Effect of artesunate-mefloquine fixed-dose combination in malaria transmission in amazon basin communities

Lucena, Santelli, Ribeiro Isabela, Daher André, Boulos Marcos, Marchesini, Dos, Magalhães Izanelda, Leon, Junger Washington, Ladislau

Description

Studies in South-East Asia have suggested that early diagnosis and treatment with artesunate (AS) and mefloquine (MQ) combination therapy may reduce the transmission of Plasmodium falciparum malaria and the progression of MQ resistance. Methods The effectiveness of a fixed-dose combination of AS and MQ (ASMQ) in reducing malaria transmission was tested in isolated communities of the Juruá valley in the Amazon region. Priority municipalities within the Brazilian Legal Amazon area were selected according to pre-specified criteria. Routine national malaria control programmatic procedures were followed. Existing health structures were reinforced and health care workers were trained to treat with ASMQ all confirmed falciparum malaria cases that match inclusion criteria. A local pharmacovigilance structure was implemented. Incidence of malaria and hospitalizations were recorded two years before, during, and after the fixed-dose ASMQ intervention. In total, between July 2006 and December 2008, 23,845 patients received ASMQ. Two statistical modelling approaches were applied to monthly time series of P. falciparum malaria incidence rates, P. falciparum/Plasmodium vivax infection ratio, and malaria hospital admissions rates. All the time series ranged from January 2004 to December 2008, whilst the intervention period span from July 2006 to December 2008. Results The ASMQ intervention had a highly significant impact on the mean level of each time series, adjusted for trend and season, of 0.34 (95%CI 0.20 – 0.58) for the P. falciparum malaria incidence rates, 0.67 (95%CI 0.50 – 0.89) for the P. falciparum/P. vivax infection ratio, and 0.53 (95%CI 0.41 – 0.69) for the hospital admission rates. There was also a significant change in the seasonal (or monthly) pattern of the time series before and after intervention, with the elimination of the malaria seasonal peak in the rainy months of the years following the introduction of ASMQ. No serious adverse events relating to the use of fixed-dose ASMQ were reported. Conclusions In the remote region of the Juruá valley, the early detection of malaria by health care workers and treatment with fixed-dose ASMQ was feasible and efficacious, and significantly reduced the incidence and morbidity of P. falciparum malaria.

Sujets

• Malaria
• ACT
• Artesunate
• Mefloquine
• Combination drug
• P. falciparum
• Brazil
• Amazon

Informations

• Publié par: biomed
• Publié le: 01 janvier 2012
• Nombre de lectures: 7
• Langue: English

Extrait

Santelli
etal.MalariaJournal
2012,
11
:286
http://www.malariajournal.com/content/11/1/286

RESEARCH

OpenAccess

Effectofartesunate-mefloquinefixed-dose
combinationinmalariatransmissioninamazon
basincommunities
AnaCSantelli
1
,IsabelaRibeiro
3*
,AndréDaher
2,3
,MarcosBoulos
4
,PaolaBMarchesini
5
,RoseliLaCortedosSantos
6
,
MarizeBFLucena
7
,IzaneldaMagalhães
7
,AntonioPLeon
8
,WashingtonJunger
8
andJoséLBLadislau
1

