The influence of biological, epidemiological, and treatment factors on the establishment and spread of drug-resistant Plasmodium falciparum

Abstract

The effectiveness of artemisinin-based combination therapies (ACTs) to treat Plasmodium falciparum malaria is threatened by resistance. The complex interplay between sources of selective pressure—treatment properties, biological factors, transmission intensity, and access to treatment—obscures understanding how, when, and why resistance establishes and spreads across different locations. We developed a disease modelling approach with emulator-based global sensitivity analysis to systematically quantify which of these factors drive establishment and spread of drug resistance. Drug resistance was more likely to evolve in low transmission settings due to the lower levels of (i) immunity and (ii) within-host competition between genotypes. Spread of parasites resistant to artemisinin partner drugs depended on the period of low drug concentration (known as the selection window). Spread of partial artemisinin resistance was slowed with prolonged parasite exposure to artemisinin derivatives and accelerated when the parasite was also resistant to the partner drug. Thus, to slow the spread of partial artemisinin resistance, molecular surveillance should be supported to detect resistance to partner drugs and to change ACTs accordingly. Furthermore, implementing more sustainable artemisinin-based therapies will require extending parasite exposure to artemisinin derivatives, and mitigating the selection windows of partner drugs, which could be achieved by including an additional long-acting drug.

The Impact of Extended Treatment With Artemether-lumefantrine on Antimalarial Exposure and Reinfection Risks in Ugandan Children With Uncomplicated Malaria: A Randomized Controlled Trial

“…Five days of AL exposes the parasite to the artemisinin component for an additional 48-hour trophozoite cycle where artemisinins are most active [ 28 ]. This additional exposure may leave fewer parasites for lumefantrine and/or the immune system to clear, reducing the risk of emergence and spread of artemisinin resistance [ 29 , 31 ]. We also observed a notable decrease in artemisinin PK with repeated dosing.…”

Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study

“…We applied an established individual-based malaria transmission model, OpenMalaria (https://github.com/SwissTPH/openmalaria/wiki), to predict the impact of next-generation SMC products on population-level outcomes. The model and parameterisations used in this work have been fully described previously 20–22 and are summarised in appendix 1.1. OpenMalaria consists of different model components representing the chain of processes from the mosquito lifecycle to malaria infection, treatment, and immunity acquisition of a human host, and captures differences in consequences of immunity on care seeking and clinical disease.…”

“…OpenMalaria consists of different model components representing the chain of processes from the mosquito lifecycle to malaria infection, treatment, and immunity acquisition of a human host, and captures differences in consequences of immunity on care seeking and clinical disease. 23 The model variant 20 used for this study includes a mechanistic within-host model component for the parasite lifecycle in humans, which describes the time-course of asexual P. falciparum parasitaemia following a single inoculation. Transmission from infected humans to mosquitoes depends on this asexual parasite density, with gametocyte densities following between ten and 20 days later.…”

“…1 OpenMalaria has multiple model components, each of which captures a different set of malaria epidemiologyand transmissionassumptions and has been fully described previously. 2–4 Here we present an overview of the relevant dynamics for the model variant used in our study, which included an explicit mechanistic model of within-host parasite dynamics 5 and incorporated flexible pharmacokinetic/pharmacodynamic (PK/PD) model for drug action. 2…”

“…2–4 Here we present an overview of the relevant dynamics for the model variant used in our study, which included an explicit mechanistic model of within-host parasite dynamics 5 and incorporated flexible pharmacokinetic/pharmacodynamic (PK/PD) model for drug action. 2…”