TOPICOUTLINE

SUMMARY&RECOMMENDATIONS
INTRODUCTION
EPIDEMIOLOGY
WHOSHOULDBESCREENED
CLINICALMANIFESTATIONSANDDIAGNOSIS
AcuteHBVinfection
ChronicHBVinfection
NATURALHISTORY
PhasesofchronicHBVinfection
Immunetolerant
Immuneactive(clearance)
Inactivecarrier
Resolutionofinfection
Reactivation
Progressiontocirrhosis
Hepatocellularcarcinoma
MANAGEMENTOFCHRONICHBV
Initialevaluation
Counselingandprevention
Monitoringofpatients
Diseaseactivity
HCCsurveillance
Selectionofpatientsfortreatment
CHOICEOFTREATMENT
Interferonalfa
Pegylatedinterferon
Efficacy
Sideeffects
Nonresponders
Lamivudine
CombinationtherapywithIFNalfa
Adefovirdipivoxil
Neweragents
MANAGEMENTOFACUTEHBV
IMMUNOPROPHYLAXIS
SUMMARYANDRECOMMENDATIONS
REFERENCES

GRAPHICSViewAll
ALGORITHMS
AlgorithmtreatmentHBVchildren
FIGURES
HBVriskmap
SerologyacuteandchronicHBV
PhasesofperinatallyacquiredhepatitisBvirusinfection
CourseperinatalchronicHBV
TABLES
SerologicmarkersHBV
InterpretationoftheHepatitisBpanel
ApproachHBVsummary
LamivudineHBVchildren

RELATEDTOPICS
AdefovirdipivoxilinthetreatmentofchronichepatitisBvirusinfection
CharacteristicsofthehepatitisBvirusandpathogenesisofinfection
Clinicalfeaturesanddiagnosisofprimaryhepatocellularcarcinoma
2013UpToDate,Inc.Allrightsreserved.|SubscriptionandLicenseAgreement|Release:21.6C21.56
ClinicalmanifestationsandnaturalhistoryofhepatitisBvirusinfection
Licensedto:AsanBookDig.Med.Lib.|SupportTag:[0604202.43.93.249404BB9CFS244013.14]

ClinicalsignificanceofhepatitisBvirusgenotypes
CombinationtherapyforchronichepatitisBvirusinfection
EntecavirinthetreatmentofchronichepatitisBvirusinfection
Epidemiologyandetiologicassociationsofhepatocellularcarcinoma
Epidemiology,transmission,andpreventionofhepatitisBvirusinfection
Generalprinciplesofinfectioncontrol
GianottiCrostisyndrome(papularacrodermatitis)
HepatitisAvirusvaccinationandpostexposureprophylaxis
HepatitisBvirusreactivationassociatedwithimmunosuppression
HepatitisBvirusvaccination
Hepatitisvirusesandthenewborn:Clinicalmanifestationsandtreatment
InvestigationaltreatmentsofchronichepatitisBvirusinfection
LamivudinemonotherapyforchronichepatitisBvirusinfection
LivertransplantationforchronichepatitisBvirusinfection
OverviewofthemanagementofhepatitisBandcaseexamples
Percutaneous,fineneedleaspiration,andlaparoscopicliverbiopsy
Preventionofhepatocellularcarcinomaandrecommendationsforsurveillanceinadultswithchronicliver
disease
RenaldiseaseassociatedwithhepatitisBvirusinfection
SerologicdiagnosisofhepatitisBvirusinfection
StandardandpegylatedinterferonforchronichepatitisBvirusinfection
Standardimmunizationsforchildrenandadolescents
TenofovirdisoproxilfumarateinthetreatmentofadultswithchronicHBVinfectionwhodonothaveHIV
infection
TreatmentofhepatitisBintheHIVinfectedpatient
OverviewofhepatitisBvirusinfectioninchildren
UpToDate

WoltersKluwerHealth

OfficialreprintfromUpToDate
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OverviewofhepatitisBvirusinfectioninchildren
Authors
AnnemarieBroderick,MB,BCh,MMedSc,FRCPI
MaureenMJonas,MD
SectionEditors
SheldonLKaplan,MD
ElizabethBRand,MD
DeputyEditor
AlisonGHoppin,MD
Disclosures
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2013.|Thistopiclastupdated:Jan21,2013.
INTRODUCTIONHepatitisBvirus(HBV)infectionremainsaglobalpublichealthproblemdespitethe
availabilityofaneffectivevaccine.
AnoverviewofHBVinfectioninchildrenwillbepresentedhere.Moredetaileddiscussionsofthemicrobiology,
pathogenesis,clinicalmanifestations,anddiagnosisarepresentedseparately.(See"CharacteristicsofthehepatitisB
virusandpathogenesisofinfection"and"ClinicalmanifestationsandnaturalhistoryofhepatitisBvirusinfection"
and"SerologicdiagnosisofhepatitisBvirusinfection".)
EPIDEMIOLOGYIntheUnitedStates,theincidenceofacutehepatitisBinchildren(<19years)hasdecreased
fromapproximately13.8casesper100,000population(10to19years)inthe1980s[1]to3.03and0.34casesper
100,000populationin1990and2002,respectively[2].Declineshavebeengreatestamongchildrenwhowereborn
after1991whenrecommendationsforuniversalhepatitisBvaccinationofinfantswereimplemented.By2007,the
incidenceofacutehepatitisBinchildren<15yearshadfallento0.02casesper100,000population[3,4].(See
"HepatitisBvirusvaccination".)
MostcasesofacutehepatitisBinfectionintheUnitedStates,andinseveralothernonendemiccountries,developin
patientsfromhighriskgroupssuchasintravenousdrugusers,homosexualmen,inthoselivingincommunitieswith
alargeproportionofimmigrantsfromregionswhereHBVisendemic,andincertaingroupswhereHBVisendemic,
suchasNativeAmericansinAlaska[5].ThemajorityofchildrenwithchronicHBVinfectionsareimmigrants,
haveimmigrantparents,orbecameexposedthroughotherhouseholdcontacts[6].
IncountrieswhereHBVisendemic,perinataltransmissionremainsthemostimportantcauseofchronicinfection
becauseofhighratesofdiseaseinpregnantwomen.Perinataltransmissionalsooccursinnonendemiccountries,
includingtheUnitedStates,mostlyinchildrenofHBVinfectedmotherswhodonotreceiveappropriateHBV

