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1、Strategy to respond to antimalarial drug resistance in AfricaStrategy to respond to antimalarial drug resistance in AfricaStrategy to respond to antimalarial drug resistance in AfricaISBN 978-92-4-006026-5(electronic version)ISBN 978-92-4-006027-2(print version)World Health Organization 2022Some rig
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6、ond to antimalarial drug resistance in Africa.Geneva:World Health Organization;2022.Licence:CC BY-NC-SA 3.0 IGO.Cataloguing-in-Publication(CIP)data.CIP data are available at http:/apps.who.int/iris.Sales,rights and licensing.To purchase WHO publications,see http:/apps.who.int/bookorders.To submit re
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8、or that reuse and to obtain permission from the copyright holder.The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user.General disclaimers.The designations employed and the presentation of the material in this publication do not impl
9、y the expression of any opinion whatsoever on the part of WHO concerning the legal status of any country,territory,city or area or of its authorities,or concerning the delimitation of its frontiers or boundaries.Dotted and dashed lines on maps represent approximate border lines for which there may n
10、ot yet be full agreement.The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by WHO in preference to others of a similar nature that are not mentioned.Errors and omissions excepted,the names of proprietary products are distingui
11、shed by initial capital letters.All reasonable precautions have been taken by WHO to verify the information contained in this publication.However,the published material is being distributed without warranty of any kind,either expressed or implied.The responsibility for the interpretation and use of
12、the material lies with the reader.In no event shall WHO be liable for damages arising from its use.iiiContentsForewordvAcknowledgementsviiAbbreviations and acronymsviiiExecutive summaryix1.Introduction11.1 Purpose of the Strategy11.2 Structure of the Strategy12.Context22.1 The malaria burden in Afri
13、ca22.2 ACTs at the heart of the response32.3 Defining and monitoring resistance43.The threat of antimalarial drug resistance in Africa63.1 Antimalarial drug resistance in Africa63.2 The need for an African-wide strategy94.Drivers of resistance124.1 Overview of drivers of resistance124.2 Background d
14、rivers of resistance124.3 Treatment-related drivers of resistance135.Interventions to mitigate the risks and respond to the emergence and spread of antimalarial drug resistance in Africa155.1 Preliminary assessment to prioritize interventions165.2 Interventions to address key drivers of antimalarial
15、 drug resistance186.Role of stakeholders and enabling mechanisms436.1 Role of key stakeholders436.2 Ensuring that key enabling mechanisms are in place44References49Annex 1.Strategy development process56Annex 2.Definitions of resistance62Annex 3.Threat and potential impact of resistance64Annex 4.Deta
16、iled resistance driver tree72Annex 5.Preliminary country assessment to prioritize interventions77Annex 6.Detailed interventions per stakeholder83vForewordDr Tedros Adhanom Ghebreyesus Director-General World Health OrganizationTackling antimalarial drug resistance in AfricaArtemisinin-based combinati
17、on therapy(ACT)is the mainstay of malaria care in Africa,where the disease is by far the most prevalent.The treatment,introduced in the early 2000s,has played a major role in lowering the burden of malaria across Africa over the last two decades.In recent years,however,WHO has been concerned by repo
18、rts of emerging drug-resistant malaria in South-East Asia,and more recently,in Africa.Parasites in some areas have developed partial resistance to artemisinin the core compound of ACTs and there are worrying signs that they may also be resistant to other drugs that are commonly partnered with artemi
19、sinin.Vigorous measures are needed to protect their efficacy.Our experience in South-East Asia shows that it is possible to prevent cases of malaria and save lives,even in the face of drug resistance.With strong leadership,sustained financing and community engagement,countries of the Greater Mekong
20、have achieved a dramatic reduction in malaria incidence over the last 10 years.Were convinced that the same can be done in Africa,with the same level of commitment,energy and momentum.The strategy in these pages contains recommendations for responding to drug resistance in the African region,buildin
21、g on our experience in South-East Asia,and on documents including the Global technical strategy for malaria 20162030,the Strategy for malaria elimination in the Greater Mekong subregion 20152030,and the Global action plan on antimicrobial resistance(2016).A top priority is to address gaps in informa
22、tion and data,which blind us to the extent of resistance,and which areas and populations need the most attention.Improving data collection and dissemination systems will help countries track and respond to drug resistance more effectively.Stimulating research and innovation will also be critical to
23、delay the spread of resistance to ACTs,and to develop viable alternative treatments.Strategy to respond to antimalarial drug resistance in AfricaviAbove all,strong health systems are the backbone of any successful response to malaria.Investments in primary health care can play a crucial role in addr
24、essing peoples health needs close to where they live and work while,at the same time,reducing the cost of care and enhancing equity.An estimated 200 million people in Africa will be newly infected with malaria this year alone.WHO stands ready to support affected countries and our partners as we work
25、 together to limit the spread of drug resistance,provide efficacious treatment for all in need,and work towards our dream of a malaria-free world.viiAcknowledgementsThe Strategy to respond to antimalarial drug resistance in Africa was developed by the World Health Organization(WHO)Global Malaria Pro
26、gramme in collaboration with the WHO Regional Office for Africa and WHO Regional Office for the Eastern Mediterranean.The work was coordinated by the WHO Global Malaria Programme,with the direct support of Boston Consulting Group and funding from the Bill&Melinda Gates Foundation.WHO would like to t
27、hank the leadership team,the members of the workstreams and the many individuals that through interviews supported the preparation of this Strategy;as well as the many individuals who participated in the open consultation,and the Malaria Policy Advisory Group(MPAG)for the review and the comments on
28、the draft document(see Annex 1).Strategy to respond to antimalarial drug resistance in AfricaviiiAbbreviations and acronymsACT artemisinin-based combination therapyCOVID-19 coronavirus diseaseGDP gross domestic productGMS Greater Mekong subregionGFATM Global Fund to Fight AIDS,Tuberculosis and Malar
29、iaGTS Global technical strategy for malariaHCW health care workerHRP histidine-rich proteinMPAG Malaria Policy Advisory GroupNMP national malaria programmePCR polymerase chain reactionPfKelch13 Plasmodium falciparum Kelch13RSA ring-stage survival assayRDT rapid diagnostic testTACT triple artemisinin
30、-based combination therapyTES therapeutic efficacy studyWHO World Health OrganizationixExecutive summaryThe Strategy to respond to antimalarial drug resistance in Africa is a technical and advocacy document,grounded in the best available evidence to date and aimed at minimizing the threat and impact
31、 of antimalarial drug resistance of Plasmodium falciparum parasites in Africa.Its objectives are to:i)improve the detection of resistance to ensure a timely response;ii)delay the emergence of resistance to artemisinin and artemisinin-based combination therapy(ACT)partner drugs;and iii)limit the sele
32、ction and spread of resistant parasites where resistance has been confirmed.Although the Strategy focuses on Africa,antimalarial drug resistance is a threat in all malaria-endemic countries.As such,the interventions highlighted in this document could be applied to other geographies,but they would ha
33、ve to be tailored to local specificities.The Strategy builds on lessons learned from past global plans and complements existing strategies,including broader efforts to respond to antimicrobial resistance.Implementing the Strategy should not divert resources from other malaria goals.It further builds
34、 on priorities highlighted in the Global technical strategy for malaria 20162030(1).ContextAfrica bears almost the entire burden of malaria,accounting for 96%of global malaria cases in 2020 and 98%of global malaria deaths;poor and vulnerable populations experience the highest burden.Children under 5
35、 accounted for about 80%of all malaria deaths in the World Health Organization(WHO)African Region in 2020.Although there have been significant efforts to tackle malaria in Africa over the last 20 years,progress has stalled and the funding gap between calculated needs and funds available has widened
36、in recent years(2).In addition,new threats in Africa,such as the emergence of artemisinin partial resistance,have made progress difficult.To treat uncomplicated P.falciparum malaria cases,WHO recommends the use of ACTs.While WHO currently recommends six ACTs,the majority of patients in Africa are tr
37、eated with either artemether-lumefantrine or artesunate-amodiaquine.Artemisinin partial resistance can be defined as delayed parasite clearance after treatment with a drug containing an artemisinin derivative.Significant reduction of treatment efficacy has not been observed in association with delay
38、ed parasite clearance after treatment with a drug containing an artemisinin derivative.However,increases in the proportion of parasites carrying P.falciparum Kelch13(PfKelch13)mutations indicate that parasites with this mutation have an advantage under current treatment strategies and transmission d
39、ynamics;this could be due to higher transmissibility or improved fitness.In the absence of partner drug resistance,delayed clearance after treatment with an ACT does not necessarily lead to increased treatment failure rates.However,partner drug resistance has been seen to cause treatment failure.Art
40、emisinin partial resistance puts partner drugs at greater risk because of the increased numbers of parasites exposed to the partner drug alone.Although not confirmed to date,there is also a concern over the potential loss of efficacy of artesunate monotherapy for severe malaria cases in the presence
41、 of artemisinin partial Strategy to respond to antimalarial drug resistance in Africaxresistance.Especially in populations with a high level of immunity,PfKelch13 mutations can be detected earlier than delayed clearance.Therefore,an increased proportion of parasites with PfKelch13 mutations can act
42、as an early warning and warrant a response.The threat of antimalarial drug resistance in AfricaRecent studies have confirmed the emergence of artemisinin partial resistance in several areas of Africa,notably in Rwanda,Uganda and Eritrea.Although resistance to the ACT partner drugs currently in use h
43、as not been confirmed,there are some worrying signals.Data are lacking from several countries and areas,meaning that resistance may be present in other areas.There are contradictory findings on ACT efficacy that need to be further assessed,particularly for artemether-lumefantrine.Given the heavy rel
44、iance on ACTs in Africa,the threat of artemisinin partial resistance and partner drug resistance must be monitored and addressed urgently.The apparent rapid spread of some mutations associated with artemisinin partial resistance means that vigorous measures must be taken before ACTs start failing in
45、 Africa.With no alternative drugs likely to become available in the near future,it is essential to preserve the therapeutic lifespan of ACTs.It should be emphasized that ACTs remain highly efficacious for the time being.However,full-blown ACT treatment failure would have tremendous consequences in A
46、frica.Researchers at Imperial College London estimated that a scenario with widespread artemisinin partial resistance and high partner drug resistance could result in 16 million additional malaria cases and 360 000 hospitalized severe cases(3).Assuming that a portion of these additional cases would
