rbm case management group, 09 june 2015 1 |1 | dr p. ringwald global malaria programme monitoring...

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


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)


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


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.


Surveillance of antimalarial drug resistance

Surveillance of antimalarial drug resistance

1. Avoiding emergence of drug resistance2. Monitoring drug efficacy3. Containing of drug resistance


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


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.


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


20072007

WHO/GMP Guidelines

PK2009

MM2010

PK2009

MM201020092009

20082008


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


Instrument o

f policy

change


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%


Major achievementsMajor achievements








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




Report on global monitoringGFATM changed procurement

policyDetection of artesunate





Proportion with treatment failure (2001-2007) in CambodiaProportion with treatment failure (2001-2007) in Cambodia


Proportion of positive cases on day 3 (2001-2007)Proportion of positive cases on day 3 (2001-2007)


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


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


Networks supported by WHONetworks supported by WHO

RAVREDAHANMAT

Mekong


EANMATRACTAP

RAOTAP 1

SANMAT

RAOTAP 2

African regional networks

RER-OI

HANMAT


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


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


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

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