How delayed and non-adherent treatment contribute to onward transmission of malaria: a modelling study
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Introduction
Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated
Plasmodium falciparum malaria. Its efficacy has been extensively assessed in clinical trials. In routine
healthcare settings, however, its effectiveness can be diminished by delayed access to treatment
and poor adherence. As well as affecting clinical outcomes, these factors can lead to increased
transmission, which is the focus of this study.
Methods
We extend a within-host model of Plasmodium falciparum to include gametocytes, the parasite
forms responsible for onward transmission. The model includes a pharmacokineticpharmacodynamic model of AL, calibrated against both immature and mature gametocytes using
individual-level patient data, to estimate the impact that delayed access and imperfect adherence to
treatment can have on onward transmission of the parasite to mosquitoes.
Results
Using survey data from 7 African countries to determine the time taken to acquire antimalarials
following fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-
fold, compared to patients treated after 24 hours. Realistic adherence behaviour, based on data
from a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold,
compared to a perfectly-adherent cohort. This was driven largely by increased rates of treatment
failure leading to chronic infection, rather than prolonged gametocytaemia in patients who have
slower, but still successful, clearance of parasites after imperfect adherence to treatment. Our
model estimated that the mean infectivity of untreated infections was 29-51 times higher than that
of treated infections (assuming perfect drug adherence), underlining the importance of improving
treatment coverage.
Conclusion
Using mathematical modelling, we quantify how delayed treatment and non-adherent treatment
can increase transmission compared to prompt effective treatment. We also highlight that
transmission from the large proportion of infections which never receive treatment is substantially
higher than those treated.
Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated
Plasmodium falciparum malaria. Its efficacy has been extensively assessed in clinical trials. In routine
healthcare settings, however, its effectiveness can be diminished by delayed access to treatment
and poor adherence. As well as affecting clinical outcomes, these factors can lead to increased
transmission, which is the focus of this study.
Methods
We extend a within-host model of Plasmodium falciparum to include gametocytes, the parasite
forms responsible for onward transmission. The model includes a pharmacokineticpharmacodynamic model of AL, calibrated against both immature and mature gametocytes using
individual-level patient data, to estimate the impact that delayed access and imperfect adherence to
treatment can have on onward transmission of the parasite to mosquitoes.
Results
Using survey data from 7 African countries to determine the time taken to acquire antimalarials
following fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-
fold, compared to patients treated after 24 hours. Realistic adherence behaviour, based on data
from a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold,
compared to a perfectly-adherent cohort. This was driven largely by increased rates of treatment
failure leading to chronic infection, rather than prolonged gametocytaemia in patients who have
slower, but still successful, clearance of parasites after imperfect adherence to treatment. Our
model estimated that the mean infectivity of untreated infections was 29-51 times higher than that
of treated infections (assuming perfect drug adherence), underlining the importance of improving
treatment coverage.
Conclusion
Using mathematical modelling, we quantify how delayed treatment and non-adherent treatment
can increase transmission compared to prompt effective treatment. We also highlight that
transmission from the large proportion of infections which never receive treatment is substantially
higher than those treated.
Date Issued
2019-12-10
Date Acceptance
2019-11-10
Citation
BMJ Global Health, 2019, 4 (6)
ISSN
2059-7908
Publisher
BMJ Publishing Group
Journal / Book Title
BMJ Global Health
Volume
4
Issue
6
Copyright Statement
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
Sponsor
Medicines for Malaria Venture
Medical Research Council (MRC)
The Royal Society
Grant Number
PO14/00561
MR/R015600/1
DH140134
Subjects
malaria
mathematical modelling
pharmacology
treatment
Publication Status
Published
Article Number
e001856
Date Publish Online
2019-12-10