Assessing availability, prices, and market share of quality-assured malaria ACT and RDT in the private retail sector in Nigeria and Uganda.

BACKGROUND: An estimated 50% of suspected malaria cases in sub-Saharan Africa first seek care in the private sector, especially in private medicine retail outlets. Quality of care in these outlets is generally unknown but considered poor with many patients not receiving a confirmatory diagnosis or the recommended first-line artemisinin-based combination therapy (ACT). In 2010, a subsidy pilot scheme, the Affordable Medicines Facility malaria, was introduced to crowd out the use of monotherapies in favour of WHO-pre-qualified artemisinin-based combinations (WHO-PQ-ACTs) in the private health sector. The scheme improved the availability, market share, and cost of WHO-PQ-ACTs in countries like Nigeria and Uganda, but in 2018, the subsidies were halted in Nigeria and significantly reduced in Uganda. This paper presents findings from six retail audit surveys conducted from 2014 to 2021 in Nigeria and Uganda to assess whether the impact of subsidies on the price, availability, and market share of artemisinin-based combinations has been sustained after the subsidies were reduced or discontinued. METHODS: Six independent retail audits were conducted in private medicine retail outlets, including pharmacies, drug shops, and clinics in Nigeria (2016, 2018, 2021), and Uganda (2014, 2019, 2020) to assess the availability, price, and market share of anti-malarials, including WHO-PQ-ACTs and non-WHO-PQ-ACTs, and malaria rapid diagnostic tests (RDTs). RESULTS: Between 2016 and 2021, there was a 57% decrease in WHO-PQ-ACT availability in Nigeria and a 9% decrease in Uganda. During the same period, non-WHO-PQ-ACT availability increased in Nigeria by 41% and by 34% in Uganda. The price of WHO-PQ-ACTs increased by 42% in Nigeria to $0.68 and increased in Uganda by 24% to $0.95. The price of non-WHO-PQ-ACTs decreased in Nigeria by 26% to $1.08 and decreased in Uganda by 64% to $1.23. There was a 76% decrease in the market share of WHO-PQ-ACTs in Nigeria and a 17% decrease in Uganda. Malaria RDT availability remained low throughout. CONCLUSION: With the reduction or termination of subsidies for WHO-PQ-ACTs in Uganda and Nigeria, retail prices have increased, and retail prices of non-WHO-PQ-ACTs decreased, likely contributing to a shift of higher availability and increased use of non-WHO-PQ-ACTs.

A cluster-randomized trial of client and provider-directed financial interventions to align incentives with appropriate case management in retail medicine outlets: Results of the TESTsmART Trial in western Kenya.

ACTs are responsible for a substantial proportion of the global reduction in malaria mortality over the last ten years, made possible by publicly-funded subsidies making these drugs accessible and affordable in the private sector. However, inexpensive ACTs available in retail outlets have contributed substantially to overconsumption. We test an innovative, scalable strategy to target ACT-subsidies to clients with a confirmatory diagnosis. We supported malaria testing(mRDTs) in 39 medicine outlets in western Kenya, randomized to three study arms; control arm offering subsidized mRDT testing (0.4USD), client-directed intervention where all clients who received a positive RDT at the outlet were eligible for a free (fully-subsidized) ACT, and a combined client and provider directed intervention where clients with a positive RDT were eligible for free ACT and outlets received 0.1USD for every RDT performed. Our primary outcome was the proportion of ACT dispensed to individuals with a positive diagnostic test. Secondary outcomes included proportion of clients tested at the outlet and adherence to diagnostic test results. 43% of clients chose to test at the outlet. Test results informed treatment decisions, resulting in targeting of ACTs to confirmed malaria cases- 25.3% of test-negative clients purchased an ACT compared to 75% of untested clients. Client-directed and client+provider-directed interventions did not offer further improvements, compared to the control arm, in testing rates(RD = 0.09, 95%CI:-0.08,0.26) or dispensing of ACTs to test-positive clients(RD = 0.01,95% CI:-0.14, 0.16). Clients were often unaware of the price they paid for the ACT leading to uncertainty in whether the ACT subsidy was passed on to the client. This uncertainty undermines our ability to definitively conclude that client-directed subsidies are not effective for improving testing and appropriate treatment. We conclude that mRDTs could reduce ACT overconsumption in the private retail sector, but incentive structures are difficult to scale and their value to private providers is uncertain. Trial registration: ClinicalTrials.gov NCT04428307.

