Download 5 - Roll Back Malaria

Monitoring antimalarial drug
efficacy and resistance:
challenges
Dr P. Ringwald
Global Malaria Programme
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RBM Case Management Group, 13 May 2017
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)
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RBM Case Management Group, 13 May 2017
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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RBM Case Management Group, 13 May 2017
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.
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RBM Case Management Group, 13 May 2017
Surveillance of antimalarial drug
resistance
 1. Avoiding emergence of drug resistance
 2. Monitoring drug efficacy
 3. Containing of drug resistance
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RBM Case Management Group, 13 May 2017
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-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
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RBM Case Management Group, 13 May 2017
2. 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.
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RBM Case Management Group, 13 May 2017
WHO 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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RBM Case Management Group, 13 May 2017
WHO/GMP Guidelines
PK
2009
2007
2008
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RBM Case Management Group, 13 May 2017
MM
2009
2010
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 monitoring
 GFATM changed choice of
drug procurement
 Detection of artesunate
resistance at Thai-Cambodia
border
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RBM Case Management Group, 13 May 2017
Countries which need ACT policy
Countries which adopted ACT
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RBM Case Management Group, 13 May 2017
Threshold levels for changing
malaria treatment policy
% clinical failures (14 d f/up)
Change
25%
% failures (14 d f/up)
Parasitological
failures
+
Action
15%
Clinical
failures
25%
Parasitological
failures
15%
10%
Alert
5%
5%
Grace
0
WHO criteria 1998
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% failures (28 d f/up)
RBM Case Management Group, 13 May 2017
0
WHO criteria 2003
0
WHO criteria 2005
Major achievements
 77 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
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RBM Case Management Group, 13 May 2017
Countries which need ACT policy
Countries which adopted ACT
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
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RBM Case Management Group, 13 May 2017
Major achievements
 77 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
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RBM Case Management Group, 13 May 2017
Countries which need ACT policy
Countries which adopted ACT
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RBM Case Management Group, 13 May 2017
Major achievements
 77 endemic countries changed
drug policy based on the
results of their therapeutic
efficacy tests
 Report on global monitoring
 GFATM changed procurement
policy
 Detection of artesunate
resistance at Thai-Cambodia
border
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RBM Case Management Group, 13 May 2017
Countries which need ACT policy
Countries which adopted ACT
Proportion with treatment failure (2001-2007) in Cambodia
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RBM Case Management Group, 13 May 2017
Proportion of positive cases on day 3 (2001-2007)
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RBM Case Management Group, 13 May 2017
PCT in Pailin study 2007
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FULLY SENSITIVE PARASITES
time (hours)
RBM Case Management Group, 13 May 2017
time (hours)
120
108
96
84
0.001
72
120
108
96
84
72
60
48
36
24
12
0.0001
0.01
60
0.001
0.1
48
0.01
1
36
0.1
10
24
1
100
12
10
1000
0
parasitaemia as % from admission
(individual data)
100
0
parasitaemia as % from admission
(geometric mean)
AS 2 mg/kg
AS 4 mg/kg & MQ
Potential for collaboration between WHO/GMP & WARN
WHO activities
– Monitoring antimalarial drug
efficacy
Possible points of
collaboration with WARN*
• 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
•
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
– Review of research and
updating methodologies
– Updating and publishing WHO
Global Drug Resistance
Database and its applications
•
Co-sponsored meeting on an ad-hoc basis
•
WARN as one source of information
• Publication of drug resistance
report
• Update of recommendations on
medicine policy
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RBM Case Management Group, 13 May 2017
*WHO collaborations with WARN will not be exclusive but open to all the scientific community
Networks supported by WHO
Mekong
RAVREDA
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RBM Case Management Group, 13 May 2017
HANMAT
African regional networks
HANMAT
RAOTAP 1
RAOTAP 2
RACTAP
EANMAT
RER-OI
SANMAT
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RBM Case Management Group, 13 May 2017
3. Containment of drug resistance
 Strengthening the strategies to avoid the emergence
of drug resistance
 Remove the pressure of the resistant medicines
 Operational research
– depends on the local situation
 Development of new antimalarial medicines
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RBM Case Management Group, 13 May 2017
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
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RBM Case Management Group, 13 May 2017
Structure of GMP's Technical Expert
Groups (TEGs)
Vector Control
Chemotherapy
of malaria
Economics, Finance
and Impact,
Implementation
and Scaling Up
Co-chair persons
Malaria Case
Management
Drug
resistance
Preventive
chemotherapy
Core Members + Co-opted Members
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RBM Case Management Group, 13 May 2017