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Update on tolerance/resistance and therapeutic efficacy ofand therapeutic efficacy of artemisinin in South East Asia
P Ri ldP. RingwaldGlobal Malaria Programme
Paper on resistancePaper on resistance
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What is antimalarial drug resistance?What is antimalarial drug resistance?Ability of a parasite strain to survive and/or multiply despite the administra-tion and absorption of a drug given in doses equal to or higher than those p g g q gusually recommended but within tolerance of the subject (WHO, 1973)
Therapeutic efficacy is used as an 'alert' to drug resistance but not all treatment failures are due to resistance. Treatment failure can be due to:– Pharmacokinetic (low absorption, increased metabolism, etc…)– Immunity (HIV pregnancy etc )Immunity (HIV, pregnancy, etc…)– Confirmed resistance
Therefore the following tools are needed to confirm resistance:g– Pharmocokinetic data– in vitro sensitivity
molecular markers
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– molecular markers
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Odder Meanchey
20
30(%) Preah Vihear
20
30(%)
Proportion of patients with treatment failure (day 28)
0
10
20
2003
0
10
2005 2006 2008 2010
Battambang
20
30(%)
Pailin(%)
0
10
2001 2002 2004 2005 2007
Ratanakiri
10
20
30(%)
Pailin
0
10
20
30( )
02003 2005 2006 2009
Kratie30(%)
2002 2004 2009 2010
Pursat
20
30(%)
0
10
20
30
2001 2003 2006
Kampong Speu
10
20
30(%)
Kampot
20
30(%)
0
10
2002 2004 2005 2007 2009
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0
10
20030
10
20
0 0 2008
Proportion of patients
positive on (day 3)
Odder Meanchey
20
30(%) Preah Vihear
10
20
30(%)
(day 3)0
10
2003
Ratanakiri30(%)
Battambang
20
30(%)
0
10
2005 2006 2008 2010
0
10
20
30
2003 2005 2006 2009Pailin(%)
0
10
2001 2002 2004 2005 2007
2003 2005 2006 2009Pailin
0
10
20
30(%)
Kratie
20
30(%)
Kampong Speu30(%)
Pursat30(%)
02002 2004 2009 2010
0
10
2001 2003 2006
0
10
20
2003
Kampot
20
30(%)0
10
20
2002 2004 2005 2007 2009
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10
20
2008
Parasite Clearance
(p=0.0001 for ∆ slopes between sites)
Thai‐Cambodia border
Thai‐Myanmar border
7 |GLOBAL
MALARIA PROGRAMMEDondorp, NEJM, 2009
PCR-adjusted efficacy of MAS3 in Mae SotPCR-adjusted efficacy of MAS3 in Mae SotC adjusted e cacy o S3 ae SotC adjusted e cacy o S3 ae Sot
Carrara PLoS One 2009
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Carrara, PLoS One, 2009
Parasite clearance with MAS3 in Mae SotParasite clearance with MAS3 in Mae Sot
Carrara PLoS One 2009
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Carrara, PLoS One, 2009
PCT in Pailin with artesunate 6 and 8 mg/kg/d
N=40
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Mechanism of artemisinin resistance?
48 hours
ArtemisininQuinine
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20Proportion (%) positive on Day 3
1
20
Parasite clearance data from 18,699 falciparum malaria patients with fully15 falciparum malaria patients with fully artemisinin sensitive parasites, treated with an artemisinin derivative
10
53%
0
P it i t l t (/ L)102 103 104 105 106
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Parasitaemia at enrolment (/uL)
Definition of artemisinin resistanceDefinition of artemisinin resistanceAbsence of consensus on the definitionWHO is using the following working definitions:
– suspected resistance: increase in parasite clearance time, id d b 10% f ith it d t t bl as evidenced by over 10% of cases with parasites detectable
on day 3 following treatment with an ACT; – confirmed resistance: treatment failure, as evidenced by confirmed resistance: treatment failure, as evidenced by
persistence of parasites at day 7 or the presence of parasites at day 3 and recrudescence within 28/42 days, after full treatment of oral artemisinin-based monotherapy with treatment of oral artemisinin-based monotherapy with adequate blood concentration
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WHO strategy for dealing with antimalarial drug resistance(adopted by the RBM Board. Dec 2009)
WHO strategy for dealing with antimalarial drug resistance(adopted by the RBM Board. Dec 2009)
Contain drug resistance
Confirm drug resistanceti
es
Monitor therapeutic efficacyActivit
Avoid emergence of resistance
time
Develop new drugs
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Structure of the containment projectStructure of the containment projectp jp j
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Objectives of containment projectObjectives of containment projectTo eliminate artemisinin tolerant parasites by detecting all malaria cases in target areas and ensuring effective treatment and gametocyte clearance
To decrease drug pressure for selection of artemisinin resistant malaria parasites (including monotherapy ban)
To prevent transmission of artemisinin tolerant malaria parasites by vector control and p p ypersonal protection
To limit the spread of artemisinin tolerant malaria parasites by mobile/migrant populations
T i / li i i f i i i i i h h h i To support containment/elimination of artemisinin resistant parasites through comprehensive behavior change communication (BCC), community mobilization and advocacy
To undertake basic and operational research to fill knowledge gaps and ensure that strategies applied are evidence basedstrategies applied are evidence-based
To provide effective management, surveillance and coordination to enable rapid and high quality implementation of the strategy
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Day 3 positivity rate > 10%
MAS3AS7
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FACTSFACTS IMPLICATIONSIMPLICATIONSClinical and parasitological cure of ACTs -not compromised
Change in parasite sensitivity not reflected in routine therapeutic efficacy resultsp p y
Fever clearance time – prolonged slightly Incorrect treatment practices
Parasite clearance time – prolonged Potentially increased risk of mortality of severe malaria which is treated with AS monotherapy
Increased gametocyte rate Increased transmission of less sensitive Increased gametocyte rate parasites
Unknown infectivity to mosquitoes Likely to increase transmission
Unknown impact on parasite biomass over period of infection
More parasites exposed to partner medicine
Increased number of de novo mutations –promoting parasite survival
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promoting parasite survival
Artemisinin resistance or tolerance?an irrelevant debate
Artemisinin resistance or tolerance?an irrelevant debatean irrelevant debatean irrelevant debate
P. falciparum has changed sensitivity to artemisinins
Implications are:– Prolonged morbidity and increased risk of mortality– Increased risk of transmission of resistant parasites– Increase risk of losing partner medicines
Malaria control and elimination efforts could be seriously compromised
IMMEDIATE AND EFFECTIVE ACTION IS WARRANTED
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Thank you Thank you for your kind attentionfor your kind attention
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