THE USE OF ANTIMALARIAL DRUGSReport of an Informal ConsultationWorld Health Organization, Geneva WHO, 2001THE USE OF ANTIMALARIAL DRUGSWHO/CDS/RBM/2001.33Roll Back Malaria World Health Organization20, avenue Appia CH-1211 Geneva 27, SwitzerlandTel: +(41) 22 791 3606, Fax: +(41) 22 791 4824, E-mail: rbm@who.intWeb site: http://www.rbm.who.int/ Copyright 2001 by Roll Back Malaria/World Health OrganizationThisdocumentisnotaformalpublicationoftheWorldHealthOrganizationandallrightsarereserved by the organization. The document may, however, be freely reviewed, abstracted, reproducedortranslated,inpartorinwhole,butnotforsalenorforuseinconjunctionwithcommercialpurposes.The designation employed and the presentation of the material in this publication, including mapsand tables do not imply the expression of any opinion whatsoever on the part of the secretariat of theWorld Health Organization concerning the legal status of any country, territory, city or area of itsauthorities,orconcerningthedelimitationofitsfrontiersorboundaries.Dottedlinesonmapsrepresent approximate border lines for which there may not yet be full agreement.The mention of specific companies or certain manufacturers products does not imply that they areendorsedorrecommendedbythe WorldHealthOrganizationinpreferencetoothersofasimilarnature that are not mentioned. Errors and omission excepted, the names of proprietary products aredistinguished by initial capital letters.Technical Review: A. Bosman, C. Delacollette, P. Olumese, R. G. Ridley, A. RietveldR. Shretta, A. TeklehaimanotText editor: S. PooleLayout and production: WHO & Graficim Cover photo courtesy of H. AnendenThe authors wish to recognise the contributions made to the writing of this report at country levelby Ministries of Health and other partners, Regional Offices of WHO, and at a global level bymission reports, partners and the RBM team.CONTENTSIntroduction...............................................................................................................................................................................................................................................................................................................5PART I POLICYIMPLICATIONS1. Current statusof antimalarial drug resistance............................................................................................................................................................................................81.1 Development of resistance.......................................................................................................................................................................................................................................81.2 Assessment of antimalarial drug susceptibility..........................................................................................................................................................................91.3 Plasmodiumfalciparumresistance.............................................................................................................................................................................................................101.4 Plasmodiumvivax resistance..............................................................................................................................................................................................................................121.5 Regional responsesto antimalarial drug resistance.........................................................................................................................................................122. Combination therapy..................................................................................................................................................................................................................................................................172.1 Definitions...................................................................................................................................................................................................................................................................................172.2 Rationalefor theuseof combination therapy.......................................................................................................................................................................172.3 Artemisinin-based combination therapy........................................................................................................................................................................................18 2.4 Implementation of combination therapy operational issues.....................................................................................................................203. Chemoprophylaxisand treatment of malaria in special groups..................................................................................................................................203.1 Chemoprophylaxisand intermittent treatment of malaria in pregnancy....................................................................................203.2 Chemoprophylaxisand stand-by treatment in travellers......................................................................................................................................213.3 Management of severemalaria......................................................................................................................................................................................................................243.4 Vivax malaria...........................................................................................................................................................................................................................................................................243.5 Formulationsfor paediatric use...................................................................................................................................................................................................................244. Antimalarial treatment policies.....................................................................................................................................................................................................................................254.1 Definition......................................................................................................................................................................................................................................................................................254.2 Purpose..............................................................................................................................................................................................................................................................................................254.3 Development............................................................................................................................................................................................................................................................................264.4 Factorsinfluencing antimalarial treatment policies.......................................................................................................................................................274.5 Health-seeking behaviour.....................................................................................................................................................................................................................................324.6 Criteria for changing treatment policy.............................................................................................................................................................................................334.7 Processof changing treatment policy: country examples.....................................................................................................................................344.8 Implementation and accessto antimalarial drugsin endemic countries......................................................................................385. Conclusionsand recommendations......................................................................................................................................................................................................................395.1 General..............................................................................................................................................................................................................................................................................................395.2 Futureresearch and other activities........................................................................................................................................................................................................41PART II ANTIMALARIAL DRUGS1. Antimalarial drugsfor malaria prevention and treatment ...................................................................................................................................................43Chloroquine...............................................................................................................................................................................................................................................................................................43Amodiaquine............................................................................................................................................................................................................................................................................................47Antifolatedrugs(sulfa drugpyrimethaminecombinations)..........................................................................................................................................50Proguanil.........................................................................................................................................................................................................................................................................................................54Mefloquine..................................................................................................................................................................................................................................................................................................56Quinine, quinidineand related alkaloids......................................................................................................................................................................................................62Halofantrine...............................................................................................................................................................................................................................................................................................67Artemisinin and itsderivatives.......................................................................................................................................................................................................................................69Primaquine..................................................................................................................................................................................................................................................................................................80Antibioticsused asantimalarial drugs................................................................................................................................................................................................................85Atovaquoneproguanil ..............................................................................................................................................................................................................................................................90Chloroquineproguanil.......................................................................................................................................................................................................................................................... 