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BACKGROUND: Rectal artesunate, an efficacious pre-referral treatment for severe malaria in children, was deployed at scale in Uganda, Nigeria, and DR Congo. In addition to distributing rectal artesunate, implementation required additional investments in crucial but neglected components in the care for severe malaria. We examined the real-world costs and constraints to rectal artesunate implementation. METHODS: We collected primary data on baseline health system constraints and subsequent rectal artesunate implementation expenditures. We calculated the equivalent annual cost of rectal artesunate implementation per child younger than 5 years at risk of severe malaria, from a health system perspective, separating neglected routine health system components from incremental costs of rectal artesunate introduction. FINDINGS: The largest baseline constraints were irregular health worker supervisions, inadequate referral facility worker training, and inadequate malaria commodity supplies. Health worker training and behaviour change campaigns were the largest startup costs, while supervision and supply chain management accounted for most annual routine costs. The equivalent annual costs of preparing the health system for managing severe malaria with rectal artesunate were US$2.63, $2.20, and $4.19 per child at risk and $322, $219, and $464 per child treated in Uganda, Nigeria, and DR Congo, respectively. Strengthening the neglected, routine health system components accounted for the majority of these costs at 71.5%, 65.4%, and 76.4% of per-child costs, respectively. Incremental rectal artesunate costs accounted for the minority remainder. INTERPRETATION: Although rectal artesunate has been touted as a cost-effective pre-referral treatment for severe malaria in children, its real-world potential is limited by weak and under-financed health system components. Scaling up rectal artesunate or other interventions relying on community health-care providers only makes sense alongside additional, essential health system investments sustained over the long term. FUNDING: Unitaid. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Community case management by community health workers has substantially reduced malaria across the Greater Mekong Subregion and Central America. To sustain current and achieve further reductions in malaria, surveillance and delivery platforms must be redesigned to ensure their continued use by key populations., Key Findings Community health workers (CHWs) detect nearly 30% of all malaria cases in remaining hotspots in Lao PDR and more than 50% of all reported malaria cases in select regions of Honduras. Despite having dedicated funding, both countries face challenges supervising, equipping, and supporting CHWs. As malaria test positivity declines, expanding CHWs' responsibilities may encourage individuals to seek care and enable CHWs to more promptly detect and treat remaining cases. Key Implications National malaria programs should assess vertical CHW network design, management, and financing to identify opportunities to promote care seeking for febrile illness. As likelihood of malaria as the primary cause of fever decreases, providing an integrated package of services will become more critical in ensuring that patients' needs are met. CHWs are a major source of malaria testing, treatment, and disease intelligence. Information systems capable of tracking their performance and progress to guide remedial action and attribute impact are essential., Background: Across the Greater Mekong Subregion (GMS) and Central America, governments commonly employ community health workers (CHWs) to improve access to and uptake of malaria services. Many of these networks are vertical in design, organized to extend malaria-only services to those remaining communities in which malaria persists. Methods: Between 2019 and 2020, national ministries of health (MOH) and Clinton Health Access Initiative conducted mixed-methods CHW program evaluations across the GMS and Central America. Routine surveillance and programmatic data were analyzed to quantify CHW contributions to malaria elimination objectives and identify gaps and challenges. Semistructured interviews were conducted with governmental and nongovernmental stakeholders from central to community level. This article draws comparisons between the Lao People's Democratic Republic (PDR) and Honduras CHW program evaluation results to distill broader hypotheses about how vertical CHW programs might evolve as their primary mission nears its end. Results: CHWs contribute substantially to malaria case detection and surveillance, diagnosing and treating 27% of malaria cases in Lao PDR and 55% in the department of Gracias a Dios, Honduras in 2019. In the same year, malaria test positivity neared less than 1% in both countries. In 2019, 80% of CHWs in Lao PDR and 74% in Gracias a Dios, Honduras did not report a single malaria case. From inception, both programs were organized as vertical (malaria-only) CHW programs reliant upon Global Fund financing for malaria commodities, training, supervision and, where applicable, remuneration. Conclusions: Although community case management by CHWs has been highly impactful in reducing malaria cases to near zero, new challenges of acceptability and effectiveness of malaria-only service delivery, feasibility of continued vertical program management, and sustainable financing have emerged. To achieve and sustain reductions in malaria, surveillance and delivery platforms must be redesigned to encourage (and reward) care seeking based on experience of symptoms and not on a patient or caregiver's presumptive diagnosis of disease. By expanding the roles and responsibilities of currently vertical malaria CHWs, malarial interventions can be optimized and sustained. Such a shift will also position existing community-based platforms to be resilient and responsive as epidemiology of disease and community need shift.

