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Antimalarial treatment and malaria transmission: insights from the field

Antimalarial treatment and malaria transmission: insights from the field - Conférence de la 8e édition du Cours international « Atelier Paludisme » - DJIMDE Abdoulaye - Mali -
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  • 1. Antimalarial treatment andmalaria transmission:insights from the fieldAbdoulaye DJIMDE PharmD, PhDMalaria Research and Training CenterUniversity of Bamako, Mali1Atelier PaludismeInstitut Pasteur Antananarivo14 – 20 Mars 2011
  • 2. 2• Drug Resistance• Spread of drugresistanceMolecular BiologyGeneticsPKPharmacogenomicsImmunologyPolicyHost-Parasite-VectorTransmission
  • 3. Outline1. Sulfadoxine-Pyrimethamine (SP) andmalaria transmission in the field2. Impact of SP on P. falciparumgametocytes infectivity in vitro3. Artemisinin-based combinations andmalaria transmission in sub-Saharan AfricaConclusion3
  • 4. P. falciparum life cycle
  • 5. Current malaria control tools• Artemisinin-based combination therapies (ACTs)• Sulfadoxine-pyrimethamine recommended for IPT inpregnant women– contemplated for IPTi and IPTc• Quinine for severe malaria• Insecticide treated nets & indoor residual spray
  • 6. Sulfadoxine-Pyrimethamine treatmentand malaria transmission in a setting ofhigh Sulfadoxine-Pyrimethamine efficacyof Mali
  • 7. Background• Chloroquine efficacy decreasing• Need alternative second line drug• Prospective in vivo tests of CQ,amodiaquine and SP7
  • 8. Study site• Kolle: rural village; 2,500people• 55 Km South of Bamako• P. falciparum malariaendemic and seasonal• Parasitemia:– 40-50% dry season(October-April)– 70-85% rainy season(May-September). Kolle
  • 9. Study design• Open randomized drug efficacy trial• Children 6 months – 5 years• Three arms: Chloroquine, Amodiaquine, SP• 28 days of follow up• In vivo, in vitro, molecular andpharmacokinetic studiesMIM Antimalarial Drug Resistance Network
  • 10. In vivo SP resistance in Mali
  • 11. 11Evolution of gametocyte carriage after SPtreatmentBeavogui et al., IJP 2010
  • 12. Molecular markers of SP resistanceAdapted from P. Wang et al. :Molecular and Biochemical Parasitology 89 (1997)161–177
  • 13. 13Mutations in pre-treatment asexualvs. post-treatment gametocytes0102030405060708090100%DHFR108DHFR59DHFR51DHPS437FRTripleQuadrupleAsexualGameto**** * p<0.001**Beavogui et al., IJP 2010
  • 14. Impact of large scale use of SP onspread of drug resistance andmalaria transmission?
  • 15. 15Methods• Drug efficacy study• Screening for gametocyte carriers• Detect molecular markers of drug resistance• Include gametocyte carriers aged 6 – 18 y.• Direct feed starved F1 generation An. gambiae• Maintain mosquitoes in lab for 8 days• Presence and number of oocysts measured bydissection• Compare the infectivity of pre-treatment vs. post-SPgametocytes to Anopheles gambiae• Protocol approved by IRBs in Bamako & Maryland
  • 16. 16
  • 17. 17Direct feeding
  • 18. 18
  • 19. 19Infectivity of Post-treatmentGametocytes* P < 0.001Beavogui et al., IJP 2010
  • 20. Summary 1• SP increase rate of gametocyte carriage• Post-SP gametocytes carry SP- resistancemutations• Post-SP gametocytes were lesstransmissible to Anopheles gambiae
  • 21. Mechanism of decreasedinfectivity of post-sulfadoxine-pyrimethamine P. falciparumgametocytes to anophelinemosquitoes21
  • 22. Infectivity of Sulfadoxine-Pyrimethamine treated P. FalciparumGametocytes to Anopheline Mosquitoes
  • 23. Candle Jar Shaker Tipper• Serum supplemented RPMI complete culture media• Gas (O2, CO2 and Nitrogen) humidity (70 - 80%)Gametocyte production
  • 24. Gametocytes follow upStage IIDay 8Stage VDay 14Exflagellation testDay 14
  • 25. Standard Membrane feeding AssayFeeding of 30mosquitoesWith each sample
  • 26. 26Sulfadoxine and Pyrimethamine Plasma concentrations in MaliSP
  • 27. Drugs Mean conc. Day 3 Day 7 Day 14Sulfa -------Pyrug/ml------------ng/ml61-----------15834------------6714---------16Drug concentrations used
  • 28. Experimental design28A = Gametocytogenesis, B = Gametocyte maturation,C = Mature gametocyte infectivity Kone A, IJP, 2010
  • 29. Results29
