Artemisinin Resistance in Africa: its emergence and evolution in Rwanda

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ABSTRACT Artemisinin combination therapies (ACTs) are the mainstay antimalarial treatment combating Plasmodium falciparum malaria around the world. While resistance is widespread in Asia, it has not yet been observed in Africa where the majority of the global morbidity and mortality occurs. Artemisinin and ACT resistance in Africa would be a serious setback as there are no next-generation antimalarials ready for deployment. Recent reports in Rwanda of validated artemisinin resistance are of grave concern. A recent therapeutic efficacy study in Rwanda found a high prevalence of patients with delayed parasite clearance, which was associated with a validated artemisinin resistance mutation R561H in the K13 gene. Thus, it appears Africa is moving closer to fully formed resistance, as seen in Southeast Asia. New evidence shows that this mutation has arisen within Africa and was not spread from Asia, and thus, represents biology unique to Africa. Given the potential devastating consequences of frank artemisinin resistance spreading across the continent, this proposal is designed to improve our understanding of the mutation and its biology, its origin, its past and ongoing spread and the factors that impact the spread. Understanding these dynamics is critical to predicting the long-term effectiveness of ACTs and to evaluating and formulating effective control efforts. In this proposal the first goal is to understand the extent of spread and how quickly it is changing with time. We will leverage an extensive collaborative network within Rwanda and in surrounding countries to perform large scale sampling and genomics studies across Rwanda and neighboring areas in other countries over time to map and study the spread of resistance. This will be accomplished using high-throughput targeted sequencing allowing us to genotype tens of thousands of samples. Using the generated rich genotyping and spatial data, we will also ask questions about parasite migration and factors that may be impacting the spread. Our second goal is to look for other mutations that may further support resistance to artemisinin or partner drugs. Based on our knowledge from Southeast Asia, there are often compensatory mutations that increase the fitness of artemisinin resistance mutations in K13. To detect compensatory mutations we will perform genome wide association studies and longitudinal analyses. Our third goal is to study the relative fitness of mutant and wild type parasites examining mutant and wildtype parasites in vivo using new statistical methods to examine polyclonal infections; and in vitro competition assays, as well as mosquito feeds, to examine differences in fitness in both the human blood stage and during transmission. Our final goal is to use the information from the above aims to build a model and predict the future spread of resistance. Together, this study will provide a comprehensive view of evolving resistance in Rwanda and provide actionable information for public health.