Investigating the efficacy of triple artemisinin-based combination therapies (TACTs) for treatingPlasmodium falciparummalaria patients using mathematical modelling

Abstract

22The first line treatment for uncomplicated falciparum malaria is artemisinin-based com-23 bination therapy (ACT), which consists of an artemisinin derivative co-administered with 24 a longer acting partner drug. However, the spread of Plasmodium falciparum resistant 25 to both artemisinin and its partner drugs poses a major global threat to malaria control 26 activities. Novel strategies are needed to retard and reverse the spread of these resistant 27 parasites. One such strategy is triple artemisinin-based combination therapy (TACT). 28 We developed a mechanistic within-host mathematical model to investigate the e cacy of 29 a TACT (dihydroartemisinin-piperaquine-mefloquine -DHA-PQ-MQ), for use in South- 30 East Asia, where DHA and PQ resistance are now increasingly prevalent. Comprehensive 31 model simulations were used to explore the degree to which the underlying resistance in-32 fluences the parasitological outcomes. The e↵ect of MQ dosing on the e cacy of TACT 33 was quantified at varying degrees of DHA and PQ resistance. To incorporate interactions 34 between drugs, a novel model is presented for the combined e↵ect of DHA-PQ-MQ, which 35 illustrates how the interactions can influence treatment e cacy. When combined with a 36 standard regimen of DHA and PQ, the administration of three 8.3 mg/kg doses of MQ 37 was su cient to achieve parasitological e cacy greater than that currently recommended 38 by WHO guidelines. 39 Introduction 40Over the last decade, significant gains have been made towards the control and elimina-41 tion of malaria. Despite this progress, almost half a billion people still die from malaria 42 2 each year. Disturbingly, in 2016 there were five million more cases of malaria than the 43 previous year (2017 WHO report (1)), emphasising the fragile nature of malaria control. 44Early diagnosis and treatment with highly e↵ective antimalarial drug regimens remains 45 central to all national malaria control activities. Artemisinin-based combination thera-46 pies (ACTs) are the first line therapy in almost all malaria endemic countries, due to 47 their high e cacy, tolerability and ability to reduce ongoing transmission of the para-48 site. ACTs are comprised of two components: an artemisinin derivative and a partner 49 drug. The artemisinin derivative has a high antimalarial potency, killing a large propor-50 tion of parasites, however, these compounds are rapidly eliminated, leaving a residual 51 parasite population that, if left untreated, will likely recrudesce. A slowly eliminated, 52 partner drug, is required to provide a sustained antimalarial activity, capable of killing 53 the remaining parasites (2). 54ACTs have remained highly e cacious for almost two decades, but are now under 55 threat from the emergence of drug resistant parasites (2, 3). In 2009, a high proportion 56 of patients with markedly delayed parasite clearance were reported from the western re-57 gion of Cambodia, and this was confirmed as being attributable to artemisinin resistance 58 (3). These parasite...