Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children

135 Pages·2013·1.39 MB·English

Monoclonal antibody for reducing the risk of respiratory
syncytial virus infection in children (Review)
Andabaka T, NickersonJW, Rojas-Reyes MX, Rueda JD, Bacic Vrca V, Barsic B
ThisisareprintofaCochranereview,preparedandmaintainedbyTheCochraneCollaborationandpublishedinTheCochraneLibrary
2013,Issue4
http://www.thecochranelibrary.com
Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review)
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Figure6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Analysis1.1.Comparison1Palivizumabversusplacebo,Outcome1HospitalisationforRSVinfection. . . . . . 89
Analysis1.2.Comparison1Palivizumabversusplacebo,Outcome2All-causemortality. . . . . . . . . . . 90
Analysis1.3.Comparison1Palivizumabversusplacebo,Outcome3TotalRSVhospitaldaysper100children. . . 90
Analysis1.4.Comparison1Palivizumabversusplacebo,Outcome4AdmissiontoICU. . . . . . . . . . . 91
Analysis1.5.Comparison1Palivizumabversusplacebo,Outcome5DaysintheICUper100children. . . . . . 92
Analysis1.6.Comparison1Palivizumabversusplacebo,Outcome6MechanicalventilationforRSVinfection. . . 92
Analysis1.7.Comparison1Palivizumabversusplacebo,Outcome7Daysofmechanicalventilationper100children. 93
Analysis1.8.Comparison 1Palivizumab versusplacebo,Outcome8Daysofsupplementaloxygentherapyper100
children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
Analysis1.9.Comparison1Palivizumabversusplacebo,Outcome9NumberofchildrenreportinganyAE. . . . 94
Analysis1.10.Comparison1Palivizumabversusplacebo,Outcome10NumberofchildrenreportingrelatedAE. . 95
Analysis1.11.Comparison1Palivizumabversusplacebo,Outcome11NumberofchildrenreportinganySAE. . . 95
Analysis1.12.Comparison1Palivizumabversusplacebo,Outcome12NumberofchildrenreportingrelatedSAE. . 96
Analysis2.1.Comparison2Palivizumabversusmotavizumab,Outcome1HospitalisationforRSVinfection. . . . 97
Analysis2.2.Comparison2Palivizumabversusmotavizumab,Outcome2RSV-specificoutpatientMALRI. . . . 97
Analysis2.3.Comparison2Palivizumabversusmotavizumab,Outcome3All-causemortality. . . . . . . . . 98
Analysis2.4.Comparison2Palivizumabversusmotavizumab,Outcome4TotalRSVhospitaldaysper100children. 99
Analysis2.5.Comparison2Palivizumabversusmotavizumab,Outcome5AdmissiontoICU. . . . . . . . . 99
Analysis2.6.Comparison2Palivizumabversusmotavizumab,Outcome6DaysintheICUper100children. . . . 100
Analysis2.7.Comparison2Palivizumabversusmotavizumab,Outcome7MechanicalventilationforRSVinfection. 101
Analysis2.8.Comparison 2Palivizumab versusmotavizumab, Outcome8Daysofmechanicalventilationper100
children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Analysis2.9.Comparison 2Palivizumab versusmotavizumab, Outcome9SupplementaloxygentherapyforRSV
infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
Analysis2.10.Comparison2Palivizumabversusmotavizumab,Outcome10Daysofsupplementaloxygentherapyper100
children. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Analysis2.11.Comparison2Palivizumabversusmotavizumab,Outcome11NumberofchildrenreportinganyAE. 104
Analysis2.12.Comparison2Palivizumabversusmotavizumab,Outcome12NumberofchildrenreportingrelatedAE. 105
Analysis2.13.Comparison2Palivizumabversusmotavizumab,Outcome13NumberofchildrenreportinganySAE. 106
Analysis2.14.Comparison2Palivizumabversusmotavizumab,Outcome14NumberofchildrenreportingrelatedSAE. 107
Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) i
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 132
Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) ii
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Monoclonal antibody for reducing the risk of respiratory
syncytial virus infection in children
TeaAndabaka1,JasonWNickerson2,MariaXimenaRojas-Reyes3,JuanDavidRueda4,VesnaBacicVrca5,BrunoBarsic6
1SchoolofMedicine,UniversityofSplit,Split,Croatia.2InstituteofPopulationHealth,Ottawa,Canada.3DepartmentofClinical
EpidemiologyandBiostatistics,FacultyofMedicine,PontificiaUniversidadJaveriana,Bogota,Colombia.4DepartamentodeCirugía,
PontificiaUniversidadJaveriana,Bogota,Colombia.5DepartmentofHospitalPharmacy,UniversityHospitalDubrava,Zagreb,Croatia.
