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1 RECHERCHE, MISE EN OEUVRE DES PROGRAMMES DE SANTE ET POLITIQUES PUBLIQUES : ENRICHISSEMENTS RECIPROQUES POUR ACCROITRE L IMPACT SUR LA SANTE DES POPULATIONS JEUDI 2 JUILLET 2015 Contrôler et prévenir les résistances : les atouts d une approche coordonnée de la recherche et de la mise en oeuvre des programmes de lutte contre le paludisme dans la région du Mékong Frederic.ariey@pasteur.fr

2 La lutte contre le paludisme

3 Diminuer le contact avec les moustiques Traiter rapidement les cas de paludisme

4 Premier programme d éradication Lancé par l OMS en 1955 DDT et Chloroquine Marche assez bien dans les zones de faible prévalence Pas vraiment une réussite en Afrique Abandon du programme fin des années 1970 : Paludisme éliminé dans 37/148 pays (27 en Europe & Amériques)

5 R O L L BAC K M A L A R I A PA R T N E R S H I P P R O G R E S S & I M PAC T S E R I E S, vol 8 Sept 2011 Eliminating malaria. Learning form the past looking ahead

6 Mortalité du Paludisme (évaluation)

7 EN 2000 L ONU Adopte les Objectifs du Millénaire

8 Moyens de lutte contre le paludisme pulvérisation intra-domiciliaire moustiquaires Traitement a base de dérivé de l artémisinine (ACT) Diagnostic Traitement préventif intermittent

9 Financement de la lutte contre le paludisme Evolution du Financement financement de la lutte Lutte contre contre le paludisme le paludisme (en (en millions de de dollars) Décaissement

10 Augmentation des moyens de lutte Distribution de Moustiquaires En millions d unités Traitement Antipaludiques distribués En million d unité Rapport OMS 2010

11 Progres & Impact

12 Senegal Artesunate + amodiaquine Diagnostic rapide moustiquaires

13 Ca marche!!

14 Le paludisme dans le monde aujourd hui L amélioration récente de la situation résulte : L augmentation des financements pour traiter et contrôler la maladie Les efforts accrus et généralisés de tous les intervenants : - Fonds Mondial - President s Malaria Initiative (USA) - Banque Mondiale - UNITAID - Fondation Gates - Coopérations bilatérales UK et France - Rotary International 14

15 EN 2000 L ONU Adopte les Objectifs du Millénaire

16 Le paludisme dans le monde aujourd hui Les efforts portent leurs fruits Mais il reste beaucoup à faire

17 Prochaine étape : L élimination du paludisme

18 Elimination

19 Elimination End goal? objectives Complete detection (Human reservoir) + Complete cure (Human reservoir) + Complete prevention (transmission) + ME & Surveillance (impact) = Malaria elimination Translational research Improving tools to detect malaria asexual and sexual Plasmodium stages in asymptomatic parasite carriers (reservoir) Monitoring antimalarial drug efficacy Deciphering mechanisms associated to drugs resistance Evaluating and testing late lead/preclinical molecules Investigating interactions between sexual parasite populations and insect vectors (transmission) Developing new vector controls tools and strategies Vaccine development Studying malaria parasite population: evolution and adaption Build rationales for testing innovative interventions

20 Elimination End goal? objectives Complete detection (Human reservoir) + Complete cure (Human reservoir) + Complete prevention (transmission) + ME & Surveillance (impact) = Malaria elimination Translational research Improving tools to detect malaria asexual and sexual Plasmodium stages in asymptomatic parasite carriers (reservoir) Monitoring antimalarial drug efficacy Deciphering mechanisms associated to drugs resistance Evaluating and testing late lead/preclinical molecules Investigating interactions between sexual parasite populations and insect vectors (transmission) Developing new vector controls tools and strategies Vaccine development Studying malaria parasite population: evolution and adaption Build rationales for testing innovative interventions

21 Elimination End goal? objectives Complete detection (Human reservoir) + Complete cure (Human reservoir) + Complete prevention (transmission) + ME & Surveillance (impact) = Malaria elimination Translational research Monitoring antimalarial drug efficacy Deciphering mechanisms associated to drugs resistance Evaluating and testing late lead/preclinical molecules

22 Artemisinin derivatives High Activity but short half live Given in Association Time

23 Protect the efficacy of ACT

24 Artemisinin Resistance

25 Artemisinin resistance in SE ASIA Same area (low endemic area with a major Artemisinin drug pressure) On going surveys conduct by IPC since 2000

26 Artemisinin resistance in SE ASIA Avoid former history of emergence of resistance in Camdodia and to his spread throughout Africa 26

27 P. falciparum artemisinin resistance Clinical phenotype: increased clearance half-life In vitro phenotype: dormancy of young ring stages Parasite genotype: presence of a mutant K13 locus Noedl et al NEJ 2008, 359:24 Dondorp et al, NEJ 2009, 361: 455 Witkowski et al, AAC : 914 Witkowski, et al LID. 2013, 13:1043 Ariey et al Nature 2014, 505:50

28 Genome editing studies: K13 is the major determinant of ART-resistance Introduction of a mutant allele into wild type parasites induces a RSA 0-3hr resistance phenotype Introduction of the wild type allele into Cambodian mutant parasites reverses the RSA 0-3hr resistance phenotype WT to C580Y WT to R539T C580Y to WT I543T to WT R539T to WT Science 2015 J Straimer, N Gnädig & D Fidock Columbia University, NY C. Amaratunga & R. Fairhurst, NIH, NIAID F. Benoit-Vical, INSERM, Toulouse

29 ART-resistance is spreading and emerging in independent foci Temporal dynamics of K13 SNPs in 6 Cambodian provinces (886 isolates) coincides with temporal and geographic spreading of ART-resistance Ariey et al Nature 2014, 505:50-5. K13 SNPs are associated with clinical ART-resistance in Myanmar and Vietnam as well as Cambodia C580Y: Independent emergence in Myanmar WHO-sponsored TRAC study Takala-Harrison, Jacob et al. submitted

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31 K13 propeler domain mutations,are linked with Artemisinin Resistance

32 Ongoing real-time risk mapping: the Institut Pasteur/WHO KARMA Project ( ) (K-13 Artemisinin Resistance Multicenter Rapid Assessment) Objectives Provide a global map of K13 alleles distribution Provide capacities and expertise (capacity building) Participants : 39 countries (Africa 22, SEAsia 8, SAmerica 3, Nat. Ref. Ctr 3) 41 partner institutions, 13 from IP