Hepatite B Coinfeção

20/02/2015
inPracticeHepatitisBManagementinSpecialPopulations
HepatitisBManagementinSpecialPopulations
Author:TramT.Tran,MD(MoreInfo)
EditorsInChief:NezamH.Afdhal,MD,FRCPIStefanZeuzem,MD
LastReviewed:4/18/14(What'sNew)
Introduction
NewertherapiesforhepatitisBhaveincreasedviralsuppressionratesandreducedratesofviralresistancefollowingtreatment
ManagementofhepatitisBinpopulationswithcomplexneedsmayrequirenovelstrategies
AlthoughnewtherapiesforhepatitisBintroducedinthepast10yearshaveimprovedtheefficacyofviralsuppressionandhavelowered
theriskofantiviralresistance,incertainpatientpopulations,thereremaincomplexissuessurroundinghepatitisBpreventionand
treatment.Thismodulereviewsthecurrentdataandrecommendationsforthesespecialpopulations,withafocusoncurrentclinical
practices.
HepatitisBVirusCoinfection:HIVandHepatitisCandDViruses
HepatitisBVirusandHIVCoinfection
Anestimated5%to10%ofglobalHBVinfectionsareinHIVcoinfectedpatients
HepatitisBisgenerallymoreaggressiveinpatientscoinfectedwithHIV,withhigherratesofchronicity,higherHBVDNAlevels,
morefrequentreactivationperiods,andmorerapidprogressiontocirrhosis[Puoti2006]
HBVcausessignificantliverrelatedmortalityinHIVinfectedpatients[Weber2006Thio2002]
HBV/HIVcoinfectedpatientsmayexhibitabnormallivertestsformultiplereasons,includingmedicationuse,steatosis,or
coinfections[Wit2002]
ConsiderusingalowerthresholdforliverbiopsyinHBV/HIVcoinfectedindividuals
EmergingdatasupportuseofnoninvasivetestsforliverdiseaseinHBVmonoinfection(A),[Marcellin2009Chang2008]
althoughliverbiopsyremainsthegoldstandard
AccordingtoguidancefromtheAmericanAssociationfortheStudyofLiverDiseases(ManagementGuidelines)[Lok2009]andthe
EuropeanAssociationfortheStudyofLiverDiseases(ManagementGuidelines)[EASLHBV]thegoaloftherapyisvirologic
suppressionofbothHBVandHIVreplication:
Inuntreatedpatientswhorequiretreatmentforbothinfections,chooseanantiretroviralregimenincluding2agentsalso
activeagainstHBV(Figure1)
DiscontinuationofantiretroviralswithactivityagainstHBVmayresultinHBVflaresifnotreplacedbyotheractiveagents
InpatientswhorequiretreatmentofHBVonly,avoiduseofentecavirortenofovir,asthesemayselectforHIVresistance
Worldwide,40millionpeopleareinfectedwithHIV,ofwhom5%to10%arecoinfectedwithhepatitisBvirus(HBV).[Alter2006]Across
sectionalstudyinBrazilcalculatedanHBVcoinfectionrateof2.5%(95%CI:1.4%to3.5%)among848HIVinfectedpersons,[Freitas2014]
whereasacoinfectionrateof5.5%wasrecentlyreportedinaretrospectivedatabasereviewconductedamong2579HIVpositive
patientsinNorthernAlberta,Canada.[Pittman2014]Similarly,inaUSregistrylinkagestudy,among31,997HBVinfectedpatients,6.3%
werealsoinfectedwithHIV.[Sanchez2014]ThemodeofHBV/HIVtransmissionvariesgeographically.InlowHBVendemicityareas,such
asNorthAmericaandEurope,druguse,multiplesexualpartners,andsexualtransmissionamongmenwhohavesexwithmenarethe
mostcommonmodesofHBV/HIVtransmission,whereasinhighHBVendemicityareas,suchasAsiaandAfrica,mostHBVinfectionsare
acquiredduringthefirst5yearsoflife,andHIVinfectionsoccurinyoungadultsalreadyinfectedwithHBV.[Puoti2008]
ThenaturalhistoryofhepatitisBinpatientscoinfectedwithHIVisgenerallymoreaggressive,withhigherratesofchronicity,higherHBV
DNAlevels,morefrequentreactivationperiods,andmorerapidprogressiontocirrhosis.[Puoti2006]Forexample,studiesofHIVinfected
adultsacquiringacuteHBVinfectionhavereportedchronicityratesrangingfrom21%to40%(A).[Hadler1991Bodsworth1991Gatanaga
2000Sinicco1997]Thoseratesarenotablyhigherthantheestimatedchronicityrateof5%amongadultsinthegeneralpopulation.[Hyams
1995]Also,severalstudieshavereportedhigherHBVDNAlevelsamongpatientswithHBV/HIVcoinfectioncomparedwithindividuals
withHBVmonoinfection.[Colin1999Bodsworth1989]Inaddition,inonestudy,therateofcirrhosiswasalsosignificantlyhigherinHIV
positivevsHIVnegativepatientsat28%vs13%,respectively(P=.04).Finally,DiMartinoandcolleagues[DiMartino2002]havereported
thatamong141patientswithHBVinfection,76ofwhomreceivedtreatmentwithinterferonalfa,therateofHBeAgseroreversionat2
yearswassignificantlyhigherinpatientswhowerecoinfectedwithHIVat39%relativeto10%inpatientswhowereHIVnegative(P=
.031).
HBValsoplaysasignificantroleinliverrelatedmortalityinHIVinfectedpatients(B).[Weber2006Thio2002]TheD:A:Dstudyprospectively
evaluatedfollowupdatafor23,441HIVinfectedpersons(76,893personyearsworthofdata)andfoundthat14%ofdeathswereliver
https://www.inpractice.com/textbooks/hepatology/ch5_hep_b_spec_populations.aspx#eulamessage
1/31
20/02/2015
related.Ofthepatientswhodiedofliverrelatedcauses,17%hadactiveHBV,66%hadactivehepatitisCvirus(HCV),and7%were
coinfectedwithbothHBVandHCV.PredictorsofliverrelateddeathwereCD4+cellcount,age,injectiondruguse,HCVinfection,and
activeHBVinfection.Inanotherlargecohortstudyinvolving5293menwhohavesexwithmen,liverrelatedmortalitywashigheramong
HBV/HIVcoinfectedpersonsat14.2/1000personyearsrelativeto1.7/1000personyears(P<.001)amongthosewithHIVinfectiononly
and0.8/1000personyearsamongthosewithHBVinfectiononly(P<.001).[Thio2002]
Inthecoinfectedpatient,abnormallivertestsmaybesecondarytomedications(specificallycertainantiretroviralagents),nonalcoholic
fattyliverdisease,herbal/alternativemedications,ortheviralinfectionsthemselves.[Wit2002]Thus,giventhemoreaggressivenatural
historyandthepossibilityofcomorbiditiescausingabnormallivertestsanddiseaseprogression,alowerthresholdforperformingliver
biopsytoassessthedifferentialdiagnosisandthestageandgradeofhistologicinjuryshouldbeconsideredinallcoinfectedindividuals.
AlthoughliverbiopsyremainsthegoldstandardfordeterminingtheseverityofliverdiseaseinHBV/HIVcoinfection,[Thio2009]studies
evaluatingnoninvasivemethods,includingserumbiomarkersandtransientelastography,showpromisingresultsinHBVmonoinfection
(A)[Marcellin2009Chang2008]andarebeginningtobeassessedinHBV/HIVcoinfection.InastudybyBotteroandcolleagues[Bottero2009]
designedtocomparetheperformancecharacteristicsof11biomarkerscoringsystemsin108patientswithHBV/HIVcoinfection,
FibroTest,Fibrometer,HepaScore,andZengsscoreprovidedthemostaccurateresultscomparedwithliverbiopsy.Theareasunderthe
receiveroperatingcharacteristicscurves(AUCs)forthese4testswere0.740.77forpatientswithsignificantfibrosis(F2),0.790.84for
patientswithadvancedfibrosis(F3),and0.870.92forcirrhosis(F4).However,thesescoresmatchedtheresultsofliverbiopsyinonly
50%ofpatients.TransientelastographyhasalsobeenassessedinHBV/HIVcoinfectedpatientsinarecentstudyinvolving59patients.
[Miailhes2011]TheresultsdemonstratedasignificantcorrelationbetweenliverstiffnessmeasuredbytransientelastographyandMETAVIR
fibrosisscore(P<.0001).TheAUCswere0.85forpatientswithsignificantfibrosis(F2),0.92forpatientswithadvancedfibrosis(F3),
and0.96forpatientswithcirrhosis.TheinvestigatorsdevelopedanalgorithmcombiningtransientelastographywithFibroTestscoresthat
resultedin97%ofpatientsbeingwellclassifiedforsignificantfibrosis.
ThegoaloftherapyisvirologicsuppressionofbothHBVandHIVreplication,leadingtoameliorationoftransaminitisandhistologicinjury
andpreventionofliverrelatedcomplications.CurrentguidelinesfromtheAmericanAssociationfortheStudyofLiverDiseases
(ManagementGuidelines)[Lok2009]andtheEuropeanAssociationfortheStudyofLiverDiseases(ManagementGuidelines)[EASLHBV]
onhepatitisBmanagementprovideguidanceonwhoisacandidateforHBVtreatment.
InanHBV/HIVcoinfectedpatientwhohasnotyetinitiatedtherapyforeitherinfection,thechoiceofHBVtreatmentdependsonwhether
thepatientrequiresantiretroviraltherapyfortheirHIVinfection.Ifso,anantiretroviralregimencontaining2agentsthatarealsoactive
againstHBV,suchastenofovirpluslamivudineortenofovirplusemtricitabine,shouldbeprescribed(Figure1).[Lok2009EASLHBVDHHS
ARTEACSART]Antiretroviralregimenscontainingonly1drugwithantiHBVactivity,suchaslamivudinewithoutconcomitanttenofovir,
shouldbeavoidedgiventhehighriskofselectingforHBVresistancetolamivudine[Benhamou2000]tenofovirmonotherapyisalsonota
preferredregimenaccordingtoavailableguidelines.[Lok2009EASLHBVDHHSARTEACSART]InpatientsonanHIVregimenthatincludes
drugstotreatHBV,cliniciansmustbeawareoftheneedforcontinuedHBVtherapyiftheHIVregimenisinterruptedduetosideeffectsor
otherissues,aswithdrawaloftheHBVcomponentoftheregimencouldresultinasignificantHBVflare.
Figure1.ManagementandtherapeuticoptionsincompensatedorcirrhoticHBV/HIVcoinfectedpatients
withanindicationforHIVtreatment.[EACSART]
2/31
20/02/2015
GuidelinesdifferregardingtheoptimalstrategyformanagingHBV/HIVcoinfectedpatientsinwhomantiretroviraltherapyisnotindicated
ordesired.TheUSDepartmentofHealthandHumanServicesguidelinesfortheuseofantiretroviraltherapy(ManagementGuidelines)
[DHHSART]
andtheEuropeanAIDSClinicalSocietyguidelines(ManagementGuidelines)[EACSART]recommendthatcoinfectedpatients
whorequireHBVtherapyshouldalsobeconsideredtohaveanindicationforstartingantiretroviraltherapy,usingacombinationregimen
withactivityagainstbothviruses,asspecifiedabove.OtherguidelinescontinuetoproviderecommendationsforHBVtherapyinpatients
whodonotwishtoorareunabletotakeantiretroviraltherapy.[Lok2009EASLHBV]InthissettingwhereHIVreplicationisnotsuppressed,
itisimportanttoensurethatthechoiceofHBVtherapydoesnotselectforHIVresistance.Thereare3firstlineHBVagents:peginterferon
alfa2a,entecavir,andtenofovir.[Lok2009EASLHBV]Ofthese,bothentecavirandtenofovirmonotherapyshouldbeavoidedinthe
coinfectedpatientwhoisnotonanantiretroviralregimenbecausethesewillselectforHIVviralresistance(A).[McMahon2007Sasadeusz
2008]Peginterferonalfamaybeusedinaselectpopulationofpatientswhofitafavorableprofile(highalanineaminotransferase,low
HBVDNAlevels,hepatitisBeantigenpositive),[Lok2009EASLHBV]althoughtheoverallresponseratesarelower.[DiMartino2002]Atthe
approvedHBVdosinglevel,adefovirhasnegligibleantiHIVactivityandcanbeconsideredforuseasHBVtreatment,althoughthereis
3/31
20/02/2015
stillatheoreticalriskofselectingforHIVresistance(B).[DHHSARTLok2009EASLHBVBenhamou2001]TheEuropeanAIDSClinical
Societyguidelinesalsoincludetelbivudineinthelistofalternativeoptionsforthispatientpopulation(ManagementGuidelines).[EACS
ART]
FormoreinformationfrominPracticeonHBV/HIVcoinfection,clickhere.
HepatitisBVirusandHepatitisCVirusCoinfection
HBVandHCVcoinfectionisespeciallyseeninareasofhighHBVprevalence,duetosharedmodesoftransmission
SuperinfectionwithHCVinpatientswithpreexistingHBV,orviceversa,canleadtomoresevereacutesymptomsandliverfailure
(B)[Liaw2004Liaw2000Lee2000Hytiroglou1995]
MostHBV/HCVcoinfectedpatientshavelowserumHBVDNAlevelsanddetectableHCVviremia:
UltrasensitiveassaysmaydetectoccultHBVinfection(HBsAgnegativebutHBVDNApositive)inHCVinfectedindividuals
(A)[Cacciola1999Squadrito2002Hollinger2010]
HCVsuppressionmayalsooccuralongsideHBVactivity,andvirologicprofilescanchangeovertime(A)[Zarski1998
Ohkawa1995]
Assessmentoffibrosisandnecroinflammationmayguidetherapeuticdecisionmakingasprogressionofliverdiseasemaybe
morerapidinHBV/HCVcoinfectedpatients
Expertopinionadvisesthattreatmentshouldbeindividualizedandtargetedtotheviruswhichappearsmostactive(Table1)
HepatitisBvirus(HBV)andhepatitisCvirus(HCV)havesomeofthesamemodesoftransmissiontherefore,coinfectionisnot
uncommon,especiallyinareaswithhighhepatitisBprevalence.LargescalestudiestodeterminethetrueprevalenceofHBV/HCV
coinfectionaregenerallylacking,butsomedatasuggestthat2%to10%ofantiHCVpositivepatientsarehepatitisBsurfaceantigen
(HBsAg)positive,and2.7%to22.0%ofchronichepatitisBpatientsareantiHCVpositive(B).[Chu2008]ArecentstudyoftheUnited
StatesNationalVeteransAffairsHCVClinicalCaseRegistryassessedpatientstestedforHCVbetween19972005.[Tyson2013]Among
102,971individualswithHCVinfection,1431hadHBVcoinfection,givingaprevalenceof1.4%(95%CI:1.3%to1.5%).Factors
independentlyassociatedwithcoinfectionwereage50yearsoryounger,malesex,HIVinfection,historyofhemophilia,sicklecell
anemiaorthalassemia,historyofbloodtransfusion,andcocaineandotherdruguse.Likelihoodofcoinfectionwasdecreasedin
Hispanicpersons.
InregionsofhighHBVendemicity,superinfectionwithHCVcanleadtomoresevereacutesymptomsandliverfailure(B).[Liaw2004]
Thesepatientsshowedhighercumulativeratesoflivercirrhosisandhepatocellularcarcinomaatfollowup.[Liaw2004]Onapositivenote,
superinfectionwithHCVhasalsobeenassociatedwithHBsAgclearance,hepatitisBeantigenseroconversion,and/orareductionin
HBsAgtiters(B).[Rautou2006Haushofer2002Dai2001]SuperinfectionofchronicallyinfectedHCVpatientswithHBV,whilelesscommon,
canalsoleadtofulminantliverfailure.[Liaw2004Liaw2000Lee2000Hytiroglou1995]
Studiesoftheinteractionbetweenthe2virusesandtheassociatedhostimmunologicresponsesuggestthatmostcoinfectedpatientswill
havelowserumHBVDNAlevelsanddetectableHCVviremia(ManagementGuidelines).[EASLHBV]Inaddition,occultHBVinfection
(HBsAgnegativebutHBVDNApositive)hasbeendescribedwithgrowingfrequencywhencheckedwithsensitiveassaysinHCV
infectedindividuals(B).[Cacciola1999Squadrito2002Hollinger2010]ThissocalledsuppressionofHBVbyHCVismediatedbytheHCV
coreproteinandisseeminglymorecommoningenotype1bHCVinfection.[Schttler2002]Thisinhibitoryeffectisnotuniversal,however,
andotherstudieshavereportedHCVsuppressionandHBVactivitytheHBVandHCVvirologicprofilescanalsochangeovertimein
coinfectedpatients.[Zarski1998Ohkawa1995]
TreatmentrecommendationsforthemanagementofHBV/HCVcoinfectedpatientsaregenerallybasedonexpertopinionratherthanthe
resultsoflargerandomizedcontrolledtrialsbecausesuchdataarelacking.However,expertsagreethattreatmentstrategiesshouldbe
guidedbywhichvirusappearstobemostactiveandshouldbeindividualizedbasedontheuniqueserologicandvirologicprofileofeach
patient(Table1).Liverbiopsy(ornoninvasiveassessmentofliverfibrosissuchaselastography)playsanimportantroleintheHBV/HCV
coinfectedpatientgivendatasuggestingafasterprogressionofhistologicliverinjuryoveraperiodasshortas3years.[Macas2009]
Therefore,determiningthedegreeofinflammationandfibrosis,alongwiththeprogressionofdisease,inthesecoinfectedpatientsmay
beusefultohelpguidethetherapeuticplan.
IfHCVappearstobeactive(ie,detectableHCVRNA)andHBVinactive(lowHBVDNAlevels),smallstudieshaveshownthatcoinfected
patientstreatedwithinterferon/ribavirinorpeginterferon/ribavirinhavecomparablesustainedvirologicresponseratescomparedwith
HCVmonoinfectedpatients(Table1).[Chu2008Liu2003Liu2009]Itmustbementionedthatreciprocalviralinterferencecandevelop
whenHCVistreatedwithinterferonbasedregimensandmayleadtolowerHBVDNAclearance,reactivationsofHBV,andflareswhen
ontherapy.[Chu2008]TherearecurrentlynodataontheeffectofcombiningtheHCVproteaseinhibitors,boceprevirortelaprevir,with
peginterferon/ribavirininHBV/HCVcoinfectedpatients.