immunoprophylaxisatbirth[7,8].(See"Epidemiology,transmission,andpreventionofhepatitisBvirusinfection"
and"ClinicalsignificanceofhepatitisBvirusgenotypes".)
WHOSHOULDBESCREENEDScreeningforHBVinfectionshouldbeperformedbytestingforHBsAgand
antiHBs.Patientswhoarenegativeforthesemarkersshouldbevaccinated.(See"HepatitisBvirusvaccination".)
ThefollowinggroupsshouldbescreenedforHBVinfection[9]:
Adolescentswhoengageinhighriskbehaviors.Thisincludesthosewhouseintravenousorintranasaldrugs,
haveunprotectedsexwithaninfectedpartnerormorethanonepartner,menwhohavesexwithmen,and
thosewithahistoryofsexuallytransmitteddisease[10].
Allinternationallyadoptedchildren
Immigrantsfromhighprevalenceareas(regionsinwhichtheHBsAgprevalenceismorethan2percent).
TheseincludeallofAfricaandAsia,theCapeVerdeislands,mostofEasternandMediterraneanEurope,the
Caribbean,andpartsofSouthAmerica(figure1).(See"Epidemiology,transmission,andpreventionof
hepatitisBvirusinfection",sectionon'Epidemiology'.)
ChildrenlivingincommunitieswhereHBVisendemic(includingchildrenborntoimmigrantparentsfrom
endemicareas)
HouseholdcontactsofindividualswithHBVinfection
InfantsborntowomenwithHBVinfection(HBeAgpositiveornegative).InfantswhoreceivedhepatitisB
immuneglobulinandhepatitisBvaccineatbirth,followedbytwoadditionalimmunizations,shouldbetested
forantiHBsandHBsAgat9to18monthsofage.Thisisimportantbecauseabout5percentofsuchinfants
developchronicHBVinfectionevenafteroptimalimmunoprophylaxis.Thoseinfantswhowerenot
immunizedshouldbetestedassoonasidentified.InfantsborntomotherswhowerenottestedforHBsAg
duringpregnancyshouldalsoreceivehepatitisBvaccinebeforehospitaldischarge(asisrecommendedfor
infantsborntoHBsAgpositivemothers),andthematernalHBsAgstatusshouldbedeterminedassoonas
possible.(See"Hepatitisvirusesandthenewborn:Clinicalmanifestationsandtreatment",sectionon
'HepatitisB'.)
CLINICALMANIFESTATIONSANDDIAGNOSISInfectionwithHBVisassociatedwithcharacteristic
changesintheserumlevelsofhepatitisBantigensandantibodies(table1ABandfigure2).Thesemarkersare
usedtodefinedifferentclinicalstates.(See"SerologicdiagnosisofhepatitisBvirusinfection".)
AcuteHBVinfectionThediagnosisofacutehepatitisBisbaseduponthedetectionofHBsAg(hepatitisB
surfaceantigen)andIgMantiHBc(IgMantibodytohepatitisBcoreantigen).HBeAg(hepatitisBeantigen)is
positiveintheearlyphase,thenconvertstonegativeasantiHBe(antibodytohepatitisBeantigen)appears(figure
2).
AcuteHBVinfectioninchildrenhasavariablecourserangingfromasymptomaticinfectiontofulminanthepatitis.
UniversalHBVvaccinationhassubstantiallyreducedthefrequencyoffulminanthepatitis.Asanexample,mortality
inTaiwandecreasedfrom5.36to1.71per100,000duringthelasttwodecadesofthe20thcentury[11].
Clinicalmanifestationsinchildrenwhodevelopsymptomsaresimilartothoseinadults.Theincubationperiodlasts
onetofourmonths.Aserumsicknesslikesyndromemaydevelopduringtheprodromalperiod,followedby
constitutionalsymptoms,anorexia,nausea,jaundiceandrightupperquadrantdiscomfort.Thesymptomsand
jaundicegenerallydisappearafteronetothreemonths,butsomepatientshaveprolongedfatigueevenafter
normalizationofserumaminotransferaseconcentrations.(See"Clinicalmanifestationsandnaturalhistoryof
hepatitisBvirusinfection".)
However,somefeaturesareseenmorecommonlyincertainagegroups:
Theproportionofpatientsprogressingtochronicinfectionismuchhigherinneonates(upto90percent)
comparedwith1to5percentinadultsandintermediatevaluesinyoungchildren.
MostolderchildrenandadolescentshavemildconstitutionalsymptomsduringacuteHBVinfection.
Fulminanthepatitisisrare,butcanalsobeseen,particularlyininfantsborntomotherswhoareHBsAg
positiveandHBeAgnegative[12].HepatitisBvaccinationdoesnotconsistentlyprotectagainstthe
developmentoffulminanthepatitisBininfantsorolderchildren.
GianottiCrostisyndrome(characterizedbypapularacrodermatitisoftheface,extremities,andtrunk
accompaniedbylymphadenopathy)isseenininfantsandyoungchildrenwithacuteHBVinfectioninwhom
itmaybetheonlyclinicalmanifestation.ThesyndromeisnotspecifictoHBVinfection,sinceitcanbeseen
withotherformsofviralinfectionaswell.(See"GianottiCrostisyndrome(papularacrodermatitis)".)
ChronicHBVinfectionThediagnosisofchronicHBVinfectionisbasedonpersistenceofHBsAgformorethan
sixmonthsIgGantiHBcispositive,whileIgMantiHBcisnegative(table1ABandfigure2).
MostchildrenwithchronicHBVinfectionareasymptomaticandgrowanddevelopnormally.Somechildrennote
vaguerightupperquadrantdiscomfortandfatigue.
ChronicHBVinfectionisoccasionallyassociatedwithextrahepaticmanifestationsincludingpolyarteritisnodosa
andglomerulonephropathythelatterisobservedprincipallyinchildren.HBVinfectioncaninduceboth
membranousnephropathyand,lessoften,membranoproliferativeglomerulonephritis.Thetypicalpresentationis

withnephroticrangeproteinuria.Approximately30to60percentofchildrenwithHBVrelatedmembranous
nephropathyundergospontaneousremission,usuallyinassociationwithHBeAgtoantiHBeseroconversion(ie,
conversionfromHBeAgpositivetonegative,andfromantiHBenegativetopositive).TheincidenceofHBV
associatedmembranousnephropathyisfallingasratesofHBVvaccinationincrease[13].(See"Renaldisease
associatedwithhepatitisBvirusinfection".)
NATURALHISTORYThenaturalhistoryofchronicHBVinfectioninchildrenisvariable,dependinguponage,
modeofacquisition,andethnicity.Thesedifferencesarelikelyduetoimmunetolerancethatdevelopswhen
infectionoccursatanearlyage.Theexactmechanismsthroughwhichimmunetolerancedevelopsareunknown.
ChildrenfromendemiccountriesinwhomHBVwasacquiredperinatallyusuallyremainHBeAgpositiveand
havehighlevelsofviralreplication,althoughhistologicinjuryistypicallymild[14,15].Inanillustrative
reportfromTaiwan,whichfollowedacohortofchildrenwithHBVinfectionbornbeforetheimplementation
ofuniversalHBVimmunization,approximately66percentofchildrenremainedHBeAgpositiveat10years
ofage[16].Ratesofspontaneousseroconversionarelessthan2percentperyearinchildrenyoungerthan
threeyearsofage,and4to5percentafteragethree.Thefrequencyofspontaneousseroconversionincreases
duringpuberty[17,18].Inboys,therateofseroconversionisassociatedwithtestosteronelevelsandearlier
onsetofpuberty[19].
Bycontrast,childreninnonendemiccountriesarelesslikelytohaveacquiredthediseaseperinatally.Inthis
case,theyfrequentlyclearHBeAgandHBVDNAfromserumduringthefirsttwodecadesoflife[20].Ina
29yearlongitudinalstudyofItalianchildrenwithchronicHBVwhounderwentHBeAgseroconversion,95
percent(81/85)ofthosewithoutcirrhosishadinactiveHBVinfectionatmostrecentfollowup,and15percent
(13/89)clearedHBsAg[21].Childrenwhoseroconvertspontaneouslytendtohavehigheralanine
aminotransferase(ALT)levelsearlyinlifeascomparedwiththosewhodonotseroconvertspontaneously.
PhasesofchronicHBVinfectionIndividualswithperinatallyacquiredchronicHBVinfectiontypicallyenteran
immunetolerantphase,fromwhichtheyeventuallymoveontoanimmuneactivephaseandthencetospontaneous
clearanceoftheinfectionortoaninactivecarrierstate.Thetimingofthisprogressionvariesbetweenindividuals,
andtheseverityofliverinjurymaydependonthelengthoftheimmuneactivephase(figure3AB).Somepatients
mayprogressrapidlythroughoneormoreofthesephases,soeachstepmaynotbeclinicallyapparent.(See
"ClinicalmanifestationsandnaturalhistoryofhepatitisBvirusinfection".)
ImmunetolerantThisphaseischaracterizedbynormalormildlyelevatedserumaminotransferaseactivity(ALT
<2timestheupperlimitofnormal)andevidenceofactiveHBVreplication(HBVDNA>20,000IU/mLor10(5)
copies/mL).HBsAgandHBeAgarepositive.Youngchildrenwithverticallytransmitteddiseasetypicallyenterthis
phase,whichcontinuesformonths,years,orevendecadesbeforeenteringtheimmuneactivephase.Treatmentof
patientsinthisphaseisnotrecommendedbecausepatientsareunlikelytorespond,andtreatmentwithnucleosideor
nucleotideanalogsmayinducedrugresistanceandevencrossresistancetonewermedications.(See'Selectionof
patientsfortreatment'below.)
Immuneactive(clearance)Thisphaseischaracterizedbyelevatedserumaminotransferaseactivity(ALT>1.5to
2timestheupperlimitofnormal)andactiveHBVreplication(HBVDNAistypically>20,000IU/mLor10(5)
copies/mL).HBsAgandHBeAgarepositive.PatientsinthisphasearemorelikelytoclearHBeAgspontaneouslyor
torespondtotreatmentthanthoseintheimmunetolerantphase.SpontaneousclearanceofHBeAgearlyinlifeis
lesslikelyforpatientswithgenotypeCascomparedwithothergenotypes[22].Thereisincreasingevidencethat
individualswithprolongedimmuneactivephaseofHBVareathighriskforprogressiveliverdisease,promptinga
moreproactiveapproachtotreatmentofchildreninthisphase.(See'Selectionofpatientsfortreatment'belowand
"ClinicalsignificanceofhepatitisBvirusgenotypes".)
InactivecarrierThisphase(alsoknownasthenonreplicativeorlatentphase)ischaracterizedbynormallevelsof
serumaminotransferaseactivityandloworundetectablelevelsofHBVreplication.HBsAgispositivebutHBeAgis
negative.Upto20percentofpatientshaveoneormorereversionstotheimmuneactivephase,and20to30percent
reactivateintoHBeAgnegativeHBV[23].Theseconversionsmayoccuratanytime,soregularmonitoringis
necessary.ThesepatientsalsoremainatriskforcomplicationsofHBVsuchashepatocellularcarcinoma.(See
'Monitoringofpatients'belowand'Hepatocellularcarcinoma'below.)
ResolutionofinfectionAminorityofpatientswhoclearHBeAgalsogoontocleartheHBVinfection,heralded
byclearanceofHBsAgandappearanceofantiHBs.Withrareexceptions,theseindividualswillnotreverttoactive
HBVinfection,buttheyremainatriskforhepatocellularcarcinoma.(See'Hepatocellularcarcinoma'below.)
Reactivation20to30percentofpatientsprogresstoareactivationphase,alsoknownasHBeAgnegative
chronicHBV[9].ViralDNAlevelsincrease,andALTisnormalorelevated,butHBeAgremainsundetectable.
Patientsinthisphasetendtohavemorevirulentliverdisease.Antiviraltherapy(interferon,andsometimesadefovir
orentecavir)maybeindicatedtominimizeliverdamage,althoughlongtermclearanceofHBVisrare.(See
'Hepatocellularcarcinoma'belowand"OverviewofthemanagementofhepatitisBandcaseexamples",sectionon
'PredictionofresponseinHBeAgnegativepatients'.)
ProgressiontocirrhosisCirrhosisappearstobeaninfrequentcomplicationofHBVinfectionduringchildhood.
Oneofthelargeststudiesincluded292consecutivechildrenwhowereHBsAgpositiveandhadelevatedserumALT
levels[24].Cirrhosiswasfoundin10patients(3percent)atameanage4.03.3years.However,childrenwith
cirrhosishadahigherprevalenceofHepatitisDvirus(HDV)infectionandweremorelikelytohavehadblood

