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

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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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