Parasite Resistance to Artemisinins
WHO/MMV ARTEMISININ CONFERENCE 2009
"Ensuring Sustainable API Supply to Meet Global ACT Demand"
28th – 30th September 2009 in Mumbai, India
Dr Kamini Mendis Global Malaria Programme
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80 countries are using ACTs as first-line malaria treatment
Countries with P.falciparum and no ACT
Countries which adopted ACT as 1st-line treatment
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Could reverse the malaria control achievements of the past decade…….
But not inevitable, if the correct course of action is taken
Parasite Resistance to Artemisinins
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What is antimalarial drug resistance?
Ability of a parasite strain to survive and/or multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within tolerance of the subject” (WHO, 1973).
Therapeutic efficacy is used to detect resistance
Treatment failure ≠ drug resistance (host and/or parasite factors)
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Experience in Thailand with successive drug regimens
MefloquineQuinine
Sulphadoxine-pyrimethamine
Chloroquine
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Rapid development of resistanceto monotherapies
Quinine 1632 1910
Chloroquine 1945 1957 12 years
Proguanil 1948 1949 1 year
Sulfadoxine-pyrimethamine 19671967 <1 year
Mefloquine 1977 1982 5 years
Atovaquone 1996 1996 <1 year
Antimalarial drug
Year of introducti
on
1st case of
resistance
Artemisinin derivatives 1990 - 2000 2009 9-20 years?
Paper on resistance
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Artemisinin resistance
Events leading up to the confirmation of artemisinin resistance
Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO
– 2003 and 2005 High failure rate and increase parasite clearance time with ACTs detected
Trat
Pailin
Vietnam
Thailan
d Lao PDR
Proportion with treatment failure (2001-2007) in Cambodia
Proportion of positive cases on day 3 (2001-2007)
Noedl. et al. New England Journal of Medicine, 2009, 361: 5401.
„ETF“ with AS/MEF
Treatment failures with 7 days artesunate monotherapies
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Trat
Pailin
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Parasite clearance time with AS+MQ in Trat province
No of P. falciparum positives cases
0
0
1(4.5%)
0
2 (4.5%)
D7
3.75 (16.1%)14(45.1%)312007Trat
3.37(21.8%)10 (31.2%)322006Trat
2.32 (9%)7 (31.8%)222005Trat
2.12 (13.3%)2 (13.3%)152004Trat
2.07 (15.9%)14 (31%)442003 Trat
PCT(days)D3D2NYearProvince
Mae Sot
Trat
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PCR-adjusted parasitological efficacy of MAS3 at Day 42
80
85
90
95
100
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Years
MA
S 3 p
aras
itolo
gica
l eff
icac
y (in
%)
n=482 n=276
n=29
n=170 n=280
n=98
n=406
n=212 n=252
n=338 n=400
n=176
Noedl. et al. New England Journal of Medicine, 2009, 361: 5401.
Higher drug concentrations needed toinhibit parasite growth
Pfmdr1 (≥ 2) copy number trend
0%
10%
20%
30%
40%
50%
60%
70%
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006
Incr
ease
d in
cop
y nu
mbe
r (2+
)cn
Years
Incr
ease
d co
py n
umbe
r in
%
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Mae Sot
Trat
Events leading up to the confirmation of artemisinin resistance
Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO
– 2003 and 2005 High failure rate and increase parasite clearance time with ACTs detected 2005 - WHO raised concern over artesunate resistance in "Drug
Resistance Global Report"
2005 -Publication by CNM Cambodia and WHO of 2 articles on ACT failure
2006 - AFRIMS detected 2 suspected cases of artesunate resistance in Tasanh (published in 2008)
Events leading up to the confirmation of artemisinin resistance
Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO
– 2003 and 2005 High failure rate and increase parasite clearance time with ACTs detected 2005 - WHO raised concern over artesunate resistance in "Drug
Resistance Global Report"
2005 -Publication by CNM Cambodia and WHO of 2 articles on ACT failure
2006 - AFRIMS detected 2 suspected cases of artesunate resistance in Tasanh (published in 2008) 2007 January - WHO informal consultation on containment of malaria multidrug resistance on Cambodia-Thailand border, Phnom Penh
2007 November - ARC3 project funded by BMGF (3.2 M)
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Objectives of the ARC3 project
Confirm clinically relevant artemisinin resistance– Characterize clinically relevant artemisinin resistance in-vivo
by conducting clinical and pharmacokinetic-pharmacodynamic assessments of artesunate, at sites where artemisinin resistance has been reported, where parasite clearance is prolonged but treatment failure not yet manifest, and where artesunate efficacy is preserved;
– Establish a reference repository of parasite isolates from clinically validated cases of resistance.