transfusionssuggestingthatcoinfectionwithHDVorHepatitisCvirus(HCV)mayhavecontributedtodisease
progressioninsomechildren.Nochilddevelopedcirrhosisduringfollowup(rangingfrom1to10years).
Althoughfrankcirrhosisisunusualduringchildhood,developmentofmoderateorseverefibrosisisrelatively
common.Inaseriesof76childrenwithchronicHBeAgpositiveHBVandelevatedALT,atleasthalfhadmoderate
toseverefibrosis[25].ThesefindingssuggestthatmanyindividualswithperinatallyacquiredchronicHBVareat
riskfordevelopingcirrhosisinthelongterm.(See"ClinicalmanifestationsandnaturalhistoryofhepatitisBvirus
infection",sectionon'SequelaeandprognosisofchronicHBVinfection'.)
TheriskofprogressiontocirrhosisamongadultsdiagnosedwithchronicHBVinfectionisdiscussedseparately.The
riskishigheramongindividualsfromareasendemicforHBVinfection,mostofwhomacquirethedisease
perinatally,andindividualswhoabusealcoholprobablyhaveaccelerateddiseaseprogression.Malesalsohave
higherriskforexacerbationsofHBV,cirrhosis,andhepatocellularcarcinomaascomparedtofemales.(See"Clinical
manifestationsandnaturalhistoryofhepatitisBvirusinfection",sectionon'Sequelaeandprognosisofchronic
HBVinfection'.)Intransgenicmice,hepatitisBvirusactsasasexhormoneresponsivevirus,whichmayexplain
thelowerratesofhepatocellularcarcinoma(HCC)andHBVviralloadseeninwomencomparedwithmenhuman
correlationisawaited[26,27].
HepatocellularcarcinomaHepatocellularcarcinoma(HCC)inchildrenandadultswithHBVinfectionhasbeen
describedinbothAsianandWesternpopulations[2832].AdultswithperinatallyacquiredHBVdevelopHCCata
rateofabout5percentperdecade[33].Theriskisrelatedtothedurationofdisease,thedegreeofhistologicinjury,
andthereplicativestateofthevirus(HBVDNAlevels).TheriskishigherinpatientswhoareHBeAgpositivefor
extendedperiodsoftimeandforthosewithprecoremutants.Theriskisincreasedfurtherinthepresenceof
cirrhosisorconcomitantinfectionwithHCVorHIV.However,HCChasbeendescribedinchildrenwhohad
undergoneearlyHBeAgseroconversion,indicatingthatthereisstillariskforHCCevenafterviralreplication
ceases[34].(See"Epidemiologyandetiologicassociationsofhepatocellularcarcinoma",sectionon'HepatitisB'.)
Becauseoftheserisks,wesuggestsurveillanceforHCCinindividualsinallphasesofHBVinfection,including
thosewhohaveundergoneseroconversion(convertedtoHBeAgnegative),eitherspontaneouslyoraftersuccessful
treatment.(See'Monitoringofpatients'below.)
HBVgenotypemayinfluenceHCCdevelopmentinchildrendifferentlythaninyoungadults.InTaiwan,the
majorityofchildrenwithHCCandchronicHBVinfectionhaveHBVgenotypeB[35].Incontrast,moststudiesin
youngadultsreportanassociationbetweenHBVgenotypeCandHCC.(See"ClinicalsignificanceofhepatitisB
virusgenotypes",sectionon'Hepatocellularcarcinoma'.)
UniversalchildhoodvaccinationhasledtoamajordeclineintheincidenceofHCCinendemiccountries.InTaiwan,
forexample,theaverageannualincidenceinchildrensixtonineyearsofagehasdecreasedfrom0.7to0.57to0.36
per100,000betweentheyears1981to1986,1986to1990,and1990to1994,respectively[36].Longtermstudies
havesubstantiatedthisfinding[37].
MANAGEMENTOFCHRONICHBVManagementofchildrenwithchronicHBVinfectioninvolvesgeneral
measuressuchascounselingofthepatientandfamily,surveillancefordiseaseprogressionanddevelopmentof
complications,andconsiderationfortreatment(algorithm1)[9,38].Guidelinesforthemanagementofchronic
HBVinfectioninadultshavebeenproposedbytheAmericanAssociationfortheStudyofLiverDisease(AASLD)
[39]someelementsareapplicabletochildrenandarereflectedinthediscussionbelow.(See"Overviewofthe
managementofhepatitisBandcaseexamples".)
InitialevaluationInitialevaluationofpatientswithchronicHBVinfectionshouldinclude:
AhistoryemphasizingriskfactorsforcoinfectionwithHCVand/orHIV,useofalcohol,andfamilyhistoryof
HBVinfection,liverdisease,andlivercancer.Physicalexaminationshouldassesssignsofchronicliver
disease(suchasspidertelangiectasias,palmarerythema,hepatosplenomegaly,jaundice,ascites,edema,
wasting,andgynecomastiainboys)aswellasgrowthparameters.
Laboratorytests:completebloodcountwithplatelets,liverbiochemicaltests(AST,ALT,totalbilirubin,
alkalinephosphatase),albumin,prothrombintime,andtestsforHBVreplication(HBeAg,antiHBe,HBV
DNA).TestingforimmunitytohepatitisAvirus(HAV)withaserumHAVIgGshouldbeconsideredin
patientsfromhighendemicityareaswhoarenotknowntobeimmune.
Evaluationforothercausesofliverdisease(suchashepatitisC)canbeconsideredinchildrenwithrisk
factors,particularlyifapretreatmentliverbiopsysuggestsadditionalcausesofchronicliverdisease.Wedo
notroutinelytestforothercausesifthereisnoheightenedclinicalsuspicionforthesedisorders.
Screeningforhepatocellularcarcinomawitharightupperquadrantultrasoundandserumalphafetoprotein.
OngoingmonitoringforhepatocellularcarcinomaisalsorecommendedforpatientsinanyphaseofHBV
infection[9].(See'Monitoringofpatients'belowand"Clinicalfeaturesanddiagnosisofprimary
hepatocellularcarcinoma".)
Liverbiopsyforpatientswhomeetcriteriaforchronichepatitis(ie,HBsAgpositivefor>6months,serum
HBVDNA>10(5)copies/mL,persistentelevationinALT/ASTlevels)andwhoarebeingconsideredfor
treatment.(See"Percutaneous,fineneedleaspiration,andlaparoscopicliverbiopsy".)
CounselingandpreventionAllpregnantwomenshouldbescreenedforHBVinfectionandcasemanagement
proceduresputinplacetopreventperinatalinfectionoftheirinfant[40].HBsAgpositivepregnantwomenshould