Global risk of selection and spread of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions.

In the thirteen years since the first report of pfhrp2-deleted parasites in 2010, the World Health Organization (WHO) has found that 40 of 47 countries surveyed worldwide have reported pfhrp2/3 gene deletions. Due to a high prevalence of pfhrp2/3 deletions causing false-negative HRP2 RDTs, in the last five years, Eritrea, Djibouti and Ethiopia have switched or started switching to using alternative RDTs, that target pan-specific-pLDH or P. falciparum specific-pLDH alone of in combination with HRP2. However, manufacturing of alternative RDTs has not been brought to scale and there are no WHO prequalified combination tests that use Pf-pLDH instead of HRP2 for P. falciparum detection. For these reasons, the continued spread of pfhrp2/3 deletions represents a growing public health crisis that threatens efforts to control and eliminate P. falciparum malaria. National malaria control programmes, their implementing partners and test developers desperately seek pfhrp2/3 deletion data that can inform their immediate and future resource allocation. In response, we use a mathematical modelling approach to evaluate the global risk posed by pfhrp2/3 deletions and explore scenarios for how deletions will continue to spread in Africa. We incorporate current best estimates of the prevalence of pfhrp2/3 deletions and conduct a literature review to estimate model parameters known to impact the selection of pfhrp2/3 deletions for each malaria endemic country. We identify 20 countries worldwide to prioritise for surveillance and future deployment of alternative RDT, based on quickly selecting for pfhrp2/3 deletions once established. In scenarios designed to explore the continued spread of deletions in Africa, we identify 10 high threat countries that are most at risk of deletions both spreading to and subsequently being rapidly selected for. If HRP2-based RDTs continue to be relied on for malaria case management, we predict that the major route for pfhrp2 deletions to spread is south out from the current hotspot in the Horn of Africa, moving through East Africa over the next 20 years. We explore the variation in modelled timelines through an extensive parameter sensitivity analysis and despite wide uncertainties, we identify three countries that have not yet switched RDTs (Senegal, Zambia and Kenya) that are robustly identified as high risk for pfhrp2/3 deletions. These results provide a refined and updated prediction model for the emergence of pfhrp2/3 deletions in an effort to help guide pfhrp2/3 policy and prioritise future surveillance efforts and innovation.

Correction: Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study.

[This corrects the article DOI: 10.1371/journal.pmed.1004189.].

Pre-referral rectal artesunate is no "magic bullet" in weak health systems.

Severe malaria is a potentially fatal condition that requires urgent treatment. In a clinical trial, a sub-group of children treated with rectal artesunate (RAS) before being referred to a health facility had an increased chance of survival. We recently published in BMC Medicine results of the CARAMAL Project that did not find the same protective effect of pre-referral RAS implemented at scale under real-world conditions in three African countries. Instead, CARAMAL identified serious health system shortfalls that impacted the entire continuum of care, constraining the effectiveness of RAS. Correspondence to the article criticized the observational study design and the alleged interpretation and consequences of our findings.Here, we clarify that we do not dispute the life-saving potential of RAS, and discuss the methodological criticism. We acknowledge the potential for confounding in observational studies. Nevertheless, the totality of CARAMAL evidence is in full support of our conclusion that the conditions under which RAS can be beneficial were not met in our settings, as children often failed to complete referral and post-referral treatment was inadequate.The criticism did not appear to acknowledge the realities of highly malarious settings documented in detail in the CARAMAL project. Suggesting that trial-demonstrated efficacy is sufficient to warrant large-scale deployment of pre-referral RAS ignores the paramount importance of functioning health systems for its delivery, for completing post-referral treatment, and for achieving complete cure. Presenting RAS as a "magic bullet" distracts from the most urgent priority: fixing health systems so they can provide a functioning continuum of care and save the lives of sick children.The data underlying our publication is freely accessible on Zenodo.

Health worker compliance with severe malaria treatment guidelines in the context of implementing pre-referral rectal artesunate in the Democratic Republic of the Congo, Nigeria, and Uganda: An operational study.

