global plan for in resistance

8/6/2019 Global Plan for in Resistance

http://slidepdf.com/reader/full/global-plan-for-in-resistance 1/93



Global PlaNFoR aRtemisiNiNResistaNce

coNtaiNmeNt(GPaRc)



WHO Library Cataloguing-in-Publication Data

Global plan or artemisinin resistance containment (GPARC).

1.Antimalarials – therapeutic use. 2.Artemisinins – therapeutic use. 3.Drug resistance. 4.Malaria – drug

therapy. 5.Plasmodium alciparum – drug eects. 5.Health programs and plans. I.World Health Organization.

II.Global Partnership to Roll Back Malaria.

ISBN 978 92 4 150083 8 (NLM classication: QV 256)

© Wold Hlth Onzton 2011

All rights reserved. Publications o the World Health Organization can be obtained rom WHO Press, World

Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; ax: +41 22 791

4857; e-mail: [email protected]). Requests or permission to reproduce or translate WHO publications

– whether or sale or or noncommercial distribution – should be addressed to WHO Press, at the above

address (ax: +41 22 791 4806; e-mail: [email protected]).

The designations employed and the presentation o the material in this publication do not imply theexpression o any opinion whatsoever on the part o the World Health Organization concerning the legal

status o any country, territory, city or area or o its authorities, or concerning the delimitation o its rontiers

or boundaries. Dotted lines on maps represent approximate border lines or which there may not yet be ull

agreement.

The mention o specic companies or o certain manuacturers’ products does not imply that they are

endorsed or recommended by the World Health Organization in preerence to others o a similar nature that

are not mentioned. Errors and omissions excepted, the names o proprietary products are distinguished by

initial capital letters.

All reasonable precautions have been taken by the World Health Organization to veriy the inormation

contained in this publication. However, the published material is being distributed without warranty o any

kind, either expressed or implied. The responsibility or the interpretation and use o the material lies with

the reader. In no event shall the World Health Organization be liable or damages arising rom its use.

Dsn nd lyot: paprika-annecy.com

Photo cdt: Image licensed by Ingram Publishing

Lyot coodnton nd mps: Claudia Corazzola, WHO/GRA

Cov: Photo retouching and Illustration by Denis Meissner, WHO/GRA

Printed by WHO/DUP



CeAcknowledgements .................................................................................................................................... 1

Abbreviations .............................................................................................................................................. 4

Foreword .................................................................................................................................................... 5

Executive summary .................................................................................................................................... 7

Introduction ...............................................................................................................................................15

1. Context ..................................................................................................................................................19

2. Recommendations ................................................................................................................................ 23

3. Summary recommendations by tier ..................................................................................................... 29

4. Stop the spread o resistant parasites .................................................................................................. 35

4.1 Preventive measures to reduce transmission ............................................................................. 35

4.2 Malaria control or mobile and migrant populations .................................................................... 36

5. Increase monitoring and surveillance to evaluate the threat o artemisinin resistance ........................ 39

6. Improve access to diagnostics and artemisinin-based combined therapy ............................................ 43

6.1 Consistent, accurate diagnostic testing ....................................................................................... 43

6.2 Access to aordable, quality-assured artemisinin-based combination therapy ........................... 45

6.3 Removal o oral artemisinin-based monotherapy ........................................................................ 47

6.4 Removal o substandard and countereit drugs ........................................................................... 49

7. Invest in research on artemisinin resistance ......................................................................................... 51

7.1 Laboratory research ...................................................................................................................... 51

7.2 Research and development .......................................................................................................... 52

7.3 Applied and eld research ............................................................................................................ 55

7.4 Operational research .................................................................................................................... 56

7.5 Mathematical modelling ............................................................................................................... 58

8. Motivate action and mobilize resources ............................................................................................... 59

8.1 Stakeholder motivation ................................................................................................................ 59

8.2 Resource mobilization ................................................................................................................. 60

9. Stakeholders’ priorities ......................................................................................................................... 65

10. Emergency mobilization plan .............................................................................................................. 69

Reerences ............................................................................................................................................... 73

Annex 1. Case study o containment o artemisinin resistance in Cambodia ........................................... 75

Annex 2. Subregional monitoring o therapeutic ecacy o antimalarial medicines ................................ 79

Annex 3. Current use o diagnostic testing or malaria............................................................................. 81

Annex 4. Current availability o ACTs in endemic countries ..................................................................... 83

Annex 5. Removal o oral artemisinin-based monotherapies ................................................................... 85



1

AcweeeThe Global Plan or Artemisinin Resistance Containment (GPARC) was developed in consultation with

members o each o the constituencies o the Roll Back Malaria Partnership. The work was coordinated by

the World Health Organization (WHO) Global Malaria Programme, with the direct support o The Boston

Consulting Group and unding rom the Bill & Melinda Gates Foundation. WHO Global Malaria Programme

would like to thank the many individuals and institutions that participated in the preparation o the GPARC

or invaluable advice provided through interviews and consultations, comments on the initial act base on

artemisinin resistance or review o the nal document.

Olusoji Adeyi, The Global Fund to Fight AIDS, Tuberculosis and Malaria (Aordable Medicines Facility –

malaria)

Paul Aliu, Novartis International AG, Basel, Switzerland

Pedro Alonso, Barcelona Centre or International Health Research, Barcelona, Spain

Abdinasim Amin, ICF Macro, Rockville, Maryland, United States o America (USA)Girindre Beeharry, Bill & Melinda Gates Foundation, Seattle, Washington, USA

David Bell, Global Malaria Programme, WHO, Geneva, Switzerland

Silvia Bertagnolio, HIV/AIDS, WHO, Geneva, Switzerland

Delia Bethell, Armed Forces Research Institute o Medical Sciences, Bangkok, Thailand

Fred Binka, University o Ghana, Accra, Ghana

Steve Bjorge, WHO Country Oce, Phnom Penh, Cambodia

François Bompart, sano-aventis, Paris, France

Andrea Bosman, Global Malaria Programme, WHO, Geneva, Switzerland

David Brandling-Bennett, Bill & Melinda Gates Foundation, Seattle, Washington, USA

Joel Breman, Fogarty International Center, National Institutes o Health, Bethesda, Maryland, USA

Keith Carter, WHO Regional Oce or the Americas, Washington District o Columbia, USA

Noel Chisaka, The World Bank, Washington, District o Columbia, USA

Eva Christophel, WHO Regional Oce or the Western Pacic, Manila, PhilippinesJe Chung, Clinton Health Access Initiative, New York City, New York, USA

Awa Coll-Seck, Roll Back Malaria Partnership, WHO, Geneva, Switzerland

Alan Court, Oce o the United Nations Secretary-General’s Special Envoy or Malaria, New York City,New York, USA

Janice Culpepper, Bill & Melinda Gates Foundation, Seattle, Washington, USA

Charles Delacollette, Mekong Malaria Programme, WHO, Bangkok, Thailand

Abdoulayé Djimbé, Malaria Research and Training Center, University o Bamako, Mali

Arjen Dondorp, Mahidol–Oxord Tropical Medicine Research Unit, Faculty o Tropical Medicine, Mahidol

University, Bangkok, Thailand

Ogobara Doumbo, Malaria Research and Training Center, University o Bamako, Mali

Erin Eckert, ICF Macro, Rockville, Maryland, USA

Alexandra Farnum, Bill & Melinda Gates Foundation, Seattle, Washington, USA

Richard Feachem, Global Health Group, University o Caliornia, San Francisco, Caliornia, USAMark Fukuda, Global Emerging Inectious Surveillance, Armed Forces Health Surveillance Center,

Silver Spring, Maryland, USA

Oumar Gaye, University o Dakar, Dakar, Senegal

Philippe Guérin, WorldWide Antimalarial Resistance Network, Nueld Department o Clinical Medicine,

University o Oxord, Headington, Oxord, United Kingdom o Great Britain and Northern Ireland

Najibullah Habib, WHO Country Oce, Phnom Penh, Cambodia

Max Hardiman, International Health Regulations Coordination, WHO, Geneva, Switzerland

Emily Hertzer, The Boston Consulting Group, Chicago, Ill inois, USA

Jerey Hii, WHO Country Oce, Manila, Philippines



3

Rima Shretta, Management Sciences or Health, Cambridge, Massachusetts, USA

Carol Sibley, WorldWide Antimalarial Resistance Network, Nueld Department o Clinical Medicine,

University o Oxord, Headington, Oxord, United Kingdom o Great Britain and Northern Ireland

Jackson Sillah, Inter-country Support Team or West Arica, Ouagadougou, Burkina Faso

Inder Singh, Clinton Health Access Initiative, New York City, New York, USA

Laurence Slutsker, Centers or Disease Control and Prevention, Atlanta, Georgia, USA

Frank Smithuis, Medical Action Myanmar, Yangon, Myanmar

Duong Socheat, National Centre or Parasitology, Entomology and Malaria Control,

Phnom Penh, Cambodia

Angus Spiers, Population Services International, Nairobi, Kenya

Lori Spivey, The Boston Consulting Group, Boston, Massachusetts, USA

Guy Stallworthy, Bill & Melinda Gates Foundation, Seattle, Washington, USA

Rick Steketee, Malaria Control and Evaluation Partnership in Arica, PATH, Seattle, Washington, USA

Trish Stroman, The Boston Consulting Group, Washington, District o Columbia, USA

Marcel Tanner, Swiss Tropical and Public Health Institute, Basel, Switzerland

Krongthong Thimasarn, WHO Regional Oce or South-East Asia, New Delhi, IndiaTa Tinh, National Institute o Malariology, Parasitology and Entomology, Hanoi, Viet Nam

Steve Ward, Liverpool School o Tropical Medicine, Liverpool, United Kingdom o Great Britain and

Northern Ireland

Tom Wellems, National Institute o Allergy and Inectious Diseases, National Institutes o Health, Rockville,

Maryland, USA

Tim Wells, Medicines or Malaria Venture, Geneva, Switzerland

Chris White, Population Services International, Washington, District o Columbia, USA

Nick White, Mahidol–Oxord Tropical Medicine Research Unit, Faculty o Tropical Medicine, Mahidol

University, Bangkok, Thailand

Christopher Whitty, Department or International Development, London, United Kingdom o Great Britain

and Northern Ireland

Chansuda Wongsrichanalai, United States Agency or International Development, Bangkok, Thailand

Wendy Woods, The Boston Consulting Group, Boston, Massachusetts, USASerge Xuere, Global Fund to Fight AIDS, Tuberculosis and Malaria, Geneva, Switzerland

Shunmay Yeung, ACT Consortium, London School o Hygiene and Tropical Medicine, London,

United Kingdom o Great Britain and Northern Ireland

Ray Yip, Bill & Melinda Gates Foundation, Beijing, China

Tim Ziemer, United States Agency or International Development, President’s Malaria Initiative,

Washington, District o Columbia, USA

The nal drat was edited by Elisabeth Heseltine.

For more inormation, please contact:

Dr Pascal Ringwald

Drug Resistance and Containment Unit

Global Malaria Programme

World Health Organization

20 avenue Appia

1211 Geneva 27

Switzerland

Tel.: +41 22 791 3469

Fax: +41 22 791 4878

E-mail: [email protected]



5

Global Plan or Artemisinin Resistance Containment

FewStepped up eorts to control malaria are producing impressive results. Over the past decade, the

number o malaria cases has allen by more than hal in 40% o malaria endemic countries, and estimates

suggest that nearly 750 000 lives have been saved in Arica alone. But this progress is ragile. One o

the major threats to sustained malaria control and elimination is the emergence o malaria parasites that

are resistant to artemisinins. These medicines are the basis or artemisinin-based combination therapies

(ACTs), our most potent weapon in treating alciparum malaria.

Evidence o resistance to artemisinins has been identied and conrmed on the Cambodia-Thailand

border. Other suspected oci have been identied in the Greater Mekong subregion, but are not yet

conrmed. Although the extent o the problem is still being investigated, the world needs to mobilize

immediately to contain artemisinin resistance in these hotspots and to stop its spread to new areas. The

threat must be taken seriously. Resistance to previous generations o antimalarials spread rapidly around

the world, resulting in increases in child mortality and an untold number o deaths. We believe containingand preventing artemisinin resistance is achievable, but it will require a commitment to both accelerate

malaria control eorts and implement a modest number o additional activities.

The Global Plan or Artemisinin Resistance Containment (GPARC) is a call to action or all members o

the Roll Back Malaria (RBM) Partnership. The document is a companion to the Global report on antimalarial

drug efcacy and drug resistance: 2000–2010 , which provides the extensive evidence on which the GPARC

was based. The GPARC sets out a high-level plan o attack to protect ACTs as an eective treatment or

Plasmodium alciparum malaria.

WHO, working with aected countries and with support rom a variety o donors and partners, has

taken a leading role in characterizing artemisinin resistance and in eorts to contain it in the Greater

Mekong subregion. WHO will continue to be closely involved in this eort and will work to coordinate global

implementation o the GPARC. Given the need or a broad-based response, successul implementation othe GPARC will require the commitment not only o the many stakeholders rom the malaria community

but also rom non-health sectors including education, nance, and immigration.

Endemic countries are on the ront line o resistance management, and they should lead implementation

o the GPARC. To be successul, they will need support, both nancial and technical, to translate the global

plan into an operational program – customized to their regional specicities and level o threat – and to

implement it at the local level. The WHO Global Malaria Programme, as well as WHO Regional and Country

Oces together with RBM partners, will support endemic countries to put simple and eective plans into

place to contain or prevent resistance. Endemic countries will also need support rom nongovernmental

organizations, private sector, academic institutions and other partners, as well as additional unding or

implementation. Ultimately, we must all come together to act now i we are to sustain the gains we have

made so ar and reach the health-related Millennium Development Goals.

Dr Margaret Chan

Director-General

World Health Organization




7

Execie a

PurPosE oF thE PlAn

The goal o the GPARC is to protect ACTs as an eective treatment or P. alciparum malaria. The GPARC

comes at a critical juncture. Artemisinin1 resistance has been conrmed in a limited area within the Greater

Mekong subregion, and evidence rom other potential oci in this region is being reviewed. Experts agree

that there is a limited window o opportunity to contain or eliminate the resistant parasites beore they

spread to areas o higher transmission, putting at risk recent progress in malaria control. The urgency

is increased by the act that no other antimalarial medicines are available that oer the same level o

ecacy and tolerability as ACTs, and ew promising alternatives are available in the immediate research and

development pipeline. While eorts to contain and prevent artemisinin resistance at global and local levels

have begun, they are not sucient and must be expanded, intensied and better coordinated.

The GPARC is intended to mobilize global and local stakeholders or the containment and ultimate

elimination o artemisinin resistance where it has emerged and or the prevention o its emergence in or

spread to new locations. While economic development, improvements to health systems, and integrated

eorts to improve maternal and child health, will also improve management o malaria and resistance, these

activities are beyond the scope o this document. The objectives o the GPARC are to:

• dene priorities or the containment and prevention o artemisinin resistance;

• motivate action and describe responsibilities by constituency;

• mobilize resources to und the containment and prevention o artemisinin resistance;

• increase collaboration and coordination or artemisinin resistance containment and prevention

among relevant stakeholders; and

• dene governance mechanisms and indicators or continual assessment o progress made in

implementing the GPARC.

The GPARC was developed by the WHO Global Malaria Programme through consultation with over 100

malaria experts. The GPARC builds on a WHO Global Malar ia Programme Strategy paper on management

o antimalarial drug resistance presented at the Seventeenth RBM Board meeting in December 2009. As

many o the activities involved in containing and preventing artemisinin resistance are consistent with

good malaria control, the GPARC also builds on existing WHO policies and guidelines or malaria and on

the RBM Global Malaria Action Plan. The GPARC is not a synthesis o the literature on malaria control, but

addresses the additional actions needed to prevent artemisinin resistance. It does not represent policy

or technical guidance but is rather a call to action and a high-level plan o attack. For technical guidance

in making an operational plan, including country-specic operational goals and timelines, national malaria

control programmes should reer to the WHO guidelines or malaria control and elimination available on

the WHO Global Malaria Programme website and can consult their regional oces or assistance and

support (http://www.who.int/malaria).

1 Unless otherwise indicated, the word ‘artemisinin’ is used in this document to reer to artemisinin and its derivatives, artesunate,

artemether and dihydroartemisinin.




Executive summary

IssuEs And rECommEndAtIons

While many unknowns remain with regard to artemisinin resistance, several commonly acceptedhypotheses orm the basis o the response outlined in the GPARC. In particular, experts agree that

common ailures in malaria control programmes are likely to contribute to the emergence and spread o

artemisinin resistance. Challenges in each component o malaria control – routine monitoring, prevention,

diagnosis and treatment – must be addressed. Thus, one o the most important components o successul

artemisinin resistance containment and prevention is intensied, sustained malaria control or elimination

in all endemic regions.

Given the emergence o artemisinin resistance in the Greater Mekong subregion and the threat o its

spread to other areas, additional resistance containment activities are required to prevent the loss o ACTs

as eective treatment. The activities described in Figure 1 are all important or successul management o

artemisinin resistance. Applying these recommendations immediately in areas or which there is credible

evidence o resistance is o the utmost priority.

Figure 1. GPARC goals and recommendations

Contain or eliminate artemisinin resistance

where it already exists

Prevent artemisinin resistance where it has not yet appeared

Invest in

artemisinin

resistance-related

research

Motivate action and mobilize resources5

Increase

monitoring and

surveillance to

evaluate the

artemisinin

resistance threat

2

Improve access

to diagnostics

and rational

treatment

with ACTs

3

Stop the

spread of

resistant

parasites

1 4

8



9


1. sp h prd rn pr. In areas or which there is evidence o artemisinin

resistance, an immediate, comprehensive response with a combination o malaria control and

elimination measures is needed to stop the survival and spread o resistant parasites. In areaswithout known resistance, malaria control can reduce transmission, lowering the risk that resistant

parasites will spread into those regions and minimizing the potential public health eect i resistance

were to take hold. Increased coverage with preventive measures, especially vector control, is a

priority, as are programmes to control malaria in mobile and migrant populations. Where artemisinin

resistance is conrmed, national malaria control programmes may also consider a range o

epidemiological or transmission-reduction tools, including ocused screening and treatment, active

case detection, mass screening and treatment or mass drug administration, in accordance with the

latest evidence and guidelines.

2. inr nrng nd urn u h hr rnn rn. Regular monitoring and surveillance are critical to identiy new oci rapidly and to provide inormation

or containment and prevention activities. WHO recommends that countries endemic or malaria

perorm routine monitoring o antimalarial drugs at sentinel sites every 24 months in order to

detect changes in their therapeutic ecacy (WHO, 2009). An immediate priority is to assess ACT

therapeutic ecacy in countries where no studies have been perormed in the previous 2 years.

Emphasis should be placed on data quality. Regions or which there is evidence o resistance

should consider adding urther sentinel sites to acilitate early detection o additional oci. In high-

risk areas, especially in those with no active sentinel sites, routine surveillance o conrmed malaria

cases, deaths and (especially) treatment ailures should be strengthened.

3. ipr dgn nd rn rn wh act. Increasing access to

aordable, quality-assured diagnostics and treatment with ACTs improves patient outcomes

and limits opportunities or resistance to both artemisinins and partner drugs (WHO, 2010a).

Programmes should include complementary activities to ensure consistent, accurate diagnostic

testing, better access to ACTs or conrmed cases, compliance with ACT treatment and removal

o oral artemisinin-based monotherapies and substandard and countereit drugs. Education and

communication campaigns ocused on diagnosis and treatment, with messages tailored to patients,

providers and retailers, should be a component o these eorts.

4. in n rnn rn-rd rrh. Research is important to improve

understanding o resistance and the ability to manage it. Research in ve disciplines should be a

priority: laboratory research (e.g. to identiy a molecular marker or artemisinin resistance), research

and development (e.g. o novel non-artemisinin-based antimalarial combinations), applied and eld

research (e.g. pilot studies o transmission reduction tools, such as mass screening and treatment or

mass drug administration), operational research (e.g. scalable2 programmes or mobile populations)

and mathematical modelling (e.g. o the potential impact o resistance on the malaria burden).

5. m n nd z rur. Successul implementation o the GPARC will depend

on motivating many stakeholders at global, regional and national levels to support or conduct

the recommended activities. Additional unding will be required, and leadership and sustained

cooperation in the malaria community wil l be needed to stimulate relevant individuals, organizations

and governments to support artemisinin resistance containment and prevention.

2 In the context o this document, ‘scalable’ reers to expanding the scope o a tool or programme to reach a larger population or area.



10

APPlyIng rECommEndAtIons At Country lEvEl

In view o regional dierences and varying levels o artemisinin resistance, each endemic country isexpected to evaluate its level o risk and then to apply the GPARC recommendations accordingly in designing

a containment or prevention programme. Dierent levels o response may be required or dierent areas

in a country.

In areas or which there is credible evidence o artemisinin resistance, dened as ‘tier I’, an immediate,

multiaceted response is recommended to contain or eliminate resistant parasites as quickly as possible.

As described in the Global report on antimalarial drug efcacy and drug resistance, 2000–2010 (section

4.5, Figures 24 and 25), tier I areas included several suspected oci in the Greater Mekong subregion in

November 2010. As the situation is evolving, readers should consult the WHO Global Malaria Programme

website (http://www.who.int/malaria) or the most recent evidence. In tier I areas, malaria control eorts

should be accelerated to reach universal coverage o at-risk populations as soon as possible, with the aim

o universal parasitological diagnostic testing, access to and rational use o quality-assured ACTs or all

conrmed malaria cases, use o primaquine as appropriate to block transmission and use o suitable vectorcontrol. Specic activities to contain or eliminate resistant parasites should also be implemented, including

increased monitoring o ACT therapeutic ecacy around known oci, programmes or mobile and migrant

populations, enorcement to eliminate the use o oral artemisinin-based monotherapies and poor-quality

drugs, and consideration o epidemiological or transmission-reduction tools. Regular monitoring, evaluation

and timely reporting o progress to a central, publicly available site is another important component o tier

I containment programmes.

