Pharma Focus Asia

Defining the In Vivo Phenotype of Artemisinin-Resistant Falciparum Malaria: A Modelling Approach

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, Fran├žois 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

Data from 1,518 patients on the Thai-Myanmar and Thai-Cambodian borders with parasite half-life assessments after artesunate treatment were analysed. Half-lives followed a bimodal distribution. A statistical approach was developed to infer the characteristics of the component distributions and their relative contribution to the composite mixture.

A model representing two parasite subpopulations with geometric mean (IQR) parasite half-lives of 3.0 (2.4-3.9) hours and 6.50 (5.7-7.4) hours was consistent with the data. For individual patients, the parasite half-life provided a predicted likelihood of an artemisinin-resistant infection which depends on the population prevalence of resistance in that area. Consequently, a half-life where the probability is 0.5 varied between 3.5 and 5.5 hours. Using this model, the current 'day-3' cut-off value of 10% predicts the potential presence of artemisinin-resistant infections in most but not all scenarios. These findings are relevant to the low-transmission setting of Southeast Asia. Generalisation to a high transmission setting as in regions of Sub-Saharan Africa will need additional evaluation.

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.

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