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TRANSCRIPT
9/02/10
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Clinical and Laboratory Assessment of Antimalarial Drug Efficacy
in the Lao P.D.R
Presentation Plan 1. Introduction
2. Studies conducted before 2000 (in-vivo)
3. Studies after 2000:
- In-vitro study
- Molecular study
- Clinical trials
Abbreviations
CQ = Chloroquine
SP = Fansidar
QN = Quinine
A = Artesunate
M = Mefloquine
AL = Artemether-lumefantrine (Coartem)
DP = Dihydroartemisinin-piperaquine
(Artekin)
Before 2005… • Malaria: important cause of morbidity & mortality in Laos (Prevalence ~ 14%)
• Chloroquine (CQ) & sulfadoxine-pyrimethamine (SP): did not work anymore in neighboring countries
• But CQ & SP: Lao nationally recommended antimalarials for treatment of uncomplicated malaria !
A Lao child with severe malaria
A Lao technician said in 2000:
“…..in Laos, chloroquine still works OK and
there is no resistance of malaria parasites. If
you don’t believe me, let’s see in your
study….”
Efficacy of Antimalarial Drugs in Laos before 2000
1. Ebisawa et al., 1970 (Japan J Exp Med 40: 151-157)
- Antimalarial drugs: CQ, SP, QN + SP - Nam-Ngum dam, Vientiane (1968); N = 108
Results CQ SP QN+SP (n=64) (n=26) (n=18)
Sensitive 59 (92%) 25 (96%) 18 (100%)
RI 5 (8%) 1 (4%) 0
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2. AL Tawil, 1977 (Bull WHO: 230-237)
- Antimalarial drug: CQ
- Nam-Ngum dam, Vientiane (1975-76)
- N = 48 (follow up: 7 days) Results Sensible = 28 (58%)
RI = 8 (17%)
RII = 10 (21%)
RIII = 2 (4%)
42%
3. Giboda et al., 1992 (Southeast Asian J Trop Med Pub Hlth 23: 383-388)
- Antimalarial drug: CQ - Nam-Ngum dam, Vientiane (1989) - N = 15 (10 days of follow up ?)
Results
Sensitive = 9 (60%)
RI = 2 (13%)
RII = 2 (13%)
RIII = 2 (13%)
40%
4. Pillai et al., 2001 (JID 183: 789 - 95)
- Antimalarial drug: CQ (28 days – DOT) - Vangvieng District, Vientiane (1998-99) - N = 39
Results
Sensitive = 21 (54%)
RI = 5 (13%)
RII - RIII = 13 (33%)
46%
5. Guthmann et al., 2002 (Ann Trop Med Parasitol 96: 553 -7)
- Antimalarial drug: CQ (28 days – DOT) - Sekong Province (1999 - 2000) - N = 88
Results
ARC = 53 (60%)
ETF = 6 (7%) LTF = 29 (33%)
40%
CMPE - LAOS
Centre of Malariology,
Parasitology & Entomology
(CMPE), Ministry of
Health, Laos
Station of Malariology,
Parasitology & Entomology, Savannakhet Provincial
Health, Laos
FEUANG
XEPON PHALANXAY
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Log drug concentrations 1 2 3 4 5 6 7 8 ng/ml
EC 50
Emax
Eff
ects
(par
asite
kill
ing)
In vitro antimalarial susceptibility patterns of P. falciparum malaria in Laos
(Phanlanxay District, Savannakhet 2003 - 2004)
P. falciparum isolates defined as resistant (N = 108):
* Chloroquine 65 %
* Quinine 40 %
* Mefloquine 08 %
(Mayxay et al., 2007: Am J Trop Med Hyg 76:245-50)
- Blood spots collected on filter papers
- DNA extraction
- PCR to study gene
mutation
Normal gene (DHFR)
Mutation of gene (DHFR)
Enzyme structure Target of drug
Change of enzyme structure