Tier II areas are those with signicant infows o mobile and migrant populations rom tier I areas or

shared borders with tier I areas. The recommendations or tier II countries are intensied malaria control

to reduce transmission and limit the risk or emergence or spread o resistant parasites, with access to

parasitological diagnostic testing, quality-assured ACTs or conrmed malaria cases (plus primaquine as

appropriate), elimination o oral artemisinin-based monotherapies and poor-quality drugs and eective

coverage with suitable vector control. Countries with tier II areas should also implement activities to

manage the spread o resistance, including programmes to reach mobile and migrant populations. Activities

to increase monitoring o the therapeutic ecacy o ACTs in high-risk areas should be considered in order

to detect and report possible new oci rapidly.

In tier III areas, dened as P. alciparum endemic areas which have no evidence o artemisinin resistance

and limited contact with tier I areas, prevention and preparedness should ocus on scaling up control

measures to increase coverage with parasitological diagnostic testing, quality-assured ACTs and vector

control. Tier III areas should also routinely monitor the therapeutic ecacy o ACTs in order to detect signs

o emerging resistance promptly. In countries where oral artemisinin-based monotherapies or poor-quality

drugs are used extensively, regulation and enorcement should be increased to eliminate the use o these

products.

rolE oF stAkEholdErs

Most malaria control and elimination activities are also o benet or the containment and prevention o

artemisinin resistance. Stakeholders are encouraged to continue and, where possible, expand or accelerate

the malaria control activities that they conduct or support. The GPARC will help stakeholders to identiy and

understand additional areas to which they can contribute in order to manage artemisinin resistance.

Executive summary



11


The GPARC was designed with input rom all o the constituencies o the RBM Partnership and is

intended to motivate actions among each o these groups. Given the complexity o the required response

to artemisinin resistance, stakeholders outside the traditional malaria or public health communities will alsohave to be engaged. The priorities or action by constituency are shown in Table 1 and are described in more

detail in chapter 9 o the GPARC.

TabLe 1. Primary and secondary areas o involvement by stakeholder segment

Globalpolicy and

norms

Surveillanceand

reporting

Containmentand

implementation

Resource

mobilization

Endemic countries(tier I, II and III)

Multilateralorganizations

WHO Global Malaria Programme


WHO regional and country offices


all other

Research andacademia

Nongovernmentalorganizations

Private sector

Funding agencies

and bilateraldonors

Primary Secondary

*

Emergencyresponse

Advocacy andpolitical

engagementResearch

Local policy

andregulation

* Research part conducted by Special Programme or Research and Training in Tropical Diseases, WHO.

The GPARC will be implemented mainly by malaria-endemic countries, which will have a major role

in all unctions. Given WHO’s mandate to represent and support countries, the areas o involvement o

WHO Global Malaria Programme will mirror those o countries, ocusing on policy guidance, global

surveillance and technical expertise. Having led the development o the GPARC, WHO Global Malaria

Programme will continue to oversee and coordinate its implementation. In order to do so, a new unit

dedicated to antimalarial drug resistance has been created, the Drug Resistance and Containment unit.

WHO Global Malaria Programme will rely on WHO regional and country oces to coordinate assessments

o the threat o artemisinin resistance, prepare detailed and actionable response plans, build capacity ormonitoring and mobilize the necessary stakeholders and resources.

Successul implementation o the GPARC will depend on the support and cooperation o many other

groups. For example, research and academic institutions may lead the planning and execution o artemisinin

resistance-related research and support surveillance and reporting; they may play a secondary role in resource

mobilization and advocacy. Funding agencies, including The Global Fund to Fight AIDS, Tuberculosis and



12

Malaria (GFATM) and bilateral donors, have a primary role in resource mobilization, advocacy and political

engagement. As unders, their support is critical to the success o all activities. Nongovernmental organizations

will play a primary role as partners o national malaria control programmes in implementing containment andprevention programmes and will support resource mobilization and advocacy. The private sector has a variety

o cross-cutting roles to play, including support o containment programmes, advocacy and research.

rEsourCE mobIlIzAtIon

Given the overlap between malaria control and artemisinin resistance containment, a ully unded and

implemented malaria control agenda, as outlined in the Global Malaria Action Plan, would address many o

the needs or the containment and prevention o artemisinin resistance. Nonetheless, additional unding

will be needed or specic initiatives to manage artemisinin resistance, the immediate priority being unding

or programmes in current tier I and II areas.

On the basis o experience with the programme or artemisinin resistance containment and elimination

(ARCE) in Cambodia and Thailand, tier I and II containment and prevention programmes are estimated to cost

US$ 10–20 and US$ 8–10 per person at risk annually, respectively. The exact cost will depend on the intensity

o the eort required and the existing capacity and inrastructure. Additional unding will be needed or tier

III programmes and also or global and regional coordination o GPARC implementation. The estimated cost

or accelerating research and development o non-artemisinin-based antimalarial medicines and high-priority

laboratory research is US$ 60–65 million annually. In total, ull unding o artemisinin resistance containment

and prevention would be upwards o US$ 175 million per year globally, with just over US$ 100 million or

programme support. These estimates are based on the assumption that tier I and II areas are limited to those

in and around the currently suspected oci in Cambodia, Myanmar, Thailand and Viet Nam.

A relatively small investment in containment now, beore artemisinin resistance spreads beyond the

Greater Mekong subregion, will avoid a much larger subsequent investment. I artemisinin resistance

emerges in another region, the costs o managing it will increase dramatically, particularly i the aectedregion has high malaria transmission. Despite recent increases in malaria unding, however, there is still

a signicant shortall or both malaria control and artemisinin resistance containment and prevention. This

unding gap presents a risk or both malaria control and artemisinin resistance activities. In order to contain

resistance successully, the unding gap must be reduced, requiring greater global and country engagement

and more ocus and cooperation among stakeholders.

mEAsurEmEnt And EvAluAtIon

Measurement, evaluation and transparent reporting o the GPARC’s implementation are critical to

the successul management o artemisinin resistance. Not only do regular reporting and tracking o key

indicators motivate action, but the availability o timely, good-quality data is essential to evaluate the

evolving threat o artemisinin resistance, track progress in managing it and guide uture containment andprevention activities.

Measurement and evaluation should be conducted at all levels – global, regional, national and area (tier)

– and should include regular, ormal reporting. Evaluation will cover a mix o process, outcome and impact

measures. To minimize resources, the measures will, where possible, be based on data that are already

collected or malaria control and elimination. Continued cooperation with the research community will

urther widen and deepen the pool o available inormation. In some cases, new indicators, and processes

to measure them, will be identied and developed. Data quality should be a strong ocus, as a useul

Executive summary



13


assessment o the progress o the GPARC will rely on good data. WHO Global Malaria Programme will

lead global coordination in tracking and communication o key indicators. In order to ensure independent,

transparent evaluation o progress and achievements, WHO Global Malaria Programme will establish atechnical expert group on drug resistance to review and evaluate progress reports regularly.

EmErgEnCy mobIlIzAtIon

The GPARC was designed on the basis o current knowledge about where artemisinin resistance exists

and on assumptions about the timerame or its potential spread. The seriousness o the situation today

requires an immediate, intense, well-coordinated response. Should artemisinin resistance spread more

rapidly than originally anticipated, an escalated response will be required. The emergency mobilization plan

outlined in the GPARC has three elements: global advocacy to place artemisinin resistance at the top

o health and development agendas; intensive, coordinated containment activities in areas with newly

conrmed artemisinin resistance; and a signicant increase in unding. The emergency mobilization plan

builds on the recommendations outlined in the GPARC but adds intensity and magnitude to meet theincreased threat.

IssuEs And rECommEndAtIons

There is a nite window o opportunity to contain artemisinin resistance beore it spreads. I the current

oci o artemisinin-resistant parasites are not contained or eliminated, the costs, both human and nancial,

could be great. Areas with high transmission and low coverage with malaria interventions are particularly

vulnerable to increases in malaria-related morbidity and mortality. I artemisinin resistance were to take

hold in such regions, continued high transmission could lead to the rapid spread o resistant parasites and

the eventual loss o ACTs as an eective treatment, potentially resulting in a signicant increase in malaria-

related deaths. Thus, while the rst priority is immediate implementation o containment programmes in

the Greater Mekong subregion, it is also important to ocus on prevention and preparedness, including

sustainable surveillance, in other malaria-endemic countries. The global community must come together

now to address this signicant threat beore the situation deteriorates.



15


Ici

PurPosE oF thE PlAn

The goal o the GPARC is to protect ACTs or treatment o P. alciparum malaria. The GPARC comes at

a critical juncture. Artemisinin resistance has been conrmed in a limited area within the Greater Mekong

subregion, and evidence rom other potential oci in this region is under review. Experts agree that we

have a limited window o opportunity to contain or eliminate the resistant parasites beore they spread to

higher-transmission areas, putting at risk recent progress in malaria control. The urgency is increased by the

act that no other antimalarial medicines are available that oer the same levels o ecacy and tolerability

as ACTs, and ew promising alternatives are available in the immediate research and development pipeline.

While eorts have begun at both global and local levels to prevent and contain artemisinin resistance, they

are not sucient and must be expanded, intensied and better coordinated.

The objective o the GPARC is to mobilize global and local stakeholders to contain and ultimately

eliminate artemisinin resistance where it has emerged and to prevent its emergence in or spread to new

locations. The GPARC is part o a larger initiative by WHO and global health partners to prevent and contain

antimicrobial resistance. While economic development, improvements to health systems, and integrated

eorts to improve maternal and child health, will also improve management o malaria and resistance, these

activities are beyond the scope o this document. The objectives o the GPARC are to:

• dene priorities or the containment and prevention o artemisinin resistance;

• motivate action and describe responsibilities by constituency;

• mobilize resources to und the containment and prevention o artemisinin resistance;

• increase collaboration and coordination or artemisinin resistance containment and prevention in

the malaria community and among relevant stakeholders more broadly; and

• dene governance mechanisms and indicators or continual assessment o progress made inimplementing the GPARC.

I the current known oci o artemisinin-resistant parasites are not contained or eliminated, the

costs, both human and nancial, could be great. Areas with high transmission and low coverage with

malaria interventions are particularly vulnerable to increased malaria-associated morbidity and mortality. I

artemisinin resistance were to take hold in such regions, continued high transmission could lead to rapid

spread o resistant parasites and the eventual loss o ACTs as an eective treatment, potentially resulting in

a signicant increase in malaria-related deaths. Thus, while the rst priority is immediate implementation o

containment programmes in the Greater Mekong subregion, it is also important to ocus on prevention and

preparedness, including sustainable surveillance, in other malaria-endemic countries.

The GPARC was developed by the WHO Global Malaria Programme through consultation with over

100 global malaria experts. The GPARC builds on the WHO Global Malaria Programme Strategy paper on management o antimalarial drug resistance presented at the Seventeenth RBM Board meeting in

December 2009. Because many o the activities or containing and preventing artemisinin resistance are

consistent with good malaria control (Figure 2), the GPARC also builds on the RBM Global Malaria Action

Plan and existing WHO policies and guidelines or malaria. The GPARC is not a synthesis o the existing

literature on malaria control, but rather ocuses on the additional actions needed to address artemisinin

resistance; it does not represent policy or technical guidance but is a call to action and a high-level plan o

attack. For technical guidance in preparing an operational plan, including country-specic operational goals



16

and timelines, national malaria control programmes should reer to existing WHO guidelines on malaria

control and elimination on the WHO Global Malaria Programme website and may also consult their regional

oces or assistance and support (http://www.who.int/malaria).

Figure 2. Overlap between malaria control and artemisinin resistance containment andprevention

Malaria control

and elimination

Artemisinin resistance

containment and prevention

Examples:

Access to ACTs, diagnostics,

vector control

Research and development

Education and training

Examples:

Increased drug efficacy monitoring and

surveillance

Strategy for mobile populations

Removal of monotherapies

Examples:

Vaccine research and

development

Insecticide resistance

management

Note: Not drawn to scale.

WorkIng dEFInItIons And AssumPtIons

WHO denes resistance as “the ability o a parasite strain to survive and/or multiply despite the

administration and absorption o a drug given in doses equal to or higher than those usually recommended

but within tolerance o the subject” (WHO, 1967).3 For the purposes o the GPARC, we consider that

a signicant increase in parasite clearance time is an early warning sign o artemisinin resistance and

deserving o a response similar to that or conrmed resistance. In this document, the term ‘artemisinin

resistance’ is a working denition used to reer to:

• an increase in parasite clearance time, as evidenced by 10% o cases with parasites detectable

on day 3 ater treatment with an ACT (suspected resistance); or

• treatment ailure ater treatment with an oral artemisinin-based monotherapy with adequate

antimalarial blood concentration, as evidenced by the persistence o parasites or 7 days, or the

presence o parasites at day 3 and recrudescence within 28/42 days (conrmed resistance). 4

3 This denition was later modied to include the sentence: “The orm o the drug active against the parasite must be able to gain

access to the parasite or the inected erythrocyte or the duration o the time necessary or its normal action.”

4 This denition is prone to conounding actors (known and unknown) such as splenectomy, haemoglobin abnormalities and reduced

immunity.

Introduction



17


The GPARC primarily addresses artemisinin and its derivatives, which are the common components

in all ACTs. In order or ACTs as a class to remain viable, however, both artemisinins and partner drugs

must be protected rom parasite resistance. I resistance to one drug evolves, the other potentially actsas a monotherapy, increasing the likelihood that resistance will also be selected or the second drug. As a

result, actors that select or parasite resistance to partner drugs may have consequences or artemisinins,

jeopardizing ACTs as a class.

Given the many unknowns surrounding artemisinin resistance, the GPARC relies on several high-level

assumptions, which establish a common starting point and serve as the basis or the recommendations

(Box 1).

box 1. HiGH-level assUmPtioNs UseD iN DesiGNiNG tHe GPaRc

• Exposure o malaria parasites to suboptimal doses o artemisinin is a primary cause o the spread oresistance.

• Delayed parasite clearance likely indicates reduced susceptibility, which may eventually lead to higherresistance.

• To our knowledge, artemisinin resistance exists only in the Greater Mekong subregion; however, thepossibility that artemisinin resistance will arise in other areas or regions or spread beyond the Greater

Mekong subregion must be considered.

• Preventing resistance to partner drugs is important. I the partner drug is not eective, the ACT becomesan artemisinin-based monotherapy, so that the parasite receives an inadequate dose o artemisinin asmonotherapy.

• With sucient resources and coordination, a molecular marker or artemisinin resistance could be ound;once a molecular marker is available, it can be translated into useul surveillance tools.

• Eliminating P. alciparum malaria in aected regions might be necessary in order to eliminate the threat oresistance.

struCturE oF thE PlAn

The GPARC and WHO’s Global report on antimalarial drug efcacy and drug resistance, 2000–2010 are

companion documents. The latter provides a detailed history o artemisinin resistance and the state o the

problem today, and the GPARC describes the recommended response.

The GPARC consists o 10 chapters. Chapter 1 provides the context o the plan and a brie overview

o the artemisinin resistance problem. Chapter 2 summarizes the ve core recommendations. Chapter 3

describes how these recommendations should be applied locally, with specic recommendations depending

on the magnitude o the artemisinin resistance risk in a country or area. The next ve chapters describe

each o the recommendations in more detail, including the underlying issues and potential solutions. The

nancial requirements to support the GPARC are described in chapter 8. Chapter 9 summarizes the prioritiesor action by constituency; it is intended to help stakeholders identiy areas in which they can contribute

to implementation o the GPARC. Chapter 10 outlines an escalated response plan, with the activities that

would be needed i artemisinin resistance spreads more rapidly than originally anticipated.



19


1. Cex

hIstory And EvIdEnCE

The global community has recently had many successes in malaria control. The number o malaria

cases has allen by more than 50% in 43 countries over the past decade (WHO, 2010b). A recent modelling

analysis o malaria prevention in 34 Arican countries suggested that about 730 000 lives were saved

between 2000 and 2010, with nearly three quarters o those since 2006 (Eisele et al., 2010). Funding

commitments or malaria have increased nearly 15-old, rom approximately US$ 100 million in 2003 to

nearly US$ 1.6 billion in 2010; and interest and commitment at global and country level are very high

(Johansson, Cibulskis & Steketee, 2010). The current upward trajectory in unding must be maintained in

order to sustain and expand these successes.

A looming threat to malaria control is the emergence o parasites that are resistant to antimalarial

medicines. Resistance has developed to every antimalarial medicine used so ar (see Global report on

antimalarial drug efcacy and drug resistance, 2000–2010 , section 1.2 or details), and the malaria burden

rebounded due to consequent treatment ailures. For example, the spread o P. alciparum resistance to

chloroquine in the 1970s and 1980s was linked to a subsequent increase in child mortality in Arica (Trape,

2001; Dondorp et al., 2010).

As history predicted, resistance to artemisinins, the key component o all ACTs, was identied and

conrmed on the Cambodia–Thailand border in a series o studies conducted between 2001 and 2009.

More recently, evidence o artemisinin resistance has been reported in other areas o the Greater Mekong

subregion (see Global report on antimalarial drug efcacy and drug resistance, 2000–2010 , sections 4.1

and 4.5 or a more comprehensive discussion o the evidence rom therapeutic ecacy studies, including

the latest available data or the Cambodia–Thailand border). It is noteworthy that resistance to chloroquine,

suladoxine–pyrimethamine and mefoquine all rst emerged in this area. Resistance to chloroquine andsuladoxine–pyrimethamine then spread rom the Greater Mekong subregion to Arica and also emerged in

and spread through other regions. We cannot be certain that the pattern o spread o artemisinin resistance

will be similar to that o other antimalarial medicines. Ideally, artemisinin resistance will be contained at

current oci beore it causes signicant treatment ailures or spreads to other areas.

unknoWns In ArtEmIsInIn rEsIstAnCE

Much remains to be elucidated about the emergence and spread o artemisinin resistance. Scientists

do not know the mechanism o resistance nor what denitively contributes to the emergence and spread

o resistant parasites. The extent o artemisinin resistance today – and specically whether it has spread

beyond the Greater Mekong subregion – is unknown, and scientists are unable to predict whether it will

emerge in new oci or how quickly it could spread rom current oci. There are also unanswered questionsabout which tools and methods will be most eective in addressing artemisinin resistance (see Global

report on antimalarial drug efcacy and drug resistance, 2000–2010 , chapter 2 or details). Much o the

inormation contained in the GPARC is based on knowledge and experience gained with resistance to other

antimalarial medicines.



20

hyPothEsEs For thE EmErgEnCE And sPrEAd oF

ArtEmIsInIn rEsIstAnCE

Several commonly accepted hypotheses orm the basis o the response outlined in the GPARC. In

particular, experts agree that common ailures in malaria control programmes contribute to the emergence

and spread o artemisinin resistance. Challenges in each component o malaria control – routine monitoring,

prevention, diagnosis and treatment – are described below and shown in Figure 3.

mnrng nd urn

WHO recommends routine monitoring o therapeutic ecacy to track antimalarial drug ecacy and guide

treatment policy (WHO, 2009). As oral artemisinin-based monotherapy is not recommended or rst-line

treatment o uncomplicated malaria, routine monitoring is usually o the ecacy o ACTs. When therapeutic

ecacy studies provide evidence o early resistance (e.g. increased proportion o patients with prolonged

parasite clearance time), conrmatory studies must be conducted to determine the extent o resistance

and guide action. Unortunately, a signicant number o countries endemic or P. alciparum do not routinely

monitor ACT therapeutic ecacy, and comprehensive understanding o where artemisinin resistance exists

today is not available. Without this knowledge, it is dicult to initiate appropriate containment activities,

which may allow resistant parasites to survive and spread silently.

Prnn

Malaria control programmes should promote the use o preventive measures to reduce malaria

transmission. Common measures include use o long-lasting insecticidal nets or other insecticide-treated

products and indoor residual spraying (WHO, 2002; WHO, 2006). National malaria control programmes

should also provide malaria prevention and treatment measures to mobile and migrant populations, which

are believed to contribute to the spread o antimalarial resistance. Unortunately, use o vector control

tools remains inconsistent in many areas, and eorts to reach migrant and mobile populations are limited.In the absence o concerted eorts to reduce transmission, malaria continues to be transmitted, creating

opportunities or resistance to spread.

