An update of artemisinin resistance and its

containment efforts

P. RingwaldDrug Resistance and Containment Unit

0 1 2 3 4 WEEKS

Drug level

A

B

N. White, 1999

ACT: a different type of combinationT

ota

l par

asit

e b

iom

ass

Failure rates after treatment with an artemisinin-based combination therapy, Cambodia (20012011)

artemisinin resistance containment project zone 1

Pailin

0

10

20

30

2002 2004 2009 2010 2011

(%)

Battambang

0

10

20

30

2001 2002 2004 2005 2007

(%)Odder Meanchey

0

10

20

30

2003

(%)

Ratanakiri

0

10

20

30

2003 2005 2006 2010 2011

(%)

Preah Vihear

0

10

20

30

2005 2006 2008 2010

(%)

Kratie

0

10

20

30

2001 2003 2006

(%)

Kampong Speu

0

10

20

30

2003

(%)Kampot

0

10

20

30

2008

(%)

0

2

4

6

8

10

12

14

16

1 2 3

Artemether-lumefantrine (D28)

Artesunate-mefloquine (D42)

Dihydroartemisinin-piperaquine (D42)

Pursat

0

10

20

30

2002 2004 2005 2007 2009 2011

(%)

Day 3 positivity rate after treatment with an artemisinin-based combination therapy, Cambodia (20012011)

artemisinin resistance containment project zone 1

Odder Meanchey

0102030

2003

(%)

Ratanakiri

0

10

20

30

2003 2005 2006 2010 2011

(%)

Preah Vihear

0102030

2005 2006 2008 2010

(%)

Kratie

010

2030

2001 2003 2006

(%)

Pailin

01020304050

2002 2004 2009 2010 2011

(%)

Battambang

010203040

2001 2002 2004 2005 2007

(%)

Kampong Speu

0102030

2003

(%)

Pursat

0

10

20

30

02 04 05 07 09 11

(%)

Kampot

0102030

2008

(%)

Parasite clearance time with AS+MQ in Trat province

No of P. falciparum positives cases

Province Year N D2 D3 D7PCT

(days)

Trat 2003 44 14 (31%) 7 (15.9%) 2 (4.5%) 2.0

Trat 2004 15 2 (13.3%) 2 (13.3%) 0 2.1

Trat 2005 22 7 (31.8%) 2 (9%) 1 (4.5%) 2.3

Trat 2006 32 10 (31.2%) 7 (21.8%) 0 3.3

Trat 2007 31 14 (45.1%) 5 (16.1%) 0 3.7

Courtesy Wichai Satimai & Saowanit Vijaykadga, 2008

PCT in Pailin study 2007

AS 2 mg/kgAS 4 mg/kg & MQ

0 12 24 36 48 60 72 84 96 108

120

0.0001

0.001

0.01

0.1

1

10

100

time (hours)

par

asi

taem

ia a

s %

fro

m a

dm

issi

on

(geo

met

ric

mea

n)

0

12 24

36

48 60

72

84 96

10

8

12

0

0.001

0.01

0.1

1

10

100

1000

time (hours)

par

asi

taem

ia a

s %

fro

m a

dm

issi

on

(in

div

idu

al d

ata)

FULLY SENSITIVE PARASITES

Dondorp, NEJM, 2009

Parasite Clearance

(p=0.0001 for slopes between sites)

Thai-Cambodia border

Thai-Myanmar

border

Dondorp, NEJM, 2009

Definition of artemisinin resistance

● WHO is using working definition as below: an increase in parasite clearance time, as evidenced

by greater than 10% of cases with parasites detectable on day 3 following treatment with an ACT (suspected resistance); or

a treatment failure as evidenced by presence of parasites at day 3 and either persistence of parasites on day 7 or recrudescence after day 7 of parasites within 28/42 days, after treatment with an oral artemisinin-based monotherapy, with adequate blood concentration (confirmed resistance)

WHO recommendations

● Monitoring of ACTs is not only essential for timely changes to treatment policy and allows evaluation of the proportion of patients who still have parasites on day 3

● Each country should monitor first- and second-line drugs every 2 years

● Therefore, based on the results of the routine monitoring of ACT efficacy two different recommendations can be made: Policy change of ACTs should be initiated when the treatment

failure rate exceeds 10% at the end of follow-up (28 or 42 days, depending on the half life of the medicines), independently to the proportion of patients positive at day 3.

If therapeutic efficacy studies find that the threshold of 10% of patient parasitemic at day 3 is reached, studies using oral artesunate monotherapy should be initiated to confirm artemisinin resistance in the area.

