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

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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.