Dgn

Parasitological diagnosis, typically with a rapid diagnostic test (RDT) or microscopy is recommended

by WHO or all persons with suspected malaria to ensure that only conrmed cases receive treatment

with an ACT (WHO, 2010a). In many settings, however, diagnostic tests are not used regularly, and, even

when a test is used, the results are sometimes ignored. As a result, symptomatic patients are requently

treated presumptively with antimalarial medicines. The resulting overuse o ACTs may increase resistance,

particularly to the longer-acting partner drugs that are a critical component o ACTs.

trn

WHO recommends treatment o conrmed malaria cases with a ull course o quality-assured ACTs

(WHO, 2010a). Lack o access to aordable, quality-assured ACTs may, however, result in use o less eective

medicines, including oral artemisinin-based monotherapies, substandard and countereit treatments and

drugs other than artemisinins, such as chloroquine or suladoxine–pyrimethamine. Although oral artemisinin-

based monotherapies can be eective when taken or the ull 7-day course, patients oten stop taking

them prematurely, as symptoms generally subside ater only a ew days. Consequently, parasites may

be exposed to subcurative dosing regimens. Substandard and countereit drugs, which are widespread in

1. Context



21


P r e v e n t i o n

D i a g n o s i s

T r e a t m e n t

P o t e n t i a l o u t c o m e

V e c t o r

c o n t r o l

m e t h o d s

f a i l

M o s q u i t o e s

c o n t i n u e t o

t r a n s m i t

m a l a r i a

P a t i e n t i s

p r o p e r l y

d i a g n o s e d

N u m b e r o f

m a l a r i a

c a s e s

i n c r e a s e s

P a r a s i t o l o g i c a l

d i a g n o s i s n o t

a v a i l a b l e

D i a g n o s i s b y

c l i n i c a l

s u s p i c i o n o n l y

P a t i e n t s e l f -

d i a g n o s e s o r

e l e c t s n o t t o

u s e d i a g n o s t i c s

P a r a s i t e s t h a t a r e

r e s i s t a n t t o t r e a t m e n t

s u r v i v e a n d m a y s p r e a d

M o n i t o r i n g a n d s u r v e i l l a n c e

N o n - m a l a r i a l c a s e s t r e a t e d w i t h

a r t e m i s i n i n -

b a s e d m o n o t h e r a p y

N o n - m a l a r i a l c a s e s t r e a t e d

w i t h A C T s

M i n i m a l s e l e c t i o n f o r

p a r a s i t e r e s i s t a n c e

S e l e c t i o n f o r

p a r a s i t e

r e s i s t a n c e t o p a

r t n e r d r u g




p a r a s i t e

r e s i s t a n c e t o a r

t e m i s i n i n s

a n d / o r p a r t n

e r d r u g

F a i l u r e t o d e t e c t

c a s e s o f

r e s i s t a n c e

T r e a t m e n t

A d h e r e n c e

P a t i e n t t r e a t e d w i t h A C T

P a t i e n t t r e a t e d w i t h s u b s t a n d a r d A C T

o r c o u n t e r f e i t w i t h i n s u f f i c i e n t a r t e m i s i n i n

a c t i v e p h a r m a c e u t i c a l i n g r e d i e n t

P a t i e n t t r e a t e d w i t h

c o u n t e r f e i t ( n o a r t e m i s i n i n ) a c t i v e

p h a r m a c e u t i c a l i n g r e d i e n t

P a t i e n t t r e a t e d w i t h

a r t e m i s i n i n - b a s e d m o n o t h e r a p y

F e v e r p a t i e n t s

m i s d i a g n o s e d

w i t h m a l a r i a



P a t i e n t c o m p l e t e s

f u l l c o u r s e o f t r e a t m e n t

P a

t i e n t f a i l s t o c o m p l e t e f u l l

c o u r s e o f t r e a t m e n t

P a t i e n t c o m p l e t e s f u l l


P a

t i e n t f a i l s t o c o m p l e t e f u l l



p a r a s i t e

r e s i s t a n c e t o a r

t e m i s i n i n s

F i g u r e

3 .

P r o g r a m m e f a i l u r e s t h a t p o t e n t i a l l y c o n t r i b u t e t o r

e s i s t a n c e t o a n t i m a l a r i a l m e d i c i n e

s



22

many endemic countries, pose a similar problem because they may contain subtherapeutic amounts o

artemisinins. While sensitive parasites are eliminated, resistant parasites can multiply unrestrained and

later be transmitted. These actors probably result in continuous selection in avour o the parasites that arethe most resistant to either artemisinins or the partner drug.

Prnn nd nnn d

Several eorts to contain and prevent artemisinin resistance have been initiated. For example, a

multiaceted, multisectoral containment project has been launched at the Cambodia–Thailand border. These

activities, coordinated by WHO and unded largely by the Bill & Melinda Gates Foundation, the GFATM and

the United States Agency or International Development, are described in detail in the Global report on

antimalarial drug efcacy and drug resistance, 2000–2010 (section 4.6). Additional containment projects in

other suspected oci in the Greater Mekong subregion are being discussed.

WHO, the World Health Assembly and the RBM Partnership have each called or action to address

artemisinin resistance (Box 2), mainly by encouraging endemic countries to halt the marketing and use ooral artemisinin-based monotherapies. Several other organizations and programmes are also contributing

to the management o resistance. For example, the WorldWide Antimalarial Research Network is a

collaboration ormed to acilitate research and inormation exchange related to antimalarial resistance.

The Medicines or Malaria Venture conducts research and develops new treatments or malaria, including

alternatives to artemisinin-based medicines. The MALACTRES consortium and the Broad Institute are

leading activities to identiy molecular markers. The United States Pharmacopeia Promoting the Quality o

Medicines programme addresses substandard and countereit drugs in the developing world. The GFATM

has launched the Aordable Medicines Facility – malaria, an innovative nancing mechanism to expand

access to quality-assured ACTs, which is still in the pilot phase. This list is not exhaustive, and many other

organizations contribute directly or indirectly to combating antimalarial drug resistance, oten by providing

overall support to malaria control and el imination initiatives. These eorts could have a greater impact i there

were a coordinated, global eort to increase the visibility o the issue and mobilize the malaria community

and other relevant stakeholders to action. The GPARC will serve as a platorm or this coordinated global

eort.

box 2. calls to actioN oN ResistaNce to aRtemisiNiNs

• 2005, WHO report on Susceptibility o Plasmodium alciparum to antimalarial drugs : WHO began to callattention to the danger o artemisinin resistance.

• May 2007, Sixtieth World Health Assembly: The Health Assembly adopts resolution WHA 60.18,which called or cessation o provision in both the public and the private sector o oral artemisinin

monotherapies.

• September 2009, Regional Committee or Arica: The Committee adopts a resolution to encourageprevention and control o drug resistance to human immunodeciency virus, tuberculosis and malariatreatment.

• December 2009, Seventeenth RBM Board meeting: Global Malaria Programme submits a Strategy paper

on management o antimalarial drug resistance as requested by the Board.

• May 2010, Eighteenth RBM Board meeting: Calls or withdrawal o oral artemisinin-based monotherapiesin order to prolong the useulness o therapeutic artemisinin derivatives. A commitment to eliminate oralartemisinin-based monotherapies is signed by representatives rom 40 countries.

• May 2010, World Health Assembly: The United Nations Secretary-General’s Special Envoy or Malaria

gives an address, emphasizing that the development and spread o artemisinin resistance could be apublic health disaster.

1. Context



23


2. receaiGiven the emergence o artemisinin resistance in the Greater Mekong subregion and the threat o its

spread to other areas, actions to contain artemisinin resistance are required to prevent the loss o ACTs

as an eective treatment. The recommendations below should be implemented both globally and locally in

P. alciparum-endemic countries. Applying these recommendations immediately in areas or which there is

credible evidence o resistance is o utmost priority.

As part o a coordinated eort to contain or eliminate artemisinin resistance where it already exists

and to prevent artemisinin resistance where it has not yet appeared, the ollowing actions should be taken

(Figure 4).

Figure 4. GPARC goals and recommendations

Contain or eliminate artemisinin resistance

where it already exists

Prevent artemisinin resistance where it has not yet appeared

Invest in

artemisininresistance-related

research

Motivate action and mobilize resources5

Increase

monitoring andsurveillance to

evaluate the

artemisinin

resistance threat

2

Improve access

to diagnosticsand rational

treatment

with ACTs

3

Stop the

spread ofresistant

parasites

1 4

1. sp h prd rn pr. In areas or which there is evidence o artemisinin

resistance, an immediate, comprehensive response with a combination o malaria control and

elimination measures is needed to stop the survival and spread o resistant parasites. In areas without

known resistance, malaria control can reduce transmission, lowering the risk that resistant parasites

will spread into those regions and minimizing the potential public health eect i resistance were to

take hold. Increased coverage with preventive measures, especially vector control, is a priority, as

are programmes to control malaria in mobile and migrant populations. Where artemisinin resistance

is conrmed, national malaria control programmes may also consider a range o epidemiological

or transmission-reduction tools, including ocused screening and treatment, active case detection,

mass screening and treatment or mass drug administration, in accordance with the latest evidence

and guidelines.




24

2. inr nrng nd urn u h hr rnn rn. Regular monitoring and surveillance are critical to identiy new oci rapidly and to provide inormation

or containment and prevention activities. WHO recommends that countries endemic or malariaperorm routine monitoring o antimalarial drugs at sentinel sites every 24 months in order to

detect changes in their therapeutic ecacy (WHO, 2009). An immediate priority is to assess ACT

therapeutic ecacy in countries where no studies have been perormed in the previous 2 years.

Emphasis should be placed on data quality. Regions or which there is evidence o resistance

should consider adding urther sentinel sites to acilitate early detection o additional oci. In high-

risk areas, especially in those with no active sentinel sites, routine surveillance o conrmed malaria

cases, deaths and (especially) treatment ailures should be strengthened.

3. ipr dgn nd rn rn wh act. Increasing access to

aordable, quality-assured diagnostics and treatment with ACTs improves patient outcomes

and limits opportunities or resistance to both artemisinins and partner drugs (WHO, 2010a).

Programmes should include complementary activities to ensure consistent, accurate diagnostic

testing, better access to ACTs or conrmed cases, compliance with ACT treatment and removal

o oral artemisinin-based monotherapies and substandard and countereit drugs. Education and

communication campaigns ocused on diagnosis and treatment, with messages tailored to patients,

providers and retailers, should be a component o these eorts.

4. in n rnn rn-rd rrh. Research is important to improve

understanding o resistance and the ability to manage it. Research in ve disciplines should be a

priority: laboratory research (e.g. to identiy a molecular marker or artemisinin resistance), research

and development (e.g. o novel non-artemisinin-based antimalarial combinations), applied and eld

research (e.g. pilot studies o transmission reduction tools, such as mass screening and treatment or

mass drug administration), operational research (e.g. scalable5 programmes or mobile populations)

and mathematical modelling (e.g. o the potential impact o resistance on the malaria burden).

5. m n nd z rur. Successul implementation o the GPARC will depend

on motivating many stakeholders at global, regional and national levels to support or conductthe recommended activities. Additional unding will be required, and leadership and sustained

cooperation in the malaria community wil l be needed to stimulate relevant individuals, organizations

and governments to support artemisinin resistance containment and prevention.

The ollowing chapters describe each recommendation in more detail, including the underlying issues

and ways in which they might be addressed. Various potential solutions are provided that can be considered

by national malaria control programmes and other stakeholders in implementing each recommendation.

The solutions described in the GPARC have been prioritized relative to other options based on two criteria:

expected relative impact and easibility.

• Expected relative impact is based on whether a solution addresses the most critical problem or

multiple issues simultaneously, has the greatest potential eect on malaria cases and deaths, has

an eect within a short time and is sustainable.

• Feasibility is based on the cost and overall resource requirements o the solution (human, nancial,

operational and scientic), relative simplicity o implementation, the risks and the likelihood o

success and the availability o appropriate leader(s), willing partner(s) or support.

5 In the context o this document, ‘scalable’ reers to expanding the scope o a tool or programme to reach a larger population or area.

2. Recommendations



25


APPlyIng rECommEndAtIons At Country lEvEl

Each solution described is not suitable or every country or area. Given dierences in regions and in thelevel o the threat o artemisinin resistance, each country is expected to evaluate its level o risk and apply

the recommendations accordingly to design and implement a containment or prevention programme. To

guide implementation, countries should consider the ollowing three classications:

tr i Areas or which there is credible evidence o artemisinin resistance;

tr ii Areas with signicant infows o people rom tier I areas, including those immediately bordering

tier I;

tr iii Areas with no evidence o artemisinin resistance and limited contact with tier I areas.

Chapter 3 describes how the recommendations or management o artemisinin resistance might

be applied depending on a country’s tier classication. Areas within a country might be classied into

dierent tiers; or example, while most o a country may be tier III, i it shares a border with an area

with conrmed or suspected artemisinin resistance, the immediate border region may be classied as

tier II. Tier classications should be re-evaluated regularly. Countries or which there is credible evidenceo artemisinin resistance should move rapidly to conrm resistance while simultaneously taking steps to

launch containment activities suitable to tier I.

WHO Global Malaria Programme will work with endemic countries to evaluate the accuracy and integrity

o data suggesting artemisinin resistance. On the basis o its evaluation o the credibility o the data,

WHO Global Malaria Programme, in consultation with its technical expert group on antimalarial drug

resistance will recommend whether an area should be reclassied as tier I. Neighbouring countries or

countries with signicant infows o people rom the aected area should then consider reclassiying their

border regions as tier II.

rolE oF stAkEholdErs

Successul implementation o the GPARC recommendations requires coordinated action by stakeholders at

multiple levels. Containment and prevention o artemisinin resistance is primarily the responsibility o endemic

countries. Many endemic countries will need the support o partners, in the malaria community including

multilateral organizations, unding agencies and bilateral donors, nongovernmental organizations, researchers

and the private sector. Given the complexity o the required response, stakeholders outside the traditional

malaria or public health communities will have to be involved. The roles o specifc stakeholders are highlighted

in the discussion o each recommendation and priorities by constituency are summarized in chapter 9.

WHO Global Malaria Programme will oversee and coordinate implementation o the GPARC. It will

also contribute to execution o the GPARC by providing technical expertise, global surveillance and policy

guidance. To ulll this dual role, WHO Global Malaria Programme has created a new unit dedicated to

antimalarial drug resistance. The new unit will receive guidance and oversight rom its external technical

expert group on antimalarial drug resistance. Given WHO Global Malaria Programme’s unique role its

priorities will be discussed separately rom those o other multilateral organizations in the remainder o the

GPARC.



26

mEAsurEmEnt And EvAluAtIon

Measurement, evaluation and reporting o the GPARC’s implementation are critical to successulcontainment and prevention o artemisinin resistance. Not only does regular reporting and tracking o

indicators tend to motivate action, but the availability o timely data is essential or evaluating the evolving

threat o artemisinin resistance, tracking progress in managing it, guiding the allocation o limited resources

and guiding uture containment and prevention activities.

Measurement and evaluation at all levels – global, regional, national and area (tier) – should include regular,

ormal reporting. Data quality should be a strong ocus, as the progress o the GPARC can be assessed

only rom good data. The tracking and communication o indicators is an essential part o the GPARC

implementation. In order to ensure independent, transparent evaluation o the GPARC, WHO Global Malaria

Programme will ask the technical expert group to review and evaluate progress and achievements regularly.

The evaluation will be based on a mix o process, outcome and impact indicators. To minimize use o

resources, the indicators will be based on data that have already been collected or malaria control and

elimination, where possible. Cooperation with the research community could also widen and deepen thepool o inormation. In some cases, new indicators (such as the number o conrmed treatment ailures

or the percentage o ACT takers with a conrmed malaria diagnosis) will have to be identied, and new

mechanisms will be needed to track and report them.

Some o the key indicators or evaluating implementation o the GPARC are listed in Table 2.

TabLe 2. Indicators or tracking progress in implementation o the GPARC

imPlemeNtatioNaRea

iNDicatoRs

Malaria burden• No. o confrmed P. falciparum malaria cases (N)

• No. o reported treatment ailures (N)

Monitoring o drugecacy

• No. o countries endemic or P. falciparum that monitored ACT therapeutic efcacy in

the past 24 months (R and G)

• No. o countries with confrmed artemisinin resistance (R and G)

Diagnosis• Percentage o recorded suspected malaria cases tested with RDTs or microscopy (N)

• Percentage o patients taking ACTs who have a confrmed parasitological diagnosis (N)

Treatment

• Proportion o confrmed malaria cases receiving ACTs and other antimalarial medicines

by sector (N)

• Median and average ACT price by sector as reported in outlet surveys (N)

• Rate o ACT stock-outs (N)

Prevention

• No. o programmes targeting mobile and migrant populations (N or R)

• Proportion o high-risk groups (e.g. orest workers, gem miners, military) with targeted

programmes (N or R)

• Proportion o targeted population protected by appropriate vector control (N)

Drug manuactureand distribution

• No. o companies marketing monotherapies (R or G)

• No. o countries enorcing the ban on monotherapies (N)

• Availability o countereit or substandard antimalarial drugs as reported in surveys (N)

• No. o manuacturing countries committed to addressing illegal drug manuacture (R

or G)

G, global; N, national; R, regional.

2. Recommendations



27


WHO Global Malaria Programme will work with the RBM Monitoring and Evaluation Reerence Group to

refne the indicators and provide detailed descriptions, including methods o measurement and the assumptions

underlying them. Some o the indicators, such as the number o P. falciparum-endemic countries in which ACTtherapeutic efcacy is monitored, apply only at global or regional level; others, such as the percentage o

recorded suspected malaria cases tested by RDTs or microscopy, are relevant only at national level. In some

instances, such as the number o reported treatment ailures, indicators measured at national level will be

applied at the regional or global level to give a view o progress on a broader scale. Additional indicators will

probably be identifed at national or area level, especially in tier I and II areas where containment is o the

highest priority.



3. summay ecommendaion by ieRecommendations will be implemented at varying degrees o intensity and resource commitment,

depending on the country or area and the perceived threat o artemisinin resistance. Countries are

encouraged to review the evidence or artemisinin resistance within and along their borders in order to

evaluate their risk and classiy themselves into a tier (as described in chapter 2). Countries can work with

WHO regional oces or WHO Global Malaria Programme as needed, especially when new evidence o

resistance has emerged. In areas o low or inconsistent transmission, stratication and mapping techniques

may be used to target interventions, resulting in more ecient use o resources.

Recommendations by tier are illustrated in gure 5 and summarized below; more detailed

recommendations or each tier are given in Table 3 at the end o this chapter.

Figure 5. Recommendations by tier

Tier III

Good Control

More routine monitoring

Eliminate monotherapies

and poor-quality drugs

Tier II

Intensied and

accelerated control

Intensied monitoring,

especially on border

near foci

Actively eliminate

monotherapies

and poor-quality drugs

Lower transmission; focus

on mobile and migrantpopulations

Tier I

Intensied and

accelerated control

to universal coverage

Intensied monitoring,

especially around foci

Aggressively eliminate

monotherapies and

poor-quality drugs

Lower transmission; focus

on mobile and migrantpopulations

Consider ACD, MSAT,

FSAT or MDA

ACD, active case detection; FS AT, ocused screening and treatment; MDA, mass drug administration ; MSAT, mass screening and treatment.

tIEr I

In areas or which there is credible evidence o artemisinin resistance n d, ud

rpn hud unhd. The goal is to contain and, i easible, eliminate the resistant parasites. As

described in the Global report on antimalarial drug efcacy and drug resistance , 2000–2010 (section 4.5,

Figures 24 and 25), tier I areas included several suspected oci in the Greater Mekong subregion in November

2010. As the situation is evolving, readers should consult the WHO Global Malaria Programme website

(http://www.who.int/malaria) or the most recent evidence. Containment activities should continue until

malaria or the resistant parasites have been eliminated or it is deemed no longer easible (e.g. due to

signicant spread o resistant parasites to other areas). Early data rom the ARCE programme in Thailand and

Cambodia imply that a containment programme is easible (see Box 3 or preliminary ndings rom the ARCE

programme). Containment programmes are resource-intensive. Constant eorts are needed to mobilize and

maintain sucient unding, inrastructure and human resources.

29




30

box 3. aRce PRoGRamme iN camboDia aND tHailaND

The ARCE programme is an ambitious cross-border strategy or eliminating artemisinin-resistant parasites rom

the Cambodia–Thailand border. The project was initiated by WHO in close cooperation with the ministries ohealth o the two countries and many other partners.

It began in 2009 and is still in progress. A ull description o its objectives and preliminary results is available inthe Global report on antimalarial drug efcacy and drug resistance , 2000–2010, section 4.6.The early results show:

•intensivescreeningtondandtreathiddencasesofresistantmalariaintargetvillagesisworking;

•vectorcontroltools,likelong-lastinginsecticide-treatedmosquitonets,areeffectiveforreducing

transmission in the Greater Mekong subregion;•villagemalariaworkerscanimprovetheaccesstodiagnosisandtreatmentofhard-to-reachpopulations.

Readers are invited to visit the project website or additional inormation and the nal report to be posted at the

end o the project (http://www.who.int/malaria/diagnosis_treatment/arcp/en/index.html).

The recommended response or tier I areas is a combination o intensied malaria control and tools or

elimination:

• Intensiy and accelerate malaria control to reach universal coverage o at-risk populations as soon as

possible, including:

•parasitologicaldiagnosisforallpatientswithsuspectedmalaria;

• afullcourseofquality-assuredACTsplusprimaquineforconrmedcases,incompliancewithcurrent

WHO treatment guidelines (when the risk or glucose 6-phosphate dehydrogenase deciency is

considered low or testing or deciency is available) (WHO, 2010a); and

• vectorcontrol,as locally appropriate, tolowertransmissionand minimizethe spreadof resistant

parasites.

• Launch specic activities to contain or eliminate resistant parasites:

• intensiedmonitoringoftherapeuticefcacynearcurrentfocitotrackthespreadofartemisinin

resistance and ensure that the recommended rst-line treatments remain eective;

• educationandenforcementtoeliminateuseoforalartemisinin-basedmonotherapiesandsubstandard

and countereit antimalarial medicines;

• programmes toreach mobile and migrant populations with adequate prevention, diagnosis and

treatment; and

• epidemiologicalortransmission-reductiontools,whichmayincludemassscreeningandtreatment,

ocused screening and treatment, active case detection or mass drug administration, in accordance

with the latest evidence or guidelines, i and when they become available.

Regular, publicly available reports on progress should be a key component o tier I containment

programmes. Reporting should include documentation o current containment activities, achievements

(such as rates o coverage with key interventions), challenges and quantitative measures o the evolution

o artemisinin resistance. Such measures might include the results o therapeutic ecacy studies, trends

in the numbers o conrmed malaria cases and deaths at health acilities and at community level (where

community case management programmes exist), malaria positivity rates with diagnostic tests, trends in

treatment ailure rates and the results o any special surveys conducted in the aected area (either as part

o the artemisinin resistance response, such as ocused screening and treatment, or or routine purposes,

such as a malaria indicator survey). Timely inormation is critical to guide the global response and, more

importantly, to enable national malaria control programmes to adjust their activities appropriately. Formal

reporting should be done at least quarterly, and the reports should be distributed to stakeholders and made

publicly available. Ongoing reporting requires resources and will depend on close collaboration between

countries, unders and WHO.

