A MULTIPLE FIRST-LINE THERAPIES MODEL FOR PLASMODIUM FALCIPARUM MALARIA: FACTORS INFLUENCING THE SPREAD OF ARTEMISININ RESISTANCE IN HIGH AND LOW TRANSMISSION REGIONS

Abstract

Malaria is a parasitic, vector-transmitted, febrile illness endemic to nearly 100 countries and responsible for more than half a million deaths in 2014. Following the advent of highly efficacious antimalarials in the post-World War II era, some began to plan for worldwide eradication of the disease. However, these goals were thwarted by political instability, administrative issues, and, most importantly, the spread of drug resistance. Starting in 2001, artemisinin combination therapies (ACTs) became the recommended first-line treatment for uncomplicated P. falciparum infections. Shortly thereafter, resistance to artemisinin was detected in the Greater Mekong Subregion, threatening recent gains in malaria mortality and morbidity and mimicking the prior emergence of resistance to chloroquine and sulphadoxine-pyrimethamine in the latter half of the 20th century. Unlike these historical examples, there is no non-artemisinin based substitute expected to enter the marketplace for at least five to ten more years should resistance continue to spread. In light of this concern, this research utilizes a multiple first-line therapies (MFTs) based evolutionary-epidemiology model to examine what factors about the Greater Mekong Subregion foster the emergence of antimalarial resistance. Though the original hypothesis of this research focused on modeling high versus low transmission areas and comparing their difference in population-level immunity and drug pressure, it ultimately became clear that the true segregating factor is the level of disease endemicity. The models demonstrate how in areas of high endemic disease, rapid transmission and immunity work together to minimize the amount of drug pressure exerted on the parasite population. Without a high level of drug pressure, the fitness of resistant parasites is decreased and the trait is less likely to spread throughout the population. In the future, drug deployment and distribution strategies should focus on alleviating the level of drug pressure in areas of low disease endemicity to mitigate the emergence and spread of resistance.