Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to high Plasmodium falciparum transmission and currently depends on the administration of sulfadoxine-pyrimethamine plus amodiaquine. However, poor regimen adherence and the increased frequency of parasite mutations conferring sulfadoxine-pyrimethamine resistance might threaten the effectiveness of SMC. Guidance is needed to de-risk the development of drug compounds for malaria prevention. We aimed to provide guidance for the early prioritisation of new and alternative SMC drugs and their target product profiles. METHODS: In this modelling study, we combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic and pharmacodynamic models. We modelled SMC drug attributes for several possible modes of action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum parasite killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions. FINDINGS: Model predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When children younger than 5 years receive four SMC cycles with high levels of coverage (ie, 69% of children receiving all cycles), drug candidates require a duration of protection half-life higher than 23 days (elimination half-life >10 days) to achieve reductions higher than 75% in clinical incidence and severe disease (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is crucial to achieve these targets, requiring more than 60% of children to receive all SMC cycles and more than 90% of children to receive at least one cycle regardless of the protection duration of the drug. INTERPRETATION: Although efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determining cycle timing. Explicitly designing or selecting drug properties to increase community uptake is paramount. FUNDING: Bill & Melinda Gates Foundation and the Swiss National Science Foundation.

Supply-side and demand-side factors influencing uptake of malaria testing services in the community: lessons for scale-up from a post-hoc analysis of a cluster randomised, community-based trial in western Kenya.

OBJECTIVES: Maximising the impact of community-based programmes requires understanding how supply of, and demand for, the intervention interact at the point of delivery. DESIGN: Post-hoc analysis from a large-scale community health worker (CHW) study designed to increase the uptake of malaria diagnostic testing. SETTING: Respondents were identified during a household survey in western Kenya between July 2016 and April 2017. PARTICIPANTS: Household members with fever in the last 4 weeks were interviewed at 12 and 18 months post-implementation. We collected monthly testing data from 244 participating CHWs and conducted semistructured interviews with a random sample of 70 CHWs. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure was diagnostic testing before treatment for a recent fever. The secondary outcomes were receiving a test from a CHW and tests done per month by each CHW. RESULTS: 55% (n=948 of 1738) reported having a malaria diagnostic test for their recent illness, of which 38.4% were tested by a CHW. Being aware of a local CHW (adjusted OR=1.50, 95% CI: 1.10 to 2.04) and belonging to the wealthiest households (vs least wealthy) were associated with higher testing (adjusted OR=1.53, 95% CI: 1.14 to 2.06). Wealthier households were less likely to receive their test from a CHW compared with poorer households (adjusted OR=0.32, 95% CI: 0.17 to 0.62). Confidence in artemether-lumefantrine to cure malaria (adjusted OR=2.75, 95% CI: 1.54 to 4.92) and perceived accuracy of a malaria rapid diagnostic test (adjusted OR=2.43, 95% CI: 1.12 to 5.27) were positively associated with testing by a CHW. Specific CHW attributes were associated with performing a higher monthly number of tests including formal employment, serving more than 50 households (vs <50) and serving areas with a higher test positivity. On demand side, confidence of the respondent in a test performed by a CHW was strongly associated with seeking a test from a CHW. CONCLUSION: Scale-up of community-based malaria testing is feasible and effective in increasing uptake among the poorest households. To maximise impact, it is important to recognise factors that may restrict delivery and demand for such services. TRIAL REGISTRATION NUMBER: NCT02461628; Post-results.

Modelling to inform next-generation medical interventions for malaria prevention and treatment.

Global progress against malaria has stagnated and novel medical interventions to prevent malaria are needed to fill gaps in existing tools and improve protection against infection and disease. Candidate selection for next-generation interventions should be supported by the best available evidence. Target product profiles and preferred product characteristics play a key role in setting selection criteria requirements and early endorsement by health authorities. While clinical evidence and expert opinion often inform product development decisions, integrating modelling evidence early and iteratively into this process provides an opportunity to link product characteristics with expected public health outcomes. Population models of malaria transmission can provide a better understanding of which, and at what magnitude, key intervention characteristics drive public health impact, and provide quantitative evidence to support selection of use-cases, transmission settings, and deployment strategies. We describe how modelling evidence can guide and accelerate development of new malaria vaccines, monoclonal antibodies, and chemoprevention.

