Novel anti-malarial drug strategies to prevent artemisinin partner drug resistance: A model-based analysis

Emergence of resistance to artemisinin and partner drugs in the Greater Mekong Subregion has made elimination of malaria from this region a global priority; it also complicates its achievement. Novel drug strategies such as triple artemisinin combination therapies (ACTs) and chemoprophylaxis have been proposed to help limit resistance and accelerate elimination. The objective of this study was to better understand the potential impacts of triple ACTs and chemoprophylaxis, using a mathematical model parameterized using data from Cambodia. We used a simple compartmental model to predict trends in malaria incidence and resistance in Cambodia from 2020-2025 assuming no changes in transmission since 2018. We assessed three scenarios: a status quo scenario with artesunate-mefloquine (ASMQ) as treatment; a triple ACT scenario with dihydroartemisinin-piperaquine (DP) plus mefloquine (MQ) as treatment; and a chemoprophylaxis scenario with ASMQ as treatment plus DP as chemoprophylaxis. We predicted MQ resistance to increase under the status quo scenario. Triple ACT treatment reversed the spread of MQ resistance, but had no impact on overall malaria incidence. Joint MQ-PPQ resistance declined under the status quo scenario for the baseline parameter set and most sensitivity analyses. Compared to the status quo, triple ACT treatment limited spread of MQ resistance but also slowed declines in PPQ resistance in some sensitivity analyses. The chemoprophylaxis scenario decreased malaria incidence, but increased the spread of strains resistant to both MQ and PPQ; both effects began to reverse after the intervention was removed. We conclude that triple ACTs may limit spread of MQ resistance in the Cambodia, but would have limited impact on malaria incidence and might slow declines in PPQ resistance. Chemoprophylaxis could have greater impact on incidence but also carries higher risks of resistance. Aggressive strategies to limit transmission the GMS are needed to achieve elimination goals, but any intervention should be accompanied by monitoring for drug resistance. Author summary Artemisinin combination therapies (ACTs) consisting of an artemisinin derivative plus a partner drug are used to treat malaria worldwide. In Cambodia, resistance to artemisinin is widespread, and resistance to the partner drugs mefloquine and piperaquine has also emerged. We used a mathematical model to compare two strategies with the current status quo in Cambodia: first, a triple ACT scenario in which first-line treatment is an artemisinin derivative combined with two different partner drugs, and second, a chemoprophylaxis scenario in which one ACT is used for first-line treatment and a separate one is used as chemoprophylaxis. The triple ACT scenario limited the spread of mefloquine resistance but had minimal impact on the number of malaria cases. In some sensitivity analyses, it also slowed declines in piperaquine resistance. Chemoprophylaxis reduced the number of malaria cases and increased resistance, but both of those effects were short-lived. We conclude that triple ACTs may prevent the spread of partner drug resistance, but could be less effective against pre-existing resistance in the population. Additionally, triple ACTs would need to be coupled with other interventions to decrease cases. Chemoprophylaxis could immediately reduce malaria transmission, but risks include spread of resistance and a post-intervention rebound in cases.