93Artemetherlumefantrine......................................................................................................................................................................................................................................................94Mefloquinesulfadoxinepyrimethamine.....................................................................................................................................................................................................962. Statusand potential of combination therapies.....................................................................................................................................................................................972.1 Past or present co-administered (non-fixed) combinations.............................................................................................................................972.2 Combinationsundergoing consideration or trial.............................................................................................................................................................972.3 Potential combinationsunder consideration or trial with not yet availabledrugs.........................................................99ReferencesAnnex 1. List of participants.....................................................................................................................................................................................................................................................117 Annex 2. Guidanceon theselection of drugsfor national antimalarial treatment policies......................................................120Annex 3. Common antimalarial drugsthat should beconsidered in drug selection........................................................................ 136Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000ABBREVIATIONSACR adequate clinical responseACT artemisinin-based combination therapyAIDS acquired immunodeficiency syndromeAQ amodiaquineART artemisininASU artesunateAT atovaquoneATM artemetherAUC area under curve (timeconcentration)Cmaxmaximum plasma concentrationCD clindamycinCNS Central NervousSystemCQ chloroquineCT combination therapyD doxycyclineDHFR dihydrofolate reductaseDHPS dihydropteroate synthetaseEANMAT East African Network for Monitoring Antimalarial TreatmentsETF early treatment failureGI Gastro-intestinalG6PD glucose-6-phosphate dehydrogenaseHAL halofantrineHIV human immunodeficiency virusHPLC-ECD high-performance liquid chromatography-electron capture detectionLTF late treatment failureLUM lumefantrineMQ mefloquineP. falciparum PlasmodiumfalciparumP. ovale PlasmodiumovaleP. malariae PlasmodiummalariaeP. vivaxPlasmodiumvivax PAHO Pan American Health OrganizationPQ primaquineQ quinineRDT rapid diagnostic testSP sulfadoxinepyrimethamineT tetracyclineWHO World Health Organization4THE USE OF ANTIMALARIAL DRUGSINTRODUCTIONThe WHO Informal Consultation on the Use of Antimalarial Drugswasheld from 13 to17 November 2000 in Geneva, Switzerland. The participantsreflected a broad range of expertisein the development and use of antimalarial drugs, and in the implementation and adaptation ofantimalarial treatment policies(see Annex 1 for List of participants). Early diagnosisand prompt treatment are fundamental componentsof the WHO globalstrategy for malaria control (1). Correct use of an effective antimalarial drug will not only shortenthe duration of malaria illness but also reduce the incidence of complications and the risk ofdeath. Antimalarial drug resistance hasspread and intensified over the last 1520 years(24),however, leading to a dramatic decline in the efficacy of the most affordable antimalarial drugs.Development of new drugsisnot keeping pace (5), and problemsrelated to the distribution anduse of these drugshave compounded the situation. In many malariousareas, a majority of thepopulationdoes nothavereadyaccess toantimalarialdrugs andtoreliableandconsistentinformation about malaria treatment and prevention (6). Moreover, those drugsthat are availableare frequently obtained from informal sourcesand may be counterfeit; they are of variable quality,maybepartiallyorcompletelyineffectiveagainstlocalparasitestrains,andareoftenusedininappropriate dosages(7). Many endemic countriesare beginning to face a situation in which there are no affordable,effective antimalarial drugsavailable. Combination therapy offershope for preserving the efficacyof antimalarial drugsand prolonging their useful therapeutic life (811), although it may notnecessarilyprovidebettertreatmentforconsumers.Thedevelopmentofartemisininanditsderivativesthe most rapidly acting of all the current antimalarial drugsand recognition oftheir potential role asa component of combination therapy (8, 9, 12, 13) have led to several largetrialsaimed at assessing different combinationsof existing drugs, and to the specific developmentofnewcombinationdrugs.Inaddition,severalcountries havefelttheneedtoevaluate,aspotential first-line treatments, drug combinationsthat do not include artemisinin. These changeshave provided an impetusfor updating and rationalizing antimalarial treatment policies.National antimalarial treatment policiesare essential to provide countrieswith a frameworkforthesafeandeffectivetreatmentofuncomplicatedandseveremalariaas wellas fortheprevention of malaria in travellersand in vulnerable groups, such aspregnant women and youngchildren. Asa general principle, such policiesshould aim at the greatest possible reduction ofmalaria mortality and morbidity, while containing the development of resistance and remainingcompatible with limited national health budgetsand health care infrastructures. All health careprovidersin both the public and private health sectorsmust be aware of, understand the rationalefor, and implement the national policy. Such national policiesshould be updated to take accountof the development of antimalarial drug resistance in the country. A framework for thispurposehasbeen developed for use in Africa (14). The treatment of severe malaria iscovered comprehensively in the Transactionsof theRoyalSocietyof Tropical Medicineand Hygienesupplement Severe falciparum malaria (15). The use ofantimalarialdrugs forchemoprophylaxis andthepreventionandtreatmentofuncomplicatedmalaria waslast reviewed at a WHO informal consultation in September 1995 (16), which alsoconsidereddiagnosis andtheprinciples ofclinicalmanagement.Sincethen,considerableadditional experience hasbeen gained in the use of existing and new antimalarial drugs, alone andin combination. 5Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000In view of the new evidence available on malaria prevention and treatment and on thefurtherspreadofresistancetoantimalarialdrugs,WHOconsideredittimelytoconveneaninformal consultation to: reviewandupdaterecommendations ontheuseofantimalarialdrugs formalariaprevention and the treatment of uncomplicated malaria; assessthe implicationsof the latest drug developmentsfor national antimalarial treatmentpolicies.The informal consultation took the form of presentationsof prepared papers, followed bydiscussionsduringwhichspecificconclusionsandrecommendationswereagreed.Theproceedingsof the consultation and the working papersform the basisof thisreport.Thereportis aimedatmanagers ofnationalmalariacontrolprogrammes andthoseinvolvedinimplementingantimalarialtreatmentpolicies.PartIprovides informationonthecurrentstatus ofantimalarialresistancethroughouttheworld,considers thepotentialforcombination therapy, updatesrecommendationson the prevention and treatment of malaria inspecifictargetgroups,andoutlines thedevelopmentandimplementationofanantimalarialtreatment policy. Part II describesthe antimalarial drugsand recommended regimensin currentuseformalariapreventionandforthetreatmentofuncomplicatedmalaria.Italsocoversantimalarial drugsunder development. The report also presentsoptionsfor different treatmentscenariosaccording to specific epidemiological situations. Individual countrieswill need to adaptthe recommendationsmade in thisreport to their own epidemiological and health care context. 