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.

Investigating the drivers of the spatio-temporal patterns of genetic differences between Plasmodium falciparum malaria infections in Kilifi County, Kenya.

Knowledge of how malaria infections spread locally is important both for the design of targeted interventions aiming to interrupt malaria transmission and the design of trials to assess the interventions. A previous analysis of 1602 genotyped Plasmodium falciparum parasites in Kilifi, Kenya collected over 12 years found an interaction between time and geographic distance: the mean number of single nucleotide polymorphism (SNP) differences was lower for pairs of infections which were both a shorter time interval and shorter geographic distance apart. We determine whether the empiric pattern could be reproduced by a simple model, and what mean geographic distances between parent and offspring infections and hypotheses about genotype-specific immunity or a limit on the number of infections would be consistent with the data. We developed an individual-based stochastic simulation model of households, people and infections. We parameterized the model for the total number of infections, and population and household density observed in Kilifi. The acquisition of new infections, mutation, recombination, geographic location and clearance were included. We fit the model to the observed numbers of SNP differences between pairs of parasite genotypes. The patterns observed in the empiric data could be reproduced. Although we cannot rule out genotype-specific immunity or a limit on the number of infections per individual, they are not necessary to account for the observed patterns. The mean geographic distance between parent and offspring malaria infections for the base model was 0.5 km (95% CI 0.3-1.5), for a distribution with 68% of distances shorter than the mean. Very short mean distances did not fit well, but mixtures of distributions were also consistent with the data. For a pathogen which undergoes meiosis in a setting with moderate transmission and a low coverage of infections, analytic methods are limited but an individual-based model can be used with genotyping data to estimate parameter values and investigate hypotheses about underlying processes.

Can trials of spatial repellents be used to estimate mosquito movement?

BACKGROUND: Knowledge of mosquito movement would aid the design of effective intervention strategies against malaria. However, data on mosquito movement through mark-recapture or genetics studies are challenging to collect, and so are not available for many sites. An additional source of information may come from secondary analyses of data from trials of repellents where household mosquito densities are collected. Using the study design of published trials, we developed a statistical model which can be used to estimate the movement between houses for mosquitoes displaced by a spatial repellent. The method uses information on the different distributions of mosquitoes between houses when no households are using spatial repellents compared to when there is incomplete coverage. The parameters to be estimated are the proportion of mosquitoes repelled, the proportion of those repelled that go to another house and the mean distance of movement between houses. Estimation is by maximum likelihood. RESULTS: We evaluated the method using simulation and found that data on the seasonal pattern of mosquito densities were required, which could be additionally collected during a trial. The method was able to provide accurate estimates from simulated data, except when the setting has few mosquitoes overall, few repelled, or the coverage with spatial repellent is low. The trial that motivated our analysis was found to have too few mosquitoes caught and repelled for our method to provide accurate results. CONCLUSIONS: We propose that the method could be used as a secondary analysis of trial data to gain estimates of mosquito movement in the presence of repellents for trials with sufficient numbers of mosquitoes caught and repelled and with coverage levels which allow sufficient numbers of houses with and without repellent. Estimates from this method may supplement those from mark-release-recapture studies, and be used in designing effective malaria intervention strategies, parameterizing mathematical models and in designing trials of vector control interventions.

Efficacy of Mobile Phone Short Message Service (SMS) Reminders on Malaria Treatment Adherence and Day 3 Post-Treatment Reviews (SMS-RES-MAL) in Kenya: A Study Protocol.

