Maximising the impact of chemoprevention on the malaria burden in children in areas of seasonal transmission

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Epidemiology and Population Health

Abstract

Malaria is a parasitic disease transmitted by mosquitoes that kills approximately 850,000 people every year, mostly children under five years of age living in sub-Saharan Africa. Prevention of malaria is key to achieving Millennium Development Goals.
The epidemiology or disease pattern of malaria varies widely across Africa, both in terms of intensity (the number of infections individuals are exposed to), and seasonality (how the pattern of risk varies over the course of the year).
In areas of Africa where malaria is only a problem during a short rainy season, monthly courses of antimalarial drugs can prevent malaria in children very effectively. This approach, called seasonal malaria chemoprevention (SMC), may also be useful in places where malaria is transmitted for longer each year. However, the impact in such areas is not well understood.
Another form of prevention that would be easier for African countries to put into practice would be to treat malaria patients with long-lasting artemisinin combination therapies (LACTs), which prevent further malaria infections for several weeks. Malaria does not affect all children equally: a fraction of children repeatedly experience malaria, while other children remain healthy. Repeated malaria leads to severe anaemia, an important cause of death in areas where malaria is endemic.
LACTs would prevent some repeated malaria attacks, and may be a simple and effective way to target limited resources at the individuals who most need protection. This may be particularly beneficial in areas with seasonal malaria transmission because repeated malaria attacks are likely to occur close together in time. In such areas, LACTs could help ensure that a child's first attack each year is their last.
Dr Matthew Cairns, an epidemiologist based at the London School of Hygiene & Tropical Medicine, will use a multi-disciplinary approach to investigate these issues.
Studies of malaria conducted in West Africa will provide data on the epidemiology of malaria in different areas. Data will be analysed to quantify the fraction of the total malaria and anaemia burden that occurs soon after a previous malaria attack, and which might therefore be prevented by replacing standard antimalarials with LACTs. This analysis will also determine the situations in which malaria is most unevenly focused on a small sub-group of children, and identify characteristics associated with high risk. This could lead to changes in which antimalarials are recommended as policy in some parts of Africa.
A mathematical model developed by Dr Cairns will be extended to determine the impact of LACTs and SMC in a range of areas, using a range of assumptions about the effectiveness of drugs and the use of treatment by different children. The model will also allow exploration of the impact of combining these two interventions, which might be very expensive to do in a clinical trial. If the predicted impact of SMC is sufficient, this could lead to expansion of the area where SMC is deployed. Data from a clinical trial in Ghana investigating these two forms of prevention (arranged outside the fellowship), will be analysed to determine the real-life impact of these interventions, and help improve the accuracy of the model predictions.
Computer based simulations including rainfall and other climatic data will then be used to identify the geographical areas where SMC and LACTs are likely to be useful, and their potential impact on disease and on transmission of malaria. Maps will be produced showing results at sub-country level.
Results of the research will help policy makers at the World Health Organisation and in malaria-endemic countries to make decisions on the recommended treatment for malaria, and to plan and prioritise where to deploy these two forms of malaria prevention. Both interventions could have an important impact on the health of African children within the next five years.

Technical Summary

Aims and Objectives
Understand where replacing standard antimalarials with LACTs would be useful by quantifying the burden of repeated malaria and the heterogeneity in malaria risk in different epidemiological settings.
Evaluate the potential for extended SMC and LACT in different epidemiological situations using a mathematical model and data from a clinical trial of SMC and LACT.
Use a spatial modelling framework to determine the geographical areas where SMC and/or LACTs are likely to be advantageous, estimate the population at risk and the public health impact.

Methodology
Statistical models will be fitted to data from clinical trials to quantify dispersion in malaria incidence, and frailty models used to explore event dependence. The burden of repeat malaria will be determined and factors associated with high risk will be identified. A compartmental mathematical model of SMC and treatment of malaria will be fitted to trial data and extended to include multiple exposure/susceptibility strata, variable treatment access, and correlation of access with exposure. Sensitivity analyses will indicate the range in impact. Receiver-operating characteristic analysis will identify climatic predictors of suitable epidemiology for SMC and LACT. Areas will be mapped using high resolution climatic data, the populations at risk estimated using spatial population data, and the malaria burden estimated using published methods. The fitted compartmental model will be incorporated into an individual-based simulation to allow impact, effect on transmission, and effect of other control tools to be explored.

Scientific opportunities
Understanding heterogeneity in malaria risk is important for predicting the impact of all interventions accurately. The research may establish LACTs as a novel form of chemoprevention.

Medical opportunities
The research has direct implications for policy changes that could reduce morbidity and death from malaria among African children.

