Impact of piperaquine resistance in Plasmodium falciparum on malaria treatment effectiveness in The Guianas: a descriptive epidemiological study

Celia Florimond (1, 2, 3) , Franck de Laval (4, 5) , Angela Early (6, 7) , Swaélie Sauthier (1, 2, 3) , Yassamine Lazrek (1, 2, 3) , Stephane Pelleau (1, 2, 3, 8) , Wuelton Monteiro (9, 10) , Maxime Agranier (1, 2, 3) , Nicolas Taudon (11) , François Morin (4) , Magda Magris (12) , Marcus Lacerda (9, 13) , Giselle Viana (14) , Sócrates Herrera (15) , Malti Adhin (16) , Marcelo Ferreira (17, 18) , Charles Woodrow (19, 20) , Ghulam Awab (19, 21) , Horace Cox (22) , Maria-Paz Ade (23) , Emilie Mosnier (5) , Félix Djossou (24) , Daniel Neafsey (6, 7) , Pascal Ringwald (25) , Lise Musset (1, 2, 3)

1 Laboratoire de Parasitologie [Cayenne, Guyane française]
2 CNR - laboratoire associé - Centre National de Référence du Paludisme [Cayenne, Guyane française]
3 CCOMS - Centre Collaborateur OMS pour la surveillance de la résistance aux antipaludiques [Cayenne, Guyane française]
4 CESPA - Centre d'épidémiologie et de santé publique des armées [Marseille]
5 SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale
6 Broad Institute [Cambridge]
7 Harvard T.H. Chan School of Public Health
8 Epidémiologie et Analyse des Maladies Infectieuses - Infectious Disease Epidemiology and Analytics
9 FMT-HVD - Fundação de Medicina Tropical Doutor Heitor Vieira Dourado
10 UEA - Universidade do Estado do Amazonas
11 IRBA - Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge]
12 SACAICET - Servicio Autónomo Centro Amazónico de Investigación y Control de Enfermedades Tropicales "Simón Bolívar"
13 ILMD - Instituto Leônidas e Maria Deane - Fiocruz Amazônia [Manaus, Brésil]
14 Ministry of Health [Brasília, Brazil]
15 Caucaseco scientific research center = Centro de Investigación Científica Caucaseco
16 UVS - Anton de Kom Universiteit van Suriname - Anton de Kom University of Suriname [Paramaribo]
17 USP - Universidade de São Paulo = University of São Paulo
18 NOVA - Universidade Nova de Lisboa = NOVA University Lisbon
19 Mahidol University [Bangkok]
20 University of Oxford
21 Ministry of Public Health [Afghanistan]
22 Ministry of Public Health [Georgetown, Guyana]
23 PAHO - Pan American Health Organization [Washington]
24 Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]
25 OMS / WHO - Organisation Mondiale de la Santé / World Health Organization Office

Background: Plasmodium falciparum is an apicomplexan parasite responsible for lethal cases of malaria. According to WHO recommendations, P falciparum cases are treated with artemisinin-based combination therapy including dihydroartemisinin-piperaquine. However, the emergence of resistant parasites against dihydroartemisinin-piperaquine was reported in southeast Asia in 2008 and, a few years later, suspected in South America. Methods: To characterise resistance emergence, a treatment efficacy study was performed on the reported patients infected with P falciparum and treated with dihydroartemisinin-piperaquine in French Guiana (n=6, 2016-18). Contemporary isolates collected in French Guiana were genotyped for P falciparum chloroquine resistance transporter (pfCRT; n=845) and pfpm2 and pfpm3 copy number (n=231), phenotyped using the in vitro piperaquine survival assay (n=86), and analysed through genomic studies (n=50). Additional samples from five Amazonian countries and one outside the region were genotyped (n=1440). Findings: In field isolates, 40 (47%) of 86 (95% CI 35·9-57·1) were resistant to piperaquine in vitro; these phenotypes were more associated with pfCRTC350R (ie, Cys350Arg) and pfpm2 and pfpm3 amplifications (Dunn test, p<0·001). Those markers were also associated with dihydroartemisinin-piperaquine treatment failure (n=3 [50%] of 6). A high prevalence of piperaquine resistance markers was observed in Suriname in 19 (83%) of 35 isolates and in Guyana in 579 (73%) of 791 isolates. The pfCRTC350R mutation emerged before pfpm2 and pfpm3 amplification in a temporal sequence different from southeast Asia, and in the absence of artemisinin partial resistance, suggesting a geographically distinctive epistatic relationship between these genetic markers. Interpretation: The high prevalence of piperaquine resistance markers in parasite populations of the Guianas, and the risk of associated therapeutic failures calls for caution on dihydroartemisinin-piperaquine use in the region. Furthermore, greater attention should be given to potential differences in genotype to phenotype mapping across genetically distinct parasite populations from different continents.

Domaines: Sciences du Vivant [q-bio]

Celia Florimond, Franck de Laval, Angela Early, Swaélie Sauthier, Yassamine Lazrek, et al.. Impact of piperaquine resistance in Plasmodium falciparum on malaria treatment effectiveness in The Guianas: a descriptive epidemiological study. The Lancet Infectious Diseases, inPress, ⟨10.1016/S1473-3099(23)00502-9⟩. ⟨pasteur-04366762⟩