47、lead to additional deaths,this scenario could result in an excess 80 000 deaths per year.The yearly economic impact would be US$1 billion across the continent in that same scenario.Drivers of resistanceUnderstanding the factors that play a role in driving the emergence and spread of resistance is cr
48、itical to effectively respond to the threat of antimalarial drug resistance.A broad literature review and consultation process led to the identification of two categories of factors driving resistance:background drivers and treatment-related drivers.Background drivers include intrinsic factors linke
49、d to the parasite,host and drugs used,as well as environmental factors.Treatment-related drivers are those affecting how often,at what dose,and for how long a parasite population is exposed to a given drug.This Strategy focuses primarily on identifying practical interventions to address treatment-re
50、lated drivers of resistance,while calling for increased research on background drivers.The risk of the emergence and spread of resistance increases when a high number of parasites are exposed to drugs,when parasites are exposed to one drug only,when parasites are exposed to subtherapeutic drug level
51、s,when parasites that are not fully sensitive are more likely to be transmitted,and when parasites are exposed to drugs to which they are not fully sensitive.Detailed treatment-related drivers of resistance are outlined in Fig.4 in section 4.3 of the document.xiInterventions to mitigate the risks an
52、d respond to the emergence and spread of antimalarial drug resistance in AfricaThe Strategy addresses the threat of antimalarial drug resistance in Africa through four pillars.Each pillar consists of a set of interventions(20 in total,see Fig.6 in section 5.2 in the document)that can be implemented
53、at the local,regional and global levels.While this Strategy gives a comprehensive overview of the gamut of interventions that can be implemented,implementing countries need to tailor the Strategy to their local context.An initial country assessment is needed to enable countries to focus on the facto
54、rs that are most likely to drive the emergence and spread of resistance in their context,and to prioritize their efforts in responding to resistance.Pillar I:Strengthen surveillance of antimalarial drug efficacy and resistanceOur ability to respond appropriately and in a timely manner to the spread
55、of artemisinin partial resistance and the potential emergence of resistance to partner medicines is hindered by the lack of up-to-date information.This information is gathered through efficacy studies,surveys and genotyping to evaluate the prevalence of molecular markers of drug resistance,and the u
56、se of additional tools such as in vitro testing and blood level measurement to confirm resistance.However,these efforts are limited by many factors:insufficient capacity,lack of funding,limited political commitment and will,non-compliance with standards(or lack of standards)and protocols to ensure d
57、ata of comparable quality,lack of planning to ensure that data are available from the areas where they are most needed,and sometimes years of delay between data collection and findings being shared with relevant stakeholders.This pillar calls for strengthened surveillance capacity,as well as increas
58、ed technical and laboratory capacity to provide expanded coverage of the data on antimalarial drug efficacy and resistance in Africa.It builds upon the significant investments already made in regional networks and in-country collaborations.Pillar II:Optimize and better regulate the use of diagnostic
59、s and therapeutics to limit drug pressure through pre-emptive measuresProtecting the efficacy of existing ACTs is an immediate priority.The suboptimal use of existing diagnostics and therapeutics can increase drug pressure on the parasite population.From a supply perspective,factors such as the inab
60、ility to enforce stringent regulatory standards,the lack of availability of a diversified portfolio of quality-assured drugs at country level,and the circulation of substandard or falsified drugs and non-recommended monotherapies can increase drug pressure unnecessarily.From a demand perspective,the
61、 lack of demand for alternative drugs to artemether-lumefantrine and artesunate-amodiaquine,as well as the inappropriate use of available antimalarial drugs and diagnostics due to provider or patient behaviour could further contribute to the emergence and spread of antimalarial drug resistance.This
62、pillar calls for a more deliberate use of diagnostics and antimalarials to reduce drug pressure,notably through better adherence to WHO recommendations and full use of the diversity of tools available in the set of antimalarial compounds.To ensure the availability,affordability and quality of these
63、tools,the global malaria community should use its combined market-shaping power to achieve healthier malaria commodity markets,while being mindful of the need to promote innovation,in support of African-led efforts.Strategy to respond to antimalarial drug resistance in AfricaxiiPillar III:React to r
64、esistance by limiting the spread of antimalarial drug-resistant parasitesEfforts to limit the transmission of malaria will affect both resistant and sensitive parasites.However,to limit the risk of resistant parasites being selected and spreading,the focus should be on prioritizing optimal vector co
65、ntrol and other preventive measures,such as chemoprevention and vaccines,in priority areas;restricting transmission from recrudescent cases;and limiting any advantage that higher gametocyte carriage could potentially confer to resistant parasites.Although the risk in different areas and groups shoul
66、d be assessed and is likely to differ by population,country and region,additional resources and efforts should be mobilized towards areas where resistance is confirmed,border areas where there is evidence of resistance in neighbouring areas,and towards areas with significant inflows of mobile and mi
67、grant populations from areas with known resistance.Underserved areas and hard-to-reach populations(e.g.displaced populations,migrant populations,forest goers)should not be omitted.Lastly,promoting collaboration across borders could ensure that resistance detected in one country is addressed through
68、a regional response.Pillar IV:Stimulate research and innovation to better leverage existing tools and develop new tools against resistanceAn effective response to the threat,limiting the potential impact of antimalarial drug resistance,relies on a robust and sustainable pipeline of both therapeutic
69、and non-therapeutic tools.According to WHOs latest World malaria report,funding for malaria-related research and development reached just over US$619 million in 2020.Between 2021 and 2030,it is estimated that an average annual investment of US$851 million in research and development is needed(2).Thi
70、s pillar calls for innovative approaches to better use current tools,for the development of new tools,and for increased modelling and research to characterize resistance,its impact,drivers and how corrective interventions might address those drivers.These interventions will rely on strong,endemic-co
71、untry-led collaborations among African regional and global research communities and partners to conduct studies and implement pilots in order to test new approaches and improve the overall knowledge on malaria drug resistance.The time to act is now.Antimalarial drug resistance poses a serious threat
72、 to achieving further gains in the fight against malaria in Africa.In light of recent evidence confirming the emergence of artemisinin partial resistance in Africa,the malaria community must act now and mount a swift and coordinated response to this major threat.11.Introduction1.1 Purpose of the Str
73、ategyThe Strategy to respond to antimalarial drug resistance in Africa is a technical and advocacy document,based on the best available evidence.It is an overarching strategy to provide guidance to key stakeholders in the malaria community.The goal of the Strategy is to minimize the threat and impac
74、t of antimalarial drug resistance of Plasmodium falciparum in Africa.It should be noted that antimalarial drug resistance is a threat across all malaria-endemic countries,and that the interventions outlined in this document could be applied to other geographies,although they would have to be tailore
75、d to local specificities.The Strategy has three objectives that are instrumental to achieving the goal:Improve the detection of resistance to ensure a timely response.Delay the emergence of resistance to artemisinin and artemisinin-based combination therapy(ACT)partner drugs.Limit the selection and
76、spread of resistant parasites where resistance has been confirmed.To achieve these strategic objectives,factors driving the emergence and spread of resistance have been identified.Addressing these drivers will have a direct impact on antimalarial drug resistance and improve the overall quality of ca
77、re.Finally,the Strategy identifies practical interventions that should be implemented at the global,regional and country levels to address the drivers of antimalarial drug resistance.1.2 Structure of the StrategyThe core document provides a comprehensive overview of the current situation of antimala
78、rial drug resistance in Africa,identifies key drivers of resistance and offers a detailed set of interventions to respond to the threat of resistance.Chapter 2 describes the context in which resistance is being considered.Chapter 3 analyses the current situation in Africa and calls stakeholders to a
79、ction.Chapter 4 looks at the elements that drive the emergence,selection and subsequent spread of antimalarial drug resistance.Chapter 5 lists recommended interventions to respond to resistance and provides guidance on how to conduct a baseline assessment at country level to select the most relevant
80、 interventions for each setting.Chapter 6 advocates for enabling mechanisms to be in place to facilitate the implementation of the interventions by key stakeholders.Six annexes provide technical content.Annex 1 describes the methodology and process involved in the development of the Strategy.Annex 2
81、 includes a list of working definitions and technical background on resistance.Annex 3 estimates the health and economic cost of inaction.Annex 4 provides a granular view of the treatment-related drivers of resistance.Annex 5 guides countries in assessing their starting point in terms of resistance
82、and their health systems maturity.Annex 6 describes how interventions should be addressed by each category of key stakeholders.Strategy to respond to antimalarial drug resistance in Africa22.Context2.1 The malaria burden in AfricaMalaria is still a major health problem worldwide.Nearly half of the w
83、orlds population is at risk of being infected with malaria,in 85 endemic countries.According to the World Health Organization(WHO)World malaria report 2021,there were an estimated 241 million malaria cases and an estimated 627 000 deaths globally in 2020(2).In addition,there is a vast number of asym
84、ptomatic malaria cases;these cases contribute greatly to the continuing transmission of malaria parasites and can have a negative health impact on those infected(4).Africa1 bears almost the entire burden of malaria.In 2020,96%of global malaria cases(232 million)were estimated to have occurred in Afr
85、ica.Five African countries with the highest estimated malaria burden accounted for more than half of the malaria cases globally:Nigeria(27%),the Democratic Republic of the Congo(12%),Uganda(5%),Mozambique(4%)and Angola(3%).Africa also bears almost the entire burden of estimated global malaria deaths
86、 at 98%(612 000)in 2020.P.falciparum,the deadliest malaria parasite,accounted for 99.7%of malaria cases in the WHO African Region in 2020(2).In Africa,the poorest and most marginalized populations are at greatest risk of being infected by P.falciparum.Once infected,some population groups are more vu
87、lnerable to severe disease and death,as they have relatively little immunity against the disease.These groups include children under 5 years of age,pregnant women,people living with HIV/AIDS and populations with low immunity moving to areas with high transmission,such as travellers,migrant workers a