Planned Impact

The research aims to identify the areas where two forms of drug-based prevention of malaria would be appropriate and estimate their impact, informing policy decisions on the following issues:

1) Changes in antimalarial treatment policy from recommendation of any artemisinin combination therapy (ACT), to a specific recommendation of long-acting ACTs (LACTs) such as dihydroartemisinin-piperaquine. This fellowship will be the first research undertaken to investigate this issue. A priori this is expected to be most appropriate in countries with seasonal malaria transmission. Research outputs will affect antimalarial treatment policy formally recommended by WHO, and drugs adopted in practice by National Malaria Control Programmes (NMCPs) in Africa.

2) Expansion of the area where seasonal malaria chemoprevention (SMC) is recommended from the current area of highly seasonal transmission only, to include seasonal areas with more months of malaria transmission. The research output may change policy regarding the area in which SMC is recommended to include a wider area, covering large highly populated areas of Africa with a high malaria burden (e.g. Ghana, Nigeria, others).

Specific beneficiaries
African children living in areas where policy is changed will benefit from improved health, specifically, fewer attacks of malaria and prevention of consequences of repeated malaria (severe anaemia and mortality). Children living in rural areas are likely to bear the greatest burden of repeat malaria; these approaches may help reduce health inequalities.
Parents of African children will benefit from reduced impact of malaria on lives and livelihood (in seasonal areas, the peak in malaria and agricultural workload coincide), and lower financial and opportunity costs of repeated healthcare visits with their children.
Public hospitals and health centres in malaria endemic areas will benefit from a reduced burden of malaria, particularly during the transmission peak, when capacity can be overwhelmed by paediatric malaria. Reductions in severe malaria and anaemia are likely to result in reduced transfusions and other resources needed for inpatients.
Policy makers in African Countries and NMCP managers. Outputs from the modelling will indicate, at sub-country level, which areas would benefit from these interventions and what the impact would be. A decision-making tool will be produced, enabling informed planning of where to deploy or prioritise deployment of SMC or LACTs.
Global health policy makers (WHO): Reduction in the malaria burden is essential to achieving Millennium Development Goals. Recommendation of first-line antimalarials are periodically changed to reflect changes in drug resistance, etc. Changing antimalarials used for treatment in seasonal transmission areas on the basis that they would be more effective is novel, but would be a simple policy change and one that could have an immediate and important impact.
Manufacturers of long-acting antimalarials may profit in areas where this becomes a recommended policy. However, I have no contact with such companies, nor any vested interest in this impact.

Time scales
Changing treatment policy could be implemented relatively rapidly. Allowing for dissemination of results, impact within 3-5 years is possible since the drugs needed are already licensed and approved for treatment of malaria in children. SMC will be recommended in 2012 in some countries in the Sahel, extension to a wider area is possible, but may depend on successful deployment in highly seasonal areas first to establish feasibility. Children involved in the clinical trial in Ghana arranged outside the context of the fellowship will benefit as soon as results are available, because community based delivery of antimalarials in the district is ongoing, and the drug used could be changed. Skills developed by the fellow working on the project will be applicable in future research (see Career Intentions).

Publications

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Asante KP (2016) Non-malaria fevers in a high malaria endemic area of Ghana. in BMC infectious diseases

 
Guideline Title Seasonal malaria chemoprevention with sulfadoxine-pyrimethamine plus amodiaquine in children: A field guide
Description Referenced in WHO guidelines on Seasonal Malaria Chemoprevention
Geographic Reach Africa 
Policy Influence Type Citation in clinical guidelines
Impact Our work on mapping areas where seasonal malaria chemoprevention (SMC) would be appropriate was used to guide the initial policy recommendation on SMC in 2012. This work was cited in the WHO field guidelines on SMC, and the maps and ongoing work within the fellowship are currently (2014-15) being used to guide the implementation of SMC in the areas where it would be most effective.
 
Description Submission / Presentation to WHO Evidence Review Group (ERG) on Intermittent Screening and Treatment of malaria in Pregnancy (ISTp)
Geographic Reach Africa 
Policy Influence Type Participation in a advisory committee
 
Description Use of modelling / population estimates to support implementation and scale-up of seasonal malaria chemoprevention
Geographic Reach Africa 
Policy Influence Type Influenced training of practitioners or researchers
Impact Maps and estimates of populations living in areas of seasonal malaria transmission produced during this fellowship have been used to guide implementation and scale up of seasonal malaria chemoprevention in the Sahel and sub- Sahel regions of Africa. This role is ongoing as SMC is expanded in this region of Africa
 
Description Sir Halley Stewart Trust
Amount £35,000 (GBP)
Organisation Sir Halley Stewart Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2012 
End 11/2013
 
Description Collaboration with Kintampo Health Research Centre, Kintampo, Ghana 
Organisation Kintampo Health Research Centre
Country Ghana 
Sector Hospitals 
PI Contribution I contributed to PhD supervision of Dr KP Asante, and now collaborate with him on a number of malaria epidemiology projects
Collaborator Contribution Dr Asante and Dr Owusu-Agyei have provided access to data collected by KHRC, and expertise on malaria epidemiology in Ghana.
Impact Several publications on malaria epidemiology have now been published as a result of this collaboration
Start Year 2012
 
