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Antimalarial treatment and malaria transmission: insights from the field

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Antimalarial treatment and malaria transmission: insights from the field. Conférence de la 8ème édition du Cours international « Atelier Paludisme » - DJIMDE Abdoulaye

Antimalarial treatment and malaria transmission: insights from the field. Conférence de la 8ème édition du Cours international « Atelier Paludisme » - DJIMDE Abdoulaye

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  • Malaria eradication/elimination will require new, safe and truely gametocytocidal drug• Need more sensitive gametocyte assays that could indicate gametocyte viability in addition to prevalence and density.• Field oriented studies need to be as close as possible to natural conditions. Too much cleaning of experimental design may yield nice results but with little relevance to real life.
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  • 1. Atelier Paludisme Institut Pasteur Antananarivo 14 – 20 Mars 2011Antimalarial treatment and malaria transmission: insights from the field Abdoulaye DJIMDE PharmD, PhD Malaria Research and Training Center University of Bamako, Mali 1
  • 2. Molecular BiologyImmunology Genetics • Drug ResistancePolicy PK • Spread of drug resistance PharmacogenomicsHost-Parasite-Vector Transmission 2
  • 3. Outline1. Sulfadoxine-Pyrimethamine (SP) and malaria transmission in the field2. Impact of SP on P. falciparum gametocytes infectivity in vitro3. Artemisinin-based combinations and malaria transmission in sub-Saharan AfricaConclusion 3
  • 4. P. falciparum life cycle
  • 5. Current malaria control tools• Artemisinin-based combination therapies (ACTs)• Sulfadoxine-pyrimethamine recommended for IPT in pregnant women – contemplated for IPTi and IPTc• Quinine for severe malaria• Insecticide treated nets & indoor residual spray
  • 6. Sulfadoxine-Pyrimethamine treatment and malaria transmission in a setting ofhigh Sulfadoxine-Pyrimethamine efficacy of Mali
  • 7. Background• Chloroquine efficacy decreasing• Need alternative second line drug• Prospective in vivo tests of CQ, amodiaquine and SP 7
  • 8. Study site• Kolle: rural village; 2,500 people• 55 Km South of Bamako• P. falciparum malaria endemic and seasonal• Parasitemia: – 40-50% dry season (October-April) – 70-85% rainy season Kolle (May-September).
  • 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 and pharmacokinetic studiesMIM Antimalarial Drug Resistance Network
  • 10. In vivo SP resistance in Mali
  • 11. Evolution of gametocyte carriage after SP treatment Beavogui et al., IJP 2010 11
  • 12. Molecular markers of SP resistance Adapted from P. Wang et al. :Molecular and Biochemical Parasitology 89 (1997) 161–177
  • 13. Mutations in pre-treatment asexual vs. post-treatment gametocytes 100 90 80 70 * 60 * * * p<0.001 % 50 * * 40 Asexual 30 * Gameto 20 10 0 le 59 51 le 8 7 10 43 ip up FR FR Tr FR PS dr H H FR H ua H D D D D Q Beavogui et al., IJP 2010 13
  • 14. Impact of large scale use of SP on spread of drug resistance and malaria transmission?
  • 15. Methods• 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-SP gametocytes to Anopheles gambiae• Protocol approved by IRBs in Bamako & Maryland 15
  • 16. 16
  • 17. Direct feeding 17
  • 18. 18
  • 19. Infectivity of Post-treatment Gametocytes * P < 0.001 Beavogui et al., IJP 2010 19
  • 20. Summary 1• SP increase rate of gametocyte carriage• Post-SP gametocytes carry SP- resistance mutations• Post-SP gametocytes were less transmissible to Anopheles gambiae
  • 21. Mechanism of decreasedinfectivity of post-sulfadoxine- pyrimethamine P. falciparum gametocytes to anopheline mosquitoes 21
  • 22. Infectivity of Sulfadoxine-Pyrimethamine treated P. Falciparum Gametocytes to Anopheline Mosquitoes
  • 23. Gametocyte production• Serum supplemented RPMI complete culture media• Gas (O2, CO2 and Nitrogen) humidity (70 - 80%) Candle Jar Shaker Tipper
  • 24. Gametocytes follow up Day 8 Day 14 Day 14Stage II Stage V Exflagellation test
  • 25. Standard Membrane feeding Assay Feeding of 30 mosquitoes With each sample
  • 26. Sulfadoxine and Pyrimethamine Plasma concentrations in Mali S P 26