3. Summary recommendations by tier



31


tIEr II

In areas with signicant infows o mobile or migrant populations rom tier I areas or shared borderswith a tier I area, the main goal is to prevent the emergence o artemisinin resistance, as the movement

o populations might spread resistant parasites into tier II areas. As in tier I areas, the recommendations

largely mirror those or malaria control. The specic recommendations or tier II areas are:

• Intensiy and accelerate malaria control activities, including:

•parasitologicaldiagnosisforallpeoplesuspectedofhavingmalaria;

• afullcourseofquality-assuredACTsplusprimaquineforconrmedcases,incompliancewithcurrent

WHO treatment guidelines (when the risk or glucose 6-phosphate dehydrogenase deciency is

considered low or testing or deciency is available) (WHO, 2010a); and

• vector control, as locally appropriate, to lower transmission, prevent the spread of artemisinin

resistance or limit the potential impact o resistance i it were to emerge.

• Implement specic tactics to manage the potential spread o resistant parasites rom tier I areas,including programmes to reach mobile and migrant populations, especially those moving between tier I

and tier II areas, with eective prevention, diagnosis and treatment.

• Launch activities specic or the prevention o resistance, including:

• intensiedmonitoringoftherapeuticefcacytotrackthespreadofartemisininresistanceandensure

that the recommended rst-line treatment remains eective; and

• education and enforcement to eliminate the use of oral artemisinin-based monotherapies and

substandard and countereit antimalarial medicines.

tIEr III

In areas in which there is no evidence o artemisinin resistance and limited contact with tier I areas,the main goal is to prevent the emergence o artemisinin resistance. As artemisinin resistance is a less

immediate threat than in other areas, implementation and scaling-up o eective control measures should be

continued, including increasing access to parasitological diagnosis or all patients suspected o having malaria,

improving access to quality-assured ACTs or conrmed cases and increasing coverage with vector control to

limit malaria transmission. In addition, tier III areas should undertake two other components o good control:

• Monitor the therapeutic efcacy o frst- and second-line treatments every 24 months, as recommended

by WHO. This is an immediate priority or any P. falciparum -endemic country with a sufcient number

o malaria cases in which studies o the efcacy o ACTs have not been conducted in the past 2 years.

• In areas in which there is extensive use o oral artemisinin-based monotherapies or poor-quality drugs,

introduce or enorce actions to eliminate their use.



32

TabLe 3. Detailed recommendations or tier I, II and III areas

tieR i RecommeNDatioNs

Monitoring and surveillance

•Urgentlycommunicatesuspicionofanewfocusofartemisininresistanceto

WHO Global Malaria Programme or review.•Whenartemisininresistanceissuspected,conductadditionalconrmatorystudies

immediately.

•Revitalizeregionalmonitoringnetworkstocomplementcountrymonitoring.

•Monitormalariatreatmentfailuresregularly;whensignicantincreasesarereported,

examine the efcacy o current treatments.

•Considerincreasingthenumberofsentinelsitesinareassurroundingfociofsuspected

artemisinin resistance as institutional capacity and resources permit.

Diagnostics and treatment:

consistent, accurate

diagnostic testing

•Accelerateuniversalcoverageinthepublicsectorandtheformalprivatesectordeliverychannels as rapidly as possible.

•SetuppilotprogrammestoexpandaccesstoanduseofRDTsintheinformalprivate

sector.


access to ACTs

•Accelerateeffortstoreach100%coveragewithACTsofconrmedmalariacasesinboth

the public and the private sector delivery channels.

•MakesurethatprogrammesincludeactivitiestoimproveaccesstoACTsinremote

areas.

•Encouragethemanufactureanduseofxed-dosecombinationsandprovidepreferential

unding or such ormulations in areas where the recommended treatment is available as

a fxed-dose combination.

•ConsideraddingasingledoseofprimaquinetoACTtreatmentforallconrmedcases

at or near oci o artemisinin resistance as an antigametocyte to prevent transmission,

in compliance with current WHO treatment guidelines (when the risk or glucose-6-

phosphate dehydrogenase defciency is considered low or testing or defciency is

available).

Note: WHO currently recommends primaquine or use in low-transmission settings.

Primaquine should always be administered in compliance with current WHO

recommendations.


removal o monotherapies

•Withdrawmarketingauthorizationfororalartemisinin-basedmonotherapiesandremove

these medicines rom the national Essential Medicines List.

•Interruptimportationanddistributionoforalartemisinin-basedmonotherapies.

•Commitpublicprovidersandretailerstoensureeffectivewithdrawalandincreaseother

activities to encourage removal.

•Atgloballevel,workwithcountriesandpharmaceuticalcompaniestostopmanufactureand export.


removal o substandard and

countereit drugs

•Atgloballevel,putpressureoncountriesinwhichthereareillegaldrugmanufacturersto

stop production and distribution o substandard and countereit drugs.

•Provideincentivesandtoolstoretailerstoidentifyandremovepoor-qualitydrugsfrom

their acilities.

•Conductqualitycontrolscreeningandeldoperationstoremovepoor-qualityproducts.


education

•Continuecampaignstoeducatepatientsandprovidersaboutmalariacontrol,with

increased emphasis on the dangers o using oral artemisinin-based monotherapies and

poor-quality drugs and the importance o rational use o ACTs (adherence to treatment).

Broadcast messages through locally appropriate channels.

•Encouragetheministryofhealthtoconducteducationcampaignsforpublichealth

providers on diagnosis and treatment, including the importance o diagnosis beore

prescribing ACTs and compliance and appropriate use o ACTs.

•Launcheducationcampaignsforprivateretailersoneffectivediagnosisandtreatment,including the risks linked to oral artemisinin-based monotherapies and the regulations

banning their marketing and use, tools to detect poor-quality drugs and the importance

o confrming malaria with an RDT beore treatment with ACTs.

Stop the spread o resistant

parasites: preventive measures

•Accelerateeffortstoreach100%coveragewithlocallyappropriatevectorcontrol.


parasites: mobile and migrant

populations

•Designprogrammestodelivermalariainterventionstomobileandmigrantpopulations

through a mix o public and private sector delivery channels.

•Atgloballevel,conductoperationalresearchtoidentifybestpracticesandscalable *

models to reach mobile and migrant populations.

Novel solutions and tools

•Considertheuseofmassdrugadministration,massscreeningandtreatment,focused

screening and treatment or active case detection where there is sufcient local

experience in implementation or where policy guidance recommends such measures.

* In the context o this document, ‘scalable’ means potential upgrading o a programme to expand its scope and reach.




33


tieR ii RecommeNDatioNs


•For countries in which studies have not been conducted within > 24 months, theimmediate priority is to conduct routine studies o ACT efcacy.

•Urgently communicate suspicion o a new ocus o artemisinin resistance toWHO Global Malaria Programme or review.

•When artemisinin resistance is suspected, conduct additional confrmatory studiesimmediately.

•Revitalize regional monitoring networks to complement national activities.

•Monitor malaria treatment ailures regularly; when signifcant increases are reported,

examine the efcacy o current treatments.

•Consider increasing the number o sentinel sites in areas surrounding suspected ocio artemisinin resistance as institutional capacity and resources permit.

Diagnostics and treatment:consistent, accurate

diagnostic testing

•Accelerate universal coverage in the public sector and the ormal private sectordelivery channels as rapidly as possible.

•Set up pilot programmes to expand access to and use o RDTs in the inormal private

sector delivery channels.


access to ACTs

•Accelerate eorts to reach 100% coverage with ACTs o confrmed malaria cases in

both the public and the private sector delivery channels.•Make sure that programmes include activities to improve access to ACTs in remote

areas.

•Encourage the manuacture and use o fxed-dose combinations and providepreerential unding or such ormulations in areas where the recommended

treatment is available as a fxed-dose combination.

•Consider adding a single dose o primaquine to ACT treatment or all confrmed cases

at or near oci o artemisinin resistance as an antigametocyte to prevent transmission,in compliance with current WHO treatment guidelines (when the risk or glucose-6-

phosphate dehydrogenase defciency is considered low or testing or defciency isavailable).


removal o monotherapies

•Withdraw marketing authorization or oral artemisinin-based monotherapies, and

remove these medicines rom the national Essential Medicines List.

•Interrupt importation and distribution o oral artemisinin-based monotherapies.

•Commit public providers and retailers to ensure eective withdrawal, and increase

other activities to encourage removal.

•At global level, work with countries and pharmaceutical companies to stopmanuacture and export.

Diagnostics and treatment:removal o substandard and

countereit drugs

•At global level, put pressure on countries in which there are illegal drug manuacturersto stop production and distribution o substandard and countereit drugs.

•Provide incentives and tools to retailers to identiy and remove poor-quality drugsrom their acilities.

•Conduct quality control screening and feld operations to remove poor-qualityproducts.


education

•Continue campaigns to educate patients and providers about malaria control, with

increased emphasis on the dangers o using oral artemisinin-based monotherapiesand poor-quality drugs and the importance o rational use o ACTs (adherence to

treatment). Broadcast messages through locally appropriate channels.

•Encourage the ministry o health to conduct education campaigns or public health

providers on diagnosis and treatment, including the importance o diagnosis beoreprescribing ACTs and compliance and appropriate use o ACTs.

•Launch education campaigns or private retailers on eective diagnosis and

treatment, including the risks linked to oral artemisinin-based monotherapies and theregulations banning their marketing and use, tools to detect poor-quality drugs and

the importance o confrming malaria with an RDT beore treatment with ACTs.



•Accelerate eorts to reach 100% coverage with locally appropriate vector control.

Stop the spread o resistantparasites: mobile and migrant

populations

•Designprogrammestodelivermalariainterventionstomobileandmigrantpopulations

through a mix o public and private sector channels.

•Atgloballevel,conductoperationalresearchtoidentifybestpracticesandscalable *

models to reach mobile and migrant populations.

* In the context o this document, ‘scalable’ means potential upgrading o a programme to expand its scope and reach.



34

tieR iii RecommeNDatioNs


•For countries in which studies have not been conducted within > 24 months, the

immediate priority is to conduct routine studies o ACT ecacy.•Urgently communicate suspicion o a new ocus o artemisinin resistance to

WHO Global Malaria Programme or review.

•When artemisinin resistance is suspected, conduct additional conrmatory studiesimmediately.

•Revitalize regional monitoring networks to complement national activities.

•Monitor malaria treatment ailures regularly; when signicant increases are reported,

examine the ecacy o current treatments.

•Consider increasing the number o sentinel sites in areas surrounding oci osuspected artemisinin resistance as institutional capacity and resources permit.

Diagnostics and treatment:consistent, accurate

diagnostic testing

•Continue current programme to achieve universal coverage.


access to ACTs

•Continue current programme to ensure 80% coverage with ACTs or conrmedcases o malaria, consistent with control and elimination programme.

•Encourage the manuacture and use o xed-dose combinations and provide

preerential unding or such ormulations in areas where the recommendedtreatment is available as a xed-dose combination.

Diagnostics and treatment:removal o monotherapies

•Withdraw marketing authorization or oral artemisinin-based monotherapies, and

remove these medicines rom the national Essential Medicines List.•Interrupt importation and distribution o oral artemisinin-based monotherapies.

•Commit public providers and retailers to ensure eective withdrawal, and increaseother activities to encourage removal.

•At global level, work with countries and pharmaceutical companies to stopmanuacture and export.

Diagnostics and treatment:removal o substandard and

countereit drugs

•At global level, put pressure on countries in which there are illegal drug

manuacturers to stop production and distribution o substandard and countereitdrugs.

•Conduct quality-control screening. I the results indicate a high prevalence o poor-quality drugs:

- conduct eld operations to remove poor-quality drugs rom shelves (consider nes or

closing oending shops); and- provide incentives and tools to selected retailers to enable them to identiy and

remove poor-quality drugs rom their acilities.


education

•Continue campaigns to educate patients and providers about malaria control, with

increased emphasis on the dangers o using oral artemisinin-based monotherapiesand poor-quality drugs and the importance o rational use o ACTs (adherence to

treatment). Broadcast messages through locally appropriate channels.

•Encourage the ministry o health to conduct education campaigns or public healthproviders on diagnosis and treatment, including the importance o diagnosis beore

prescribing ACTs and compliance and appropriate use o ACTs.•Launch education campaigns or private retailers on eective diagnosis and

treatment, including the risks linked to oral artemisinin-based monotherapies and theregulations banning their marketing and use, tools to detect poor-quality drugs and

the importance o conrming malaria with an RDT beore treatment with ACTs.



•Continue current programme to achieve ≥ 80% coverage with current tools.


parasites: mobile and migrantpopulations

•Set up targeted prevention and inormation programmes at main points o entry or

migrants rom regions with oci o artemisinin resistance.




35


4. sp e pea f eia

paaieIn areas where artemisinin resistance exists, national malaria control programmes and their partners

should combine control and elimination programmes to stop the survival and spread o resistant parasites

and ultimately contain or eliminate them. In areas with no known resistance, control measures should

be used to reduce transmission, lowering the risk that resistant parasites will spread into the area and

minimizing the potential public health impact o resistance i it were to emerge. In particular, national

malaria control programmes and their partners should use preventive measures to reduce transmission and

expand eorts to reach mobile and migrant populations with eective malaria interventions.

4.1 Pevenive meaue o educe anmiionEective preventive measures are important or interrupting malaria transmission and decreasing the

number o malaria cases. Vector control methods, including nets and indoor residual spraying, prevent

human contact with the vector and reduce the number o vectors (WHO, 2002; WHO, 2006). When these

preventive measures are used correctly, the incidence and prevalence o parasite inection and clinical

malaria decrease. Unortunately, many regions endemic or malaria still have low or inconsistent coverage

with recommended vector control interventions. In the Greater Mekong subregion, questions were

raised about the eectiveness o insecticide-treated nets in some orest settings, but new experience

suggests that current tools are eective in reducing transmission in most eco-epidemiological settings in

the subregion.6 The biting behaviour o the most ecient orest malaria vectors (Anopheles minimus and

An. dirus) peaks ater 22:00 h. There are some exceptions to this rule, and earlier biting might have

implications or the eectiveness o treated nets (Trung et al., 2005).

PotEntIAl solutIons

The rst solution described below, rapid scale-up o vector control measures, is a well-documented

component o malaria control. It is emphasized here because it is o particular importance or containing

and preventing artemisinin resistance. An additional solution, treating symptomatic patients with an ACT

plus primaquine in low-transmission settings at or near oci o artemisinin resistance, is also discussed.

While primaquine would be administered as part o a treatment regimen, it is included here because o its

transmission-blocking eects.

Epidemiological or transmission-reduction tools, including mass screening and treatment, ocused

screening and treatment, active case detection and mass drug administration, may also be considered, in

accordance with the latest evidence or guidelines. In some areas, enough evidence may exist or a national

malaria control programme to choose to implement one o these interventions locally. To date, however,

there is insucient evidence or technical consensus to recommend these interventions or resistance

containment; instead, these interventions are discussed urther in the research section.

6 According to interviews conducted by The Boston Consulting Group between May and July 2010.



36

1. Rpd -up rndd r nr ur, nudng prn prn

nd qu n ur, n r r whh hr dn rnn

rn r hgh r r h prd rnn rn (see Annex 1 or a descriptiono a case study on the role o vector control in containment on the Cambodia–Thailand border).

The scaling-up o preventive measures should include increasing the distribution and improving the

maintenance o existing vector control measures (insecticide-treated nets, long-lasting insecticide

nets, long-lasting insecticide hammock nets and indoor residual spraying) and ensuring their regular

and proper use. Control activities should be intensied at and near areas o suspected or conrmed

artemisinin resistance. Potential tactics to accelerate scale-up include use o work-site or employer-

based programmes or distribution, channeling more preventive measures through existing

distribution networks and expanding and enhancing education activities.

2. cndr ddng prqun rn r nfrd , rdu rnn, r

nr rnn rn n w-rnn r. Primaquine, a gametocytocidal

medicine that can reduce transmission o P. alciparum, is recommended by WHO or use in

combination with ACTs, particularly in some low-transmission settings and in the context o a pre-

elimination or elimination programme (WHO, 2010a). National malaria control programmes should

consider treating all conrmed cases o P. alciparum with an ACT plus a single dose o primaquine

in low-transmission areas at or near artemisinin resistance oci, when the risk or haemolysis due

to glucose 6-phosphate dehydrogenase deciency is considered to be low or when testing or

deciency is easible.

4.2 maaia c f ie a iappai

The movement o populations within and between malaria-endemic areas is believed to be a major

contributor to the spread o antimalarial resistance. Mobile and migrant populations are a heterogeneous

group, which includes individuals and groups who are temporarily moving either within or outside theirhome country, oten or temporary or seasonal work; internally displaced persons moving to new areas due

to political confict or other reasons; and national security orces, which are oten clustered near borders.

Travellers are also considered part o this group. A variety o approaches to address the needs o these

populations is critical to limit the spread o resistant parasites.

For unique reasons, mobile and migrant populations are more likely than other groups to carry and

spread resistant parasites: these populations oten live and work in areas with high malaria transmission,

high human–vector contact and limited access to health services, such as eective malaria prevention,

diagnosis and treatment with ACTs. As the presence o some migrants in a country is undocumented, they

may mistrust any channel perceived as ocial, including public health care acilities. In other cases, ormal

health care services may not be accessible or the cost o care may be prohibitive. As a result, migrant

populations are more likely to seek care rom unregulated, private vendors, which may increase their risk

o exposure to substandard and countereit drugs or oral artemisinin-based monotherapy. Once artemisininresistance has emerged, the requent movement o these groups makes it dicult to enumerate, track and

treat suspected cases and increases the chances that resistance will spread to new areas.

Mobile and migrant populations oten cluster near provincial or national borders, and these regions can

present unique challenges or implementation and coordination. Neighbouring countries may be unwilling

or unable to cooperate because o political tensions, cross-border conficts, competing priorities, lack o

resources or inrastructure or insucient implementation capacity. These actors may undermine malaria

4. Stop the spread o resistant parasites



39


5. Iceae ii a

eiace eaae eea f aeiii eiace

WHO recommends that countries endemic or malaria routinely monitor the ecacy o antimalarial

drugs in order to detect changes in their therapeutic ecacy and guide national treatment policy.7 Regular

monitoring and surveillance are critical or identiying new oci o artemisinin resistance rapidly and guiding

containment and prevention activities. Until molecular markers o resistance are identied, measurement

and reporting o parasite clearance on day 3 ater treatment with ACTs is particularly important, as this is

one o the rst signals o artemisinin resistance available today.

According to the WHO protocol, national malaria control programmes should evaluate the ecacy o

rst- and second-line antimalarial drugs at sentinel sites at least once every 24 months (WHO, 2009). Theexperience gained in the project or conrmation, characterization and containment o artemisinin resistance

in Thailand and Cambodia suggests that when more than 10% o patients have detectable parasites on day

3, conrmatory studies should be conducted, which include studies o the ecacy o a 7-day treatment with

artesunate. In some instances, it may be appropriate to initiate containment activities when ≥ 3% but < 10%

o cases have parasites detectable on day 3 ater treatment with an ACT.

Despite the WHO recommendations, many endemic countries do not routinely monitor therapeutic

ecacy (Figure 6). O the 106 endemic countries (92 o which are endemic or P. alciparum), 75 have a

sucient burden o malaria to permit routine monitoring o ACT ecacy. As o August 2010, 44 o the 75

countries had not conducted studies in compliance with WHO recommendations within the past 2 years, due

to insucient unding and other resources, extenuating circumstances such as war or natural disaster or a

perceived lack o urgency (WHO, 2010c). As a result, understanding o where artemisinin resistance exists is

incomplete.

Routine monitoring o the therapeutic ecacy o ACTs is not conducted more widely because o the

several constraints (Vestergaard & Ringwald, 2007). These studies can be logistically dicult in some settings,

may not be easible in areas o very low transmission (because o small numbers o malaria cases) and are not

always conclusive or detecting resistance, as host actors (e.g. immunity, previous drug intake) can conound

the results. Even when therapeutic ecacy studies are conducted, the results are oten not made available

rapidly, especially when studies are conducted outside o the national malaria control programme.

PotEntIAl solutIons

National malaria control programmes and their partners should consider:

1. a n d prr, nr h hrpu f act ud h n n

prrd whn h p 2 r. To obtain a comprehensive understanding o where parasites

are resistant to artemisinins, the ecacy o ACTs must be known in all endemic countries.8 For the

44 countries in which studies have not been conducted in compliance with WHO guidelines since the

7 Although therapeutic ecacy monitoring should be a routine activity o national malaria control programmes, rather than individualor isolated research projects, because o the complexity o the protocol, monitoring is conducted through what are reerred to astherapeutic ecacy studies (also called in vivo studies). Accordingly, the individual activites are reerred to as ‘studies’, even though

monitoring is an ongoing, routine activity.

8 The phrases ‘all endemic countries’ and ‘all endemic regions’ used in the context o routine monitoring reer to countries or regions

with sucient numbers o malaria cases to monitor therapeutic ecacy.



40

end o 2007, an immediate priority is to determine the ecacy o currently used rst- and second- line

drugs. The studies should be perormed in compliance with the most recent WHO protocol, with a

strong emphasis on data quality (WHO, 2009). A nancial commitment rom donors is required toensure the sustainability o therapeutic ecacy studies in endemic countries.