Serine
Asparagines
108
108
Target of drug
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Distribution of P. falciparum molecular markers associated with SP & CQ in Laos
Collaboration with Dr. Tim Anderson, Texas, USA
* Countrywide survey
* ~884 blood spot samples on
filter paper from 17 provinces
* Molecular markers:
PfDHFR & DHPS, PfCRT
Phongsaly n = 2
Luang Namtha n = 23
Bokeo n = 12
Xaya- buly
n = 6
Udomxai n = 12 Luang
Phabang n = 36
Huaphan n = 0
Xiengkhuang n = 4
Special zone n = 1
Vientiane n = 27
Vientiane Capital (no malaria transmission)
Borikhamxai n = 11
Savannakhet n = 392
Khammuan n = 16
Saravan n = 33
Champasack
n = 33
Xekong n = 28
Attapeu n = 24
No resistance mutations
1 mutation
2 mutations
3 mutations
4 mutations
Dhfr gene mutation in parasites (resistant to P)
from 17 provinces of Laos
(Mayxay et al., 2007:
Am J Trop Med Hyg 77: 36 - 43)
Phongsaly n = 2
Luang Namtha n = 23
Bokeo n = 12
Xaya- buly
n = 7
Udomxai n = 15 Luang
Phabang n = 35
Huaphan n = 0
Xiengkhuang n = 4
Special zone n = 1
Vientiane n = 29
Vientiane Capital (no malaria transmission)
Borikhamxai n = 10
Savannakhet n = 416
Khammuan n = 21
Saravan n = 34
Champasack
n = 31
Xekong n = 27
Attapeu n = 18
(Mayxay et al., 2007:
Am J Trop Med Hyg 77: 36 - 43)
No resistance mutations
1 mutation
2 mutations
3 mutations
4 mutations
Dhps gene mutation in parasites (resistant to S)
from 17 provinces of Laos Phongsaly n = 2
Luang Namtha n = 53
Bokeo n = 14
Xaya- buly
n = 7
Udomxai n = 23 Luang
Phabang n = 39
Huaphan n = 3
Xiengkhuang n = 7
Special zone n = 1
Vientiane n = 47
Vientiane Capital (no malaria transmission)
Borikhamxai n = 12
Savannakhet n = 452
Khammuan n = 25
Saravan n = 49
Champasack
n = 41
Xekong n = 36
Attapeu n = 25
76-K (Wild type)
76-T (Mutant type)
pfCRT 76-allele frequency in parasites (resistant to CQ) from 17
provinces of Laos
(Mayxay et al., 2007:
Am J Trop Med Hyg 77: 36 - 43)
Distribution of P. falciparum molecular markers associated with SP & CQ resistance in Laos
• Countrywide (884 blood spot samples on from 17 provinces)
• Molecular markers: pfdhfr & pfdhps; pfcrt
• Proportion of mutation:
* Pf-dhfr (resistant to pyrimethamine): 77% with >1 mutations (164 frequency = 6%)
* Pf-dhps (resistant to sulphadoxine): 21% with >1 mutations
* Pf-crt (resistant to chloroquine): 85% with 76T mutations
(Mayxay et al., 2007. Am J Trop Med Hyg 77: 36–43)
- Patients take antimalarial drugs - Follow up (7, 14, 28, 42, 63… days) - Assessment: * Cure rate * Fever clearance time * Parasite clearance time
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(Schwobel et al., 2001. Trop Med Intl Health 8: 19-24)
Attapeu Province (14 day-follow up) N = 107
Results CQ SP CQ+SP MQ (n=29) (n=28) (n=24) (n=26)
ACR 16 (55%) 23 (82%) 20 (83%) 26 (100%)
ETF 3 (10%) 1(4%) 1(4%) 0
LTF 10 (35%) 4 (14%) 3 (13%) 0 45% 18% 17%
Therapeutic Efficacy of Chloroquine plus Sulphadoxine/Pyrimethamine Compared with Monotherapy with Either Chloroquine or Sulphadoxine/ Pyrimethamine in Uncomplicated Falciparum Malaria in Laos
