed. Mortality for alternative strategies are reported in comparison to the base case (current strategy): risk ratio, excess mortality rate per 100,000 HIV-exposed infants, and excess annual deaths. CTX = cotrimoxazole.</p

Sensitivity analysis (Mozambique)—Conservative scenarios.

Sensitivity analysis exploring the effect of varying assumptions on the RR for deaths (6 weeks to 2 years) compared to the current WHO strategy for Mozambique: (1) Cotrimoxazole uptake at 40% rather than 100% assumed in the base model, (2) mortality reduction from cotrimoxazole while on ART decreased from 43% to 15%, (3) mortality reduction from cotrimoxazole while not on ART decreased from 43% to 15%, (4) EID coverage increased to 100% rather than 82.9% EID coverage for Mozambique, (5) perinatal MTCT reduced from to 6% to 1%, (6) postnatal MTCT decreased from 7.5% to 6.5%. (7) Conservative estimate concurrently combining sensitivity scenarios 1–6. CTX, cotrimoxazole; ART, antiretroviral therapy; EID, early infant diagnosis at 6 weeks; MTCT, mother-to-child transmission; 12m, 12 months; 9m, 9 months; 6m, 6 months; 3m, 3 months; RR, risk ratio; WHO, World Health Organization.</p

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BackgroundWorld Health Organization (WHO) guidelines recommend cotrimoxazole prophylaxis for children who are HIV-exposed until infection is excluded and vertical transmission risk has ended. While cotrimoxazole has benefits for children with HIV, there is no mortality benefit for children who are HIV-exposed but uninfected, prompting a review of global guidelines. Here, we model the potential impact of alternative cotrimoxazole strategies on mortality in children who are HIV-exposed.Methods and findingsUsing a deterministic compartmental model, we estimated mortality in children who are HIV-exposed from 6 weeks to 2 years of age in 4 high-burden countries: Côte d’Ivoire, Mozambique, Uganda, and Zimbabwe. Vertical transmission rates, testing rates, and antiretroviral therapy (ART) uptake were derived from UNAIDS data, trial evidence, and meta-analyses. We explored 6 programmatic strategies: maintaining current recommendations; shorter cotrimoxazole provision for 3, 6, 9, or 12 months; and starting cotrimoxazole only for children diagnosed with HIV.Modelled alternatives to the current strategy increased mortality to varying degrees; countries with high vertical transmission had the greatest mortality. Compared to current recommendations, starting cotrimoxazole only after a positive HIV test had the greatest predicted increase in mortality: Mozambique (961 excess annual deaths; excess mortality 339 per 100,000 HIV-exposed children; risk ratio (RR) 1.06), Uganda (491; 221; RR 1.04), Zimbabwe (352; 260; RR 1.05), and Côte d’Ivoire (125; 322; RR 1.06). Similar effects were observed for 3-, 6-, 9-, and 12-month strategies. Increased mortality persisted but was attenuated when modelling lower cotrimoxazole uptake, smaller mortality benefits, higher testing coverage, and lower vertical transmission rates. The study is limited by uncertain estimates of cotrimoxazole coverage in programmatic settings; an inability to model increases in mortality arising from antimicrobial resistance due to limited surveillance data in sub-Saharan Africa; and lack of a formal health economic analysis.ConclusionsChanging current guidelines from universal cotrimoxazole provision for children who are HIV-exposed increased predicted mortality across the 4 modelled high-burden countries, depending on test-to-treat cascade coverage and vertical transmission rates. These findings can help inform policymaker deliberations on cotrimoxazole strategies, recognising that the risks and benefits differ across settings.</div

Schematic illustration of model structure (scenarios and strategies).

Panel A (Scenarios): Scenarios considered were (1) children with HIV (diagnosed), (2) children with HIV (undiagnosed), or (3) HEU. Superscripts denote applied mortality estimates: (a) age-specific baseline mortality estimates for infants with HIV and no ART, based on Newell and colleagues [3]. (b) Age-specific baseline mortality estimates for HEU infants based on Arikawa and colleagues [15], (c) 77% uptake of ART following positive HIV test based on Luo and colleagues [17], (d) 76% mortality reduction from ART based on CHER [18], (e) 43% mortality reduction from CTX in a child with HIV based on CHAP [7], (f) 0% mortality reduction from CTX in an HEU child based on Botswana and South Africa trials [8,9]. Panel B (Strategies): Illustration of considered programmatic strategies. Pink represents period of programmatic CTX provision. Blue represents period of risk of HIV transmission due to breastfeeding (18 months). Strategies illustrated are (1) current WHO strategy (2) initiating CTX at 6 weeks and stopping at 12 months, (3) initiating CTX at 6 weeks and stopping at 9 months, (4) initiating CTX at 6 weeks and stopping at 6 months, (5) initiating CTX at 6 weeks and stopping at 3 months, and (6) initiating CTX prophylaxis only once a positive HIV test result is confirmed and the child is started on ART. CTX, cotrimoxazole; ART, antiretroviral therapy; EID, early infant diagnosis at 6 weeks; 9mo, 9-month HIV test; EoB, end of breastfeeding; HEU, HIV-exposed uninfected.</p