BackgroundRectal artesunate (RAS), an efficacious pre-referral treatment for severe malaria in children, was deployed at scale in Uganda, Nigeria and DR Congo. In addition to distributing RAS, implementation required additional investments in crucial but neglected components in the care for severe malaria. We examined the real-world costs and barriers to RAS implementation.MethodsWe collected primary data on baseline health system gaps and subsequent RAS implementation expenditures. We calculated the equivalent annual cost of RAS implementation per child under 5 at risk of severe malaria, from a health system perspective, separating neglected routine health system components from incremental RAS introduction costs.FindingsThe largest baseline gaps were irregular health worker supervisions, inadequate referral facility worker training, and inadequate malaria commodity supplies. Health worker training and behaviour change campaigns were the largest startup costs, while supervision and supply chain management accounted for most annual routine costs. The equivalent annual costs of preparing the health system for treating severe malaria with RAS were $2.31, $2.20 and 4.15 per child at risk in Uganda, Nigeria and DRC. The incremental costs of introducing RAS, net of routine neglected components, accounted for a minority at $0.72, $0.59 and $0.94.InterpretationWhile RAS has been touted as a cost-effective pre-referral treatment for severe malaria in children, its real-world potential is limited by weak and under-financed continuums of care. Scaling up RAS or other interventions relying on community healthcare providers only makes sense alongside additional, essential health system investments sustained over the long-term.FundingUnitaid

IntroductionChildren who receive prereferral rectal artesunate (RAS) require urgent referral to a health facility where appropriate treatment for severe malaria can be provided. However, the rapid improvement of a child’s condition after RAS administration may influence a caregiver’s decision to follow this recommendation. Currently, the evidence on the effect of RAS on referral completion is limited.MethodsAn observational study accompanied the roll-out of RAS in three malaria endemic settings in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Community health workers and primary health centres enrolled children under 5 years with suspected severe malaria before and after the roll-out of RAS. All children were followed up 28 days after enrolment to assess their treatment-seeking pathways.ResultsReferral completion was 67% (1408/2104) in DRC, 48% (287/600) in Nigeria and 58% (2170/3745) in Uganda. In DRC and Uganda, RAS users were less likely to complete referral than RAS non-users in the pre-roll-out phase (adjusted OR (aOR)=0.48, 95% CI 0.30 to 0.77 and aOR=0.72, 95% CI 0.58 to 0.88, respectively). Among children seeking care from a primary health centre in Nigeria, RAS users were less likely to complete referral compared with RAS non-users in the post-roll-out phase (aOR=0.18, 95% CI 0.05 to 0.71). In Uganda, among children who completed referral, RAS users were significantly more likely to complete referral on time than RAS non-users enrolled in the pre-roll-out phase (aOR=1.81, 95% CI 1.17 to 2.79).ConclusionsThe findings of this study raise legitimate concerns that the roll-out of RAS may lead to lower referral completion in children who were administered prereferral RAS. To ensure that community-based programmes are effectively implemented, barriers to referral completion need to be addressed at all levels. Alternative effective treatment options should be provided to children unable to complete referral.Trial registrstion numberNCT03568344; ClinicalTrials.gov.

Background For a full treatment course of severe malaria, community-administered pre-referral rectal artesunate (RAS) should be completed by post-referral treatment consisting of an injectable antimalarial and oral artemisinin-based combination therapy (ACT). This study aimed to assess compliance with this treatment recommendation in children under 5 years. Methods and findings This observational study accompanied the implementation of RAS in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda between 2018 and 2020. Antimalarial treatment was assessed during admission in included referral health facilities (RHFs) in children under 5 with a diagnosis of severe malaria. Children were either referred from a community-based provider or directly attending the RHF. RHF data of 7,983 children was analysed for appropriateness of antimalarials; a subsample of 3,449 children was assessed additionally for dosage and method of ACT provision (treatment compliance). A parenteral antimalarial and an ACT were administered to 2.7% (28/1,051) of admitted children in Nigeria, 44.5% (1,211/2,724) in Uganda, and 50.3% (2,117/4,208) in DRC. Children receiving RAS from a community-based provider were more likely to be administered post-referral medication according to the guidelines in DRC (adjusted odds ratio (aOR) = 2.13, 95% CI 1.55 to 2.92, P < 0.001), but less likely in Uganda (aOR = 0.37, 95% CI 0.14 to 0.96, P = 0.04) adjusting for patient, provider, caregiver, and other contextual factors. While in DRC, inpatient ACT administration was common, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349). Study limitations include the unfeasibility to independently confirm the diagnosis of severe malaria due to the observational nature of the study. Conclusions Directly observed treatment was often incomplete, bearing a high risk for partial parasite clearance and disease recrudescence. Parenteral artesunate not followed up with oral ACT constitutes an artemisinin monotherapy and may favour the selection of resistant parasites. In connection with the finding that pre-referral RAS had no beneficial effect on child survival in the 3 study countries, concerns about an effective continuum of care for children with severe malaria seem justified. Stricter compliance with the WHO severe malaria treatment guidelines is critical to effectively manage this disease and further reduce child mortality. Trial registration ClinicalTrials.gov (NCT03568344).