2. Rz urgn nwr uppr nn nrng. To complement monitoring

activities in countries, subregional monitoring networks should be revitalized or redesigned.

Networks can provide important benets, including encouragement and incentives or countries

to conduct regular monitoring, identication o subregional trends, coordination o a subregional

response when required and sharing data regarding border areas. I subregional networks are to

play a signicant role in responding to the threat o artemisinin resistance, sustainable nancing and

stable network management structures are needed (see Annex 2 or a description o subregional

monitoring networks).

3. Urgn un upn nw rnn rn. Any inormation

suggesting new oci o artemisinin resistance should be communicated immediately to

WHO Global Malaria Programme, which will work with scientists, including the technical expertgroup on antimalarial drug resistance, to evaluate the accuracy and integrity o the data. I resistance

is conrmed, the data should also be shared with relevant policy-makers and global malaria partners

or a timely, well-coordinated response. Current data dissemination systems should be enhanced

so that all stakeholders are kept up to date as the situation evolves. This recommendation applies

not only to national malaria control programmes which routinely monitor the ecacy o ACTs, but

also to researchers and pharmaceutical companies involved in studies on the therapeutic ecacy

o ACTs or artesunate.

4. Whn dn rnn rn rd , ndr ddng nw nn

nr rnn rn. As it is dicult to extrapolate inormation on resistance rom

an isolated ocus to nearby areas, adding new sentinel sites near areas or which there is already

evidence o artemisinin resistance can clariy whether and where artemisinin resistance has spread.

National malaria control programmes should work with WHO Global Malaria Programme and otherexperts to determine whether additional sites would be benecial in their context. I new sites are

to be added, the malaria control programme should coordinate and oversee their establishment

and the conduct o studies but may involve other partners as needed.

5. srnghn run urn r. In high-risk areas, and especially in areas with

no active sentinel sites, national malaria control programmes should consider strengthening

routine surveillance o conrmed malaria cases and deaths, and especially treatment ailures. The

programmes should introduce a mechanism whereby health care providers can identiy and report

treatment ailures. Although it may be dicult to obtain such data rom private providers, this is

important in areas where a large proportion o the population seeks care privately. When regular

surveillance indicates an increased number o treatment ailures or increases in the numbers

o cases or deaths rom malaria, additional studies should be conducted to rule out artemisinin

resistance as the cause. Increases in treatment ailures and in morbidity or mortality are late

indicators o resistance9 but may be useul when therapeutic ecacy is not routinely monitored.

9 Increases in morbidity and mortality can be due to many actors, only one o which is the emergence or spread o artemisininresistance. By the time artemisinin resistance has led to a noticeable increase in morbidity or mortality, resistance is probably alreadywell entrenched locally, and the extent o geographical spread would not be known immediately. Thus, increases in morbidity andmortality provide only a very late indicator o resistance.

5. Increase monitoring and surveillance to evaluate the threat o artemisinin resistance



41


Figure 6. Status o therapeutic ecacy monitoring in 106 countries endemic or malaria

N u m b e r o f e n d e m i c c o u n t r i e s ,

a s o f 2 0 1 0 150

100

50

0Studies

conducted in2008-2009

Studies not

conducted in2008-2009

but planned

in 2010-2011

Last studies

conducted 3-5years ago

31

Last studies

conductedmore than 5

years ago

Difficulty in

conductingstudies*

No falciparum

malaria(only vivax malaria )

All

106

14

17

44

31

14

17

Vivax only

Difficult toconduct studies

Not in compliance

In compliance

13

19

12

* Very small number o cases makes it dicult to conduct studies in these countries.Source: WHO Global Malaria Programme database on antimalarial therapeutic ecacy monitoring by country (accessed August 2010).



43


43


6. Ipe acce iaic

a aeiii-aeciai eapie

Improving access to aordable, quality-assured diagnostic testing and treatment with ACTs improves

patient outcomes and limits the opportunities or emergence o resistance to both artemisinins and partner

drugs. Programmes should have a multiaceted approach that improves access to both consistent, accurate

diagnostic testing and quality-assured ACTs or conrmed cases, while removing oral artemisinin-based

monotherapies and substandard or countereit drugs rom the market. Each o these issues requires

understanding and education o and dialogue with patients, providers and retailers. The proposed solutions

or each issue are complementary and, wherever possible, should be coordinated.

6.1 Cie, accae iaic eiConfrmation o malaria by parasitological diagnosis is important to prevent unnecessary overuse o

antimalarial medicines and limit the opportunities or emergence o resistance to both artemisinins and

partner drugs. Administration o an ACT to a person who does not have malaria does not cause drug

resistance; the problem arises when that person is later exposed to malaria. I this occurs relatively soon ater

the ACT is taken, the presence o the two drugs makes selection o a resistant parasite unlikely; i exposure

occurs later, when only the partner drug may be present in the blood at a subtherapeutic level, resistant

parasites may be selected. High-transmission areas are o greatest concern, because people in these areas

are more likely to be bitten by an inected mosquito at a t ime when only the partner drug is present in blood.

I the partner drug becomes less eective or ineective, it no longer provides adequate protection or the

artemisinin derivative in the ACT. As a result, artemisinin and its derivatives may be threatened.

ACTs are requently used to treat causes o ever other than malaria. It has been shown that a median

o 78% o patients treated or malaria in Arica may not actually have malaria, and this proportion has

increased over time (d’Acremont, Lengeler & Genton, 2010). As malaria control programmes continue to

reduce both malaria transmission and malaria burden, the proportion o evers due to malaria will continue

to decrease.Without appropriate diagnosis, more ACTs will be wasted on non-malarial ebrile illnesses,

potentially increasing the risk or selecting resistant parasites. To reduce the number o patients without

malaria taking ACTs, all suspected cases o malaria should be diagnosed parasitologically beore treatment,

as recommended by WHO (WHO, 2010a).

Diagnostic testing also plays a critical role in ascertaining possible cases o antimalarial resistance.

Patients who ail to improve clinically or who improve but have a subsequent relapse should return to a health

care provider or re-evaluation. Microscopy should be used to determine i parasitaemia is still present, as

RDTs may give positive results or varying lengths o time, even ater successul treatment. I a pattern o

increasing therapeutic ailures emerges, ollow-up studies should be conducted to investigate the cause.

Although the availability and use o parasitological diagnosis is increasing, there are clear opportunities or

improvement (see Annex 3 or a case study on the use o parasitological diagnosis). By 2009, about 35% o

suspected malaria cases in endemic countries o the WHO Arican Region were tested by microscopy or an

RDT (WHO, 2010b). Although this represents a signifcant increase since 2004, most suspected cases in these

endemic countries are still not tested, even in the public sector. Various challenges preclude more widespread

adoption o diagnostics, including problems o distribution (Renshaw et al., 2009), and variability in the



44

quality and perormance o RDTs, including sensitivity, specifcity, heat stability and longevity (WHO, 2010d).

Furthermore, some providers and patients are still unaware o the harm associated with treating cases without

malaria with ACTs, and in some settings patients with negative results rom a diagnostic test still receive andtake antimalarial medicines (Hamer et al., 2007; Reyburn et al., 2007; J. Cohen, unpublished data).

Measures are being taken to address these challenges. Recent successes include improvement o

the supply chain to ensure that high-quality RDTs are available where and when needed; testing o RDT

products and lots by WHO, the Special Programme or Research and Training in Tropical Diseases, the

Centers or Disease Control and Prevention and the Foundation or Innovative New Diagnostics; and

intensive provider training programmes, oten accompanied by supervision. There are also eorts under

way to improve provider and patient compliance with the results o testing. 10 In the United Republic o

Tanzania, proper provider training and regular supervision were shown to encourage compliance with

testing results (d’Acremont, personal communication). In Ghana, in health acilities with no previous access

to malaria diagnostic testing, the introduction o RDTs led to a signicant reduction in overprescription o

antimalarial medicines (Ansah et al., 2010). Nevertheless, ensuring the use o RDTs and compliance with

the results in the inormal private sector is likely to be a tremendous challenge. For example, in a study inKenya, there was demand or RDTs in the private sector at low prices, but access to RDTs only modestly

improved targeting o ACTs because most patients with negative test results purchased ACTs anyway

(J. Cohen, unpublished data).

PotEntIAl solutIons

Four parallel activities are proposed to encourage the use o parasitological diagnosis and compliance

with the results.

1. ar unr rg wh prg dgn n h pu r nd

h r pr r.11 In order to prevent overuse o ACTs, universal access and use o

parasitological diagnosis in public and ormal private sector health acilities should be achieved assoon as possible. Access can be increased by strengthening the distribution networks o RDTs,

improving supply chain management, improving quality assurance and strengthening community

health services. Use might be increased by more training o health care workers in microscopy and

use o RDTs and introducing quality assurance systems to veriy that the tests are administered

regularly and properly. Donors should consider increasing unding or diagnostics and the systems

needed to implement and properly maintain programmes or universal diagnostic testing.

2. cnnu nw pprh nr nd u prg dgn

n h nr pr r.12 More operational research and pilot tests are needed to identiy

the most eective strategies or increasing use o diagnostics in the inormal private sector. For

example, more data are required to understand how the cost o RDTs infuences use and whether

subsidizing RDTs at country level or globally is easible.

3. cnnu pr h qu RDt. Activities to ensure the quality, consistency andreliability o RDTs and their supply chains should continue, in collaboration with RDT manuacturers.

For example, the RDT product testing and lot-quality testing programmes conducted by WHO,

the Special Programme or Research and Training in Tropical Diseases, the Centers or Disease

Control and Prevention and the Foundation or Innovative New Diagnostics provide data to endemic

countries to guide their purchase o high-quality diagnostics and encourage manuacturers to

improve the quality o their products (WHO, 2010d).


11The ‘ormal private sector’ is the regulated part o the market.

12 The ‘inormal private sector’ is the unregulated (unregistered premises or practitioner) part o the market.

6. Improve access to diagnostics and artemisinin-based combination therapies



45


4. intensfy efforts to educate provders and patents about the mportance of dagnostc

testng. To convince providers and patients o the importance o diagnostic testing beore

treatment, current education and training initiatives should be expanded or reviewed, with robustmonitoring and evaluation to ensure eectiveness. At community level, patients should be

inormed about the importance o timely, accurate diagnosis o malaria and o not taking ACTs

without a confrmed parasitological diagnosis. Additional training, supervision and access to the

necessary commodities are also important to enable health care providers to diagnose and treat

patients when the RDT is negative.

6.2 Acce affae, ai-aeaeiii-ae ciai eap

ACTs are an eective, rapid treatment or P. alciparum malaria. When manuactured and administered in

adherence with treatment guidelines, combination therapies are not only more eective than monotherapies,

but the mutual protection provided by two drugs reduces the chance that resistance will emerge. A

3-day course o a recommended ACT generally results in rapid clearance o parasites and resolution o

symptoms. In addition, the artemisinin component o the combination reduces gametocyte carriage, thus

reducing malaria transmission. Because ACTs have multiple advantages over other antimalarial treatments,

WHO recommends ACTs as rst-line treatment or conrmed cases o uncomplicated P. alciparum malaria

(WHO, 2010a). The current list o recommended ACTs is given in the WHO guidelines or treatment o

malaria, which is available at: http://www.who.int/malaria/publications/atoz/9789241547925/en/index.html.

The choice o ACT depends on local data on the sensitivity o P. alciparum to dierent ACTs.

Despite the availability o WHO guidelines or treatment and the act that most endemic countries

have adopted ACTs as rst-line treatment, non-artemisinin-based therapies and oral artemisinin-based

monotherapies are still the dominant orms o treatment in many malaria-endemic countries, especially in

the private sector. Initiatives to expand access to ACTs ace signicant challenges in both the public and theprivate sector. In the public sector, challenges include recurrent stock-outs o ACTs due to procurement and

supply chain diculties and problems o geographical access to public health acilities. In the private sector,

challenges include the act that ACTs are more expensive than other, readily available antimalarial medicines;

poor regulation and enorcement mechanisms; and lack o access by remote and mobile populations.

While access to ACTs remains inconsistent in endemic countries, in areas where a concerted eort is

made to adhere to WHO guidelines or treatment and adequate resources are committed, it is possible to

improve ACT access signicantly (see Annex 4 or the availability o ACTs in selected endemic countries).

PotEntIAl solutIons

National malaria control programmes and their partners should consider the activities described below

to improve access to aordable, quality-assured ACTs or conrmed cases o malaria. Patients should be

encouraged to seek care in the public or the ormal private sector whenever possible. As all patients may

not have access to these acilities and many people turn to the inormal private sector or care, solutions

should be identied to reach inormal private sector outlets.



47


box 4. tHe aFFoRDable meDiciNes Facility–malaRia

The Aordable Medicines Facility – malaria, is a nancing mechanism to expand access to ACTs and displace

less eective or undesirable monotherapies, including oral artemisinin-based monotherapies. The AordableMedicines Facility – malaria benets buyers rom all sectors and it has three elements: price reductions throughnegotiations with ACT manuacturers, a buyer subsidy through a ‘co-payment’ at the top o the supply chain, andsupporting interventions to promote appropriate use o ACTs. It is hosted and managed by the GFATM.

Co-payment

Funders/

GFATM

Multiple eligible

ACT

manufacturers

Private buyers

NGOs buyers

Public buyers

Distributors

Central medical

stores

Retailers and

private clinic

Public health

facilities

Patients

Medicines

*

Money

* with or without payments, depending on country policy and practice.

NGOs, nongovernmental organizations.

Pn nf:

•Increasesaffordabilityanduseofrst-lineACTsformalariacases,therebysavingmorelivesthanwouldbe

the case without the Aordable Medicines Facility – malaria;•Displacesoralartemisinin-basedmonotherapies,thusreducingriskofartemisininresistancebelowwhat

might happen without Aordable Medicines Facility – malaria;•Throughimplementationresearch,providesopportunitiestolearnhowtheprivatesectorcanbeusedto

expand access to health technologies, including rapid diagnostic tests.

Pn r:

•Somedistributorsinthesupplychainmaycapturemuchofthesubsidy,reducingthebenetstosome

patients;•Withoutuniversaluseof,andcompliancewith,diagnostictestsinAffordableMedicinesFacility–malaria

phase 1, it increases the use o rst-line ACTs or non-malarial ebrile illnesses.

6.3 rea f a aeiii-aeeapie

Unlike ACTs, which require only 3 days to result in high cure rates, oral artemisinin-based monotherapies

require 7 days or comparable ecacy, and many patients stop taking them ater only a ew days, when

their symptoms have diminished signicantly. When adherence is incomplete, parasites in a patient’s blood

are exposed to a subcurative dose; while the most sensitive parasites are eliminated, the more resistant

ones can survive and be transmitted to others. As a result, the use o oral artemisinin-based monotherapies

may hasten the spread o artemisinin resistance.

WHO has worked with pharmaceutical companies to halt the production o oral artemisinin-basedmonotherapies since 2005 (see Annex 5 or a description o WHO’s activities in removing oral artemisinin-

based monotherapies). Initially, 76 companies were known to be producing and marketing these ormulations,

and this number has decreased to 43 (see Annex 5 or a l ist o areas o the world in which oral artemisinin-

based monotherapies are produced). While these results are encouraging, it will be dicult to infuence

the remaining small producers, which continue to exploit the niche markets created by the withdrawal

o big pharmaceutical companies. The continued manuacture and distribution o oral artemisinin-based

monotherapies and poor regulation o drug markets in many countries endemic or malaria contribute to

persistent use o these drugs. Despite the work o WHO, the RBM Partnership and other stakeholders, as



48

o December 2010, the national drug regulatory authorities in 25 endemic countries still allowed marketing

o oral artemisinin-based monotherapies or use in the private sector (see Annex 5 or a list o countries

that still allow marketing o oral artemisinin-based monotherapies or use in the private sector and Annex1 or a description o the successul interruption o the importation and sales o oral artemisinin-based

monotherapies in Cambodia). No data are available on the number o treatment courses o oral artemisinin-

based monotherapy produced throughout the world annually.

PotEntIAl solutIons

Four parallel eorts are proposed to reduce the production and marketing o oral artemisinin-based

monotherapies.

1. Wr wh grnn nd nuurr p prdun, rng nd pr

r rnn-d nhrp hrugh rgd rgur nrnn. National

and municipal governments should withdraw manuacturing and export licenses and marketingauthorization or oral artemisinin-based monotherapies. The initiatives could include taking

punitive action against companies that ail to cease manuacture, marketing or export; increasing

the capacity o national drug regulatory authorities and making them accountable or eectively

withdrawing manuacturing licenses; and involving local police and drug inspectors in enorcement.

In parallel, the 43 known pharmaceutical companies that still provide oral artemisinin-based

monotherapies to the private sector should be engaged. This will require a communication

campaign or shareholders or owners about the risks associated with these ormulations,

negotiating a deadline with manuacturers by which they will stop manuacture or export o such

products, determining what assistance companies need to stop production and perhaps change

to production o ACTs and supporting companies in developing plans to implement changes.

As the production o oral artemisinin-based monotherapies decreases, WHO will work with

selected companies to ensure the availability o prequalied oral artemisinin-based tablets or

specic, careully controlled uses, including therapeutic ecacy studies and the treatment o

severe malaria.

2. inrrup prn nd wh ung r rnn-d nhrp.

Malaria-endemic countries should implement and enorce regulations to halt the importation and

wholesale buying o oral artemisinin-based monotherapies by the private sector. Regulations

could include stopping import licenses and suspending new marketing authorization or nished

products; withdrawing marketing authorization and manuacturing licenses or nished products;

regulating re-packaging and re-branding by domestic companies; removing oral artemisinin-based

monotherapies rom national lists o registered drugs; and ensuring that national drug regulatory

authorities, the police and other relevant government agencies and departments enorce removal o

oral artemisinin-based monotherapies rom the country. In many cases, implementation will require

investment to strengthen drug regulatory authorities.

3. a ngg rr nd hr prdr nur whdrw

nhrp. Retailers and other providers should be inormed about the risks caused by

oral artemisinin-based monotherapies, how the emergence o resistance could aect outcomes

in patients, especially children and about the measures taken to halt marketing and use and the

penalties that shops might incur i they continue to sell these products. Assuming aordable ACTs

are available through private sector delivery channels, initiatives should be taken to track, report on

and remove oral artemisinin-based monotherapies. Activities may include: implementing routine

eld investigations and reporting the ndings to national drug regulatory authorities so they can

take ollow-up action i needed; identiying and reporting the sources o such products to WHO




49


and relevant enorcement bodies; certiying and accrediting retailers that sell only quality-assured

ACTs; and ning retailers that continue to sell oral artemisinin-based monotherapies and other non-

approved antimalarial medicines.

4. inr pn u h r d wh ng r rnn-d

nhrp n rdr rdu dnd. An education campaign is needed or patients and

caregivers in endemic countries to explain clearly the potential harm o taking oral artemisinin-

based monotherapies and the potential impact o antimalarial resistance on outcomes, especially

or children. Patients should be educated to take only recommended drugs, instructed on how to

identiy quality-assured ACTs and made aware o the importance o completing the prescribed

treatment.

6.4 removal of ubandad and counefei dugBecause substandard and countereit antimalarial medicines contain insucient levels o artemisinin

derivatives, they threaten the health o patients and may lead to the development and spread o artemisinin

resistance, as regular use o such products may allow resistant parasites to survive and multiply.

‘Substandard drugs’ are medicines that do not meet the correct scientic specications or composition

and ingredients and are consequently ineective and potentially dangerous or the patient. ‘Countereit

drugs’ are a category o substandard drugs that are deliberately and raudulently mislabelled or prot-making

purposes. Countereits may contain only traces o active ingredients or no active ingredient at all (WHO,

2010e).

Substandard antimalarial medicines are prevalent in many malaria-endemic countries. In a study in

Senegal in 2008, or example, 44% o 62 drug samples rom the public, private and inormal sectors did not

meet requirements in a ull quality control test (United States Pharmacopeia Drug Quality and Inormation

Program, 2010). Countereit drugs are also a signicant problem in many endemic countries. In a studyconducted between 1999 and 2006 in South-East Asia, 50% o 391 samples o medicines marked as

artesunate were ound to be countereit ater careul examination o the packaging and drug quality testing

(Newton et al., 2008). Modern chemical, mineralogical and biological techniques and analyses o packaging

can help inspectors to determine the origin o drugs, and concerted and coordinated eorts can achieve

notable results in removing poor-quality drugs rom the market (see Annex 1 or a description o a successul

initiative in Cambodia to remove poor-quality drugs).

PotEntIAl solutIons

Four initiatives are proposed to reduce the production and use o poor-quality drugs.

1. sur h qu drug gud p rndn nd rgun. In countrieswhere the prevalence o substandard and countereit drugs is not known, countries should consider

initiating targeted drug screening at representative sites. To complement these surveys, countries

should set up educational campaigns to inorm providers and shop owners about regulatory policies

and should collect random samples rom drug retailers. To support drug screening, new tools are

needed to help enorcement agencies, retailers and consumers identiy substandard, countereit

and unregistered drugs (Phanouvong & Blum, 2004). Research is also needed to develop simple,

sensitive tools and analytical methods or rapid use in the eld.



50

2. t d rgur n p h nuur nd wh purh

unr drug. In order to stop the manuacture, importation and distribution o countereit

antimalarial medicines, their origin must be known. I the source is unknown, eorts should bemade to trace countereit drugs back to their site o production, starting with the retail outlet at

which it was purchased. Pressure should be placed on countries with illegal drug manuacturing

acilities to stop production and better regulate exportation and distribution. For these eorts to

be eective there must be close coordination among health proessionals, distributors, health

authorities, drug regulatory authorities, the police and Interpol, and customs departments. The

WHO International Medical Products Anti-countereiting Taskorce15 could work with Interpol and

others to share data on sources o poor quality drugs in various countries in order to shut down

illegal manuacturing acilities.16

3. Prd nn nd hp nn drug rgur uhr, prdr nd

rr dn nd r undrd drug r h r. On the basis o the

results o surveys to identiy substandard drugs, countries should establish regular monitoring o the

quality o drugs in both the ormal and the inormal market and set up enorcement mechanisms to

enable drug inspectors to conscate and destroy medicines ound to be substandard. The capacity

o national drug regulatory authorities to deal with substandard drugs should be improved urgently.