6DepartmentofIntensiveCare,UniversityofZagreb,SchoolofMedicine,HospitalforInfectiousDiseases,Zagreb,Croatia
Contactaddress:TeaAndabaka,SchoolofMedicine,UniversityofSplit,Soltanska2,Split,21000,[email protected].
Editorialgroup:CochraneAcuteRespiratoryInfectionsGroup.
Publicationstatusanddate:New,publishedinIssue4,2013.
Reviewcontentassessedasup-to-date: 8August2012.
Citation: AndabakaT,NickersonJW,Rojas-ReyesMX,RuedaJD,BacicVrcaV,BarsicB.Monoclonalantibodyforreducingtherisk
ofrespiratorysyncytialvirusinfectioninchildren.CochraneDatabaseofSystematicReviews2013,Issue4.Art.No.:CD006602.DOI:
10.1002/14651858.CD006602.pub4.
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Respiratorysyncytialvirus(RSV)isoneofthemostimportantviralpathogenscausingacuterespiratoryinfectionsinchildren.Itresults
inabout3.4millionhospitalisationsannuallyinchildrenunderfive.Palivizumabisananti-RSVmonoclonalantibody,administered
intramuscularlyatadoseof15mg/kgonceevery30days.Theefficacyandsafetyofpalivizumabhasbeenevaluatedinmulticentre,
randomisedcontrolledtrials(RCTs)andalargenumberofeconomicevaluations(EEs)havetesteditscost-effectiveness.
Objectives
Toassesstheeffectivenessandsafetyofpalivizumabprophylaxiscomparedwithplacebo,oranothertypeofprophylaxis,inreducing
theriskofcomplications(hospitalisationduetoRSVinfection)inhigh-riskinfantsandchildren.Toassessthecost-effectiveness(or
cost-utility)ofpalivizumabprophylaxiscomparedwithnoprophylaxisininfantsandchildrenindifferentriskgroups.
Searchmethods
WesearchedCENTRAL2012,Issue7,MEDLINE(1996toJulyweek4,2012),EMBASE(1996toAugust2012),CINAHL(1996to
August2012)andLILACS(1996toAugust2012)forstudiesofeffectivenessandsafety.WesearchedtheNHSEconomicEvaluations
Database (NHS EED 2012, Issue 4), Health Economics Evaluations Database (HEED, 9 August 2012) and Paediatric Economic
Database Evaluations (PEDE, 1980 to2009), MEDLINE (1996 toJuly week4, 2012) and EMBASE (1996 toAugust 2012) for
economicevaluations.
Selectioncriteria
WeincludedRCTscomparingpalivizumabprophylaxiswithaplacebo,noprophylaxisoranothertypeofprophylaxisinpreventing
seriouslowerrespiratorytractdiseasecausedbyRSVinpaediatricpatientsathighrisk.Weincludedcost-effectivenessanalysesand
cost-utilityanalysescomparingpalivizumabprophylaxiswithnoprophylaxis.
Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) 1
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Datacollectionandanalysis
TworeviewauthorsindependentlyassessedriskofbiasfortheincludedstudiesandextracteddataforboththeRCTsandEEs.We
calculatedriskratios(RRs)andtheirassociated95%confidenceintervals(CIs)fordichotomousoutcomesandforadverseevents(AEs).
We provided a narrative summary of results for continuous outcomes, due to missing data on standard deviations. We performed
fixed-effectmeta-analysesfor theestimation ofpooledeffectswhenevertherewas noindication of heterogeneitybetweenincluded
RCTs.WesummarisedtheresultsreportedinincludedEEs,suchasincrementalcosts,incrementaleffectiveness,andincrementalcost-
effectivenessand/orcost-utilityratios(ICERs),andwecalculatedICERpresentvaluesin2011Eurosforallstudies.
Mainresults
OfthesevenavailableRCTs,threecomparedpalivizumabwithaplaceboinatotalof2831patients,andfourcomparedpalivizumab
withmotavizumabinatotalof8265patients.AllRCTsweresponsoredbythedrugmanufacturingcompany.Theoverallqualityof
RCTswasgood,butformostoftheoutcomesassessedonlydatafromtwostudiescontributedtotheanalysis.Palivizumabprophylaxis
wasassociatedwithastatisticallysignificantreductioninRSVhospitalisations (RR0.49,95%CI0.37to0.64)whencomparedto
placebo.Whencomparedtomotavizumab,palivizumabrecipientsshowedanon-significantincreaseintheriskofRSVhospitalisations
(RR1.36,95%CI0.97to1.90).Inbothcases,theproportionofchildrenwithanyAEoranyAErelatedtothestudydrugwassimilar
betweenthetwogroups.
Intermsofeconomicevidence,weincluded34studiesthatreportedcost-effectivenessand/orcost-utilitydataforpalivizumabprophy-
laxiscomparedwithnoprophylaxis,inhigh-riskchildrenwithdifferentunderlyingmedicalconditions.TheoverallqualityofEEswas
good,butthevariationsinmodellingapproacheswereconsiderableacrossthestudies,leadingtobigdifferencesincost-effectiveness
results.Thecost-effectivenessofpalivizumabprophylaxisdependsontheconsumptionofresourcestakenintoaccountbythestudy
authors;andonthecost-effectivenessthresholdsetbythehealthcaresectorineachcountry.
Authors’conclusions
ThereisevidencethatpalivizumabprophylaxisiseffectiveinreducingthefrequencyofhospitalisationsduetoRSVinfection,i.e.in
reducingtheincidenceofseriouslowerrespiratorytractRSVdiseaseinchildrenwithchroniclungdisease,congenitalheartdiseaseor
thosebornpreterm.
Resultsfromeconomicevaluationsofpalivizumabprophylaxisareinconsistent,implyingthateconomicfindingsmustbeinterpreted
withcaution.ICERvaluesvariedconsiderablyacrossstudies,fromhighlycost-effectivetonotcost-effective.Theavailabilityoflow-
costpalivizumabwouldreduceitsinequitabledistribution,sothatRSVprophylaxiswouldbeavailabletothepoorestcountrieswhere
childrenareatgreatestrisk.
PLAIN LANGUAGE SUMMARY
PalivizumabforreducingtheriskofsevereRSVinfectioninchildren
Respiratory syncytial virus (RSV) infection is a major cause of acute respiratory infections in children. RSV infection can lead to
morbidityandmortalityinchildren,resultinginhospitalisation,admissiontoanintensivecareunit,theneedforintensivemedical
therapiesanddeath.
Mostinfectedchildrensufferlittleconsequence.However,childrenwhohaveotherserioushealthproblemsareknowntobeathigher
riskofcomplications fromRSVinfection.Thisreviewexaminedtheuseofapassiveimmunisation -palivizumab -topreventand
modifytheseverityofRSVinfectioninthesechildrenandtodetermineifitiscost-effective.
Theresultsfromthisreviewarebasedondatafromsevenstudies(allsponsoredbythedrugmanufacturingcompany)involving11,096
participantsreportingonefficacyandsafetyofpalivizumab,and34studiesreportingonitscost-effectiveness.
OurfindingssuggestafavourableeffectofpreventiveuseofpalivizumabinchildrenwhoareathigherriskofacquiringsevereRSV
infection,whencomparedtoplacebo.Childrentreatedwithpalivizumabwerelessoftenhospitalised,spentfewerdaysinthehospital,
wereadmittedtoanintensivecareunitlessoften,andhadfewerdaysofoxygentherapythanchildrenwhoreceivedaplacebo.
Consideringtheunderlyinghealthproblemsinthispopulationofinfantsandchildren,highratesofadverseeventsarequiteexpected.
Our findings showed that children treated with palivizumab experienced adverse events similarly as often as children treated with
placebo.
Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) 2
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Palivizumabwasshowntobeeffectiveinreducingthehospitalisations,butwhetheritisalsocost-effectiveisnoteasytodetermine.
Thisreviewfoundlargedifferencesincost-effectivenessresultsacrossthestudies.Duetothehighcostsofthedrug,inmanycountries
palivizumabprophylaxismightnotbeavailableasastandardtreatment.
Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) 3
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
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Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) 4
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
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Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) 5
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
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Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) 6
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
BACKGROUND
for approximately half an hour on hands, reinforcing the need
forstringentinfectioncontrolpolicieswithinhealthfacilitiesto
Descriptionofthecondition reduce nosocomial infections. Transmission of the virus among
householdandchildcarecontactsiscommon.
Respiratorysyncytialvirus(RSV)isoneofthemostimportantviral
RSV initially manifests in infants as an upper respiratory tract
pathogenstocauseacuterespiratoryinfections(ARIs)inchildren
infection,butprogressestoalowerrespiratorytractinfectionin
(Nair2010),withvirtuallyallchildrenhavingbeeninfectedwith
approximately 20% to 30% of infants with varying degrees of
RSVatleastoncebytheirsecondbirthday(RedBook2012).Inthe
severity,rangingfrommildtolife-threateningrespiratoryfailure
UnitedStates(US),RSVinfectionisassociatedwithsubstantial
(RedBook2012).Bronchiolitisusuallydevelopsonetothreedays
childhoodmorbidity,necessitatinginpatientandoutpatientcare
followingcommoncoldsymptomssuchasnasalcongestionand
(Hall2009a).
discharge,mildcough,feverandreducedappetite.Astheinfec-
RSVinfectioncarriesaconsiderablediseaseburden,withanesti-
tionprogressesandthesmallairwaysareaffected,othersymptoms
mated2.1millionchildrenunderfiveyearsofagerequiringmed-
maydevelop,suchasrapidbreathing,wheezing,persistentcough
icalcareintheUSeachyear.AmongchildrenwithRSV-related
anddifficultyfeeding,whichcanresultindehydration.Apnoea(a
illnesses,approximately3%arehospitalised, 25% aretreatedin
pauseinbreathingformorethan15or20seconds)isthepresent-
emergency departments and 73% are treated by paediatricians.
ingsymptominupto20%ofinfantsadmittedtohospitalwith
In the US eachyear,it is estimatedthat in childrenunder five,
RSVandmaybethefirstsymptomofbronchiolitis(Arms2008;
RSVinfectionaccountsforoneoutofevery334hospitalisations,
Hall1979; Ralstone 2009). Whilemostcases of RSV infection
oneoutof38visitstoanemergencydepartmentandoneoutof
arenotsevere,inseverecasesoxygenationmayworsenandachild
13 visits to a primary care physician (Hall 2009a). Globally, it
maydevelopacuterespiratoryorventilatoryfailure,necessitating
isestimatedthatRSVcausesabout34millionepisodesofacute
mechanical ventilation and admission to an intensive care unit
lowerrespiratorytractinfectionsinchildrenunderfive,resulting
(ICU).Approximately1%to3%ofallchildrenunder12months
inabout3.4millionhospitalisationseachyear(Nair2010).RSV
ofagewillrequirehospitalisationforthetreatmentoflowerrespi-
hasalsobeenshowntobethemostimportantviralcauseofdeath
ratorytractinfectionresultingfromRSV(RedBook2012).
