decompensation

JournalofHepatology50(2009)xxx–xxx

/locate/jhep

EASLClinicalPracticeGuidelines:

ManagementofchronichepatitisB

EuropeanAssociationfortheStudyoftheLiver*

Keywords:HepatitisBvirus;EASLguidelines;Treatment;Interferonalpha;Nucleoside/nucleotideanalogues

uction

OurunderstandingofthenaturalhistoryofhepatitisB

virus(HBV)infectionandthepotentialfortherapyofthe

lnewandeffective

antiviralagentshavebeenevaluatedandlicendsincethe

EASLInternationalConnsusConferenceonhepatitisB

heldin2002[1].TheobjectiveoftheEASLClinical

PracticeGuidelines(CPGs)istoupdaterecommendations

fortheoptimalmanagementofchronichepatitisB(CHB).

TheCPGsdonotfocusonpreventionandvaccination.

Severaldifficultiesremaininformulatingtreatmentsfor

CHB;rent

timeclinicians,patientsandpublichealthauthoritiesmust

continuetomakechoicesonthebasisofevidencethatis

notfullymatured.

t

iologyandpublichealthburden

Approximatelyonethirdoftheworld’spopulationhasro-

logicalevidenceofpastorprentinfectionwithHBVand

ctrum

ofdiaandnaturalhistoryofchronicHBVinfectionis

diverandvariable,rangingfromalowviremicinactive

carrierstatetoprogressivechronichepatitis,whichmay

evolvetocirrhosisandhepatocellularcarcinoma(HCC).

HBV-relatedendstageliverdiaorHCCareresponsible

forover1milliondeathsperyearandcurrentlyreprent

5−10%ofcasoflivertransplantation[2−5].Hostand

viralfactors,aswellascoinfectionwithothervirus,

inparticularhepatitisCvirus(HCV),hepatitisDvirus

*EASLLiaisonBureau,c/oKenesInternational,1−3ruedeChante-

poulet,POBox1726,CH-1211Geneva,Switzerland.

Tel:+41229069151;fax:+41227322852.

E-mailaddress:easlliaisonbureau@.

(HDV),orhumanimmunodeficiencyvirus(HIV)together

withotherco-morbiditiesincludingalcoholabuand

overweight,canaffectthenaturalcourofHBVinfection

aswellastheefficacyofantiviralstrategies.

CHBmayprenteitherashepatitisBeantigen

(HBeAg)--positive

CHBisduetoso-called“wildtype”cally

reprentstheearlyphaofchronicHBVinfection.

HBeAg-negativeCHBisduetoreplicationofnaturally

occurringHBVvariantswithnucleotidesubstitutionsinthe

precoreand/orbasiccorepromoterregionsofthegenome

prevalenceoftheHBeAg-negativeformofthediahas

beenincreasingoverthelastdecadeasaresultofHBV-

infectedpopulationagingandreprentsthemajorityof

casinmanyareas,includingEurope[6−8].

MorbidityandmortalityinCHBarelinkedtopersistence

-

gitudinalstudiesofpatientswithCHBindicatethat,after

diagnosis,the5-yearcumulativeincidenceofdeveloping

cirrhosisrangesfrom8to20%.The5-yearcumulative

incidenceofhepaticdecompensationisapproximately20%

withthe5-yearprobabilityofsurvivalbeingapproximately

80−86%inpatientswithcompensatedcirrhosis[4,9−13].

Patientswithdecompensatedcirrhosishaveapoorprog-

nosiswitha14−35%probabilityofsurvivalat5years.

TheworldwideincidenceofHCChasincread,mostly

duetoHBVandHCVinfections;prentlyitconstitutes

thefifthmostcommoncancer,reprentingaround5%of

ualincidenceofHBV-relatedHCC

inpatientswithCHBishigh,rangingfrom2%to5%

whencirrhosisistablished[13].However,theincidence

ofHBV-relatedHCCappearstovarygeographicallyand

correlateswiththeunderlyingstageofliverdia.

Populationmovementsandmigrationarecurrently

changingtheprevalenceandincidenceofthediain

verallowendemicitycountriesinEuropeandelwhere.