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).

Pre-referral rectal artesunate: no cure for unhealthy systems.

Pre-referral rectal artesunate suppositories can save the lives of children with severe malaria if patients receive adequate post-referral care. A multi-country randomised controlled trial reporting on the efficacy of rectal artesunate informed the current WHO guidelines. In October, 2022, we reported on the findings of the Community Access to Rectal Artesunate for Malaria (CARAMAL) project, a carefully monitored roll-out of quality-assured rectal artesunate into established community-based health-care systems in DR Congo, Nigeria, and Uganda. The aim of the project was to understand the challenges involved in the successful real-world implementation of pre-referral rectal artesunate and to inform subsequent scale-up in endemic countries. In our study, we found that children treated with pre-referral rectal artesunate in routine clinical practice did not have an increased chance of survival, most likely explained by shortfalls along the continuum of care. A substantial proportion of the more than 6200 severely ill children that were followed up 28 days after treatment initiation did not receive comprehensive severe malaria care, either due to an incomplete referral to a secondary facility, or due to incomplete post-referral treatment. The observational study design allowed for a realistic assessment of the obstacles involved in implementing pre-referral rectal artesunate in settings where malaria mortality remains high. Without improving the entire continuum of care, children will continue to die from severe malaria and promising interventions will fail to meet their full potential.

Health system readiness and the implementation of rectal artesunate for severe malaria in sub-Saharan Africa: an analysis of real-world costs and constraints.

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.

Effectiveness of rectal artesunate as pre-referral treatment for severe malaria in children under 5 years of age: a multi-country observational study.

BACKGROUND: To prevent child deaths from severe malaria, early parenteral treatment is essential. Yet, in remote rural areas, accessing facilities offering parenteral antimalarials may be difficult. A randomised controlled trial found pre-referral treatment with rectal artesunate (RAS) to reduce deaths and disability in children who arrived at a referral facility with delay. This study examined the effectiveness of pre-referral RAS treatment implemented through routine procedures of established community-based health care systems. METHODS: An observational study accompanied the roll-out of RAS in the Democratic Republic of the Congo (DRC), Nigeria and Uganda. Children <5 years of age presenting to a community-based health provider with a positive malaria test and signs of severe malaria were enrolled and 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. RESULTS: Post-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; 13.8% (865/6286) of patients were sick on day 28. The CFR was higher after RAS roll-out in Nigeria (16.1 vs. 4.2%) and stable in DRC (6.7 vs. 6.6%) and Uganda (0.7 vs. 0.3%). In DRC and Nigeria, children receiving RAS were more likely to die than those not receiving RAS (aOR=3.06, 95% CI 1.35-6.92 and aOR=2.16, 95% CI 1.11-4.21, respectively). Only in Uganda, RAS users were less likely to be dead or sick at follow-up (aOR=0.60, 95% CI 0.45-0.79). Post-referral parenteral antimalarials plus oral artemisinin-based combination therapy (ACT), a proxy for appropriate post-referral treatment, was protective. However, in referral health facilities, ACT was not consistently administered after parenteral treatment (DRC 68.4%, Nigeria 0%, Uganda 70.9%). CONCLUSIONS: Implemented at scale to the recommended target group, pre-referral RAS had no beneficial effect on child survival in three highly malaria-endemic settings. RAS is unlikely to reduce malaria deaths unless health system issues such as referral and quality of care at all levels are addressed. TRIAL REGISTRATION: The study is registered on ClinicalTrials.gov : NCT03568344.

Prereferral rectal artesunate and referral completion among children with suspected severe malaria in the Democratic Republic of the Congo, Nigeria and Uganda.

INTRODUCTION: Children 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. METHODS: An 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. RESULTS: Referral 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). CONCLUSIONS: The 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 NUMBER: NCT03568344; ClinicalTrials.gov.

How do malaria testing and treatment subsidies affect drug shop client expenditures? A cross-sectional analysis in Western Kenya.