BACKGROUND: Mobile phone short messaging services (SMS) have been investigated in health information reporting, provider performance, drug and diagnostic stock management and patient adherence to treatment for chronic diseases. However, their potential role in improving patients' adherence to malaria treatment and day 3 post treatment reviews remains unclear. METHODS/DESIGN: A "proof of concept" open label randomised controlled trial will be conducted at four sites in Western Kenya. Principal research questions are: 1) Can mobile phone SMS reminders improve patient adherence to malaria treatment? 2) Can mobile phone SMS reminders improve day 3 post treatment reviews? Eligible caregivers (n=1000 per arm) of children under five years old with uncomplicated malaria will be randomly assigned (one to one) to: a) the current standard of care (provider counselling and health education); and b) the current standard of care plus SMS reminders. Within each arm, caregivers will be further randomized to three different categories. In categories 1 and 2, 300 caregivers per arm per category will be visited at home on day 1 and 2 of follow up respectively, to measure appropriate timing and adherence of the second Artemether-Lumefantrine (AL) dose and doses 3 and 4. Further, caregivers in categories 1 and 2 will be required to come to the health facility for the day 3 post treatment reviews. Finally, in category 3, 400 caregivers per arm will be visited at home on day 3 to measure adherence for the full AL course. Each category will be visited at home only once to avoid biases in the measures of adherence as a result of home consultations. Primary outcomes will be adherence to the full AL course (category 3), as well as, the proportion of patients reporting back for day 3 post treatment reviews (categories 1 and 2). The primary analysis will be intention-to-treat. Costs of the intervention will be measured over the period of the intervention, and a cost-effectiveness ratio will be estimated. DISCUSSION: If successful, evidence from this trial could improve malaria treatment adherence and offer pragmatic approaches for antimalarial drug resistance surveillance and risk mitigation in Africa. CURRENT CONTROLLED TRIALS: ISRCTN39512726.

Completeness of malaria indicator data reporting via the District Health Information Software 2 in Kenya, 2011-2015.

BACKGROUND: Health facility-based data reported through routine health information systems form the primary data source for programmatic monitoring and evaluation in most developing countries. The adoption of District Health Information Software (DHIS2) has contributed to improved availability of routine health facility-based data in many low-income countries. An assessment of malaria indicators data reported by health facilities in Kenya during the first 5 years of implementation of DHIS2, from January 2011 to December 2015, was conducted. METHODS: Data on 19 malaria indicators reported monthly by health facilities were extracted from the online Kenya DHIS2 database. Completeness of reporting was analysed for each of the 19 malaria indicators and expressed as the percentage of data values actually reported over the expected number; all health facilities were expected to report data for each indicator for all 12 months in a year. RESULTS: Malaria indicators data were analysed for 6235 public and 3143 private health facilities. Between 2011 and 2015, completeness of reporting in the public sector increased significantly for confirmed malaria cases across all age categories (26.5-41.9%, p < 0.0001, in children aged <5 years; 30.6-51.4%, p < 0.0001, in persons aged ≥5 years). Completeness of reporting of new antenatal care (ANC) clients increased from 53.7 to 70.5%, p < 0.0001). Completeness of reporting of intermittent preventive treatment in pregnancy (IPTp) decreased from 64.8 to 53.7%, p < 0.0001 for dose 1 and from 64.6 to 53.4%, p < 0.0001 for dose 2. Data on malaria tests performed and test results were not available in DHIS2 from 2011 to 2014. In 2015, sparse data on microscopy (11.5% for children aged <5 years; 11.8% for persons aged ≥5 years) and malaria rapid diagnostic tests (RDTs) (8.1% for all ages) were reported. In the private sector, completeness of reporting increased significantly for confirmed malaria cases across all age categories (16.7-23.1%, p < 0.0001, in children aged <5 years; 19.4-28.6%, p < 0.0001, in persons aged ≥5 years). Completeness of reporting also improved for new ANC clients (16.2-23.6%, p < 0.0001), and for IPTp doses 1 and 2 (16.6-20.2%, p < 0.0001 and 15.5-20.5%, p < 0.0001, respectively). In 2015, less than 3% of data values for malaria tests performed were reported in DHIS2 from the private sector. CONCLUSIONS: There have been sustained improvements in the completeness of data reported for most key malaria indicators since the adoption of DHIS2 in Kenya in 2011. However, major data gaps were identified for the malaria-test indicator and overall low reporting across all indicators from private health facilities. A package of proven DHIS2 implementation interventions and performance-based incentives should be considered to improve private-sector data reporting.