  • 30. A. Induction of gametocytogenesis30NF 135 Stage II NF135 Stage V
  • 31. B. NF 135 Gametocyte development31Controls Pyrimethamine- treated Sulfadoxine- treatedKone A, IJP, 2010
  • 32. C. Effect of S, P and SP on gametoinfectivity32Kone A, IJP, 2010
  • 33. Effect of S, P and SP on oocyst density33Kone A, IJP, 2010
  • 34. Effect of Day3 levels of S or SP onmosquito survival34Kone A, IJP, 2010
  • 35. Summary 2• Sulfadoxine and pyrimethamine have complex effects onthe biology of gametocytogenesis.• Induce differentiation into sexual forms• Treatment of young gametocytes impaired their furtherdevelopment into mature stage V gametocytes.• Drug + mature gametocytes => decreased infectivity• SP also kills vector A. stephensi35
  • 36. Artemisinine-based combinationtherapies and Malaria transmissionin the field
  • 37. ACTs and malaria transmission• “A single intramuscular injection of 5 mg/kg artemisinin (togametocytemic rhesus monkeys) resulted in complete loss ofmosquito infectivity within 24 h of drug administration” DuttaGP, et al. 1989• “artemisinin derivatives reduced gametocyte carriage 18.5 fold”and “were found to reduce the transmission potential offalciparum malaria” Price RN et al.,1996• “Artemesinin-based combination therapies (ACT) forfalciparum malaria reduce gametocyte carriage, and thereforereduce transmission”.37
  • 38. ACTs and malaria transmission (2)• NASBA study in Kenya “data suggest that the potential ofmalaria transmission remains high even after treatmentwith artemisinin combination therapy” Schneider P. et al,IJP, 2006• “An efficacious antimalarial regimen with no specificgametocytocidal properties but a long prophylactic timewas estimated to be more effective at reducingtransmission than a short-acting ACT in the highest-transmission setting”. Okell LC, PLoS Med, 200838
  • 39. ObjectiveMeasure the impact of AS/AQ, AS/SPand AR-L on malaria transmission.
  • 40. Day 28 Efficacynon-Corrected vs. PCR Corrected** P < 0.05
  • 41. 41Evolution of gametocyte carriage by treatment arm onfollow up days
  • 42. 42How infectious are the post-ACTgametocytes?
  • 43. 43Methods• Drug efficacy study• Screening for gametocyte carriers• Detect molecular markers of drug resistance• Include gametocyte carriers aged 6 – 18 y.• Direct feed starved F1 generation An. gambiae• Maintain mosquitoes in lab for 8 days• Presence and number of oocysts measured by dissection• Compare the infectivity of pre-treatment vs. post-SPgametocytes to Anopheles gambiae• Protocol approved by Ethics Committee of FMPOS
  • 44. Study site• Bougoula-Hameau: peri-urban village; 5000 people~400 Km South of Bamako• P. falciparum malariahyper endemic• No Insectaries around!!
  • 45. Bougoula-Hameau, Sikasso, Mali45
  • 46. 46
  • 47. 47
  • 48. 48
  • 49. 49Direct feeding
  • 50. 50
  • 51. 51Comparing Ctrl vs. all post-ttt Oocyst positive051015202530354045 CtrlASSPASAQARLTreatment armsOocyst +******NS
  • 52. 52Summary 3• ACTs decreased gametocyte carriageHOWEVER• Would all ACTs reduce malaria transmission inhigh transmission settings?
  • 53. Discussion• “Overall, infectivity was about three-times higher fordirect feeding than for membrane feeding (p < 0.001)”Diallo M., et al Malaria Journal 2008• MFA “Blood cells were separated from plasma bycentrifugation and plasma was replaced by a similarvolume of normal human plasma known to sustain malariatransmission. This step was performed to avoid thepossible interference (blocking or enhancing) antibodies togametocytes in the donor’s plasma”.53
  • 54. Conclusions• Malaria eradication/elimination will requirenew, safe and truely gametocytocidal drug• Need more sensitive gametocyte assays thatcould indicate gametocyte viability inaddition to prevalence and density.• Field oriented studies need to be as close aspossible to natural conditions. Too muchcleaning of experimental design may yieldnice results but with little relevance to reallife. 54
  • 55. Acknowledgements• MRTC• Study sites &participants• Pr. Doumbo O &MRTC staff• Nijmegen• Adrian Luty• Robert Sauerwein• Support• Government of Mali• MIM/TDR• NIAID/NIH• FIC/NIH• Ministère Français dela Recherche (Pal +)• Sanofi-Aventis55
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