informtheirproviderssothattheirinfantscanreceivehepatitisBimmunoglobulinandvaccineimmediatelyafter
delivery.(See"Hepatitisvirusesandthenewborn:Clinicalmanifestationsandtreatment",sectionon'HepatitisB'.)
HouseholdmembersofchildrenwithchronicHBVshouldbevaccinatediftheytestnegativeforHBVserologic
markers.Thechildrenandtheirfamiliesshouldbecounseledregardingtheriskoftransmissiontoothers,including
perinataltransmissionandriskofenvironmentalexposurefromblood.Householdmembersshouldnotshareutensils
suchastoothbrushesorrazors,whichmaybecomecontaminatedwithblood.AlthoughHBVDNAhasbeen
detectedinvariousbodilysecretionsofhepatitisBcarriers,thereisnofirmevidenceofHBVtransmissionviabody
fluids.Adolescentsshouldbeadvisedregardingpreventionofsexualtransmission(ie,vaccinationofsexpartnersin
individualswithmonogamouspartnersandsafesexpracticeincludinguseofcondomsinsubjectswithmultiple
partners).(See"Epidemiology,transmission,andpreventionofhepatitisBvirusinfection",sectionon'Modesof
transmission'.)
ChildrenwithchronicHBVinfectionshouldbeallowedtoparticipateinallregularactivitiesandshouldnotbe
excludedfromregularschoolandparticipationinsports[41].Nospecialarrangementsneedtobemadeotherthan
practicinguniversalprecautionsindaycarecenters,schools,sportsclubsandcamps.(See"Generalprinciplesof
infectioncontrol".)
AdolescentswithchronicHBVinfectionshouldbeadvisedthatheavyuseofalcohol(>40g/day)anddrugabuse
hasbeenassociatedwithworseningliverdiseaseandanincreasedriskofHCC.Patientswhoarenotimmuneto
hepatitisAshouldbevaccinated.(See"HepatitisAvirusvaccinationandpostexposureprophylaxis".)
MonitoringofpatientsExpertpanelssuggestregularmonitoringofchildreninallphasesofHBVinfection,to
evaluateforhepaticdecompensationanddiseaseprogression,andforsurveillanceofhepatocellularcarcinoma
(HCC)[9].Guidelinesforadultssuggestmonitoringofliverbiochemicaltestseverythreetosixmonths.(See
"OverviewofthemanagementofhepatitisBandcaseexamples",sectionon'Monitoringofpatients'.)
Becausechildrengenerallyhavemilderdiseaseactivity,somewhatlessfrequentmonitoringisreasonableunless
specificriskfactorsarepresent.
DiseaseactivityPatientswhoareintheimmunetolerantphaseofHBVinfection(ie,HBsAgpositive,HBeAg
positive,serumHBVDNA>20,000copies/mL)shouldundergomonitoringofliverbiochemicaltestsevery6to12
months.IftheALTbecomeselevated,biochemicaltestsandserologiesshouldbemeasuredmorefrequently.Inthis
case,thepatientisprobablyenteringanimmuneactivephase,andmayundergospontaneousseroconversion,or
becomeeligiblefortreatmentsuchpatientsarealsoatriskforhepaticdecompensation.
PatientswhoareintheinactivecarrierphaseofhepatitisBinfection(ie,HBsAgpositive,HBeAgnegative,anti
HBepositive,persistentlynormalALT/ASTlevels,serumHBVDNA<10(5)copies/mL)shouldundergo
monitoringofliverbiochemicaltestsevery6to12months[42].IftheALTbecomeselevated,HBVserologiesand
HBVDNAshouldbemeasured.Thediseasemayreactivateevenafteryearsofquiescence4to20percentof
inactivecarriershaveoneormorereversionsbacktoHBeAg[43].
HCCsurveillancePeriodicmeasurementsofhepaticultrasoundshavebeenrecommendedinadults,orserum
alphafetoproteinlevelsifultrasoundisnotavailable.ThebenefitofsurveillanceforHCChasnotbeenwell
established,andtheserecommendationsarebaseduponobservationaldataandexpertopinion.(See"Preventionof
hepatocellularcarcinomaandrecommendationsforsurveillanceinadultswithchronicliverdisease".)
TheoptimalmonitoringprotocolforHCCandthebenefitofmonitoringinchildrenhavenotbeenestablished.
However,wegenerallymonitorliverultrasoundandserumalphafetoprotein(AFP)every12months.Forpatients
withelevatedAFP,cirrhosis,orafamilyhistoryofhepatocellularcarcinoma,wemonitormoreclosely.Becausethe
riskforHCCincreaseswithage,itisreasonabletoscreensomewhatlessfrequently(eg,everytwotothreeyears)in
youngpatientsintheimmunetolerantphase,ifbaselineAFPandultrasoundarenormal.
HCCcandevelopinpatientswithHBVinfection,regardlessofwhetherthevirusisactivelyreplicating.Therefore,
wecontinuesurveillanceforHCCinindividualsinallphasesofHBVinfection,includingthosewhohave
undergoneseroconversion(convertedtoHBeAgnegative),eitherspontaneouslyoraftersuccessfultreatment.
SelectionofpatientsfortreatmentTherearefewlargetrialsinchildrentoguidetreatmentdecisionsforchronic
HBV.Todate,theefficacyoftreatmenthasonlybeenmeasuredthroughintermediateoutcomessuchaschangesin
shorttermvirologic,biochemical,andhistologicparameters.
Theultimategoaloftreatmentistoreducetherisksofprogressiontocirrhosisandhepatocellularcarcinoma(HCC).
Effectsoftreatmentontheselongtermoutcomesareinferredfromtheintermediatevirologicandbiochemical
outcomesoftreatmenttrials,butarenotclinicallyproven[33].Becauseprogressiontocirrhosisappearstobe
associatedwiththeintensityanddurationofchronicinflammatoryactivity,itisreasonabletoinferthatsuccessful
treatmentofHBVprobablyreducestheriskofcirrhosis[33].Itisnotclearwhethertreatmentreducestheriskfor
HCC.(See'Hepatocellularcarcinoma'above.)
Noneoftheavailabletreatmentsishighlyefficacious.Furthermore,undersomecircumstances,prolongedtreatment
withlamivudineorothernucleosideornucleotideanalogsinducesdrugresistanceinasubstantialpercentageof
patients.Therefore,thechoiceofwhetherandwhentotreatdependsonseveralpatientspecificcharacteristicswhich