IfbothHCVandHBVappeartobeactive,fewdataexistbuttreatmentwithpeginterferonplusribavirincanbeused(B).[Chu2008Jamma
2010]
Inonelargeprospectivetrialofpeginterferonalfa2aplusribavirinfor2448weeksdependingonHCVgenotype(48weeksfor
genotype1and24weeksforgenotypes2/3)inHBV/HCVcoinfectedpatients,morethantwothirdsof161patientsachieved
undetectableHBVDNAattheendofthetreatmentandhighratesofsustainedvirologicresponseforHCVwereachieved(73%for
genotype1patientsand83%forgenotype2/3patients).[Liu2009]However,36%ofpatientswithundetectableHBVDNAatbaseline
4/31
20/02/2015
experiencedHBVDNAreboundduringtreatmentorfollowup.Inaddition,10%ofpatientsachievedHBsAgclearance.[Liu2007]Ifthis
regimendoesnotresultinanadequateHBVresponse,theadditionofanucleos(t)ideduringorafterpeginterferon/ribaviriniscompleted
maybeareasonableoption(Table1),[Chu2008Jamma2010]butfurtherstudiesareneededtoelucidateresponserateswiththese
combinationregimens.
IfHCVdoesnotappeartobeactiveandHBVisthemoreactivevirus,treatmentofHBValoneasperclinicalguidelinesforHBVtherapyis
indicated(Table1).
Table1.StrategiesfortheTreatmentofHBV/HCVCoinfectedPatients[Chu2008]
HCVStatus
HBVStatus
AntiHCVpositive
HCVRNApositive
AntiHCVpositive
HCVRNApositive
AntiHCVpositive
HCVRNAnegative
HBsAgpositiveornegative
HBeAgnegative
HBVDNA<104 IU/mL
HBsAgpositive
HBeAgpositiveornegative
HBVDNA104 IU/mL
HBsAgpositive
HBVDNApositive
Recommendations
Peginterferonplusribavirin
canachievecomparableresults
asforHCVmonoinfection
Reciprocalviralinterference
candevelopduringoraftertherapy
Veryfewdataareavailable
peginterferonplusribavirin
mightbeinadequateaddition
ofanucleos(t)ideanalogue
appearstobeafeasibleoption
butthebesttreatmentregimen
remainstobedetermined
Treataspatientswith
chronicHBVinfection
HBeAg,hepatitisBeantigen.
HepatitisBandDViruses
HDVoccursinpatientswithapreexistingHBVinfection
PatientsfromendemicareasshouldbescreenedforantiHDVantibodies.Positivetestsshouldbeconfirmedby
immunohistochemistryorbyserumHDVRNA
DiseaseprogressionismoreaggressiveinHBV/HDVcoinfectioncomparedwithHBVmonoinfection[Fattovich2000]
Availabledatasuggestthathighdoseinterferonalfa(9MU3timesweekly)orpeginterferonalfafor48weeksshouldbethe
preferredtherapy(ManagementGuidelines)[Lok2009]
Amanagementalgorithmhasbeenproposed(Figure2)[Hughes2011]
HepatitisDinfectionoccursonlyinthesettingofcoexistinghepatitisBvirus(HBV)infection,eitheracutelyorchronically.Thecoinfection
rateisestimatedtobe5%ofHBVinfectedpersons,withhigherratesofhepatitisDvirus(HDV)infectioninLatinAmerica,Eastern
Europe,andtheMediterraneanregions.[Farci2003]However,overallratesofHDVandHBVaredecliningintheseareasbecauseof
implementationofHBVvaccinationprotocols,universalinfectionprecautions,anddiseaseawareness.[Hughes2011]LikeHBV/hepatitisC
viruscoinfection,HBV/HDVcoinfectionisalsocharacterizedbymoreaggressivediseaseprogression[Fattovich2000]therefore,prompt
diagnosisandtreatmentareimportant.
TheonlycommerciallyavailabletestforHDVintheUnitedStatesusesantiHDVantibodies.CheckingforantiHDVisindicatedin
individualsfromendemicareas.Althoughnotmandatedatthistime,a1timetestingforantiHDVantibodiesinhepatitisBsurface
antigen(HBsAg)positivepatientsmaybebeneficial.[Gish2013]IftheHDVtestispositive,resultscanbeconfirmedby
immunohistochemistryontissueorbyserumHDVRNAreversetranscriptionpolymerasechainreactionassay.
TreatmentforHDVinfectionhasbeenstudiedwithinterferonalfa,whichhasbeenusedatadoseof3or9MU,3timesweekly(B).[Niro
2005Farci1994]Thehigherdoseofinterferonhasbeenfoundtoelicitbettervirologic,biochemical,andhistologicresponseratesvsthe
lowerdose,andthisbenefitseemstopersistforyearsinthosewithhistologicresponse,despitevirologicrelapse.[Farci1994]Morerecent
studieshavesuggestedaroleforpeginterferonalfainthetreatmentofHDV.Inonestudy,90patientswithHDVinfectionfromGermany,
Turkey,andGreecewererandomizedtoreceiveeitherpeginterferonalfa2a180g/kgweeklyplusadefovir10mgdaily,oreitherdrug
aloneplusplacebofor48weeks(B).[Wedemeyer2011]Virologicandbiochemicalresponserateswerethesamebetweenthe2groups,but
thecombinationpeginterferon/adefovirgrouphadlowerHDVRNAlevels.InvestigatorsreportedtheinitialresultsoftheHIDIT2study,a
randomizedtrialofpeginterferonalfa2a180g/kgweeklyplustenofovirorplaceboforthetreatmentofpatientswithHDV.[Wedemeyer
5/31
20/02/2015
2013]After96weeksoftreatment,adverseevents,HDVRNAsuppression,HBsAgreduction,andalanineaminotransferasenormalization
weresimilarforpatientstreatedwithpeginterferonalfa2aplustenofovirvspeginterferonalfa2aalone.Theanalysisremainsongoingfor
5yearsaftertherapy.
Therefore,availabledatasuggestthathighdoseinterferonalfa(9MU3timesweekly)orpeginterferonalfafor48weeksshouldbethe
preferredcoursesoftherapy(ManagementGuidelines).[Lok2009]Hughesandcolleagues[Hughes2011]havesuggestedthemanagement
algorithmshowninFigure2.AdditionalstudieshavenotbeenabletoshowanyactivityofribavirinorlamivudineagainstHDV.[Niro2006
Yurdaydin2008]
Furtherstudieswithinterferonalfa,prolongedpeginterferon,ornewernucleos(t)idecombinationtreatmentsforHBV/HDV
arewarranted.Arecentcasereportdescribedasuccessfulresponsetopeginterferonalfa2aandentecavirinamanwithHBVandHDV
dualinfection.[Chen2013]
Figure2.SuggestedalgorithmformanagementofapatientwithHDV.[Hughes2011]
FormoreinformationfrominPracticeonHBV/HDVcoinfection,clickhere.
ManagementofHepatitisBinWomenofChildbearingAge
Inregionsofhighendemicity,mostcasesofHBVtransmissionoccurininfantsviaperinataltransmissionorhorizontal
transmissionfrominfectedfamilymembers[Puoti2008]
HepatitisBvirus(HBV)iseffectivelytransmittedviapercutaneousormucosalexposuretoinfectiousbloodorbodilyfluidsthatcontain
blood.Inregionsofhighendemicity,mostcasesofHBVtransmissionoccurbeforetheageof5yearsthroughperinataltransmissionor
horizontaltransmissionfrominfectedfamilymembers.[Puoti2008]Twogroupsofwomenwillbediscussedinthissection:HBVpositive
womenofchildbearingageandchronicallyinfectedHBVpositivepregnantwomen.
HepatitisBVirusInfectedWomenofChildbearingAge
WomenwithhepatitisBwhoareofchildbearingagearelikelytobeintheimmunetolerantstageofdisease,[Chang1995]withhigh
HBVDNAandnormalALT
Treatmentshouldbedeferredinwomenwithimmunetolerantdisease.Otherwomenrequirecarefulhistorytakinganda
discussionoffamilyplanningaspartoftreatmentdecisionmaking
Inwomenwhoplantobecomepregnantsoon,treatmentmaybedeferreduntilafterpregnancyorinitiatedinthethirdtrimesterto
reducetransmissionrisk(Table2)
Mostwomenofchildbearingage(intheir20sand30s)arelikelytobeintheimmunetolerantstageofdisease.[Chang1995]Thisstagein
thenaturalhistoryofhepatitisBischaracterizedbyahighHBVDNAandpersistentlynormalalanineaminotransferase(ALT)levels.[Chu
1985]TheimmunetolerantpatientisnotacandidateforhepatitisBvirus(HBV)therapybasedoncurrentguidelinesfromtheAmerican
AssociationfortheStudyofLiverDiseases(ManagementGuidelines)[Lok2009]andtheEuropeanAssociationfortheStudyofLiver
Diseases(ManagementGuidelines)[EASLHBV],andtreatmentshouldbedeferreduntilshehasanindicationfortherapy(ie,abnormal
6/31
20/02/2015
ALT,activesignificantviremia,and/orhistologicinjury).IfsheisnotintheimmunetolerantstageandhasanindicationforHBVtreatment,
acarefulhistoryshouldbetakenandfamilyplanningshouldbediscussed.
Ifthewomanisplanningtobecomepregnantsoon,theclinicianmayopttodefertreatmentuntilafterthepregnancyiscomplete(ortreat
onlyinthethirdtrimestertoreducetransmissionriskamoredetaileddiscussiononthistopiccanbefoundinthenextsection)(Table2).
PeginterferonisafirstlineagentthatcanbeconsideredinthispatientbecauseafinitecourseoftherapymayleadtohepatitisBe
antigenseroconversionandlessimmuneactivity,lowerviremia,andlessactivediseasebeforeundergoingpregnancyatalatertime.
However,thelikelihoodoftreatmentefficacywithpeginterferonismuchlowerinpatientswithhighvirallevelsandnormalALT.[Buster
2009]
Table2.ManagementStrategiesforWomenofChildbearingAgeWithHBVInfection [EASLHBV]
Circumstance
Options
RequiringtreatmentforHBVinfection
andconsideringpregnancy
Mayoptforfinitecourseofpeginterferontherapybeforebecomingpregnant,or
Maydefertreatmentuntilafterpregnancyifclinicaldiseaseisstable,or
Maytreatonlyinthethirdtrimesterofpregnancytoreducetransmissionrisk
Becamepregnantwhilereceiving
treatmentforHBVinfection
Decisiontocontinueorstoptreatmentshouldbeindividualizedbasedon:
Thetrimesterthatthepregnancywasdiscovere
Theseverityofunderlyingliverdisease
Theriskadversityofthemothertomedicationsduringpregnancy(especially
inearlypregnancy)
Theriskofflareswhenstoppingthemedications(seediscussionofchoiceof
antiHBVagentsforpregnantwomeninalatersection)
Iftreatmentiscontinued,thechoiceofagentsshouldbereconsidered
Peginterferonalfashouldbediscontinuedandtherapycontinuedwitha
nucleos(t)ideanalogue
FDAcategoryCnucleos(t)ideanaloguesshouldbereplacedwithcategoryB
agentstenofovirispreferred
Pregnantandtreatmentnotclinically
indicatedforHBVinfection
Defertreatmentuntilafterpregnancy,or
Treatonlyinthethirdtrimestertoreducetransmissionrisk
FDA,USFoodandDrugAdministration.
HepatitisBVirusInfectedPregnantWomen
NaturalHistory
DataonHBVinfectionduringpregnancyareconflicting:Somedatasuggestnoworseningofliverdiseaseinmostwomen(A),
[Terrault2007]whereascasereportsshowhepaticexacerbationsandfulminanthepaticfailures[Yang2004Rawal1991]
SomereportssuggestHBVisassociatedwithadversepregnancyoutcomes,includinghigherratesofpretermbirth,gestational
diabetes,andantepartumhemorrhage[Tse2005Lao2007]
DataonthenaturalhistoryofhepatitisBvirus(HBV)infectionduringpregnancyareconflicting.Somedatasuggestnoworseningofliver
diseaseinthemajorityofHBVinfectedpregnantwomen,[Terrault2007]whilecasereportsshowhepaticexacerbationsandfulminant
hepaticfailuresduringpregnancy.[Yang2004Rawal1991]
SomereportssuggestthatHBVinfectionisalsoassociatedwithseveraladversepregnancyoutcomes.[Tse2005Lao2007]Indeed,the
outcomesof253hepatitisBsurfaceantigen(HBsAg)positivewomenwerecomparedwiththoseof253controlsin1studyandshowed
thattheHBsAgcarriershadhigherincidencesofpretermbirthat<34weeks(4.7%vs1.2%P=.033),higherincidencesofthreatened
pretermlaborat<37weeks(11.9%vs6.3%P=.030),higherratesofgestationaldiabetes(19%vs11%P=.012),andhigherratesof
antepartumhemorrhage(11.5%vs5.5%P=.026).[Tse2005]AnotherstudyshowedthatwomenwithHBVinfection(n=1138)hada
significantlyincreasedriskofdevelopinggestationaldiabetesvswomennotinfectedwithHBV(n=12,545oddsratio:1.24[drug:95%
CI:1.011.51]).[Lao2007]Finally,childrenborntoHBVinfectedpregnantwomenwereshowntohavelowerApgarscoresat1and5
minutespostbirthvsthoseborntoHBVuninfectedwomeninonestudy(P=.001andP=.007,respectively).[Tse2005]
HepatitisBVirusTestinginPregnantWomen
AllpregnantwomenshouldbetestedforHBsAgduringthefirsttrimesterofeachpregnancy,accordingtotheAASLD
(ManagementGuidelines)(A)[Lok2009]andtheEASL(ManagementGuidelines)[EASLHBV]
7/31
20/02/2015
AnypregnantwomanwhoisnotimmunetoHBVandhasriskfactorsforinfectionshouldbegiventhehepatitisBadultvaccine
series
HBsAgnegativewomenwithcontinuedhighriskbehaviorduringpregnancy,andthosewithoutascreeningresult,shouldbe
testedforHBsAgatadmissionfordelivery
WomentestingpositiveforHBsAgshouldbereferredforadditionaltesting,counseling,andmedicalmanagement
AllpregnantwomenshouldberoutinelytestedforhepatitisBsurfaceantigen(HBsAg)duringtheirfirsttrimesterineachpregnancy
accordingtotheAmericanAssociationfortheStudyofLiverDiseases(ManagementGuidelines)(A)[Lok2009]andtheEuropean
AssociationfortheStudyofLiverDiseases(ManagementGuidelines)[EASLHBV].ThehepatitisBadultvaccineissafeatallstagesof
pregnancythus,anypregnantwomanwhoisnotimmuneandhasriskfactorsshouldbegiventhevaccineseries.
ForadditionalinformationfrominPracticeonhepatitisBvaccination,clickhere.
WomentestingnegativeforHBsAginthefirsttrimesterwhoengageinhighriskbehaviorduringpregnancyandthosewhodidnothave
earlierscreeningshouldalsobetestedatthetimeofadmissionfordelivery.IfawomantestspositiveforHBsAg,sheshouldbereferred
foradditionaltesting,counseling,andmedicalmanagement.
HepatitisBVirusTreatmentDuringPregnancyforMaternalHealth
InpregnantwomenwithHBVwhorequiretreatmentfortheirownhealth,therapyselectionshouldbebasedonantiviralefficacy,
riskofresistance,humansafetydata,andpregnancyclassofthedrug(Table3)
InwomenwithHBVwhobecomepregnantwhileontherapy,considerwhethertocontinueorstoptreatmentonanindividual
basis
Decisionmakingshouldbebasedonpregnancystage,severityofliverdisease,theriskadversityofthemotherto
medicationsduringpregnancy,andtheriskofflareswhenstoppingmedications(Table2)
Treatmentduringpregnancyshouldonlybestoppediftherisksofdiscontinuationoutweighthepotentialbenefit
Ifapregnantwomanhasadvanceddiseaseortheclinicianoptstoinitiatetherapyforotherreasons,considerationswhenselectingan
antihepatitisBvirus(HBV)agentincludeantiviralefficacy,riskofresistance,humansafetydata,andpregnancyclassofthedrug.The
choiceofantiHBVagentsforpregnantwomenisdiscussedbelow.
IfawomanofchildbearingagebecomespregnantwhilealreadyonHBVtherapy,thedecisiononwhethertocontinuetreatmentorstop
shouldbeindividualizedbasedonthetrimesterthatthepregnancywasdiscovered,theseverityofherunderlyingliverdisease,therisk
adversityofthemothertomedicationsduringpregnancy(especiallyinearlypregnancy),andtheriskofflareswhenstoppingthe
medications(Table2).WithregardtobalancingtheriskofcontinuingthewomansHBVmedicationvstheriskofflaresiftherapyis
discontinued,therateofbirthdefectsinthegeneralpopulationfrom19892003was2.72per100livebirths(95%CI:2.682.76),andthe
prevalenceofbirthdefectsper100livebirthsdiagnosedduringthefirst7daysoflife(earlydiagnosis)was2.09(95%CI:2.072.12).
[APRSC2013]AlthoughthesedatacannotbepreciselycomparedwiththeAntiretroviralPregnancyRegistrydataonbirthdefectswithHBV
medicationsduetotheselfreportednatureandlimitationsoftheregistry,thereportedrateofbirthdefectswithanytenofovircontaining
regimenisreportedtobe2.3%inthefirsttrimesterand2.1%inthesecond/thirdtrimester(Table3).[APRSC2013]Thesedatasuggestthat
tenofovirduringpregnancydoesnotappeartoincreasetheriskofbirthdefectsbecausetheratesofbirthdefectsinchildrenbornto
womeninthegeneralpopulationwassimilar.[APRSC2013]Thus,treatmentduringpregnancyshouldonlybestoppediftherisksof
discontinuationoutweighthepotentialbenefit.
Table3.AdvantagesandDisadvantagesofAntiHBVAgentsDuringPregnancy[APRSC2013]
AntiviralAgent
FDA
Pregnancy
Category
Defects/Live
BirthWhen
ExposedDuring
FirstTrimester,
%*(n/N)
Defects/Live
BirthWhen
ExposedDuring
Second/third
Trimester,%
(n/N)
Adefovir
0
(0/48)
0
(0/0)
Notrecommended
Entecavir
0
(2/55)
0
(0/2)
Notrecommended
Lamivudine
3.1
(136/4360)
2.8
(198/6989)
Advantages/Disadvantagesof
UsingDuringPregnancy
Extensivehumansafety
data
Notapreferredfirstline
agentintreatment
guidelines
Associatedwithhighrates
ofantiviralresistance
8/31
20/02/2015
Telbivudine
0
(0/10)
0
(0/14)
Tenofovir
2.3
(46/1982)
2.1
(20/959)
Positivehumansafetydata
pregnancyclass
Fewerdatathanlamivudine
ortenofovir
agentintreatment
guidelines
data,pregnancyclass
*Prevalenceofdefectsisreportedforfirsttrimesterexposurestodrugswithadenominatorof200.
