An update of artemisinin resistance and its containment efforts P. Ringwald Drug Resistance and...
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![Page 1: An update of artemisinin resistance and its containment efforts P. Ringwald Drug Resistance and Containment Unit.](https://reader035.fdocuments.in/reader035/viewer/2022081516/5697c0031a28abf838cc3c8c/html5/thumbnails/1.jpg)
An update of artemisinin resistance and its
containment efforts
P. RingwaldDrug Resistance and Containment Unit
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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
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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
(%)
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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
(%)
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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
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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
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Parasite Clearance
(p=0.0001 for slopes between sites)
Thai-Cambodia border
Thai-Myanmar
border
Dondorp, NEJM, 2009
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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)
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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.
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Percentage of positive cases on day 3 after ACT
Phuoc Long
Eastern Shan
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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
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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
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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
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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
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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
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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
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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