Abstract
Background:
StudiesinSouth-EastAsiahavesuggestedthatearlydiagnosisandtreatmentwithartesunate(AS)
andmefloquine(MQ)combinationtherapymayreducethetransmissionof
Plasmodiumfalciparum
malariaandthe
progressionofMQresistance.
Methods:
Theeffectivenessofafixed-dosecombinationofASandMQ(ASMQ)inreducingmalariatransmission
wastestedinisolatedcommunitiesoftheJuruávalleyintheAmazonregion.
PrioritymunicipalitieswithintheBrazilianLegalAmazonareawereselectedaccordingtopre-specifiedcriteria.
Routinenationalmalariacontrolprogrammaticprocedureswerefollowed.Existinghealthstructureswerereinforced
andhealthcareworkersweretrainedtotreatwithASMQallconfirmedfalciparummalariacasesthatmatch
inclusioncriteria.Alocalpharmacovigilancestructurewasimplemented.Incidenceofmalariaandhospitalizations
wererecordedtwoyearsbefore,during,andafterthefixed-doseASMQintervention.Intotal,betweenJuly2006
andDecember2008,23,845patientsreceivedASMQ.Twostatisticalmodellingapproacheswereappliedtomonthly
timeseriesof
P.falciparum
malariaincidencerates,
P.falciparum/Plasmodiumvivax
infectionratio,andmalaria
hospitaladmissionsrates.AllthetimeseriesrangedfromJanuary2004toDecember2008,whilsttheintervention
periodspanfromJuly2006toDecember2008.
Results:
TheASMQinterventionhadahighlysignificantimpactonthemeanlevelofeachtimeseries,adjustedfor
trendandseason,of0.34(95%CI0.20
–
0.58)fortheP.
falciparum
malariaincidencerates,0.67(95%CI0.50
–
0.89)
forthe
P.falciparum/P.vivax
infectionratio,and0.53(95%CI0.41
–
0.69)forthehospitaladmissionrates.Therewas
alsoasignificantchangeintheseasonal(ormonthly)patternofthetimeseriesbeforeandafterintervention,with
theeliminationofthemalariaseasonalpeakintherainymonthsoftheyearsfollowingtheintroductionofASMQ.
Noseriousadverseeventsrelatingtotheuseoffixed-doseASMQwerereported.
Conclusions:
IntheremoteregionoftheJuruávalley,theearlydetectionofmalariabyhealthcareworkersand
treatmentwithfixed-doseASMQwasfeasibleandefficacious,andsignificantlyreducedtheincidenceand
morbidityof
P.falciparum
malaria.
Keywords:
Malaria,ACT,artesunate,mefloquine,Fixed-dosecombination,P.falciparum,Brazil,Amazon

*Correspondence:[e-mail]
3
InstitutodeTecnologiaemFármacos-Farmanguinhos,FundaçãoOswaldo
Cruz,RiodeJaneiro,Brazil
Fulllistofauthorinformationisavailableattheendofthearticle
©2012Santellietal.;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreative
CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and
reproductioninanymedium,providedtheoriginalworkisproperlycited.

Santelli
etal.MalariaJournal
2012,
11
:286
http://www.malariajournal.com/content/11/1/286

Background
Artemisinin-basedcombinationtherapy(ACT)iscon-
sideredthebestavailabletreatmentforuncomplicated
Plasmodiumfalciparum
malaria,andisattheheartof
theglobalstrategyformalariacontrol[1].Oneofthe
betterdocumentedformofACTisthatcombiningarte-
sunate(AS)andmefloquine(MQ)(ASMQ)[2].
TheuseofASMQwasconsideredinAsiaasastrategy
tomitigateresurgenceofmalariaandtheintensifying
spreadofanti-malarialdrugresistancewellbeforethe
WorldHealthOrganization(WHO)recommendedusing
ACT.Overthelast20years,inthelowtransmission
areasoftheThaiBurmeseborder,thecombinationof
ASandMQhasshownhighefficacyandhasbeenof
greatbenefitinconsiderablyreducingthetransmission
ofmultidrugresistantmalaria,aswellasreversingthe
trendofincreasingMQresistance.[2-8].
Safe,rapid,andreliablyeffective,thecombinationofAS
andMQisoneoffiveformsofACTcurrentlyrecom-
mendedbytheWHOasafirst-lineanti-malarialtreat-
ment.TheWHOalsorecommendsthatfixed-dose
combinations(FDC)beusedwheneverpossible[1]toin-
creasecompliancetotreatment.In2002,inordertoad-
dressthetreatmentneedsofpeoplemostthreatenedby
malariaandunderscoringtheneedforpublicleadership,
theFixed-DoseArtesunate-BasedCombinationTherapies
(FACT)Consortium,createdbytheDrugsforNeglected
Diseasesinitiative(DNDi)andtheSpecialProgrammefor
ResearchandTraininginTropicalDiseases(TDR),devel-
opedASMQasa(FDC).WithintheFACTConsortium,
Farmanguinhoswasthefirstmanufacturingpartnerof
ASMQFDC.BydevelopingaFDCofwell-establisheduse,
DNDianditspartnersaimedtoimprovetreatmentcom-
pliance,extenditsuseinmalariaendemiccountriesand
fightmoreefficientlyagainstresistancedevelopment.
[9,10].Thisuser-friendlynewtabletco-formulation,which
simplifiestreatmentwithasingledailydoseof1or2
tabletsforthreedays,representsaninnovationthatcould
haveconsiderableimpactinthetreatmentofuncompli-
cated
P.falciparum
malaria.Fixed-dosecombinations
eliminatethepossibilityofpatientstakingonlyonecom-
ponentofthecombinationandareexpectedtoimprove
patientcompliance[1].Withspecificpresentationsfor
childrenagedbetween6monthsand11years,ASMQ
FDCaddressestheneedsofchildren,theprimaryvictims
ofmalariaworldwide.
In2008,approximately320,000casesof
P.falciparum
malariawerereportedinLatinAmerica,whereBrazil
hasthehighestmalariaburden[11].InBrazil,99.8%of
malariatransmissionoccursineightstates(Acre,
Amapá,Amazonas,MatoGrosso,Pará,Rondônia,Ror-
aima,TocantinsandpartofMaranhão)thattogether
formtheLegalAmazon[12].Withameanincidenceof
500,000cases/year,malariaaffectsallagegroupsequally,