predicttheefficacyoftreatment,includingpersistentlyabnormalALTlevels,andactivediseaseshownonliver
biopsy(ifperformed),aswellasonthepatient'svaluesandpreferences(algorithm1).
Trialsinadultsandchildrendemonstratethatthelikelihoodofresponsetoanyofthecurrentlyavailabledrugs
dependshighlyuponthedegreeofelevationoftheserumaminotransferases[6,44,45].Thisobservationleadsto
severalgeneralrecommendationsabouttreatment:
WesuggesttreatmentformostpatientswithHBVDNApositivechronichepatitiswhoareintheimmune
activephase(usuallydefinedasALT>2xULNandHBVDNA>20,000IU/mLor10(5)copies/mL,forat
leastfourtosixmonths)[42].AlmostallchildrenwithchronicHBVareHBeAgpositive,buttherapycan
alsobeconsideredforthefewinwhomHBeAgisnegativeprovidedthatactiveHBVinfectionisdocumented
bydemonstrationofviremiaof>104copies/mLandALTispersistentlyabnormal.
WesuggestNOTtreatingpatientswithALTlevelslessthan1.5to2timestheupperlimitofnormal,evenif
HBVDNAlevelsarehigh.Thesefindingsgenerallyindicatethatthepatientisintheimmunetolerantphase
ofHBVinfection,andinthisphasetreatmentwithanyofthecurrentlyavailabledrugsdoesnotresultin
higherratesofHBeAgseroconversioncomparedwithnotreatment[33,45,46].Moreover,treatmentof
patientsinthisphaseusinglamivudineorothernucleosideornucleotideanalogsisassociatedwith
developmentofdrugresistance,whichcoulddiminishresponsivenesstothesameorrelatedmedicationsata
laterdate,whenhepaticinjuryisactive.
WesuggestinitialobservationforchildrenwithALTvaluesgreaterthan10timestheupperlimitofnormal
butwithconcomitantlowHBVDNAlevelsthesechildrenmaybeintheprocessofspontaneous
seroconversion,andmaynotrequiretreatment.Instead,thesepatientsshouldbeobservedforseveralmonths
withserialserologictesting.Treatmentshouldthenbeinitiatedifthepatienthasnotundergone
seroconversiontotheinactivecarrierstate(ie,convertedfromHBeAg+toHBeAg,withundetectableHBV
DNA).Inthisstate,HBeAbisusuallypositivebutshouldbemonitoredperiodicallybecausesomeindividuals
haveamutantHBVwhichisassociatedwithactiveliverdiseasedespitelowlevelsofHBeAg(see"Serologic
diagnosisofhepatitisBvirusinfection",sectionon'HepatitisBeantigenandantibody').Ifthereisevidence
ofhepaticdecompensation,suchasjaundiceorcoagulopathy,treatmentshouldbeinitiatedearlier[47,48].
Interferoncannotbeusedinpatientswithdecompensateddisease.
Severalotherconsiderationsmayberelevanttotreatmentdecisionsforindividualpatients,suchasthosecoinfected
withHCV,HIVorHDV.Alimitedcourseoftreatmentmayalsobeappropriateinsomechildrenwhowillbe
undergoingimmunosuppression(suchaschemotherapy,antitumornecrosisfactoralphatreatments,ororgan
transplantation),eveniftheyareintheimmunetolerantorinactivecarrierphaseofHBVinfection.Inthiscase,
lamivudineoranothernucleos(t)ideisoftenusedinanefforttopreventreactivationthesedrugsmaybe
discontinuedafterimmunereconstitutionandifHBVDNAremainsundetectable.Issuesrelatedtoscreeningand
prophylaxisaredescribedseparately.(See"OverviewofthemanagementofhepatitisBandcaseexamples",section
on'Whoshouldbetreatedandhow'and"TreatmentofhepatitisBintheHIVinfectedpatient"and"HepatitisB
virusreactivationassociatedwithimmunosuppression".)
CHOICEOFTREATMENTSeveraldrugscurrentlyareapprovedfortreatmentofchronicHBVinfectionin
adults(lamivudine,interferonalfa,adefovirdipivoxil,entecavir,pegylatedinterferonalfa2a,andtelbivudine)(
table2).Thefirsttwo,lamivudineandinterferon(IFN),arelicensedforuseinchildrenintheUnitedStates.
Adefovirhasbeenevaluatedinaclinicaltrialinchildrenandisapprovedforuseinthoseover12yearsofageinthe
UnitedStates[49].IFNisnotagoodoptioninchildrenwithanunderlyingautoimmunedisorder,organtransplant,
orseriousneuropsychiatricdisease.(See"OverviewofthemanagementofhepatitisBandcaseexamples".)
AnadvantageofIFNoverlamivudineisthatithasafinitedurationoftreatmentandisnotassociatedwiththe
developmentofresistantvariants.Developmentofresistanceduringlamivudinetreatmentisparticularlylikely
amongpatientswithminimaldiseaseactivityand/orpoorcompliancewithtreatment[43].
Thus,inourpracticewegenerallyuseIFNalfaasthefirstlinetreatmentforthepatientswhoaremostlikelyto
respond(ie,forpatientswithserumALTmorethantwicetheupperlimitofnormal,havepositiveHBeAg,whoare
committedtoadheringtothetreatment,andhavenocomorbiddiseasesthatmightbeexacerbatedbyan
immunostimulatoryagent).IfthepatientdoesnotrespondtoIFNalfa(definedbydetectableHBVDNAand
elevatedserumALTsixmonthsaftercompletionofthecourseofIFNalfa),thereisacontraindicationtoIFN,orthe
patient/familychoosenottoreceiveIFN,anucleoside/nucleotideanalogsuchaslamivudineoradefovircanbeused
ifliverdiseaseissignificant.However,lamivudineandadefovirarenotconsideredpreferredagents,and,unless
advancedliverdiseaseispresent,itmaybeprudenttoawaitavailabilityofdrugswithhighpotencyandhighbarrier
todevelopmentofresistance.Inourpractice,weenrollthesechildreninclinicaltrialsofagentsshowntobemore
efficaciouswithlowerresistancerates,suchasentecavir.Iflamivudineoradefovirisused,itshouldbe
discontinuedifthereisnovirologicresponse(persistentdetectableHBVDNA)after24weeks,inordertominimize
theriskofresistance[50].Ifanucleoside/nucleotideanalogisused,itshouldbecontinuedforatleast12months
afterHBeAgseroconversionisdocumented[38].
GenotypetestingisnotanestablishedfactorformakingthechoicebetweenIFNandnucleoside/nucleotidetherapy.
However,itmaybeconsideredforHBeAgpositivepatientswhoareconsideringIFNtherapy,sincepatientswith
genotypeAandBhaveamorefavorableresponsetoIFN,andthosewithgenotypeCgenerallyarelesslikelyto
respond.(See"OverviewofthemanagementofhepatitisBandcaseexamples"and"Clinicalsignificanceof
hepatitisBvirusgenotypes".)