OBJECTIVES: To examine how drug shop clients' expenditures are affected by subsidies for malaria diagnostic testing and for malaria treatment, and also to examine how expenditures vary by clients' malaria test result and by the number of medications they purchased. DESIGN: Secondary cross-sectional analysis of survey responses from a randomised controlled trial. SETTING: The study was conducted in twelve private drug shops in Western Kenya. PARTICIPANTS: We surveyed 836 clients who visited the drug shops between March 2018 and October 2019 for a malaria-like illness. This included children >1 year of age if they were physically present and accompanied by a parent or legal guardian. INTERVENTIONS: Subsidies for malaria diagnostic testing and for malaria treatment (conditional on a positive malaria test result). PRIMARY AND SECONDARY OUTCOME MEASURES: Expenditures at the drug shop in Kenya shillings (Ksh). RESULTS: Clients who were randomised to a 50% subsidy for malaria rapid diagnostic tests (RDTs) spent approximately Ksh23 less than those who were randomised to no RDT subsidy (95% CI (-34.6 to -10.7), p=0.002), which corresponds approximately to the value of the subsidy (Ksh20). However, clients randomised to receive free treatment (artemisinin combination therapies (ACTs)) if they tested positive for malaria had similar spending levels as those randomised to a 67% ACT subsidy conditional on a positive test. Expenditures were also similar by test result, however, those who tested positive for malaria bought more medications than those who tested negative for malaria while spending approximately Ksh15 less per medication (95% CI (-34.7 to 3.6), p=0.102). CONCLUSIONS: Our results suggest that subsidies for diagnostic health products may result in larger household savings than subsidies on curative health products. A better understanding of how people adjust their behaviours and expenditures in response to subsidies could improve the design and implementation of subsidies for health products. TRIAL REGISTRATION NUMBER: NCT03810014.

Community access to rectal artesunate for malaria (CARAMAL): A large-scale observational implementation study in the Democratic Republic of the Congo, Nigeria and Uganda.

The key to reducing malaria deaths in highly endemic areas is prompt access to quality case management. Given that many severe cases occur at peripheral level, rectal artesunate (RAS) in the form of suppositories was developed in the 1990s, allowing for rapid initiation of life-saving antimalarial treatment before referral to a health facility with full case management capabilities. One randomized controlled trial published in 2009 showed a protective effect of RAS pre-referral treatment against overall mortality of 26%, but with significant differences according to study sites and length of referral. Two important issues remained unaddressed: (1) whether the mortality impact of RAS observed under controlled trial conditions could be replicated under real-world circumstances; and (2) clear operational guidance for the wide-scale implementation of RAS, including essential health system determinants for optimal impact. From 2018 to 2020, the Community Access to Rectal Artesunate for Malaria (CARAMAL) project was conducted as a large-scale observational implementation study in the Democratic Republic of the Congo (DRC), Nigeria, and Uganda (registered on ClinicalTrials.gov as NCT03568344). CARAMAL aimed to provide high-quality field evidence on the two issues above, in three remote settings with high malaria endemicity. A number of complementary study components were implemented. The core of the CARAMAL study was the Patient Surveillance System (PSS), which allowed tracking of cases of severe febrile illness from first contact at the periphery to a referral health facility, and then on to a Day 28 visit at the home of the patient. Community and provider cross-sectional surveys complemented the PSS. Here we describe in some detail RAS implementation, as well as the key CARAMAL study components and basic implementation experience. This manuscript does not intend to present key study results, but provides an extensive reference document for the companion papers describing the impact, referral process, post-referral treatment and costing of the RAS intervention.

Evaluating Vertical Malaria Community Health Worker Programs as Malaria Declines: Learning From Program Evaluations in Honduras and Lao PDR.

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.

A comparative evaluation of mobile medical APPS (MMAS) for reading and interpreting malaria rapid diagnostic tests.