6THE USE OF ANTIMALARIAL DRUGSPART IPOLICY IMPLICATIONS8THE USE OF ANTIMALARIAL DRUGS1. CURRENT STATUS OF ANTIMALARIAL DRUG RESISTANCE1.1 Developmentofresist anceAnt imalarial drug resist ance is t he abilit y ofa parasit e st rain t o surviveand/ or mult iply despit e t he administ rat ion and absorpt ion ofa drug givenin doses equal t o or higher t han t hose usually recommended, butwit hinthe limits of tolerance of the subject (17).Resistance to antimalarial drugsarisesasa result of spontaneously-occurring mutationsthataffect the structure and activity at the molecular level of the drug target in the malaria parasite oraffect the accessof the drug to that target (18). Mutant parasitesare selected if antimalarial drugconcentrationsare sufficient to inhibit multiplication of susceptible parasitesbut are inadequatetoinhibitthemutants,aphenomenonknownas drugselection(11,19). This selectionisthought to be enhanced by subtherapeutic plasma drug levelsand by a flat doseresponse curveto the drug. TheevolutionofdrugresistanceinPlasmodiumis notfullyunderstoodalthoughthemolecular basisfor resistance isbecoming clearer. The development of resistance to chloroquineprobably requiressuccessive gene mutationsand evolvesslowly. Recent evidence indicatesthat forP.falciparum someofthesemutations occurinatransporter-likegeneonthesurfaceoftheparasite food vacuole (20). Preliminary reportssuggest that a different set of mutationsisprobablyinvolvedinchloroquineresistanceforP.vivax(20).Themolecularbasis forresistancetoantifolates,suchas sulfadoxinepyrimethaminehas beenwellcharacterized.P.falciparumresistancetosulfadoxinepyrimethamineis primarilyconferredbysuccessivesingle-pointmutations inparasitedhfr, thegenethatencodes thetargetenzymedihydrofolatereductase(DHFR), and by additional mutationsin dhps, which encodesfor the enzyme dihydropteroatesynthetase (DHPS) (21).Variousfactorsrelating to drug, parasite and human host interactionscontribute to thedevelopment and spread of drug resistance. The molecular mechanism of drug action isa criticalelementinthespeedatwhichresistancedevelops.Inaddition,drugs withalongterminaleliminationhalf-lifeenhancethedevelopmentofresistance,particularlyinareas ofhightransmission. Similarly, increased drug pressure isa significant contributor to drug resistance. Asincreased amountsof a drug are used, the likelihood that parasiteswill be exposed to inadequatedrug levelsrisesand resistant mutantsare more readily selected (22). Parasite factorsassociatedwithresistanceincludethePlasmodiumspecies concernedandtheintensityoftransmission.Humanhostfactors includethewidespreadand/orirrationaluseofantimalarialdrugs andpossiblythelevelofhostimmunity. Theroleofhostimmunityinpropagatingresistanceisunclear. However, immunity actssynergistically with chemotherapy and can enhance therapeuticeffectsand even parasite clearance of drug-resistant infections.The increase in chloroquine resistance in East Africa hasled to a rise in malaria mortality(4). Similarly, a significant rise in malaria mortality in children under 5 yearsof age hasbeenobseved in Senegal in West Africa, coinciding with the emergence of chloroquine resistance in thearea(23). Theincidenceofseveremalariahas risenwithincreasingchloroquineresistancein9Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000Malawi and Democratic Republic of the Congo (24). Antimalarial drug resistance hasalso beenimplicated in the increasing frequency and severity of epidemics(3).Conditionsfor the development and spread of drug resistance differ between the Asian andAfrican continents. Migration of individualscarrying resistant gametocyteshasprobably been ofmajor importance for the spread of chloroquine resistance between different endemic areasin Asiaand Oceania and the initial introduction of chloroquine resistance to East Africa.1.2 Assessmentofant imalarial drug suscept ibilit yParasite susceptibility to antimalarial drugscan be assessed by in vitroor in vivotechniques.In vitrotechniquesrely on the collection of parasitized blood from patientsand the testing ofparasite susceptibility to drugsin culture or by the use of molecular techniquessuch asPCR. Invivotechniquesrely on monitoring of the symptomsassociated with malaria, such asfever, andparasitaemia (25).A major purpose of assessing the therapeutic efficacy of antimalarial drugsin confirmedmalaria patientsisto monitor efficacy over time, especially in vulnerable groupsin highly endemicareas, and to guide treatment policy. Antimalarial drug responsesare assessed clinically from ratesofsymptomresolutione.g.feverclearance,comarecovery,orparasitologicallyfromparasiteclearance and overall cure rates. Until the end of the 1980s, most in vivostudiesfocused on the parasitological response toa given drug, and infectionswere classified assensitive (S), or resistant (R) at one of three levels,RI,RIIorRIII.AnRIresponsecorresponds toaninitialclearanceofparasitaemiaandthenrecrudescence8ormoredays aftertreatment;anRIIresponseis theclearanceorsubstantialreduction of parasitaemia with recrudescence of parasitaemia on day 7; and an RIII response refersto a situation in which there isno initial reduction of asexual parasitaemia and the levelsmayactually increase (17). Follow-up of treated patientsfor evidence of recurrence of parasitaemia maycontinue for 7, 14 or 28 days, depending on the investigators interest in detecting lower levelsofresistance and on budgetary limitations(2628). Protocols have been modified and simplified to facilitate their use in high-transmissionareasin Africa, where populationsmay have asymptomatic parasitaemia in the absence of clinicalmanifestation. The generally accepted objective of malaria treatment in these areasisnot so muchthe clearance of parasitaemia but the resolution of clinical symptomsand acute febrile illnessasmeasured by the adequate clinical response (ACR) and early and late treatment failure (ETF andLTF)(29).Thetherapeuticresponseis classifiedas ETFifthepatientdevelops clinicalorparasitological symptomsduring the first 3 daysof follow up; and asLTF if the patient developssymptomsduring the follow-up period from day 4 to day 14, without previously meeting thecriteria for ETF. ACR isdefined aseither the absence of parasitaemia on day 14 (irrespective ofaxillary temperature), or the absence of clinical symptomson day 14 (irrespective of parasitaemia),in patientswho did not meet the criteria of ETF or LTF before. Although the measurement ofclinical response isof value in areasof high transmission, the impact of asymptomatic residualparasitaemia on other malaria-related conditions, such asanaemia and malnutrition, hasnot beenexamined (2).WHO hasfurther adapted a protocol for use in areaswith moderate or low endemicity(large areas in South-East Asia, the Western Pacific region, the Eastern Mediterranean region,South America and Central America, and partsof tropical Africa) using the same classification.10THE USE OF ANTIMALARIAL DRUGSHowever, in these areas, the objective of malaria treatment isthe clearance of the parasitaemia aswell asthe resolution of clinical symptoms.Experienceinmalariacontrolprogrammes has shownthatinvitro tests ofparasitesusceptibility to antimalarial drugscannot substitute for in vivoobservationson malaria therapy.However, they are a useful research tool to provide background information for the developmentandevaluationofdrugpolicies andcanprovideanearlywarningoftheappearanceofdrugresistance. They are best used to define specific aspectsof the temporal and geographical responseto drugs: longitudinal follow-up of drug susceptibility of the parasitesin areaswhere changesareintroduced compared with those where such changesare not implemented; longitudinal follow-up of susceptibility to a drug previously withdrawn because of an unacceptable level of resistance;monitoring of cross-resistance patterns; and the establishment of baseline data on responsesto anew antimalarial drug prior to itsdeployment for treatment. The application and usefulnessof invitrotestsisrestricted by the need for trained personnel and their labour-intensive nature.1.3 Pl asmodi um f al ci par um resist ance A global picture of reduced susceptibility of P.falciparum to variousantimalarial drugsisprovided in figure 1.ChloroquineStrainsof P.falciparum resistant to chloroquine were first suspected in Thailand in 1957and found in patientsin Colombia and Thailand in 1960. Since then, resistance to thisdrug hasspread widely and there isnow high-level resistance to chloroquine in South Asia, South-EastAsia, Oceania, the Amazon Basin and some coastal areasof South America. In Africa, chloroquineresistance wasfirst documented in the United Republic of Tanzania in 1979 and hasspread andintensified in the last 20 years. In most countriesof East Africa and in Ethiopia more than 50%ofpatients currentlyexperiencearecurrenceofparasitaemiawithsymptoms byday14aftertreatment. Moderate levelsof resistance are found in central and southern Africa. In West Africa,reported ratesof resistance vary widely but tend to be lower than in central and southern Africa.Strainsof P. falciparum remain sensitive to chloroquine in Central America north of the PanamaCanal,theislandofHispaniola(HaitiandtheDominicanRepublic)andinElFaiymgovernorate in Egypt.AmodiaquineAlthough amodiaquine isgenerally more effective than chloroquine against chloroquine-resistantstrains ofP.falciparum (30),thereis cross-resistanceandmoderate-to-highlevels ofamodiaquine resistance have been reported from Papua New Guinea, East Africa and the AmazonBasin. Thisdrug continuesto be efficaciousasa single drug in most of West and central AfricaandonthenorthernPacificCoastofSouthAmericawhere,insomecountries,itis usedincombination with sulfadoxinepyrimethamine.Sulfadoxinepyrimet hamineHighlevels ofresistancetothis drugarefoundintheAmazonBasinandthroughoutSouth-East Asia, with the possible exception of some areasin eastern Cambodia and northernViet Nam. In East Africa resistance ratesare variable, ranging from 1050% in 14-day therapeutic11Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000efficacy trials. Low levelsof resistance (80%) of the imported casesof malaria reported in the EuropeanRegion are acquired in Africa. The largest number of caseshasbeen recorded in France, Germany,Italy and United Kingdom. At present P. falciparumaccountsfor almost 70% of cases. In theperiod 19891999, 680 people are known to have died from malaria in the European Region.17Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 20002. COMBINATION THERAPY2.1 Def init ionsCombination therapy with antimalarial drugs (CT) is the simultaneous use oftwo or more blood schizonticidal drugs with independent modes of action anddifferent biochemical targets in the parasite.Art emisinin-based combinat ion t herapy (ACT) is ant imalarial combinat iontherapy with an artemisinin derivative as one component of the combination.Combinat ion t herapies can be eit her fixed-combinat ion medicinal product s,in which the components are co-formulated in the same tablet or capsule, ormultiple-drug therapy, in which the components are co-administered in separatetablets or capsules.Note1. In accordance with these definitions, the following multiple-drug therapiesare NOTconsidered to be combination therapy: use of an antimalarial drug with a non-antimalarial drug that may enhance itsaction (e.g. chloroquine pluschlorpheniramine), use of a blood schizonticidal drug with a tissue schizonticidal or gametocytocidal drug(e.g. chloroquine plusprimaquine).Note2. Certain medicinal productsthat strictly speaking fit the criteria of synergistic fixed-dosecombinations are operationally considered as single synergistic products in that neither of theindividual componentsin itself would be given alone for antimalarial therapy. Examplesinclude: sulfadoxinepyrimethamine, chlorproguanildapsone, atovaquoneproguanil.2.2 Rat ionale f or t he use ofcombinat ion t herapyFixed-combinationandmultiple-drugtherapies areusedtoexploitthesynergisticandadditivepotentialofindividualdrugs.Theaimis toimproveefficacyandtoretardthedevelopment of resistance to the individual componentsof the combination. Thisconcept hasbeen realized in multiple-drug therapy for leprosy, tuberculosisand cancer and, more recently, inantiretroviral treatments. It hasalso already been realized to some extent in the field of malariawith the development of such drugsassulfadoxine-pyrimethamine, atovaquone-proguanil andmefloquine-sulfadoxine-pyrimethamine. Because of the continued increase of resistance to antimalarial drugsin many regionsof theworld, with the resultant effect on morbidity and mortality (23), it isessential to ensure rationaldeployment of the few remaining effective drugs, to maximize their useful therapeutic life whilestill ensuring that safe, effective and affordable treatment isaccessible to those at risk. Thisrequire-18THE USE OF ANTIMALARIAL DRUGSment hasresulted in a re-examination of the potential of combinationsof existing productsandthe development of new combination drugs.The rationale for the impact of CT on drug resistance isbased on the assumption that drugresistance essentially dependson mutation. Provided that the constituent drugsadministered inthe combination have independent modesof action, the probability that a mutant will arise thatissimultaneously resistant to both drugsisthe product of the respective mutation rates, multipliedby the number of parasite cellsexposed to the drugs(8, 10, 44). For example, if two drugsareused, and for each one a single mutational event conferscomplete resistance and such eventsoccurwith a frequency of 1:1010nuclear divisions, then the probability of a mutation resistant to bothdrugs is 1:1020.Thenumberofasexualparasites (parasitebiomass)duringanacutemalariainfection isusually between 109and 1014(44). 