88、nd mobile populations.Children under 5 accounted for about 80%of all deaths in the WHO African Region in 2020(2,5).Over the last 20 years,there have been significant efforts to tackle malaria in Africa.Between 2000 and 2020,a 35%reduction in malaria incidence was achieved(2).Morocco and Algeria were
89、 certified as malaria-free in 2010 and 2019,respectively.However,progress has stalled and the funding gap has widened in recent years(2).Even before the emergence of the coronavirus disease(COVID-19)pandemic,global gains against malaria had levelled off,and the world was not on track to reach the 20
90、20 milestones of the Global technical strategy for malaria 20162030(GTS)(1).During the COVID-19 pandemic,the situation worsened as many countries experienced disruptions to malaria prevention,diagnosis and treatment.Mainly because of these disruptions to services,the incidence of malaria increased i
91、n 2020.In addition,progress has been made difficult by new threats in Africa,such as the emergence of artemisinin partial resistance;spread of parasites that go undetected by the most widely used rapid diagnostic tests(RDTs)due to P.falciparum histidine-rich protein 2 and 3(Pfhrp2/3)gene deletions;v
92、ector resistance to insecticides;and reports from an increasing number of African countries of invasion by Anopheles stephensi,an urban malaria vector originally confined to Asia.Despite these threats,the funding gap between the amount invested and the resources needed has widened dramatically in re
93、cent years,increasing from US$2.3 billion in 2018 to US$2.6 billion in 2019 and US$3.5 billion in 2020(2).The emergence and spread of antimalarial drug resistance will most likely further increase the need for funding,as it may force countries to switch to newer and more expensive products(6).1 Cons
94、idering the WHO African Region as well as the WHO Eastern Mediterranean countries on the African continent(Djibouti,Egypt,Libya,Morocco,Somalia,Sudan,and Tunisia).32.2 ACTs at the heart of the responseThere has been widespread antimalarial drug resistance in Africa in the past.In 2001,WHO recommende
95、d the use of ACTs in countries where P.falciparum malaria was resistant to previously efficacious treatments,such as chloroquine,sulfadoxine-pyrimethamine and,to a lesser extent,amodiaquine(7,8).An ACT consists of a combination of an artemisinin derivative and a partner drug.ACTs are recommended for
96、 the treatment of uncomplicated P.falciparum malaria.The role of the artemisinin derivative is to rapidly reduce the parasite biomass,while the role of the partner drug is to eliminate the remaining parasites after artemisinin has been cleared from the blood(see Fig.1).Even if used as a monotherapy,
97、in the absence of resistance,a full dose of any partner drug included in the six WHO-recommended ACTs artemether-lumefantrine,artesunate-amodiaquine,dihydroartemisinin-piperaquine,artesunate-mefloquine,artesunate+sulfadoxine-pyrimethamine and artesunate-pyronaridine can clear parasitaemia and cure p
98、atients.Due to the very short half-life of the artemisinin derivative,the partner drug acts as a monotherapy starting shortly after the administration of the last dose of ACT.Consequently,ACTs differ from most other combination therapies,in that they include drugs with very different pharmacokinetic
99、s;accordingly,they could be characterized as artemisinin-boosted antimalarials.Figure 1.Evolution of parasite biomass in the body following ACT administrationArtemisinin acts by rapidlyreducing the parasite biomassIndexedIllustrativeTimeParasite biomass11Partner drug eliminates remaining parasites2A
100、rtemisinins in bloodstreamPartner drug in bloodstream2Strategy to respond to antimalarial drug resistance in Africa4While WHO currently recommends six ACTs,the majority of patients are treated with either artemether-lumefantrine or artesunate-amodiaquine.Artemether-lumefantrine is the most widely us
101、ed treatment course,representing over 85%of ACTs procured by the Global Fund to Fight AIDS,Tuberculosis and Malaria(GFATM),followed by artesunate-amodiaquine representing 10%(9).Several factors explain this pre-eminence.Artemether-lumefantrine was the first ACT to be developed,and it is the first-li
102、ne therapy in most African countries.Artemether-lumefantrine and artesunate-amodiaquine are the most affordable options,at US$0.60 and US$0.78 per adult treatment course,respectively,versus US$23 for other ACTs(10).Artemether-lumefantrine is also the most accessible ACT,with prequalified artemether-
103、lumefantrine being produced by nine suppliers with significant production capacity(11).2.3 Defining and monitoring resistanceThere are two main working definitions of resistance:Antimalarial drug resistance is defined as the ability of a parasite strain to survive and/or multiply despite the adminis
104、tration and absorption of a drug given in doses equal to or higher than those usually recommended,but within tolerance of the subject.Artemisinin partial resistance can be defined as delayed clearance after treatment with a drug containing an artemisinin derivative of a parasite strain carrying a pa
105、rticular mutation or set of mutations that are validated as associated with this delayed clearance,despite the administration and absorption of the drug given in doses equal to or higher than those usually recommended,but within tolerance of the subject.Detailed definitions of antimalarial drug resi
106、stance are provided in Annex 2.Significant reduction of treatment efficacy has not been observed in association with changes in P.falciparum sensitivity to artemisinin derivatives.So far,artemisinin partial resistance appears to only affect the P.falciparum ring stage,leading to delayed clearance of
107、 parasitaemia.Consequently,after three days of treatment,a larger biomass remains,which must be eliminated by the partner drug.This delayed clearance has been found to be associated with P.falciparum Kelch13(PfKelch13)mutations.However,even in areas of high prevalence of PfKelch13 mutations,a seven-
108、day artesunate treatment has shown over 90%efficacy,suggesting that delayed clearance does not meet the standard definition of antimalarial drug resistance(12).The observed delayed clearance is,therefore,termed artemisinin partial resistance(see Annex 2).There is no evidence that changes in sensitiv
109、ity to artemisinin derivatives affect any asexual stage other than the ring stage and no evidence of artemisinin full resistance,i.e.leading to treatment failure following a full dose of artesunate.There are indications that PfKelch13 mutations could facilitate the spread of artemisinin partial resi
110、stance.In the Greater Mekong subregion(GMS),some strains carrying PfKelch13 mutations associated with partial resistance appear to have an increased capability to generate gametocyte carriage(13).This has not been confirmed in Africa;however,the increases in the proportion of parasites carrying PfKe
111、lch13 mutations now observed in some countries in Africa indicate that parasites with this mutation have an advantage under current treatment strategies and transmission dynamics;this could be due to higher transmissibility or improved fitness.5In areas with artemisinin partial resistance,delayed cl
112、earance after treatment with an ACT does not necessarily lead to an increase in treatment failure rates in the absence of partner drug resistance.However,partner drug resistance can cause treatment failure.In the GMS,ACTs have remained efficacious despite the presence of artemisinin partial resistan
113、ce,provided that there is no resistance to partner drugs.Artemisinin partial resistance puts partner drugs at greater risk by exposing an increased number of parasites to the partner drug alone.As such artemisinin partial resistance likely played a role in the rapid spread of resistance to the ACT p
114、artner drug piperaquine across countries in the GMS.Although not confirmed to date,there is also a concern over the potential loss of efficacy of artesunate monotherapy for severe malaria cases in the presence of artemisinin partial resistance.Continuous monitoring is crucial.Therapeutic efficacy st
115、udies(TESs)remain the gold standard for determining antimalarial drug efficacy.These studies are prospective evaluations of patients clinical and parasitological responses to treatment for uncomplicated malaria.TESs are conducted with a diagnosis validated by microscopy,using a quality-assured treat
116、ment and supervised drug administration.Despite their limitations,these studies provide decision-makers with an indication of the efficacy of drugs for treating malaria.To be comparable across countries and over time,it is crucial to use standardized protocols.TESs alone are not sufficient to confir
117、m drug resistance;this must be confirmed through other means(14):Molecular marker analyses(genotypes)identify genetic changes in the parasite genome that are associated with a change in parasite susceptibility to antimalarial drugs.Ex vivo and in vitro assays(phenotypes)test the sensitivity of fresh
118、 or culture-adapted parasites to antimalarial drugs by exposing them to different concentrations of a drug(typically for 42 hours)or to a pulse of a high concentration of a drug(in ring-stage survival assay RSA)and observing the effect on parasite survival.Measurements of drug levels in the blood al
119、low monitoring of the concentration of drug that malaria parasites are exposed to and can help to distinguish whether a treatment failure is due to insufficient antimalarial drug exposure or due to resistance.Strategy to respond to antimalarial drug resistance in Africa63.The threat of antimalarial
120、drug resistance in Africa3.1 Antimalarial drug resistance in Africa3.1.1 Artemisinin partial resistance in AfricaEvidence of the selection and spread of parasites with partial resistance to artemisinin derivatives has been documented in the following areas of Africa(see Fig.2):Rwanda:Two studies con
121、ducted by the national malaria programme(NMP)between 2013 and 2015 reported a clonal expansion of the PfKelch13 R561H mutation,and RSA confirmed that this mutation conferred reduced susceptibility to dihydroartemisinin(15).However,no evidence of treatment failure rates above 10%for artemether-lumefa
122、ntrine or dihydroartemisinin-piperaquine was reported.In a third study conducted in 2018 with the support of the United States Centers for Disease Control and Prevention,expansion of the PfKelch13 R561H mutation was confirmed(16).This mutation was associated with delayed clearance;nonetheless,arteme
123、ther-lumefantrine displayed continued excellent efficacy.Similarly,a fourth study reported a higher prevalence of the PfKelch13 R561H mutation(22%)that was also associated with delayed clearance,but with conserved artemether-lumefantrine efficacy(94%)(17).This suggests that the partner drugs and ACT
124、 regimens were still effective in Rwanda at the time of the evaluations.Uganda:Surveys reported an elevated prevalence of the PfKelch13 C469Y and A675V mutations in multiple districts in northern Uganda(18).More recently,isolates with C469Y and A675V mutations were associated with clinical delayed c
125、learance in patients who were administered intravenous artesunate followed by artemether-lumefantrine.The A675V mutation was also associated with in vitro RSA reduced susceptibility(19).Unpublished evidence also shows in vitro reduced susceptibility for C469Y(20).However,ACTs remained effective in U
126、ganda at the time of the surveys.Horn of Africa:The R622I mutation has been reported in several countries in the Horn of Africa,but correlation with delayed parasite clearance has so far only been assessed in Eritrea,where this mutation was shown to induce reduced susceptibility to artemisinin using
127、 RSA in 2019(Eritrea NMP,unpublished data).Data are lacking from several countries and areas,meaning that artemisinin partial resistance may be present in other areas.7Figure 2.Countries with more than 5%of parasites with PfKelch13 mutations and main mutations identified(20152020)(21)84.7%85.8%91.2%
128、96.3%15.3%14.2%8.8%3.7%Rwanda(n=425)Eritrea(n=769)Africa(n=18 327)Uganda(n=2 872)Wild TypeMutations0.3%1.8%5.0%5.00.6%10.8%4.5%13.9%3.3%3%2.5%R622IA675VC469YR561HR622IA675VC469YMutations:OthersOthersOthersOthersR561Hn=number of samples collected Figure 2 describes the prevalence of mutations detecte