InterferonalfaInterferonshaveantiviral,antiproliferative,andimmunomodulatoryeffects.Interferonalfa(IFN
alpha)andIFNbetahavepredominantlyantiviraleffects,whileIFNgammahasmoremarkedimmunoregulatory
butlesspotentantiviralactivity.
IFNalfa(IntronA)wasthefirsttreatmentapprovedforchronicHBVinfectioninmostcountries.Itleadstoa
beneficialresponsein30to40percentofpatientswithchronicHBVinfection.However,itisexpensiveandmaybe
accompaniedbyfrequentandunpleasantsideeffects,asdescribedbelow.(See'Sideeffects'below.)
ForchildrenwithHBeAgpositivechronicHBVinfectionwetypicallytreatwithasixmonthcourseofinterferon
alfa2b,sixmillionunits(MU)perm(2)(maximum10MU)threetimesaweekfor24weeks,followedbyan
observationperiodof6to12months.AyearoftreatmentmaybepreferableinthosewithHBeAgnegativechronic
HBVinfection,basedupondatainadults.Patientsshouldbemonitoredregularlyforhepatitisflaresduringthefirst
fewmonthsafterthedrugisdiscontinued.(See"StandardandpegylatedinterferonforchronichepatitisBvirus
infection".)
PegylatedinterferonTheattachmentofpolyethyleneglycoltoaprotein(pegylation)reducesitsrateof
absorptionfollowingsubcutaneousinjection,reducesrenalandcellularclearance,anddecreasesthe
immunogenicityoftheprotein.Alloftheseeffectstendtoenhancethehalflifeofthepegylatedversusthenative
protein.Pegylatedinterferon(incombinationwithribavirin)hasbecomethetreatmentofchoiceforpatientswith
chronichepatitisCvirusinfectionitisalsoatherapeuticoptionforadultswithHBV.
TheefficacyofpegylatedinterferonsinchildrenwithchronicHBVinfectionhasnotbeenestablished,butisunder
investigationinclinicaltrials.However,basedonitsefficacyinadultsandexperienceinusingitfortreatmentof
HCVinchildren,wefeelthatitisareasonablechoiceforchildrenwithHBVwhoareintheimmuneactivephaseof
HBVinfectionasdescribedabove,inthecontextofaclinicaltrial,usinga48weekcourseoftreatmentasis
recommendedforadults.Outsideofthecontextofaclinicaltrial,pegylatedinterferonshouldbeusedwithcaution
inyoungchildrenwithHBVifatall,becauseitsefficacyhasnotbeenestablishedinthisagegroup,andbecauseof
potentialsideeffects,whichincludegrowthsuppressioninprepubertalchildren.Althoughpegylatedinterferonnot
yetlicensedforHBVinpatientsyoungerthan18years,itmaybeacceptableastherapyforpostpubertalchildren
withactivehepaticdisease,butshouldbeavoidedifcirrhosisispresent.(See"Standardandpegylatedinterferonfor
chronichepatitisBvirusinfection".)
EfficacySeveralcontrolledtrialsinchildrenhaveevaluatedtheefficacyofstandardIFNalfaindifferentregions
oftheworld[45,5157].Responserates(usuallydefinedasHBeAgseroconversionand/orlossofHBVDNA)have
generallybeenhighestinWesterncountries(20to58percentoftreatedpatientscomparedwith8to17percentof
controls)[5155].ResponserateshavebeenmuchlowerinAsiancountries(approximately17percent)[58,59].
ThelowerresponserateinpopulationsfromAsiancountriesisprimarilyexplainedbythehigherproportionof
individualswhowereinfectedatbirthandtendtohaveaprolongedimmunetolerantphaseofinfection.Forreasons
thatareincompletelyunderstood,suchpatientsappeartobelesslikelytorespondtoantiviraltreatment.(See
"ClinicalmanifestationsandnaturalhistoryofhepatitisBvirusinfection".)
HBVgenotypeCismorecommonamongAsianpopulationsandappearstobeassociatedwithlowerratesof
seroconversionandresponsetotreatmentascomparedwithHBVgenotypeB.Whetherimmunetoleranceand
genotypeexertindependenteffectsonseroconversionhasnotbeenestablished.(See"Clinicalsignificanceof
hepatitisBvirusgenotypes".)
Predictorsofresponseotherthanimmunetolerancewereexaminedinalargemultinationalstudythatincluded
AsianandnonAsianpatientswhoseserumALTwasatleast1.5timestheupperlimitofnormal(indicatingthatthey
wereinthereplicativeratherthantheimmunetolerantphaseofinfection)[55].Responseratesweresimilarin
AsianandnonAsianpatients(22versus26percent),suggestingethnicityitselfisnotanindependentpredictorof
response.
HBeAgseroconversionisgenerallyassociatedwithhistologicimprovementinstudiesofadults.Therearerelatively
fewstudiesshowinghistologicchangesinchildren,sincearepeatliverbiopsyaftertreatmentisuncommonly
performed.Onesuchstudyinvolved10pairedbiopsysamples,sixofwhichwerefromresponders[55].The
histologicactivityindex(HAI)improvedsignificantlyinallresponders.Italsoimprovedintwoofthenon
responders,butworsenedintheothertwo.
SideeffectsTreatmentwithinterferonisassociatedwithmultiplesideeffects.Nevertheless,mostchildrenare
abletocompletetheircourseoftherapy,althoughnotalwayswiththeinitialdose.
Almostallchildrenexperienceflulikesymptoms(eg,fever,myalgia,headache,arthralgiaandanorexia),which
usuallyremitafterafewdoses(usuallywithinaweek).Flulikesymptomscanbereducedbybeginningtreatment
withalowdoseandincreasingoveraweektotherecommendedfulldoseof6millionunits/m(2).Prophylactic
acetaminophenand/oribuprofenmaybeusedtomitigatethesesymptoms.
Bonemarrowsuppression,especiallyneutropenia,isobservedinapproximately20to40percentofchildren[55,60
].Severeneutropeniaresultingininfectionsisrare.Inoneofthelargestcontrolledtrials,thedosewasreduced
becauseofbonemarrowsuppressionorfeverin23percentofchildren[55].

Avarietyofothersideeffectshavebeendescribed:
Changesinpersonality(mostlyirritabilityandtempertantrums),whicharereversibleuponwithdrawalof
treatment[55,60].Therearenostudiesregardinguseofantidepressantmedicationsinchildrenreceiving
IFN.Itisprudenttoreferchildrenforevaluationiftheydevelopmoderatedepressionorbehavioral
symptoms.Treatmentshouldbestoppedinchildrenwhodevelopseveredepression.
FeversarecommonafterthefirstfewdosesofIFNalfainchildren[61].
Weightloss(whichistypicallyregainedonceIFNisdiscontinued)[62,63].Longtermeffectsongrowthand
growthvelocityarenotknown.
Decreasedqualityoflifebecauseofmedicationsideeffectsandfearofinjections[60].Qualityoflifereverts
tobaselinewithinthreemonthsofcessation.
Becauseofthesesideeffects,interferonalfaisnotagoodoptionforpatientswithanunderlyingautoimmune
disorder,organtransplant,decompensatedliverdisease,orseriousneuropsychiatricdisease[47].
NonrespondersAsnotedabove,themajorityofpatientstreatedwithinterferondonotachieveseroconversion.
Thelongtermoutcomeofsuchpatientshasnotbeenwelldescribed.Smallstudiessuggestthatthediseaseremains
relativelystableintheshortterm[64].
Treatmentoptionsforsuchpatientscouldincludelamivudine,orneweragents,whenclinicaltrialsinvolving
childrenarecompleted.AsecondcourseofIFNatherapydoesnotappeartoincreasetheratesofseroconversion[
65].(See"InvestigationaltreatmentsofchronichepatitisBvirusinfection".)Peginterferonhasnotyetbeen
evaluatedinanylargetrialofchildrenwithchronichepatitisB.(See'Pegylatedinterferon'above.)
LamivudineLamivudine(3TC)(EpivirHBV)isanucleosideanalog,the()enantiomerof2',3'dideoxy3'
thiacytidine.Itisphosphorylatedtothetriphosphate(3TCTP),whichcompeteswithdCTPforincorporationinto
growingDNAchains,causingchaintermination.Forchildren,lamivudineisgivenatadoseof3mgperkgofbody
weighttoamaximaldoseof100mg.(See"LamivudinemonotherapyforchronichepatitisBvirusinfection".)
Theavailabledataindicatethatlamivudineissafeandsometimeseffectiveinchildren,butthebenefitmustbe
carefullybalancedagainsttheriskofselectingresistantmutants.
Lamivudineisusuallyasecondlinetreatmentchoice.Iftreatmentisnecessaryinpreadolescentchildren(whichis
notveryoften),wegenerallyuseinterferonratherthanlamivudine.Forthisagegroup,wesometimesuse
lamivudineinspecialcircumstancesinwhichitsuseisexpectedtobeshortterm(eg,aroundchemotherapy).For
adolescents,optionsotherthanlamivudineincludeentecavirandadefovirdipivoxil.(See'Adefovirdipivoxil'below
and'Neweragents'below.)
Thelargestcontrolledtrialincluded288childrenwhowererandomlyassignedtoreceivelamivudineorplacebofor
52weeks[46].Avirologicresponseattheendoftreatment(lossofHBeAgandreductioninserumHBVDNAto
undetectablelevelsusingthebranchedDNAassay[lowerlimitofdetection0.7mEqpermL])wasobserved
significantlymoreofteninchildrenwhoreceivedlamivudine(23versus13percent)(table3).Onmultivariable
analysis,avirologicresponsewasassociatedwithhigherbaselineALTvaluesandHistologicActivityIndex(HAI).
Treatmentwaswelltolerated.
Afteroneyear,213patientswhoremainedHBeAgpositive(79placeboand134priorlamivudine)wereenrolledin
atwoyear,openlabellamivudinetreatmentphase[66].Attheendoffollowup,HBeAgseroconversionwas
observedin23of77(30percent)patientswhohadpreviouslyreceivedplacebo,and28of133(21percent)ofthose
whohadpreviouslyreceivedlamivudine.ThesedataconfirmthatsomepatientswhodonothaveHBeAg
seroconversioninitiallymightdosowithlongerdurationoftreatment.Amongthosewhoreceivedadditional
lamivudinetreatment,lamivudineresistantmutationsweredetectedin34of70(49percent)priorplaceboand66of
103(64percent)priorlamivudinepatients.PatientswholostHBeAgduringyearonewerefollowedforan
additionaltwoyears46of54(85percent)patientswhoremainedintheobservationarmhadsustainedvirologic
response.
ChildrenwithhigherpretreatmentALTandHAIscoresonliverbiopsyweremorelikelytorespondtolamivudine.
OtherfactorssuchasHBVDNAlevels,age,gender,race,ethnicity,bodyweightandbodymassindexdidnot
appeartosignificantlyinfluenceresponsetolamivudinetreatmentinchildren[67].
Theoptimaldurationoftherapyisunclear.Lamivudineshouldbeusedforatleastoneyear,andprobablyforatleast
sixmonthsafterHBeAgseroconversion[33].LongerdurationoftreatmentincreasesthelikelihoodofHBeAg
seroconversionbutalsoincreasesthedevelopmentofresistance.Inthosechildrenwhodonotdevelopresistance,up
tothreeyearsofcontinuoustherapyisassociatedwithfurthervirologicresponses[66].Inaddition,responsesto
lamivudinewereatleastasdurableasnaturalseroconversionsinchildrenfollowedforuptofiveyears[68].
Prolongedtreatmentofnonrespondersisnotindicated[66].
Becauseofconcernsaboutthedevelopmentofresistancetolamivudine,childrenwhoreceivethisoranyother
nucleos(t)ideantiviraltherapyshouldbemonitoredwithserialHBVDNAandALTlevelsduringtreatment[9](see
"LamivudinemonotherapyforchronichepatitisBvirusinfection",sectionon'Durationandendpointsoftherapy').
AnincreaseofatleastoneloginHBVDNAduringlamivudinetreatmentsuggeststhatthepatient'svirushas
becomeresistant.Inthiscase,weusuallydiscontinuelamivudineifthepatienthasonlymildliverdisease,orweadd

