31 march dundorp 1
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Is there Artemisinin Resistance in Western Cambodia?
Preliminary results, February 2008
Arjen Dondorp on behalf of the “Task Force on Antimalarial Drug Resistance in Cambodia”
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French Guiana 2002-2003; hypoxanthine uptake at 48 hours; no clinical data.Jambou et al. Lancet 2005; 366: 1960-63.
Artemether
S769N PfATPase6 mutation
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Cambodia 2001; hypoxanthine uptake at 48 hours.Jambou et al. Lancet 2005; 366: 1960-63.
Artesunate
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Antimalarial drug use in Western Cambodia
• 1955-9: DDT ± weekly mass drug administration
• 1960-61: Distribution of 77 tons of sea salt containing 0.05% pyrimethamine to a population of 20,000
• 1961-62: Distribution of 75 tons of salt containing 0.6% chloroquine
• Now: ACT (MAS3) first line treatment for uncomplicated falciparum malaria. However: substantial artesunate monotherapy use in the private sector
Verdrager 1986; Shunmay Yeung 2007
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ACT efficacy in Western Cambodia
• Coartem 28 day cure rate– Batambang 2002 (no food): 71.1% (but low day 7 blood levels)– Batambang 2003 (with food): 86.5%
• Artesunate-mefloquine 28 day cure rate– Batambang 2001: 96%– Pailin 2002: 86%– Batambang 2003: 92.4%– Pailin 2004: 90%– Trat province Thailand (just across the border) with a 2 days
regimen: 79%• Unconfirmed reports of prolonged parasite clearance
times (as PD measure for the artemisinins)
WHO 2007, TM&IH 2006;11:1800-07; Vijaykadga et al 2006
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Study site
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SCREENED: 92
INITIALLY ENROLLED: 43
ENROLLED: 40
EXCLUDED: 32 PARASiTAEMIA < 10,000/Ul
1 MIXED INFECTION
AS 2 MG/KG/DAY FOR 7 DAYS: 20
AS 4 MG/KG/DAY FOR 3 DAYSMQ 15&10 MG/KG/DAY DAY 3&4:
20
63 DAYS FOLLOW UP:20
63 DAYS FOLLOW UP: 1949 DAYS FOLLOW UP: 1
RECRUDESCENCE (Pf): 6 (30%)
(1 MIXED INFECTION)
REINFECTION (WITH MIXED Pf/Pv): 1
RECURRENT INFECTION (MIXED Pf/Pv):1
(genotyping follows)
RECURRENT INFECTION (Pv): 6
(1 MIXED INFECTION)
RECURRENT INFECTION (Pv): 7
(2 MIXED INFECTION)
CURE (FROM PRIMARY Pf INFECTION): 14
CURE(FROM PRIMARY Pf INFECTION): 19
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P (log-rank)=0.035
Genotyping will follow
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0 12 24 36 48 60 72 84 96 108
120
0.0001
0.001
0.01
0.1
1
10
100AS 2 mg/kgAS 4 mg/kg & MQ
time (hours)
para
sita
emia
as
% fr
om a
dmis
sion
(geo
met
ric m
ean)
parasite clearance curves (n=40)
0 12 24 36 48 60 72 84 96 108
120
0.001
0.01
0.1
1
10
100
1000black: AS7 (2mg/kg)red: MAS3 (4 mg/kg)green: relapse (all after AS7)
time (hours)
para
sita
emia
as
% fr
om a
dmis
sion
(indi
vidu
al d
ata)
FULLY SENSITIVE PARASITES
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Parasite reduction ratio at 48 hours
AS 2 mg/kg/dMedian (range): 114 (9-3956)
AS 4 mg/kg/d & MQMedian (range): 119 (10-1696)
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Parasite clearance time (hours)
AS 2 mg/kg/dMedian (range): 87 (42-120)
AS 4 mg/kg/d & MQMedian (range): 78 (36-114)
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0
10
20
30
40
104 105 106Prop
ortio
n (%
) par
asita
emic
at d
ay 3
(72h
)
Baseline parasitaemia (/uL)
50
Thai-Myanmar border, 2002-2006 n=1288
Cambodia-Thai border, 2007 Pailin; n=40 55% still parasitaemic at day 3
95%CI
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Gametocytocaemic during follow up: 8/40 (20%)(high compared to historical SMRU data (3%))
Arm Patient NoAdm.
P countGametocyte detection (Hour) PCT(Hour)
AS7(n=20) P002 25/1000 72 until 78 90
P013 2/1000 36 (once) 42
P022 9/1000 78 (once) 96
P035 4/1000 0 until 120 48MAS3(n=20) P015 7/1000 30 until 336 66
P027 24/1000 72 until 336 102
P029 9/1000 24 until 144 60
P034 3/1000 8 (once) 36
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No correlation PCT and IC50 (hypoxanthine uptake after 24 h)
Frederique Ariey, preliminary data
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• ‘Trophozoite inhibition assay’• Parasitemia/ 1000 red cells
and stage assessed• Parasite development assessed
in 200 asexual parasites• % trophozoites compared to
control well without drug.
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Kesinee Chotivanich, preliminary data
r2 =0.63
P=0.033
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Conclusions• Prolonged parasite clearance times confirmed,
with unacceptably high failure rate in AS7 arm• Not explained by inadequate drug levels;
variability in Cmax and AUC is considerable• No dose (or concentration)-response relationship
within current range of [AS]• Increased dose/ split dose? • No/ just 1 failure in MAS3 arm suggests continued
susceptibility to mefloquine• In vitro test under evaluation• Molecular marker?