  • 27. Drug concentrations usedDrugs Mean conc. Day 3 Day 7 Day 14Sulfa - ug/ml 61 34 14 ------ ------------ ----------- ------------ ---------Pyr ng/ml 158 67 16
  • 28. Experimental designA = Gametocytogenesis, B = Gametocyte maturation, 28 Kone A, IJP, 2010C = Mature gametocyte infectivity
  • 29. Results 29
  • 30. A. Induction of gametocytogenesis NF 135 Stage II NF135 Stage V 30
  • 31. B. NF 135 Gametocyte development Controls Pyrimethamine- treated Sulfadoxine- treated 31Kone A, IJP, 2010
  • 32. C. Effect of S, P and SP on gameto infectivity 32Kone A, IJP, 2010
  • 33. Effect of S, P and SP on oocyst density 33Kone A, IJP, 2010
  • 34. Effect of Day3 levels of S or SP on mosquito survival 34Kone A, IJP, 2010
  • 35. Summary 2• Sulfadoxine and pyrimethamine have complex effects on the biology of gametocytogenesis.• Induce differentiation into sexual forms• Treatment of young gametocytes impaired their further development into mature stage V gametocytes.• Drug + mature gametocytes => decreased infectivity• SP also kills vector A. stephensi 35
  • 36. Artemisinine-based combinationtherapies and Malaria transmission in the field
  • 37. ACTs and malaria transmission• “A single intramuscular injection of 5 mg/kg artemisinin (to gametocytemic rhesus monkeys) resulted in complete loss of mosquito infectivity within 24 h of drug administration” Dutta GP, et al. 1989• “artemisinin derivatives reduced gametocyte carriage 18.5 fold” and “were found to reduce the transmission potential of falciparum malaria” Price RN et al.,1996• “Artemesinin-based combination therapies (ACT) for falciparum malaria reduce gametocyte carriage, and therefore reduce transmission”. 37
  • 38. ACTs and malaria transmission (2)• NASBA study in Kenya “data suggest that the potential of malaria transmission remains high even after treatment with artemisinin combination therapy” Schneider P. et al, IJP, 2006• “An efficacious antimalarial regimen with no specific gametocytocidal properties but a long prophylactic time was estimated to be more effective at reducing transmission than a short-acting ACT in the highest- transmission setting”. Okell LC, PLoS Med, 2008 38
  • 39. ObjectiveMeasure the impact of AS/AQ, AS/SP and AR-L on malaria transmission.
  • 40. Day 28 Efficacynon-Corrected vs. PCR Corrected * P < 0.05 *
  • 41. Evolution of gametocyte carriage by treatment arm on follow up days 41
  • 42. How infectious are the post-ACT gametocytes? 42
  • 43. Methods• 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-SP gametocytes to Anopheles gambiae• Protocol approved by Ethics Committee of FMPOS 43
  • 44. Study site• Bougoula-Hameau: peri- urban village; 5000 people~400 Km South of Bamako• P. falciparum malaria hyper endemic• No Insectaries around!!
  • 45. Bougoula-Hameau, Sikasso, Mali 45
  • 46. 46
  • 47. 47
  • 48. 48
  • 49. Direct feeding 49
  • 50. 50
  • 51. Comparing Ctrl vs. all post-ttt Oocyst positive 45 40 *** 35 30 *** 25 Oocyst + 20 NS 15 10 5 0 l P L Q tr SS R SA C A A A Treatment arms 51
  • 52. Summary 3• ACTs decreased gametocyte carriageHOWEVER• Would all ACTs reduce malaria transmission in high transmission settings? 52
  • 53. Discussion• “Overall, infectivity was about three-times higher for direct feeding than for membrane feeding (p < 0.001)” Diallo M., et al Malaria Journal 2008• MFA “Blood cells were separated from plasma by centrifugation and plasma was replaced by a similar volume of normal human plasma known to sustain malaria transmission. This step was performed to avoid the possible interference (blocking or enhancing) antibodies to gametocytes in the donor’s plasma”. 53
  • 54. Conclusions• Malaria eradication/elimination will require new, safe and truely gametocytocidal drug• Need more sensitive gametocyte assays that could indicate gametocyte viability in addition to prevalence and density.• Field oriented studies need to be as close as possible to natural conditions. Too much cleaning of experimental design may yield nice results but with little relevance to real life. 54
  • 55. Acknowledgements• MRTC • Support• Study sites & • Government of Mali participants • MIM/TDR• Pr. Doumbo O & • NIAID/NIH MRTC staff • FIC/NIH • Ministère Français de• Nijmegen la Recherche (Pal +)• Adrian Luty • Sanofi-Aventis• Robert Sauerwein 55