RoleofHepatitisBVirusTherapyinPreventingTransmission
TreatmentinthethirdtrimesterofpregnancymaylowerriskofperinatalHBVtransmission
Maternalviremiaplaysasignificantroleinperinataltransmission.Studieshavereportedincreasedriskoftransmissionwithhigh
levelsofviremia(>8log10 copies/mLor~7.3log10 IU/mL)[Burk1994Xu2009vanZonneveld2003]
Treatmentwithlamivudine,telbivudine,ortenofovirmaybeconsideredinthethirdtrimesterinmotherswithhighviremia,with
carefuldiscussionoftherisksandbenefits(Figure3)[EASLHBV]
Iftherapyisadministeredonlyforpreventionofmothertochildtransmission,itmaybediscontinuedwithinthefirst3monthsafter
delivery[EASLHBV]
DataontheroleofelectiveCesareansectioninpreventingmothertochildtransmissionofHBVareconflicting,[Zou2010Pan2013
Hu2013]
andthisstrategyisnotcurrentlyrecommended(B)[CDC2006]
TreatmentofthepregnantwomanwithchronichepatitisBremainscontroversial,butmoredataareaccumulatingthatsuggestthat
selectivetreatmentinthethirdtrimesterofpregnancymaylowerriskofperinatalhepatitisBvirus(HBV)transmission.However,studies
havereportedanincreasedriskofHBVtransmissiontotheneonateborntomotherswithhighlevelsofviremia(>8log10 copies/mLor~
7.3log10 IU/mL)(B),[Burk1994Xu2009vanZonneveld2003]arguingfortreatmenttoreducetheHBVDNAlevelpriortodelivery.
Indeed,maternalviremiaplaysasignificantroleinperinataltransmission.Burkandcolleagues[Burk1994]evaluatedtheimpactof
maternalHBVDNAonperinataltransmissioninanestedcasecontrolstudycohortof773hepatitisBsurfaceantigen(HBsAg)positive
Taiwanesewomen.TheinvestigatorsfoundasignificantrelationshipbetweenthemothersserumHBVDNAlevelandtherateof
persistentinfectioninherinfant.Thelikelihoodofhavingapersistentlyinfectedinfantwas147foldhigherforhepatitisBeantigen
(HBeAg)positivemotherswithanHBVDNAlevel1.4ng/mLvsthosewithanHBVDNAlevel<0.005ng/mL.Eveninmotherswho
wereHBeAgnegative,highserumHBVDNAlevelsresultedinanincreasedriskofmaternalfetalHBVtransmission.[Burk1994]Similarly,
Wenandcolleagues[Wen2013]reportedastepwiseincreaseintheriskofchronicinfectionininfantsborntoHBsAgpositivemothers
accordingtomaternalHBVDNA.Among303motherinfantpairs,predictedratesofinfectionatmaternalHBVDNAlevelsof7,8,and9
log10 copies/mLwere6.6%(95%CI:0.5%to12.6%P=.033),14.6%(95%CI:5.6%to23.6%P=.001),and27.7%(95%CI:13.1%to
42.4%P<.001),respectively,followingadjustmentforotherfactorslikelytoinfluencetransmission.
Inaddition,Xuandcolleagues[Xu2009]conductedamulticenter,randomized,doubleblind,placebocontrolledstudyof114HBsAg
positivepregnantwomeninChinaandthePhilippineswhohadhighserumHBVDNAlevels(definedas>1000mEq/mLor~8.3log10
IU/mL)(A).At1yearofage,only18%oftheinfantswhoreceivedthehepatitisBpediatricvaccineandhepatitisBimmuneglobulinand
whosemothersreceivedlamivudinewereHBsAgpositive(vs39%intheplacebogroupP=.014)andonly20%wereHBVDNApositive
(vs46%intheplacebogroupP=.03).Noadverseeventswerenotedinthelamivudinetreatedcohort.
In2011,Hanandcolleagues[Han2011]reportedon229HBeAgpositivemotherswithhighviremia(>107copies/mLor~6.3log10 IU/mL)
whoweregiveneithertelbivudinefromWeeks20to32(n=135)ornotherapy(n=94).AllinfantsreceivedhepatitisBimmuneglobulin
andthehepatitisBpediatricvaccineperprotocol.Investigatorsfoundthattelbivudineadministrationwasassociatedwithamarked
reductioninHBVDNAandHBeAglevelsandnormalizationofalanineaminotransferasebeforedelivery.Theoverallincidenceof
perinataltransmissionwas0%inthetelbivudinetreatedgroupcomparedwith8%inthecontrolgroup(P=.002)7monthsafterdelivery.
Inastudyreportedin2010,telbivudineadministeredforanaverageof15weeksattheendofpregnancyplusactivepassive
immunizationtoneonatesreducedverticaltransmissionratesfrom23%to4%overimmunizationalone.[Pan2010]Liuandcolleagues[Liu
2013]
reportedfromanobservationalstudyof86womenwithchronichepatitisBwhoreceivedtelbivudineduringpregnancy.Noneofthe
infantswasHBsAgpositiveat6months,andoveralltreatmentwasconsideredsafe.
Hanandcolleagues[Han2013a]reportedthelongtermsafetyandefficacyresultsoftelbivudineadministeredtoHBeAgpositivemothers
during2232weeksofgestation.Aftera4yearfollowup,noneofthe202infantswasinfectedwithHBV.Nobirthdefectswerereported
therewereseveralinstancesofadverseevents,buttheseeventsweredeterminedtobeunrelatedtotelbivudineexposureduring
9/31
20/02/2015
pregnancy.Thetreatmentwasconsideredsafeduringthe4yearfollowupperiod.InasecondstudybyHanandcolleagues,[Han2013b]a
systematicreviewof3databases(literature,PeriodicSafetyUpdateReport,andAntiretroviralPregnancyRegistry)wasperformedto
analyzetelbivudinetreatmentofpregnantwomenwithchronicHBVinfection.Thereviewidentified1695pregnancies.Overall,treatment
withtelbivudineresultedinasignificantreductioninperinataltransmissionandwasassociatedwithafavorablesafetyprofile.
EmergingreportssuggestthattherewerenomajorsafetyissuesassociatedwithearlytenofovirDFtreatmentinpregnantwomen.Among
14pregnantwomenintheFrenchreallifecohort(VIREALstudy),12womenreceivedtenofovirDFfromthefirsttrimesterthroughout
pregnancy.[GanneCarrie2013]ThemediandurationoftenofovirDFexposureduringpregnancywas35weeks(range:539weeks).In10
of12patientsassessed,HBVDNAwas<6logIU/mLatdelivery.NoneoftheinfantswaspositiveforHBsAg,andtherewerenoadverse
eventsorbirthdefectsassociatedwithtenofovirDFuseduringpregnancyorduringbreastfeeding.Similarresultswereobservedamong
21pregnantpatientswhoreceivedtenofovirDF300mg/dayfromWeeks1827ofgestation.[Celen2013]Theinfantsalsoreceived
hepatitisBimmuneglobulin200IUwithin24hourspostpartumandrecombinantHBVvaccine20gat4,8,and24weeks.At28weeks
ofage,noneoftheinfantshadimmunoprophylaxisfailure.Finally,thirdtrimestertreatmentwithtenofovirDFmayalsobebeneficial.
Recently,60womenwithahighHBVDNA(>7logIU/mL)receivedtenofovirDFstartingat32weeksofgestation.[Greenup2013]Children
borntothesemothershadamedianbirthHBVDNAof4.56logIU/mL,andofthe34babiesavailablefortesting,allwereHBsAgnegative
at9monthsofage.Again,therewerenotreatmentrelatedbirthdefectsobserved.
InarecentstudyoftreatmentnaiveHBeAgpositivemotherswithHBVDNA>6log10 copies/mL,theuseof100mg/dayoflamivudinein
thesecondvsthirdtrimesterwascomparedforthepreventionofverticaltransmissionofHBV.[Yi2013]Thestudyenrolled155consecutive
motherswhoweretreatedwithlamivudine(secondtrimester,n=61thirdtrimester,n=94)andincluded89matcheduntreatedmothers
withcomparablebaselinevaluesallinfantsreceivedappropriateimmunoprophylaxis.Noneoftheinfantsofthemotherswhoinitiated
treatmentinthesecondorthirdtrimesterwaspositiveforHBsAgorhaddetectableHBVDNAat28weeks.Inaddition,therewasno
significantdifferenceintransmissionrateswhetherlamivudinewasinitiatedinthesecondorthirdtrimester.Itshouldbenoted,however,
thatinitiationoflamivudinelateinpregnancyresultedintheemergenceofdrugresistantviralvariantsinseveralreports.[Yuen2013Ayers
2013]
Overall,treatmentmaybeconsideredwithlamivudine,telbivudine,ortenofovirDFinthethirdtrimesterinmotherswithhighlevelsofHBV
DNA,withcarefuldiscussionoftherisksandbenefits(Figure3).[EASLHBV]Iftherapyisadministeredonlyforpreventionofmotherto
childtransmission,itmaybediscontinuedwithinthefirst3monthsafterdelivery.[EASLHBV]DataontheroleofelectiveCesareansection
inpreventingmothertochildtransmissionofHBVareconflicting,[Zou2010Pan2013Hu2013]andthisstrategyisnotcurrently
recommended.[CDC2006]
Figure3.AlgorithmforthemanagementofHBVinfectionduringpregnancy.[Tran2009a]
10/31
20/02/2015
ChoiceofAntiHepatitisBVirusAgentsinHepatitisBVirusInfectedPregnantWomen
OptionsfortreatingaHBVinfectedpregnantwomanincludelamivudine,telbivudine,andtenofovir.Eachofferdistinctadvantages
anddisadvantages(Table3)
LamivudinehasbeenwellstudiedandhasapregnancyclassCclassification(B).[APRSC2013]However,itisnota
preferredagentintheAmericanAASLDHBVguidelines(ManagementGuidelines)[Lok2009]ortheEASLHBVguidelines
(ManagementGuidelines),[EASLHBV]andisassociatedwithhighratesofantiviralresistance
TelbivudinehasapregnancyclassBdesignation,[APRSC2013]butislesswellstudiedinpregnancythanlamivudine
TenofovirhasanFDApregnancyclassBclassification,[APRSC2013]iswellstudiedinpregnancy,andisapreferredagent
intreatmentguidelines[Lok2009EASLHBV]
Peginterferonalfa2aiscontraindicatedinpregnancy
Therearefewdatatosupportuseofentecavirinpregnancy
The3mostviableoptionsfortreatingahepatitisBvirus(HBV)infectedpregnantwomanarelamivudine,telbivudine,andtenofovir.The
advantagesanddisadvantagesofeachantiviralusedtotreatHBVinfectionduringpregnancy,includingtherateofbirthdefects,are
describedinTable3.
LamivudinemaybeconsideredduringpregnancybecauseofitsextensivehumandatareferencedintheAntiviralPregnancyRegistry.
[APRSC2013]
Inaddition,lamivudinehasaUSFoodandDrugAdministration(FDA)pregnancyclassCclassification,[APRSC2013]which
suggeststhatitisrelativelysafeinthispopulation,butnotasidealasagentswithFDApregnancyclassBclassifications.The
disadvantagesofusinglamivudineinthispopulationarethatitisnotapreferredagentintheAmericanAssociationfortheStudyofLiver
DiseasesHBVguidelines(ManagementGuidelines)[Lok2009]ortheEuropeanAssociationfortheStudyofLiverDiseasesHBV
guidelines(ManagementGuidelines)[EASLHBV]andthatitisassociatedwithhighratesofantiviralresistancethatwouldaffectlongterm
treatment(A).[Lok2009EASLHBV]Therefore,iflamivudineischoseninpregnancy,discontinuationofthemedicationafterbirthwouldbe
appropriatewithmonitoring.
TheefficacyandsafetyoftelbivudinehavealsobeenreportedinHBVinfectedpregnantwomen,[Pan2010]althoughthereismuchless
experiencewiththisagentinpregnancythanlamivudine.However,telbivudinehasapregnancyclassBdesignation,[APRSC2013]
suggestingapossibleadvantageofthisagentoverlamivudineforuseinpregnancy.
11/31
20/02/2015
Tenofovirhasrobusthumanexperience,mainlyfromtheHIVfield,anFDApregnancyclassBclassification,[APRSC2013]andisa
preferredagentintreatmentguidelines,[Lok2009EASLHBV]suggestingitmaybethepreferredagentforuseduringpregnancyif
treatmentischosen.[Lok2010]However,therearenofirmguidelinestodatethatsuggesttheoptimalagentforuseduringpregnancy.
Bothofthe2remainingfirstlineHBVagents,entecavirandpeginterferonalfa2a,havebeenassignedapregnancycategoryC
classification.Peginterferonalfa2aiscontraindicatedinpregnancy,andentecavirhasfewdatasupportingitsuseinthispopulation.
PostpartumFollowup
NeonatesofHBsAgpositivemothersshouldreceivethehepatitisBpediatricvaccineandhepatitisBimmuneglobulinwithin12
hoursofbirth(ManagementGuidelines)[Mast2005]
2additionaldosesofthehepatitisBpediatricvaccineseriesshouldbegivenat4weeksto2monthsofage,and6monthsofage.
FollowupHBsAgandHBsAbtitersshouldbetestedat915monthsofage[Mast2005]
ThemothershouldbefollowedpostpartumforHBVflaresduetodiscontinuationofmedicinesorothercauses[Tan2008Kim2013a
Giles2013]
CurrentrecommendationsfromtheCDCsupportbreastfeedingimmediatelyafterbirthinthispopulation.[Mast2005]Breast
feedingshouldbepausedinmotherswithcrackedorbleedingnipples
AnewborninfantwhosemotherischronicallyinfectedwithhepatitisBvirus(HBV)andshowsserologicevidenceofviralreplication
(hepatitisBsurfaceantigen[drug:HBsAg]positive,hepatitisBeantigenpositive)isathighriskforchronicHBVinfection,rangingfrom
70%to90%bytheageof6monthsintheabsenceofpostexposureprophylaxisintheformofhepatitisBimmuneglobulinandthe
hepatitisBpediatricvaccine.[Mast2004]Therefore,cliniciansshouldimmediatelydeliverthehepatitisBpediatricvaccineandhepatitisB
immuneglobulintotheneonateofaHBsAgpositivemotherwithin12hoursofbirthbecauseefficacyofthevaccinedeclineswithtime
afterbirth(ManagementGuidelines).[Mast2005]ThehepatitisBvaccineseriesshouldthenbecontinuedwith2additionaldoses(totalof3
doses,givenatbirth,4weeksto2monthsofage,and6monthsofage),andfollowupHBsAgandHBsAbtitersshouldbetestedat915
monthsofage(A).[Mast2005]
Themothershouldalsobefollowedpostpartumforevidenceofflaresduetodiscontinuationofmedicinesor,ifnottreated,duetoother
causesofflaresthathavebeenreportedpostpartum(B).[Tan2008Kim2013aGiles2013]Thisactivepassiveprophylaxisregimen
successfullypreventsneonatalinfection,withasuccessraterangingfrom95%to100%,[Mast2005]althougheffectiveimplementationof
thisprogramisquitevariabledependingonthecountryandthehealthcaresystem.ArecentstudybyCareyandcolleagues[Carey2013]of
HBsAgpositivepregnantpatientssuggestsvirologicandimmunologicmarkers,suchashighlevelsofHBVDNA(>4log10 IU/mL)and
interferongammainducibleprotein10(IP10>200pg/mL)duringthesecondtrimesterofpregnancy,maybepredictiveofpostdelivery
HBVflares.
AnadditionalclinicalconcernoftenraisedinearlyinfancyistheriskofHBVtransmissionthroughbreastfeeding.Althoughsomedata
showsmallamountsofHBsAginbreastmilk,[Lee1978]strongerevidenceisavailablethatbreastfeedingdoesnotincreasetheriskof
HBVinfectionintheinfantofanHBsAgpositivemother(B).[Beasley1975]Inaddition,aninfantthathasreceivedthehepatitisBimmune
globulinandhepatitisBpediatricvaccineisprotectedduringthistimeframe.Therefore,thecurrentrecommendationsfromtheCenters
forDiseaseControlandPreventionsupportbreastfeedingimmediatelyafterbirthinthissetting,[Mast2005]althoughfromapractical
perspective,breastfeedingshouldbepausedinnursingmotherswithcrackedorbleedingnipples.
PatientsatRiskforHepatitisBVirusReactivation
HBVreactivationinvolveslossofHBVimmunecontrolinapatientwithaninactiveoraresolvedHBVinfection.Viralreplication
increasesandliverdamageoccursduringorafterimmunereconstitution[Feld2010]
ReactivationofHBVoccursin20%to50%ofinfectedpatientswhoundergoimmunosuppressiveorcancerchemotherapy[Lok
2009]
andcanresultinliverfailureordeath(B)[Roche2011]
Corticosteroids,rituximab,alemtuzumab,intraarterialchemoembolization,andantitumornecrosisfactortherapieshavebeen
associatedwithHBVreactivation(B)[Rutgeerts2009Vassilopoulos2007Moses2006Park2005]
AdditionalpredictorsofchemotherapyinducedHBVreactivationinclude:
HighprechemotherapyserumHBVDNAlevels[Yeo2009Yeo2004Zhong2004]
Malesex[Yeo2009Yeo2000Lok1991]
Lymphomaorbreastcancer[Yeo2004Yeo2009]
ItisnotclearwhetherHBeAgpositivepatientsaremoresusceptibletoHBVreactivation[Yeo2000Lok1991]
ConsensusguidelinesfromtheAASLDHBVguidelines(ManagementGuidelines),[Lok2009]theEASLHBVguidelines
(ManagementGuidelines),[EASLHBV]andtheCDC(ManagementGuidelines)[Weinbaum2008]recommendscreeningforhepatitis
Bpriortoinitiatingimmunosuppressivetherapies
Patientsshouldbemanagedaccordingtotheirscreeningresults(Table4)[Lok2009EASLHBV]
HepatitisBcarrierswhoareHBsAgpositiveandthosewhoareHBsAgnegativebutpositiveforantiHBcwithdetectable
HBVDNAshouldreceiveprophylacticantiviraltherapyfromtheonsetofimmunosuppressivetherapyuntil12monthsafter
itscompletion
HepatitisBcarrierswithisolatedantiHBcpositivityshouldbemonitoredevery13monthsandantiviraltherapyshouldbe
12/31
20/02/2015
initiatedintheeventofHBVreactivation,beforeALTiselevated
Nucleos(t)ideanaloguetherapyisoftenineffectiveinpreventingtheclinicalconsequencesofHBVreactivationoncea
flarehasoccurred[Yeo1999]
ReactivationofchronichepatitisBvirus(HBV)infectionoccursin20%to50%ofinfectedpatientswhoundergoimmunosuppressiveor
cancerchemotherapy.[Lok2009]ThisreactivationisdefinedasalossofHBVimmunecontrolinapatientwithaninactiveoraresolved
HBVinfection,resultinginareappearanceorincreaseinviralreplicationwithliverdamageoccurringeitherduringorfollowingimmune
reconstitution.[Feld2010]HBVreactivationcanresultinsubclinicaltosevereconsequences,includingariseinHBVDNA(withorwithout
areturnofhepatitisBeantigen)andanincreaseinalanineaminotransferaseultimately,somepatientsmayprogresstoliverfailureor
evendeath.[Roche2011]
Specificmedications,suchascorticosteroidsandrituximabcontainingchemotherapeutics,intraarterialchemoembolizationfor
hepatocellularcarcinoma,andantitumornecrosisfactortherapiesforinflammatoryboweldiseaseandrheumatoidarthritis,havebeen
implicatedinHBVreactivation(B).[Rutgeerts2009Vassilopoulos2007Moses2006Park2005]Corticosteroids,acomponentofchemotherapy
regimensforhematologicmalignancies,havebeenfoundtobeanindependentpredictorofreactivationbecauseHBVcontainsa
glucocorticoidresponsiveelementthatisstimulatedbysteroidaltherapies.[Cheng1996]Recentstudieshavedemonstratedthatnewer
agentssuchastherapeuticmonoclonalantibodies(rituximab,ofatumumab,andalemtuzumab)mayalsoprecipitateHBVreactivation.