0168-8278/$34.00©htsrerved.

doi:10.1016/.2008.10.001

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

2EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx

Substantialhealthcareresourceswillberequiredforcontrol

oftheworldwideburdenofdia.

lhistory

ural

historyofCHBcanbeschematicallydividedintofive

phas,whicharenotnecessarilyquential.

(1)The“immunetolerant”phaischaracterizedby

HBeAgpositivity,highlevelsofHBVreplication

(reflectedbyhighlevelsofrumHBVDNA),normal

orlowlevelsofaminotransferas,mildornoliver

necroinflammationandnoorslowprogressionof

fibrosis[3,5].Duringthispha,therateofspontaneous

firstphaismore

frequentandmoreprolongedinsubjectsinfected

perinatallyorinthefieofhigh

levelsofviremia,thepatientsarehighlycontagious.

(2)The“immunereactivepha”ischaracterizedby

HBeAgpositivity,alowerlevelofreplication(as

reflectedbylowerrumHBVDNAlevels),incread

orfluctuatinglevelsofaminotransferas,moderate

orverelivernecroinflammationandmorerapid

progressionoffibrosiscomparedtotheprevious

pha[3,5].Itmaylastforveralweekstoveral

tion,therateofspontaneousHBeAgloss

amayoccurafterveralyears

ofimmunetoleranceandismorefrequentlyreachedin

subjectsinfectedduringadulthood.

(3)The“inactiveHBVcarrierstate”mayfollowro-

ischaracterizedbyveryloworundetectablerum

resultofimmunologicalcontroloftheinfection,this

stateconfersafavourablelong-termoutcomewitha

verylowriskofcirrhosisorHCCinthemajorityof

ossandroconversiontoanti-HBs

antibodiesmayoccurspontaneouslyin1−3%ofcas

peryear,usuallyafterveralyearswithpersistently

undetectableHBVDNA[14].

(4)“HBeAg-negativeCHB”mayfollowroconversion

fromHBeAgtoanti-HBeantibodiesduringtheimmune

reactivephaandreprentsalaterphainthe

aracterizedbyperiodic

reactivationwithapatternoffluctuatinglevelsof

HBVDNAandaminotransferasandactivehepati-

atientsareHBeAg-negative,andharbour

HBVvariantswithnucleotidesubstitutionsinthe

precoreand/orthebasalcorepromoterregionsunable

-

negativeCHBisassociatedwithlowratesofprolonged

portantand

sometimesdifficulttodistinguishtrueinactiveHBV

carriersfrompatientswithactiveHBeAg-negativeCHB

inwhomphasofspontaneousremissionmayoccur.

Theformerpatientshaveagoodprognosiswithavery

lowriskofcomplications,whilethelatterpatientshave

activeliverdiawithahighriskofprogression

toadvancedhepaticfibrosis,cirrhosisandsubquent

complicationssuchasdecompensatedcirrhosisand

ulasssmentofthepatientisneeded

andaminimalfollow-upofoneyearwithrum

alanineaminotransfera(ALT)andHBVDNAlevels

every3monthsusuallyallowsdetectionoffluctuations

ofactivityinpatientswithactiveHBeAg-negative

CHB[15].

(5)Inthe“HBsAg-negativepha”afterHBsAgloss,

low-levelHBVreplicationmaypersistwithdetectable

HBVDNAintheliver[16].Generally,HBVDNAis

notdetectableintherumwhileanti-HBcantibodies

oss

isassociatedwithimprovementoftheoutcomewith

reducedriskofcirrhosis,decompensationandHCC.

TheclinicalrelevanceofoccultHBVinfection(de-

tectableHBVDNAintheliverwithlow-level[<200

internationalunits(IU)/ml]HBVDNAinblood)isun-

clear[16].Immunosuppressionmayleadtoreactivation

inthepatients[17,18].

ology

TheEASLCPGshavebeendevelopedbyaCPGPanel

ofexpertschonbytheEASLGoverningBoard;the

recommendationswerepeer-reviewedbyexternalexpert

reviewersandapprovedbytheEASLGoverningBoard.

