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RBM Case Management Group, 21 April 20231 |
Dr P. RingwaldGlobal Malaria Programme
Monitoring antimalarial drug efficacy and resistance:
challenges
Monitoring antimalarial drug efficacy and resistance:
challenges
RBM Case Management Group, 21 April 20232 |
What is antimalarial drug resistance?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).
The drug must gain access to the parasite or the infected red blood cell for the duration of the time necessary for its normal action (WHO, 1986).
Drug resistance treatment failure (host and/or parasite factors)
RBM Case Management Group, 21 April 20233 |
Consequences of antimalarial drug resistance
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 transmissionEconomic impact
– increases cost to health services (to both provider and patient) because of returning treatment failures
Greater frequency and severity of epidemicsModification of malaria distributionGreater reliance on informal private sector
– with the risk of using monotherapies, sub-standard and counterfeit medicines which in turn will increase drug resistance
RBM Case Management Group, 21 April 20234 |
Monitoring antimalarial drug efficacy fits squarely within WHO’s six core functions Monitoring antimalarial drug efficacy fits squarely within WHO’s six core functions
• Providing leadership on matters critical to health and engaging in partnerships where joint action is needed;
• Shaping the research agenda and stimulating the generation, translation and dissemination of valuable knowledge;
• Setting norms and standards, and promoting and monitoring their implementation;
• Articulating ethical and evidence-based policy options; • Providing technical support, catalysing change, and building
sustainable institutional capacity;• Monitoring the health situation and assessing health trends.
RBM Case Management Group, 21 April 20235 |
Surveillance of antimalarial drug resistance
Surveillance of antimalarial drug resistance
1. Avoiding emergence of drug resistance2. Monitoring drug efficacy3. Containing of drug resistance
RBM Case Management Group, 21 April 20236 |
1. Strategies to avoid drug resistance1. 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-package or 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
RBM Case Management Group, 21 April 20237 |
2. Monitoring drug efficacy2. Monitoring drug efficacy
Countries must closely monitor the efficacy of antimalarial medicines recommended in their treatment guidelines and rapidly change drug policy when no longer effective, to avoid emergence of multidrug-resistance.
RBM Case Management Group, 21 April 20238 |
WHO roleWHO 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 chargeTraining
– Protocol and microscopy (+++)Report and publication
RBM Case Management Group, 21 April 20239 |
20072007
WHO/GMP Guidelines
PK2009
MM2010
PK2009
MM201020092009
20082008
RBM Case Management Group, 21 April 202310 |
Major achievements of WHO's coordination and global database on drug efficacy
Major achievements of WHO's coordination and global database on drug efficacy
77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests
Report on global monitoringGFATM changed choice of
drug procurementDetection of artesunate
resistance at Thai-Cambodia border
Countries which need ACT policy
Countries which adopted ACT
RBM Case Management Group, 21 April 202311 |
Instrument o
f policy
change
RBM Case Management Group, 21 April 202312 |
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%
RBM Case Management Group, 21 April 202313 |
Major achievementsMajor achievements
77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests
Report on global monitoringGFATM changed choice of
drug procurementDetection of artesunate
resistance at Thai-Cambodia border
Countries which need ACT policy
Countries which adopted ACT
RBM Case Management Group, 21 April 202314 |
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
RBM Case Management Group, 21 April 202315 |
Major achievementsMajor achievements
77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests
Report on global monitoringGFATM changed choice of
drug procurementDetection of artesunate
resistance at Thai-Cambodia border
Countries which need ACT policy
Countries which adopted ACT
RBM Case Management Group, 21 April 202316 |
RBM Case Management Group, 21 April 202317 |
Major achievementsMajor achievements
77 endemic countries changed drug policy based on the results of their therapeutic efficacy tests
Report on global monitoringGFATM changed procurement
policyDetection of artesunate
resistance at Thai-Cambodia border
Countries which need ACT policy
Countries which adopted ACT
RBM Case Management Group, 21 April 202318 |
Proportion with treatment failure (2001-2007) in CambodiaProportion with treatment failure (2001-2007) in Cambodia
RBM Case Management Group, 21 April 202319 |
Proportion of positive cases on day 3 (2001-2007)Proportion of positive cases on day 3 (2001-2007)
RBM Case Management Group, 21 April 202320 |
PCT in Pailin study 2007PCT in Pailin study 2007
AS 2 mg/kgAS 4 mg/kg & MQ
0
12
24
36
48
60
72
84
96
10
8
12
0
0.0001
0.001
0.01
0.1
1
10
100
time (hours)
par
asit
aem
ia a
s %
fro
m a
dm
issi
on
(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)
par
asit
aem
ia a
s %
fro
m a
dm
issi
on
(in
div
idu
al d
ata)
FULLY SENSITIVE PARASITES
RBM Case Management Group, 21 April 202321 |
Potential for collaboration between WHO/GMP & WARNPotential for collaboration between WHO/GMP & WARN
– Monitoring antimalarial drug efficacy
• Technical and financial support to regional sub-regional networks (workshops)
• Capacity strengthening in countries through technical (training) and financial support
• Provision of quality assured medicines and other relevant supplies
• QC of data (through site visits at beginning, middle and end of the study and data review and validation-CRF, parasitology)
• Collection of data from countries• Collection of blood samples for in
vitro, MM, and PK
– Review of research and updating methodologies
– Updating and publishing WHO Global Drug Resistance Database and its applications
• Publication of drug resistance report
• Update of recommendations on medicine policy
• Participation of WARN members to promote WARN activities
• Participation of consultants designated within WARN
• Promote country data sharing with WARN• Disseminate samples to WARN reference
labs
• Co-sponsored meeting on an ad-hoc basis
• WARN as one source of information
WHO activities Possible points of collaboration with WARN*
*WHO collaborations with WARN will not be exclusive but open to all the scientific community
RBM Case Management Group, 21 April 202322 |
Networks supported by WHONetworks supported by WHO
RAVREDAHANMAT
Mekong
RBM Case Management Group, 21 April 202323 |
EANMATRACTAP
RAOTAP 1
SANMAT
RAOTAP 2
African regional networks
RER-OI
HANMAT
RBM Case Management Group, 21 April 202324 |
3. Containment of drug resistance3. Containment of drug resistance
Strengthening the strategies to avoid the emergence of drug resistance
Remove the pressure of the resistant medicinesOperational research
– depends on the local situationDevelopment of new antimalarial medicines
RBM Case Management Group, 21 April 202325 |
Recommendations to countries and partners
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 good ACTs
Remove the sale and use of monotherapies– support surveys on drug quality
Support transmission reduction
RBM Case Management Group, 21 April 202326 |
Structure of GMP's Technical Expert Groups (TEGs)
Structure of GMP's Technical Expert Groups (TEGs)
Chemotherapy of malaria
Vector ControlEconomics, Finance
and Impact, Implementation and Scaling Up
Malaria Case Management
Drug resistance
Preventive chemotherapy
Co-chair persons
Core Members + Co-opted Members