129、d in PfKelch13 genotypes as a percentage of the total samples genotyped in the country during the 20152020 period.The prevalence of mutations varies among countries but also locally within a given country.The prevalence of mutations reported at country level is impacted by the location and number of
130、 studies conducted.Typically,more studies are done in areas where high prevalence has previously been detected.3.1.2 Resistance to ACT partner drugs in AfricaResistance to currently used ACT partner drugs has not been confirmed despite some worrying signals.Significant levels of resistance to an ACT
131、 partner drug in the presence of artemisinin partial resistance would result in low efficacy of the ACT.Published and unpublished data compiled in the WHO database allow for a deep analysis of the efficacy of the main ACTs.Results from some studies should be interpreted with caution,as deviations fr
132、om WHO standard protocols can lead to underestimation or sometimes overestimation of the efficacy of some ACTs.The conclusions of an analysis of more than 400 studies conducted between 2009 and 2019 are described in the following paragraphs(14):Artemether-lumefantrine:Treatment failure rates greater
133、 than 10%after treatment with artemether-lumefantrine were reported in several countries in Africa between 2009 and 2019.Recently,high(i.e.over 10%)treatment failure rates were reported at some sites in Angola(22),Burkina Faso(23),the Democratic Republic of the Congo(24)and Uganda(25).Concerns were
134、raised about the quality of microscopy in Burkina Faso(26).Analysis using a Bayesian algorithm(as for the studies in Angola,the Democratic Republic of the Congo and Uganda)is not recommended by WHO for reporting treatment outcomes and can,in high transmission settings,yield higher treatment failure
135、rates than the 2008 WHO standard polymerase chain reaction(PCR)genotyping methodology(updated in 2021(27)to distinguish between reinfection Strategy to respond to antimalarial drug resistance in Africa8and recrudescence after treatment.Moreover,the interpretation of the cause of failures is hampered
136、 by the lack of lumefantrine drug levels and the lack of predictive genotypes for lumefantrine resistance.High failure rates were simultaneously reported for artemether-lumefantrine and dihydroartemisinin-piperaquine in Burkina Faso,the Democratic Republic of the Congo and Uganda.Lumefantrine and pi
137、peraquine cross-resistance is biologically improbable,putting these results into question.If there is a signal of treatment failure for more than one ACT with no biological explanation of the associated results,there should be close examination to check whether methodological issues potentially conf
138、ounded the results.Artesunate-amodiaquine:Treatment failure rates close to 10%after treatment with artesunate-amodiaquine have been identified in two studies conducted in Liberia in 20172018(28).Additional studies have been initiated to gather further data.Overall,surveillance of artesunate-amodiaqu
139、ine efficacy and amodiaquine resistance has been neglected since WHO first recommended ACTs in 2001 and artesunate-amodiaquine was introduced.Dihydroartemisinin-piperaquine:Except for the studies in Burkina Faso(23)and the Democratic Republic of the Congo(24),where treatment failures with dihydroart
140、emisinin-piperaquine were systematically associated with treatment failures with artemether-lumefantrine(see above),high treatment failure rates after treatment with dihydroartemisinin-piperaquine have not been reported in any other African countries(noting that dihydroartemisinin-piperaquine is not
141、 widely used in Africa),and resistance to piperaquine has not been confirmed in Africa.Other ACT partner drugs:Very few treatment failures have been reported after treatment with artesunate-pyronaridine or artesunate-mefloquine in Africa,although there has been minimal drug pressure to date.Resistan
142、ce to sulfadoxine-pyrimethamine is widespread in Africa.Therefore,the use of artesunate+sulfadoxine-pyrimethamine is not recommended for the treatment of uncomplicated malaria in Africa.Sulfadoxine-pyrimethamine,however,is used for chemoprevention,either alone or in combination with amodiaquine.Ther
143、e are contradictory findings that require further assessment regarding treatment failures with artemether-lumefantrine,the most commonly used ACT in Africa:Some TESs have highlighted signals of high treatment failure rates,as mentioned above;however,sometimes studies deviated from WHO protocols.Duri
144、ng a TES,many confounders may potentially obscure measures of artemether-lumefantrine treatment failure:poor drug absorption,non-adherence(as the second daily dose is often unsupervised),and the short half-life of lumefantrine leading to high reinfection rates,with some reinfections potentially misc
145、lassified as recrudescence during laboratory analysis.There have been reports of artemether-lumefantrine treatment failures in travellers returning from Africa to Portugal(29),Sweden(30)and the United Kingdom of Great Britain and Northern Ireland(31).However,information on lumefantrine blood levels
146、was often unavailable,and anecdotal failures in non-immune individuals do not prove the existence of drug resistance.In addition,artemether-lumefantrine treatment failures in 9travellers were successfully cured with a second treatment of artemether-lumefantrine in Sri Lanka(32)and Trkiye(33).A few r
147、eports have shown higher in vitro 50%inhibitory concentrations(i.e.mean drug concentration that inhibits 50%of the parasite growth)for lumefantrine;however,the in vitro lumefantrine resistance threshold has not been defined and trends are difficult to analyse,in part due to limitations in the standa
148、rdization of the in vitro lumefantrine test.High treatment failure rates with artemether-lumefantrine have not been reported in Lao Peoples Democratic Republic or Myanmar,where artemether-lumefantrine is the first-line therapy,despite high prevalence of artemisinin partial resistance(34).3.2 The nee
149、d for an African-wide strategyGiven the heavy reliance on ACTs in Africa,the threat of artemisinin partial resistance and partner drug resistance must be monitored and addressed urgently.The apparent rapid spread of some mutations associated with artemisinin partial resistance means that vigorous me
150、asures must be taken before ACTs start failing in Africa.There is an urgent need to preserve the therapeutic lifespan of ACTs.Given the current drug pipeline outlook,it is unlikely that drugs with a different mechanism of action will become available soon,with the most promising non-artemisinin-base
151、d combination,ganaplacide-lumefantrine,in the patient exploratory phase(Phase IIb).Although such a formulation would address a situation of artemisinin partial or full resistance,its reliance on lumefantrine poses a risk should resistance to that partner drug be confirmed.ACT treatment failure due t
152、o resistance is likely to result in an increased number of cases,leading to additional severe cases and ultimately excess deaths.A study by researchers at Imperial College London published in 2016(3)provided preliminary estimates for Africa,showing that a scenario with widespread artemisinin partial
153、 resistance(54%of infected individuals experiencing delayed parasite clearance)and high partner drug resistance(45%of treated individuals recrudescing)could result in an additional 16 million cases per year in Africa a 7%increase in cases compared to a scenario with no resistance.Under the same scen
154、ario,the additional severe cases derived from the increased transmission were estimated at around 365 000 per year.Ultimately,assuming that a portion of these additional cases would lead to additional deaths,this scenario could result in an additional 80 000 deaths per year,assuming that around 20%o
155、f hospitalized severe cases lead to death(see Annex 3).Although such a scenario is hypothetical and there are many limitations to the model used,this could lead to an economic impact of US$11.1 billion in additional costs per year across Africa.This figure includes the direct health costs that would
156、 be borne by individuals and health service providers(e.g.additional diagnostic tests and treatments,additional cost for inpatient care due to excess severe malaria cases,incremental cost of a new commodity following the introduction of a new first-line treatment)and lost productivity(e.g.absenteeis
157、m in the workplace due to disease burden or the need to care for a sick child,lost productivity due to premature death).At the same time,these are conservative estimates,since they do not account for the dramatic consequences that resistance would have in other areas,such as the impact on economic g
158、rowth,the long-term effects on children linked to education disruptions Strategy to respond to antimalarial drug resistance in Africa10and the effect on the populations overall well-being.Finally,it is likely that population groups most at risk of malaria,such as poor,mobile and rural populations,an
159、d the most vulnerable women and children would be disproportionally affected,further widening the inequality gap.The Strategy to respond to antimalarial drug resistance in Africa needs to build on lessons learned from past global plans and complement existing strategies.These include the Global plan
160、 for artemisinin resistance containment(35)and the Strategy for malaria elimination in the Greater Mekong Subregion(20152030)(36),which highlight the need for adequate surveillance,strong regional collaboration,involvement of a large panel of stakeholders including NMPs and communities,and sustained
161、 financing(see Fig.3).The Strategy also takes place within the context of a broader effort to respond to antimicrobial resistance.Strategic objectives outlined by the Global action plan on antimicrobial resistance(37)were leveraged in the development of the Strategy,including the need to tackle stru
162、ctural issues such as inequity,fractured health systems and entrenched poverty,and need to improve awareness and understanding of antimicrobial resistance through effective communication,education and training.Finally,the Strategy uses key elements of the“High burden to high impact”approach,a countr
163、y-led response,catalysed by WHO and the RBM Partnership to End Malaria,in which 11 African countries1 actively participate,in addition to India(38).In the GMS,the initial response to resistance developed into escalated efforts to achieve malaria elimination,a goal likely to be reached within the nex
164、t few years.The scale of the challenge and the multitude of different settings in Africa vastly exceed those of the GMS.In some countries,elimination may be a feasible short-term goal,either nationwide or at the subnational level.However,in many countries,the near-term goal needs to be the optimizat
165、ion and expansion of activities based on the interventions outlined in this Strategy.This Strategy should not divert resources away from efforts on other malaria goals.This Strategy further builds on the priorities highlighted in the GTS:the need to protect the efficacy of ACTs and develop new non-a
166、rtemisinin-based combinations(1).It will also contribute to broader malaria control objectives by ensuring access to malaria prevention,diagnosis and treatment as part of universal health coverage.1 Burkina Faso,Cameroon,Democratic Republic of the Congo,Ghana,Mali,Mozambique,Niger,Nigeria,Uganda and
167、 the United Republic of Tanzania,with the addition of Sudan in April 2022.11Figure 3.High-level learnings from the response to resistance in the GMSAdequate surveillance Surveillance has been a top priority,from increasing surveillance of antimalarial drug efficacy and resistance to strengthening ov
168、erall malaria surveillance of drug quality,number of cases and deaths.Various tools have been leveraged,from app enabling collection of real-time data to the implementation of a regional malaria elimination database.Regional collaboration A coordinated response towards the fight against malaria has
169、been encouraged between countries,for instance through regional grants and sharing of best practice and strategies.Cross-border interventions have been fostered to target hard-to-reach populations and foci of resistance,such as mobile populations in forested and remote areas.Involvement of a large p