asecondagent(suchasadefovirdipivoxil)ifthepatienthassignificantliverdisease.Neweragentscanbe
consideredforolderpatients.(See"LamivudinemonotherapyforchronichepatitisBvirusinfection",sectionon
'Patientswhodevelopresistance'.)
Initialdatasuggestedthatcontinuedtreatmentofpatientswhodevelopresistancemightbebeneficialinthosein
whomHBVDNAcontinuestobesuppressed.However,longtermfollowupofsuchpatientssuggeststhatthe
diseasecontinuestoprogress.Thus,itmaybeprudenttodiscontinuelamivudineinchildrenwhodevelop
lamivudineresistantHBV.Patientsshouldbemonitoredregularlyforhepatitisflaresduringthefirstfewmonths
afterthedrugisdiscontinued.Forthosewhorequireadditionaltherapy,optionsarelimitedatthistime.Forthis
reason,initiationoftreatmentshouldbereservedforthosechildrenwithhistologicevidenceofsignificantchronic
hepatitisorfibrosis.(See"LamivudinemonotherapyforchronichepatitisBvirusinfection",sectionon'Resistance'
.)
CombinationtherapywithIFNalfaThecombinationoflamivudineandinterferonseemslogicalbecause
monotherapywitheachagentiseffective,andlamivudineandinterferonhavedifferentmechanismsofaction.
However,disparateresultshavebeendescribedincontrolledtrialsinadults.(See"Combinationtherapyforchronic
hepatitisBvirusinfection".)
Inoneuncontrolledstudy,inwhich23immunetolerantchildrenwithperinatallyacquiredHBVweretreatedwith
lamivudineforeightweeksfollowedbylamivudineandIFNaincombinationfor10months,fivepatients
seroconvertedtoantiHBeduringtreatmentorwithin18monthsoftheendoftreatmentandfourofthesefive
becamepersistentlyHBsAgnegative[69].However,anotherstudy,comparingIFNalonewithIFNandlamivudine
intwodifferentregimensfailedtodemonstrateadifferenceamongthegroupsinlongtermresponse[70].
AdefovirdipivoxilAdefovirdipivoxil(Hepsera)isanucleotideanalogofadenosinemonophosphate,whichcan
inhibitreversetranscriptaseandDNApolymeraseactivitylevels.Inadultsitissomewhatlesseffectivethan
lamivudineinreducingHBVDNAlevelsandinducingseroconversion,butalsoislesslikelytoinduceviral
resistance.AdefovirhasbeenevaluatedasprimarymonotherapyforadultswithchronichepatitisBandthosewho
developedresistancetolamivudine.Pharmacokineticstudiesinchildrenhavebeencompleted,andarandomized
controlledtrialhasbeencompleted.IntheUnitedStates,adefovirdipivoxilisapprovedforchildrenwithchronic
HBVinfectionaged12yearsandolder.
Adefovirdipivoxilwasaseffectiveinadolescentsasinadultsinachievingvirologicresponse(definedasadecrease
inHBVDNAtoundetectablelevelsandnormalizationofALT)[49].Amongadolescents,adefovirwas
significantlymoreeffectivethanplaceboinachievingtheprimaryefficacyendpoint(23percentachievedHBV
DNA<1,000copies/mL,ascomparedwithzeropercentofthosetreatedwithplacebo).Thisresponsewasnotseen
clearlyinyoungerchildren,butsomeoftheyoungerchildrenhadHBeAgseroconversionswhiletakingadefovir
dipivoxil.
TheroleofadefovirdipivoxilinthetreatmentofchildrenwithchronicHBVhasnotbeenestablished.Inour
practice,wemayuseadefovirdipivoxilinpatientswhoareover12yearsofageandwhohavefailedIFNalfa
treatmentandlamivudineorinthosewhohavedevelopedlamivudineresistance.Inthecaseoflamivudine
resistance,treatmentisdiscontinuediftheliverdiseaseismild.Ifthereissignificantliverdiseaseoranother
indicationtocontinuetreatmentinapatientwithlamivudineresistance,adefovirisaddedtolamivudine,ratherthan
switchingfromlamivudinetoadefovir.Thelatterpracticeissupportedbyasmalltrialinadolescentswhohad
developedlamivudineresistance[71].Patientstreatedwithadefovirandongoinglamivudinehadamorerapid
declineinHBVDNAtiterandweremorelikelytohaveundetectableHBVDNAlevelsat24weeks,ascompared
withpatientswhoswitchedtoadefoviralone.(See"AdefovirdipivoxilinthetreatmentofchronichepatitisBvirus
infection".)
NeweragentsTenofovirdisoproxilfumarate(DF)hasdemonstratedexcellentviralsuppressionandgoodsafety
profileintwoyearsofuse,andislicensedbytheUSFoodandDrugAdministration(FDA)foruseinadolescents12
yearsandolder.Inarandomizedtrial,adolescents12to<18yearsofageweretreatedfor72weekswitheither
tenofovirDForplacebo(NCT00734162)[72].HBVDNAdecreasedto<400copies/mLin89percent(46/52)of
patientswhoreceivedtenofovirDF,ascomparedwith0percent(0/54)ofthosewhoreceivedplacebo.HBeAg
seroconversionswererare.However,dataregardingHBeAgseroconversionwithlongertreatmentarelacking,and
theoptimaldurationoftherapyhasnotbeendefined.Therefore,justaswiththeotheragents,appropriateselection
ofpatientsfortreatmentisstillanimportantfactor.AstudyoftenofovirDFinyoungerpatientsisplanned.(See
"TenofovirdisoproxilfumarateinthetreatmentofadultswithchronicHBVinfectionwhodonothaveHIV
infection".)
EntecavirislicensedintheUnitedStatesforadolescents16yearsofageandolder.Aphase2studyofthesafetyand
pharmacokineticsofentecavirinchildrenhasbeencompleted[73](NCT00423891)andaphase3studyis
underway(NCT01079806).(See"EntecavirinthetreatmentofchronichepatitisBvirusinfection".)
MANAGEMENTOFACUTEHBVAcuteHBVinfectioninchildrenisgenerallytreatedwithsupportive
managementalone.Therearenodataontreatmentofchildrenwithacuteinfection.Forthosewithsevereacute
hepatitis,treatmentwithanucleoside/tideanalogmightbeconsidered.However,trialsinadultsdidnotshow
clinicalbenefit.ForindividualswithfulminanthepatitiscausedbyHBV,livertransplantmaybenecessary.Therisk
ofreinfectionwithHBVaftertransplantationforfulminantHBVisrelativelylow,incontrasttothehigherriskfor
reinfectionafterlivertransplantationforchronicHBV.(See"LivertransplantationforchronichepatitisBvirus