If clinical resistance is confirmed, further characterize this resistance to define resistant in vitro phenotypes and genotypes for use in global surveillance for artemisinin resistance
To establish the prevalence on substandard and fake drugs on the Thai-Cambodia border
Develop strategies to combat the spread of artemisinin resistant malaria within Southeast Asia and internationally
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ARC3 project
Funded by BMGF (3.2 M)
Coordinated by GMP/HQ
Major partners:– Wellcome Trust-Mahidol University, Oxford Tropical Medicine Research
Programme, Bangkok, THAILAND– US Armed Forces Research Institute of Medical Sciences (AFRIMS),
Bangkok, THAILAND– Réseau des Instituts Pasteur, Cambodge, Phnom Penh, CAMBODIA– University of Vienna, Vienna, AUSTRIA– University of Maryland School of Medicine, Baltimore, Maryland, USA– University of South Florida, Tampa, Florida, USA– USP, Rockville, Madison, USA– National Malaria Control Programme, Phnom Penh, CAMBODIA– National Malaria Control Programme, Bangkok, THAILAND– WHO Mekong project, Bangkok, THAILAND– Western Pacific Regional Office, Manila, PHILIPPINES
(Pailin )MORU( )Completed Artesunate 2 mg/kg over 7 days vs artesunate 4 mg/kg over 3 days +
sequential mefloquine 25 mg/kgover 2 days
If< 6 patients with PCT < 96 h
→ Artesunate 6 mg/kg/over 7 days vs artesunate 8 mg/kg over 3 days + sequential mefloquine 25 mg/kg
(over 2 days )split
(Mae Sot )SMUR (completed)
Same design as Pailin
(Bandarban )University of Vienna
Artesunate 2 mg/kg vs 4 mg/kg vsquinine+tetracycline over 7 days
(Tasahn )AFRIMS
Artesunate 2 mg/kg vs 4mg/kg vs 6 mg/kg over 7 days
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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)
para
sita
emia
as
% fr
om a
dmis
sion
(geo
met
ric
mea
n)
0 12 24 36 48 60 72 84 96 108
120
0.001
0.01
0.1
1
10
100
1000
time (hours)
para
sita
emia
as
% fr
om a
dmis
sion
(indi
vidu
al d
ata)
FULLY SENSITIVE PARASITES
Parasite Clearance(p=0.0001 for ∆ slopes between sites)
Thai-
Cambodia border
Thai-Myanmar border
PCT in Pailin with artesunate 6 and 8 mg/kg/d
N=40
ArtemisininQuinine
48 hours
Mechanism of artemisinin resistance?
Inexorable, contiguous spread of chloroquine resistance from limited foci following rare,
complex genetic event
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Spread of chloroquine resistant P.falciparum
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Preliminary conclusions
• The proportion of patients who are parasitaemic on day 3 is the best measure of slow parasite clearance from available clinical trial data.
• The in vivo phenotype does not correlate to standard in vitro assays:
• There is no correlation between artesunate IC50s and PRR at 24 h and 48 h, proportions of patient still
parasitemic on day 1, day 2 or day 3 or PCT;• The lack of in vitro correlation may be because we are
using the wrong tool, therefore there is a need to develop novel in vitro studies.
• There was no correlation between a number of different mutations (pfSERCA or mtDNA mutations -
coxIII gene) or pfmdr1 copy number and clinical outcomes.
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Artemisinin resistance: research priorities
• What is it?
• What is it caused by?
• How can it be readily detected?
• How far has it spread?
• How should artemisinin resistance infections
be treated?
• How can it be eliminated?