Innovative mechanisms should be ound and evaluated to help providers and retailers in veriying

the quality and authenticity o ACTs beore they buy them, including working with manuacturers

to incorporate registration numbers, bar codes or coloured signals that are not visible to the naked

eye on packaging; an easy, rapid test or the authenticity o a product; and teaching providers and

retailers to detect substandard drugs. To help patients purchase quality-assured ACTs, countries

might consider accrediting ‘approved’ retailers or using text messaging (short message service, or

SMS) to validate the authenticity and quality o a drug.17

4. edu pn n h prn ung qu-urd dn. Because consumers

may nd it dicult to distinguish between quality-assured ACTs and substandard or sophisticated

countereit drugs, education campaigns should ocus on alerting patients to unreliable sources

o medicines in the private sector and encouraging them to seek treatment in accredited health

acilities.18 Where applicable, campaigns should encourage patients to seek care in the public

sector; i this is not possible, patients should be encouraged to use certied sellers o antimalarial

drugs to minimize the risk o purchasing a poor-quality drug.

15 The International Medical Products Anti-countereiting Taskorce was created in 2006 by WHO to raise awareness and encourageaction against ake medicines. Its aim is to build coordinated networks in and between countries to halt the production, trade andsale o countereit medicines and to protect people rom buying and taking them.

16 According to interviews conducted by The Boston Consulting Group between May and July 2010 and the terms o reerence o theInternational Medical Products Anti-countereiting Taskorce.






51


7. Ie i eeac aeiii

eiaceAs so little is known about the development and spread o artemisinin resistance, the research community

has a critical role to play in understanding and containing the threat. Many o the priorities already identied

or research in malaria control and elimination will be relevant, but they will not be sucient, and additional

initiatives are needed in the ve areas listed in Table 4. Some o the research needs in each o these

categories are described in the ollowing section, which is not, however, intended to be a comprehensive

research agenda.

TabLe 4. Categories o research required on artemisinin resistance

cateGoRy GPaRc PRioRity

Laboratory research To allow aster detection o resistance

Research and developmentTo ensure the availability o new drugs to replace thosethat become ineective because o resistance

Applied and eld researchTo determine whether new tools or existing toolsapplied or combined in novel ways can be used tocontain or prevent artemisinin resistance

Operational researchTo improve the eectiveness in the eld o currentand new tools, interventions and programmes or

combating artemisinin resistance

Mathematical modellingTo predict the potential spread and eects o artemisininresistance and the eects o interventions to contain orprevent it

7.1 laa eeacThere is currently no molecular marker or specic in vitro test to identiy artemisinin resistance, and

national malaria control programmes and others rely on therapeutic ecacy studies, which are time-

consuming and costly, to detect and conrm resistance. As screening or molecular markers could be done

more easily in more settings than in vitro testing, identication o a molecular marker is a high priority.

The availability o such a marker would dramatically improve the speed and accuracy o detection o

artemisinin resistance by allowing more ecient population-level screening. Testing or molecular markers

is logistically easible, because samples are easily obtained, transported and stored, and national malaria

control programmes, in conjunction with research institutions, could use these tests routinely in a large

population. I initial screening showed evidence o artemisinin resistance, programmes could then conduct

therapeutic ecacy studies to conrm it.

Laboratory research on the mechanism o artemisinin resistance is another priority. Although several

groups are studying this topic, why and how resistance develops and what actors cause it to spread

remain largely unknown. Understanding the molecular basis o artemisinin resistance and the associated

genotypes and phenotypes will provide insight into the mechanism and may help to predict the spread o

resistant parasites. It might also indicate whether the resistance will aect all artemisinin derivatives or is

drug-specic. Research to identiy other actors that aect artemisinin resistance, such as transmission

intensity and drug use patterns, could also help to identiy areas in which artemisinin resistance might

emerge or spread.



52

To answer these research questions, new approaches to collaboration and data-sharing are needed.

Initiatives are already under way to improve collaboration in laboratory research. For instance, the World Wide

Antimalarial Resistance Network has set up the Artemisinin Resistance Marker Platorm, a collaborativeeort to identiy genetic loci linked to delayed parasite clearance time and to validate candidate markers

o resistance emerging rom these and other studies (http://www.wwarn.org). Another example is the

Inectious Disease Initiative o the Broad Institute, which brings together genomics scientists studying

the mechanisms behind malaria, who apply this knowledge to its prevention and treatment (http://www.

broadinstitute.org/science/programs/inectious-disease-initiative/inectious-disease-initiative).

7.2 reeac a eepeResearch and development on artemisinin resistance should ocus rst on nding new, non-artemisinin-

based antimalarial medicines. New transmission-blocking antimalarial medicines and new diagnostics are

also needed.

nEW AntImAlArIAl mEdICInEs

The emergence and potential spread o resistance to artemisinins means that artemisinins, and

consequently ACTs, could be lost as an eective treatment or P. alciparum malaria. At present, no other

antimalarial medicines are available that oer the same level o ecacy and tolerability as ACTs, and there

are ew promising candidates in the pipeline. The ideal drug would be a co-ormulated combination, suitable

or mass administration and administered at a single encounter, which oers radical cure o malaria caused

by all lie-cycle stages o all ve human malaria species. Such a ‘single exposure radical cure and prophylaxis’

drug would eventually allow malaria elimination and eradication (The malERA Consultative Group on Drugs,

2011). In the absence o such a drug, investment in research and development o other, sae, eective, non-

artemisinin alternatives is critical.

Currently, ewer than 30 antimalarial drugs are under development rom the preclinical stage to phase

IV, and an additional 15 candidate drugs are in early stages o research (Figure 7). Much o the development

is coordinated by the Medicines or Malaria Venture. Only a limited number o the drugs in development

are potential alternatives to artemisinin-based therapies. Six candidates are endoperoxides or synthetic

artemisinins, including arterolane / OZ 277 (phase IIb / III) and OZ 439 (phase IIa). It is not known whether

synthetic artemisinins will be eective against artemisinin-resistant parasites. I endoperoxides prove to be

ineective, antibiotic combinations are the next most promising candidates. Clindamycin–osmidomycin is

in phase II, and another antibiotic combination, azithromycin–chloroquine, is being developed or intermittent

preventive treatment o pregnant women and not specically to address artemisinin resistance. Apart rom

endoperoxides and antibiotics, there are only two other candidates in the pipeline, and the earliest any o

them could be available is 2016. The most promising candidate in this group is NITD 609. I its saety and

tolerability are acceptable, it would be the rst non-artemisinin non-peroxide to be studied or proo-o-

concept (http://www.mmv.org).

nEW trAnsmIssIon-bloCkIng FormulAtIons

At present, primaquine is the only transmission-blocking drug available, and taenoquine is the only other

candidate in the pipeline. Primaquine causes variable haemolysis in glucose 6-phosphate dehydrogenase-

decient people and is thereore not recommended or those with severe deciency o this enzyme. Most

patients are, however, not aware o their deciency status. Thus, although WHO recommends the use

o primaquine against P. alciparum malaria, particularly in low-transmission settings and in the context o

7. Invest in research on artemisinin resistance



53


F i g u r e

7 .

C u r r e n t r e s e a r

c h a n d d e v e l o p m e n t p i p e l i n e o f a n

t i m a l a r i a l m e d i c i n e s

T D R , S p e c i a l P r o g r a m m e f o r R e s e a r c h a n d T r a i n i n g i n T r o p i c a l D i s e a s e s , W

H O .

S o u r c e : p o r t f o l i o ,

f o r t i m e t o a n d l i k e l i h o o d o f

l a u n c h ,

M e d i c i n e s f o r M a l a r i a V e n t u r e s a s o f N o v e m b e r 2 0 1 0 .



55


7.3 Appie a fie eeac

Applied and eld research is needed to determine whether the existing interventions can be used in newways to contain or prevent artemisinin resistance. As a short-term priority, the ecacy o epidemiological

or transmission-reduction tools or addressing artemisinin resistance should be evaluated, with a ocus on

mass screening and treatment, ocused screening and treatment, active case detection and mass drug

administration. Other applied research priorities are likely to emerge; or example, the use o surveillance

to reduce transmission requires additional applied research. More research is also needed to determine

whether multiple rst-line therapies could be eective in delaying resistance. In this approach, a country’s

drug policy allows the presence o several dierent antimalarial therapies in both the public and the private

sector, and patients and providers choose the therapy they wish to use. Mathematical modelling suggests

that the availability o multiple rst-line therapies might delay the emergence o resistant strains more

eectively than single-line or rotated therapies (Boni, Smith & Laxminarayan, 2008), but eld experience is

required to validate this hypothesis. The approach might be dicult to introduce in some countries, because

additional training would be required and the logistics and supply chain would be more complex. Beore this

policy can be recommended, cost-eectiveness studies would also be needed.

EPIdEmIologICAl And trAnsmIssIon-rEduCtIon tools

Mass screening and treatment, ocused screening and treatment and mass drug administration are

being considered or use in pre-elimination and elimination programmes or micro-epidemiological analysis

and transmission reduction. As discussed previously, they might also be useul or containing artemisinin

resistance. Use o these methods is controversial and requires careul consideration. Each method is

designed to reduce the parasite volume dramatically and thereby reduce the potential pool o resistant

parasites.

In mass screening and treatment, all persons within a broad geographical area are screened, regardless

o whether they have symptoms o malaria. Those or whom a test is positive are given complete malariatreatment. This is a thorough approach, but it can be resource-intensive and logistically challenging. The

approach o ocused screening and treatment is being applied in high-transmission villages in some areas

o western Cambodia within the ARCE programme. Like mass screening and treatment, this approach

involves screening all persons within a dened geographical area, but the area is smaller, so that it is less

resource-intensive and more easible logistically. As ocused screening and treatment is a more targeted

approach and is not delivered synchronously, however, it is unlikely to result in elimination o all resistant

parasites and is instead more o an epidemiological tool. Both mass and ocused screening and treatment

usually rely on PCR or screening, so there is a potential lag o 3 days or more between screening and

treatment, making it dicult to ollow and treat patients with positive results, especially or migratory,

transient or undocumented populations.

The objective o mass drug administration is to eliminate P. alciparum parasites rom an entire

population20 by treatment o all persons within a geographical area. This approach is easier than mass or

ocused screening and treatment because no screening is involved, and so patients with a positive result

do not have to be re-identied between screening and treatment. Numerous risks are, however, associated

with mass drug administration. It can be expensive, depending on the drug(s) used. As treatment is provided

indiscriminately, the incidence o adverse side-eects may increase; this is a special problem or people in

the early stages o pregnancy or who have other contra-indications. Indiscriminant use o ACTs may also

increase the opportunities or the emergence o resistance to artemisinins. As mass drug administration

20 Active case detection is another tool in pre-elimination or elimination phases, designed to reduce parasitaemia and transmissiondramatically. This is discussed in section 7.4, as it is recommended or use in pre-elimination and elimination.



56

does not involve screening, no inormation is gathered on the prevalence o inection, and national malaria

control programmes and their partners cannot target ollow-up interventions to areas with the greatest

remaining malaria burden.

In September 2010, WHO Global Malaria Programme convened a group o experts to evaluate the

available evidence or use o mass drug administration on the Cambodia–Thailand border. The experts

supported the concept o mass drug administration as a potential element o an integrated strategy to

contain and eliminate artemisinin resistance, but they identied a number o operational issues that should

be addressed beore this approach can be pursued broadly. The group thereore recommended that a

pilot study o this approach in western Cambodia and eastern Thailand be conducted in late 2011. Lessons

rom the pilot study will orm the basis o a decision on whether to recommend the use o mass drug

administration more broadly in tier I containment areas.

Limited evidence is currently available on the eectiveness or long-term eect o mass and ocused

screening and treatment and mass drug administration in reducing parasitaemia and transmission. For

example, the long-term benets o mass drug administration are heavily debated, some experts suggestingthat it probably has no long-term eect on the malaria burden, while others consider that artemisinin-

resistant parasites would be eliminated even i malaria is eliminated only temporarily: i malaria returns,

the resistant parasites may not.21 More evidence on the long-term eects o transmission-reduction tools

would aid policy-making and guide decision-makers in determining which approach is advisable. Applied and

eld research is needed to:

• evaluate the relative ecacy o each method in reducing parasitaemia and transmission in both the

short and the long term in pilot studies careully designed or learning and potential up-scaling;

• understand how baseline transmission intensity, population density, health service capacity and

other actors infuence eectiveness;

• determine which method is most eective in reducing the pool o resistant parasites in both the

short and the long term; and

• understand the longer-term implications o these interventions on the emergence and spread oresistant parasites.

When conducting such studies, researchers should also consider which drugs should be used and where,

the potential adverse eects or drug–drug interactions, how to mitigate risks to pregnant women and their

oetuses and how to treat people with conditions such as glucose 6-phosphate dehydrogenase defciency.

7.4 opeaia eeacVarious tools and programmes are already being used to contain and prevent artemisinin resistance.

Operations research should ocus on improving the eectiveness o these tools and programmes and on

developing scalable approaches, so that the most successul tools can be used in larger populations and

new locations.

sCAlAblE modEls For rEAChIng mobIlE And mIgrAnt

PoPulAtIons

The highest priority in operational research is to design scalable models or reaching mobile and

migrant populations with malaria interventions. The movement and migration o populations inected with





57


artemisinin-resistant parasites may drive the spread o resistant parasites rom existing oci to other areas.

This is a particular concern in the Greater Mekong subregion, where large mobile and migrant populations

requently move within countries and across borders. Limited operational research has been conducted todetermine how to reach these populations, and there is no guidance or programme development.

Operational research should be conducted to design and test programmes to address the many questions

associated with reaching mobile and migrant populations. For example, what models are most eective or

providing interventions or these populations? How can mobile and migrant populations be enumerated and

their social networks mapped to allow eective targeting? How can the private retail sector improve access

to hard-to-reach populations? Could the programmes be scaled up and at what cost? To what extent can

best practices in one setting be applied to another? What types o cross-border collaboration are needed

or increased coverage and a decreased malaria burden? Researchers should also study ways to increase

eectiveness, such as the ‘village malaria worker’ approach used in Cambodia. Identication o the best

methods or monitoring, training, supervising, retaining and motivating community-based providers would

help national malaria control programmes to reach mobile and migrant populations.

bEhAvIourAl And soCIAl rEsEArCh

Behavioural and social research should study the behaviour patterns that make some groups more

vulnerable to poor health outcomes. Such research might explain why use o oral artemisinin-based

monotherapies persists and how best to intervene to increase demand or ACTs and compliance with dosing

regimens. The ndings o such research could be used to improve the design o inormation, education,

communication and behavioural change interventions to address these challenges.

othEr PrIorItIEs

Operational research should also address other aspects o the containment and prevention o

artemisinin resistance, such as tracking suspected treatment ailures. A signicant increase in the

number o suspected ACT treatment ailures can indicate the presence o resistance to artemisinins

or to the partner drug. This inormation is inrequently tracked and rarely reported. Health care acilities

must record suspected treatment ailures continuously and have a system or reporting their ndings to

the national malaria control programme, or use by policy-makers. This can be dicult in many endemic

areas, as patients may not return to a health acility at which they received ineective treatment, and,

even i a patient does return to the same acility, it can be dicult to distinguish the old inection rom a

new one.22 Operational research can indicate the best approach or identiying and reporting suspected

treatment ailures.

Another area in which operational research could be helpul is active case detection. Active case detection

involves deliberate ollow-up o positive cases to fnd new cases. Thus, ater a patient is ound to have malaria,

a team screens everyone within a specifed range, or example 2 kilometers, o the patient’s residence,and all positive cases are then treated. This type o ollow-up can be difcult to do in remote areas and or

mobile and migrant populations, but it can be useul to identiy oci o transmission. Active case detection is

recommended and used today in many pre-elimination and elimination settings. Researchers should evaluate

which approaches have been most eective and compile best practices or replication elsewhere.




58

7.5 maeaica ei

As little is known about the mechanism o artemisinin resistance, it is dicult to predict how andwhen it will spread and to identiy which strategies and interventions will be most eective or containing

or preventing it. There is also no clear understanding o the impact o artemisinin resistance on malaria-

related morbidity and mortality. In such a situation, modelling can guide planning o artemisinin resistance

containment, although the results must be interpreted careully in view o the uncertainties. Several models

have been created to guide malaria policy and programmes (Maude et al., 2009; Chitnis et al., 2010).

New models could be designed to estimate the speed and extent o the spread o artemisinin

resistance under dierent conditions, including dierent transmission intensities; to compare the ecacy,

duration and cost o elimination and containment strategies, especially when eld studies are not possible;

to evaluate the ecacy and predict the eectiveness o various interventions in reducing parasitaemia

and transmission; and to identiy regional dierences that would infuence the choice o containment or

prevention interventions. Models to estimate the numbers o lives saved should be broadened to include

treatment as a variable. These models could then be used to understand how a decrease in the ecacy oACTs might aect the number o malaria-related deaths.

While models can be helpul, they have limitations. Results obtained with mathematical models should

be interpreted in the context o other evidence and broader policy considerations. Field experience should

be ed back regularly into the models, so that they can be rened to give more accurate predictions.

Although modelling is a lower priority in research on artemisinin resistance, work on artemisinin resistance-

related models should continue. Once the mechanisms o resistance are understood, modelling may

become more important.




59


8. miae aci a iie

eceSuccessul implementation o the GPARC depends on motivating many stakeholders at global, regional

and national levels to support or conduct the recommended artemisinin resistance-related activities.

Additional unding specically or artemisinin resistance will be required. Motivating individuals, organizations

and governments to support artemisinin resistance containment and prevention will require a concerted

eort by leaders in the malaria community.

8.1 saee iaiMalaria control and elimination initiatives have accelerated in recent years mainly because o the support

rom a robust malaria community. Due to the close links between artemisinin resistance management and

malaria control and the scope o the eort required, successul implementation o the GPARC depends on

motivating the malaria community to support or conduct the recommended activities. The complexity o the

response to artemisinin resistance will also require a collaborative, multisectoral approach, with actors rom

health and other sectors, including education, deense, customs and economic development.

As the coordinator o GPARC implementation, WHO Global Malaria Programme will advocate or support

o the GPARC. When requested, WHO Global Malaria Programme can help stakeholders to identiy and set

priorities or providing support. Coordinated implementation o the GPARC will be the shared responsibility

o malaria-endemic countries, WHO Global Malaria Programme and other RBM partners, including: other

multilateral organizations, unding agencies, bilateral donors and nongovernmental organizations. For

advocacy and implementation o the GPARC, stakeholders can be categorized into the various constituencies

described below, with dierent interests, expertise and modes o operation. Specic priorities or each o

the constituencies described below are summarized in chapter 9.

mr-nd unr: in particular, national malaria control programmes and ministries o

health. To be eective, they should adopt a multisectoral approach involving all relevant government

agencies and departments. Relevant groups will dier by country but could include ministries o nance,

economic development, trade and commerce, customs and import and export, transport and migration;

and the police and army. For example, military and security orces should acilitate control in sensitive

borders areas; likewise, ministries o nance should support government unding or the GPARC;

mur rgnzn: international organizations ormed rom collaboration among three or

more countries to address global economic and humanitarian issues;

Fundng gn nd r dnr: include governments or governmental agencies, private or

amily oundations and other donors, including or-prot companies and private individuals;

Rrh nd d: organizations conducting laboratory, operational and drug-related research

and development, including universities and research centres, product development partnerships and

public–private partnerships, research and development units o pharmaceutical companies and other

research-based organizations;

Nngrnn rgnzn: usually not-or-prot, including both large multinational

organizations and community-based organizations;



mnuurr nd drur r drug nd qupn: pharmaceutical and

manuacturing companies producing, marketing and distributing antimalarial drugs, diagnostics and vector

control equipment, including insecticide-treated nets.

The development and launch o the GPARC highlights the importance o artemisinin resistance

containment and prevention on the agenda o each o these groups. Signicant, continuous eort will be

required, however, to secure political commitment at the highest levels in governments and organizations,

to acilitate cross-sectoral collaboration and to make high-level commitment to artemisinin resistance

containment and prevention a day-to-day activity o each group. Eorts by WHO Global Malaria Programme

and the wider RBM partnership to motivate stakeholders will be supported by:

• a central repository or GPARC-related inormation;

• a compelling set o messages customized or each group;

• regular communication and dissemination o inormation on progress and needs;

• identication o opportunities or introducing updates and messages on the GPARC into large

meetings organized by stakeholders;• a clear plan o engagement with endemic countries, especially those in which resistance is

suspected or which are close to areas with artemisinin resistance; and

• a network o high-prole ocials to spread messages ormally and inormally.

8.2 rece iiai

EstImAtEd FundIng rEquIrEmEnts For ContAInIng

ArtEmIsInIn rEsIstAnCE

Containment o artemisinin resistance in the Greater Mekong subregion and prevention o its emergence

or spread to other regions is a priority or unding in the short term. Given the signicant overlap betweenmalaria control and artemisinin resistance containment, a ully unded and implemented malaria control

agenda would address many o the needs to manage artemisinin resistance. Maintaining and, where

possible, increasing unding or malaria overall should be a priority in implementation o the GPARC.

Additional resources will be required specically or artemisinin resistance containment and prevention.