[Yeo2009Moses2006FDA2013]
Indeed,theUSFoodandDrugAdministrationapprovedtheadditionofaboxedwarningtothe
prescribinginformationofrituximabandofatumumababoutthisriskandrecommendsthathealthcareprofessionals[FDA2013]:
MeasurehepatitisBsurfaceantigen(HBsAg)andhepatitisBcoreantibody(antiHBc)levelstodetermineifapatientisinfected
withHBVbeforebeginningtherapywithrituximaborofatumumab
IfscreeningidentifiespatientsatriskofHBVreactivationduetoevidenceofpreviousHBVinfection,consultwithhepatitisexperts
priortouseoftheseagents
IftreatingpatientswithevidenceofpreviousHBVinfectionwithrituximaborofatumumab,monitorforclinicalandlaboratorysigns
ofhepatitisBorHBVreactivationduringtherapyandforseveralmonthsthereafter
ImmediatelydiscontinuerituximaborofatumumabinpatientswhodevelopreactivationofHBVwhileontherapyandstart
appropriatetreatmentforHBVinaddition,anychemotherapythepatientisreceivingshouldbediscontinueduntiltheHBV
infectioniscontrolledorresolved
AdditionalkeypredictorsofchemotherapyinducedHBVreactivationinclude:
HighprechemotherapyserumHBVDNAlevels(B)[Yeo2009Yeo2004Zhong2004]
Malesex[Yeo2009Yeo2000Lok1991]
Adiagnosisoflymphomaorbreastcancer[Yeo2004Yeo2009]
ConflictingdataexistsaboutwhetherpatientswithhepatitisBeantigen(HBeAg)seropositivityaremoresusceptibletoHBVreactivation.
[Yeo2000Lok1991]
Forimmunemodulatoryagents,theriskofHBVreactivationappearstovaryaccordingtothetypeofdruganditspotency(B).[Carroll2010
PrezAlvarez2011]
Theresultsofasystemicliteraturereviewidentified6casesofclinicallysymptomatichepatitisamong35HBsAg
positivepatientsreceivingtumornecrosisfactoralphainhibitors(infliximab:n=17etanercept:n=12adalimumab:n=6).All6cases
wereassociatedwithinfliximabtreatment.Althoughtheseresultssuggestapotentialincreasedriskwithinfliximabvsothertumor
necrosisfactoralphainhibitors,itisalsopossiblethattheassociationresultedfromreportingbias.Arecentobservationalstudyof1149
patientsreceivingchemotherapyforsolidorgantumorsinanareaofhighHBVendemicityreported3casesofHBVreactivation,allof
whichoccurredinunscreenedpatientswhoreceiveddoxorubicin(3outof214treated1.4%).[Ling2013]
Consensusguidelines,includingtheAmericanAssociationfortheStudyofLiverDiseasesHBVguidelines(ManagementGuidelines),
[Lok2009]
theEuropeanAssociationfortheStudyofLiverDiseasesHBVguidelines(ManagementGuidelines),[EASLHBV]andthe
CentersforDiseaseControlandPrevention(ManagementGuidelines)[Weinbaum2008]recommendscreeningforhepatitisBpriorto
initiatingimmunosuppressivetherapies.Table4providesrecommendationsforthevariousgroupsofpatientsbasedontheirscreening
results[Lok2009EASLHBV]IfanHBsAgpositivepersoninitiatesantiviraltherapy,virologicandserologictestsshouldbeadministered
andtheresultsmonitoredthroughoutthecourseofimmunosuppressivetreatment.Patientsshouldcontinueantiviraltherapyfor12
monthsafterthediscontinuationofchemotherapy/immunosuppression.[EASLHBV]
IfthepatientisHBsAgnegativebutantihepatitisBcoreantibody(HBc)positive(withorwithoutantiHBs),hepatitisBreactivationcan
stilloccurandclosemonitoringofHBVDNAandalanineaminotransferase(ALT)levelsduringimmunosuppressivetherapyiswarranted
(Table4).Therisksassociatedwiththisreactivationcanbegreatandseveralcasestudieshavereportedfatalreactivehepatitisinanti
HBcpositivepatientswhoreceivedrituximabcontainingchemotherapyforlymphoma(B).[Law2005Sera2006Dervite2001Sarrecchia2005
Westhoff2003]SuchpatientswithdetectableHBVDNAshouldbetreatedsimilarlytoHBeAgpositivepatients.[EASLHBV]Forsuchpatients
withundetectableHBVDNA,HBVDNAandALTshouldbemonitoredfrequently,every13monthsdependingonthetypeof
immunosuppressivetherapyandcomorbidities.ManycliniciansmayopttoinitiateprophylacticantiHBVtherapyifhighrisk
immunosuppressivetherapies,suchasrituximab,aretobeused.[Lubel2010EASLHBV]Inaddition,antiviralprophylaxishasbeen
recommendedbysomeifcloselyfollowingtheHBVDNAlevelsandlabsisnotfeasible.[EASLHBV]
13/31
20/02/2015
Inarecentrandomizedstudy,80patientswithlymphomaandunresolvedhepatitisBreceivedaprophylacticentecavirregimen,
beginningbeforechemotherapyandending3monthsafter,orreceivedentecavirtherapeuticallyatHBVreactivationorHBsAg
seroconversionafterchemotherapy.[Huang2013a]SeventythreepercentofpatientswerepositiveforHBsAgand63%hadundetectable
HBVDNA.During18monthsoffollowup,therateofHBVreactivationwassignificantlylowerinpatientsreceivingprophylacticentecavir
(2.4%vs17.9%P=.027).Aftertreatmentwithrituximab,antiHBstiterssignificantlydeclinedinboththeprophylacticandtherapeutic
entecavirgroups(P<.05).[Huang2013b]ThedegreeofdeclinewasnotgreaterinthosepatientswithHBVreactivation.
Theinterimanalysisofa54HBsAgnegative,antiHBcpositivepatientsreceivingrituximabcontainingchemotherapyandentecavir
therapyhasalsobeenreported.[Seto2013]ThepatientshadundetectableHBVDNA(<10IU/mL)atbaselineandreceivedentecavir
whenHBVDNAbecamedetectable(>10IU/mL).Overall,HBVreactivationwasmorelikelytooccurwithinthefirst6monthsvs612
monthsofrituximabtreatment(19.3%vs6.2%,respectivelyP=.024),withthe1yearcumulativerateofHBVreactivationbeing27.4%.
Aftermorethan1yearoffollowup,therewerenocasesofHBVreactivation.HBVreactivationwasnotassociatedwithageorbaseline
antiHBslevels.
Table4.RecommendationsforHepatitisBCarriersWhoRequireImmunosuppressiveorCytotoxic
Therapy[Lok2009EASLHBVLubel2010]
HBVTestResult
Action
HBsAgnegative,antiHBc
negative,andantiHBs
negative
AdministerthehepatitisBadultvaccineandadministercancerchemotherapyorother
immunosuppressivetherapy
HBsAgpositive,or
positive,
HBVDNApositive
positive,
HBVDNAnegative
Initiateprophylacticantiviraltherapyattheonsetofchemotherapyorimmunosuppressive
therapyandfor12mosfollowingtheendoftreatment,regardlessofALTorHBVDNAlevels
HepatitisBreactivationcanoccurmonitorHBVDNAandALTlevelscloselyduringcancer
chemotherapyorotherimmunosuppressivetherapy
Frequency:every13mos
InitiateprophylacticantiviraltherapyuponconfirmationofHBVreactivationbeforeALT
elevation
ManifestationsofhepatitisflaresinthesettingofHBVreactivationrangefrommild,asymptomaticincreasesinserumaminotransferases
tofulminanthepaticfailure,andmortalityratesafterreactivationarehigh,upto71%insomeseries,althoughareportingbiasispossible.
[Yeo2000Vassiliadis2005]
HBVreactivationcomplicateschemotherapytreatmentsbecauseitoftennecessitatesdelayorpremature
terminationofcancertreatment(B).[Lubel2010]Moreover,patientswithhepatitisflaresandsubsequenthepaticfailurearegenerally
precludedfromreceivinglivertransplantsduetothepresenceofanonhepaticmalignancy.SinceHBVantiviraltherapyisgenerallyless
effectiveinreducinghepaticinjuryandprogressiontofrankhepaticfailureduringchemotherapyinducedflares,preemptiveor
prophylactictherapyisrecommendedforpatientspriortostartingchemotherapyaccordingtocurrentguidelines.[Lok2009Lau2003]
TheoralnucleosidelamivudinehasbeenfoundtobeeffectiveatreducingtheincidenceofhepatitisBreactivationduringchemotherapy
andstemcelltransplantationwheninitiatedpriortochemotherapyinpatientswithlowHBVDNAlevelsandalowriskofresistance.[Lau
2002Long2011Keam2011]
However,nucleos(t)ideanaloguetherapyisoftenineffectiveinpreventingtheclinicalconsequencesofHBV
reactivationonceaflarehasoccurred.[Yeo1999]Inoneseries,initiationoflamivudineafterahepatitisflarewasassociatedwitha
mortalityrateof67%.[Lim2002]InpatientswhorequirelongtermantiviraltherapyandthosewithhighHBVDNAlevelsatbaseline,agents
withalowerresistanceriskandhigherpotency,suchastenofovirorentecavir,aremoreappropriate(B).[Lok2009EASLHBV]
ClickheretoviewaVideoInsightinwhichAnnaS.F.Lok,MD,discussestheimportanceofpreventingreactivationofhepatitisBand
approachesforitsmanagement.
ClickhereforaJournalHighlightdiscussingrecommendationsforearlyidentificationofHBVreactivationandthepossibleuseofantiviral
therapyforpreventionofHBVreactivationinpatientswithresolvedHBVinfectionwhorequirerituximabplus
cyclophosphamide/doxorubicin/vincristine/prednisonechemotherapyforlymphoma.
VideoInsight:PreventionandManagementofHBVReactivation
InthisVideoInsight,recordedinBoston,Massachusetts,duringthe2012annualmeetingoftheAmericanAssociationfortheStudyof
14/31
20/02/2015
LiverDiseases,AnnaS.F.Lok,MD,ProfessorofInternalMedicineandDirectorofClinicalHepatologyattheUniversityofMichiganin
AnnArbor,discussestheimportanceforscreeningforHBVinpatientsatriskforHBVreactivation,thepotentialconsequencesofHBV
reactivation,andstrategiestomanagementofHBVreactivation.
PreventingandManagingHBVReactivation
LiverTransplantationRecipients
SurvivalafterlivertransplantationforhepatitisBrelateddiseaseshassignificantlyimproved(B)[Steinmller2002]
IntheUS,hepatitisBislessfrequentlythecauseoflivertransplantation[Singal2013]
ThemanagementofhepatitisBinlivertransplantationhasevolvedsignificantlyoverthepast2decades.Priortotheintroductionof
antiviralsandimmunoprophylaxiswithhepatitisBimmuneglobulin,hepatitisBvirus(HBV)infectionwasconsideredarelative
contraindicationtolivertransplantationduetothefrequentrecurrenceofthevirusposttransplantationcombinedwithpoorsurvivalrates.
[Steinmller2002]
Indeed,recurrentHBVinfectionpreviouslyoccurredin70%to90%ofpatientswhowerehepatitisBsurfaceantigen
positiveatthetimeoftransplantationwithoutimmunoprophylaxis.[Todo1991]PatientswithhighserumHBVDNAlevelsandhepatitisBe
antigenpositivityhadthehighestrateofrecurrenceposttransplantation,withacorrespondingdecreaseinpatientandgraftsurvival.
[Steinmller2002Lake2008]
However,patientsurvivalaftertransplantationforHBVrelateddiseasesisnowsignificantlyimproved(B).
[Steinmller2002]
PatientstransplantedforHBVcurrentlyhaveoneofthehighestgraftsurvivalratesamongalladultdiseases.Today,
hepatitisBremainsthemostcommonetiologyforlivertransplantationsinAsiabutaccountsforonly5%to10%ofallliver
transplantationsintheUnitedStates.[Jiang2009]ArecentevaluationoflivertransplantationsoccurringwithintheUSUnitedNetworkfor
OrganSharingdatabasebetween19942009foundthattransplantationsrelatedtoHBVinfectiondecreasedovertime,perhapsa
reflectionofimprovementsinHBVtherapy.[Singal2013]
PretransplantManagement
PatientswithHBVwhoareviremicatthetimeoftransplantationhaveahigherrateofrecurrenceposttransplantation[Samuel2007]
AntiviraltherapygivenbeforetransplantaimstoreduceserumHBVDNAtoloworundetectablelevels.Thismaydelayoreven
preventtheneedfortransplantation
TenofovirandentecavirarerecommendedforuseinHBsAgpositivepatientsundergoinglivertransplantationforend
stageliverdiseaseorhepatocellularcarcinoma[EASLHBV]
Riskoflacticacidosiswithoralantiviralagentsishigherinpatientswithadvancedliverdisease.[EntecavirPI
TenofovirPI]
Cautionshouldbeusedwhentreatingsuchpatientswitheithertenofovirorentecavir
Interferonmaybeeffectiveinselectedcompensatedcirrhoticpatientsbutispoorlytoleratedindecompensatedcirrhotic
patients[Perrillo1995Hoofnagle1993]
Lamivudinehasbeenshowntoimproveliverfunction,decreasehepatocellularcarcinoma,andreducefibrosisin
pretransplantpatients(A)[Dienstag2003Lok2003Fontana2003Perrillo2001]butpresentsasignificantriskofdrugresistance
Adefovirislesspotentthanotherantiviralsandhasbeenassociatedwithnephrotoxicity
OneofthegoalsofantiviraltherapyinthepretransplantpatientistoreducetheserumHBVDNAtoloworundetectablelevelsbecause
patientswhoareviremicatthetimeoftransplantationhaveahigherrateofrecurrenceposttransplantation(B).[Samuel2007]Reducing
serumHBVDNAlevelshelpstostabilizethedisease,therebydelayingorpossiblypreventingtheneedfortransplantation,aswellasto
15/31
20/02/2015
decreasetheriskofrecurrenthepatitisBaftertransplantation.Indeed,reversalofhepaticfibrosisandovertdecompensationcanbeseen
inpatientswithendstageliverdiseasewhohavesustainedvirologicsuppressionbyoraltherapy,sometimesobviatingtheneedfora
livertransplantation.[Kim2009]
Interferonisnotwelltoleratedinthedecompensatedcirrhoticpatient.[Perrillo1995Hoofnagle1993]Ithasbeenreportedtobeeffectivein
somecarefullyselectedcompensatedcirrhoticpatientshowever,itsuseisnotcommonpriortotransplantationbecausetherisks
(decompensationduetoanimmuneflareworsenedthrombocytopeniaandneutropenia)usuallyoutweighthepotentialbenefits.[Buster
2007]
Initialstudiessupportedthesafetyandefficacyoflamivudineandadefovirforthepretransplantpatient.[Lok2003Fontana2003Perrillo2001]
Indeed,lamivudinehasbeenshowntoimproveliverfunction,decreasetheoccurrenceofhepatocellularcarcinoma,andreducefibrosis,
therebyreducingtheneedforlivertransplantation(A).[Dienstag2003Lok2003Fontana2003Perrillo2001]However,thedevelopmentof
significantlamivudineresistancehashampereditsuse.Althoughadefovirhasalowerrateofresistancethanlamivudine,itisaless
potentantiviral,withreportsofresponseaslowas25%to50%.[Lo2005Leemans2008]Inaddition,adefovirhasbeenimplicatedin
nephrotoxicity,whichmakesitsusenotidealinlivertransplantpatients.
