Population biology and antimalarial resistance: The transmission of antimalarial drug resistance in Plasmodium falciparum

Abstract

Malaria morbidity and mortality continue to increase across sub-Saharan Africa. This is largely as a result of the continued use of chloroquine and sulfadoxine-pyrimethamine, despite widespread resistance. Although eliminating the asexual stages of Plasmodium falciparum is the focus of treatment of individual symptomatic patients, at a population level, reducing the carriage of gametocytes - the sexual stage responsible for infection of the mosquito vector - is necessary to limit the transmission of malaria parasites and the spread of antimalarial resistance. The probability of a mosquito being infected depends on the prevalence, duration and density of viable gametocyte carriage in the human host, although additional humoral and leukocyte factors also affect transmissibility. There is a log-sigmoid relationship between gametocyte density in the patients' blood and infectivity to the mosquito. The infectivity and thus transmission potential associated with a particular antimalarial treatment can be characterised as a function of blood gametocyte density and time, summing these over the acute and all subsequent recrudescences of that infection. Gametocyte carriage and infectivity to mosquitoes is consistently higher in patients infected with drug resistant compared with drug sensitive malaria parasites. It is the ratio of transmission potential in drug resistant versus sensitive infections that drives the spread of resistance. Early access to highly effective antimalarial treatment reduces the risk of disease progression and limits gametocyte carriage. The remarkable spread of sulfadoxine-pyrimethamine (SP) resistance across vast regions results from the very high post-treatment prevalence and density of gametocyte carriage following SP treatment. In areas of low intensity malaria transmission, the gametocyte-reducing effect of widespread use of artemisinin-based combination therapy has resulted in a sustained decrease in malaria transmission and a decrease in the spread of resistance. Malaria treatment policy should be based primarily on therapeutic efficacy against asexual stages, but should also consider transmission reduction potential. Artemisinin-based combination therapies are the only antimalarials currently available which rapidly reduce both asexual and gametocyte stages of the P. falciparum lifecycle.