Follow up of patient at home
3 Days COMPARISON OF PARASITE CLEARANCE TIMES
2
1
0 CQ + SP AM AL
PCT
- Mea
n (S
D)
*
* Significant difference compared to other two groups P < 0.001
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50 Hours
* Significant difference compared to other two groups P < 0.001
COMPARISON OF FEVER CLEARANCE TIMES
40
20
30
10
0 CQ + SP AM AL
FCT
- Mea
n (S
D)
* 30 % GAMETOCYTAEMIA AFTER TREATMENT
20
10
0 CQ + SP AM AL
28/110 (25.5%)
4/110 (3.6%) 5/110 (4.5%)
*
* Significant difference compared to the other two groups (P < 0.001)
AM CQ+SP AL
*
*
*
%
* Significant difference from other groups
Neuro-psychiatric
PROBABLE SIDE EFFECTS AFTER TREATMENT
(Mayxay et al., 2006: Trop Med Intl Health 11: 1157-65 )
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3 Days
COMPARISON OF PARASITE CLEARANCE TIMES
2
1
0 AM DP
PCT
- Mea
n (S
D)
P = 0.14
30
Hours
P = 0.85
COMPARISON OF FEVER CLEARANCE TIMES
20
10
0
AM DP
FCT
- Mea
n (S
D)
Checking body temperature
PROBABLE SIDE EFFECTS AFTER TREATMENT
AM AK
%
* Significant difference between groups (P < 0.05)
*
*
*
*
*
*
* But the problem is…
Chinese GMP vs ICH GMP
A Phase III, randomized, non-inferiority trial, to assess the
efficacy and safety of Dihydroartemisinin+Piperaquine (DHA
+PPQ, Artekin) in comparison with Artesunate+Mefloquine
(AS+MQ) in patients affected by acute, uncomplicated
Plasmodium falciparum malaria in Asia
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Treatment outcome (63 days follow up)
* Median (range)
(Mayxay et al., in preparation)
Side Effects After Treatment
• % patients with at least one recorded potential side effect was significantly higher in AM [43/98 (44%)] compared to DP [64/202 (32%)] groups (P = 0.039).
• Incidence of post treatment dizziness, nausea, insomnia, and anorexia were all significantly higher in AM compared to DP recipients (P < 0.01).
CONCLUSION: DP is not inferior to AM in the treatment of uncomplicated falciparum malaria in southern Laos and was associated with fewer adverse effects.
Conclusions 1. Chloroquine & sulphadoxine-pyrimethamine are not
longer efficacious for the treatment of uncomplicated falciparum malaria in Laos
2. Artemisinin combination therapy (artesunate + mefloquine, artemether –lumefantrine or coartem, dihydroartemisinin-piperaquine or artekin): work very well in Laos
STUDY TEAM Mayfong Mayxay Samlane Phompida Siamphai Keola
Paul N Newton Rattanaxay Phetsouvanh Ratsuda Yapom Nicholas J White Maniphone Khanthavong Anna Annerberg Alan Brockman Tiengkham Pongvongsa Kasia Stepniewska Niklas Lindegardh Vonthalome Thongpaseuth Shalini Nair Marion Barends Bouakham Vannachone Tim Anderson
ACKNOWLEDGEMENTS Vanphanom Sychareun Souksavanh Bouachanh Syvoraphanh
Stephane Proux Francois Nosten Kai-Amphon Keopasert
Pitta Odai Xaisithideth Chanthala Vilaihong
Phomma Manisack Phommasansack Bounpon
Bangthon Thonglien Singnort Vilayphone
Minit Bounmy ……. Wellcome Trust of Great Britain
Lao children after malaria treatment