Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors That Affect Treatment Outcomes for P. falciparum Malaria After Artemether-Lumefantrine and Artesunate-Amodiaquine

Meera Venkatesan , Nahla Gadalla , Kasia Stepniewska (1) , Prabin Dahal (2) , Christian Nsanzabana , Clarissa Moriera , Ric Price (3) , Andreas Martensson (4) , Philip Rosenthal , Grant Dorsey (5) , Colin Sutherland (6) , Philippe Guerin (7) , Timothy Davis , Didier Ménard (8) , Ishag Adam , George Ademowo , Cesar Arze (9) , Frederick Baliraine , Nicole Berens-Riha , Anders Bjorkman (10) , Steffen Borrmann (11) , Francesco Checchi (12) , Meghna Desai , Mehul Dhorda (13) , Abdoulaye Djimde (14) , Badria El-Sayed , Teferi Eshetu , Frederick Eyase , Catherine Falade , Jean-François Faucher (15) , Gabrielle Fröberg , Anastasia Grivoyannis , Sally Hamour , Sandrine Houzé (16) , Jacob Johnson , Erasmus Kamugisha , Simon Kariuki , Jean-René Kiechel (17) , Fred Kironde , Poul-Erik Kofoed , Jacques Lebras (16) , Maja Malmberg , Leah Mwai (18) , Billy Ngasala (19) , François Nosten (20) , Samuel Nsobya (21) , Alexis Nzila (22) , Mary Oguike , Sabina Dahlström Otienoburu , Bernhards Ogutu (18) , Jean-Bosco Ouédraogo (23) , Patrice Piola (24) , Lars Rombo , Birgit Schramm (25) , A. Fabrice Somé , Julie Thwing , Johan Ursing (4) , Rina Wong , Ahmed Zeynudin , Issaka Zongo , Christopher V Plowe (9) , Carol Hopkins Sibley (24)

1 Centre for Tropical Medicine and Global Health, University of Oxford
2 WWARN - WorldWide Antimalarial Resistance Network
3 Global Health Division
4 Malaria Research - Department of Microbiology, Tumour and Cell biology [Stockholm, Sweden]
5 UC San Francisco - University of California [San Francisco]
6 LSHTM - London School of Hygiene and Tropical Medicine
7 LECEMO - LECEMO - Les Cultures de l'Europe Méditérranéenne Occidentale - EA 3979
8 Institut Pasteur du Cambodge
9 University of Maryland School of Medicine
10 Karolinska Institutet [Stockholm]
11 DZIF - German Center for Infection Research - partner site Hannover-Braunschweig
12 Department of Infectious and Tropical Diseases
13 University of Oxford
14 UCAD - Université Cheikh Anta Diop de Dakar [Sénégal]
15 NET - Neuroépidémiologie Tropicale
16 AP-HP - Hôpital Bichat - Claude Bernard [Paris]
17 Drugs for Neglected Diseases Initiative
18 KEMRI - Kenya Medical Research Institute
19 Muhimbili University of Health and Allied Sciences
20 SMRU - Shoklo Malaria Research Unit [Mae Sot, Thailand]
21 MAK - Makerere University [Kampala, Ouganda]
22 KFUPM - King Fahd University of Petroleum and Minerals
23 INSSA - Institut de Recherche en Sciences de la Santé Bobo Dioulasso
24 WWARN - WorldWide Antimalarial Resistance Network
25 Epicentre [Paris] [Médecins Sans Frontières]

Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 - 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36-17.97, P < 0.001 : were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.

Domaines: Maladies infectieuses; Parasitologie; Pharmacologie

Meera Venkatesan, Nahla Gadalla, Kasia Stepniewska, Prabin Dahal, Christian Nsanzabana, et al.. Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors That Affect Treatment Outcomes for P. falciparum Malaria After Artemether-Lumefantrine and Artesunate-Amodiaquine. American Journal of Tropical Medicine and Hygiene, 2014, 91 (4), pp.833-843. ⟨10.4269/ajtmh.14-0031⟩. ⟨hal-02560672⟩