The estimated unding requirements, by activity, are described below and shown in Table 5. As experience

in artemisinin resistance containment and prevention is limited, urther analysis will be needed in order to

veriy these estimates and to estimate the cost o implementation o programmes in each context.

tr i nd ii r: The most important unding priority or artemisinin resistance containment and

prevention is programme implementation in tier I and II areas. In the ARCE programme in Thailand and

Cambodia, containment and prevention programmes cost US$ 10–20 in tier I and US$ 8–10 in tier II areas

annually per person at risk. The exact cost o other containment programmes will vary by area, depending

on the intensity o eort required and the existing capacity and inrastructure.

tr iii r: In tier III areas, the ocus is on malaria control. Modest additional costs are anticipated

or increased monitoring o drug ecacy (when it is not done already) and enorcement o bans on

monotherapies and substandard and countereit drugs. These additional costs are estimated to be US$ 50 000

–100 000 per country per year or monitoring23 and roughly US$ 500 000 per country per drug quality

enorcement programme, depending on the sophistication o the national drug regulatory authority.

23 WHO Global Malaria Programme estimate.

8. Motivate action and mobilize resources

60



61

Global Plan or Artemisinin Resistance ContainmentGlobal Plan or Artemisinin Resistance Containment

G nd rgn rdnn: Global and regional coordination is estimated to cost US$ 8–14

million per year, with US$ 3–4 million per year or global and regional coordination o the response plan and

an additional US$ 5–10 million or coordination o monitoring and surveillance.

Rrh: On the basis o estimates by the Medicines or Malaria Venture, the cost o accelerating

research and development or non-artemisinin antimalarial medicines will be US$ 240–250 million over

5 years, or about US$ 50 million per year. The unding requirements or artemisinin resistance-specic

laboratory research, beyond what is unded today, are estimated to be US$ 10–15 million annually.24

Incremental investment to support applied or operational research is incorporated in the person-at-risk cost

estimates or tiers I and II and is thereore not included as a separate research cost.

TabLe 5. Estimated annual unding requirements or containing artemisinin resistanceby tier

cost cateGoRy activities

estimateD aNNUal

cost (Us$)

Tier I

•Treatment(includingACTs,transmission-blockingdrugs

and management o monotherapies, countereits andsubstandard drugs)

•Drugefcacymonitoringandsurveillance

•Diagnosis(RDTsandmicroscopy)

•Prevention:vectorcontrol

•Artemisininresistance-speciceducationandtraining

•Strategiesformobileandmigrantpopulations

~ 10–20 per person at

risk (depending on level

o inrastructure)

Tier II•AlltierIcosts,exceptfocusedscreeningandtreatment

and conrmatory studies~ 8–10 per person at

risk

Tier III

•MonitoringofACTefcacy*

•Additionalcoststoenforcebansonmonotherapiesand

countereit and substandard drugs

~ 50 000–100 000 **

~ 500 000 ** *

Global

•Overall

•CoordinationoftheGPARC

•Monitoringandsurveillance

~ 8–14 million

~ 3–4 million

~ 5–10 million

Research

•Overall

•Additionalnon-artemisinindrugdevelopmentcosts

•Accelerationoflaboratoryresearch(includingmolecular

markers)

~ 60–65 million

~ 50 million

~ 10–15 million

* Applies only to tier III countries that are not yet monitoring the therapeutic ecacy o ACTs in compliance with the WHO protocol; ** Assumes per country

US$ 50 0 00–100 0 00 or three studies per year or six studies in a given 24-month period (source WHO Global Malaria Programme); *** Cost varies signicantly by

country, rom approximately US $ 260 0 00 per year or an advanced national drug regulatory authority to over US $ 700 0 00 per year or the least developed national

drug regulatory authorities (source: United States Pharmacopeia Promoting the Quality o Medicines programme).

In total, ull unding o artemisinin resistance containment and prevention would be upwards o US$ 175

million per year globally, with just over US$ 100 million or programme support and about US$ 65 million or

research and development. These estimates are based on the assumption that tier I and II areas are limited

to those in and around the currently suspected oci in Cambodia, Myanmar, Thailand and Viet Nam.

When the unding requirements or managing artemisinin resistance are added to the estimates or

malaria control and elimination described in the Global Malaria Action Plan (US$ 6.9 billion in 2010, including

US$ 6.2 billion or control and elimination and US$ 0.7 billion or research), the total cost o controlling malaria

and containing artemisinin resistance is estimated to be US$ 6–7 billion annually through 2015 (Figure 8).

24 Estimate based on current unding or laboratory research.



62

Figure 8. Estimated unding required or both malaria control and artemisinin resistancecontainment

US$ (billion)

8

6

4

2

02010 2011 2012 2013 2014 2015

7.1

6.6 6.5 6.46.2

6.0

GMAP implementation GMAP research GPARC research GPARC implementation

Global Malaria Action Plan (GMAP) implementati on costs include diagnosis and treatment (ACTs, R DTs and severe case management), monitoring and evaluation,

malaria programme (including community health workers, training, inrastructure and institutional strengthening) and prevention.

FundIng gAPs For mAlArIA Control And ArtEmIsInIn

rEsIstAnCE ContAInmEnt

Much o the recent success in malaria control can be attributed to a dramatic increase in unding. In

2009, total unding or malaria was estimated to be nearly US$ 3 billion, including:

• nearly US$ 1.6 billion disbursed by the GFATM, the President’s Malaria Initiative, the World

Bank and Organization or Economic Co-operation and Development countries or malaria

control programmes, as stated in the 2010 RBM Malaria Funding and Resource Utilization report

(Johansson, Cibulskis & Steketee, 2010);

• an estimated US$ 923 million spent by endemic countries, households and other sources (RBM,

2008; WHO, 2008);

• US$ 542 million or malaria research and development contributed by the United States National

Institutes o Health, the Bill & Melinda Gates Foundation and other research and development

donors; and

• approximately US$ 40 million to manage artemisinin resistance (Johansson, Cibulskis & Steketee,

2010).

Despite the increase in unding, more than US$ 4 billion is still needed to ully control malaria and

contain artemisinin resistance, based on the cost estimates in the Global Malaria Action Plan (Figure 9).




63


Figure 9. Gap in unding or malaria control and artemisinin resistance containmentand prevention

US$ (billion)

8

6

4

2

0

3.0

4.1 7.1

Current funding Gap Required funding

Malaria control:implementation

Artemisinin resistancecontainment

Malaria control:research

Sources or existing malaria unding or implementation: GFATM (actual disbursements through round 8), the President’s Malaria Initiati ve (actual disbursements),

the World Bank (disbursements assumed to be equal to those in 2 008, rom project appraisal documents or, i not available, by assuming a constant fow o unds

throughout the lie o a project), the United States Agency or International Development (rom malaria budget: http://www.usaid.gov/policy/budget/cbj2007/si/

malaria.html), national spending and other international donors (rom World malaria report 2008, Annex 7) and private household spending (rom Global Malaria

Action Plan , appendix on unding estimates). Sources o existing unding or research and development: United States Agency or International Development

(http://www.usaid.gov/our_work/global_health/ home/Funding/unding_rd.html), Bill & Melinda Gates Foundation and pharmaceutical companies (G-Finder

reports 200 8 and 2009, assuming that research and development spending was constant in 2009 and will continue at that level) , National Institutes o Health and

other research and development sources (historical) through 2006 rom malaria strategy work , above; or 2007 onwards, r om G-Finder assuming that it is constant

since 2008) . The Boston Consulting Group analysis.

Insucient unding or malaria control and artemisinin resistance containment could have severe

consequences in tier I and II areas, including more rapid spread o resistance. Inadequate unding in tier III

areas would mean that those areas would not be suciently protected i artemisinin resistance emerged or

spread, nor are they likely to have resources in place to identiy decreased drug ecacy promptly. Fundingartemisinin resistance containment in the Greater Mekong subregion today is an investment to prevent

artemisinin resistance rom reaching high-transmission areas, including much o Arica. I artemisinin

resistance were to emerge in another region, the cost o managing it would increase dramatically, particularly

i the aected region had higher transmission. Closing the malaria unding gap, even incrementally, will not

only improve malaria outcomes overall but will increase the likelihood that artemisinin resistance can be

contained eectively.

InCrEAsIng And sustAInIng FundIng

Like all aspects o the GPARC, increasing and sustaining sucient unding or malaria control and

artemisinin resistance containment will require commitment rom stakeholders at global, regional and

country levels. At the global level, multilateral organizations, unding agencies and bilateral donors should

increase and accelerate unding or malaria control in all endemic countries. In addition, they should und

activities or artemisinin resistance containment and prevention, especially in tier I and II areas. Coordination

is important in order to match unders to relevant projects and ensure that resources are allocated as

eectively as possible. Tracking unding and implementation globally and within programmes and grants

should be a priority or unders as a means o ollowing progress, increasing the eectiveness o their unding

and guiding uture investments. Table 6 gives additional details o priorities or global engagement.



64

TabLe 6. Global priorities in unding malaria activities

aRea stakeHolDeR activities

Increase undingFunding agencies, bilateraldonors and endemiccountries

Increase and accelerate unding or malaria control or all tierareas.

Fund specic projects and programmes or containing andpreventing artemisinin resistance, especially in tier I and tierII areas.

Coordinate unding

WHO, Bill & MelindaGates Foundation,

GFATM, United StatesAgency or InternationalDevelopment andPresident’s MalariaInitiative, others unders

Predict the resources needed or global and countryactivities, and update as required.

Identiy existing donors or malaria control and new donors

interested in unding containment o artemisinin resistance;prepare specic approaches or each donor.

Help to match donors to projects or areas.

Work with endemic countries in planning resource use,including increasing domestic unding or malaria control.

Track progress inuse o unds

WHO, Bill & MelindaGates Foundation, othersunders (with individualmonitoring o each grant)

Track use o unds, monitor progress and provideaccountability.

Coordinate regional and country activities, and share bestpractices.

Make a contingency plan, with coordination o emergencyunds, in case o rapid spread o artemisinin resistance.

At country level, the ministries o health and nance should work together to ensure adequate unding

or malaria control in general and artemisinin resistance containment or prevention specically. Beore they

identiy and allocate unds, the ministries should rst evaluate the requirements or implementation o the

GPARC in their country. The resource requirements will vary signicantly among countries and even areas

within a given country, depending on the tier classication. In subsequent resource planning, new unding

or artemisinin resistance containment and prevention should be sought when possible. All potential

unding sources should be explored, including domestic organizations, international sources like the GFATM

and other unding agencies or bilateral agreements. Nongovernmental and community-based organizations

should continue to advocate or unding to secure grants or specic containment-related projects, in order

to supplement resources mobilized by the government.

The rapid increase in resources or malaria in the past decade may be entering a much slower growth

period due, in large part, to the global nancial crisis. Signicant progress towards closing the malaria

unding gap may be dicult. Fortunately, even partial unding can be valuable, especially i it is used or the

highest priority activities. In view o the resource constraints, the rst priority or unding agencies should

be containment programmes in areas or which there is evidence o artemisinin resistance. A second

priority should be monitoring and surveillance o drug ecacy in endemic countries, especially in those

in which studies have not been conducted in recent years. In order to maximize the impact o availableresources, unding agencies and other stakeholders should harmonize their investments.




65


9. saee’ piiieThe GPARC was developed with input rom all o the constituencies o the RBM Partnership and is

designed to serve as a rallying cry or all members o these groups. Given the complexity o the required

response to artemisinin resistance, stakeholders outside the traditional malaria or public health communities

will also need to be engaged. In this section, the priorities or each stakeholder or constituency in supporting

successul implementation o the GPARC are summarized.

As most o the current malaria control and elimination activities, outlined in the Global Malaria Action Plan,

will also benet the containment and prevention o artemisinin resistance, stakeholders are encouraged to

continue, expand or accelerate the activities they currently conduct or support. The purpose o this section

is to help stakeholders identiy additional areas in which they can contribute specically to the urgent issue

o artemisinin resistance containment and prevention. Items o high priority or action are highlighted or

each constituency. The expectation is that each stakeholder will use these recommendations as a basis or

designing a specic programme or containment or prevention o artemisinin resistance that is consistentwith its mandate.

It is anticipated that stakeholders will work closely together, each ocusing on activities within its

unctional area o expertise, to address cross-cutting issues in artemisinin resistance. For example, ensuring

timely monitoring o therapeutic ecacy will involve resource mobilization, technical guidance rom

WHO Global Malaria Programme and other partners, studies in the eld, the reporting o results and,

potentially, changes in national policies. In order to determine the priority actions, each stakeholder’s ability

to contribute in eight unctional areas was analyzed: global policy and norms, surveillance and reporting,

containment and implementation, resource mobilization, advocacy and political engagement, research,

local policy and regulation, and emergency response.

Table 7 summarizes the areas in which each constituency can act. As malaria-endemic countries will

implement the GPARC, they are involved in all unctions. In view o WHO’s mandate to represent andsupport countries, the areas o involvement o WHO Global Malaria Programme largely mirror those o

the countries, with a ocus on policy guidance, global surveillance and technical expertise. WHO Global

Malaria Programme will continue to monitor and coordinate implementation o the GPARC and, to do so,

has created a new unit dedicated to antimalarial drug resistance, the Drug Resistance and Containment

unit. WHO Global Malaria Programme will also rely on WHO regional and country oces in coordinating

assessment o the level o threat o artemisinin resistance in a given area, prepare a detailed, easible

response, build capacity or monitoring and mobilize the necessary stakeholders and resources.

Successul implementation o the GPARC depends on the support and cooperation o many other

groups. For example, research and academic institutions should conduct research on artemisinin resistance

and support monitoring and surveillance in collaboration with national malaria control programmes; they

may play a secondary role in resource mobilization and advocacy. The main role o unding agencies,

including the GFATM and bilateral donors, is resource mobilization, advocacy and political engagement, and

their unding should support activities in all unctions. Nongovernmental organizations should support the

implementation o containment and prevention programmes and will also support resource mobilization and

advocacy. The private sector has a variety o roles to play, including supporting containment programmes,

advocacy and research. The specic priorities by constituency are listed below.



66

TabLe 7. Primary and secondary areas o involvement by stakeholder segment

Global

policy and

norms

Surveillance

and

reporting

Containment

and

implementation

Resource

mobilization

Endemic countries(tier I, II and III)


WHO Global Malaria Programme


WHO regional and country offices


all other

Research and

academia

Nongovernmentalorganizations

Private sector

Funding agenciesand bilateral

donors

Primary Secondary

*

Emergency

response

Advocacy and

political

engagement

ResearchLocal policy

and

regulation

mAlArIA-EndEmIC CountrIEs

• Conduct routine studies o therapeutic ecacy to identiy or monitor artemisinin resistance and

classiy areas o the country by risk level.

• Prepare a context-specic containment or prevention plan, consistent with the recommendations

o the GPARC.

• Secure unding or malaria control and artemisinin resistance containment or prevention; make

sure that grant applications or operational plans or international unding include containment or

prevention activities, and secure domestic unding where possible.

• Design and enorce policies and regulations on the manuacture, distribution (import and export)

and use o oral artemisinin-based monotherapies and substandard and countereit treatments.

• Participate actively in subregional monitoring networks and in cross-border collaboration to ensure

that malaria interventions reach populations in border areas.

Who globAl mAlArIA ProgrAmmE

• Provide leadership, oversight and coordination o the GPARC, including increasing awareness

about the urgency o the threat o artemisinin resistance, supporting resource mobilization and

communicating regularly with implementing partners.

• Prepare, communicate and promote adoption o norms, standards and policy guidelines on

artemisinin resistance, with advice rom the technical expert group.

9. Stakeholders’ priorities

* Research part conducted by Special Programme or Research and Training in Tropical Diseases, WHO.



68

• Accelerate eorts to attain universal access to prevention, diagnosis and treatment o all conrmed

malaria cases in tier I and II areas, and continue malaria control activities in tier III areas.

• Provide technical assistance and support to national malaria control programmes and ministries ohealth to conduct therapeutic ecacy studies and surveillance.

• Conduct training and education or prevention, diagnosis and treatment, or health care providers,

retailers (inormal private sector) and patients.

• Advocate or sustained malaria control and resource mobilization.

PrIvAtE sECtor

cpn h nuur r r qu-urd act

• Continue to produce, distribute and advocate or quality-assured ACTs, in accordance with current

WHO Guidelines or the treatment o malaria and the Essential Medicines Lists o endemic

countries; provide adapted inormation and educational materials on the rational use o each ACT to

national drug regulatory authorities, national malaria control programmes and other stakeholders.

• Increase eorts to ensure that ACTs reach high-priority areas and to avoid shortages o quality-

assured ACTs.

• For antimalarial medicines that exist as xed-dose combinations, phase out co-blistered or loose

associations in avour o xed-dose combinations as soon as possible.

• Promptly share new data rom monitoring and surveillance o artemisinin resistance.

cpn h nuur r r nhrp r undrdrnn-d drug

• Halt production and distribution o oral artemisinin-based monotherapies and substandard

antimalarial drugs.

• Set up operations that abide by national regulations or WHO guidelines on monotherapies and

substandard drugs and adhere to the policy that is most stringent.• Make the production o xed-dose combinations a priority.

cpn h nuur r r dgn r r nr

• Increase capacity to produce and distribute vector control supplies and high-quality diagnostics in

tier I and II areas.

• Provide additional training and support to containment programmes in tier I areas.

• Consider regional marketing approaches to help patients recognize and properly use recommended

malaria interventions.

FundIng AgEnCIEs And bIlAtErAl donors

• Fund programmes or containing and preventing artemisinin resistance in tier I and II areas.• Increase unding or malaria control to accelerate universal coverage (especially in tier I and II areas)

and support monitoring and surveillance o drug ecacy in endemic countries.

• Support research priorities and capacity development or research, including the development o

non-artemisinin-based drugs, laboratory science and operational research.

• Design mechanisms or rapid mobilization o resources when resistance is identied or an

emergency response plan is triggered.

• Act as an advocate on key issues, such as putting pressure on countries with producers o

monotherapies and countereit antimalarial medicines to enorce WHO medicines.

9. Stakeholders’ priorities



69


10. Eeec iiai paAs described in the introduction, the GPARC is based on current inormation about where artemisinin

resistance exists and on assumptions about the speed o its potential spread. The severity o the situation

today necessitates an immediate, intense, well-coordinated response. Should artemisinin resistance spread

more rapidly than originally anticipated, an escalated response will be needed. The emergency mobilization

plan is not a separate plan but builds on GPARC recommendations or preventing and containing artemisinin

resistance. The goal o the emergency mobilization plan is to prevent artemisinin resistance rom spreading

to a high-transmission area or, i resistance appears in a high-transmission setting, to contain it as quickly

as possible.

tWo sCEnArIos thAt trIggEr An EmErgEnCy rEsPonsE

Two potential scenarios in which artemisinin resistance appears to have spread beyond the Greater

Mekong subregion should trigger emergency mobilization to varying degrees (Figure 10). In scenario A,

artemisinin resistance is no longer contained in a ocal geographical area. Its presence outside o the Greater

Mekong subregion (e.g. in another country in Asia) would suggest not only an immediate threat to the area

in which it appears but also an increasing likelihood that resistance will spread to high-transmission areas.

In scenario B, artemisinin resistance has emerged in or spread to a high-transmission area (e.g. in Arica).

In either scenario, artemisinin resistance should be conrmed, in accordance with WHO recommendations,

beore a ull-scale emergency response is launched. In view o the urgency o the threat, however, i there

is credible evidence or either scenario, containment eorts should be planned and implemented in parallel

with conrmatory studies. The technical expert group on antimalarial drug resistance, to be convened

by WHO Global Malaria Programme, will dene trigger points or each scenario. As needed, the group

will evaluate the evidence and determine when those trigger points have been reached and emergency

mobilization is required.

Figure 10. Two potential scenarios that will trigger emergency mobilization

Situation today Scenario A Scenario B


contained in Greater

Mekong subregion


spreads beyond

Greater Mekong

subregion


emerges in or spreads

to high-transmission

tier III area

Severity of impact

on malaria-related

deaths

Current situation requires

an immediate, intense and

well coordinated response

Unanticipated, rapid spread

of resistance requires an

escalated response



70

thrEE ElEmEnts oF thE EmErgEnCy mobIlIzAtIon PlAn

I either scenario occurs, three actions should be launched immediately and simultaneously:

• global advocacy to escalate artemisinin resistance to the top o global health and developmentagendas and motivate the global community to coordinated action;

• intensive, coordinated containment activities in areas with newly conrmed artemisinin resistance

(in accordance with tier I recommendations in the GPARC) and rapid scaling-up o precautionary

measures in all neighbouring areas (in accordance with tier II recommendations); and

• a signicant increase in unding and, i necessary, potential reallocation o unding rom existing tier I

areas to new tier I areas in order to ocus the response on the resistance ‘rontier’.

The intensity o the emergency response will depend on the scenario and the severity o the threat o

spread o resistance.

G d

The emergence o artemisinin resistance in the Greater Mekong subregion is o serious concern, but its

rapid spread o beyond this subregion would make it an even greater global threat. To refect the heightened

urgency o such a situation, global advocacy would be required to mobilize a large-scale, coordinated

containment response and to escalate the issue to the top o global health and development agendas.

WHO would initiate advocacy, and other multilateral organizations, donors and other stakeholders could

continue and expand it.

Advocacy should ocus on the ollowing objectives:

• Ensure that artemisinin resistance containment becomes an immediate, urgent priority.

• Spur immediate action by all relevant stakeholders, especially national malaria control programmes

and their partners responsible or on-the-ground containment.

• Mobilize resources or broad containment eorts, including rapid identication o donors and rapid

disbursement o unds.