Page2of12

exceptindividualsbelowoneyearandolderthan60years
ofage,forwhomincidenceislower.Transmission
increasesduringtheseasonalpeak,whenclimaticcondi-
tionsarefavourabletovectorproliferation.Newurban
growthhasbeenrelatedtomalariaburdenincities,such
asCruzeirodoSul[12].Adecreaseinmalariacaseswas
observedasof2006,whichhasbeenrelatedtoseveral
factors,namelytheintroductionofACTfor
P.falcip-
arum
malariatreatment,greaterinvestments,capacity
buildingonpreventionandcontrol,andepidemiologic
dataanalyses,whichallowafocusonmalariaburdensin
realtime,bothfromdecisionmakersandthepopula-
tionsinvolved[12].MalariariskinBrazilisclassified
accordingtotheAnnualParasiteIncidence(API).High
riskareashaveanAPIof
≥
50/1000inhabitants,inter-
mediateareasof10
–
49/1000inhabitants,andlowrisk
areashaveanAPI<10/1000inhabitants.From2003
–
2007,intheAcre,AmazonasandRoraimastatesofthe
LegalAmazon,79municipalitieswereclassifiedashigh
risk,includingelevenwithanAPI>300/1000inhabi-
tants,threeofwhichwereareasintheJuruávalleyof
theAcreStateincludedinthepresentstudy:Rodrigues
Alves,MâncioLimaandCruzeirodoSul(Figure1).
EfficacystudiesinitiatedbytheAmazonNetworkfor
theSurveillanceofAntimalarialDrugResistance(RAV-
REDA),createdin2001tomonitor
Plasmodium
resist-
ance,showedcureratesbelow90%forquininesulphate
anddoxycycline(atthetime,thefirst-lineregimen)for
P.falciparum
treatment,andpromptedtheintroduction
ofACTin2006bytheNationalMalariaControl
Programme(PNCM).Chloroquineandprimaquine
0,50mgbase/kgduringsevendaysremainthetreatment
for
P.vivax
malaria[13].
ThisarticlepresentstheresultsofaphaseIVdeploy-
mentstudyinvestigatingtheimpactoffixed-dose
ASMQcombinationon
P.falciparum
incidence,
P.vivax
and
P.falciparum
ratio,andonthenumberofhospital
admissionsinthreemunicipalitiesintheAmazonBasin
(Brazil),characterizedbyhighmalariaincidenceand
concernsofincreasinganti-malarialresistancetoquin-
ine-doxycycline.Thestudyaimedtoassessthesuitability
ofreplacingquininesulphateanddoxycyclineasana-
tionalfirst-linetreatmentpolicyforchildrenandadults
withuncomplicated
P.falciparum
malariainLatin
America.Thisstudyisthelargesttodateonthepro-
grammaticuseofASMQinLatinAmerica.
Studyareadescriptionandpopulationselection
ThestudyincludeddatacollectedbetweenJuly2004
andDecember2008.TheASMQinterventionwascar-
riedoutbetweenJuly2006andDecember2008inthree
municipalitiesintheJuruávalley,withinthestateof
AcreinBrazil:CruzeirodoSul,MancioLimaandRodri-
guesAlves(Figure1).Themunicipalitieswereselected

Santelli
etal.MalariaJournal
2012,
11
:286
http://www.malariajournal.com/content/11/1/286

Figure1
Locationofthestudyarea.

becausetheyhadrecordedmorethan20
P.falciparum
malariacasespermonthbetween2003and2004,and
hadastablepopulation(definedby<15%proportionof
importedcases),aswellassupportiveandcooperative
localhealthauthorities.
Acrestate,situatedinthemostoccidentalregionof
LegalAmazon(Figure1)hasapopulationof680,073
inhabitants;15.2%(103,371)ofthepopulationlivein
CruzeirodoSul,MâncioLimaandRodriguesAlves,and
accountfor86%ofAcre
’
smalariacases.Thestateof
Acrehasatropicalclimate,wi