Description Collaboration with Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana 
Organisation Kwame Nkrumah University of Science and Technology (KNUST)
Department School of Public Health
Country Ghana 
Sector Academic/University 
PI Contribution I was a co-PI on a trial of seasonal malaria chemoprevention carried out in the Ashanti Region of Ghana. I was responsible for design of the study, writing of the protocol, submission for ethical approval, overseeing data management (blind to treatment allocation), drafting of the analysis plan, carrying out the analysis, writing the manuscript, submission of the paper for publication, and presentation at conferences.
Collaborator Contribution The study team at KNUST were responsible for carrying out the field study, data collection, community engagement/sensitisation, dissemination of study results to community leaders, and contributed to paper writing, and presentation at conferences. The co-PI based in Ghana was jointly responsible for ethical approval, development of the protocol, and was responsible for oversight of trial staff.
Impact A number of papers on malaria in pregnancy, and seasonal malaria chemoprevention in children have been published (see publication list). Main disciplines are clinical trials, epidemiology, statistics. The work on malaria in pregnancy was discussed at a meeting of the WHO Evidence Review Group in July 2015.
Start Year 2010
 
Description Collaboration with Liverpool School of tropical medicine on malaria in pregnancy 
Organisation Liverpool School of Tropical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributed statistical/epidemiological input as well as input as a mathematical modeller to working group on intermittent screening for malaria in pregnancy malaria in pregnancy. Ongoing work to model alternative interventions for malaria in pregnancy, as well as understanding how/where existing interventions would be best deployed
Collaborator Contribution Provided expertise on malaria in pregnancy as related to intermittent screening and treatment, support in developing work for the WHO evidence review group, and other useful input to work on malaria in pregnancy/chemoprevention more generally.
Impact publications on malaria in pregnancy, as well as evidence submitted to policy makers, as described in other sections of the output.
Start Year 2011
 
Description MRC Centre for Outbreak Analysis and Modelling (Imperial College London) 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have collaborated with a number of members of the group on studies of malaria modelling, and malaria epidemiology. I have also provided access to data from field studies to support the work of modellers in the group. I am now an Honourary Lecturer at ICL as a result of this collaboration.
Collaborator Contribution Several members of the group have contributed their expertise on mathematical modelling, as well as providing informal training in R and other software packages. I received formal training in Spatial Epidemiology as part of an MSc Epidemiology course run at ICL (in early 2014).
Impact A number of papers have been published as listed elsewhere in this submission Work carried out as part of this collaboration was used by the WHO in making their policy recommendation on seasonal malaria chemoprevention in 2012, in developing field guidelines for SMC, and in guiding implementation of SMC. Current work is being used to address a number of important practical questions related to SMC.
Start Year 2007
 
Description WHO Global Malaria Program 
Organisation World Health Organization (WHO)
Country Global 
Sector Public 
PI Contribution Member of the Evidence Review Group that considered the evidence for intermittent screening and treatment of malaria in pregnancy (ISTp) in July 2015. Presented work on long-acting artemisinin-based combination therapies (LACTs) undertaken during Population Health Scientist Fellowship as a WHO Technical Seminar in January 2016.
Collaborator Contribution Input on aims of fellowship before and during the fellowship (in terms of focus, outputs, etc.). More recently discussions on future policy applications of work undertaken during the fellowship.
Impact A number of publications as listed elsewhere in this submission. Two policy decisions on measures for malaria control on seasonal malaria chemoprevention in children, and on intermittent screening and treatment of malaria in pregnancy.
Start Year 2010
 
Title Clinical trial of seasonal malaria chemoprevention in areas of extended seasonal transmission (rainy season longer than six months) 
Description Seasonal malaria chemoprevention is currently WHO-recommended policy for the prevention of malaria in children in areas with a short rainy season. This study evaluated SMC in an area of extended seasonal transmission, representative of large and highly populated areas of West Africa. Current consideration is being given to adapting SMC to allow it to be used in areas with a longer rainy season, results from this trial will help support those decisions. 
Type Preventative Intervention - Nutrition and Chemoprevention
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact In addition to the results on effectiveness, results related to intervention coverage and qualitative research on acceptability are being used to refine use of SMC in similar areas. 
 
Description Presentation on Malaria Chemoprevention to Medecins Sans Frontieres 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I gave a 45-minute lecture to students on the MSF course Global Health and Humanitarian Medicine, followed by a question and answer session.

This was later made available online to students following the MSF course remotely.
Year(s) Of Engagement Activity 2015
 
Description Presentation to policy-makers at WHO global malaria programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact I was invited to present work from my MRC-funded Population health scientist Fellowship at the WHO global malaria programme in January 2016
Year(s) Of Engagement Activity 2016
 
Description Talk at MSF on chemoprevention (July 2016) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presented on various malaria chemoprevention strategies to MSF programme staff developing malaria control packages.
Year(s) Of Engagement Activity 2016