Efficacy of text-message reminders on paediatric malaria treatment adherence and their post-treatment return to health facilities in Kenya: a randomized controlled trial.

BACKGROUND: Short Message Service (SMS) reminders have been suggested as a potential intervention for improving adherence to medications and health facility attendance. METHODS: An open-label, randomized, controlled trial to test the efficacy of automated SMS reminders in improving adherence to artemether-lumefantrine (AL) and post-treatment attendance in comparison with standard care was conducted at four health facilities in western Kenya. Children below five years of age with uncomplicated malaria were randomized to intervention (SMS reminders) or control groups. Within each study group they were further randomized to three categories, which determined the timing of home visits to measure adherence to complete AL course and to individual AL doses. A sub-set of caregivers was advised to return to the facility on day 3 and all were advised to return after 28 days. The primary outcomes were adherence to medication and return on day 3. The primary analysis was by intention-to-treat. RESULTS: Between 9 June, 2014 and 26 February, 2016, 1677 children were enrolled. Of 562 children visited at home on day 3, all AL doses were completed for 97.6% (282/289) of children in the control and 97.8% (267/273) in the intervention group (OR = 1.10; 95% CI = 0.37-3.33; p = 0.860). When correct timing in taking each dose was considered a criteria for adherence, 72.3% (209/289) were adherent in the control and 69.2% (189/273) in the intervention group (OR = 0.82; 95% CI = 0.56-1.19; p = 0.302). Sending SMS reminders significantly increased odds of children returning to the facility on day 3 (81.4 vs 74.0%; OR = 1.55; 95% CI = 1.15-2.08; p = 0.004) and on day 28 (63.4 vs 52.5%; OR = 1.58; 95% CI = 1.30-1.92; p < 0.001). CONCLUSIONS: In this efficacy trial, SMS reminders increased post-treatment return to the health facility, but had no effect on AL adherence which was high in both control and intervention groups. Further effectiveness studies under the real world conditions are needed to determine the optimum role of SMS reminders. Trial registration ISRCTN39512726.

A national health facility survey of malaria infection among febrile patients in Kenya, 2014.

BACKGROUND: The use of malaria infection prevalence among febrile patients at clinics has a potential to be a valuable epidemiological surveillance tool. However, routine data are incomplete and not all fevers are tested. This study was designed to screen all fevers for malaria infection in Kenya to explore the epidemiology of fever test positivity rates. METHODS: Random sampling was used within five malaria epidemiological zones of Kenya (i.e., high lake endemic, moderate coast endemic, highland epidemic, seasonal low transmission and low risk zones). The selected sample was representative of the number of hospitals, health centres and dispensaries within each zone. Fifty patients with fever presenting to each sampled health facility during the short rainy season were screened for malaria infection using a rapid diagnostic test (RDT). Details of age, pregnancy status and basic demographics were recorded for each patient screened. RESULTS: 10,557 febrile patients presenting to out-patient clinics at 234 health facilities were screened for malaria infection. 1633 (15.5%) of the patients surveyed were RDT positive for malaria at 124 (53.0%) facilities. Infection prevalence among non-pregnant patients varied between malaria risk zones, ranging from 0.6% in the low risk zone to 41.6% in the high lake endemic zone. Test positivity rates (TPR) by age group reflected the differences in the intensity of transmission between epidemiological zones. In the lake endemic zone, 6% of all infections were among children aged less than 1 year, compared to 3% in the coast endemic, 1% in the highland epidemic zone, less than 1% in the seasonal low transmission zone and 0% in the low risk zone. Test positivity rate was 31% among febrile pregnant women in the high lake endemic zone compared to 9% in the coast endemic and highland epidemic zones, 3.2% in the seasonal low transmission zone and zero in the low risk zone. CONCLUSION: Malaria infection rates among febrile patients, with supporting data on age and pregnancy status presenting to clinics in Kenya can provide invaluable epidemiological data on spatial heterogeneity of malaria and serve as replacements to more expensive community-based infection rates to plan and monitor malaria control.

Health systems readiness and management of febrile outpatients under low malaria transmission in Vanuatu.