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Artemisinin resistance
Events leading up to the confirmation of artemisinin resistance
Since 2001 - Routine surveillance system in Cambodia & Thailand - coordinated by WHO
– 2003 and 2005 High failure rate and increase parasite clearance time with ACTs detected 2005 - WHO raised concern over artesunate resistance in "Drug
Resistance Global Report"
2005 -Publication by CNM Cambodia and WHO of 2 articles on ACT failure
2006 - AFRIMS detected 2 suspected cases of artesunate resistance in Tasanh (published in 2008) 2007 January - WHO informal consultation on containment of malaria multidrug resistance on Cambodia-Thailand border, Phnom Penh
2007 November - ARC3 project funded by BMGF (3.2 M) 2008 January - WHO meeting on containment of artemisinin
tolerance, Geneva
2008 February - ARC3 Clinical trial meeting, Bangkok– Informal consultation to define strategy to contain/eliminate P.
falciparum parasites with altered response to artemisinin, Bangkok Thailand
2008 June - Informal consultation on resource mobilisation for the containment of artemisinin tolerant malaria on the Cambodia-Thailand border
2008 November - Containment project funded by BMGF (22.5 M)
Structure of the containment project
Objectives of containment project
1. To eliminate artemisinin tolerant parasites by detecting all malaria cases in target areas and ensuring effective treatment and gametocyte clearance
2. To decrease drug pressure for selection of artemisinin resistant malaria parasites (including monotherapy ban)
3. To prevent transmission of artemisinin tolerant malaria parasites by mosquito control and personal protection
4. To limit the spread of artemisinin tolerant malaria parasites by mobile/migrant populations
5. To support containment/elimination of artemisinin resistant parasites through comprehensive behavior change communication (BCC), community mobilization and advocacy
6. To undertake basic and operational research to fill knowledge gaps and ensure that strategies applied are evidence-based
7. To provide effective management, surveillance and coordination to enable rapid and high quality implementation of the strategy
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Dealing with the threat of parasite resistance
WHO strategies to prevent and contain parasite resistance
Global Malaria Portfolio - May 2008
Coartem Coartem-DPyramaxTafenoquine
Nat ProductNITD
DHFRNITD
ImmucillinsEinstein
BiartemidesNITD
MacrolidesGSK
OZ439
Pyridone 932121
Isoquine
PyridonesGSK Artemifone
MK4815
MacrolideGSK
FalcipainsGSK
AminoindoleBroad/Genzyme
HSP90Broad/Genzyme
Likelihood toLaunch
72% 90%27% 38%14%
RegistrationLead Opt Phase II Phase IIIPreclinical Phase I
Translational Development
DHODH
Launch*
Iv artesunate
Artemifone
Eurartesim
Pyramax
CoarsucamAS/AQ
AS/MQ
*Note 1: Lead Optimisation projects only includes MMV 2: Launch following registration by stringent authority or WHO-PQ
SAR116242Trioxanes
MMV projects
Blue AQ
FerroquineFosmidomyci
n Azithromycin
Azithromycin
chloroquine
Arterolane PQP
SAR97276Choline
AQ13Immtech
NPC1161cMississippi
Mirincamycin
Other projectsUnprecedented targets
Research
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Consequences of antimalarial
drug resistance Increased morbidity and mortality – including anaemia, low birth weight
Increased of transmission– switch to effective drug combinations in situations of low to moderate
endemicity has always resulted in a dramatic decrease in transmission
Economic impact– increases cost to health services (to both provider and patient) because of
returning treatment failures
Greater frequency and severity of epidemics
Modification of malaria distribution
Greater reliance on informal private sector– with the risk of using monotherapies, sub-standard and counterfeit medicines
which in turn will increase drug resistance
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To deal with the threat of drug resistance
Develop new medicines
. Monitor drug efficacy
Avoid emergence of drug resistance
Contain the spread of drug resistance
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Surveillance of drug resistance
Early detection of tolerance / resistance to artemisinins
Routinely monitor therapeutic efficacy of ACTs– In vivo studies on ACTs
WHO supported routine surveillance of drug resistance– Standardized methodologies, tools and technical
assistance– To countries and regional and sub-regional networks
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RAVREDA
Mekong
HANMAT
Regional and sub-regional networks on monitoring drug efficacy
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WHO/GMP Guidelines
2007
20092008
Planned: guidelines on pharmacokinetic and molecular markers for drug resistance
2003
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2. Monitoring drug efficacy
Countries must closely monitor the efficacy of antimalarial medicines recommended in their treatment guidelines to detect resistance early, and rapidly change drug policy when no longer effective, to avoid the further selection and spread of multidrug-resistance.