TheantihepatitisBvirusagentstenofovirandentecavirarepotentandhavehighbarrierstoresistance(A).[Tenney2009Lok2010]
Therefore,itisrecommendedthattheseagentsbeconsideredforuseinallhepatitisBsurfaceantigenpositivepatientsundergoingliver
transplantationforendstageliverdiseaseorhepatocellularcarcinoma.[EASLHBV]Itshouldbenotedthatrecentdataontheuseof
entecavirinpatientswithdecompensatedliverdisease(B)[Liaw2011aShim2010]hasledtoanexpandedindicationofthisagentthat
specificallyincludesitsuseinthispopulation.[EntecavirPI]Furthermore,inadirectcomparisonofentecavirvsadefovirin191
decompensatedpatients(ChildTurcottePugh7),57%ofpatientsintheentecavirarmvsonly20%ofpatientsintheadefovirarm
achievedHBVDNA<57IU/mLatWeek48oftherapy(P<.0001).[Liaw2011a]Treatmentwitheitheragentresultedinimprovementor
stabilizationofapatientsChildTurcottePughstatusandasimilarsafetyprofilewasobserved.[Liaw2011aShim2010]Recentdatahave
alsobeenreportedontheuseoftenofovirinthedecompensatedpopulation.Indeed,Liawandcolleagues[Liaw2011b]showedthatafter
48weeksoftreatment,HBVDNAwas<69IU/mLin70.5%of112patientstreatedwithtenofovirandin87.8%ofpatientstreatedwith
emtricitabine/tenofovirandnounexpectedsafetysignalswereobserved.However,thesedatahavenotledtoaspecificindicationfor
tenofovirinthispopulation.[TenofovirPI]Theriskoflacticacidosisinpatientstreatedwithoralantiviralagentsishigherinthosewith
advancedliverdiseasevsthosewithmoremildliverdisease[EntecavirPITenofovirPI]therefore,cautionshouldbeusedwhentreating
suchpatientswitheitheragent.Finally,anadditionalconcernwithtenofovirinthetransplantpopulationistheriskofnephrotoxicitythat
hasbeenobservedinHIVstudies(B),[Kohler2009Cooper2010]particularlyintransplantrecipientswhoreceivesimultaneouscalcineurin
inhibitors.Arecentreporthasdescribed2casesofFanconissyndromeinpatientswithchronichepatitisBthatwereassociatedwith
tenofoviruse.[Gracey2013]
PosttransplantManagement
PosttransplantimmunosuppressioncanincreaseorinduceHBVreplicationinpatientsundergoinglivertransplantationforchronic
hepatitisB
ThecurrentrecommendationforposttransplantationprophylaxisofhepatitisBrecurrenceislifelonghepatitisBimmuneglobulin
plusanoralantiviralagent(A)[EASLHBV]
Currentguidelinessuggestthattenofovirandentecavirshouldbeconsidered,duetotheirpotencyandlowerratesof
resistance(ManagementGuidelines)[EASLHBV]
Otherposttransplantationtreatmentstrategies,includingearlydiscontinuationofhepatitisBimmuneglobulin,areunder
investigation
InpatientsundergoinglivertransplantationforchronichepatitisB,posttransplantimmunosuppressioncanincreaseorinduceviral
replication.However,the3yearposttransplanthepatitisBvirus(HBV)recurrencerateis<10%withtheuseofnucleos(t)ideanalogues
bothpreandposttransplantationinconjunctionwithpostoperativehepatitisBimmuneglobulin.[Dumortier2003]
Therefore,thecurrentrecommendationforposttransplantprophylaxisofhepatitisBrecurrenceisthecombinationoflifelonghepatitisB
immuneglobulinplusanoralantiviralagent.[EASLHBV]However,thelifelonguseofhepatitisBimmuneglobulinhaslimitations,
includingitshighcost,limitedsupplyinsomecountries,parenteraladministrationroute,andtheneedforfrequentlaboratorymonitoring.
Dataareavailableonposttherapytransplantwithbothlamivudineandadefovir.[Lo2005Perrillo2001]However,theseagentsarenotthe
mostcommonlyusedagentsinthissettingtoday,andcurrentguidelinessuggestthatthemorepotentagentswithlowerratesof
resistance,tenofovirandentecavir,shouldbeconsidered(ManagementGuidelines).[EASLHBV]Arecentstudyofentecavirprophylaxis
monotherapyin80HBVinfectedpatientswhoreceivedalivertransplantsupporttheseguidelines.ThisstudyshowedthathepatitisB
surfaceantigenlosswasachievedin86%and91%ofpatientsafter1and2yearsoftherapy,respectively,and98%ofpatientsachieved
undetectableHBVDNAattheirlastexamination(medianfollowuptime:26months).[Fung2011]Afurtheruncontrolledstudyof65patients
whoreceivedhepatitisBimmuneglobulinandentecavirafterlivertransplantationforchronichepatitisBfoundthatall61evaluable
patientsmaintainedundetectableHBVDNAthrough72weeksoffollowup.[Perrillo2013]HepatitisBsurfaceantigen(HBsAg)reappeared
in2patientsbutbothremainedHBVDNAnegative.Recently,aretrospectiveanalysisof155patientswhoreceivedprophylaxiswitha
combinationofhepatitisBimmuneglobulinandentecavirforHBVreoccurrenceafterlivertransplantationdeterminedtheoverallratesof
16/31
20/02/2015
HBVrecurrencewere1.3%at1year,4.7%at3years,and6.8%at5years.[Kim2013b]Furthermore,inpatientswhoreceivedprophylaxis
withhepatitisBimmuneglobulinandentecavir,recurrenthepatocellularcarcinomawasanindependentriskfactorofHBVrecurrence
(HR:13.595%CI:2.474.4P=.003).
Otherposttransplantationtreatmentstrategiesarecurrentlybeinginvestigated.SomeinvestigatorshavediscontinuedhepatitisBimmune
globulintherapyafteradefinedperiodoftimeposttransplantationandhavecontinuedoralantiviralmedicationsonly(B).[Saab2011Wong
2007]Indeed,inonestudy,61patientsundergoingtransplantationwereconvertedfromhepatitisBimmuneglobulinpluslamivudineto
dualcombinationtherapywith1nucleosideand1nucleotideanalogue12monthsaftertransplantation.[Saab2011]HBVrecurrence
occurredinonly2patients(3.3%),aratesimilartothatachievedwithcontinuedhepatitisBimmuneglobulinpluslamivudine.[Dan2006]
Similarly,inasecondstudy,20patientswhounderwenttransplantationwereconvertedfromhepatitisBimmuneglobulinplusasingle
nucleos(t)idetocombinationnucleosidenucleotideanalogueprophylaxisatleast12monthsaftertransplantation.[Khemichian2013]The
meantimeaftertransplantationtoconversiontocombinationnucleosidenucleotideanalogueprophylaxiswas75.7months(range:12
132months).Mostpatientsconvertedtolamivudine/tenofovir(n=12patients).Othercombinationsincludedentecavir/adefovir(n=7
patients),andlamivudine/adefovir(n=1patient).Afterameanof17.9months,19patientswereHBsAgandHBVDNAnegative.
OtherreportshaveindicatedthatpatientswithHBVDNAlevels<100,000copies/mL(or~4.3log10 IU/mL)priortotransplantationhad
similarrecurrenceratesonlongtermlamivudinemonotherapy(aftercompletingamonthcourseofhepatitisBimmuneglobulinand
lamivudine)aspatientswhoreceivedlongtermcombinationhepatitisBimmuneglobulin/lamivudinetreatment(B).[Buti2003Dodson2000
Buti2013]
Lamivudineresistanceisofparticularconcerninpatientswhoareimmunosuppressed.Inrecentstudies,resistancewas
detectedin45%ofimmunosuppressedpatientswithinthefirstyearoftreatmentfollowinglivertransplantation.[Jiang2009]Becauseof
theseresistanceconcerns,manytransplantationcentershavenowtransitionedtotheuseofthefirstlineHBVoralagents(entecavirand
tenofovir).Inarecentstudy,patientsweretreatedwith24weeksofposttransplantationtenofovir/emtricitabineplushepatitisBimmune
globulinandwerethenrandomizedtotenofovir/emtricitabinealone(n=18)orcontinuedtenofovir/emtricitabineplushepatitisBimmune
globulin(n=19)through96weeks.[Teperman2013]Tenofovir/emtricitabinewaswelltoleratedwithnoseriousadverseeventsconsidered
toberelatedtotheseagents.Meanserumcreatininelevelsandmeancreatinineclearanceremainedsteadyovertimethrough96weeks.
Inaddition,nopatientexperiencedHBVrecurrencewhilereceivingrandomizedtreatmentandnocasesoftenofoviroremtricitabine
resistancewasobserved.
ClickhereforaJournalHighlightdiscussingthepossibilityoforalnucleos(t)ideanalogueswithouthepatitisBimmunoglobulinfor
preventionofHBVreinfectionfollowinglivertransplantation.
ManagementofPatientsReceivingHepatitisBCoreAntibodyPositiveDonorLivers
TransplantationofHBsAgpositivepatientswithantiHBcpositivedonorliversiscommon.TransmissionofHBVtorecipientsmay
occur
SeveralapproachestopreventinghepatitisBreactivationordenovohepatitisBafterantiHBcpositiveliverdonationhavebeen
showntobeeffective,includingposttransplantationhepatitisBimmuneglobulin,lamivudine,orthecombinationofbothagents
HepatitisBcoreantibody(antiHBc)positivedonorlivershavebeenusedformanyyearsinhepatitisBsurfaceantigen(HBsAg)positive
recipients.TransmissionofhepatitisBvirus(HBV)torecipientsvariesdependingonrecipientantiHBcstatus:InantiHBcnegative
recipients,thetransmissionratewasshowntobe33%to100%comparedwith0%to13%forantiHBcpositiverecipientsintheabsence
ofprophylaxis.[Munoz2002Prieto2001]Inaddition,thepresenceofantiHBsintherecipientmayalsobeprotective.Inananalysisof47
casesofrecipientspositiveforbothantiHBsandantiHBcbeforetransplantationfromantiHBcpositivedonorsin10studies,only4.3%
developeddenovohepatitisBintheabsenceofprophylaxis.[Pan2011]
SeveralapproachestopreventinghepatitisBreactivationordenovohepatitisBafterantiHBcpositiveliverdonationhavebeenshown
tobeeffective,includingposttransplantationhepatitisBimmuneglobulin,lamivudine,orthecombinationofbothagents.However,itis
notclearifhepatitisBimmuneglobulinorantiviraltherapyneedstobegiventoallrecipientsofantiHBcpositiveorgans.Inasystematic
literaturereview,Cholongitasandcolleagues[Cholongitas2010]showedthattherateofdenovoHBVinfectionamong788HBsAgnegative
recipientswas28.2%withoutposttransplantationprophylaxisvs8.2%withposttransplantationprophylaxis(P<.001)(B).Amongpatients
whodidnotreceiveHBVprophylaxis,denovoinfectionratesvariedaccordingtopretransplantationserologicstatuswith47.8%of
patientswhowereantiHBcandantiHBsnegativebecominginfectedvs13.1%ofpatientswhowereantiHBcpositiveandantiHBs
negative,1.4%ofpatientswhowereantiHBcpositiveandantiHBspositive,and9.7%ofpatientswhowereonlyantiHBspositive.Itis
importanttonotethattherateofantiHBsseroprotectionfromthehepatitisBadultvaccineislowerinpatientswithliverdiseaseand
cirrhosis,somanyrecipientsmayremainantiHBsnegativedespitevaccination.[Domnguez2000]Regardingthedifferentapproachesto
HBVprophylaxis,thestudybyCholongitasandcolleagues[Cholongitas2010]showedthatamongantiHBcandantiHBsnegative
patients,theratesofdenovoHBVinfectionwere27%withhepatitisBimmuneglobulinalone,3.4%withlamivudinealone,and0%with
bothagents(P=.005).AsthecombinationofhepatitisBimmuneglobulinandlamivudinedidnotoffermuchbenefitrelativeto
lamivudinealoneinHBsAgnegativerecipientsofantiHBcpositivelivertransplantations,theauthorsofthisstudyconcludedthat
lamivudinemonotherapymaybethebestapproachinthesepatients.Itremainstobedeterminedifnewernucleos(t)ideanalogueswith
improvedresistanceprofileswouldprovidemorecosteffectiveapproachestolongtermprophylaxis,astheseagentsaremore
expensivethanlamivudine.
CulturalBarrierstoHepatitisBVirusManagementinSpecificEthnicGroups
Culturalbarriersincludinglanguage,religiousbeliefs,andculturalattitudesmaybeimportantfactorsineffectivemanagementof
17/31
20/02/2015
hepatitisBinminorityethnicgroups
PatientswithHBVinfectionmayexperiencestigmatizationwithintheircommunitiesandfromfriendsandfamily
Thepatientsrelationshipwithhisorherhealthcareproviderisanimportantdeterminantofthequalityofcareandthepatients
willingnesstocontinuetoreceivecare
Concordancebetweenpatientandproviderinlanguageandcultureisahelpfulstrategyformanagingpatientsfromminority
ethnicgroups
EffectivemanagementofhepatitisBisdifficultincertainethnicgroups,particularlyinAsiansandPacificIslanders,duetoavarietyof
culturalbarriers.ThereisaneedforhepatitisBvirus(HBV)providerstounderstandthesebarriersandmakeeffortstoovercomethemin
theirpatientpopulation.
Limitedproficiencyinaconcordantlanguagewiththehealthcareproviderisalarge,ifnotthelargest,barriertoeffectivemanagementof
chronicHBVinfectioninethnicpopulations.IntheUnitedStates,onethirdofKorean,Taiwanese,Chinese,Hmong,andBangladeshi
households,andalmostonehalfofVietnamesehouseholds,arelinguisticallyisolated,withlimitedabilitytocommunicatewithhealthcare
providers.[APIAHFComm]
AnimmigrantpatientsreligiousbeliefsandculturalattitudestowardWesternmedicinemayalsomakethesuccessfulmanagementofthe
diseasedifficult.[Tran2009b]ManyAsianAmericansareBuddhistswhobelievethatsufferingisanintegralpartoflifeproactivelyseeking
medicalcaremaynotbeimperativeforthem.Distrustof,orunfamiliaritywith,WesternmedicinemayalsodelaytheinitiationofWestern
medicalcare,andtheresultingpooroutcomesmaybefalselyattributedtoWesternmedicineitself.Indeed,someLaotianswillnot
immunizetheirbabiesagainstHBVbecausetheybelievethatimmunizationsaredangerousforababysspirit.[Tran2009b]
Finally,infectionwithHBVcarriesastigmaaboutthemodeoftransmissionthatcaninterferewithpatientsdailylives.Astudyofattitudes
aboutHBVfoundthatHBVinfectedpatientsfeellesswelcometostayovernightorsharethesamebathroomatfriendsorrelatives
houses,thatnoninfectedpersonsfearthatthediseasemaybepassedtothembyHBVpositivefriends,andthatHBVinfectedpatients
areconcernedaboutwhethertheirchoicesmayhaveledtotheinfection.[Spiegel2007]
Thepatientsrelationshipwithhisorherhealthcareproviderisanimportantdeterminantofthequalityofcareandthepatients
willingnesstocontinuetoreceivecare.Thebestpossiblescenarioisconcordanceinlanguageandculture.Asianculturesemphasize
politeness,respectforauthority,filialpiety,andavoidanceofshame.BecauseAsianpatientsoftenviewphysiciansasauthorityfigures,
theymaynotaskquestionsorvoicereservationsorfearsabouttheirtreatmentregimensinstead,theymayexpresstheiragreementwith
physiciansadvice,butmayhavenointenttoreturnorfollowinstructions.Therefore,thebestapproachmaybetoseethepatientover
severalvisitsinordertofullyexplainthenaturalhistoryofthedisease,familiarizethefamilymemberswiththeplanofcare,anddiscuss
anyconcernswiththetherapy.
PrimaryCareEssentials
HBV/HIVcoinfectedpatientsoftenpresentwithcharacteristicsthatdonotfitneatlyintothetreatmentalgorithmsprovidedbymajor
guidelines
HBV/HIVcoinfectedpatientsmayexhibitabnormallivertestsduetosteatosis,coinfections,ortherapeutics[Wit2002]
ThegoaloftherapyistosuppressbothHBVandHIVreplication(B)[Lok2009EASLHBV]
HBV/HCVcoinfectedpatientsareatanincreasedriskofsuperinfection,leadingtomoresevereacutesymptomsandliverfailure
(B)[Liaw2004Liaw2000Lee2000Hytiroglou1995]
Treatmentstrategiesshouldbeguidedbywhichvirusappearstobemostactiveandshouldbeindividualizedbasedon
theuniqueserologicandvirologicprofileofeachpatient
HBV/HDVcoinfectedpatientsshouldbetreatedwithhighdoseinterferonalfa(9MU3timesweekly)orpeginterferonalfafor48
weeksasthepreferredcoursesoftherapy[Lok2009]
WomenwithhepatitisBwhoarepregnantshouldreceivetreatmentbasedonantiviralefficacy,riskofresistance,humansafety
data,andthepregnancyclassofthedrug
InwomenwithHBVinfectionwhobecomepregnantwhilereceivingtherapy,thedecisionwhethertostoporcontinuetreatment
shouldbebasedonpregnancystage,severityofliverdisease,theriskadversityofthemothertomedicationsduringpregnancy,
andtheriskofflareswhenstoppingmedications
Duetotheriskofreactivationandliverfailure,HBVinfectedpatientswhoundergoimmunosuppressiveorcancerchemotherapy
requirespecialtreatmentandmonitoring
HBVstatusrequirespretransplantationandposttransplantationmanagement[Steinmller2002]
Priortolivertransplantation,antiviraltherapythatreducesserumHBVDNAtoloworundetectablelevelsmaydelayor
preventtheneedfortransplantation
Tenofovirandentecaviraretherecommendedantiviraltherapiesforpatientsundergoinglivertransplantation[EASLHBV]
VariousguidelineshaveprovidedtreatmentalgorithmsforthemanagementofpatientswithchronichepatitisBvirus(HBV)infection,but
oftenpatientspresentwithcharacteristicsthatdonotfitneatlyintothesetreatmentalgorithms.Forexample,HBVisgenerallymore
aggressiveinpatientscoinfectedwithHIV,withhigherratesofchronicity,higherHBVDNAlevels,morefrequentreactivationperiods,
morerapidprogressiontocirrhosis,andsignificantliverrelatedmortality.[Puoti2006Weber2006Thio2002]Itisimportanttokeepinmind
thatHBV/HIVcoinfectedpatientsmayexhibitabnormallivertestsduetosteatosis,coinfections,ortherapeutics.[Wit2002]Whentreating
HBV/HIVcoinfectedpatients,thegoaloftherapyistosuppressbothHBVandHIVreplication(B).[Lok2009EASLHBV]Ifthepatient
requirestreatmentforbothinfections,theantiretroviralregimenshouldinclude2agentsthatarealsoactiveagainstHBV(Figure1).Ifthe
antiretroviralswithactivityagainstHBVarediscontinued,HBVflaresmayoccuriftheyarenotreplacedbyotheractiveagents.Inaddition,
18/31
20/02/2015
forthosepatientswhorequiretreatmentofHBVonly,entecavirandtenofovirshouldbeavoided,astheseagentsmayselectforHIV
resistance.[McMahon2007Sasadeusz2008]
PatientscoinfectedwithHBVandhepatitisCvirus(HCV)areatanincreasedriskofsuperinfection,leadingtomoresevereacute
symptomsandliverfailure(B).[Liaw2004Liaw2000Lee2000Hytiroglou1995]MostHBV/HCVcoinfectedpatientshavelowserumHBVDNA
levelsanddetectableHCVviremiahowever,ultrasensitiveassaysmaydetectoccultHBVinfection(hepatitisBsurfaceantigen[HBsAg]
negativebutHBVDNApositive)inHCVinfectedindividuals.[Cacciola1999Squadrito2002Hollinger2010]HCVsuppressionmayalsooccur
alongsideHBVactivity,andvirologicprofilescanchangeovertime.[Zarski1998Ohkawa1995]Treatmentstrategiesshouldbeguidedby
whichvirusappearstobemostactiveandshouldbeindividualizedbasedontheuniqueserologicandvirologicprofileofeachpatient.