BACKGROUND: Vanuatu, an archipelago country in Western Pacific harbouring low Plasmodium falciparum and Plasmodium vivax malaria transmission, has been implementing a malaria case management policy, recommending parasitological testing of patients with fever and anti-malarial treatment for test-positive only patients. A health facility survey to evaluate the health systems readiness to implement the policy and the quality of outpatient management for patients with fever was undertaken. METHODS: A cross-sectional, cluster sample survey, using a range of quality-of-care methods, included all health centres and hospitals in Vanuatu. The main outcome measures were coverage of health facilities and health workers with commodities and support interventions, adherence to test and treatment recommendations, and factors influencing malaria testing. RESULTS: The survey was undertaken in 2014 during the low malaria season and included 41 health facilities, 67 health workers and 226 outpatient consultations for patients with fever. All facilities had capacity for parasitological diagnosis, 95.1 % stocked artemether-lumefantrine and 63.6 % primaquine. The coverage of health workers with support interventions ranged from 50 to 70 %. Health workers' knowledge was high only regarding treatment policy for uncomplicated P. falciparum malaria (83.4 %). History taking and clinical examination practices were sub-optimal. Some 35.0 % (95 % CI 23.4-48.6) of patients with fever were tested for malaria, of which all results were negative and only one patient received anti-malarial treatment. Testing was significantly higher for patients age 5 years and older (OR = 2.33; 95 % CI 1.48-5.02), seen by less qualified health workers (OR = 2.73; 95 % CI 1.48-5.02), health workers who received malaria case management training (OR = 2.39; 95 % CI 1.28-4.47) and patients with increased temperature (OR = 2.56; 95 % CI 1.17-5.57), main complaint of fever (OR = 5.82; 95 % CI 1.26-26.87) and without runny nose (OR = 3.75; 95 % CI 1.36-10.34). Antibiotic use was very high (77.4 %) with sub-optimal dispensing and counselling practices. CONCLUSIONS: Health facility and health worker readiness to implement policy is higher for falciparum than vivax malaria. Clinical and malaria testing practices are sub-optimal, however adherence to test negative results is nearly universal. Use of antibiotics is irrational. Quantitative and qualitative improvements of ongoing interventions are needed to re-inforce clinical practices in this area characterized by difficult access, human resource shortages but aspiring towards malaria elimination.

Development of a text-messaging intervention to improve treatment adherence and post-treatment review of children with uncomplicated malaria in western Kenya.

BACKGROUND: Patients' low adherence to artemisinin-based combination therapy has been reported in areas of Kenya bordering the Lake Victoria region, where the burden of malaria remains high. A randomized controlled trial is underway to determine the efficacy of short message service (SMS) text reminders on adherence to artemether-lumefantrine and post-treatment review of children under the age of five. This paper reports on the iterative process of intervention and delivery system development. METHODS: An intervention development workshop involving the research team and other stakeholders was held to determine the content of the text messages. Three focus group discussions were conducted to test caregivers' understanding of the messages developed during the workshop. The tested messages were refined and incorporated into an automated SMS distribution system and piloted with 20 caregivers drawn from facilities neighbouring the study sites. The automated SMS distribution system was repeatedly refined following the pilot and implemented at the start of the trial. RESULTS: The content of SMS messages underwent major revisions following the focus group discussions. Technical terms and abbreviations were replaced with simplified general terms. Message sign-off was modified to reflect the name of health facility, removing references to health workers. Day 3 post-treatment review visit reminder was modified to state the purpose of the visit while wording 'day 28' was added to the last post-treatment review visit reminder to help the caregiver recall the appointment date. The unscheduled visit prompt was modified to reflect flexibility and practicality of taking the child back to the facility if unwell. Reception of SMS reminders during the pilot was low with only 169/240 (70%) of scheduled messages delivered to the caregivers. The automated distribution system underwent major refinement and repeated testing following the pilot until effective delivery of all scheduled messages was achieved and sustained over a period of 3 months. CONCLUSIONS: Text message interventions should be carefully developed, tested and refined before implementation to ensure they are written in the most appropriate way for their target population. SMS distribution systems should be rigorously tested to ensure efficient delivery of the messages before they are deployed.