Lisa J. White, Jennifer A. Flegg, Aung Pyae Phyo, Ja Hser Wiladpai-ngern, Delia Bethell, Christopher Plowe, Tim Anderson, Standwell Nkhoma, Shalini Nair, Rupam Tripura, Kasia Stepniewska, Wirichada Pan-Ngum, Kamolrat Silamut, Ben S. Cooper, Yoel Lubell, Elizabeth A. Ashley, Chea Nguon, François Nosten, Nicholas J. White, Arjen M. Dondorp
Abstract
Background
Artemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker ‘Kelch 13’ and in vitro sensitivity tests. However, current cut-off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment ('day-3'), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions.
Methods and Findings
The analysis involved data from 1,518 patients residing on the Thai-Myanmar and Thai-Cambodian borders who underwent artesunate treatment, with parasite half-life assessments conducted. The distribution of half-lives exhibited two distinct peaks. A statistical method was devised to infer the characteristics of the individual distributions and their relative contribution to the overall mixture.
A model was constructed to represent two parasite subpopulations, each with a geometric mean (IQR) half-life. The first subpopulation had a half-life of 3.0 (2.4-3.9) hours, while the second subpopulation had a half-life of 6.50 (5.7-7.4) hours, which aligned well with the collected data. By assessing an individual patient's parasite half-life, it was possible to estimate the likelihood of an artemisinin-resistant infection based on the prevalence of resistance in the population of that particular area. Consequently, the half-life value at which the probability reached 0.5 ranged between 3.5 and 5.5 hours. Utilizing this model, the current "day-3" cut-off threshold of 10% could predict the presence of potential artemisinin-resistant infections in most scenarios, although not in all cases. These findings hold significance for low-transmission regions in Southeast Asia. However, further investigation is necessary to evaluate their applicability to high transmission settings, such as those found in Sub-Saharan Africa.
Conclusions
Characterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearance and artemisinin resistance, as well as the predictive value of the 10% cut-off in 'day-3' parasitaemia. The findings are important for the interpretation of in vitro sensitivity tests and molecular markers for artemisinin resistance and for contextualising the ‘day 3’ threshold to account for initial parasitaemia and sample size.
Citation: White LJ, Flegg JA, Phyo AP, Wiladpai-ngern JH, Bethell D, et al. (2015) Defining the In Vivo Phenotype of Artemisinin-Resistant Falciparum Malaria: A Modelling Approach. PLoS Med 12(4): e1001823. doi:10.1371/journal.pmed.1001823
Academic Editor: Thomas A. Smith, Swiss Tropical & Public Health Institute, SWITZERLAND
Received: January 21, 2014; Accepted: March 27, 2015; Published: April 28, 2015
Copyright: © 2015 White et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Funding:
The study was part of the Wellcome-Trust Major Overseas Programme in SE Asia (grant number 077166/Z/05/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests:
NJW is a member of the editorial board of PLOS Medicine. The opinions or assertions contained herein are the views of the authors and are not to be construed as reflecting the views of the Department of the Army or the US Department of Defense.
Abbreviations: ACT, Artemisinin combination therapy; SNPs, single nucleotide polymorphisms
Acknowledgments
We thank all the field teams and patients involved in the original studies which provided data for the current study.
Author Contributions
Conceived and designed the experiments: LJW AMD. Performed the experiments: LJW JAF WPN. Analyzed the data: LJW JAF WPN. Wrote the first draft of the manuscript: LJW AMD. Contributed to the writing of the manuscript: JAF APP JHW DB CP TA SNk SNa RT KSt WPN KSi BSC YL EAA CN FN NJW. ICMJE criteria for authorship read and met: LJW JAF APP JHW DB CP TA SNk SNa RT KSt WPN KSi BSC YL EAA CN FN NJW AMD. Agree with manuscript results and conclusions: LJW JAF APP JHW DB CP TA SNk SNa RT KSt WPN KSi BSC YL EAA CN FN NJW AMD.