2.3 Art emisinin-based combinat ion t herapyThe particular features of ACT relate to the unique mode of action of the artemisinincomponent, which includesthe following: rapid and substantial reduction of the parasite biomass, rapid parasite clearance, rapid resolution of clinical symptoms, effective action against multidrug-resistant P. falciparum, reductionofgametocytecarriage,whichpotentiallyreduces transmissionofresistantalleles. There are also few reported adverse clinical effects(45), although preclinical toxicology dataon many artemisinin derivativesare limited. Because of the short half-life of artemisinin derivatives, their use asmonotherapy requiresdaily dosesover a period of 7 days. Combination of one of these drugswith a longer half-lifepartner antimalarial drug allowsa reduction in the duration of antimalarial treatment while atthe same time enhancing efficacy and reducing the likelihood of resistance development. Themajorimmediateeffectoftheartemisinincomponentis toreducetheparasitebiomass. The residual biomassisexposed to maximum concentrationsof the partner drug, well above its minimuminhibitoryconcentration,resultinginalesserlikelihoodofresistantmutationsbreaking through. In most of the artemisinin-based combinationscurrently in use or being evaluated, e.g.artesunatemefloquine,thepartnerdrugis eliminatedslowly.Thepartnerdrugis thereforeunprotected once the artemisinin has been eliminated from the body and operates a selectivepressure on new infections. The implicationsof thispharmacokinetic mismatch are not fullyunderstood at present, particularly in areasof high transmission in Africa. The safest approach isto use a drug partner that hasa residual half-life asshort aspossible, while still enabling parasiteclearance with a 3-day treatment. However, thisisdifficult to achieve given the limited range ofantimalarial drugsavailable.There isa growing interest in using antimalarial combinationscontaining an artemisininderivativeas first-linetreatment. Theaimis toprovideefficacious andsafeantimalarialdrugtreatmentwhileprobablydelayingtheonsetandspreadofresistancetobothdrugs inthecombination.This interestresults fromexperiencewiththecombinationofartesunateand19Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000mefloquine on the Thai-Myanmar border (12, 13, 4649). Following the introduction of thecombination there have been four principal clinical and epidemiological effects: the efficacy of the combination hasexceeded 95% at a time when high-dose mefloquinewasshowing a failure rate of approximately 25%, thishigh efficacy hasbeen sustained over the past 7 years, the transmission of P.falciparum hasbeen reduced (with reduced gametocyte carriagefrom the artesunate), the in vitrosensitivity of mefloquine hasincreased, suggesting that the combination hasreversed the previousdecline in mefloquine sensitivity.These studieshave been conducted in areaswhere there isa high level of medical serviceprovisionandmalariatransmissionis low.Itis notyetknownwhethersimilarresults canbeachieved in Africa and other high-transmission regions. Moreover, evidence of the effectivenessofACT in delaying the development of resistance isnot yet available in Africa. Clinical trialsusingcombinations ofartesunatewithamodiaquine,chloroquine,sulfadoxinepyrimethamineormefloquine are currently in progressto assessthe efficacy and safety of ACT for treating uncom-plicated falciparum malaria in Africa, South America and Asia. Factorsfor and against the introduction of ACT are summarized in Table 5. ACT shouldbeconsideredintwodifferentsettings.Inplaces wherethecombinationis presentlymoreefficaciousthan available monotherapies, such aspartsof South-East Asia, it hasa clear role. Inareaswhere monotherapy isstill efficaciousbut where thismay change if the drug concerned isnot protected from resistance, the justification for introducing ACT islessclear at the operationallevel.AlthoughthegeneraltheorybehindthepromotionofACTis widelyaccepted,doubtsremain about the quantitative impact it will have in real-life situations. Ministriesof health arethereforereluctanttocommittoahigh-costACTstrategywherethemerits ofthedifferentoptionsavailable remain unclear and significant operational barriersstill need to be overcome.Time is a major constraint to this process: a change is needed now in several countrieswhere chloroquine haspoor efficacy. There are profound concernsthat a change from chloro-quine to sulfadoxinepyrimethamine monotherapy might affect the future utility of some ACTs,in particular sulfadoxinepyrimethamine plusartesunate, and chlorproguanildapsone (LapDap)plusartesunate. Urgent information isneeded on the effectivenessof chloroquine or amodiaquinecombinedwithsulfadoxinepyrimethamineas apossibleinterimmeasurewhileattempts aremade to assessand improve on the cost-effectivenessof ACTsin the African context. Tabl e 5. Fact ors for and agai nstt he i nt roduct i on of art emi si ni n-based combi nat i on t herapyFOR Theneedt oreplaceinadequat edrugregimenst hatare leading t o increased malaria-relat ed mort alit y andmorbidit y Pot ent ialavoidanceoft helossofavailableeffect iveand affordable ant imalarial drugs, especially in Africa Excellent efficacy(bot hclinicalandparasit ologicalcl earance)of art emi si ni nderi vat i ves,w i t hnoresist ancereport edfromSout h-East Asiadespit eext ensive use Pot ent ialreduct ionint ransmission(especiallyofresist ant mut ant s)duet ot hegamet ocyt ocidaleffectof art emisinin derivat ives AGAINST Higher cost Problemsofadherencet onon-fixedcombinat ionsand t heir rat ional use, part icularly in t he home Lackofext ensiveclinicalexperiencew it hmost oft hecombinat ions current ly under invest igat ion LackofevidencesofarinAfricaofit seffect iveness in delaying t he developmentof resist ance Import anceofnot misusingart emisininderivat ives in viewof their role in the treatment of severe malaria 20THE USE OF ANTIMALARIAL DRUGS2.4 Implement at ion ofcombinat ion t herapyoperat ional issuesItwouldappearlogicalthat,ifCTis todelaythedevelopmentofresistance,existingmonotherapy with either of itscomponentsshould cease, although thishasnot been rigorouslyproven. In order to minimize monotherapy with the componentsof a particular CT, therefore, itis necessarytoguaranteeconsistentaccess totheCTandrestrictaccess torelateddrugsthroughout the health sector, both private (formal and informal) and public. Fixed-combinationproducts arepreferredtomultiple-drugtherapyas this willimprovetheeaseofuseandcompliance, while minimizing the potential use of componentsof the combination asmono-therapy. Price to the user and to the health system must be competitive with alternativesandaffordable to the poorest, otherwise the public health value of CT may be compromised. Other areaswhere improvement iscritical for successful implementation of CT relate togeneric issuesof policy implementation. They include training and motivation of health workers,public confidence in and use of health facilities, reliable drug supplies, a regulated private sectorand good quality control to prevent infiltration of counterfeit drugs.With the increased use of new combinations, safety assessments, monitoring of potentialdrug interactionsand strategiesfor the treatment and protection of pregnant women are urgentlyrequired.Similarstrategies forapplicationincomplexemergencysituations,withaparticularemphasison compliance, are also essential. With support from external agencies, implementationof CT in the short term, in defined areas, may be feasible. However, greater effortsand resourcesareneededinisolatedareas withpoorservices toensurethesustainabilityofpolicies andprogrammes. It isanticipated that, in some settings, CT could be introduced to protect the life span ofa still effective antimalarial monotherapy. In these cases, CT will be of long-term benefit to thecommunity rather than of immediate benefit to the patient. The substantially higher cost of CTsisprobably the major obstacle to the implementation of thisstrategy, especially in sub-SaharanAfrica.As apublichealthmeasuresubsidies couldbejustified,butassuranceis neededthatfinancial mechanismswill be sustainable. 3. CHEMOPROPHYLAXIS AND TREATMENT OF MALARIA IN SPECIAL GROUPSTheprinciples oftheuseofantimalarialdrugs forprotectionagainstmalariaandthetreatmentofuncomplicatedmalariawerereviewedin1995(16).This sectionconsiders theparticular requirementsfor chemoprophylaxisin pregnant women and for chemoprophylaxisandstand-bytreatmentintravellers.Italsocomments onthemanagementofseveremalaria,thetreatment of vivax malaria and the need for antimalarial formulationsfor paediatric use.3.1 Guiding principles ofchemoprophylaxis and int ermit t entt reat mentofmalaria during pregnancyMalaria infection in pregnancy posesa substantial risk to the mother, the fetusand thenewborn infant. Pregnant women are lesscapable of coping with and clearing malaria infections.In areasof low transmission of P. falciparum, where levelsof acquired immunity are low, womenaresusceptibletoattacks ofseveremalaria,whichmayresultinstillbirths orspontaneous21Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000abortions,orthedeathofthemother.Inareas ofhighP.falciparum transmission,levels ofacquired immunity tend to be high and women may have asymptomatic infections, which mayresult in maternal anaemia and placental parasitaemia. Both of these conditionscan lead to lowbirth weight, an important contributor to neonatal mortality.In programmesfor the prevention or treatment of malaria in pregnant women, two majorissues arethesafetyandeffectiveness oftheantimalarialdrugregimen.Theprogrammaticeffectivenessof a given drug isdetermined by the efficacy of that drug against the parasite and bythe drugscharacteristics, including affordability, availability, acceptability to the target population,and deliverability in termsof dosing requirementsand incorporation into existing antenatal caredelivery systems. Weeklychloroquinechemoprophylaxis andpreventiveintermittenttreatmentwithsulfadoxinepyrimethamineduringpregnancyhavebothbeenshowntoreducetherateofplacental parasitaemia and low birth weight (50). Many