Percentage of positive cases on day 3 after ACT

Phuoc Long

Eastern Shan

ACT efficacy in Pailin Province, Cambodia (2002-2011)

8.9

20.0

38.0

26.4

35.9

45.0

14.3

24.1

7.92.00.0

9.9

27.6

10.6

8.1

0

10

20

30

40

50

2002 2004 2008 2009 2010 2011

% Pos Day 3 % TF Day 28 % TF Day 42

artesunate mefloquine dihydroartemisinin piperaquine

GPARC action pillars

Contain or eliminate artemisinin resistance where it already exists

Prevent artemisinin resistance where it has not yet appeared

Motivate action and mobilize resources5

Invest in artemisinin resistance-

related research

Increase monitoring & surveillance to evaluate

the AR threat

2

Improve access to

diagnostics & rational treatment with ACTs

3

Stop the spread of resistant parasites

1 4

Malaria containment/elimination zoning overview: Thailand - Cambodia

13

Zone 1: Elimination strategy

Zone 2:Intensified malaria control strategy

Zone 3: Routine malaria control

Note: The boundaries and names shown and the designations used on this map do not imply official endorsement or acceptance by the United NationsSource: FAO GAUL – Release January 2007; Department of Geography; Royal Government of Cambodia; Global Containment Project, WHO

Example of GPARC Implementation in Tier 1: ARCE project on Cambodia-Thailand border

• Ambitious cross-border strategy to eliminate artemisinin resistant parasites

• Coordinated by WHO working closely with Cambodian and Thailand Ministries of Health; largely funded by BMGF, GFATM, and USAID

Target areas

Zone 1: areas where artemisinin tolerance detected

• Cambodia: ~ 270K people in 4 provinces

• Thailand: ~110K people

Zone 2: areas without evidence of tolerance, but high risk (close to zone 1)

• Cambodia: 9 provinces / ~4M people

• Thailand: 7 provinces / ~7M people

Program combines proven malaria prevention & treatment strategies

Activities designed for specific cultural, social, scientific context

• Large-scale distribution of LLINs

• Free early diagnosis and treatment of malaria at the village level

• 24-hour health facilities to diagnose and treat malaria

• Intensive surveillance of positive cases

• Education programs

• Innovative approaches to reach mobile populations

• Efforts to stop the sale of fake and substandard drugs

• Stringent measures to stop the sale and use of monotherapies

• Pilot intensive screening in most malaria-affected border villages

• Basic and operational research

P.f cases

150

100

50

0

10

Sep

-11

Jun-

11

23

Nov

-10

9

Oct

-10

18

Sep

-10

21

Aug

-10

8

Jul-1

0

14

Jun-

10

14

May

-11

6

Apr

-11

12

Mar

-11

5

Feb

-11

4

Jan-

11

8

Dec

-10

17

Nov

-09

12

Oct

-09

25

Sep

-09

103

Aug

-09

121

Jul-0

9

139

Jun-

09

135

May

-09

102

Apr

-09

63

Mar

-09

31

Feb

-09

43

Jan-

09

63

Dec

-08

43

May

-10

5A

pr-1

02

Mar

-10

12F

eb-1

0

26Ja

n-10

14

Dec

-09

31

Nov

-08

99

Oct

-08

30

Sep

-08

140A

ug-0

8

60

Jul-0

8

74

Jun-

08

112

May

-08

23

Apr

-08

5

Mar

-08

11

Feb

-08

29

Jan-

08

13

Jul-1

1

Aug

-11

1510

Cases diagnosed in Pailin province

ARCE interventions

P.f cases diagnosed by microscopy and RDT at health facilities in Pailin province (Z1), Jan 2008-Jun 2011

Tier I

Tier I (inactive)

Tier II

Tier II (inactive)

Myanmar

Thailand

Viet Nam

Cambodia

Areas of artemisinin resistance and containment

Confirmed artemisinin resistance according to WHO working definition

Consequences of artemisinin resistanceFACTSFACTS IMPLICATIONSIMPLICATIONS

(ACPR) Clinical and parasitological cure of ACTs - not compromised

Change in parasite sensitivity not reflected in routine therapeutic efficacy results

Clinical resolution (fever clearance time – prolonged slightly)

May lead to dissatisfied patients and incorrect treatment practices

Parasite clearance time – prolongedCould potentially increased risk of mortality associated with severe and complicated malaria (which is treated with AS monotherapy)

Incidence of infections with patent gametocytaemia – Needs more data

Increased risk of transmission of less sensitive parasites – Needs more research

Infectivity to mosquitoes – data not available

Needs more research

Total parasite biomass over period of infection increased

More parasites exposed to partner medicine alone

Likely to increased propensity for parasite de novo mutations – which favour parasite survival