StrategiesforthetreatmentofHBV/HCVcoinfectedpatientsareoutlinedinTable1.Liverbiopsy(ornoninvasiveassessmentofliver
fibrosissuchaselastography)playsanimportantroleintheHBV/HCVcoinfectedpatient.[Macas2009]Therefore,determiningthedegree
ofinflammationandfibrosis,alongwiththeprogressionofdisease,inthesecoinfectedpatientsmaybeusefultohelpguidethe
therapeuticplan.
HBVpatientsmayalsobecoinfectedwithhepatitisDvirus(HDV),withpositivetestsconfirmedbyimmunohistochemistryorbyserum
HDVRNAreversetranscriptionpolymerasechainreactionassay.Patientsshouldbetreatedwithhighdoseinterferonalfa(9MU3times
weekly)orpeginterferonalfafor48weeksasthepreferredcoursesoftherapy.[Lok2009]Hughesandcolleagues[Hughes2011]have
suggestedthemanagementalgorithmshowninFigure2.
AnotherpopulationofpatientswhorequirespecialmanagementiswomenwithhepatitisBwhoareofchildbearingageorwhoare
pregnant.ManagementstrategiesforwomenofchildbearingagewithHBVinfectionisoutlinedinTable2.Duringthefirsttrimesterof
eachpregnancy,pregnantwomenshouldbetestedforHBsAg.[Lok2009EASLHBV]PregnantwomenwithoutimmunitytoHBVandwith
riskfactorsforinfectionshouldreceivethehepatitisBadultvaccineseries,whichissafeatallstagesofpregnancy.[Lok2009EASLHBV]
WomentestingpositiveforHBsAgshouldbereferredforadditionaltesting,counseling,andmedicalmanagement.HBVtreatment
selectionshouldbebasedonantiviralefficacy,riskofresistance,humansafetydata,andthepregnancyclassofthedrug.Asummaryof
thevariousantiHBVagents,aswellastheiradvantagesanddisadvantageforuseduringpregnancy,arefoundinTable3.Inwomen
withHBVinfectionwhobecomepregnantwhilereceivingtherapy,thedecisionwhethertostoporcontinuetreatmentshouldbebasedon
pregnancystage,severityofliverdisease,theriskadversityofthemothertomedicationsduringpregnancy,andtheriskofflareswhen
stoppingmedications.Iftherapyisadministeredonlyforthepreventionofmothertochildtransmission,itmaybediscontinuedwithinthe
first3monthsafterdelivery.[EASLHBV]InfantsshouldreceivethehepatitisBpediatricvaccineandhepatitisBimmuneglobulinwithin12
hoursofbirthwith2additionaldosesofthehepatitisBpediatricvaccineseriesgivenat4weeksto2monthsofageandat6monthsof
age.[Mast2005]FollowupHBsAgandHBsAbtitersshouldbetestedat915monthsofage.[Mast2005]Themothershouldbefollowed
postpartumforHBVflares(A).[Tan2008Kim2013aGiles2013]
SpecialtreatmentandmonitoringisalsorequiredforHBVinfectedpatientswhoundergoimmunosuppressiveorcancerchemotherapy
reactivationofHBVoccursin20%to50%ofthesepatients[Lok2009]andcanresultinliverfailureordeath.[Roche2011]Corticosteroids,
rituximab,alemtuzumab,intraarterialchemoembolization,andantitumornecrosisfactortherapieshavebeenassociatedwithHBV
reactivation(B).[Rutgeerts2009Vassilopoulos2007Moses2006Park2005]PatientsshouldbescreenedforhepatitisBbeforeinitiating
immunosuppressivetherapies.[EASLHBVLok2009Weinbaum2008]Table4summarizestherecommendationsforHBVcarriers,with
patientsmanagedaccordingtotheirscreeningresults.[Lok2009EASLHBV]
WhereassurvivalafterlivertransplantationforhepatitisBrelateddiseaseshassignificantlyimproved,HBVstatusstillrequires
pretransplantationandposttransplantationmanagement.[Steinmller2002]Priortolivertransplantation,antiviraltherapyisadministeredto
reduceserumHBVDNAtoloworundetectablelevels.Infact,thismaydelayorevenpreventtheneedfortransplantation.InHBsAg
positivepatientsundergoinglivertransplantationforendstageliverdiseaseorhepatocellularcarcinoma,tenofovirandentecavirarethe
recommendedantiviraltherapies.[EASLHBV]However,cautionshouldbeusedwhentreatingadvancedliverdiseasepatientswitheither
tenofovirorentecavirduetoahigherriskoflacticacidosis.[EntecavirPITenofovirPI]Interferoncanbeusedinselectcompensatedcirrhotic,
butnotdecompensatedcirrhotic,patients(B).[Perrillo1995Hoofnagle1993]Lamivudinehasbeenshowntoimproveliverfunction,decrease
hepatocellularcarcinoma,andreducefibrosisinpretransplantationpatients[Dienstag2003Lok2003Fontana2003Perrillo2001]butpresents
asignificantriskofdrugresistance.Adefovirislesspotentthanotherantiviralsandhasbeenassociatedwithnephrotoxicity.For
posttransplantationprophylaxis,lifelonghepatitisBimmuneglobulinplusanoralantiviralagent,suchastenofovirorentecavir,is
recommended.[EASLHBV]Otherposttransplantationtreatmentstrategies,includingearlydiscontinuationofhepatitisBimmuneglobulin,
areunderinvestigation.
SupportingAssets
Figure1|Figure2|Figure3|Table1|Table2|Table3|Table4|Video1
Figure1.ManagementandtherapeuticoptionsincompensatedorcirrhoticHBV/HIVcoinfectedpatients
withanindicationforHIVtreatment.[EACSART]
19/31
20/02/2015
Figure2.SuggestedalgorithmformanagementofapatientwithHDV.[Hughes2011]
20/31
20/02/2015
Figure3.AlgorithmforthemanagementofHBVinfectionduringpregnancy.[Tran2009a]
Table1.StrategiesfortheTreatmentofHBV/HCVCoinfectedPatients[Chu2008]
21/31
20/02/2015
HCVStatus
AntiHCVpositive
HCVRNApositive
AntiHCVpositive
HCVRNApositive
AntiHCVpositive
HCVRNAnegative
HBVStatus
Recommendations
Peginterferonplusribavirin
canachievecomparableresults
asforHCVmonoinfection
Reciprocalviralinterference
candevelopduringoraftertherapy
HBsAgpositiveornegative
HBeAgnegative
HBVDNA<104 IU/mL
Veryfewdataareavailable
peginterferonplusribavirin
mightbeinadequateaddition
ofanucleos(t)ideanalogue
appearstobeafeasibleoption
butthebesttreatmentregimen
remainstobedetermined
HBsAgpositive
HBVDNA104 IU/mL
HBsAgpositive
HBVDNApositive
Treataspatientswith
chronicHBVinfection
HBeAg,hepatitisBeantigen.
Table2.ManagementStrategiesforWomenofChildbearingAgeWithHBVInfection [EASLHBV]
Circumstance
Options
RequiringtreatmentforHBVinfection
andconsideringpregnancy
Mayoptforfinitecourseofpeginterferontherapybeforebecomingpregnant,or
Maydefertreatmentuntilafterpregnancyifclinicaldiseaseisstable,or
Maytreatonlyinthethirdtrimesterofpregnancytoreducetransmissionrisk
Becamepregnantwhilereceiving
treatmentforHBVinfection
Decisiontocontinueorstoptreatmentshouldbeindividualizedbasedon:
Thetrimesterthatthepregnancywasdiscovere
Theseverityofunderlyingliverdisease
Theriskadversityofthemothertomedicationsduringpregnancy(especially
inearlypregnancy)
Theriskofflareswhenstoppingthemedications(seediscussionofchoiceof
antiHBVagentsforpregnantwomeninalatersection)
Iftreatmentiscontinued,thechoiceofagentsshouldbereconsidered
Peginterferonalfashouldbediscontinuedandtherapycontinuedwitha
nucleos(t)ideanalogue
FDAcategoryCnucleos(t)ideanaloguesshouldbereplacedwithcategoryB
agentstenofovirispreferred
Pregnantandtreatmentnotclinically
indicatedforHBVinfection
Defertreatmentuntilafterpregnancy,or
Treatonlyinthethirdtrimestertoreducetransmissionrisk
Table3.AdvantagesandDisadvantagesofAntiHBVAgentsDuringPregnancy[APRSC2013]
AntiviralAgent
Adefovir
FDA
Pregnancy
Category
Defects/Live
BirthWhen
ExposedDuring
FirstTrimester,
%*(n/N)
Defects/Live
BirthWhen
ExposedDuring
Second/third
Trimester,%
(n/N)
Advantages/Disadvantagesof
UsingDuringPregnancy
Notrecommended
22/31
20/02/2015
(0/48)
(0/0)
Entecavir
0
(2/55)
0
(0/2)
Lamivudine
3.1
(136/4360)
2.8
(198/6989)
Telbivudine
0
(0/10)
0
(0/14)
Tenofovir
2.3
(46/1982)
2.1
(20/959)
Notrecommended
data
agentintreatment
guidelines
Associatedwithhighrates
ofantiviralresistance
Positivehumansafetydata
pregnancyclass
Fewerdatathanlamivudine
ortenofovir
agentintreatment
guidelines
data,pregnancyclass
*Prevalenceofdefectsisreportedforfirsttrimesterexposurestodrugswithadenominatorof200.
Table4.RecommendationsforHepatitisBCarriersWhoRequireImmunosuppressiveorCytotoxic
Therapy[Lok2009EASLHBVLubel2010]
HBVTestResult
negative,andantiHBs
negative
Action
AdministerthehepatitisBadultvaccineandadministercancerchemotherapyorother
immunosuppressivetherapy
HBsAgpositive,or
positive,
HBVDNApositive
positive,
HBVDNAnegative
Initiateprophylacticantiviraltherapyattheonsetofchemotherapyorimmunosuppressive
therapyandfor12mosfollowingtheendoftreatment,regardlessofALTorHBVDNAlevels
HepatitisBreactivationcanoccurmonitorHBVDNAandALTlevelscloselyduringcancer
chemotherapyorotherimmunosuppressivetherapy
Frequency:every13mos
InitiateprophylacticantiviraltherapyuponconfirmationofHBVreactivationbeforeALT
elevation
PreventingandManagingHBVReactivation
23/31
20/02/2015
References
AlterMJ.EpidemiologyofviralhepatitisandHIVcoinfection.JHepatol200644:S6S9.[Alter2006]
Asian&PacificIslanderAmericanHealthForum.Diversecommunities,diverseexperiences:thestatusofAsianAmericansandPacific
IslandersintheU.S.Availableat:
http://www.aapcho.dreamhosters.com/download/PDF/Diverse%20Communities%20Diverse%20Experiences.pdf.AccessedApril15,
2014.[APIAHFComm]
AntiretroviralPregnancyRegistrySteeringCommittee.AntiretroviralPregnancyRegistryInternationalInterimReportfor1January1989
through31July2013.Wilmington,NC:RegistryCoordinatingCenter2013.Availableat:
http://www.apregistry.com/forms/interim_report.pdf.AccessedApril15,2014.[APRSC2013]
AyresA,YuenL,JacksonKM,etal.ShortdurationoflamivudineforthepreventionofhepatitisBvirustransmissioninpregnancy:lackof
potencyandselectionofresistancemutations.JViralHepat.2013[Epubaheadofprint].[Ayers2013]
BeasleyRP,StevensCE,ShiaoIS,MengHC.EvidenceagainstbreastfeedingasamechanismforverticaltransmissionofhepatitisB.
Lancet.19752:740741.[Beasley1975]
BenhamouY,BochetM,ThibaultV,etal.LongtermincidenceofhepatitisBvirusresistancetolamivudineinhumanimmunodeficiency
virusinfectedpatients.Hepatology.200031:10301031.[Benhamou2000]
BenhamouY,BochetM,ThibaultV,etal.SafetyandefficacyofadefovirdipivoxilinpatientscoinfectedwithHIV1andlamivudine
resistanthepatitisBvirus:anopenlabelpilotstudy.Lancet.2001358:718723.[Benhamou2001]
BodsworthN,DonovanB,NightingaleBN.TheeffectofconcurrenthumanimmunodeficiencyvirusinfectiononchronichepatitisB:a
studyof150homosexualmen.JInfectDis.1989160:577582.[Bodsworth1989]
BodsworthNJ,CooperDA,DonovanB.Theinfluenceofhumanimmunodeficiencyvirustype1infectiononthedevelopmentofthe
hepatitisBviruscarrierstate.JInfectDis.1991163:11381140.[Bodsworth1991]
BotteroJ,LacombeK,GuchotJ,etal.Performanceof11biomarkersforliverfibrosisassessmentinHIV/HBVcoinfectedpatients.J
Hepatol.200950:10741083.[Bottero2009]
BurkRD,HwangLY,HoGY,etal.OutcomeofperinatalhepatitisBvirusexposureisdependentonmaternalvirusload.JInfectDis.
1994170:14181423.[Burk1994]
BusterEH,HansenBE,DelwaideJ,etal.Peginterferonalpha2BissafeandeffectiveinHBeAgpositivechronichepatitisBpatientswith
advancedfibrosis.Hepatology.200746:388394.[Buster2007]
BusterEH,HansenBE,LauGK,etal.FactorsthatpredictresponseofpatientswithhepatitisBeantigenpositivechronichepatitisBto
peginterferonalfa.Gastroenterology.2009137:20022009.[Buster2009]
ButiM,MasA,PrietoM,etal.ArandomizedstudycomparinglamivudinemonotherapyafterashortcourseofhepatitisBimmuneglobulin
(HBIg)andlamivudinewithlongtermlamivudineplusHBIginthepreventionofhepatitisBvirusrecurrenceafterlivertransplantation.J
Hepatology.200338:811817.[Buti2003]
ButiM,MasA,PrietoM,etal.Tenyearfollowupofarandomizedstudycomparinglamivudinevslamivudine+HBIGforthepreventionof
hepatitisBvirusrecurrenceafterlivertransplantation.Hepatology.201358.Abstract64.[Buti2013]
24/31
20/02/2015
CacciolaI,PollicinoT,SquadritoG,etal.OcculthepatitisBvirusinfectioninpatientswithchronichepatitisCliverdisease.NewEnglJ
Med.1999341:2226.[Cacciola1999]
CareyI,HornerM,BruceMJ,McLeodMA,AgarwalK.ChronichepatitisBinpregnancy:canvirological,serologicalandimmunological
markersduringpregnancypredictpostdeliveryhepaticflares?Hepatology.201358.Abstract915.[Carey2013]
CarrollMB,ForgioneMA.UseoftumornecrosisfactoralphainhibitorsinhepatitisBsurfaceantigenpositivepatients:aliteraturereview
andpotentialmechanismsofaction.ClinRheumatol.201029:10211029.[Carroll2010]
CentersforDiseaseControlandPrevention,WorkowskiKA,BermanSM.MMWRRecommRep.200655:194.[CDC2006]
CelenMK,MertD,AyM,etal.Efficacyandsafetyoftenofovirdisoproxilfumarateinpregnancyforthepreventionofverticaltransmission
ofHBVinfection.WorldJGastroenterol.201319:93779382.[Celen2013]
ChangMH,HsuHY,HsuHC,NiYH,ChenJS,ChenDS.ThesignificanceofspontaneoushepatitisBeantigenseroconversionin
childhood:withspecialemphasisontheclearanceofhepatitisBeantigenbefore3yearsofage.Hepatology.199522:13871392.
[Chang1995]
ChangPE,LuiHF,ChauYP,etal.ProspectiveevaluationoftransientelastographyforthediagnosisofhepaticfibrosisinAsians:
comparisonwithliverbiopsyandaspartatetransaminaseplateletratioindex.AlimentPharmacolTher.200828:5161.[Chang2008]
ChenGY,SuTH,KaoJH.SuccessfultreatmentofchronichepatitisBandDwithpegylatedinterferonplusentecavir.JFormosMed
Assoc.201320.pii:S09296646(13)001782.[Chen2013]
ChengAL.SteroidfreechemotherapydecreasestheriskofhepatitisflareupinhepatitisBviruscarrierswithnonHodgkinslymphoma.
Blood.199687:1202.[Cheng1996]
ChengAL,HsiungCA,SuIJ,etal.SteroidfreechemotherapydecreasesriskofhepatitisBvirus(HBV)reactivationinHBVcarrierswith
lymphoma.Hepatology.200337:13201328.[Cheng2003]
CholongitasE,PapatheodoridisGV,BurroughsAK.LivergraftsfromantihepatitisBcorepositivedonors:asystematicreview.JHepatol.
201052:272279.[Cholongitas2010]
ChuCM,KarayiannisP,FowlerMJ,MonjardinoJ,LiawYF,ThomasHC.NaturalhistoryofchronichepatitisBvirusinfectioninTaiwan:
studiesofhepatitisBvirusDNAinserum.Hepatology.19855:431434.[Chu1985]
ChuCJ,LeeSD.HepatitisBvirus/hepatitisCviruscoinfection:epidemiology,clinicalfeatures,viralinteractionsandtreatment.J
GastroenterolHepatol.200823:512520.[Chu2008]
ColinJF,CazalsHatemD,LoriotMA,etal.InfluenceofhumanimmunodeficiencyvirusinfectiononchronichepatitisBinhomosexual
men.Hepatology.199929:13061310.[Colin1999]
CooperRD,WiebeN,SmithN,KeiserP,NaickerS,TonelliM.Systematicreviewandmetaanalysis:renalsafetyoftenofovirdisoproxil
fumarateinHIVinfectedpatients.ClinInfectDis.201051:496505.[Cooper2010]
SchttlerCG,FiedlerN,SchmidtK,etal.SuppressionofhepatitisBvirusenhancer1and2byhepatitisCviruscoreprotein.JHepatol.
200237:855862.[Schttler2002]
DaiCY,YuML,ChuangWL,etal.InfluenceofhepatitisCvirusontheprofilesofpatientswithchronichepatitisBvirusinfection.J
GastroenterolHepatol.200116:636640.[Dai2001]
DanYY,WaiCT,YeohKG,LimSG.ProphylacticstrategiesforhepatitisBpatientsundergoinglivertransplant:acosteffectiveness
analysis.LiverTranspl.200612:736746.[Dan2006]
DerviteI,HoberD,MorelP.AcutehepatitisBinapatientwithantibodiestohepatitisBsurfaceantigenwhowasreceivingrituximab.N
EnglJMed.2001344:6869.[Dervite2001]
USDepartmentofHealthandHumanServices.GuidelinesfortheuseofantiretroviralagentsinHIV1infectedadultsandadolescents.