national antimalarial treatment policiesinclude a recommendation for chloroquine chemoprophylaxis. It israrely implemented, however,because of problemswith compliance, fearsabout adverse effectsof the drug during pregnancy,and the concern of health workersthat use of drugsfor thispurpose may deplete stocksneededfor the treatment of acute infections.An increasing number of countries, e.g. Malawi, are implementing intermittent treatmentwith 2- or 3-dose treatment regimensof sulfadoxinepyrimethamine: once in the second andonce or twice in the third trimester (5153) to prevent malaria in pregnancy. In HIV-positivewomen, the 3-dose treatment issignificantly more efficaciousthan the 2-dose regimen (51). It hasbeensuggestedthatsulfadoxinepyrimethamineshouldideallybereservedforpreventiveintermittenttreatmentinpregnancy(R.Steketee,personalcommunication,2000).Inmanyendemicareas wheresulfadoxinepyrimethamineis oneofthefewreplacementtherapies forchloroquine, thismay not be a viable option.3.2 Guiding principles ofchemoprophylaxis and st and-by t reat mentin t ravellersThespreadandintensificationofdrugresistanceworldwidehas greatlycomplicatedrecommendationsfor the prevention of malaria in travellers. Travel to malariousareasison theincrease, while many countriesare experiencing a resurgence of malaria. Asa short-term measure,chemoprophylaxisisrecommended for international and national travellersfrom non-endemicareas,andforsoldiers,policeandlabourforces servingorworkinginhighlyendemicareas.Detailedrecommendations fortheprotectionoftravellers againstmalariaareupdatedandpublished annually by WHO in International travel and health: vaccination requirementsand healthadvice(54).All travellersto malariousareasshould be clearly informed of: the risk of malaria; howthey can best protect themselvesagainst mosquito bites; the use of chemoprophylaxiswhereverappropriate; and the need to seek early diagnosisand treatment if symptomssuggestive of malariaoccur. Malaria must alwaysbe suspected if fever, with or without other symptoms, developsat anytime between one week after the first possible exposure to malaria and two months(55), or evenlonger in exceptional cases, after the last possible exposure. Nearly all travellerswho acquire a P. falciparum infection will have developed symptomswithin 3 monthsof exposure (56). Medicalattention should be sought and a blood sample examined for malaria parasites. If no parasitesarefoundbutsymptoms persist,aseries ofbloodsamples shouldbetakenandexaminedat22THE USE OF ANTIMALARIAL DRUGSappropriate intervals. Relapsesof vivax and ovale malaria are not prevented by chemoprophylaxiswith currently used prophylactic regimens.Malaria chemoprophylaxisshould be selected on the basisof an individual risk assessmentof the traveller, an assessment of the safety and efficacy of potential chemoprophylactic regimens,and drug resistance and the extent of malaria transmission in the region to be visited. Weeklyprophylactic antimalarial regimensshould normally be started one week before travel. Daily drugssuch asproguanil and doxycycline should be started the day before travel. Drugsshould then betaken with unfailing regularity for the duration stay in the area of malaria risk, and continued for4 weeks after leaving the endemic area. The exception is atovaquone/proguanil, which can bestoppedoneweekafterleavingtheareawithmalariarisk. Mefloquineprophylaxis shouldpreferably be started 2-3 weeksbefore departure, so that adequate blood levelsare attained, andadversereactions canbedetectedbeforetravel,allowingconsiderationofalternativedrugregimens. Antimalarial drugsshould be taken with food and swallowed with plenty of water.In general, travel areasare classified as: Areas with P. vivax transmission only. Chloroquine-sensitiveMalarious areas wherechloroquineresistancehas notbeendocumentedoris notwidelypresent;theseincludeHaiti,theDominicanRepublic,Central America north-west of the Panama Canal and partsof the Middle East. Chloroquine-resistantMost of Africa, South America, Oceania and Asia. Chloroquine- and mefloquine-resistantResistance to both chloroquine and meflo-quineis notasignificantproblemexceptinruralforestedregions alongthebordersbetween Cambodia, Myanmar and Thailand, which are infrequently visited by tourists;mefloquineresistanceinvaryingdegrees has beenreportedfromBrazil,Cambodia,China (in vitro), French Guyana, Myanmar, Thailand and Viet Nam.Dataontheincidenceofmalariaandtheeffectiveness andtoleranceofcurrentlyrecommended chemoprophylaxisand self-treatment regimensfor long-term travellersare limited.Chloroquineandmefloquinehas beenshowntobesafeforatleast3 years.Inchloroquine-resistant regions, mefloquine ismore efficaciousthan the chloroquine plusproguanil combination(57,58).Inonestudy,chemoprophylaxis withatovaquoneproguanilfor20weeks andwithprimaquine for 50 weekshad no significant adverse effects(59, 60). Malaria prevention in young travellersChildrenareatspecialriskofmalariasincetheymayrapidlybecomeseriouslyill.Persuading young children to take antimalarial medicationsmay be difficult because of the lackof paediatric formulationsand the bitter taste of many drugs. Furthermore, some chemoprophy-lacticdrugs arecontraindicatedinchildren.Chloroquineremains thedrugofchoiceinareaswheremalariaremains sensitivetothis drug,whilemefloquineis thepreferredagentinchloroquine-resistant areas. Although the manufacturer recommendsthat mefloquine should notbe given to children who weigh lessthan 5 kg, it should be considered for chemoprophylaxisofall children at high risk of acquiring chloroquine-resistant P.falciparum malaria.Atovaquoneproguanil may be a safe and effective chemoprophylactic alternative to doxycyline for childrenunder 8 yearsof age who weigh more than 11 kg and are travelling to mefloquine-resistant areas.23Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000Malaria prevention for travellers during pregnancyIn non-immune pregnant travellers, malaria increasesthe risk of maternal and neonataldeath, miscarriage and stillbirth. When travelling to malariousareas, pregnant women should takespecial care to avoid mosquito bites.Chloroquine isknown to be safe in pregnancy, but itsusefulnessislimited to a few areaswith chloroquine-sensitive strainsof P. falciparum. Available data indicate that mefloquine issafeas achemoprophylacticagentafterthefirsttrimester.Becomingpregnantwhiletakingmefloquinechemoprophylaxis is notanindicationforterminationofthepregnancy.Thecombination of chloroquine plusproguanil issafe in pregnancy and providesmore protectionthan chloroquine alone in areaswith known chloroquine-resistant strains, but issignificantly lessefficaciousthan mefloquine (61, 62). Doxycycline and primaquine are contraindicated duringpregnancy. Data on the safety of atovaquoneproguanil during pregnancy are insufficient, althoughstudieswith thiscombination are currently under way.Stand-by emergency treatment for travellersMost travellersto urban or major tourist areaswill be able to obtain prompt and reliablemedicalattentionwhenmalariais suspected.However,aminoritymaybetravellingtosuchisolated locationsthat they will have no accessto competent medical attention within 24 h aftertheonsetofsymptoms,aweekormoreafterfirstpossibleexposure.Insuchcases,stand-byemergencytreatmentshouldbeprescribedtothetravellerforself-administrationshouldsymptoms occur(6366).Preciseinstructions shouldbegivenontherecognitionofmalariasymptomsand the need to take the full treatment dose of the drug, and information should beprovided on possible adverse reactions. Travellersmust also be made aware that they should seekattention assoon aspossible after symptomsappear and they begin their stand-by treatment, andthatstand-bytreatmentis notasubstitutefordiagnosis andtreatmentbyqualifiedmedicalpersonnel.Because of the potential for additive toxicity and reduced efficacy, individualswho are onchemoprophylaxis shouldneverattemptstand-by-treatmentwiththesamedrug.Followingcompletion of the treatment, individualsshould resume effective malaria chemoprophylaxis. Asageneralguide,chemoprophylaxis shouldberestartedoneweekafterthefirsttreatmentdose.Whenthestand-by-treatmentis quinine,however,mefloquinechemoprophylaxis shouldberestarted one week after the last dose (54). Chloroquine,sulfadoxinepyrimethamine,mefloquine,quinineplus tetracycline,ato-vaquoneproguanilandartemetherlumefantrinecanbeprescribedas stand-bytreatments,depending on the drug-resistance statusof the parasitesin the areasto be visited. Halofantrine isnot recommended owing to the fact that it can result in ventricular dysrhythmiasand prolongationof QTc intervalsin susceptible individuals. While the antimalarial drugsdescribed above are allusedforstand-bytreatment,artemetherplus lumefantrineis theonlytherapyregisteredbyanational drug regulatory authority for thispurpose (67). Efficacy, safety and ease of administrationshould be considered for the selection of stand-by treatment, but there issome concern about theuse of drugsfor thispurpose in travellerswho may have accessto medical facilities. 24THE USE OF ANTIMALARIAL DRUGS3.3 Managementofsevere malariaTreatment with antimalarial drugshasa major role to play in preventing severe malaria anddeath. It reducesfever promptly and effectively to interrupt the progression of infection or mildillnessto severe disease, and reducesfatality ratesin severe malaria. Since the great majority ofpatientswith fever or other symptomssuggestive of malaria receive their initial treatment at home,improving home management of fever isa critical component of thisprocess. Patientsand theirfamiliesneed up-to-date and practical guidance on when and how to use antimalarial drugsathome, on how to recognize when a patient isnot responding to therapy in order to seek medicalattention,andontheimportanceofcorrectlyfollowing,athome,therecommendations andtreatmentsthat are given in health centresand hospitals. Thisguidance should be complementedwith more user-friendly treatment regimens, improved formulations, especially for the treatmentof children, and pre-packaging of antimalarial tablets.At the health post or health centre level, availability of effective drugsiscrucial. Healthworkersneed clear guidelineson how antimalarial drugsshould be used and how to deal withpotential adverse reactions. In addition, there should be facilitiesto administer fluids, glucose,antibiotics, and anticonvulsantsto severely ill patients. In suspected casesof severe malaria, rectalformulationsof the artemisinin drugsand other preparationscan be used asan emergency pre-referral treatment when parenteral antimalarial therapy isnot available, and have the potential toreduce early mortality. In hospitals, prompt confirmation of diagnosis, rapid assessment of theseverity of disease and the administration of prompt specific and supportive treatment, includingsafe blood for transfusion, are all critical. These issuesare covered thoroughly elsewhere (15).3.4 Vivax malariaP.vivaxis thepredominantmalariaspecies inmostofAsia(includingtheIndiansubcontinent),Oceania,NorthAfrica,andCentralandSouthAmericaandis estimatedtoaccount for about 55% of the total malaria incidence outside subtropical Africa. In recent