infection",sectionon'Riskfactorsforreinfection'.)
IMMUNOPROPHYLAXISIssuesrelatedtovaccination,postexposureprophylaxis,andbreastfeedingare
discussedseparately.(See"HepatitisBvirusvaccination"and"Epidemiology,transmission,andpreventionof
hepatitisBvirusinfection"and"Standardimmunizationsforchildrenandadolescents",sectionon'HepatitisB
vaccine'.)
SUMMARYANDRECOMMENDATIONS
IntheUnitedStates,themajorityofchildrenwithchronicHBVinfectionareimmigrantsfromareaswith
endemicHBVinfection(figure1),haveimmigrantparents,orbecameexposedthroughotherhousehold
contacts.PerinataltransmissionofHBVdeclinedsharplyafter1991whenrecommendationsforuniversal
hepatitisBvaccinationofinfantswereimplemented.(See'Epidemiology'above.)
ThenaturalhistoryofchronicHBVinfectioninchildrenisvariable,dependinguponage,modeofacquisition,
ethnicityand/orHBVgenotype.ChildrenwithperinatallyacquiredHBVusuallyremainHBeAgpositiveand
havehighlevelsofviralreplicationforprolongedperiods,althoughhistologicinjuryistypicallymild(figure
3B).Bycontrast,childreninnonendemiccountriestendtohavehigherALTelevationsandfrequentlyclear
HBeAgandHBVDNAfromserumduringthefirsttwodecadesoflife.(See'Naturalhistory'above.)
ThediagnosisofhepatitisBismadebyserologictestingforHBsAgandantiHBc.ThepresenceofHBsAg
indicatesHBVinfection,andthepresenceofIgGantiHBc(withnegativeantiHBcIgM)indicatesthatthe
infectionischronic(figure3Bandtable1A).(See'Clinicalmanifestationsanddiagnosis'above.)
PatientswithserologicevidenceofHBVshouldbefurtherevaluatedwithaminotransferases,HBVDNA,and
HBeAg.Othercausesofliverdiseaseshouldbeexcluded.PatientsshouldbevaccinatedagainsthepatitisAif
notalreadyimmune.(See'Initialevaluation'aboveand'Counselingandprevention'above.)
OnlycarefullyselectedpatientswithchronicHBVinfectionshouldbetreatedduringchildhood.Thisis
becausenoneoftheavailabletreatmentsishighlyefficacious.Furthermore,undersomecircumstances,
treatmentisassociatedwithahighlikelihoodofdrugresistance.Therefore,thechoiceofwhethertotreat
dependsonseveralpatientspecificcharacteristicswhichpredicttheefficacyoftreatment,including
persistentlyabnormalALTlevels,andactivediseaseshownonliverbiopsy(ifperformed),aswellasonthe
patient'svaluesandpreferences(algorithm1).
WesuggestthatpatientswhoareintheimmunetolerantorinactivephasesofchronichepatitisBNOTbe
treated(Grade2B)thisisdefinedasHBsAgpositiveandpersistentlynormalALT/ASTlevels,HBeAg
positiveornegative,eveniftheHBVDNAlevelsarehigh.Instead,theyshouldundergomonitoringofliver
biochemicaltestsevery6to12monthstolookforevidenceofimmuneactivationorreactivationafterHBeAg
seroconversion(figure3A).(See'Selectionofpatientsfortreatment'aboveand'Monitoringofpatients'
above.)
WesuggestthatpatientswithchronichepatitisBintheimmuneactivestagebetreated(Grade2B)the
immuneactivestageisusuallydefinedasALT>2xtheupperlimitofnormalandHBVDNA>20,000IU/mL
or10(5)copies/mL(algorithm1).MostchildrenwiththisprofilewillbeHBeAgpositive(figure3A).
ChildrenwithlowerALTlevelsareunlikelytorespondtotreatment.ThosewithmarkedlyelevatedALT
levels(greaterthan10timestheupperlimitofnormal)andlowHBVDNAlevelsmaybeintheprocessof
spontaneousseroconversion,andthusshouldbeobservedforseveralmonthsbeforeconsideringtreatment.
(See'Selectionofpatientsfortreatment'above.)
Whenadecisiontotreathasbeenmade,interferonalfaisthefirstlinechoiceformostpatientsuntilthenewer
agentsarestudiedandlicensedinchildren.Lamivudineisasecondlinechoice,becauseoflimitedefficacy
andbecauseitislikelytoinducedrugresistancewithlongtermuse.Therefore,lamivudineisgenerallyused
onlyforchildrenwithspecificshorttermrisksforHBVexacerbation,suchasthoseundergoing
chemotherapy.(See'Choiceoftreatment'above.)
NeweragentscurrentlyunderinvestigationforchildrenwithHBVincludethefollowing:
PegylatedinterferonalfaTheefficacyofpegylatedinterferonsinchildrenwithchronicHBVinfectionhas
notbeenestablished.BasedonitsefficacyinadultsandexperienceinusingitfortreatmentofHCVin
children,wefeelthatitisareasonablechoiceforchildrenwithHBVwhoareintheimmuneactivephaseof
HBVinfection,inthecontextofaclinicaltrial.(See'Pegylatedinterferon'above.)
AdefovirdipivoxilLicensedintheUnitedStatesforuseinpatients12yearsofageandolder.Itmaybeused
asprimarytherapy,ortotreatthosewhohavebecomerefractorytolamivudinetreatmentbyaddingadefovir
dipivoxiltoongoinglamivudinetherapy.(See'Adefovirdipivoxil'above.)
Tenofovirdisoproxilfumarate(DF)LicensedintheUnitedStatesforadolescents12yearsandolder,after
demonstratingexcellentviralsuppressionandagoodsafetyprofileintwoyearsofuse.However,data
regardingHBeAgseroconversionarelacking,andtheoptimaldurationoftherapyhasnotbeendefined.(See
'Neweragents'above.)
EntecavirLicensedintheUnitedStatesforadolescents16yearsofageandolder.(See'Neweragents'
above.)
Becauseoflimitedoptionswithcurrentdrugs,itmaybeappropriatetotreatolderadolescentswithimmune
activeHBVwithoneoftheseneweragentsusingadultprotocols,ortoenrollchildreninclinicaltrialsof
neweragents,orevenwithholdtreatmentuntilthepatientisoldenoughtobetreatedasadults(ifliverfibrosis
isonlymild).
WesuggestthatchildrenwithchronichepatitisBbesurveyedperiodicallyfordevelopmentofhepatocellular

carcinoma(Grade1C).Thisisusuallyperformedwithayearlyrightupperquadrantultrasoundandalpha
fetoproteinlevel.(See'HCCsurveillance'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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