BACKGROUND: The World Health Organization recommends confirmatory diagnosis by microscopy or malaria rapid diagnostic test (RDT) in patients with suspected malaria. In recent years, mobile medical applications (MMAs), which can interpret RDT test results have entered the market. To evaluate the performance of commercially available MMAs, an evaluation was conducted by comparing RDT results read by MMAs to RDT results read by the human eye. METHODS: Five different MMAs were evaluated on six different RDT products using cultured Plasmodium falciparum blood samples at five dilutions ranging from 20 to 1000 parasites (p)/microlitre (µl) and malaria negative blood samples. The RDTs were performed in a controlled, laboratory setting by a trained operator who visually read the RDT results. A second trained operator then used the MMAs to read the RDT results. Sensitivity (Sn) and specificity (Sp) for the RDTs were calculated in a Bayesian framework using mixed models. RESULTS: The RDT Sn of the P. falciparum (Pf) test line, when read by the trained human eye was significantly higher compared to when read by MMAs (74% vs. average 47%) at samples of 20 p/µl. In higher density samples, the Sn was comparable to the human eye (97%) for three MMAs. The RDT Sn of test lines that detect all Plasmodium species (Pan line), when read by the trained human eye was significantly higher compared to when read by MMAs (79% vs. average 56%) across all densities. The RDT Sp, when read by the human eye or MMAs was 99% for both the Pf and Pan test lines across all densities. CONCLUSIONS: The study results show that in a laboratory setting, most MMAs produced similar results interpreting the Pf test line of RDTs at parasite densities typically found in patients that experience malaria symptoms (> 100 p/µl) compared to the human eye. At low parasite densities for the Pf line and across all parasite densities for the Pan line, MMAs were less accurate than the human eye. Future efforts should focus on improving the band/line detection at lower band intensities and evaluating additional MMA functionalities like the ability to identify and classify RDT errors or anomalies.

Incentivizing appropriate malaria case management in the private sector: a study protocol for two linked cluster randomized controlled trials to evaluate provider- and client-focused interventions in western Kenya and Lagos, Nigeria.

BACKGROUND: A large proportion of artemisinin-combination therapy (ACT) anti-malarial medicines is consumed by individuals that do not have malaria. The over-consumption of ACTs is largely driven by retail sales in high malaria-endemic countries to clients who have not received a confirmatory diagnosis. This study aims to target ACT sales to clients receiving a confirmatory diagnosis using malaria rapid diagnostic tests (mRDTs) at retail outlets in Kenya and Nigeria. METHODS: This study comprises two linked four-arm 2 × 2 factorial cluster randomized controlled trials focused on malaria diagnostic testing and conditional ACT subsidies with the goal to evaluate provider-directed and client-directed interventions. The linked trials will be conducted at two contrasting study sites: a rural region around Webuye in western Kenya and the urban center of Lagos, Nigeria. Clusters are 41 and 48 participating retail outlets in Kenya and Nigeria, respectively. Clients seeking care at participating outlets across all arms will be given the option of paying for a mRDT-at a study-recommended price-to be conducted at the outlet. In the provider-directed intervention arm, the outlet owner receives a small monetary incentive to perform the mRDT. In the client-directed intervention arm, the client receives a free ACT if they purchase an mRDT and receive a positive test result. Finally, the fourth study arm combines both the provider- and client-directed interventions. The diagnosis and treatment choices made during each transaction will be captured using a mobile phone app. Study outcomes will be collected through exit interviews with clients, who sought care for febrile illness, at each of the enrolled retail outlets. RESULTS: The primary outcome measure is the proportion of all ACTs that are sold to malaria test-positive clients in each study arm. For all secondary outcomes, we will evaluate the degree to which the interventions affect purchasing behavior among people seeking care for a febrile illness at the retail outlet. CONCLUSIONS: If our study demonstrates that malaria case management can be improved in the retail sector, it could reduce overconsumption of ACTs and enhance targeting of publicly funded treatment reimbursements, lowering the economic barrier to appropriate diagnosis and treatment for patients with malaria. TRIAL REGISTRATION: ClinicalTrials.gov NCT04428307 , registered June 9, 2020, and NCT04428385 , registered June 9, 2020.

Subsidise the test, the treatment or both? Results of an individually randomised controlled trial of the management of suspected malaria fevers in the retail sector in western Kenya.

