Mass drug administration of ivermectin and dihydroartemisinin-piperaquine as an additional intervention for malaria elimination

Since 2000, there has been a substantial decrease of the malaria burden in sub-Saharan Africa due to the scale up of vector control interventions such as long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS), and better case management with artemisinin-based combination therapy (ACT). Though some African countries such as The Gambia and Senegal have achieved excellent coverage of standard control interventions, malaria transmission has not been interrupted. This is probably due to two major factors, namely (i) the large and hidden human reservoir of infection, meaning individuals without any symptom but infected with malaria and thus able to infect the mosquito vector, and (ii) vector-related factors, e.g. vector behaviour and insecticide resistance, allowing vectors to escape standard control interventions such as LLIN and IRS. These two factors maintaining transmission require additional interventions specifically targeting them.

Mass Drug Administration (MDA) consists in administering at regular intervals a full antimalarial treatment to the whole population. This intervention has been identified as a potential tool to further reduce transmission where coverage of vector control activities is already high as it would clear malaria infection from asymptomatic carriers and thus reduce the human reservoir of infection. An ACT administered to the whole population should decrease the number of malaria-infected individuals and thus may have an effect on transmission. Ivermectin (IVM) is a mosquitocidal agent that is safe for humans but toxic to Anopheles mosquitoes when feeding on individuals recently treated with it. Combining an ACT with an IVM may have a synergistic effect because the former would reduce the human reservoir of infection while the latter would kill mosquitoes that have escaped standard vector control interventions. In addition, combining an ACT with IVM would also reduce the minimal coverage required by MDA to have an effect on transmission. Transmission models suggest that adding IVM to a MDA intervention may interrupt transmission where standard MDA would be insufficient. However, this has never been rigorously evaluated in a well-designed cluster-randomized trial.

This community-based, cluster-randomized trial will be carried out in the Upper River Region of The Gambia. Thirty two villages (clusters) at least 3-4km apart and with 200-600 inhabitants will be randomized to either the intervention or the control arm. MDA with IVM and dihydroartemisinin-piperaquine (DP) will be implemented in 16 intervention villages and any other human settlement in the buffer zone around intervention villages (2km). MDA will consist of 3-monthly rounds per year during the malaria transmission season for two years. Malaria prevalence at the peak of each transmission season and the mosquito population age structure will be compared between intervention and control arms. We will also collect qualitative social science data on coverage, potential bottlenecks for the intervention, adherence and acceptability; a health economics study will determine the cost of the intervention in relation to malaria infections and malaria patients prevented.

We propose to evaluate a novel approach to decrease and possibly stop residual malaria transmission; it consists of mass drug administration (MDA) with an artemisinin-based combination treatment, dihydroartemisinin-piperaquine (DP), and a systemic endectocidal drug, ivermectin (IVM), toxic to Anopheles mosquitoes when biting treated individuals. This intervention will be tested through a community-based, cluster-randomized trial to be implemented in the Upper River Region of The Gambia where there is still residual malaria transmission despite high coverage of standard malaria control activities. Thirty two villages (clusters) at least 3-4 km apart and with 200-600 inhabitants will be randomized to either the intervention or the control arm. MDA with IVM and DP will be implemented in 16 intervention villages and a buffer zone of 2 km around each of them, and will consist of 3-monthly rounds per year during the malaria transmission season for two years.

At the peak of each transmission season, a cross-sectional survey to determine malaria prevalence (200 individuals per cluster) will be carried out in both study arms. The vector population will be monitored throughout the transmission season. In addition, qualitative social science data on coverage, potential bottlenecks for the intervention, adherence and acceptability will be collected; a health economics study on the cost-effectiveness of the intervention will be carried out.

The primary outcomes will be malaria prevalence (by molecular methods) in all age groups and vector's parous rates after 2 MDA seasonal cycles (3 rounds each). Secondary outcomes will include incidence of clinical malaria, serological markers of recent infection or recent exposure to the vector, other entomological variables, intervention coverage, and cost-effectiveness of the intervention.

We are proposing to evaluate ivermectin with dihydroartemisinin-piperaquine administered in three rounds per year (malaria season) to the whole population (mass drug administration, MDA) to further decrease malaria transmission. The trial will be carried out in the eastern part of The Gambia, an area of stable, seasonal malaria transmission where malaria has persisted during a substantial decrease observed in other Gambian regions, and despite high coverage of standard control interventions.

Though MDA with an antimalarial treatment cannot be considered as new, adding ivermectin, a systemic endectocidal drug toxic to Anopheles mosquitoes when biting treated individuals, is new and has never been rigorously evaluated in a well-designed cluster-randomized trial, and this despite the recent interest of the World Health Organization (WHO) that recognizes the potential of ivermectin for reducing malaria transmission.

Results of the proposed trial would be essential for formulating recommendations by the WHO on the use MDA to reduce local transmission in low transmission areas and the use of ivermectin as part of MDA. Its results would be applicable to African countries with malaria endemicity similar to The Gambia, particularly those in which coverage of standard intervention is already high while malaria transmission is still on-going. The trial will also provide information on ways to achieve and maintain the highest possible coverage for MDA, an essential element for its success. National Malaria Control Programs in sub-Saharan Africa as well as international agencies and donors interested in malaria elimination will benefit of the results of this trial as they will be provided with a new intervention to reduce and possibly interrupt malaria transmission, together with information on how to achieve optimal coverage for MDA and the costs involved.

In case of positive results, communities living in malaria endemic areas will benefit of the substantial reduction or interruption of malaria transmission, which will result in a reduction of the malaria burden.