170、anel of stakeholders Coordination between a large panel of stakeholders has been promoted:funders,multilateral agencies,technical partners,academia and researchers,private sector,governments and communities have been enrolled in the strategy,through region-wide initiatives and dedicated steering bod
171、ies(e.g.the Mekong Malaria Elimination programme).Community involvement Building community malaria networks,by leveraging village and mobile malaria workers has been crucial in implementing the strategy and reaching populations at risk of resistance.Financing A well funded approach is key to financi
172、ng broad and innovative interventions,such as intensive training and procurement of commodities,in order to foster coordination between countries,fund operational research,and so on.Strategy to respond to antimalarial drug resistance in Africa124.Drivers of resistance4.1 Overview of drivers of resis
173、tanceEffectively responding to the threat of antimalarial drug resistance requires an understanding of the factors that play a role in driving the emergence and spread of resistance.The emergence of drug-resistant parasites happens in two stages:first,the initial random genetic event that makes a pa
174、rasite less sensitive to a drug,and second,the survival,selection and subsequent spread of parasites carrying one or more mutations that provide some degree of protection from the effect of a drug.The role the different factors play in driving the emergence,selection and spread of resistance will va
175、ry by drug and context.There is good consensus on the factors that may drive the emergence and spread of resistance,but knowledge of their relative importance is limited by the lack of available data and evidence.A broad literature review and consultation process led to the identification of two cat
176、egories of factors driving resistance:background drivers and treatment-related drivers(see Fig.4 and Annex 4).Background drivers include intrinsic factors linked to the parasite,host and drugs used,as well as environmental factors.Treatment-related drivers are those affecting how often,at what dose,
177、and for how long a parasite population is exposed to a given drug.This Strategy focuses primarily on identifying practical interventions to address treatment-related drivers of resistance,while calling for increased research on background drivers.An initial country assessment is needed to enable cou
178、ntries to focus on the factors that are most likely to drive the emergence and spread of resistance in their context,and to prioritize their efforts in responding to resistance(see Annex 5).4.2 Background drivers of resistanceParasite genetic background can influence the degree to which a mutation a
179、ffects drug sensitivity and the likelihood that the mutation will spread(39).Certain genetic backgrounds or additional mutations can improve resistant parasites ability to compete with other parasites,even in the absence of drug pressure.Consequently,the effect and potential for spread of a mutation
180、 can differ between P.falciparum parasite strains from Africa and those from other malaria-endemic regions.The level of transmission could impact the risk of spread(40).Higher malaria transmission results in many strains circulating in a population and a higher chance of mixing genetic material duri
181、ng a parasites sexual reproduction.Therefore,higher malaria transmission increases the risk that some potential background resistance mutations will be lost and increases the competition with other parasite strains.Additionally,populations living in higher transmission areas have some level of acqui
182、red immunity,meaning that the host is better able to eliminate parasites regardless of the level of drug resistance(41).A range of additional setting-specific factors affect the emergence and spread of resistance.These factors include human migration from areas with resistance,the ability of local 1
183、3mosquitoes to spread the resistant strain(42),and climate change,which alters temperature,humidity and rainfall,potentially shifting the geography and seasonality of transmission(43).4.3 Treatment-related drivers of resistanceDrug pressure drives the selection and spread of resistant parasites.Mala
184、ria parasites are exposed to different antimalarial drugs that are intended to cure patients by eliminating the parasites.However,continuous or repeated exposure to a drug can select parasites with reduced susceptibility to the drug in subsequent administrations.Drug pressure depends on the proporti
185、on of overall malaria infections that are treated and the rate at which people use antimalarial drugs.The exposure of a parasite population to drugs depends on a range of issues,including access to quality diagnosis and treatment,and other use of antimalarial drugs such as for chemoprevention.Chemop
186、revention strategies can impact resistance and select parasites that are less sensitive to the drug used for chemoprevention.This impact will depend on the drugs used,the prevalence of resistance,the epidemiology and health system of the target area,the population covered,and the quality of the chem
187、oprevention intervention.Chemoprevention with a drug not used for treatment could potentially decrease the risk of losing treatment drugs to resistance.However,the key challenge in the use of chemoprevention as part of a resistance strategy is the few drugs available.Pressure on a parasite populatio
188、n from a drug increases the risk of selection and spread of parasites resistant to that drug(42).When a parasite population is mainly exposed to one drug,the competitive advantage of having resistance to that drug and thus the risk of selection increases.In the past,uncomplicated P.falciparum was tr
189、eated with chloroquine and sulfadoxine-pyrimethamine.Resistance to these drugs spread globally,reaching very high levels of prevalence.Although the current recommendation is treatment with an ACT combining an artemisinin component and a partner drug,this recommendation is sometimes not followed,mean
190、ing that some patients are still treated with monotherapies.Furthermore,while the ACT is a combination of two drugs,the partner drug is alone in the blood for an extended period of time after the short-acting artemisinin component has been cleared.Exposing parasites to subtherapeutic drug levels is
191、thought to be an important selective force in the spread of resistance(42).Subtherapeutic drug concentrations in the blood allow resistant infections to be maintained and transmitted.The exposure of parasites to subtherapeutic drug concentrations can be caused by a variety of factors,including the u
192、se of substandard or falsified drugs,use of non-pharmaceutical forms of Artemisia such as Artemisia tea(44),poor compliance with treatment regimens or suboptimal dosing of an antimalarial drug.Resistance can spread when parasites with reduced drug sensitivity are significantly more likely to be tran
193、smitted.This can happen when parasites with reduced drug sensitivity cause recrudescence(45)and are subsequently transmitted,or when parasites with reduced drug sensitivity have increased gametocyte carriage(13).Exposing parasites to drugs to which they are not fully sensitive enables the parasites
194、to multiply and be transmitted.Delays in detecting resistance and in responding to this problem by changing the treatment policy enable resistant parasites to spread and reach high levels of prevalence.Strategy to respond to antimalarial drug resistance in Africa14Figure 4.Drivers of resistanceEnvir
195、onmental factorsDegree to which local vectorscan transmit resistant parasites Climate changeImportation risk due to mobility of vectorsNote:flying area of vectors is limitedHost and drug-relatedfactorsPatient genetic factors(e.g.poor metabolizer)Drug properties(e.g.half life,gametocidal component)Pa
196、rasite factorsDegree of resistance conferredby the genetic changeFitness cost of the resistancemechanismComplexity of mutations(monogenic or complex genetic traits)Background driversRisk of losing supporting geneticbackground during crossover eventRisk of resistant parasites being outcompeted depend
197、ing on transmission intensityLevel of immunity(e.g.low levels increasing the competitive advantage of resistant parasites)Intrinsic frequency with which the genetic changes occur and co-occur with other genetic changes facilitating the spread of resistant parasitesImportation risk due to migration p
198、atterns and mobility of populations from neighbouring areas carrying resistant parasites Affected by transmission intensityParasites exposed to subtherapeutic levelsof a drugSubstandard and falsified drugsBroad use of non-pharmaceutical formsof ArtemisiaIncomplete treatment(patient behavioural drive
199、rs)Inadequate treatment(provider-related drivers)Individuals with lowdrug blood levels infectedwith malariaPatient factors affectingblood levels(e.g.age,pregnancy,pharmacogenomics)(addressable by new formulations)Parasites exposedto one drug onlyMisuse and overuse ofmonotherapiesReliance on a few AC
200、T treatmentsCombination of drugswith mismatchedpharmacokinetic profileswithin the same treatmentHigh number andproportion of parasitesexposed to a drugFailure to limit malariaburden with means otherthan antimalarial drugsBroad use of antimalarialsfor unconfirmed casesWidescale use of a drugas chemop
201、reventionPatterns of drug use andfrequency of exposureParasites not fullysensitive more likely to be transmittedRecrudescent casestransmit malariaIncreased gametocyte carriage of resistant infectionsParasites carrying mutations linked to artemisinin partial resistance as well as other mutations that
202、 could favour their spreadParasites exposed toa drug to which theyare not fully sensitiveTreatment failurefollowed by treatment with the same drugLack of information onefficacy and resistance toinform treatmentImpediments to drugpolicy changes followingtreatment failure rate 10%Treatment-related dri
203、versLow level ofacquired immunityDegree to which specific species(transmitting resistant parasites)are sensitive to the existing vector control interventions155.Interventions to mitigate the risks and respond to the emergence and spread of antimalarial drug resistance in AfricaThis regional Strategy
204、 addresses the threat of antimalarial drug resistance in Africa through four pillars(see Fig.5):I.Strengthen surveillance of antimalarial drug efficacy and resistance.II.Optimize and better regulate the use of diagnostics and therapeutics to limit drug pressure through pre-emptive measures.III.React
205、 to resistance by limiting the spread of antimalarial drug-resistant parasites.IV.Stimulate research and innovation to better leverage existing tools and to develop new tools against antimalarial drug resistance.Each pillar consists of a set of interventions that can be implemented at the local,regi
206、onal and global levels(see Fig.6).The relevance of each intervention to address the drivers of resistance has been assessed through a broad consultation process.Although this Strategy is applicable to the wider population of Africa,there is no one-size-fits-all recipe for success.While this document
207、 gives a comprehensive overview of the interventions that could be leveraged,the outcome of an intervention will vary depending on the implementation setting.It should also be noted that the interventions outlined in this document could be applied to other malaria-endemic regions.Therefore,the immed
208、iate next step should be for each country to conduct an assessment of its current situation and,based on the results of the assessment,to use the Strategy to guide the development of recommendations tailored to the local context,with the support of global and regional stakeholders.An initial country
209、 assessment is required to prioritize the interventions,and estimate the resources and changes required to implement this Strategy in a given setting.Details of this assessment are included below in section 5.1 and in Annex 5.The resulting recommendations may be included in broader national strategi
210、c plans for malaria and/or antimicrobial resistance action plans.Key enabling mechanisms will be needed at all levels to ensure the feasible,impactful and sustainable implementation of each intervention.These mechanisms are further detailed in Chapter 6.Countries should monitor and evaluate their im