INTRODUCTION: In many malaria-endemic countries, the private retail sector is a major source of antimalarial drugs. However, the rarity of malaria diagnostic testing in the retail sector leads to overuse of the first-line class of antimalarial drugs known as artemisinin-combination therapies (ACTs). The goal of this study was to identify the combination of malaria rapid diagnostic test (RDT) and ACT subsidies that maximises the proportion of clients seeking care in a retail outlet that choose to purchase an RDT (RDT uptake) and use ACTs appropriately. METHODS: 842 clients seeking care in 12 select retail outlets in western Kenya were recruited and randomised into 4 arms of different combinations of ACT and RDT subsidies, with ACT subsidies conditional on a positive RDT. The outcomes were RDT uptake (primary) and appropriate and targeted ACT use (secondary). Participants' familiarity with RDTs and their confidence in test results were also evaluated. RESULTS: RDT uptake was high (over 96%) across the study arms. Testing uptake was 1.025 times higher (98% CI 1.002 to 1.049) in the RDT subsidised arms than in the unsubsidised groups. Over 98% of clients were aware of malaria testing, but only 35% had a previous experience with RDTs. Nonetheless, confidence in the accuracy of RDTs was high. We found high levels of appropriate use and targeting of ACTs, with 86% of RDT positives taking an ACT, and 93.4% of RDT negatives not taking an ACT. The conditional ACT subsidy did not affect the RDT test purchasing behaviour (risk ratio: 0.994; 98% CI 0.979 to 1.009). CONCLUSION: Test dependent ACT subsidies may contribute to ACT targeting. However, in this context, high confidence in the accuracy of RDTs and reliable supplies of RDTs and ACTs likely played a greater role in testing uptake and adherence to test results.

Introducing malaria rapid diagnostic tests in private medicine retail outlets: A systematic literature review.

BACKGROUND: Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs. To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures. This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions. METHODS: Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed. Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings. Outcomes were extracted from publications or provided by principal investigators. RESULTS: Six published and six unpublished studies were found. Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies. None of the studies assessed large-scale implementation in PMRs. RDT uptake varied widely from 8%-100%. Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies. Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies. Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results. Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges. CONCLUSIONS: Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials. However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.

Expanding access to parasite-based malaria diagnosis through retail drug shops in Tanzania: evidence from a randomized trial and implications for treatment.

BACKGROUND: Tanzania has seen a reduction in the fraction of fevers caused by malaria, likely due in part to scale-up of control measures. While national guidelines require parasite-based diagnosis prior to treatment, it is estimated that more than half of suspected malaria treatment-seeking in Tanzania initiates in the private retail sector, where diagnosis by malaria rapid diagnostic test (RDT) or microscopy is illegal. This pilot study investigated whether the introduction of RDTs into Accredited Drug Dispensing Outlets (ADDOs) under realistic market conditions would improve case management practices. METHODS: Dispensers from ADDOs in two intervention districts in Tanzania were trained to stock and perform RDTs and monitored quarterly. Each district was assigned a different recommended retail price to evaluate the need for a subsidy. Malaria RDT and artemisinin-based combination therapy (ACT) uptake and availability were measured pre-intervention and 1 year post-intervention through structured surveys of ADDO owners and exiting customers in both intervention districts and one contiguous control district. Descriptive analysis and logistic regression were used to compare the three districts and identify predictive variables for testing. RESULTS AND DISCUSSION: A total of 310 dispensers from 262 ADDOs were trained to stock and perform RDTs. RDT availability in intervention ADDOs increased from 1% (n = 172) to 73% (n = 163) during the study; ACT medicines were available in 75% of 260 pre-intervention and 68% of 254 post-intervention ADDOs. Pre-treatment testing performed within the ADDO increased from 0 to 65% of suspected malaria patients who visited a shop (95% CI 60.8-69.6%) with no difference between intervention districts. Overall parasite-based diagnosis increased from 19 to 74% in intervention districts and from 3 to 18% in the control district. Prior knowledge of RDT availability (aOR = 1.9, p = 0.03) and RDT experience (aOR = 1.9, p = 0.01) were predictors for testing. Adherence data indicated that 75% of malaria positives received ACT, while 3% of negatives received ACT. CONCLUSIONS: Trained and supervised ADDO dispensers in rural Tanzania performed and sold RDTs under real market conditions to two-thirds of suspected malaria patients during this one-year pilot. These results support the hypothesis that introducing RDTs into regulated private retail sector settings can improve malaria testing and treatment practices without an RDT subsidy. Trial registration ISRCTN ISRCTN14115509.