BackgroundAppropriate clinical management of severe malaria is critical to avert morbidity and death. Recommended treatment consists of an injectable antimalarial followed by a full course of oral artemisinin-based combination therapy (ACT). Children who cannot access prompt parenteral treatment should be administered a single dose of rectal artesunate (RAS) and promptly referred to an appropriate facility for further care. This study aimed to assess compliance with the treatment recommendation in children under 5 years diagnosed with severe malaria and admitted to referral facilities in 3 high-burden sub-Saharan African countries.Methods and FindingsThis study accompanied the implementation of RAS as a pre-referral treatment in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children under 5 who were admitted at a referral health facility (RHF) with a diagnosis of severe malaria were included. Type and dosage of antimalarial treatment at RHFs was assessed for children referred from a community-based provider and those directly attending the RHF. We used multivariable regression models to assess factors associated with administration of compliant treatment.RHF data of 7,983 children was analysed for compliance with regards to antimalarials, a subsample of 3,449 children was assessed in more detail for schedule and dosage compliance and method of ACT provision. Overall, 42.0% (3,356/7,983) of admitted children were administered full treatment consisting of a parenteral antimalarial and an ACT, with large variation among study countries (2.7% in Nigeria, 44.5% in Uganda and 50.3% in DRC). Children receiving RAS from a community-based provider were more likely to be administered compliant post-referral medication at RHFs in DRC (adjusted odds ratio (aOR)=2.19, 95% CI 1.60-2.99), but less likely in Uganda (aOR = 0.43, 95% CI 0.19-0.96). Use of injectable antimalarials was very high in all three countries (99.2% (1,344/1,355) in Uganda, 98.1% (413/421) in Nigeria and 94.4% (1,580/1,673) in DRC), with most children receiving the recommended minimum of three doses (99.0% (1,331/1,344) in Uganda, 95.5% (1,509/1,580) in DRC and 92.0% (380/413) in Nigeria). Rather than being administered in the RHF, ACTs were often prescribed at discharge in Nigeria (54.4%, 229/421) and Uganda (53.0%, 715/1,349), while this was rarely done in DRC (0.8%, 14/1,669) where inpatient administration was more common.ConclusionsDirectly observed treatment with both a parenteral antimalarial and an ACT was rare and variable between countries, bearing a high risk for incomplete parasite clearance and disease recrudescence. Parenteral artesunate not followed up with a full course of oral ACT constitutes an artemisinin monotherapy and may favour the selection or development of resistant parasites. Stricter health worker compliance with the WHO severe malaria treatment guidelines is therefore needed to effectively manage this disease and further reduce child mortality.

BackgroundTo prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, higher-level facilities offering parenteral antimalarials are often difficult to access. A randomised controlled trial found pre-referral rectal artesunate (RAS) to reduce death and disability in children who delay arriving at a referral facility. This study examined the effectiveness of pre-referral RAS treatment in established community-based health care systems.MethodsAn observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo, Nigeria and Uganda. Children < 5 years presenting to a community-based health provider with a positive malaria test and signs of severe malaria were followed-up during admission and after 28 days to assess their health status and treatment history. The primary outcome was death; covariates of interest included RAS use, referral completion, and post-referral treatment.FindingsPost-roll-out, RAS was administered to 88% of patients in DRC, 52% in Nigeria, and 70% in Uganda. The overall case fatality rate (CFR) was 6.7% (135/2011) in DRC, 11.7% (69/589) in Nigeria, and 0.5% (19/3686) in Uganda; 865/6286 patients were sick at follow-up. In all countries, the CFR was higher after RAS-roll-out (6.7 vs. 6.6% in DRC, 16.1 vs. 4.2% in Nigeria, 0.7 vs. 0.3% in Uganda). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR = 3.31, 95% CI 1.43-7.65 and aOR = 2.42, 95% CI 1.25-4.70, respectively). In Uganda, RAS users were less likely to be dead or sick at follow-up (aOR = 0.61, 95% CI 0.46-0.80). Post-referral parenteral antimalarials were protective in all countries; however, the effect of ACT administration was inconsistent.InterpretationRAS pre-referral treatment had no beneficial effect on child survival in three highly malaria endemic settings. RAS is unlikely to reduce malaria deaths unless health system shortfalls such as referral and post-referral treatment are addressed.