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Acknowledgements
• Staff Pailin Referral Hospital• Mallika Imwong, Kesinee Chotivanich, Joel Tarning, Frederique
Ariey, Shunmay Yeung, Nick Day, Nick White• Staff of Mahidol - Oxford Tropical Medicine Research Unit • National Malaria Control Programme, Cambodia (Dr. Duong
Socheat)• Institut Pasteur, Pnomh Penh• AFRIMS, Bangkok• FHI, Bangkok• Li Ka Shing Foundation• WHO• Wellcome Trust
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Pailin, SW Cambodia
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Pailin clinical trial
• Inclusion:– Uncomplicated P. falciparum infection– Parasitaemia > 10,000/ uL– No mixed infection on light microscopy
• But 11/40 (28%) mixed Pf/Pv by PCR– No pregnancy– No previous antimalarial treatment (48H)
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Randomisation
• Artesunate 2 mg/kg bw per day for 7 days(AS7)
OR• Artesunate 4 mg/kg bw per day for 3 days
& mefloquine 15 and 10 mg/kg bw per day on day 3 and 4
(MAS3)
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Outcome measures
• Clinical and parasitological cure• Parasite clearance times• In vitro sensitivity tests• Molecular markers
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Molecular marker for artemisinin resistance?
• pfmdr1 mutation and copy no.• pfserca• pf mitochondrial DNA
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Single copy noMultiple copy no
Pfmdr1 copy no
$0
$0
$0
$0
$0
$1
$1
$1
$1
$1
$1
MaeSot06 Trat07 (n=32) Pailin06 (n=23) Pailin07 (n=40)
Freq
uenc
ies
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Pfserca SNP: full length sequence75 3132 3282 3580 3739 4068
89465464 759 847
pfserca mutation
0.00
0.20
0.40
0.60
0.80
1.00
1.20
I89T (n=17) 464(n=36) N465S(n=36) R759K (n=36) E847K (n=36)
Freq
uenc
ies
wild typemutant typeGap
SNP
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pf mitochondrial DNAcoxIII CoI CYTB
20474 1776772 2175
pf mitochondrial DNA (n=40)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
A74T C204T G772A T1776C T2175C
Fre
qu
enci
es
wild type
mutant type
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0.1
1.0
10.0
100.0
1000.0
0 2 4 6 8 10 12
TIME (hr)
DHA
ARTS
ID=2, GROUP=AS7
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Dosing regimeEvery 12 hours for a week
daily
twice‐daily
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Molecular mechanisms of resistanceDrug Low to medium level
resistance High-level resistance
Chloroquine CRT; 76 CRT; 76 & othersMDR; 86, + others
Mefloquine, halofantrine, lumefantrine
MDR; amplification of wild-type gene
Pyrimethamine DHFR; 108 then 51 and 59 DHFR; 108 + 51 + 59 + 164
Cycloguanil, chlorcycloguanil DHFR; 16 + 108 DHFR; 108 + 51 + 59 + 164
Sulfonamides and sulfones DHPS; 436, 437, 540, 581, 614
Atovaquone None reported Cytochrome b; 133 ± 280
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DHA
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0 1 2 3 4 5 6 14 21 28 35 42 49 56 63
25
30
35
40
45
50
artesunate 2 mg/kg bs (for 7 days)artesunate 4 mg/kg bw (for 3 days) & mefloquine on day 4 and 5
Days after admission
Hae
mat
ocrit
(%, m
ean,
SD
)
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P. falciparum IC50 (ng/mL)Mean (95%CI)
Lab strain (TM267) 0.7 (0.5-0.9)
Isolates from
Pailin,Cambodia 13 (7-19)(N=9)
Mae Sot, Thailand 3.9 (0-16)(N=3)
Trophozoite inhibition IC50 (preliminary data)
Kesinee Chotivanich
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AS7 (2 mg/kg) MAS3 (4 mg/kg)DHA Mean % CV min max Mean % CV min max
Cmax (ng/mL) 802 75% 142 2780 1819 54% 771 4680AUC (hr*ng/mL) 1400 58% 482 4027 3543 29% 1708 5182C60min (ng/mL) 564 84% 6 1720 1103 71% 24 2570C90min (ng/mL) 469 60% 61 1100 1227 52% 141 2380C180min (ng/mL) 218 72 20 506 695 41% 211 1100
ARTS 20-300 foldCmax (ng/mL) 269 103% 28 897 411 91% 34 1620AUC (hr*ng/mL) 160 54% 53 340 317 48% 122 738C60min (ng/mL) 65 93% 0.3 244 252 141% 6 1620C90min (ng/mL) 27 80% 1.3 68 85 84% 3 260C180min (ng/mL) 6 131% 0 22 14 128% 0 54
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• Recrudescent P. falciparum infection:– N=6 (all in AS7 arm)
• Recrurrent P. falciparum infection:– N=1 (MAS3 arm; genotyping follows)
• Recurrent P. vivax infection:– N=13 (7 in AS7 arm; 6 in MAS3 arm)
• Recurrent mixed infection:– N=2 (1 in each arm, 1 included in total Pf recurrence;
1 still needs genotyping)
Summary of recurrent infections: