Efficacy of Second Generation Direct-Acting Antiviral Agents for Treatment Naïve Hepatitis C

17 Pages·2015·0.7 MB·English

RESEARCHARTICLE
Efficacy of Second Generation Direct-Acting
Antiviral Agents for Treatment Naïve
Hepatitis C Genotype 1: A Systematic Review
and Network Meta-Analysis
ThanthimaSuwanthawornkul1☯,ThunyaratAnothaisintawee2☯*,
AbhasneeSobhonslidsuk3,AmmarinThakkinstian4,YotTeerawattananon1
1 HealthInterventionandTechnologyAssessmentProgram,MinistryofPublicHealth,Nonthaburi,Thailand,
2 DepartmentofFamilyMedicine,FacultyofMedicine,RamathibodiHospital,MahidolUniversity,Bangkok,
Thailand,3 DepartmentofMedicine,DivisionofGastroenterologyandHepatology,FacultyofMedicine,
RamathibodiHospital,MahidolUniversity,Bangkok,Thailand,4 SectionforClinicalEpidemiologyand
Biostatistics,FacultyofMedicine,RamathibodiHospital,MahidolUniversity,Bangkok,Thailand
☯Theseauthorscontributedequallytothiswork.
*[email protected]
OPENACCESS
Abstract
Citation:SuwanthawornkulT,AnothaisintaweeT,
SobhonslidsukA,ThakkinstianA,TeerawattananonY
(2015)EfficacyofSecondGenerationDirect-Acting
Background
AntiviralAgentsforTreatmentNaïveHepatitisC
Genotype1:ASystematicReviewandNetwork ThetreatmentofhepatitisC(HCV)infectionshassignificantlychangedinthepastfew
Meta-Analysis.PLoSONE10(12):e0145953.
yearsduetotheintroductionofdirect-actingantiviralagents(DAAs).DAAscouldimprove
doi:10.1371/journal.pone.0145953
thesustainedvirologicalresponsecomparedtopegylatedinterferonwithribavirin(PR).
Editor:RaviJhaveri,UniversityofNorthCarolina
However,therehasbeennoevidencefromrandomizedcontrolledtrials(RCTs)thatdirectly
SchoolofMedicine,UNITEDSTATES
comparetheefficacyamongthedifferentregimensofDAAs.
Received:September14,2015
Accepted:December10,2015 Aim
Published:December31,2015 Therefore,weperformedasystematicreviewandnetworkmeta-analysisaimingtocom-
Copyright:©2015Suwanthawornkuletal.Thisisan parethetreatmentefficacybetweendifferentDAAregimensfortreatmentnaïveHCVgeno-
openaccessarticledistributedunderthetermsofthe type1.
CreativeCommonsAttributionLicense,whichpermits
unrestricteduse,distribution,andreproductioninany
Methods
medium,providedtheoriginalauthorandsourceare
credited. MedlineandScopusweresearchedupto25thMay2015.RCTsinvestigatingtheefficacyof
DataAvailabilityStatement:Allrelevantdataare secondgenerationDAAregimensfortreatmentnaïveHCVgenotype1wereeligibleforthe
withinthepaperanditsSupportingInformationfiles.
review.DuetothelowerefficacyandmoresideeffectsoffirstgenerationDAAs,thisreview
Funding:Theauthorsreceivednospecificfunding includedonlysecondgenerationDAAsapprovedbytheUSorEUFoodandDrugAdminis-
forthiswork.
tration,thatcomprisedofsimeprevir(SMV),sofosbuvir(SOF),daclatasvir(DCV),ledipasvir
CompetingInterests:AbhasneeSobhonslidsukhas (LDV),andparitaprevir/ritonavir/ombitasvirplusdasabuvir(PrOD).Primaryoutcomeswere
receivedgrant/researchsupportfromMerck,Eisai,
sustainedvirologicalresponseatweeks12(SVR12)and24(SVR24)aftertheendoftreat-
Biotin,andBristol-MyersSquibb;actedasanadvisor
mentandadversedrugevents(i.e.seriousadverseevents,anemia,andfatigue).Efficacy
andspeakerforBristol-MyersSquibb.Theother
authorshavenoconflictsofinteresttodeclare. ofalltreatmentregimenswerecomparedbyapplyingamultivariaterandomeffectmeta-
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Direct-ActingAntiviralAgentsforTreatmentofHepatitisCGenotype1
analysis.IncidenceratesofSVR12andSVR24,andadversedrugeventsofeachtreatment
regimenwerepooledusing‘pmeta’commandinSTATAprogram.
Results
Overall,869studieswerereviewedand16studieswereeligibleforthisstudy.Compared
withthePRregimen,SOFplusPR,SMVplusPR,andDVCplusPRregimensyieldedsig-
nificantlyhigherprobabilityofhavingSVR24withpooledriskratios(RR)of1.98(95%CI
1.24,3.14),1.46(95%CI:1.22,1.75),and1.68(95%CI:1.14,2.46),respectively.Pooled
incidenceratesofSVR12andSVR24inalltreatmentregimenswithoutPR,i.e.SOFplus
LDVwith/withoutribavirin,SOFplusSMVwith/withoutribavirin,SOFplusDCVwith/without
ribavirin,andPrODwith/withoutribavirin,(pooledincidenceofSVR12rangingfrom93%to
100%,andpooledincidenceofSVR24rangingfrom89%to96%)weremuchhigherthan
thepooledincidenceratesofSVR12(51%)andSVR24(48%)inPRalone.Incomparing
SOFplusLDVwithribavirinandSOFplusLDVwithoutribavirin,thechanceofhaving
SVR12wasnotsignificantlydifferentbetweenthesetworegimens,withthepooledRRof
0.99(95%CI:0.97,1.01).Regardingadversedrugevents,riskofseriousadversedrug
events,anemiaandfatiguewererelativelyhigherintreatmentregimenswithPRthanthe
treatmentregimenswithoutPR.Themainlimitationofourstudyisthatasubgroupanalysis
accordingtodosagesanddurationoftreatmentcouldnotbeperformed.Therefore,the
doseanddurationofrecommendedtreatmenthavebeensuggestedinrangeandnotindef-
initevalue.
Conclusions
BothDAAplusPRanddualDAAregimensshouldbeincludedinthefirstlinedrugfortreat-
mentnaïveHCVgenotype1becauseofthesignificantclinicalbenefitsoverPRalone.
However,duetohighdrugcosts,aneconomicevaluationshouldbeconductedinorderto
assessthevalueoftheinvestmentwhenmakingcoveragedecisions.
Introduction
Viralhepatitishaslongbeenanunder-recognizeddiseasedespitestatisticsfromtheWorld
HealthOrganizationshowingthatthereare1.4milliondeathsfromhepatitiscomparedto1.6
millionforHIVand1.3millionfortuberculosis[1].ThehealthandeconomicburdenofHepa-
titisBvirusinfectionwasrecentlyrecognizedbyglobalpublichealthplayersandasignificant
stepforwardwasmadeviatheintroductionoftheHepatitisBvaccineinnationalimmuniza-
tionprogramsincountriesatalllevelsofeconomicdevelopment[2].However,thereisno
suchvaccineforHepatitisC,andthusitspreventionandcontrolrelyheavilyonbehavioral
interventions,detectionandtreatment.ThisresultedinarecentglobalagreementonaWorld
HealthAssemblyresolutiononhepatitisinMay2014[3]thaturgedcountriestoimprove
accessforthepreventionandtreatmentofHepatitisBandC.
ThetreatmentofhepatitisC(HCV)infectionshassignificantlychangedinthepastfew
yearswiththeintroductionofdirect-actingantiviralagents(DAAs).Thesetreatmentsare
combinedwithpegylated-interferonwithribavirin(PR)andcouldimprovethesustained
virologicalresponse(SVR)comparedtoPRalone[4–7],particularlyforthosewithgenotype
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Direct-ActingAntiviralAgentsforTreatmentofHepatitisCGenotype1
1—themostprevalenttypeofHCVworldwideandonewhichdoesnotrespondwelltoPR[8].
Nevertheless,therehasbeennoevidencefromrandomizedcontrolledtrials(RCTs)that
directlycomparethedifferentregimensofDAAsandPR.Therefore,thissystematicreview
andmeta-analysisaimstoaddressthisgapbycomparingtheclinicalefficacyandadversedrug
eventsamongtheregimensofDAAplusPR,dualDAAcombinationswithorwithoutribavi-
rin,andPRaloneforthetreatmentnaïveHCVgenotype1.DAAsconsideredinthisstudywere
onlysecondgenerationDAAsbecausefirstgenerationDAAs(i.e.boceprevirandtelaprevir)
hadmoresideeffectsandlowerefficacy,comparedtosecondgenerationDAAs.
TheresultsofthisstudywillbeusefulininformingclinicalpracticeguidelinesforHCV
genotype1treatment,futureeconomicevaluationsforreimbursementdecisions,andnewclini-
calstudiesonHepatitisCtreatment.
Methods
Literaturesearch
TheMedlineandScopusdatabasesweresearchedsincetheirinceptionupto25thMay2015for
identifyingrelevantstudies.Referencelistsofeligiblestudiesandprevioussystematicreviews
werealsoexplored.Searchtermsandsearchstrategiesforbothdatabasesaredescribedin
AppendixAandBinS1andS2Appendices,respectively.
Studyselection
Tworeviewers(T.A.andT.S.)independentlyreviewedtitlesandabstractsforselectingthe
studies.Fullarticleswereascertainedifthedecisioncouldnotbemadebasedontitlesand
abstracts.Disagreementbetweenthetworeviewerswasdecidedbyconsensuswithathird
party(A.S.).
Inclusioncriteria
RCTspublishedinEnglishwereincludedinthereviewiftheymetallofthefollowingcriteria:
(1)studiedpatientsweretreatmentnaïveHCVgenotype1;(2)comparedtheefficacyofany
pairsofthefollowingregimens:DAAplusPR,dualDAAcombinationswithandwithoutriba-
virin,orPRalone.DuetolowerefficacyandmoresideeffectsoffirstgenerationDAAs,this
reviewincludedonlysecondgenerationDAAsapprovedbytheUSorEUFoodandDrug
Administrationatthetimeofwriting,comprisingsimeprevir(SMV),sofosbuvir(SOF),dacla-
tasvir(DCV),ledipasvir(LDV),andparitaprevir/ritonavir/ombitasvirplusdasabuvir(PrOD);
(3)studiesmeasuredtheoutcomesasSVRatweeks12or24aftertheendoftreatment;and(4)
reportedthenumberofpatientshavingornothavingSVRineachtreatmentregimen.
Studieswereexcludediftheyonlycomparedtheefficacybetweendifferentdosagesofthe
sametreatmentregimens.
Dataextraction
Thebaselinecharacteristicsoftheincludedstudies(i.e.author’snames,yearofpublication,
meanage,bodymassindex(BMI),andbaselineHCVRNAofthestudy’sparticipants,percent-
agesofsex,andcirrhosis)andacross-tabulatenumberofpatientsbetweentreatmentandout-
comeswereindependentlyextractedbytwoauthors(T.A.,T.S.)usingstructuraldatarecord
forms.Thecorrespondingauthorsoftheincludedstudieswerecontactediftherewasmissing
orinadequateinformation.
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Treatmentregimensofinterest
TreatmentregimensofinterestweredividedintoDAAplusPRregimens(i.e.SMVplusPR,
DCVplusPR,andSOFplusPR),dualDAAcombinationswithandwithoutribavirinregimens
(i.e.SOFplusLDV,SOFplusSMV,SOFplusDCV,SOFplusLDVandribavirin,SOFplus
SMVandribavirin,andSOFplusDCVandribavirin,PrODandPrODplusribavirin),andPR
alone.
Outcomes
TheoutcomeofinterestwereSVRsatweeks12(SVR12)and24(SVR24)—definedasHCV
RNAlevelslowerthanthedetectablelevelspecifiedintheeligiblestudiesatweeks12and24
aftertheendoftreatment.Safetyoutcomesincludedanemia,fatigue,andseriousadversedrug
events,definedasdeathorseriousconditionswhichrequiredhospitaladmission.
Riskofbiasassessment
ThevalidityofeachstudywasassessedusingtheCochraneCollaboration’stoolforassessing
riskofbiasinrandomizedcontrolledtrials[9].Sevendomainswereevaluated:sequencegener-
ation;allocationconcealment;blindingofparticipantsandpersonnel;blindingofoutcome
assessments;incompleteoutcomedata;selectiveoutcomereporting;andotherbias.Two
reviewers(TAandTS)independentlyperformedtheriskofbiasassessment.Disagreementwas
resolvedbyconsensuswithathirdparty(YT).
Statisticalanalysis
Adirectmeta-analysiswasperformedforstudiesthathadsimilartreatmentcomparisonsifa
totalnumberofthestudieswasnotlessthan3studies.Riskratios(RR)ofSVR12andSVR24
wereestimatedforeachstudyandthenwerepooledusingtheinversevariancemethodifthere
wasnoheterogeneitybetweenstudies;otherwise,arandomeffectmodelwasapplied.Hetero-
geneitybetweenstudieswasestimatedusingtheQtestandI2statisticandwasconsideredpres-
entifthedegreeofheterogeneity(I2)washigherthan25%.Sourcesofheterogeneitywere
exploredbyfittingco-variables(i.e.meanage,BMI,baselineHCVRNA,andpercentcirrhosis)
onebyoneinameta-regression.
Forindirectcomparisons,treatmenteffectsofalltreatmentregimenswereestimatedby
applyingatwo-stagenetworkmeta-analysisasfollows:first,summarydatawereexpandedinto
individualpatientdatausing‘expand’commandinSTATA.Poissonregressionwasappliedto
estimatelog(RR)andvariance-covarianceofeachtreatmentpairwiseusingmvmeta_make
command.PooledRRsandtheir95%confidenceinterval(CI)werethenestimatedusinga
multivariaterandomeffectmeta-analysis,inwhichwithinsubject-studycorrelationwas
accountedforusingRiley’method.Treatmentrankingwasevaluatedbyrankingthelinearpre-
dictorofeachstudy.Forpredictingthetreatmenteffectinthefuture,predictiveintervalwas
estimatedbytakingintoaccountforuncertaintyofthewholenetworkusingthe‘intervalplot’
command.Theinconsistencyassumption(disagreementbetweendirectandindirectestima-
tions)wasthentestedbymeasuringtheinconsistencyfactor(differencebetweenlnRRsesti-
matedfromdirectmeta-analysisandindirectmeta-analysis).
IncidenceofadversedrugeventsandSVR12andSVR24foreachtreatmentregimenwas
pooledusing‘pmeta’command.PublicationbiaswasassessedusingEggertestandFunnel
plot.
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AllanalyseswereperformedusingSTATAversion14.0.Atwo-sidedPvaluelessthan0.05
wasconsideredstatisticallysignificantforallanalysesexceptforheterogeneitytest,inwhicha
one-sidedPvaluelessthan0.1wasappliedinstead.
Thisstudywascompliedwiththeprospectiveprotocol(seedatainS1Protocol)andPre-
ferredReportingItemsforSystematicReviewsandMeta-Analyses(PRISMA)checklist(see
datainS1Checklist).
Results
Weidentified477studiesfromMedlineand562studiesfromScopus.Afterexcludingduplica-
tions,869studieswerereviewedfortitlesandabstracts,resultinginthefinalinclusionof16
studies[4,10–24]inthereview(seeFig1).Thecharacteristicsoftheeligiblestudiesarepre-
sentedinTable1.Amongthe16studies,9studies[4,10–16,22]assessedtheefficacyofDAA
plusPRversusPRalone,while8studies[17–21,23,24]assessedtheefficacyofdualDAA
combinationswithribavirinversusthesimilarregimenwithoutribavirin.Themeanageof
participantswasaround40to50yearsoldandtheirBMIvaluesrangedfrom20to30kg/m2.
Genotype1awascommoninmoststudiesexceptforfourstudies[10–12,14]wheregenotype
1bwasthemostcommoninstead.Twelvestudiesincludedonlynon-cirrhoticpatients,while4
studies[14,16,18,23]includedbothcirrhoticandnon-cirrhoticpatients,ofwhichtheper-
centagesofcirrhoticpatientsrangedfrom7to16%.SVRwasassessedatweeks12and24after
theendoftreatmentfor15studies[4,11–24]and11studies[4,10–16,21,22,24],respectively.
Riskofbiasassessment
ResultsoftheriskofbiasassessmentarepresentedinS1Table.Allstudiesreportedlowriskof
biasinthedomainsofblindingparticipantsandpersonnel,blindingofoutcomeassessment,
selectiveoutcomereporting,andotherbias.Forthedomainsofrandomsequencegeneration
andallocationconcealment,around25%ofthestudies(4/16)hadunclearriskofbiasand
theothershadlowriskofbias.Twooutofthe16studies(13%)hadahighriskofbiasinthe
domainofincompleteoutcomedata,whiletheothershadlowriskofbias.
DAAplusPRversusPRalone
Directmeta-analysis. AmongallDAAplusPRregimens(i.e.SMVplusPR,DCVplus
PR,andSOFplusPR),thecomparisonofSMVplusPRversusPRalonehadsufficientdatafor
performingdirectmeta-analysisofSVR12(4studies[11–14],n=1,354)andSVR24(5studies
[10–14],n=1,252).PooledRRswere1.46(95%CI:1.28,1.67)forSVR12and1.46(95%
CI:1.26,1.69)forSVR24,suggestingthatpatientsreceivingtheSMVplusPRregimenwere
46%morelikelytohaveSVR12andSVR24thanpatientsreceivingPRalone(seeTable2and
S1Fig).
However,therewasmoderateheterogeneityasshownfromtheI2valuesforbothSVR12(I2
=51.7%)andSVR24(I2=30.4%).Thus,sourcesofheterogeneity(i.e.age,BMI,baselineHCV
RNAlevel)wereexploredbutnoneofthemcoulddecreasethedegreeofheterogeneityfor
SVR12;however,thisdidnotholdforSVR24,asthemeanagewasabletodecreasethedegree
ofheterogeneity(I2decreasedfrom30.4to0%).Asubgroupanalysiswasthenperformed
accordingtoagegroup,thepooledRRsofSVR24were1.42(95%CI:1.15,1.76;I2=55.1%)
and1.58(95%CI:1.28,1.96;I2=0.0%)forage<50,andage(cid:1)50years,respectively(seeS1
Fig).ThissuggestedthatalthoughthetreatmenteffectofSMVplusPRbetweenthetwoage
groupswerenotmuchdifferent,itseffectwasmorehomogenousintheolderthantheyounger
agegroups.
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Fig1.Flowchartofstudyselection.
doi:10.1371/journal.pone.0145953.g001
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Direct-ActingAntiviralAgentsforTreatmentofHepatitisCGenotype1
2 4 6 4 2 4 6 8 8
CC/CT/TT(%) 30/58/1 66/c34 29/57/1 30/54/1 35/51/1 30/52/1 27/c63 41/45/1 27/57/1 30/52/1 20/62/1 - 79/c21 32/c68 -
s
Cirrhosi(%) 0 0 0 0 8.4 0 7.4 0 0 0 15.7 0 15 0 0 -
HCV1(%) 0 45.2 1.6 56.3 41 66.8 75.5 80.9 75.8 80 67 88 - 78.5 78.3 67.3 vir
u
b
a
MeanHCVMaleRNA(%)IU/(log10mL) 6.1746.8 6.5055.2 6.0134.3 56.3 55 6.5066.8 6.4867.1 6.4768.5 6.4660.5 6.4357.7 6.3559.3 6.0761.7 -40.5 6.4666.6 6.4050.8 6.4558 mbitasvirplusdas(cid:1)eight75kg)
o w
MeanBMI,2)(kg/m - 26.62 23.59 29.47 30.59 - - 28.17 27.11 28 29.07 28.9 - 28.32 - - vir/ritonavir/ withabody
e
MeanAge(year) 50.33 44.86 51.33 47 47.35 51.25 47.55 45 49.61 52.33 50.76 48.07 - 51.6 54.56 49.21 aritapr atients
p p
DoseDuration(mg/(week)day) -48 -48 -48 -48 -48 -48 -48 -48 -48 –400/90812 –400/901224 –400/90812 400/9012 –400/1224150–400/601224 150/12100/25/500 OF,sofosbuvir;PrOD, gand1,200mg/dayin avirin
Comparator bPR bPR bPR bPR bPR bPR bPR bPR bPR SOF+LDV SOF+LDV SOF+LDV SOF+LDV SOF+SMV SOF+DCV PrOD meprevir;S<eight75k doseforrib
si w d
DoseDuration(mg/(week)day) ––5010012-24/2448–7515012-24/48 10012/24-48 15012/24-48 15012/24-48 –306048/48 ––206012-24/2448 –1004/48400––20012-24/2440048 400/908 –400/901224 400/908 400/9012 –400/1224150–400/601224 150/12100/25/400 eron-ribavirin;SMV, npatientswithbody bodyweightadjuste
studies. Intervention bSMV+PR bSMV+PR bSMV+PR bSMV+PR bSMV+PR bDCV+PR bDCV+PR bSOF+PR bSOF+PR SOF+LDVa+RBV SOF+LDVa+RBV SOF+LDVa+RBV SOF+LDVa+RBV SOF+SMVa+RBV SOF+DCVa+RBV aPrOD+RBV pegylatedinterf (1,000mg/dayi 180g/weekand
Table1.Characteristicsofincluded AuthorYearSetting Hayashi[10]2013Japan Fried[11]2013NorthAmerica,Europe,Asia-fiPacic Hayashi[12]2014Japan Jacobso[13]2014Australia,NorthAmericaEurope,Mexico,NewZealand Manns[14]2014North&SouthAmerica,Europe Pol[15]2012U.S.,France Hézode[16]2014U.S.,Australia,NorthAmerica,Europe Rodriguez-2013U.S.,PuertoRicoTorres[22] Lawitz[4]2013U.S. Kowdley[17]2014U.S. Afdhal[18]2014U.S.,Europe Lawitz[19]2014U.S. Mizokami2015Japan[23] Lawitz[20]2014U.S. Sulkowski2014U.S.[21] Kowdley[24]2014U.S. DCV,daclatasvir;LDV,ledipasvir;PR,athedoseofribavirinwasweight-basebthedoseofpegylatedinterferonwasCCC/CT+TT doi:10.1371/journal.pone.0145953.t001
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Table2. Pooledriskratioofsustainedvirologicalresponseatweeks12and24aftertheendoftreat-
mentbetweensimeprevirpluspegylatedinterferon-ribavirinandpegylatedinterferon-ribavirin.
Author Year SMVplusPR PR RR(95%CI)
Response Non-response Response Non-response
Sustainedvirologicalresponseat12weeks
Fried[11] 2013 252 57 51 26 1.23(1.04,1.46)
Hayashi[12] 2014 109 14 37 23 1.44(1.17,1.77)
Jacobson[13] 2014 210 54 65 65 1.59(1.33,1.91)
Manns[14] 2014 209 48 67 67 1.63(1.36,1.95)
PooledRR 1.46(1.28,1.67)
Sustainedvirologicalresponseat24weeks
Fried[11] 2013 250 59 50 27 1.24(1.05,1.48)
Hayashi[12] 2014 109 14 34 26 1.56(1.24,1.97)
Hayashi[10] 2013 63 16 6 7 1.73(0.95,3.14)
Jacobson[13] 2014 205 42 18 12 1.38(1.03,1.86)
Manns[14] 2014 206 47 28 33 1.77(1.34,2.34)
PooledRR 1.46(1.26,1.69)
CI,confidenceinterval;PR,pegylatedinterferon-ribavirin;RR,riskratio;SMV,simeprevir.
doi:10.1371/journal.pone.0145953.t002
Indirectmeta-analysis. Forindirectcomparisons,8[4,11–16,22](n=1,951)and9stud-
ies[4,10–16,22](n=1,859)wererespectivelyincludedintheanalysesofSVR12andSVR24.
ThenumberofparticipantswhohaveSVR12andSVR24foreachstudyarepresentedinS2
Table.Networkplotwasconstructedtomap4treatmentregimens(i.e.SMVplusPR,SOFplus
PR,DCVplusPR,andPRalone)wheredatawereavailable,seeFig2Aand2B.Sizeofnode
andedgerespectivelyreflectnumberofstudiesandpatientsforthatcomparison;whichshow
thatPRwastheonlycommoncomparatorandhadthelargestsamplesizeamongthe4treat-
mentregimens,whereastheSMVplusPRversusPRhadthelargestnumberofstudies.
Sustainedvirologicalresponseatweek12. ThepooledincidenceofSVR12forPR,SMV
plusPR,SOFplusPR,andDCVplusPRregimenswererespectively51%(95%CI:43%,59%),
83%(95%CI:79%,86%),82%(95%CI:63%,100%),and65%(95%CI:57%,73%),seeS3Table.
Atwo-stagemultivariatemeta-analysiswasappliedandsuggestedthatthechanceofhaving
SVR12wassignificantlyhigherinSMVplusPRandDCVplusPRregimenswhencompared
withPRalone.ThepooledRRsforSMVplusPRandDCVplusPRwereof1.48(95%CI:1.27,
1.72)and1.82(95%CI:1.24,2.69),respectively(seeTable3).SOFplusPRregimenalso
increasedSVR12whencomparedtoPR,butthisdidnotreachstatisticalsignificance(pooled
RR=1.52;95%CI:0.97,2.40),seeTable3.Treatmentrankingwasthenassessedbyestimating
probabilityofbeingthebesttreatment,whichyieldedprobabilitiesof65.5%,28%,and6.5%for
DCVplusPR,SOFplusPR,andSMVplusPRregimens,respectively.Thisindicatedthatthe
besttreatmentregimenwasDCVplusPRfollowedbySOFplusPR.
Thepredictiveintervalwasalsoestimatedtopredictwhethertreatmenteffectwillexistin
thefuturebytakingintoaccountuncertaintyandheterogeneity.TheplotindicatedthatSMV
plusPRandDCVplusPRregimenswillbeeffectiveinthefutureafteraccountingforuncer-
taintyandheterogeneity,seeFig3A.Theinconsistencyassumptionwasassessedbyestimating
inconsistencyfactors(i.e.differencebetweendirectandindirectlnRR),whichwere0.012
(Z=0.122,P-value=0.903),0.001(Z=0.003,P-value=0.998),and0.010(Z=0.024,P-
value=0.981)forSMVplusPR,SOFplusPR,andDCVplusPR,respectively.Thesesuggested
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Fig2.Networkplotsforsustainedvirologicalresponseatweeks12and24aftertheendoftreatment.
doi:10.1371/journal.pone.0145953.g002
Table3. Networkmeta-analysisofsustainedvirologicalresponseatweek12aftertheendof
treatment.
Treatment No.ofsubjects No.ofSVR12 PooledRR(95%CI)
DAAplusPRversusPRalone
PR 525 271 1
SMVplusPR 953 780 1.48(1.27,1.71)
SOFplusPR 144 121 1.52(0.97,2.40)
DCVplusPR 329 209 1.82(1.24,2.70)
AmongDAAplusPRregimens
SOFplusPRvsSMVplusPR - - 1.03(0.64,1.66)
DCVplusPRvsSMVplusPR - - 1.23(0.81,1.87)
DCVplusPRvsSOFplusPR - - 1.20(0.66,2.18)
CI,confidenceinterval;DCV,daclatasvir;DAA,directactinganti-viralagents;LDV,ledipasvir;PR,
pegylatedinterferon-ribavirin;RR,riskratio;SMV,simeprevir;SOF,sofosbuvir;SVR12,sustained
virologicalresponseatweek12aftertheendoftreatment.
doi:10.1371/journal.pone.0145953.t003
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Fig3.Predictiveintervalplotsforsustainedvirologicalresponseatweeks12and24aftertheendoftreatment.
doi:10.1371/journal.pone.0145953.g003
thattheestimatedtreatmenteffectsbetweendirectandindirectcomparisonswerenotsignifi-
cantlydifferent.
WhencomparingamongthedifferentDAAplusPRregimens,SVR12wasnotsignificantly
differentamongalltreatmentcomparisons.PooledRRsofSVR12betweenSOFplusPRversus
SMVplusPR,DCVplusPRversusSMVplusPR,andDCVplusPRversusSOFplusPRregi-
menswere1.03(95%CI:0.64,1.66),1.23(95%CI:0.81,1.87),and1.20(95%CI:0.66,2.18),
respectively(seeTable3).
Sustainedvirologicalresponseatweek24. PooledincidenceofSVR24forPR,SMVplus
PR,SOFplusPR,andDCVplusPRregimenswere48%(95%CI:40%,57%),83%(95%CI:
80%,86%),81%(95%CI:68%,95%),and62%(95%CI:53%,70%),respectively(seeS3Table).
WhencomparedwithPRalone,allDAAplusPRregimenssignificantlyincreasedSVR24with
pooledRRsof1.46(95%CI:1.22,1.75),1.98(95%CI1.24,3.14),and1.68(95%CI:1.14,2.46)
forSMVplusPR,SOFplusPR,andDCVplusPRregimens,respectively(seeTable4).SOF
plusPRregimenhadthehighestprobabilityforbeingthebesttreatment(74.5%),followedby
DCVplusPR(24.5%),andSMVplusPR(1%)regimen.
Fig3BillustratesthepredictiveintervalplotforSMVplusPR,SOFplusPR,andDCVplus
PR,whencomparedwithPRalone.AllthreeDAAplusPRregimensseemtobeeffectiveinthe
PLOSONE|DOI:10.1371/journal.pone.0145953 December31,2015 10/17