February12,2013.Availableat:http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.AccessedApril15,2014.[DHHS
ART]
DiMartinoV,ThevenotT,ColinJF,etal.InfluenceofHIVinfectionontheresponsetointerferontherapyandthelongtermoutcomeof
chronichepatitisB.Gastroenterology2002123:18121822.[DiMartino2002]
DienstagJL,GoldinRD,HeathcoteJ,etal.Histologicaloutcomeduringlongtermlamivudinetherapy.Gastroenterology.2003124:105
117.[Dienstag2003]
DodsonSF,DeVeraME,BonhalmCA,etal.LamivudineafterhepatitisBimmuneglobuliniseffectiveinpreventinghepatitisB
recurrenceafterlivertransplantation.LiverTransplant.20006:434439.[Dodson2000]
DomnguezM,BrcenaR,GarcaM,LpezSanromanA,NuoJ.VaccinationagainsthepatitisBvirusincirrhoticpatientsonliver
transplantwaitinglist.LiverTranspl.20006:440442.[Domnguez2000]
DumortierJ,ChevallierP,ScoazecJY,BergerF,BoillotO.CombinedlamivudineandhepatitisBimmunoglobulinforthepreventionof
25/31
20/02/2015
hepatitisBrecurrenceafterlivertransplantation:longtermresults.AmJTransplant.20033:9991002.[Dumortier2003]
EuropeanAIDSClinicalSociety.GuidelinesfortreatmentofHIVinfectedadultsinEurope.Version7.0.Availableat:
http://eacsociety.org/Portals/0/Guidelines_Online_131014.pdf.AccessedApril15,2014.[EACSART]
EuropeanAssociationfortheStudyoftheLiver.EASLClinicalPracticeGuidelines:ManagementofchronichepatitisBvirusinfection.J
Hepatol.201257:167185.[EASLHBV]
Baraclude[packageinsert].Princeton,NJ:BristolMyersSquibbOctober2010.[EntecavirPI]
FarciP,MandasA,CoianaA,etal.TreatmentofchronichepatitisDwithinterferonalfa2a.NEnglJMed.1994330:8894.[Farci1994]
FarciP.Deltahepatitis:anupdate.JHepatol.200339(suppl1):S212S219.[Farci2003]
FattovichG,GiustinaG,ChristensenE,PantalenaM,ZagniI,RealdiG,SchalmSW.Influenceofhepatitisdeltavirusinfectionon
morbidityandmortalityincompensatedcirrhosistypeB.TheEuropeanConcertedActiononViralHepatitis(Eurohep).Gut.200046:420
426.[Fattovich2000]
UnitedStatesFoodandDrugAdministration.BoxedWarningandnewrecommendationstodecreaseriskofhepatitisBreactivationwith
theimmunesuppressingandanticancerdrugsArzerra(ofatumumab)andRituxan(rituximab).Availableat:
http://www.fda.gov/downloads/Drugs/DrugSafety/UCM369436.pdf.AccessedApril15,2014.[FDA2013]
FeldJJ.HBVreactivationandcancerchemotherapy.2010.Availableat:http://www.aasld.org/education/Documents/Feld
HBV%20Reactivation%20and%20Cancer%20Chemotherapy.pdf.AccessedApril15,2014.[Feld2010]
FontanaRJ.ManagementofpatientswithdecompensatedHBVcirrhosis.SeminLiverDisease.200323:89100.[Fontana2003]
FreitasSZ,SoaresCC,TanakaTS,etal.Prevalence,riskfactorsandgenotypesofhepatitisBinfectionamongHIVinfectedpatientsin
theStateofMatoGrossodoSul,CentralBrazil.BrazJInfectDis.2014.pii:S14138670(14)00049X.[Freitas2014]
FungJ,CheungC,ChanSC,etal.EntecavirmonotherapyiseffectiveinsuppressinghepatitisBvirusafterlivertransplantation.
Gastroenterology.2011141:12121219.[Fung2011]
GanneCarrieN,CausseX,ZarskiJP,etal.EfficacyandsafetyresultsoftenofovirDF(TDF)treatmentfromthefirsttrimesterinHBV
pregnantwomeninreallifeclinicalpractice.Hepatology.201358.Abstract952.[GanneCarrie2013]
GatanagaH,YasuokaA,KikuchiY,TachikawaN,OkaS.InfluenceofpriorHIV1infectiononthedevelopmentofchronichepatitisB
infection.EurJClinMicrobiolInfectDis.200019:237239.[Gatanaga2000]
GilesM,VisvanathanK,LewinSR,etal.Clinicalandvirologicalfactorsthatpredictpostpartumflaresinpregnantwomenwithchronic
HBV.Hepatology.201358.Abstract905.[Giles2013]
GishRG,YiDH,KaneS,etal.CoinfectionwithhepatitisBandD:epidemiology,prevalenceanddiseaseinpatientsinNorthern
California.JGastroenterolHepatol.201328:15211525.[Gish2013]
GraceyDM,SnellingP,McKenzieP,StrasserSI.TenofovirassociatedFanconiSyndromeinpatientswithchronichepatitisB
monoinfection.AntivirTher.201318:945948.[Gracey2013]
GreenupAJ,TanPK,NguyenV,etal.EfficacyandsafetyoftenofovirinpregnancytopreventMothertoBabytransmissionofHBV.
Hepatology.201358.Abstract880.[Greenup2013]
HadlerSC,JudsonFN,OMalleyPM,etal.OutcomeofhepatitisBvirusinfectioninhomosexualmenanditsrelationtopriorhuman
immunodeficiencyvirusinfection.JInfectDis.1991163:454459.[Hadler1991]
HanG,ZhaoW,CaoM,etal.Aprospectiveandopenlabelstudyfortheefficacyandsafetyoftelbivudine(ltd)inpregnancyforthe
preventionofperinataltransmissionofhepatitisBvirus(HBV)totheinfants.Programandabstractsofthe61stAnnualMeetingofthe
AmericanAssociationfortheStudyofLiverDiseasesOctober29November1,2010Boston,Massachusetts.Abstract212.[Han2010]
HanGR,CaoMK,ZhaoW,etal.Aprospectiveandopenlabelstudyfortheefficacyandsafetyoftelbivudineinpregnancyforthe
preventionofperinataltransmissionofhepatitisBvirusinfection.JHepatol.201155:12151221.[Han2011]
HanGR,JiangHX,WangCM.LongtermsafetyandefficacyofinfantsborntotelbivudinetreatedhighlyviremicmotherswithHBeAg
positivechronichepatitisB(CHB)during2ndor3rdtrimester.Hepatology.201358.Abstract935.[Han2013a]
HanGR,KoehneC,TitaevskiS,DongY,TrylesinskiA.OverviewoftelbivudinetreatmentinpregnantwomenwithchronichepatitisB
virusinfection.Hepatology.201358:1191A1213A.Abstract947.[Han2013b]
HaushoferAC,HauerR,BrunnerH,etal.HepatitisBvirusactivityinpatientswithantihepatitisCvirusantibodypositivityandhepatitisB
antigenpositivity.JClinVirol.200225:S99S102.[Haushofer2002]
HollingerFB,SoodG.OcculthepatitisBvirusinfection:acovertoperation.JViralHepat.201017:115.[Hollinger2010]
HoltD,ThomasR,VanThielD,BremsJ.UseofhepatitisBcoreantibodypositivedonorsinorthotopiclivertransplantation.ArchSurg.
2002137:572575.[Holt2002]
26/31
20/02/2015
HoofnagleJH,DiBisceglieAM,WaggonerJG,ParkY.Interferonalfaforpatientswithclinicallyapparentcirrhosisduetochronichepatitis
B.Gastroenterology.1993104:11161121.[Hoofnagle1993]
HuY,ChenJ,WenJ,etal.EffectofelectivecesareansectionontheriskofmothertochildtransmissionofhepatitisBvirus.BMC
PregnancyChildbirth.201313:119.[Hu2013]
HuangYH,HsiaoLT,HongYC,etal.RandomizedcontrolledtrialofentecavirprophylaxisforrituximabassociatedhepatitisBvirus
reactivationinpatientswithlymphomaandresolvedhepatitisB.JClinOncol.201331:27652772.[Huang2013a]
HuangYH,LeeIC,HsiaoLT,LinHC,LeeSD.RituximabassociatedHBVreactivationinlymphomapatientswithresolvedhepatitisB:
kineticsofantiHBstiterswithorwithoutentecavirprophylaxis.Hepatology.201358.Abstract932.[Huang2013b]
HughesSA,WedemeyerH,HarrisonPM.Hepatitisdeltavirus.Lancet.2011378:7385.[Hughes2011]
HyamsKC.RisksofchronicityfollowingacutehepatitisBvirusinfection:areview.ClinInfectDis.199520:9921000.[Hyams1995]
HytiroglouP,DashS,HarunaY,etal.DetectionofhepatitisBandhepatitisCviralsequencesinfulminanthepaticfailureofunknown
etiology.AmJClinPathol.1995104:588593.[Hytiroglou1995]
JammaS,HussainG,LauDT.CurrentconceptsofHBV/HCVcoinfection:coexistence,butnotnecessarilyinharmony.CurrHepatRep.
20109:260269.[Jamma2010]
JiangL,JiangL,ChengN,Yan,L.CurrentprophylacticstrategiesagainsthepatitisBvirusrecurrenceafterlivertransplantation.WorldJ
Gastroenterol.200915:24892499.[Jiang2009]
KeamB,LeeJH,ImSA,etal.Why,when,andhowtopreventhepatitisBvirusreactivationincancerpatientsundergoingchemotherapy.
JNatlComprCancNetw.20119:465477.[Keam2011]
KewMC.HepatocellularcarcinomainAfrica.In:Malignantlivertumors:currentandemergingtherapies.2ndedition.ClavienPA,editor.
Boston,MA:JonesandBartlett200356.p.439448.[Kew2003]
KewMC,AsareGA.DietaryironoverloadintheAfricanandhepatocellularcarcinoma.LiverInt.200727:735741.[Kew2007]
KewMC.HepatocellularcarcinomainAfricanblacks:recentprogressinetiologyandpathogenesis.WorldJHepatol.20102:6573.[Kew
2010]
KhemichianS,LimurtiJ,HsiehMJ,etal.CombinationnucleosidenucleotideanalogtherapyiseffectivetopreventrecurrenthepatitisB
afterlivertransplantation.Hepatology.201358.Abstract1748.[Khemichian2013]
KimWR,TerraultNA,PedersenRA,etal.TrendsinwaitinglistregistrationforlivertransplantationforviralhepatitisintheUnitedStates.
Gastroenterology.2009137:16801686.[Kim2009]
KimHY,ChoiJY,ParkCH,etal.OutcomeafterdiscontinuingantiviralagentsduringpregnancyinwomeninfectedwithhepatitisBvirus.J
ClinVirol.201356:299305.[Kim2013a]
KimYK,KimSH,LeeSD,etal.ClinicaloutcomesandriskfactorsofhepatitisBvirusrecurrenceinpatientswhoreceivedprophylaxiswith
entecavirandhepatitisBimmunoglobulinfollowinglivertransplantation.Hepatology.201358.Abstract963.[Kim2013b]
KohlerJJ,HosseiniSH,HoyingBrandtA,etal.Tenofovirrenaltoxicitytargetsmitochondriaofrenalproximaltubules.LabInvest.
200989:513519.[Kohler2009]
KramvisA,KewMC.EpidemiologyofhepatitisBvirusinAfrica,itsgenotypesandclinicalassociationsofgenotypes.HepatologyRes.
200737:S9S19.[Kramvis2007]
LakeJR.DowereallyneedlongtermhepatitisBhyperimmuneglobulin?Whatarethealternatives?LiverTransplantation200814:S23
S26.[Lake2008]
LaoTT,ChanBC,LeungWC,HoLF,TseKY.MaternalhepatitisBinfectionandgestationaldiabetesmellitus.JHepatol.200747:4650.
[Lao2007]
LauGK,HeML,FongDYT,etal.PreemptiveuseoflamivudinereduceshepatitisBexacerbationafterallogeneichematopoieticcell
transplantation.Hepatology.200236:702709.[Lau2002]
LauGK,YiuHH,FongDY,etal.Earlyissuperiortodeferredpreemptivetherapyforhepatitisundergoingchemotherapy.Gastroenterol.
2003125:17421749.[Lau2003]
LawJK,HoJK,HoskinsPJ,ErbSR,SteinbrecherUP,YoshidaEM.FatalreactivationofhepatitisBpostchemotherapyforlymphomaina
hepatitisBsurfaceantigennegative,hepatitisBcoreantibodypositivepatient:potentialimplicationsforfutureprophylaxis
recommendations.LeukLymphoma.200546:10851089.[Law2005]
LeeAK,IpHM,WongVC.MechanismsofmaternalfetaltransmissionofhepatitisBvirus.JInfectDis.1978138:668671.[Lee1978]
LeeK,SmithPT.FulminantliverfailurefromacuteHCVsuperinfectioninapatientwithHIV,HBV,andHDVcoinfections.AIDSRead.
200010:398401.[Lee2000]
27/31
20/02/2015
LeemansWF,JanssenHLA,NiestersHG,etal.SwitchingpatientswithlamivudineresistantchronichepatitisBvirusfromtenofovirto
adeforvirresultsinlesspotentHBVDNAsuppression.JViralHepatitis.200815:108114.[Leemans2008]
LiawYF,YehCT,TsaiSL.ImpactofacutehepatitisBvirussuperinfectiononchronichepatitisCvirusinfection.AmJGastroenterol.
200095:29782980.[Liaw2000]
LiawYF,ChenYC,SheenIS,etal.ImpactofacutehepatitisCvirussuperinfectioninpatientswithchronichepatitisBvirusinfection.
Gastroenterology.2004126:10241029.[Liaw2004]
LiawYF,RaptopoulouGigiM,CheinquerH,etal.EfficacyandsafetyofentecavirvsadefovirinchronichepatitisBpatientswithhepatic
decompensation:arandomized,openlabelstudy.Hepatology.2011a54:91100.[Liaw2011a]
LiawYF,SheenIS,LeeCM,etal.Tenofovirdisoproxilfumarate(TDF),emtricitabine/TDF,andentecavirinpatientswithdecompensated
chronichepatitisBliverdisease.Hepatology.2011b53:6272.[Liaw2011b]
LimLL,WaiCT,LeeYM,etal.ProphylacticlamivudinepreventshepatitisBreactivationinchemotherapypatients.AlimentPharmacol
Ther.200216:19391944.[Lim2002]
LingWH,SoePP,PangAS,LeeSC.HepatitisBvirusreactivationriskvarieswithdifferentchemotherapyregimenscommonlyusedin
solidtumours.BrJCancer.2013108:19311935.[Ling2013]
LiuCJ,ChenPJ,LaiMY,KaoJH,JengYM,ChenDS.RibavirinandinterferoniseffectiveforhepatitisCvirusclearanceinhepatitisB
andCduallyinfectedpatients.Hepatology.200337:568576.[Liu2003]
LiuCJ,ChuangWL,LeeCM,etal.Anopenlabel,comparative,multicenterstudyofpeginterferonalfa2aplusribavirininthetreatmentof
patientswithchronichepatitisC/hepatitisBcoinfectionversusthosewithchronicHepatitisC.Programandabstractsofthe58thAnnual
MeetingoftheAmericanAssociationfortheStudyofLiverDiseasesNovember26,2007Boston,Massachusetts.Abstract233.[Liu
2007]
LiuCJ,ChuangWL,LeeCM,etal.Peginterferonalfa2aplusribavirinforthetreatmentofdualchronicinfectionwithhepatitisBandC
viruses.Gastroenterology.2009136:496504.[Liu2009]
LiuM,CaiH,YiW.SafetyoftelbivudinetreatmentforchronichepatitisBfortheentirepregnancy.JViralHepat.201320(suppl1):6570.
[Liu2013]
LoCM,LiuCL,LauGK,ChanSC,NgIO,FanST.LivertransplantationforchronichepatitisBwithlamivudineresistantYMDDmutant
usingaddonadefovirdipivoxilpluslamivudine.LiverTransplant.200511:807813.[Lo2005]
LokAS,LiangRH,ChiuEK,WongKL,ChanTK,ToddD.ReactivationofhepatitisBvirusreplicationinpatientsreceivingcytotoxic
therapy.Reportofaprospectivestudy.Gastroenterology.1991100:182188.[Lok1991]
LokAS,LaiC,LeungN,etal.LongtermsafetyoflamivudinetreatmentinpatientswithchronichepatitisB.Gastroenterology.
2003125:17141722.[Lok2003]
LokAS,McMahonBJ.ChronichepatitisB:update2009.Hepatology.200950:661662.[Lok2009]
LokAS.Drugtherapy:tenofovir.Hepatology.201052:743747.[Lok2010]
LongM,JiaW,LiS,etal.Asinglecenter,prospectiveandrandomizedcontrolledstudy:cantheprophylacticuseoflamivudineprevent
hepatitisBvirusreactivationinhepatitisBsantigenseropositivebreastcancerpatientsduringchemotherapy?BreastCancerResTreat.
2011127:705712.[Long2011]
LubelJS,AngusPW.HepatitisBreactivationinpatientsreceivingcytotoxicchemotherapy:diagnosisandmanagement.JGastroenterol
Hepatol.201025:864871.[Lubel2010]
MacasJ,BerenguerJ,JapnMA,etal.Fastfibrosisprogressionbetweenrepeatedliverbiopsiesinpatientscoinfectedwithhuman
immunodeficiencyvirus/hepatitisCvirus.Hepatology.200950:10561063.[Macas2009]
MarcellinP,ZiolM,BedossaP,etal.Noninvasiveassessmentofliverfibrosisbystiffnessmeasurementinpatientswithchronichepatitis
B.LiverInt.200929:242247.[Marcellin2009]
MastE,MahoneyF,KaneM,etal.HepatitisBvaccine.In:PlotkinSA,OrensteinWA,editors.Vaccines.Philadelphia,PA:Saunders2004.
p.299337.[Mast2004]
MastEE,MargolisHS,FioreAE,etal.AcomprehensiveimmunizationstrategytoeliminatetransmissionofhepatitisBvirusinfectionin
theUnitedStates:recommendationsoftheAdvisoryCommitteeonImmunizationPractices(ACIP)part1:immunizationofinfants,
children,andadolescents.MMWRRecommRep.200554:131.[Mast2005]
McMahonMA,JilekBL,BrennanTP,etal.TheHBVdrugentecavir:effectsonHIV1replicationandresistance.NEnglJMed.