211、plementation of the Strategy.Countries will need to define indicators and targets as part of the development of recommendations in order to monitor the implementation of the Strategy.Responding to antimalarial drug resistance should be a continuous process that will require adjustments based on less
212、ons learned and Strategy to respond to antimalarial drug resistance in Africa16the latest evidence collected.A robust surveillance system,including surveillance of both antimalarial drug efficacy and resistance,and routine surveillance(see Chapter 6),will inform the need and the extent of implementa
213、tion.Although each country will have to perform a detailed analysis of its own starting point,some high-level guidance can be provided based on whether artemisinin partial resistance and/or partner drug resistance is confirmed or suspected.In the event of confirmed resistance,immediate efforts shoul
214、d be focused on i)assessing the extent of the problem by strengthening and expanding drug efficacy surveillance coverage for both artemisinin and partner drugs;ii)if partner drug resistance has been confirmed,ensuring continued efficacy of malaria treatment by rapidly switching to a second-line ACT
215、if treatment failures are above a 10%threshold and by ensuring that health care workers(HCWs)are properly trained to use the new drug;and iii)limiting the onward transmission of drug-resistant parasites using both pharmacological and non-pharmacological tools.These reactive measures should be consid
216、ered priorities that can then be complemented by additional,more advanced interventions based on resource availability.Countries with no confirmed resistance should strengthen drug efficacy and resistance monitoring and implement pre-emptive measures that will limit unnecessary drug pressure and thu
217、s delay the emergence of resistance.Figure 5.High-level framework of the Strategy:preliminary assessment,strategic pillars and enablersPreliminary assessment to prioritize interventions Countries baseline with respect to the status and drivers of resistance Assessment of strengths and weaknesses of
218、the health and the regulatory systems Strengthen surveillance of antimalarial drug efficacy and resistance Optimise and better regulate the use of diagnostics and therapeutics to limit drug pressure through pre-emptive measure React to resistance by limiting the spread of antimalarial drug resistant
219、 parasites Stimulate research and innovation to better leverage existing tools and to developed new tools against antimalarial drug resistanceLiving strategy-Monitor the implementation and update based on new evidence and learningsKey enabling mechanisms Country ownership Financing Advocacy efforts
220、Regional coordinationRoutine surveillance system5.1 Preliminary assessment to prioritize interventionsTo translate the Strategy into recommendations tailored to the local context,countries should undertake an initial assessment of the elements described below.The assessment can be based on informati
221、on from routine surveillance,surveys and interviews with key stakeholders,but also on the use of in-country consultants or standardized data collected.Where no information is available,data collection can be incorporated into the proposed activities prioritized as part of a countrys national action
222、plan to progressively better target interventions.IIIIIIIV17The assessment should focus on three main areas:status of resistance and epidemiology,drivers of resistance,and overall health and regulatory systems.Annex 5 details two levels of the assessment:a first level with only critical data to be c
223、ollected,and a second level with a more comprehensive set of elements to be included,if there are sufficient resources.1.Status of resistance and epidemiologyThe assessment should include the following priority elements:Determine the status of antimalarial drug efficacy and resistance,and data avail
224、ability:a review of efficacy and resistance surveillance data in the target country,as well as in neighbouring countries,is the starting point for this assessment.Identifying high-priority areas with no recent data will inform the need for further studies.Identify the main characteristics of in-coun
225、try malaria epidemiology:factors such as the patterns of malaria transmission,parasite species,vector species and characteristics of the human population(e.g.levels of immunity)should be assessed.Analyse the mobility of the human population:understand human population movements and migration pattern
226、s.2.Drivers of resistanceThe assessment should include the following priority elements:Understand the in-country availability and use of drugs:analysis of access,current behavioural drivers of both patient and care provider choices,and patterns of drug and diagnostic use is required to design interv
227、entions to address these issues.Assess adherence to treatment guidelines:care providers access to key resources for malaria case management(e.g.national treatment guidelines)and their knowledge and understanding of the treatment guidelines should be assessed.3.Strengths and weaknesses of the health
228、and regulatory systemsThe feasibility and impact of each intervention will depend on the capabilities and resources available in each country,such as the amount of funding and human resources available,and on the capacity of each country to identify potential roadblocks,leverage past successes and e
229、xisting opportunities,and implement change.Analysis of the strengths and bottlenecks should be based on past and ongoing experiences in implementing malaria interventions.Elements that need careful assessment include the following:Strengths of the health and regulatory systems:assess the health syst
230、em structure and the institutional capacity to enforce national policies and regulations,as these will play a key role in defining the feasibility and impact of each intervention.Gaps between the plans developed by the NMP and their effective implementation:identify the bottlenecks that have hindere
231、d past or ongoing implementation of interventions to fight malaria(e.g.obstacles to the withdrawal of monotherapies).Synergies with other strategies and global plans:identify interventions that are already being deployed within the framework of other strategies,such as the Global action plan on anti
232、microbial resistance(37),which could be beneficial and further leveraged to respond to antimalarial drug resistance(e.g.raising awareness,training).Strategy to respond to antimalarial drug resistance in Africa185.2 Interventions to address key drivers of antimalarial drug resistanceThe following sec
233、tion provides more details on each pillar.Although most of the interventions could be deployed widely,in light of the threat of resistance,increased efforts should be focused on areas and populations that are deemed at higher risk of developing resistance.Once specific groups and areas have been ide
234、ntified,additional funding and resources should be dedicated to reaching them.Figure 6.Twenty interventions clustered into the Strategys four pillars to address resistanceStrengthen surveillance of antimalarial drug efficacy and resistance Enhance capacity and capabilities to generate better quality
235、 and standardised data on antimalarial drug efficacy and on parasite resistance Increase coverage of surveillance systems on efficacy and resistance Increase collection of additional,more detailed data at select sites Improve data dissemination systems to facilitate reactive and coordinated response
236、 to resistance data Develop national treatment policies that promote deliberate use of existing treatments to prevent and react to the emergence and spread of resistance Promote the availability of a diversified drug portfolio in countries Prevent exposure to subtherapeutic drug levels driven by sub
237、standard and falsified ACTs by promoting drug quality Remove non recom-mended monotherapies and ensure that other mono-therapies are used in accor-dance with WHO guidelines Promote equitable access to quality drugs Promote equitable distribution of and access to high quality diagnostics to reduce dr
238、ug pressure Empower patients,HCWs and other stakeholders to make informed decisions and provide appropriate treatmentOptimize and better regulate the use of diagnostics and therapeutics to limit drug pressure through pre-emptive measures Ensure optimal malaria vector control intervention coverage in
239、 priority areas Leverage preventive measures to reduce transmission of antimalarial drug resistant parasites Limit the risk of increased transmission of resistant parasites Strengthen cross-border collaboration on malaria activities to ensure coordinated resistance managementReact to resistance by l
240、imiting the spread of antimalarial drug resistant parasites Identify innovative approaches using currently available drugs to delay the development and spread of resistance Identify areas and populations where drug resistance is deemed more likely to develop and spread Develop new treat-ments and di
241、agnostics with the objective of delaying the emergence and spread resistance Identify and develop innovative tools to limit malaria infection and transmission Conduct modelling and research to better understand and track resistanceStimulate research and innovation to better leverage existing tools a
242、nd to develop new tools against resistanceI567334345IIIIIIV195.2.1.Pillar I:Strengthen surveillance of antimalarial drug efficacy and resistanceOur ability to respond appropriately and in a timely manner to the spread of artemisinin partial resistance and the potential emergence of resist
243、ance to partner medicines is hindered by the lack of available information.Information is gathered through efficacy studies,surveys and genotyping to evaluate the prevalence of molecular markers of drug resistance,and the use of additional tools such as in vitro testing and blood level measurement t
244、o confirm resistance.However,these efforts are limited by many factors:insufficient capacity,lack of funding,limited political commitment and will,non-compliance with standards(or lack of standards)and protocols to ensure data of comparable quality,lack of planning to ensure that data are available
245、from the areas where they are most needed,and sometimes years of delay between data collection and findings being shared with relevant stakeholders.This pillar calls for strengthened surveillance capacity,as well as increased technical and laboratory capacity to provide expanded coverage of the data
246、 on antimalarial drug efficacy and resistance in Africa.It builds upon the significant investments already made in regional networks and in-country collaborations.Four key interventions to address the challenges have been identified.They have country,regional and global components and will need to b
247、e prioritized based on the assessment of the current local drug efficacy and resistance situation,data and resource availability.Pillar I Intervention 1|Enhance capacity and capabilities to generate better quality and standardized data on antimalarial drug efficacy and parasite resistanceUnderlying
248、issueThere is a lack of available,good-quality data on antimalarial drug efficacy and resistance in many areas of Africa.The low quality and limited standardization of collected data hinder the effectiveness of the surveillance and response to resistance.For example,TESs are sometimes not conducted
249、according to WHO standard protocols,which has resulted in the need to repeat some studies in the past(46).In addition,there is insufficient capacity to conduct genetic and pharmacokinetic studies.The establishment of a strong resistance surveillance in Africa,including adequate protocols,external qu
250、ality assessment systems,laboratory capacity and data analytics,faces several challenges.Suggested interventionsPromote adherence to standard TES protocols:producing standardized data of comparable quality requires adherence to WHO standard TES protocols,available on the WHO Global Malaria Programme
251、 website(47).To conduct quality TESs,ministries of health and research institutes must be supported through continuing training,including for microscopists.Supervision and quality control around microscopy,data entry and classification should be strengthened to ensure that WHO protocols are followed