years,there hasbeen a major resurgence of vivax malaria in eastern Europe and central Asia, areaswhichhad been free of malaria for several decades. The major threat to the control of P. vivax today istheemergenceandspreadofchloroquine-resistantstrains inGuyana,India,Indonesia(IrianJaya), Myanmar and Papua New Guinea (68).The existence of strains ofP. vivax that differ in their relapse patterns and their innatesensitivity to primaquine influencesthe choice of regimen for radical cure. For strainsof P. vivaxfrom Papua New Guinea, Solomon Islandsand Vanuatu, and partsof Indonesia, a total dose ofprimaquine base of 7 mg/kg (equivalent to 420 mg in an adult) given as30 mg of primaquinebase daily for 14 days, isrequired to achieve 100% cure rates. Strainsfrom China, South-EastAsia, central Asia, the Middle East, northern Africa, and Central and South America can be curedwithhalfthis dose. Thereis limitedevidencethatstrains fromtheIndiansubcontinentmayrespond to a 5-day course of 15 mg of primaquine base (69, 70).3.5 Formulat ions f or paediat ric useIn Africa, particularly in areasof high transmission, children under 5 yearsof age are themost affected by malaria, leading to a high case fatality rate in thisage group. In spite of the25Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000importance of the disease in children and the fact that they are the major targetsfor antimalarialdrugs, there are problemswith existing paediatric formulationsand regimens: Many tablet formulations are not scored, making it difficult to break the tablets intohalvesand quartersasrequired by current treatment regimens. Confusion arisesfrom the availability on the market of some drugsat more than onestrength (e.g. chloroquine astabletsof 100 mg and 150 mg base). Different spoon sizeslead to inconsistenciesin the dosing of syrups. Syrupsare often dispensed in volumesof 100120 ml, tempting mothersto continueadministering until finished, or to save the medication for administration to other children. Confusionarises becausetherearefourdifferentagegroups fortreatmentwithchloroquine in children under 5 years. These and similar problemsinfluence patient adherence and result in both underdosingand overdosing. Increasing attention to this area through operational research is beginning tosuggestsomesolutions.Appropriatepackagingandlabellingimproves compliance,enhancesacceptability(7174)andgreatlyreduces theriskofoverdosing(7477).Adherencetoprepackaged tabletsismuch better than to syrup, and the cost of prepackaged treatmentsismuchlower (76). Training health facility workersand equipping them with packaged treatmentshavebeen shown to reduce case fatality rates(78). Prepackaging of drugsfor specific age and weightranges(76) can improve home management of malaria. It now remainsto translate these researchfindingsinto practice.4.ANTIMALARIAL TREATMENT POLICIES4.1 Def init ionAn ant imalarial t reat mentpolicy is a setofrecommendat ions and regulat ionsconcerning the availability and rational use of antimalarial drugs in a country (79).Itshould be partof t he nat ional essent ial drug policy and t he nat ional malariacontrol policy and in line with the overall national health policy.4.2 PurposeThe primary purpose of an antimalarial treatment policy isto select and make accessible tothe populationsat risk of malaria safe, effective, good quality and affordable antimalarial drugssothat malaria disease can be promptly, effectively and safely treated. The definition of effectivetreatment may vary in different epidemiological situationsasfollows:Inareasofintense transmission: clinicalcure,i.e.clinicalremissionincludingthepreventionofclinicalrecrudescence(noappearanceofsigns andsymptoms inthe14daysfollowing treatment).In areas of low transmission: parasitological or radical cure, i.e. elimination of all parasitesfrom the body. 26THE USE OF ANTIMALARIAL DRUGSIn areasof intense transmission and high population immunity, infected adultsare oftenasymptomaticandclinicalcurecanbeachievedwithoutparasitologicalcure.Inareas oflowtransmission and low population immunity, asymptomatic infectionsare rare and clinical curecan rarely be achieved without parasitological cure. A second purpose isto prevent or delay the development of antimalarial drug resistance bycorrect diagnosisand rational drug use. Incertaincountries andsituations,athirdpurposemayberadicalcureofallmalarialinfectionswith the objective of reducing transmission through the use of a gametocytocidal drug.Suchanobjectivewouldbeunrealisticinareas ofintensetransmissionandhighpopulationimmunitywhereasymptomaticinfections arecommon,butmayberealisticinareas oflowtransmission, if high treatment coverage can be achieved and/or vector control iscarried out asacomplementary measure. An effective treatment policy should aim to: reduce morbidity, halt the progression of uncomplicated disease into severe and potentially fatal disease, andthereby reduce malaria mortality, reduce the impact of placental malaria infection and maternal malaria-associated anaemiathrough chemoprophylaxisor preventive intermittent therapy, minimize the development of antimalarial drug resistance.4.3 DevelopmentThecategories forthetreatmentofmalariaincludedrugs forfirst-linetreatment(thetreatmentgiventoprobablemalaria,orconfirmedmalaria),second-andthird-linetreatment(giventotreatmentfailures),severemalaria,pregnantwomen,presumptivetreatment,self-treatment/over-the-countertreatmentandmass treatment(recommendedinepidemics). Theantimalarialtreatmentpolicymustprovideindications forallthesetreatmentcategories.However, the choice of first line treatment hasthe greatest economic implicationsand the greatestpublic health implications. The essential componentsfor developing and updating national treatment guidelinesforantimalarial drugsinclude: clear analysisof the technical, social and economic issuesrelated to malaria control, anti-malarial drug resistance, potential interventionsand the consequencesof action or inaction, analysisof the decision-making environment, consensus-buildingamongrelevantstakeholders (policy-makers,researchers,controlstaff, donors, private providers, industry and user representatives), a supervisory body to oversee the development, implementation and revision of the policy, a regulatory body to ensure adherence to policy components.Acriticalstartingpointfordevelopingorupdatingantimalarialtreatmentpolicyis anassessment of the statusof antimalarial drug efficacy. Standardized approachesfor assessing anti-malarial drug efficacy should be used to allow for trendsto be monitored and comparisonsmade.27Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 20004.4 Fact ors inf luencing ant imalarial t reat mentpoliciesAntimalarial drug resistance and policy-making are dynamic areas, and the situationsineach country may vary depending on disease epidemiology, transmission, drug resistance patternsand political-economic contexts. In general, the policy processrequiresinformation from a varietyof sources: analysisof the epidemiological situation, including type of parasite species, levelsof resistance to currently used antimalarial drugs, evaluation of the propertiesof available alternative drugs, analysisof treatment-seeking behaviourprovider and consumer behaviours, which mayreflect whether the existing policiesare rational and thusalso influence how they will beimplemented, cost-effectivenessanalysisof alternative therapies; the costsof implementing antimalarialtreatment policiesinclude the administrative and logistical costs, while costsfor changingpoliciesshould include the actual cost, dissemination of revised guidelinesand training, analysisof health system capacity to implement the revised policy, including the necessaryregulatory and legislative framework.Several factorsmay influence the selection of antimalarial therapies(see below); they areconsidered further below. Additional guidance on the selection of drugsfor antimalarial treatmentpoliciesisgiven in Annex 2.Propert ies of ant imalarial drugs t hatmay influence t heir select ionEf f icacy and half -lif eAccept abilit y and adherence t o t reat ment(including dif f erentf ormulat ions)Ef f ect ivenessQualit yAdverse ef f ect sDrug int eract ions and cont raindicat ionsUse in special groups, e.g. pregnantwomen and inf ant sCapacit y ofhealt h syst em t o implementpolicyCost , cost -ef f ect iveness, and af f ordabilit y ofvarious regimensReport ed resist ance and/or cross-resist anceUsef ul t herapeut ic lif e EfficacyDrug efficacy isdetermined by the drug sensitivity of the Plasmodium speciesconcerned,pharmacokinetics and the development of resistance as a function of time (influenced by thedrugshalf-life). In developing or revising an antimalarial treatment policy, the efficacy of alter-native regimensshould also be taken into account. 28THE USE OF ANTIMALARIAL DRUGSAccept abilit y and adherence t o t reat mentAcceptability and adherence to treatment by patientsare major componentsin the successof any public health system and are influenced by both behavioural and economic factors. Theyare determined by: duration of treatment, number of daily doses, speed of clinical response, in particular the antipyretic effect, minor adverse effects, market-price relative to household economy or affordability, presentation, packaging, health education (consistent IEC messages), taste and/or colour, and size of tablet (or volume per dose for syrupsand suspensions), reputation of the drug.Simple technology, like blister packaging of antimalarial drugs, may offer some solutionstothe problem of incorrect use (78).Effect ivenessEffectivenessisdetermined by efficacy and adherence to the treatment (see above).Qualit yDrug quality should be considered at all stagesof the drug management cycle, includingselection (80). Poor quality drugsdecrease efficacy, affect the reputation of the drug and under-mine the treatment policy. Quality assurance isan important component of pre-registration andpost-marketing surveillance.TheWHOM odelList of Essent ialDrugsEssential drugs are those drugs that satisfy the health care needs of the majority of thepopulation; they should therefore be available at all times, at a price they and the community canafford,inadequateamounts andinappropriatedosageforms (81).Inmostcountries,theselectionofessentialdrugs is atwo-stepprocess.Firstly,marketapprovalofapharmaceuticalproduct isusually granted on the basisof efficacy, safety and quality. Secondly, an evaluation ismade on the basisof a comparison between variousdrug productsfor a given indication and theirvalue for money. The WHO Model List of Essential Drugsservesasa model for the second step in thisselection processand for national and institutional essential drug lists, although inclusion of a newdrugontheWHOModelListis notaregulatorydecisionandis notbindingonnationalgovernments. The Model List currently includes306 active compoundsand isupdated every twoyears. The list containsa section on antimalarial drugs(81). Selection of drugsfor inclusion onthislist isbased on the following criteria: sound and adequate data on efficacy and safety from clinical studies, availability in a form in which quality, including adequate bioavailability, can be assured, stability under the anticipated conditionsof storage and use, cost-effectivenessof the treatment. 29Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000By the end of 1999, 146 Member Stateshad official national listsof essential drugs, whichserve asguidesfor the supply of drugs, including antimalarial drugswhere appropriate, in thepublic sector in their respective countries.Regist rat ionandregulat ionAntimalarialdrugs,likeothermedicines,areregulatedbynationaldrugregulatoryauthoritieswithin ministriesof health. The regulation and control of pharmaceutical products,including drug registration, quality assurance, and inspection of the distribution system, is inaccordancewithnationalpharmaceuticallegislationandnationaldrugpolicy.Supplementarylegislation including regulations, norms, standards, specifications, guidelinesand proceduresisalsotakenintoaccount.Indevelopingcountries,nationaldrugregulatoryauthorities areatvarious stages ofevolution.Theircorefunctions includedrugregistration,overallqualityassurance of pharmaceutical products, surveillance of drug distribution channels, and control ofinformation and promotion.Forregistrationofpharmaceuticalproducts,themostfrequentlyappliedcriteriaareefficacy, safety and quality. National drug regulatory authoritiesapproach overall quality assurancebycombiningqualityassuranceofpharmaceuticalmanufacturers (withregardtogoodmanufacturingpractices,GMP)withanefforttoensurethatthepharmaceuticalproductsavailable on the market meet the prescribed quality specifications.Assuring the quality of pharmaceutical productson the market isan expensive processinwhich a careful selection of productsto be sampled and tested hasto be made. Some countrieshave developed national regulatory laboratoriesspecifically for thispurpose, while othershavechosen to contract with external laboratoriesfor the necessary analyses. To ensure that registeredproductscontinue to comply with the regulatory requirementsafter they have been registered, acomplementofwell-trainedpharmaceuticalinspectors is neededforsurveillanceofpharma-ceuticalmanufacturingplants,ensuringadherencewithGMPas wellas ensuringthatthepharmaceutical productsavailable on the market through the variousdrug distribution channelsmeet the prescribed quality specifications. The distribution of a product, within the marketing authorization granted, islinked toscheduling of drugswithin the country, therapeutic category and specific indication(s) for theproduct, presentation of the product (dosage form), accompanying literature/information, ease ofuse of the product, and the expected level of training required to ensure safe use of the product. Cross- resist anceChemically related antimalarial drugs, e.g. chloroquine and amodiaquine, may give rise tosimilarpatterns ofresistance.However,theextenttowhichthedegreeofdevelopmentofresistance to amodiaquine isdue to resistance to chloroquine isunclear. Similarly, the extent towhich the widespread use of sulfadoxinepyrimethamine for malaria treatment or sulfametho-xazole-trimethoprim (cotrimoxazole) for bacterial infectionsmay compromise the utility of othersulfa drugs, such aschlorproguanildapsone, isnot known.Adverse effect sMild adverse effects, such asitching and gastrointestinal effectsmay influence adherence totreatment and choice of drug. The risk of severe adverse effects, such asneuropsychiatric effectsor agranulocytosis, must be considered when deciding policy.30THE USE OF ANTIMALARIAL DRUGSDrug int eract ionsSomedrugs givenconcurrentlyorsequentiallyproduceundesiredeffects.Forexample,folatesupplementationcaninhibittheactionofsulfadoxinepyrimethamine,increasingthelikelihood of treatment failure. Quinine, mefloquine and halofantrine given close together arepotentially cardiotoxic. Complementarity and potential synergistic effectsmust also be taken intoconsideration.Use in special groups Pregnancy isa contraindication for many antimalarial drugs(82). The risk to the motherand fetusmust be carefully weighed against the risk of malaria. High-risk groups, such asnon-immune refugee populations, may need a first-line drug that isdifferent to that recommended inthe national antimalarial treatment policy in hyper- and holoendemic areas. The full effectsofHIV on the efficacy and adverse effectsof antimalarial drugsare not yet known. Some preliminarydata indicate a higher risk of adverse effectswith sulfadoxinepyrimethamine in HIV-positivepatientswith Plasmodium infectionsthan in HIV-negative patients(83). The safety and effective-nessof some antimalarial drugshasnot been established in infants, e.g. atovaquoneproguanil,artemether-lumefantrine,halofantrineandmefloquine.Thetetracyclinegroupofdrugs iscontraindicated in children under 8 yearsof age because of itseffect bone growth and dentalenamel. In additon, primaquineand sulfadoxinepyrimethaminehaveage-specific contraindicationsin children.Healt h syst em capacit y t o implementt he policyIf an antimalarial treatment policy isto be successful, accessto good quality essential drugsand health care isvital. Variousnational strategiesexist to finance, distribute and dispense safe,effective and good quality drugsto those who need them. The health system requirespoliticalsupport and financial, managerial, technical and human resourcesto manage the drug supply andimplement the policy effectively. These should be assessed in the context of health sector reformand decentralization. It isalso essential to recognize that in many countrieshealth care issoughtoutside formal health facilities. The role of the government in ensuring quality of service throughthe informal private sector should also be assessed.Cost , cost -effect iveness and affordabilit y analysisTo make decisionson whether or not to change the first-line therapy for malaria and whatthe change should be, policy-makersneed information on the health outcomes, cost implicationsandcost-effectiveness ofdifferentregimens.Knowledgeofthecurrentandprojectedannualquantity of first-line and second-line treatmentsisalso critical to the decision-making process.There isa wide spectrum of costsand health outcomesand the evolution of these costsand effectsover time must be considered.Informationontheprices ofmanygenericdrugs boughtinbulkis availablefromtheInternationalDrugPriceIndicatorGuides producedbyManagementSciences forHealth,incollaboration with WHO. The average cost per treatment dependson the choice of drug and onthe formulationsused. The average cost per adult treatment with a range of antimalarial drugsand formulationsisshown in Table 6. A cost-effectivenessanalysisinvolvesconsideration of the incremental costsand health effectsof implementing an intervention, compared with either the statusquo, or a different intervention.For example, in considering the introduction of sulfadoxinepyrimethamine asa new first-line31Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000drug, a comparison could be made with the costsand effectsof continuing to use chloroquine orany other treatment. Alternatively the cost of changing immediately to sulfadoxinepyrimethaminecould be compared with changing after a delay of 3 or 5 years.The analysismust also take into account other costsinvolved in implementation, such asthe need for consultation, consensus-building and policy formulation, revision and production oftreatment guidelines, training of public and private sector health workers, and communicationandpublicity. Themanagerialcapacityrequirements andfinancialcosts oftheseactivities aresignificant. Country-specific costswill depend on the implementation activitiesselected. A retro-spective analysisshowed that the change from chloroquine to sulfadoxinepyrimethamine asthefirst-line treatment in Malawi cost about US$ 612 000 or US$ 0.06 per capita. An estimatedbudgetfortheplannedchangeintheUnitedRepublicof TanzaniaindicatedatotalcostofUS$ 424 000 over an 18-month period, equivalent to US$ 0.01 per capita, or 1% of the totalannual Ministry of Health budget for 19981999 (84, 85).In addition to the direct benefitsof reduced malaria mortality and morbidity, changing thefirst-line therapy to a more efficaciousdrug may bring other measurable improvementsasa resultof the reduction in the caseload of malarial illness. Firstly the quality of care may be improved,owing to reductionsin the frequency of drug and laboratory supply stockouts, lesspressure onstaff and reduced patient waiting time. At the same time, more patientswith other conditionsmay get accessto care. Secondly, by avoiding return visitsto formal health facilitiesand additionalvisitsto other treatment sources, such aspharmacies, shopsand traditional healers, patientswillbenefit from a reduction in direct expenditure and the time diverted from productive activitiesaswell asthe burden of anaemia and other consequencesof disease progression. In addition, the useof transmission-blocking drugssuch asartemisinin and itsderivativesmay reduce the incidenceof new cases(9), especially in low-moderate transmission areas.Cost-effectivenessmodelsare simplificationsof reality, and the relevance of assumptionsand parameter estimatesto a particular setting must be carefully considered. Such analysiscannotprovide definitive conclusionson the relative cost-effectivenessof different strategies, or resistancethresholdsabove which a change in first-line drug should definitely be made. However, it doesprovideaframeworkforconsolidatinginformationonepidemiological,costandbehaviouralfactors, and indicatesrangesfor the likely economic and health impactsof different strategies.Themainproperties ofexistingantimalarialdrugs andthoseunderdevelopmentarepresented in Annex 3. A summary of the characteristicsof selected commonly used antimalarialdrugsisprovided in Table 6. 32THE USE OF ANTIMALARIAL DRUGS4.5 Healt h-seeking behaviourThe analysis of health-seeking behaviour is essential in developing and implementing arational drug policy. For example, information on the factorsthat influence the recognition andinterpretation of childhood feversby consumersand providers, and subsequent choice of therapywillassistintheformulationofguidelines toimproveadherencetotreatmentandtreatmenteffectiveness. These in turn may influence the development of drug resistance. If a treatment doesnot produce the expected result, patientsand care-giversmay re-diagnose the cause of the fever(86).Itis widelyacceptedthathumanbehaviours leadingtoinadequatedosing,incompletecourses oftherapyandindiscriminateandinappropriatedrugusehavecontributedtotheemergence and spread of resistant parasites(87). It must also be recognized that new treatmentpoliciesthat replace long-familiar drugsand alter well-established patternsof care seeking andhealth care practice may fall short of the expectationsof patientsand care-givers.Asmost malaria treatment occursin the home, changing the first-line drug in the publicsector alone may not have a substantial impact. The role of the private sector iscrucial in ensuringthat drug distribution systemsreflect public health policy and that the recommended treatmentis availablethroughalltypes ofhealthcareoutlets usedbythepopulation.Householdandcommunity-level antimalarial drug use representsan important entry point for malaria controlprogrammesin most African nations(88). In Africa, shopsare the main source of antimalarialdrugs(8891). However, the course of treatment sold isoften suboptimal (9294). Tabl e6.Summar yoft hecharact eri st i csofcommonant i mal ari al drugst hat shoul dbeconsi deredi ndrugsel ect i on, i ncl udi ng costof an adul tt reat mentcourse.Evi dence of Report ed Adverse Treat ment Adherence COSTresi st ance resi st ance effect s durat i on (days) t o t reat ment (US$)CQ + YESa+ 3 + + 0.070SP + YESb+ + 1 + + + 0.082Q + YESc+ + 7 + 1.350AQ + YESd+ + + 3 + + 0.150ASU none yet +/ + + 7 + 2.160MQ (25 mg/kg) + YESe+ + 2 + + 3.220HAL + none yet + + + 2 + + 4.750Q + D (?) none yet + + 7 + 1.470Q + T (?) none yet + + 7 + 1.650Q + SP (?) none yet + + 3 + + 0.660CQ + SP +(?) YES+ + 3 + + 0.154MQ + ASU none yet + + 3 + + 5.380AT PR (?) none yet +(?)3 + + 42ART LUM none yet +(?) 