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WHO's role
Template protocol– English, French– According to International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use (ICH) and cleared by ERC– Inclusion, exclusion criteria, sampling methodology, CRF, informed consent, SAE
reporting…
Standardized data entry and data analysis methodology– Excel programme + SOP (English, French, Spanish)– Improves quality of the data by double entry, cross check, automatic analysis of the
data
Funding– USAID– WWARN/WHO
Antimalarial medicines for monitoring efficacy free of charge
Training– Protocol and microscopy (+++)
Report and publication
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Preventing drug resistance is a global public good and monitoring drug efficacy is WHO's responsibility
Global database on therapeutic efficacy of antimalarials:www.who.int/malaria/resistance.htm
New report in 2009
Preventing drug resistance is a global public good
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Instrument of policy
change
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Major achievements of WHO's coordination and global database on
drug efficacy 80 endemic countries
changed drug policy based on the results of their therapeutic efficacy tests
Report on global monitoring
GFATM changed choice of drug procurement
Detection of artesunate resistance at Thai-Cambodia border
Countries with P.falciparum and no ACT
Countries which adopted ACT as 1st-line treatment
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Threshold levels for changingmalaria treatment policy
Grace
Alert
Action
5%
15%
Change
25%
% clinical failures (14 d f/up)
0
WHO criteria 1998
5%
15%
25%
0
Clinicalfailures
Parasitologicalfailures
WHO criteria 2003
+
% failures (14 d f/up)
0
WHO criteria 2005
Parasitologicalfailures
% failures (28 d f/up)
10%
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Network of scientists to strengthen the scientific underpinnings of drug resistance &improve its detection and management
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Dealing with the threat of drug resistance
Develop new medicines
Monitor drug efficacy
.
Contain the spread of drug resistance
Avoid emergence of drug resistance
1. Strategies to avoid drug resistance
Use of combination therapy
October 7, 2009
A
0 1 2 3 4 WEEKS
1012
1010
108
106
104
102
0
TOTAL PARASITES
Drug level
B1
x
yA
m
n
B B1
1. Strategies to avoid drug resistance
Use of combination therapy
1. Strategies to avoid drug resistance
Use of combination therapy Effective ACTs of good quality
– widely accessible – correctly used, particularly in the private sector, which
includes:• education of the practitioners• increase compliance by use of co-formulated ACTs.• supervised drug administration can help to back up
adherence (similar to DOT)• Better diagnosis of the disease to avoid misuse of the
medicines• Fight against drugs of poor quality
Transmission control to reduce the burden and the use of antimalarial drugs (less drug pressure)
– vector control and bed-nets (South Africa)– reduction of reservoir of infection (responsible for the
spread of drug resistance) in improving therapeutic practice, in particular early diagnosis, effective treatment, and use of gametocytocidal drugs.
– vaccine
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Dealing with the threat of drug resistance
Develop new medicines
Monitor drug efficacy
Avoid emergence of drug resistance
.Contain the spread of drug resistance
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3. Containment of drug resistance
Remove the pressure of the resistant medicines– Atovaquine-proguanil (malarone TM) is being used on
the eastern border of Thailand
Operational research– depends on the local situation
Development of new antimalarial medicines
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Recommendations to countries and partners
Monitoring antimalarial drug efficacy– partners to invest in monitoring antimalarial drug efficacy
Support and improve access to early and effective treatment
– increase use of diagnosis– increase use of quality ACTs
Remove the sale and use of monotherapies and sub-standard medicines
– support surveys on drug quality
Increase efforts to reduce transmission
Ensure a steady and robust pipeline of new antimalarial combination medicines
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Tackling antimalarial drug resistance
Confirm drug
resistance
Contain drug resistance
time
Develop new drugs
Monitor therapeutic efficacyActi
vit
ies
Avoid emergence of resistance