For the response to be successul, the most senior leaders in global health should turn political leaders

into advocates to mobilize unds. Advocacy should also include a communication campaign to reach

decision-makers, donors and the populations o aected areas.

inn, rdnd nnn

I artemisinin resistance is conrmed outside the Greater Mekong subregion or in a high-transmission

setting, the area in which resistance has been conrmed should immediately be reclassied as tier

I. The new tier I area will become the ‘rontier’ o resistance and the highest priority or aggressive

containment. All recommended tier I activities, as described in chapter 3, should be implemented

immediately (Figure 11).

10. Emergency mobilization plan



72

Figure 12. Reallocation o unding to the ‘rontier’ o resistance

The amount o unding required will depend in large part on the magnitude o the required containment

eort, which in turn depends on the number o areas now considered tier I and II, the size o the population

at risk in each area and the complexity o implementation in these areas.

stEPs to EnsurE thAt thE globAl CommunIty Is

PrEPArEd

To ensure that the global community is prepared or emergency mobilization, several preliminary steps

should be taken.

• The technical expert group on antimalarial drug resistance, to be convened by WHO Global Malaria

Programme, should determine the triggers or emergency mobilization, i.e. the extent o spread o

artemisinin resistance that warrants an emergency response. The group should also be prepared

to review and assess evidence o new oci o artemisinin resistance to determine i and when the

trigger point has been reached.

• The roles and responsibilities o each stakeholder in emergency mobilization should be clearly

delineated, and each stakeholder should be aware and engaged.

• Potential unding and administrative resources should be identied, and donors should commit

unding or emergency mobilization in advance.

10. Emergency mobilization plan



73


refeeceAnsah EK et al. (2010). Rapid testing or malaria in settings where microscopy is available and peripheral

clinics where only presumptive treatment is available: a randomized controlled trial in Ghana. British

Medical Journal, 340:c930.

Boni MF, Smith DL, Laxminarayan R (2008). Benets o using multiple rst-line therapies against malaria.

Proceedings o the National Academy o Sciences o the United States o America , 105:14216–14221.

Chitnis N et al. (2010). Mathematical modelling to support malaria control and elimination. Geneva, World

Health Organization on behal o the Roll Back Malaria Partnership Secretary (Roll Back Malaria Progress& Impact Series, No. 5).

d’Acremont V, Lengeler C, Genton B (2010). Reduction in the proportion o evers associated with

Plasmodium alciparum parasitaemia in Arica: a systematic review. Malaria Journal , 9:240.

Dondorp AM et al. (2010). Artemisinin resistance: current status and scenarios or containment. Nature

Reviews in Microbiology , 8:272–280.

Eisele T et al. (2010). Saving lives with malaria control: counting down to the Millennium Development

Goals . Geneva, World Health Organization on behal o the Roll Back Malaria Partnership Secretary (Roll

Back Malaria Progress & Impact Series, No. 3).

Hamer DH et al. (2007). Improved diagnostic testing and malaria treatment practices in Zambia. Journal o

the American Medical Association, 297:2227–2231.

Johansson EW, Cibulskis RE, Steketee RW (2010). Malaria unding and resource utilization: the frst decade

o Roll Back Malaria. Geneva, World Health Organization on behal o the Roll Back Malaria Partnership

Secretary (Roll Back Malaria Progress & Impact Series, No. 1).

Maude RJ et al. (2009). The last man standing is the most resistant: eliminating artemisinin-resistant malaria

in Cambodia. Malaria Journal , 8:31.

Newton PN et al. (2008). A collaborative epidemiological investigation into the criminal ake artesunate

trade in South East Asia. PLoS Medicine, 5:e32.

Phanouvong S, Blum N (2004). Mekong malaria initiative antimalarial drug quality monitoring and evaluation.

Rockville, MD, The United States Pharmacopeial Convention.

RBM (2008). The Global Malaria Action Plan. Geneva, Roll Back Malaria Partnership.

Renshaw M et al. (2009). Tracking progress in scaling-up diagnosis and treatment or malaria. A compilation

o data on Arican malaria endemic countries’ estimates o their commodity needs and unding available.

Geneva, Roll Back Malaria and Medicines or Malaria Venture.

Reyburn H et al. (2007). Rapid diagnostic tests compared with malaria microscopy or guiding outpatient

treatment o ebrile illness in Tanzania: randomised trial. British Medical Journal, 334:403.

The malERA Consultative Group on Drugs (2011). A research agenda or malaria eradication: Drugs. PLoSMed 8(1): e1000402, in press.

Trape JF (2001). The public health impact o chloroquine resistance in Arica. American Journal o Tropical

Medicine and Hygiene , 64 (Suppl 1–2):12–17.

Trung HD et al. (2005). Behavioural heterogeneity o Anopheles species in ecologically dierent localities inSoutheast Asia: a challenge or vector control. Tropical Medicine and International Health, 10:251–262.



74

United States Pharmacopeia Drug Quality and Inormation Program (2010). Survey o the quality o selected

antimalarial medicines circulating in Madagascar, Senegal, and Uganda: November 2009. Rockville, MD,

The United States Pharmacopeial Convention.

Vestergaard LS, Ringwald P (2007). Responding to the challenge o antimalarial drug resistance by routinemonitoring to update national malaria treatment policies. American Journal o Tropical Medicine and

Hygiene , 77(Suppl 6):153–159.

WHO (1967). Chemotherapy o malaria. Report o a WHO Scientifc Group . Geneva, World Health

Organization (WHO Technical Report Series, No. 375).

WHO (2002). Instructions or treatment and use o insecticide-treated mosquito nets . Geneva, World Health

Organization.

WHO (2006). Indoor residual spraying. Use o indoor residual spraying or scaling up global malaria control

and elimination. Geneva, World Health Organization.

WHO (2008). World malaria report 2008 . Geneva, World Health Organization.

WHO (2009). Methods or surveillance o antimalarial drug efcacy . Geneva, World Health Organization.

WHO (2010a). Guidelines or the treatment o malaria . 2nd Ed. Geneva, World Health Organization.

WHO (2010b). World malaria report 2010. Geneva, World Health Organization.

WHO (2010c). Global report on antimalarial drug efcacy and drug resistance, 2000–2010 . Geneva, World

Health Organization.

WHO (2010d). Malaria rapid diagnostic test perormance. Results o WHO product testing o malaria RDTs:

round 2. Geneva, World Health Organization.

WHO (2010e). Good procurement practices or artemisinin-based antimalarial medicines. Geneva, WorldHealth Organization.

Reerences



75


Aex 1. Cae f caie

f aeiii eiace iCaia

Given the ongoing initiatives in western Cambodia to manage artemisinin resistance, this country

provides a good example o how many o the solutions described in the GPARC might be implemented

in the eld. Several experiences are described below; additional documentation, especially on the ARCE

programme, can be ound in the Global report on antimalarial drug efcacy and drug resistance, 2000–2010

(chapter 4), and a detailed summary o the activities is available on the WHO website at: http://www.who.

int/malaria/diagnosis_treatment/arcp/en/index.html.

vECtor ControlArtemisinin resistance containment in Cambodia, at the border with Thailand, includes widescale

distribution o vector control tools in two containment zones.25 Vector control in these zones includes

procurement and distribution o long-lasting insecticide nets and long-lasting insecticide hammock nets

and rapid monitoring to assess and monitor bed net distribution and coverage. High coverage has been

achieved in both zones: 92% o target villages received nets; a coverage rate o 1.79 people per net was

achieved; 96% o the long-lasting insecticide nets delivered were observed in houses during assessment;

and 70% o the long-lasting insecticide nets delivered were currently in use, 99.7% o which had been

used the previous night. While it is dicult to attribute progress to a single intervention, the high level o

vector control appears to have contributed to the initial success o the project in sustaining a low number

o malaria cases in zone 1.

ProvIdIng subsIdIzEd ACts to thE PrIvAtE sECtor

In 2002, Cambodia was the rst country to test and scale-up a programme to provide subsidized ACTs

to the private sector (D. Socheat, personal communication). The project was implemented by Population

Services International, with nancial support rom the GFATM. To promote the sale o subsidized products,

Population Services International sent teams to local shops to disseminate inormation materials. They

also undertook nationwide inormation campaigns with various communication modes and trained private

sector providers in proper case management.

Monitoring and evaluation o the project indicated encouraging results. Penetration with rst-line ACTs

increased rom 22% o sampled public sector outlets in 2004 to 40% in 2007; in 2008, the penetration

rate was 64% (http://www.actwatch.ino). The project also met various challenges. First-line ACTs were

sold at much higher prices than the recommended retail price printed on the box (US$ 1.07 on averageversus US$ 0.5 on the box). Moreover, despite the act that a large proportion o shops now stocked ACTs,

actual sales o rst-line ACTs remained low (28% o sales in 2009, versus 22% or other ACTs, 24% or oral

artemisinin-based monotherapies and 26% or non-artemisinin-based monotherapies). To address these

issues, the Cambodian malaria control programme applied or the rst phase o the Aordable Medicines

25 Zone 1 covers areas in which artemisinin resistance has been detected. In Cambodia, it covers about 270 000 people in ourprovinces: all o Pailin and parts o Battambang, Pursat and Kampot. Zone 2 covers areas in which there is no evidence o resistancebut the risk is high because they are close to zone 1. It includes nine provinces with a total population o more than 4 million

(excluding towns).



77


control programme, which also gives them about US$ 5 per month in compensation. The workers perorm

RDTs on any villager suspected o having malaria and, or positive cases, provide ACTs according to the

national guidelines. They are able to provide services or ree when needed and regularly reer severe casesto health posts.

The project has shown that village malaria workers could be an eective means o improving access

to early diagnosis and treatment o malaria. The project is also helping to move malaria treatment rom

the private to the public sector, where only recommended drugs are dispensed. Furthermore, the local

availability o quality-assured malaria treatment has signicantly reduced the use o countereit medicines.

Given the success o the programme, village malaria workers should be considered as a potential source o

additional services, including active case detection, ollow-up or mapping.

rEFErEnCEs

Moszynski P (2010). Cambodia cracks down on illegal drug vendors in bid to control antimalarial resistance.

British Medical Journal, 340:c2622.

Schwarte S et al. (2010). Regulatory action needed to stop the sale o oral artemisinin-based monotherapy.WHO Drug Inormation, 24:98–104.

Sochantha T et al. (2006). Insecticide-treated bednets or the prevention o Plasmodium alciparum malaria

in Cambodia: a cluster-randomized trial. Tropical Medicine and International Health, 11:1166–1177.

Yasuoka J et al. (2010). Assessing the quality o service o village malaria workers to strengthen community-based malaria control in Cambodia. Malaria Journal, 9:109.




79

Aex 2. seia ii

f eapeic efficac faiaaia eicie

Many o the subregional monitoring networks that once existed to complement country monitoring

are now underunded or no longer active. Beore the introduction o ACTs, seven subregional networks

monitored antimalarial ecacy (Figure A2.1). When such networks are sustainably unded and eectively

managed, they can have several important benets, including:

• encouraging and providing incentives or countries to conduct regular monitoring o drug ecacy,

including sharing o best practices in conducting therapeutic ecacy studies;

• sta training including protocols, implementation and reporting;

• more eective management o problems in border areas, by sharing data and setting up sentinel

sites on both sides o a common border;

• identication o subregional trends in resistance; and

• coordination o a subregional response when required.

Figure a2.1. Seven subregional networks established around 2001 or monitoring theecacy o antimalarial medicines beore the introduction o ACTs

Underfunded networks

Funded networds

WANMAT 1WANMAT 2

RACTAPEANMAT

HANMAT

Mekong

RAVREDA

EANMAT, East Arican Network or Monitoring Anti malarial Treatment; HANMAT, Horn o Arica Network or Monitoring Antimalarial Treatment; RACTAP, Réseau

d’Arique Centrale des Thérapeutiques Antipaludiques; RAVREDA , Red Amazónica para la V igilancia de la Resistencia a las Drogas Antimaláricas; WAN MAT, WestArican Network or Monitoring Antimalarial Treatment.




80

In 2010, only three monitoring networks remained ully operational: the Red Amazónica para la

Vigilancia de la Resistencia a las Drogas Antimaláricas, the Horn o Arica Network or Monitoring

Antimalarial Treatment and the Mekong network. Each network maintains a sentinel surveillance network inits geographical area o action, provides training to support control programmes and promotes cooperation

among member countries.

Annex 2. Subregional monitoring o therapeutic efcacy o antimalarial medicines



Annex 3. Cuen ue of diagnoiceing fo malaia

Although the availability and use o parasitological diagnosis are increasing, there are clear opportunities

or improvement (Figure A3.1). Global distribution o RDTs has increased signicantly, rom virtually 0 in

2004 to approximately 30 million tests annually in 2009. As expected, use o parasitological diagnosis also

increased during this period, and, as o 2009, approximately 35% o suspected malaria cases in endemic

countries o the WHO Arican Region were tested by microscopy or an RDT. Despite the strong increase in

the percentage o cases tested since 2004, most cases o suspected malaria in these endemic countries

are still treated presumptively.

Figure a3.1. Availability and use o parasitological diagnosis

Distribution of RDTs has increased

significantly in recent years

Although use of diagnostic testing has increased, most cases

in countries of the WHO African Region are still not tested

Global Distribution Use in countries of the WHO African Region

Millions of RDTs distributed per year

% of suspected malaria cases tested with microscopy or

an RDT

30

20

10

0

2004 2005 2006 2007 2008 2009 2004 2005 2006 2007 2008 2009

100

50

0

Various challenges continue to prevent more widespread adoption o diagnostics:26

• The WHO recommendation or universal diagnostic testing o suspected malaria cases, regardless

o age, was made only in early 2010.

• Distribution o RDTs tends to be poorer than distribution o ACTs, resulting in stock-outs and poor

access (Renshaw et al., 2009 ).

• The quality and perormance (sensitivity, specicity, heat stability and longevity) o RDTs varies

signicantly by manuacturer and by lots produced by a single manuacturer (WHO, 2010).

• Some providers and patients still believe that most evers are due to malaria.• Some providers and patients are unaware o the harm o treating cases without malaria with ACTs.

In some regions, patients with negative results rom a diagnostic test still receive and take antimalarial

medicines. For example, in Zambia in 2007, 58.4% o patients with a negative microscopy result and 35.5%

o patients with a negative RDT result received an antimalarial medicines (Hamer et al., 2007). In the United

Republic o Tanzania in the same year, 51% o patients with a negative microscopy result and 54% with a

negative RDT result received an antimalarial medicine (Reyburn et al., 2007). In Kenya in 2010, 60% o RDT-

negative patients purchased an ACT (J. Cohen, unpublished data).


81


Source: WHO Global Malaria Programme, 2010.



82

Non-compliance with the results o a diagnostic test may be due to a number o actors, including:

• the time required or a doctor to diagnose and treat non-malarial causes o ever;

• lack o aith in a negative diagnosis; where microscopy has been o poor quality or years, providersand patients have grown accustomed to ignoring diagnostic test results (Ansah et al., 2010); and

• lack o alternative diagnosis and treatment options or non–malarial ebrile illnesses.

rEFErEnCEs

Ansah EK et al. (2010). Rapid testing or malaria in settings where microscopy is available and peripheral

clinics where only presumptive treatment is available: a randomized controlled trial in Ghana. British

Medical Journal , 340:c930.

Hamer DH et al. (2007). Improved diagnostic testing and malaria treatment practices in Zambia. Journal o

the American Medical Association, 297:2227–2231.

Renshaw M et al. (2009). Tracking progress in scaling-up diagnosis and treatment or malaria. A compilationo data on Arican malaria endemic countries’ estimates o their commodity needs and unding. Geneva,

Roll Back Malaria and Medicines or Malaria Venture.

Reyburn H et al. (2007). Rapid diagnostic tests compared with malaria microscopy or guiding outpatienttreatment o ebrile illness in Tanzania: randomised trial. British Medical Journal , 334:403.

WHO (2010). Malaria rapid diagnostic test perormance. Results o WHO product testing o malaria RDTs:

round 2. Geneva, World Health Organization.

Annex 3. Current use o diagnostic testing or malaria




85

Annex 5. removal of oal aemiinin-

baed monoheapie

hAltIng ACCEss to orAl ArtEmIsInIn-bAsEd

monothErAPIEs

Since 2006, WHO has made many eorts to halt the manuacture and marketing o oral artemisinin-based

monotherapies globally and locally (Table A5.1). All national malaria control programmes have removed these

monotherapies rom the public sector. More eorts are needed to completely phase out these medicines

rom the private sector in many endemic countries (R. Newman, personal communication).

In May 2010, at the Eighteenth RBM Board meeting, representatives o 40 ministries o health committed

themselves to:27

“Express our governments’ engagement to eliminate (ban and enorce) oral artemisinin-based malaria

monotherapies and substandard ACTs rom the market through tangible policies, strategies and

regulatory measures within the next 12 months”.

The ministerial commitment was signed by representatives rom Algeria, Angola, Benin, Botswana,

Burundi, Brazil, Cameroon, Cape Verde, Chad, the Comoros, the Congo, Côte d’Ivoire, Djibouti, the

Democratic Republic o the Congo, Eritrea, Gabon, the Gambia, Ghana, Guinea, India, Kenya, Liberia,

Madagascar, Malawi, Mali, Mozambique, Namibia, the Niger, Rwanda, Sao Tome and Principe, Senegal,

Sierra Leone, South Arica, the Sudan, Swaziland, Togo, Uganda, the United Republic o Tanzania, Zambia

and Zimbabwe.

ArEAs oF thE World WIth ProduCErs oF orAl

ArtEmIsInIn-bAsEd monothErAPIEs

Since 2005, WHO has worked proactively with pharmaceutical companies to halt the production o

oral artemisinin-based monotherapies. Initially, 76 companies were known to produce and market these

products. Ater intensive eorts, this number has been decreased to 43 (http://www.who.int/malaria/

marketing_o_oral_artemisinin_monotherapies/en/index.html). The map in Figure A5.1 shows the areas o

the world in which these 43 known manuacturers are located.

27 RBM/BOM/2010/SUB.



86

TabLe a5.1. WHO and RBM actions to remove oral artemisinin-based monotherapies

Date actioN

January 2006Press release calling or an immediate halt to provision o oral artemisinin-basedmonotherapies

January–April 2006Web-based monitoring system regularly updated inormation on marketing practices andpositions o national drug regulatory agencies

April 2006

Technical brieng on malaria guidelines and artemisinin-based monotherapies;meeting with pharmaceutical companies to discuss potential risks associated withthe development o artemisinin resistance and to obtain commitments and a realisticimplementation plan

April 2006–May 2007Alignment o unding and procurement: joint work with unding agencies, multilateralorganizations, bilateral donors and international suppliers to discontinue unding o oralartemisinin-based monotherapies and to procure only WHO-recommended medicines

May 2007World Health Assembly resolution 60.18 urges Member States to cease the marketingand use o oral artemisinin-based monotherapies in both the public and the private

sectors and to promote the use o ACTs

August 2007Inormal consultation with manuacturers o artemisinin-based antimalarial medicines toreview progress and challenges in reducing reliance on monotherapies, to discuss theexpected impact o new ACT unding initiatives and to agree on mechanisms o action

December 2009WHO Global Malaria Programme submits a strategy to set out how the RBMPartnership can mitigate the risk o emerging drug resistance, including that due to useo oral artemisinin-based monotherapies

May 2010RBM ministerial meeting at which ministers rom malaria-endemic countries signed acommitment to eliminate oral artemisinin-based monotherapies rom their markets

Figure a5.1. Areas o the world in which oral artemisinin-based monotherapies are known to be produced

The Netherlands

1 company

Viet Nam

2 companies

Switzerland

1 company

The Democratic

Republic of

the Congo

1 company

Ghana

2 companies

Nigeria

5 companies

Kenya

2 companies

The United

Arab Emirates

1 company

Pakistan

1 company

India

24 companies

China

2 companies

Bangladesh

1 company

Annex 5. Removal o oral artemisinin-based monotherapies




mAlArIA-EndEmIC CountrIEs thAt stIll AlloW

mArkEtIng And usE oF monothErAPIEs

Despite eorts by WHO, RBM and other stakeholders, as o December 2010, the national drug

regulatory authorities o 28 malaria-endemic countries still allowed marketing o oral artemisinin-based

monotherapies or use in the private sector (Figure A5.2). Many o these countries are in regions o high

malaria transmission, where artemisinin resistance could spread quickly once introduced. Even in countries

where action has been taken to remove these products, enorcement remains a signicant challenge.

Figure a5.2. Current situation o removal o marketing authorization or oral artemisinin-based monotherapies

J a n - 0 6

A p r - 0 6

J u l - 0

6

O c t - 0

6

J a n - 0 7

A p r - 0

7

J u l - 0

7

O c t - 0

7

J a n - 0 8

A p r - 0

8

J u l - 0

8

O c t - 0

8

J a n - 0 9

A p r - 0 9

J u l - 0

9

O c t - 0

9

J a n - 1 0

A p r - 1 0

J u l - 1

0

O c t - 1

0

While all national malaria control programmes have banned monotherapies in

the public sector, the national drug regulatory agencies have not followed

suit by making removal mandatory

Countries providing marketing authorization of monotherapies

(as of December 2010)

80

70

60

50

40

30

20

10

0

18 never registered

35 withdrew marketing

authorization

25 allow marketing

No regulatory action

in 25 countries

14 countries in Africa• Angola, Cape Verde,

the Central African Republic,Chad, the Congo, EquatorialGuinea, the Gambia, Malawi,Namibia, Sao Tome andPrincipe, Somalia, Swaziland,Togo, Zimbabwe

6 countries in Asia

• Bangladesh, Bhutan, Myanmar,

Nepal, Timor Leste, Yemen

3 countries in West Pacific

• Papua New Guinea, Solomon

Islands, Vanuatu

2 countries in South America• Bolivia (Plurinational State of),

Colombia

87

Source: WHO Malaria Global Progam, December 2010.

global plan for in resistance

Documents