252、.All TESs must be done with preferably prequalified drugs or quality-controlled.In addition,the analysis of known molecular markers of antimalarial drug resistance(see list provided in the WHO Report on antimalarial drug efficacy,resistance and response:10 years of surveillance(20102019)(14)should b
253、e systematically included in TES protocols.When frequent treatment failures are detected in a good-quality study,additional TES studies are rapidly needed,including the Strategy to respond to antimalarial drug resistance in Africa20collection of information on drug levels in the blood on day seven,e
254、specially for lumefantrine(see section 3.1)as set out in the TES protocol(48).A major challenge in high transmission settings is to correctly distinguish recrudescence from new infection.A possible strategy in sites located in high transmission settings where high failure rates have been reported is
255、 to provide insecticide-treated nets and topical repellents for patients enrolled in TESs to limit the risk of reinfection.Nevertheless,reinfections can provide valuable information on the prophylactic effect of an antimalarial drug,which starts to decline when susceptibility to the drug is decreasi
256、ng.Reinfections could be considered early signals of emerging resistance,with the limitation that these signals should be interpreted based on the drugs half-life(49).Set up or reinforce laboratories for genomic and pharmacokinetic studies:current investments to build strong genomic expertise in Afr
257、ica through knowledge sharing and dedicated training programmes should be pursued,building on currently funded initiatives.Similarly,additional investments are also needed for increasing laboratory capacity for accurate measurement of antimalarial drug concentrations.Regional reference centres shoul
258、d be considered,using the experience gained during the COVID-19 pandemic.These regional reference centres would increase the capacity,quality and timeliness of PCR correction and surveillance of molecular markers,as well as measurements of drug levels in blood.They could conduct analyses for countri
259、es lacking internal capacity and act as training centres for neighbouring countries.Finally,strong quality control systems among laboratories are needed.Field specimens,control strains,and a mixture of both could be cross-analysed by the reference laboratories.Although in vitro/ex vivo studies can b
260、e useful tools in the absence of confirmed molecular markers,setting up dedicated laboratories at the national level,conducting external quality control and sharing blood samples will raise specific issues.Address procurement challenges:increased effort and additional financing are needed to address
261、 the procurement challenges linked to the establishment of an efficient surveillance system.Global and regional stakeholders should investigate ways to reduce delays in supplying surveillance commodities such as primers or consumables(e.g.through faster customs clearance,customs tax exemptions)and t
262、o improve the affordability of African-sourced supplies.Pillar I Intervention 2|Increase coverage of surveillance systems for efficacy and resistanceUnderlying issueThe currently insufficient coverage of TESs limits the knowledge available on delayed clearance of parasites following ACT treatment an
263、d on ACT treatment failures.According to the WHO Malaria Threats Map,18 endemic African countries have not conducted or shared TES results since 2017(21).The number and coverage of sentinel sites is constrained by limited funding and political attention,and by the lack of studies in hard-to-reach co
264、mmunities and lower transmission areas.Information on molecular markers plays an important role in tracking resistance and should be leveraged to detect early warning signals.21Suggested interventionsReview and potentially reconsider the number of sites per country to conduct TESs:the current recomm
265、endation is to conduct TESs at least every two years at each site for first-and second-line drugs.Although no definitive scientific advice can be given about the number of sites needed per country,experience suggests that ideally four to eight sites,depending on the countrys size,will strike a balan
266、ce between representativeness and practicality.In defining the number of sites,programme managers should consider the countrys geographical size,population distribution and density,malaria epidemiology or ecology,and other factors deemed important by the programme.It is critical to select a“manageab
267、le”number of sites to ensure proper monitoring and supervision(50).Based on the number and location of existing sites,countries should look at intensifying surveillance activities in areas where data are lacking or where the risk of resistance is considered high,for instance areas with an influx of
268、migrants from areas with known resistance.Studies done in populations with partial immunity can result in higher efficacy estimates and lower delayed clearance.TESs should,therefore,aim to enrol populations with no or limited immunity,such as children under 5 years of age.Collect information on mole
269、cular markers:in addition to systematically including molecular markers in TESs,further surveys of molecular markers should be done independently,as such surveys can be conducted more easily and frequently than TESs.Although there is a lack of confirmed molecular markers of resistance for most partn
270、er drugs used in Africa,available molecular markers should be used as early warning signals and as tools for tracking the spread of resistance once it has emerged.Surveys should also be leveraged to collect information on additional markers,such as Pfhrp2/3 deletions.Pillar I Intervention 3|Increase
271、 collection of additional,more detailed data at select sitesUnderlying issueThe collection of standard TES data(i.e.evidence of treatment failure or delayed clearance)is not always sufficient to confirm resistance.For instance,identifying new molecular markers will require a correlation between clin
272、ical,in vitro and genetic evidence.This calls for increased data collection during TESs in select sites,combining in vivo,in vitro and pharmacokinetic studies with good longitudinal data over time.Suggested interventionCollect additional data from select sites:such an increase in the depth of resist
273、ance surveillance should be considered preferably in sites where an academic institution can support its development.At these sites,additional resources and capacity should be dedicated to performing,consistently and over space and time,a broad spectrum of tests in addition to TESs:molecular markers
274、,in vitro resistance studies(i.e.phenotyping assays),drug levels in the blood,and monitoring trends.Strategy to respond to antimalarial drug resistance in Africa22Pillar I Intervention 4|Improve data dissemination systems to facilitate a reactive and coordinated response to resistance dataUnderlying
275、 issueA reactive and coordinated response requires consistent and timely sharing of information within and among countries.However,data are not systematically made available to NMPs;sometimes years of delay occur between data collection and results being published and made available to NMPs.Differen
276、t networks have been built to facilitate data sharing,but their sustainability needs to be ensured.Suggested interventionsRe-establish or strengthen subregional networks of antimalarial drug resistance and efficacy surveillance:these networks should facilitate transparent communication of data on dr
277、ug efficacy and resistance,and,to ensure coordination and sustainability,they should leverage WHOs experience as Secretariat for similar networks,such as the Horn of Africa Network for Monitoring Antimalarial Treatment(51)or the Greater Mekong subregion Therapeutic Efficacy Study Network(52).Collate
278、 data into a worldwide data repository:data on antimalarial drug efficacy and resistance should be collated into a single repository to enable visibility on and access to resistance trends worldwide.WHO should be leading and coordinating this effort.To this end,country,regional and subregional netwo
279、rks should more systematically share data with WHO to inform the Malaria Threats Map(21).This Strategy calls for strengthening the existing system,as the database already consolidates data on parasite drug efficacy and resistance,in addition to data on insecticide resistance in malaria vectors,paras
280、ite Pfhrp2/3 gene deletions,and invasive anopheline vectors.Currently,data are submitted by Member States,academia,research institutions and WHO partners,or are extracted from scientific publications.Leverage in-country working groups:at country level,NMPs should leverage existing working groups or
281、build dedicated ones to collect,analyse and discuss data,and to ensure that reactive measures are taken in response to high treatment failures reported in TESs.The working groups should include a diverse panel of stakeholders,such as researchers,academics,care providers,representatives of the minist
282、ry of health,and civil society,with the breadth of scope defined by each country.5.2.2.Pillar II:Optimize and better regulate the use of diagnostics and therapeutics to limit drug pressure through pre-emptive measuresProtecting the efficacy of existing ACTs is an immediate priority.The suboptimal us
283、e of existing diagnostics and therapeutics can increase drug pressure on the parasite population.From a supply perspective,factors such as the inability to enforce stringent regulatory standards,the lack of availability of a diversified portfolio of quality-assured drugs at country level,and the cir
284、culation of substandard or falsified drugs and non-recommended monotherapies can increase drug pressure unnecessarily.From a demand perspective,the lack of demand for alternative drugs to artemether-lumefantrine and artesunate-amodiaquine,as well as the inappropriate use of available antimalarial dr
285、ugs and diagnostics due to provider or patient behaviour could further contribute to the emergence and spread of antimalarial drug resistance.23This pillar calls for a more deliberate use of diagnostics and antimalarials to reduce drug pressure,notably through better adherence to WHO recommendations
286、 and full use of the diversity of tools available in the set of antimalarial compounds.To ensure the availability,affordability and quality of these tools,the global malaria community should use its combined market-shaping power to achieve healthier malaria commodity markets,while being mindful of t
287、he need to promote innovation,in support of African-led efforts.Seven interventions to address these challenges have been identified.The prioritization of these interventions should be based on each countrys baseline assessment in terms of treatment policy and enforcement capacity,access,availabilit
288、y and use of diagnostics and drugs,and current behavioural drivers of care provider and patient choices.Pillar II Intervention 1|Develop national treatment policies that promote deliberate use of existing treatments to prevent and react to the emergence and spread of resistanceUnderlying issueNot al
289、l national treatment guidelines in Africa systematically recommend different ACTs for first-and second-line treatment of uncomplicated P.falciparum cases.For first-line treatment,there is an over-reliance on a limited number of ACTs in Africa,increasing the risk of the emergence and spread of partne
290、r drug resistance.For second-line treatment,when countries do not include a different ACT in their guidelines,patients with recurrent infections(potentially recrudescent infections)are likely to be treated with the same drug again.The continued use of failing ACTs can exert additional selective pres
291、sure on malaria parasites,increasing the risk of transmitting parasites with reduced drug sensitivity.Additionally,although the private sector is often the first place that many patients go to seek treatment for febrile illness,it is often poorly regulated and unsupervised.This leads to non-complian
292、ce with national policies and guidelines.There is often no clear guidance or policies to support collaboration between the public and private sectors(53).Suggested interventionsInclude different ACTs for first-and second-line treatment of uncomplicated P.falciparum cases in all national treatment po
