Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study
The Lancet Infectious Diseases, Volume 17, No. 2, Year 2017
Notification
URL copied to clipboard!
Description
Background Western Cambodia is the epicentre of Plasmodium falciparum multidrug resistance and is facing high rates of dihydroartemisinin–piperaquine treatment failures. Genetic tools to detect the multidrug-resistant parasites are needed. Artemisinin resistance can be tracked using the K13 molecular marker, but no marker exists for piperaquine resistance. We aimed to identify genetic markers of piperaquine resistance and study their association with dihydroartemisinin–piperaquine treatment failures. Methods We obtained blood samples from Cambodian patients infected with P falciparum and treated with dihydroartemisinin–piperaquine. Patients were followed up for 42 days during the years 2009–15. We established in-vitro and ex-vivo susceptibility profiles for a subset using piperaquine survival assays. We determined whole-genome sequences by Illumina paired-reads sequencing, copy number variations by qPCR, RNA concentrations by qRT-PCR, and protein concentrations by immunoblotting. Fisher's exact and non-parametric Wilcoxon rank-sum tests were used to identify significant differences in single-nucleotide polymorphisms or copy number variants, respectively, for differential distribution between piperaquine-resistant and piperaquine-sensitive parasite lines. Findings Whole-genome exon sequence analysis of 31 culture-adapted parasite lines associated amplification of the plasmepsin 2–plasmepsin 3 gene cluster with in-vitro piperaquine resistance. Ex-vivo piperaquine survival assay profiles of 134 isolates correlated with plasmepsin 2 gene copy number. In 725 patients treated with dihydroartemisinin–piperaquine, multicopy plasmepsin 2 in the sample collected before treatment was associated with an adjusted hazard ratio (aHR) for treatment failure of 20·4 (95% CI 9·1–45·5, p<0·0001). Multicopy plasmepsin 2 predicted dihydroartemisinin–piperaquine failures with 0·94 (95% CI 0·88–0·98) sensitivity and 0·77 (0·74–0·81) specificity. Analysis of samples collected across the country from 2002 to 2015 showed that the geographical and temporal increase of the proportion of multicopy plasmepsin 2 parasites was highly correlated with increasing dihydroartemisinin–piperaquine treatment failure rates (r=0·89 [95% CI 0·77–0·95], p<0·0001, Spearman's coefficient of rank correlation). Dihydroartemisinin–piperaquine efficacy at day 42 fell below 90% when the proportion of multicopy plasmepsin 2 parasites exceeded 22%. Interpretation Piperaquine resistance in Cambodia is strongly associated with amplification of plasmepsin 2–3, encoding haemoglobin-digesting proteases, regardless of the location. Multicopy plasmepsin 2 constitutes a surrogate molecular marker to track piperaquine resistance. A molecular toolkit combining plasmepsin 2 with K13 and mdr1 monitoring should provide timely information for antimalarial treatment and containment policies. Funding Institut Pasteur in Cambodia, Institut Pasteur Paris, National Institutes of Health, WHO, Agence Nationale de la Recherche, Investissement d'Avenir programme, Laboratoire d'Excellence Integrative “Biology of Emerging Infectious Diseases”. © 2017 World Health Organization
Authors & Co-Authors
Witkowski, Benoît
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
France, Paris
Institut Pasteur, Paris
Duru, Valentine
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Khim, Nimol
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
France, Paris
Institut Pasteur, Paris
Ross, Leila Saxby
United States, New York
Columbia University Irving Medical Center
Saintpierre, Benjamin
France, Paris
Institut Pasteur, Paris
Beghain, Johann
France, Paris
Institut Pasteur, Paris
Chy, Sophy
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Kim, Saorin
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Ke, Sopheakvatey
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Eam, Rotha
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Khean, Chanra
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Ken, Malen
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Loch, Kaknika
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Domergue, Anaïs
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Ma, Laurence
France, Paris
Institut Pasteur, Paris
Bouchier, Christiane
France, Paris
Institut Pasteur, Paris
Leang, Rithea
Cambodia, Phnom Penh
National Center for Parasitology, Entomology and Malaria Control
Huy, Rekol
Cambodia, Phnom Penh
National Center for Parasitology, Entomology and Malaria Control
Nuel, Grégory
France, Paris
Université Paris Cité
Barale, Jean Christophe
France, Paris
Institut Pasteur, Paris
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
France, Paris
Cnrs Centre National de la Recherche Scientifique
Legrand, Eric
France, Paris
Institut Pasteur, Paris
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
Ringwald, Pascal
Switzerland, Geneva
Organisation Mondiale de la Santé
Fidock, David A.
United States, New York
Columbia University Irving Medical Center
Mercereau-Puijalon, Odile
France, Paris
Institut Pasteur, Paris
Ariey, Frédéric
France, Paris
Institut Pasteur, Paris
France, Paris
Inserm
Menard, Didier
Cambodia, Phnom Penh
Institut Pasteur du Cambodge
France, Paris
Institut Pasteur, Paris
Statistics
Citations: 243
Authors: 26
Affiliations: 8
Identifiers
Doi:
10.1016/S1473-3099(16)30415-7
ISSN:
14733099
Research Areas
Environmental
Genetics And Genomics
Infectious Diseases