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

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.

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.

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).