293、licies.Develop and regularly update detailed national treatment guidelines:the guidelines should take into account the latest evidence on local antimalarial drug efficacy and resistance patterns and health system capacities,as recommended by the GTS(1).Additionally,regional patterns of resistance an
294、d drug use should be considered when developing a national treatment policy.As a pre-emptive measure to delay the emergence and spread of partner drug resistance,countries could consider adding alternative ACTs recommended by WHO to their national treatment guidelines.For new ACTs to be introduced i
295、nto national policies,they should have over 95%efficacy,as demonstrated through therapeutic efficacy monitoring.For ACTs already recommended in the guidelines,a significantly declining trend in treatment efficacy over time,even if failure rates have not yet reached the 10%cut-off as per the WHO Guid
296、elines for malaria(54),should alert programmes to undertake more frequent monitoring and to prepare for a potential policy change.To this effect,and in line with the Strategy to respond to antimalarial drug resistance in Africa24GTS recommendations(1),countries should pre-plan for a rapid treatment
297、policy change,with the support of global partners including funding agencies and donors,to avoid delays when switching to another ACT.Once it has been confirmed that the failure rate is over 10%in quality-controlled studies using the WHO protocols,the treatment policy change should be implemented to
298、 ensure that patients receive efficacious treatment and to prevent the further spread or increase of any resistance.Review and revise country policies and regulations to support and promote the implementation of appropriate case management across health sectors,with an intensified effort towards the
299、 private sector(52):there should be clarity and consistency of policies and regulations regarding where antimalarials can be accessed and who can prescribe and/or sell them,as well as where and by whom RDTs can be performed,taking into account patient care-seeking practices.Where possible(e.g.in the
300、 presence of a well structured private sector),national policies should be disseminated and promoted to non-public providers.Policy-makers and regulators should also be aligned on the technical specifications required for health products(diagnostics and medicines)(53).There should be robust supervis
301、ion and enforcement of existing and new regulations,supported by training and follow-up programmes.When conducting mass drug administration and chemoprevention strategies this should be done with drugs that differ from those used for treatment:in a given country,there should be no or limited use of
302、the drugs or long-acting components of existing first-or second-line treatment in the regimens used for mass drug administration or chemoprevention strategies.Pillar II Intervention 2|Promote the availability of a diversified drug portfolio in countriesUnderlying issueA diversified drug portfolio an
303、d production capacity,especially in endemic countries,is needed to limit the reliance on a few drugs and manufacturers.This will ensure that alternative ACTs are available and countries are able to use all ACTs recommended in their national treatment guidelines.However,the diversity of antimalarial
304、drugs available globally is not necessarily reflected in the drugs available in countries in Africa.The higher cost of ACTs other than artemether-lumefantrine and artesunate-amodiaquine and the logistical challenges of managing a second-line treatment have resulted in a lack of demand for alternativ
305、e treatments(see Box 1).Lack of demand can hinder supply and generate a vicious cycle that leads to a limited number of suppliers for alternative WHO-prequalified ACTs,such as artesunate-pyronaridine and dihydroartemisinin-piperaquine.To date,there is only one supplier producing prequalified artesun
306、ate-pyronaridine,one producing prequalified artesunate-mefloquine and two producing prequalified dihydroartemisinin-piperaquine(11).This limited number of manufacturers increases the vulnerability of countries should resistance to partner drugs such as lumefantrine or amodiaquine be confirmed in Afr
307、ica.In addition to limited production,problems along the supply chain,such as stockouts,limit access to quality treatment(55).Poor country preparedness to rapidly introduce new drugs can impede a prompt and efficient response to the loss of an ACTs efficacy.25Box 1.Forecasted donor-funded ACT procur
308、ement by drug(20212024),Clinton Health Access Initiative(56)Figure 7 shows that artemether-lumefantrine is expected to maintain 7788%of the market share.Artesunate-amodiaquine volumes are expected to remain the second highest for ACTs.Dihydroartemisinin-piperaquine and,to a greater extent,artesunate
309、-mefloquine and artesunate-pyronaridine volumes are projected to stay marginal in the short term.Figure 7.Donor-funded ACT procurement from 2021 to 202423224823923002003004002023Treatments(millions)202220229729613151013artemether-lumefantrineartesunate-mefloquineartesunate-amod
310、iaquineartesunate-pyronaridinedihydroartemisinin-piperaquineSuggested interventionsStreamline local registration of ACTs:beyond continued research into new treatments,it is important to ensure that the drugs currently available globally are also available in-country when needed.An important step tow
311、ards building a diversified portfolio in-country is the promotion of ACT registration by national regulatory authorities.Countries should streamline their internal processes,for instance by creating expedited registration pathways for products that are already prequalified by WHO,to reduce time to m
312、arketing authorization(57).Globally,a concerted effort should be aimed at reducing the overall timelines for the introduction of new products from inclusion in WHO guidelines to in-country roll-out.Address production capacity issues:as for the most used treatments,artemether-lumefantrine and artesun
313、ate-amodiaquine,production capacity is geographically consolidated far from where the drugs are consumed,creating inefficiencies that can compromise the timely supply of treatments.Countries should seek to reduce their vulnerability to global supply chain disruptions as highlighted by the significan
314、t disruptions experienced during the COVID-19 pandemic.Therefore,diversifying production capacity,for instance by increasing production capacity in Africa,should be considered to ensure the availability of these treatments.The significant volumes procured should also be leveraged to further shape ma
315、rkets(see Box 2),for example by directing volumes to local manufacturers and ensuring that the market is not too fragmented so that price-breaking volumes can be achieved across multiple manufacturers.In addition to guaranteeing sustainable production of existing ACTs,this should also incentivize St
316、rategy to respond to antimalarial drug resistance in Africa26innovation to develop new medicines.However,this diversification might bring some challenges,such as higher costs(e.g.lower volumes,tariffs on imported active pharmaceutical ingredients,export taxes,limited infrastructure)and the need to e
317、nsure that international quality standards are met.Therefore,such efforts should be further analysed and discussed among relevant stakeholders.The lack of demand for other ACTs has resulted in a very limited number of manufacturers producing these alternative treatments.To encourage an increase in p
318、roduction capacity,the global malaria community should work to ensure sufficient demand for treatment alternatives to artemether-lumefantrine and artesunate-amodiaquine,starting by ensuring that ACTs are recommended and procured as second-line treatments.Box 2.Market-shaping implicationsEquitable ac
319、cess to quality and affordable therapeutics and diagnostics is a key requirement not only to ensure good malaria care,but also to prevent the emergence and spread of resistance.While the WHO Guidelines for malaria(54)currently recommend six different ACTs,artemether-lumefantrine and artesunate-amodi
320、aquine represent the bulk of ACTs procured through pooled procurement channels(85%and 15%of GFATM Pooled Procurement Mechanism orders,respectively).There is a global need for widely available and affordable alternative treatments to artemether-lumefantrine and artesunate-amodiaquine,not only as a pr
321、eventive measure to diminish drug pressure,but also as a reactive measure to enable countries to rapidly switch first-or second-line treatments in the event of suspected or confirmed partner drug resistance.The uptake of alternative treatments,such as dihydroartemisinin-piperaquine or artesunate-pyr
322、onaridine,is hampered by several market challenges,such as high prices,limited demand and few suppliers,resulting in a vicious circle of limited supply and demand.On the diagnostic front,since parasites with dual Pfhrp2 and Pfhrp3 gene deletions have been reported,there is a need for non-HRP2-only R
323、DTs,for instance RDTs targeting the Plasmodium lactate dehydrogenase protein,alone or in combination with the HRP2 protein.HRP2 RDTs still represent the vast majority of the malaria RDT market,with limited options for combination Plasmodium lactate dehydrogenase+HRP2 RDTs.Additionally,the malaria RD
324、T market faces multiple challenges,as it is extremely concentrated and heavily commoditized,with limited space for innovation.Focusing on these two product categories,there is a unique opportunity to identify and implement appropriate market interventions that could help shape these markets,with the
325、 objective of reaching price-breaking volumes while not disincentivizing investment in innovation.Lessons learned from more successful product introductions,such as that of dual active ingredient insecticide-treated nets,should be analysed and leveraged.The New Nets Project combines a volume guarant
326、ee underwritten by the Bill&Melinda Gates Foundation and MedAccess with a co-pay mechanism funded by a GFATM strategic initiative and Unitaid funding.This project has resulted in a rapid increase in the availability of dual active ingredient nets and a sharp decline in prices,while generating critic
327、al data to inform a WHO recommendation.Such initiatives will also be critical to prepare for the introduction of the next-generation therapeutics currently under development.A concerted effort will be required to commercialize the new molecules in a timely manner,widely and at an affordable price.Co
328、untry-level activities,such as updating national guidelines,registering these products and designing procurement plans,will also be crucial to make this a reality.It is now critical for global partners to join forces and address market failures.The two examples described above regarding ACT diversit
329、y and RDT alternatives should be investigated as part of a broader market-shaping strategy.Such a strategy should aim at addressing both demand-and supply-side barriers.27Further explore procurement opportunities:finally,a diversified product portfolio relies on an efficient procurement system.Regio
330、nal pooled procurement initiatives could be explored to complement global mechanisms such as the Pooled Procurement Mechanism operated by GFATM.Pooling demand could support the need for rapid procurement when changing policies(e.g.switching ACTs rapidly)and respond to the need for small batches,for
331、instance,if only a few second-line treatments are needed.In a few instances,GFATM and the United States Presidents Malaria Initiative have implemented initiatives to meet minimum order quantities,and these could be further developed in the future.Similar initiatives were piloted in Africa during the
332、 COVID-19 pandemic,such as the Africa Medical Supplies Platform for diagnostics and therapeutics and the African Vaccine Acquisition Task Team for vaccine access,under the African Union umbrella and funded through World Bank loans.Potential bottlenecks such as inventory holding cost,risk of expiry,r
333、isk of deterioration,administratively burdensome processes,and country-specific requirements should be evaluated and accounted for.At country level,efficient and flexible national procurement plans should be designed so that drugs can quickly be made available and stockouts avoided.Capacity-building to conduct local needs assessments and demand quantification should be undertaken.Incentivizing fac