3 + + 2.58AQ, amodiaquine; ARTLUM, art emet herlumefant rine; ASU, art esunat e; ATPR, at ovaquoneproguanil; CQ, chloroquine; CT, combinat ion t herapy; D, doxycycline; HAL, halofant rine; MQ, mefloquine; Q, quinine; SP, sulfadoxinepyrimet hamine; T, t et racyclineaSout h-EastAsia, Eastand Sout h AfricabSout h-EastAsia, EastAfrica, Amazon Basin, Bangladesh, OceaniacSome part s of AsiadMany areas in Asia and AfricaeThai-Cambodian and Thai-Myanmar borders (sporadic report s in ot her areas)fSelect ion depends on t he level of resist ance t o bot h component s8Price available t hrough WHO.33Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000Operationalresearchis neededtodetermineways ofimprovingprescribingpractices,involvingdrugvendors andotherinformalsectorproviders,andachievingthesuccessfulreplacement of one drug with another. Thisshould be supported by careful documentation ofprogrammeexperiences as newpolicies areimplemented.Studies haveshownthatin-servicetraining can improve the ability of health workersto diagnose and treat clinical malaria (95) andthat treatment chartsmay result in more appropriate dosing of antimalarial medication (96).4.6Crit eria f or changing t reat mentpolicyTheprimaryindicatorforchangingantimalarialtreatmentpolicyis ahighleveloftreatment failure with the currently used antimalarial drug. Conditionsthat signal a need for a re-evaluation of the policy are: evidence from therapeutic efficacy studies, evidence of increased malaria-associated mortality and morbidity, consumer and provider dissatisfaction with the current policy, evidence on new drugs, strategiesand approaches.Evidence from t herapeut ic efficacy t est sThecurrentWHOstandardprotocolfortheassessmentoftherapeuticefficacyofantimalarial drugs (29) focuses on the clinical efficacy of the drug, rather than the previouslyrecommended parasitological responses. Treatment failure rate remainsthe cardinal parameter. Itisthe most easily measured indicator of efficacy, and itsconsequencesare more or lessunderstoodand can be translated into economic terms. Incomplete parasitological cure may lead to anaemiaor return of clinical illnesswhich can progressto severe disease. An optimal antimalarial drugshould therefore succeed in achieving clinical cure, and in clearing parasitesand maintaining theparasite-free period for aslong aspossible.When t o changeThere are no well-defined criteria for determining the level of clinical or parasitologicalfailureswith the current antimalarial therapy at which a first-line drug should be replaced. Thedecisiontochangeis basedonarangeoffactors includingtheprevalenceandgeographicaldistribution of documented treatment failures, the impact of treatment failureson mortality andseveremorbidity,providerand/oruserdissatisfaction,thepolitical-economiccontext,andtheavailability of acceptable and affordable alternatives. A cut-off level of 25% treatment failuresisa widely quoted but somewhat arbitrary figure.Several relatively rich countriesin Asia and South America have decided not to accept a levelhigherthan25%,whileinparts ofAfrica,wheremalariais aneglectedproblem,changes intreatment policieshave not occurred until the frequency of treatment failureshad reached muchhigher levels. It hasbeen proposed that the dynamic processof change should be analysed on thebasisof the proportion of established clinical failures(14, 97). The variousproportionsof clinicalfailure rateshave been classified asthe grace period, alert period, action period and change period;policy-makersshould be informed of the relevance of the available information at all stages.Grace periodLowlevels ofdrug failures, 5%. Countries canbuildconsensus,conductingawiderangeofresearchstudies ontheepidemiological,socialandbehaviouralsituation,andhealthsystems analysis withouturgency.Reliablemechanisms formalariadata34THE USE OF ANTIMALARIAL DRUGScollection and analysiscan be established during thisperiod. Baseline data and trendsin drugefficacy should be determined.Alert periodTreatment failureratesof 615%. Mechanisms for the process of changeshould be set up and discussionson the rate of change of drug efficacy to the current first-linedrug and the timing of any change in policy should be initiated. The expected adverse effectsofincreased drug resistance should be evaluated.ActionperiodTreatmentfailures of1624%.Activities toinitiatechangeshouldcommence in accordance with agreed strategies. Ascertainment of treatment failures, potentialdrug alternativesand channelsof drug distribution should be evaluated. Thiswill provide theinformationneededtoprepareaplanforinterventionwhenresistancetothefirst-linedrugbecomesintolerable. ChangeperiodWhen therateof treatment failurehasreached 25% or above, consensusforchange must already have been reached so that the change can be made within the shortest periodof time possible. The actual cut-off point will depend on many factorsasindicated above.Continuous monitoringandconsensus-buildingis essentialtotheprocess leadingtochange. In vivotherapeutic efficacy studiesshould be conducted throughout the country in orderto provide an indication of the geographical pattern of resistance. The testsshould be carried outat regular intervals(18 monthsto 2 years) to provide a longitudinal perspective.4.7 Process ofchanging t reat mentpolicy: count ry examplesEt hiopiaInmostareas inEthiopia,6070%ofcases areduetoP.falciparum and3040%to P. vivax. Most of the population have no immunity to the parasite. Chloroquine resistance wasfirst detected in 1986. Although in vivostudiesconducted between 1991 and 1996 demonstratedincreasingresistancetothedrug,themethodologyusedwas variable,makingcomparisonsextremely difficult. Following the standardized WHO protocol, a series of in vivostudies wasundertakenat18sites between1997and1998.Thetotalfailurerate(ETFplus LTF)forchloroquine was65%. Evaluation of sulfadoxinepyrimethamine efficacy at four sitesdemon-strated an adequate clinical response rate of 92.3%. Following discussionsat the regional and federal levels, the Ministry of Health establishedatechnicalworkinggrouptodevelopnationalguidelines formalariacontrol.Sulfadoxinepyrimethaminewas consideredtobethemostappropriatereplacementforchloroquineforfalciparum malaria; however, it has a low efficacy against P. vivax. In 1999 four options wereconsidered by the technical working group for vivax malaria: (i) to leave the treatment of vivaxmalaria to sulfadoxinepyrimethamine; (ii) to alternate the use of sulfadoxinepyrimethamineand chloroquine (P. vivax dominatesduring the dry season, while P.falciparum occursafter therains;(iii)touseacombinationofchloroquineandsulfadoxinepyrimethamineinsituationswhere microscopy isnot possible; and (iv) to change from chloroquine to amodiaquine. Option3 wasconsidered to have potential clinical advantages, although with possible increased adverseeffectsand costs. Option 4 wasexcluded asthere was35% resistance to amodiaquine in Ethiopia.It wasdecided that sulfadoxinepyrimethamine, the current second-line treatment, should replacechloroquineforlaboratory-confirmedcases ofP.falciparum.Quininewas reservedforthetreatment of severe malaria and for second-line treatment of P.falciparum, while chloroquineremained the first-line treatment for confirmed casesof P. vivax and primaquine would be usedfor antirelapse treatment of P. vivax and for itsgametocytocidal activity during epidemics. The35Reportofan inf ormal consult at ion, WHO, Geneva, 1317 November 2000decision wasalso made to use a combination of chloroquine and sulfadoxine pyrimethamine asthe first-line treatment when laboratory diagnosiswasnot available. New treatment guidelineswere prepared accordingly. The major challengesfor implementation were dissemination of the new recommendationsto health workersand ensuring acceptance of the new policy, given human resource and financialconstraints. Other challengeswere the lack of appropriate protocolsfor monitoring the therapeuticefficacy and safety of chloroquine + sulfadoxinepyrimethamine. The main lessonslearned in theprocessof policy change were the need for strong evidence to support the rationale for change, theneed for early preparation for change in order to ensure the necessary resources, and the need toinvolve all stakeholdersearly in the process. Studieshave been planned for measuring the efficacy ofchloroquineagainst vivax malaria and to evaluatetheadverseeffectsof therecommended treatments.MalawiOver 85% of the malaria infectionsin Malawi are due to P.falciparum, with P. ovaleand P. malariaeaccounting for the remainder. In 1978 and 1980, WHO missionsfound no evidenceof chloroquine resistance, but by 1983 cliniciansnoted increasing slide-confirmed chloroquine-resistantmalariawithariseinadmissions forthedisease.Amalariacontrolprogrammewasestablished in 1984 to study chloroquine resistance, identify alternative antimalarial drugsandformulate a rational antimalarial treatment policy. Six sentinel siteswere established acrossthecountry,andthe7-day WHOin vivoefficacytestwas usedtoevaluatechloroquineefficacy. By 1990, parasitological resistance to chloroquine had increased from between 10% and 40% toabout 83% in children under 5 yearsof age. In addition, RIII resistance had increased from 8%in1984to26%in1990.From1985to1991,theproportionofoverallhospitaldeaths inchildren under 5 yearsincreased from 10% to 20%.In December 1991, it wasdecided that chloroquine would be replaced with sulfadoxinepyrimethamine asthe first-line treatment for uncomplicated malaria in all age groups. At the sametime, it wasdecided to introduce the use of a loading dose for quinine for the treatment of severemalariaandthatsulfadoxinepyrimethaminewouldbeusedforintermittenttreatmentinpregnant women. The new policy wasofficially launched in March 1993. Delaysin implemen-tation were attributed to the time taken for consensus-building and information disseminationamongkeygroups,productionoftreatmentguidelines andinformation,educationandcommunicationmaterials,andtheprocurementofadequatestocksofsulfadoxinepyrimethamine (a challenge asit wasmore expensive than chloroquine). Antipyreticswere usedin conjunction with sulfadoxinepyrimethamine, and chloroquine became a prescription-onlydrug.However,manypeoplecontinuedtobuybrandedchloroquineformulations,wh