an update of artemisinin resistance and its containment efforts p. ringwald drug resistance and...
TRANSCRIPT
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