inchildrenunderfive,especiallyinthoseyoungerthanoneyear
CharacteristicsthataremostfrequentlyassociatedwithRSVill-
(Fleming2005;Shay2001;Thompson2003).Indatacompiled
nessrequiringhospitalisationincludemalesex,chronicco-exist-
bytheCentersforDiseaseControlandPrevention(CDC),RSV
ingmedicalconditions,lowersocio-economicstatus,smokeexpo-
pneumonia causes about 2700 adultand paediatric deathseach
sure,contactwithotherchildrenandlackofbreast-feeding(Hall
yearintheUS(Thompson2003).Globally,itisestimatedtore-
2009a). Characteristics that increase the risk of severe RSV ill-
sultinupto199,000deathsperyear(Nair2010).
nessarepretermbirth,cyanoticorcomplicatedcongenitalheart
TheexacttimingoftheRSVseasonvariesbylocationandyear
disease,especiallyconditionsthatcausepulmonaryhypertension,
(Mullins2003).IntemperateclimatesoftheUS,RSVoutbreaks
chroniclungdiseaseofprematurity(formerlycalledbronchopul-
usuallybegininNovemberorDecember,peakinginJanuary or
monarydysplasia)andimmunodeficiency(Purcell2004).
FebruaryandendbyMarchorApril;whereasintropicalorsub-
tropicalclimates,RSVactivity correlateswithrainy seasonsand
may be present throughout the year (AAP 2009; Hall 2009b;
Descriptionoftheintervention
Simoes 2003). The most recent RSV season for which data are
availableintheUSwasJuly2010toJune2011,andthisRSVsea- TheobservationthatpassivelytransferredmaternalRSV-neutral-
sonhadamediandurationof19weeks(CDC2011).Knowledge isingantibodiesprovidedsomeprotectionfromseverelowerrespi-
of RSV seasonality can be used by clinicians and public health ratorytract(LRT)diseasehasledtothedevelopmentofpassiveim-
officialstodetermine whentoconsider RSVasacause of ARIs munityproductstopreventandmodifytheseverityofRSVinfec-
andwhentoprovideRSVimmunoprophylaxistochildrenathigh tion.Thefirstproductavailableforthisusewasarespiratorysyncy-
riskofseriousdisease(RedBook2012). tialvirusimmuneglobulinintravenous(RSV-IVIG,RespiGam),
Theincubationperiodofinfectionfrequentlylastsfourtosixdays. apolyclonalhumanRSV-neutralisingantibody(acombinationof
Inoculation of the virus happens through the upper respiratory differentimmunoglobulinmolecules),administeredintravenously
tract(URT),followedbyinfectionoftherespiratoryepithelium. duringRSV-riskmonths.RSV-IVIGisnolongeravailable.
Themechanismbywhichthevirusspreadsalongtherespiratory In 1996, palivizumab (Synagis) entered into clinical trials.
tractisnotclear,butmayoccurthroughcell-to-celltransferalong Palivizumabisananti-RSVmonoclonalantibody(asetofiden-
intracytoplasmicbridgesorthroughtheaspirationofnasopharyn- tical immunoglobulin molecules), administered intramuscularly
geal aspirations, and may involve the conducting airways at all atadose of 15mg/kg once every30days. The efficacyandsa-
levels(Domachowske 1999; Hall2009b).Transmission ofRSV fetyofpalivizumabhasbeenevaluatedinmulticentrerandomised
isusuallybydirectorclosecontact withRSV-contaminated se- controlledtrials(RCTs), whichintwotrialsdemonstrated45%
cretions.Theviruscansurviveforseveralhoursonsurfaces,and and55%decreasesinRSV-relatedhospitalisations(Feltes2003;
Monoclonalantibodyforreducingtheriskofrespiratorysyncytialvirusinfectioninchildren(Review) 7
Copyright©2013TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.