Poster Presentation First Malaria World Congress 2018

Can triple artemisinin-based combination therapies (TACTs) be a future treatment for Plasmodium falciparum malaria? A mathematical perspective (#271)

Saber Dini 1 , Sophie Zaloumis 1 , Pengxing Cao 2 , Ric Price 3 4 , James McCaw 1 2 , Julie Simpson 1
  1. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
  2. School of Mathematics and Statistics, University of Melbourne, Melbourne, Australia
  3. Global and Tropical Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Australia
  4. Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom

The efficacy of artemisinin-based combination therapies (ACTs) has begun declining, due to the emergence of Plasmodium falciparum parasites resistant to the artemisinins in the greater Mekong subregion. This has posed a serious threat to people’s health in malaria-endemic regions, and warranted developing alternative treatments. Presently, there are no new treatment regimens available in the final stages of the drug development pipeline that could replace ACTs. Triple artemisinin-based combination therapy (TACT), comprised of two partner drugs and an artemisinin derivative, has been suggested as a novel treatment and superior to other alternatives such as drug cycling. In this work, we developed a within-host mathematical model to investigate the efficacy of a TACT: Dihydroartemisinin-Piperaquine-Mefloquine (DHA-PQ-MQ), which is potentially deployable in South-East Asia, where DHA-PQ is rapidly losing its efficacy. Our mathematical model incorporates a high level of sophistication that allows investigation of the possible components of drug action failure separately; development of artemisinin resistance to ring form parasites, reduction in maximal killing rate, etc. Importantly, the model enabled us to demonstrate the importance of accounting for the antagonistic pharmacodynamic interaction between PQ and MQ, as it can significantly influence the efficacy of the TACT. Of particular interest, we examined which dosing scheme of TACT suffices to produce WHO recommended cure rates. Regional specific intensities of resistance were accommodated to determine the dosing schemes suitable for deployment in each region. The results show that three 8.3 mg/kg doses of MQ over three days, combined with the WHO recommended dosing regimens for DHA and PQ, can produce the desirable cure rates in all of the regions. Our findings illustrate how mathematical modelling can contribute to the selection of the partner drug and dosing scheme of TACT to be investigated in future clinical efficacy studies.