2007356:26142621.[McMahon2007]
MiailhesP,PradatP,ChevallierM,etal.Proficiencyoftransientelastographycomparedtoliverbiopsyfortheassessmentoffibrosisin
HIV/HBVcoinfectedpatients.JViralHepat.201118:6169.[Miailhes2011]
28/31
20/02/2015
MosesSE,LimZY,SudhanvaM,etal.LamivudineprophylaxisandtreatmentofhepatitisBVirusexposedrecipientsreceivingreduced
intensityconditioninghematopoieticstemcelltransplantswithalemtuzumab.JMedVirol.200678:15601563.[Moses2003]
MosesSE,LimZY,SudhanvaM,etal.LamivudineprophylaxisandtreatmentofhepatitisBVirusexposedrecipientsreceivingreduced
intensityconditioninghematopoieticstemcelltransplantswithalemtuzumab.JMedVirol.200678:15601563.[Moses2006]
MuozSJ.UseofhepatitisBcoreantibodypositivedonorsforlivertransplantation.LiverTranspl.20028:S82S87.[Munoz2002]
NiroGA,RosinaF,RizzettoM.TreatmentofhepatitisD.JViralHepat200512:29.[Niro2005]
NiroGA,CiancioA,GaetaGB,etal.Pegylatedinterferonalpha2basmonotherapyorincombinationwithribavirininchronichepatitis
delta.Hepatology.200644:713720.[Niro2006]
OhkawaK,HayashiN,YukiNetal.LongtermfollowupofhepatitisBvirusandhepatitisCvirusreplicativelevelsinchronichepatitis
patientscoinfectedwithbothviruses.JMedVirol.199546:258264.[Ohkawa1995]
PanC,HanGR,ZhaoW,JiangHX,CaoMK.Aprospectiveopenlabelstudytoevaluatetheefficacy,safety,andtolerabilityoftelbivudine
inHBeAg+chronichepatitisBpregnantwomen.Programandabstractsofthe61stAnnualMeetingoftheAmericanAssociationforthe
StudyofLiverDiseasesOctober29November2,2010Boston,Massachusetts.Abstract364.[Pan2010]
PanJJ,ThosaniN,MachicaoVI,FallonMB.CurrentuseofhepatitisBimmuneglobulinforpreventionofdenovohepatitisBinrecipients
receivingantiHBcpositivelivers.HepatolInt.20115:635643.[Pan2011]
PanCQ,ZouHB,ChenY,etal.CesareansectionreducesperinataltransmissionofhepatitisBvirusinfectionfromhepatitisBsurface
antigenpositivewomentotheirinfants.ClinGastroenterolHepatol.201311:13491355.[Pan2013]
ParkJW,ParkKW,ChoSH,etal.RiskofhepatitisBexacerbationislowaftertranscatheterarterialchemoembolizationtherapyfor
patientswithHBVrelatedhepatocellularcarcinoma:reportofaprospectivestudy.AmJGastroenterol.2005100:21942200.[Park2005]
PerrilloR,TamburroC,RegensteinF,etal.Lowdose,titratableinterferonalfaindecompensatedliverdiseasecausedbychronic
infectionwithhepatitisBvirus.Gastroenterology.1995109:908916.[Perrillo1995]
PerrilloRP,WrightT,RakelaJ,etal.AmulticenterUnitedStatesCanadiantrialtoassesslamivudinemonotherapybeforeandafterliver
transplantationforchronichepatitisB.Hepatology.200133:424432.[Perrillo2001]
PerrilloR,ButiM,DurandF,etal.EntecavirandHBIginpatientsreceivinglivertransplantforchronichepatitisB.LiverTranspl.
201319:887895.[Perrillo2013]
PittmanC,PlittS,BirseT,etal.PrevalenceandcorrelatesofHIVandhepatitisBviruscoinfectioninNorthernAlberta.CanJInfectDis
MedMicrobiol.201425:e8e13.[Pittman2014]
PrezAlvarezR,DazLagaresC,GarcaHernndezF,etal.HepatitisBvirus(HBV)reactivationinpatientsreceivingtumornecrosis
factor(TNF)targetedtherapy:analysisof257cases.Medicine(Baltimore).201190:359371.[PrezAlvarez2011]
PrietoM,GomezMD,BerenguerM,etal.DenovohepatitisBcoreantibodypositivedonorsinanareawithhighprevalenceofantiHBc
positivityinthedonorpopulation.LiverTransplant.20017:5158.[Prieto2001]
PuotiM,TortiC,BrunoR,etal.NaturalhistoryofchronichepatitisBincoinfectedpatients.JHepatol200644:S65S70.[Puoti2006]
PuotiM,MannoD,NastaP,etal.HepatitisBvirusandHIVcoinfectioninlowincomecountries:unmetneeds.ClinInfectDis.
200846:367369.[Puoti2008]
RautouPE,AsselahT,SaadounD,etal.HepatitisCviruseradicationfollowedbyHBeAgtoantiHBeseroconversionafterpegylated
interferonalpha2bplusribavirintreatmentinapatientwithhepatitisBandCcoinfection.EurJGastroenterolHepatol.200618:1019
1022.[Rautou2006]
RawalBK,ParidaS,WatkinsRP,GhoshP,SmithH.SymptomaticreactivationofhepatitisBinpregnancy.Lancet.1991337:364.[Rawal
1991]
RocheB,SamuelD.ThedifficultiesofmanagingseverehepatitisBvirusreactivation.LiverInt.201131:104110.[Roche2011]
RutgeertsP,VermeireS,VanAsscheG.Biologicaltherapiesforinflammatoryboweldiseases.Gastroenterology.2009136:11821197.
[Rutgeerts2009]
SaabS,DesaiS,TsaoiD,etal.PosttransplantationhepatitisBprophylaxiswithcombinationoralnucleosideandnucleotideanalog
therapy.AmJTransplant.201111:511517.[Saab2011]
SamuelD,RoqueAfonsoAM.NewsensitivetoolsforhepatitisBvirus(HBV)detectioninlivertransplantation:whatwillbetheirimpacton
theprophylaxisofHBVinfection.LiverTransplant.200713:10841087.[Samuel2007]
SanchezMA,ScheerS,ShallowS,PipkinS,HuangS.EpidemiologyoftheviralhepatitisHIVsyndemicinSanFrancisco:acollaborative
surveillanceapproach.PublicHealthRep.2014129(suppl1):95101.[Sanchez2014]
SarrecchiaC,CappelliA,AielloP.HBVreactivationwithfatalfulminatinghepatitisduringrituximabtreatmentinasubjectnegativefor
HBsAgandpositiveforHBsAbandHBcAb.JInfectChemother.200511:189191.[Sarrecchia2005]
29/31
20/02/2015
SasadeuszJ,AudsleyJ,MijchA,etal.TheantiHIVactivityofentecavir:amulticentreevaluationoflamivudineexperiencedand
lamivudinenaivepatients.AIDS.200822:947955.[Sasadeusz2008]
SchttlerCG,FiedlerN,SchmidtK,etal.SuppressionofhepatitisBvirusenhancer1and2byhepatitisCviruscoreprotein.JHepatol.
200237:855862.[Schttler2002]
SeraT,HiasaY,MichitakaKetal.AntiHBspositiveliverfailureduetohepatitisBvirusreactivationinducedbyrituximab.IntMed.
200645:721724.[Sera2006]
SetoWK,ChanTS,HwangYY,etal.InterimanalysisofhepatitisBreactivationinpatientswithpriorHBVexposureundergoingrituximab
containingchemotherapy:aprospectivestudy.Hepatology.201358.Abstract34.[Seto2013]
ShimJH,LeeHC,KimKM,etal.EfficacyofentecavirintreatmentnaivepatientswithhepatitisBvirusrelateddecompensatedcirrhosis.J
Hepatol.201052:176182.[Shim2010]
SingalAK,GuturuP,HmoudB,KuoYF,SalamehH,WiesnerRH.Evolvingfrequencyandoutcomesoflivertransplantationbasedon
etiologyofliverdisease.Transplantation.201395:755760.[Singal2013]
SiniccoA,RaiteriR,SciandraM,etal.CoinfectionandsuperinfectionofhepatitisBvirusinpatientsinfectedwithhuman
immunodeficiencyvirus:noevidenceoffasterprogressiontoAIDS.ScandJInfectDis.199729:111115.[Sinicco1997]
SpiegelBMR,BolusR,HanS,etal.DevelopmentandvalidationofadiseasetargetedqualityoflifeinstrumentinchronichepatitisB:the
hepatitisBqualityoflifeinstrument,version1.0.Hepatology.200746:113121.[Spiegel2007]
SquadritoG,OrlandoME,PollicinoT,etal.VirologicalprofilesinpatientswithchronichepatitisCandovertoroccultHBVinfection.AmJ
Gastroenterol.200297:15181523.[Squadrito2002]
SteinmllerT,SeehoferD,RayesN,etal.IncreasingapplicabilityoflivertransplantationforpatientswithhepatitisBrelatedliverdisease.
Hepatology.200235:15281535.[Steinmller2002]
TanHH,LuiHF,ChowWC.ChronichepatitisBvirus(HBV)infectioninpregnancy.HepatolInt.20082:370375.[Tan2008]
TenneyDJ,RoseRE,BaldickC,etal.LongtermmonitoringshowshepatitisBvirusresistancetoentecavirinnucleosidenaivepatients
israrethrough5yearsoftherapy.Hepatology.200949:15031514.[Tenney2009]
Viread[packageinsert].FosterCity,CA:GileadSciencesSeptember2011.[TenofovirPI]
TepermanLW,PoordadF,BzowejN,etal.Randomizedtrialofemtricitabine/tenofovirdisoproxilfumarateafterhepatitisB
immunoglobulinwithdrawalafterlivertransplantation.LiverTranspl.201319:594601.[Teperman2013]
TerraultNA,JacobsonIM.TreatingchronichepatitisBinfectioninpatientswhoarepregnantorareundergoingimmunosuppressive
chemotherapy.SeminLiverDis.2007(27suppl1):1824.[Terrault2007]
ThioCL,SeabergEC,SkolaskyRJr,etal.HIV1,hepatitisBvirus,andriskofliverrelatedmortalityintheMulticenterCohortStudy
(MACS).Lancet.2002360:19211926.[Thio2002]
ThioCL.HepatitisBandhumanimmunodeficiencyviruscoinfection.Hepatology.200949:S138S145.[Thio2009]
TodoS,DemetrisAJ,VanThielD,etal.OrthotopiclivertransplantationforpatientswithhepatitisBvirusrelatedliverdisease.
Hepatology.199113:619626.[Todo1991]
TranTT.ManagementofhepatitisBinpregnancy:weighingtheoptions.CleveClinJMed.2009a76(suppl3):S25S29.[Tran2009a]
TranTT.UnderstandingculturalbarriersinhepatitisBvirusinfection.CleveClinJMed.2009b76(suppl3):S10S13.[Tran2009b]
TseKY,HoLF,LaoT.TheimpactofmaternalHBsAgcarrierstatusonpregnancyoutcomes:acasecontrolstudy.JHepatol.
200543:771775.[Tse2005]
TysonGL,KramerJR,DuanZ,DavilaJA,RichardsonPA,ElSeragHB.PrevalenceandpredictorsofhepatitisBviruscoinfectionina
UnitedStatescohortofhepatitisCvirusinfectedpatients.Hepatology.201358:538545.[Tyson2013]
vanZonneveldM,vanNunenAB,NiestersHG,etal.Lamivudinetreatmentduringpregnancytopreventperinataltransmissionof
hepatitisBvirusinfection.JViralHepat.200310:294297.[vanZonneveld2003]
VassiliadisT,GaripidouV,TziomalosK,etal.PreventionofhepatitisBreactivationwithlamivudineinhepatitisBviruscarrierswith
hematologicmalignanciestreatedwithchemotherapyaprospectivecaseseries.AmJHematol.200580:197203.[Vassiliadis2005]
VassilopoulosD,CalabreseLH.Risksofimmunosuppressivetherapiesincludingbiologicagentsinpatientswithrheumaticdiseases
andcoexistingchronicviralinfections.CurrOpinRheumatol.200719:619625.[Vassilopoulos2007]
VivianiS,CarrieriP,BahE,etal.20yearsintotheGambiaHepatitisInterventionStudy:assessmentofinitialhypothesesandprospects
forevaluationofprotectiveeffectivenessagainstlivercancer.GambiaHepatitisInterventionStudy.CancerEpidemiolBiomarkersPrev.
200817:32163222.[Viviani2008]
WeberR,SabinCA,FriisMollerNetal.Liverrelateddeathsinpersonsinfectedwiththehumanimmunodeficiencyvirus:theD:A:Dstudy.
30/31
20/02/2015
ArchInternMed2006166:16321641.[Weber2006]
WedemeyerH,YurdaydnC,DalekosGN,etal.Peginterferonplusadefovirversuseitherdrugaloneforhepatitisdelta.NEnglJMed.
2011364:322331.[Wedemeyer2011]
WedemeyerH,YurdaydinC,ErnstS,etal.96weeksofpegylatedInterferonalpha2aplustenofovirorplaceboforthetreatmentof
hepatitisdelta:theHIDIT2study.Hepatology.201358.Abstract31.[Wedemeyer2013]
WeinbaumCM,WilliamsI,MastEE,etal.Recommendationsforidentificationandpublichealthmanagementofpersonswithchronic
hepatitisBvirusinfection.MMWRRecommRep.200857:120.[Weinbaum2008]
WenWH,ChangMH,ZhaoLL,etal.MothertoinfanttransmissionofhepatitisBvirusinfection:significanceofmaternalviralloadand
strategiesforintervention.JHepatol.201359:2430.[Wen2013]
WesthoffTH,JochimsenF,SchmittelA,etal.FatalhepatitisBvirusreactivationbyanescapemutantfollowingrituximabtherapy.Blood.
2003102:1930.[Westhoff2003]
WitFW,WeverlingGJ,WeelJ,JurriaansS,LangeJM.Incidenceofandriskfactorsforseverehepatotoxicityassociatedwithantiretroviral
combinationtherapy.JInfectDis.2002186:2331.[Wit2002]
WongSN,ChuC,WaiC,etal.LowriskofhepatitisBvirusrecurrenceafterwithdrawaloflongtermhepatitisBimmunoglobulinin
patientsreceivingmaintenancenucleos(t)ideanalogtherapy.LiverTransplant.200713:374381.[Wong2007]
XuWM,CuiYT,WangL,etal.LamivudineinlatepregnancytopreventperinataltransmissionofhepatitisBvirusinfection:amulticentre,
randomized,doubleblind,placebocontrolledstudy.JViralHepat.200916:94103.[Xu2009]
YangYB,LiXM,ShiZJ,MaL.PregnantwomanwithfulminanthepaticfailurecausedbyhepatitisBvirusinfection:acasereport.WorldJ
Gastroenterol.200410:23052306.[Yang2004]
YeoW,SteinbergJL,TamJS,etal.LamivudineinthetreatmentofhepatitisBvirusreactivationduringcytotoxicchemotherapy.JMed
Virol199959:263269.[Yeo1999]
YeoW,ChanPK,ZhongS,etal.FrequencyofhepatitisBvirusreactivationincancerpatientsundergoingcytotoxicchemotherapy:a
prospectivestudyof626patientswithidentificationofriskfactors.JMedVirol.200062:299307.[Yeo2000]
YeoW,ZeeB,ZhongS,etal.ComprehensiveanalysisofriskfactorsassociatingwithHepatitisBvirus(HBV)reactivationincancer
patientsundergoingcytotoxicchemotherapy.BrJCancer.200490:13061311.[Yeo2004]
YeoW,ChanTC,LeungN,etal.HepatitisBreactivationinlymphomapatientswithpriorresolvedhepatitisBundergoinganticancer
therapywithorwithoutrituximab.JClinOncol.200927:605611.[Yeo2009]
YiW,LiuM,ChenA,PanC.Theefficacyoflamivudineuseinthesecondvs.thirdtrimesterofpregnancyinpreventingvertical
transmissionofHBVinhighlyviremicmothers.Hepatology.201358.Abstract858.[Yi2013]
YuenL,AyresA,JacksonK,etal.ShortdurationoflamivudineforpreventionofHBVtransmissioninpregnancy:lackofpotencyand
selectionofresistancemutations.Hepatology.201358.Abstract1018.[Yuen2013]
YurdaydinC,BozkayaH,OnderFO,etal.Treatmentofchronicdeltahepatitiswithlamivudinevslamivudine+interferonvsinterferon.J
ViralHepat.200815:314321.[Yurdaydin2008]
ZarskiJP,BohnB,BastieA,etal.CharacteristicofpatientswithdualinfectionbyhepatitisBandCviruses.JHepatol.199828:2733.
[Zarski1998]
ZhongS,YeoW,SchroderC,etal.HighhepatitisBvirus(HBV)DNAviralloadisanimportantriskfactorforHBVreactivationinbreast
cancerpatientsundergoingcytotoxicchemotherapy.JViralHepat.200411:5559.[Zhong2004]
ZouH,ChenY,DuanZ,etal.AretrospectivestudyforclinicaloutcomeofCaesareansectiononperinataltransmissionofhepatitisB
virusininfantsborntoHBeAgpositivemotherswithchronichepatitisB(CHB).Programandabstractsofthe61stAnnualMeetingofthe
AmericanAssociationfortheStudyofLiverDiseasesOctober29November1,2010Boston,Massachusetts.Abstract235.[Zou2010]
Keywords:HepatitisB,HepatitisBSpecialPopulations,HepatitisBTreatment
inPractice
2015ClinicalCareOptions,LLC.AllRightsReserved.
ThematerialspublishedviainPracticereflecttheviewsofthereviewersorauthorsofthematerial,notthoseofClinicalCareOptions,
LLC,theaccreditedprovider,orthecompaniesprovidingeducationalgrants.Thematerialsmaydiscussusesanddosagesfor
therapeuticproductsthathavenotbeenapprovedbytheUnitedStatesFoodandDrugAdministration.Aqualifiedhealthcare
professionalshouldbeconsultedbeforeusinganytherapeuticproductdiscussed.Readersshouldverifyallinformationanddatabefore
treatingpatientsorusinganytherapiesdescribedinthesematerials.
31/31

Hepatite B Coinfeção

Hochgeladen von

Dokumentinformationen

Originalbeschreibung:

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Hepatite B Coinfeção

Hochgeladen von

Copyright:

Verfügbare Formate

20/02/2015

Das könnte Ihnen auch gefallen