TheCPGshavebeenbadasfaraspossibleonevidence

fromexistingpublications,and,ifevidencewasunavailable,

theexperts’ripts

andabstractsofimportantmeetingspublishedpriorto

denceand

recommendationsintheguidelineshavebeengraded

accordingtotheGradingofRecommendationsAsss-

mentDevelopmentandEvaluation(GRADE)

strengthofrecommendationsthusreflectsthequalityof

nciplesoftheGRADEsystem

lityoftheevidencein

theCPGshasbeenclassifiedinoneofthreelevels:

high(A),moderate(B)orlow(C).TheGRADEsystem

offerstwogradesofrecommendation:strong(1)or

weak(2)(Table1).TheCPGsthusconsiderthequality

ofevidence:thehigherthequalityofevidence,themore

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx3

Table1

Gradingofevidenceandrecommendations(adaptedfromtheGRADEsystem)[19−25]

NotesSymbol

Gradingofevidence

High-qualityevidenceFurtherrearchisveryunlikelytochangeourconfidenceintheestimateofeffectA

Moderate-qualityevidenceFurtherrearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectand

maychangetheestimate

B

Low-orverylow-qualityevidenceFurtherrearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateof

imateofeffectisuncertain

C

Gradingofrecommendation

StrongrecommendationwarrantedFactorsinfluencingthestrengthoftherecommendationincludedthequalityoftheevidence,

presumedpatient-importantoutcomes,andcost

1

WeakerrecommendationVariabilityinpreferencesandvalues,ormoreuncertainty:morelikelyaweakrecommendationis

warranted.

Recommendationismadewithlesscertainty;highercostorresourceconsumption

2

likelyastrongrecommendationiswarranted;thegreater

thevariabilityinvaluesandpreferences,orthegreaterthe

uncertainty,themorelikelyaweakerrecommendationis

warranted[19−25].

TheCPGPanelmembersconsideredthefollowing

questions:

•Howshouldliverdiabeassdbeforetherapy?

•Whatarethegoalsandend-pointsoftreatment?

•Whatarethedefinitionsofrespon?

•Whatistheoptimalapproachtofirst-linetreatment?

•Whatarethepredictorsofrespon?

•Whatdefinitionsofresistanceshouldbeappliedand

howshouldresistancebemanaged?

•Howshouldtreatmentbemonitored?

•Whencantreatmentbestopped?

•Howshouldspecialgroupsbetreated?

•Whatarethecurrentunresolvedissues?

ines

rapeuticasssmentofliverdia

Asafirststep,thecausalrelationshipbetweenHBV

infectionandliverdiahastobeestablishedandan

asssmentoftheverityofliverdianeedstobe

patientswithCHBhavepersistently

tsintheimmunetol-

erantphahavepersistentlynormalALTlevelsanda

proportionofpatientswithHBeAg-negativeCHBmayhave

oreappropriate,

longitudinallong-termfollow-upiscrucial.

(1)Theasssmentoftheverityoftheliverdia

shouldinclude:biochemicalmarkers,includingas-

partateaminotransfera(AST)andALT,gamma-

glutamyltranspeptida(GGT),alkalinephosphata,

prothrombintimeandrumalbumin;bloodcounts;

andhepaticultrasound.(A1)Usually,ALTlevelsare

r,whenthedia

progresstocirrhosis,theratiomaybereverd.

Aprogressivedeclineinrumalbuminconcentrations

andprolongationoftheprothrombintime,oftenaccom-

paniedbyadropinplateletcounts,arecharacteristically

obrvedaftercirrhosishasdeveloped.

(2)HBVDNAdetectionandHBVDNAlevelmeasurement

isntialforthediagnosis,decisiontotreatand

subquentmonitoringofpatients.(A1)Follow-up

usingreal-timePCRquantificationassaysisstrongly

recommendedbecauoftheirnsitivity,specificity,

accuracyandbroaddynamicrange[26−29].(A1)The

WorldHealthOrganization(WHO)hasdefinedan

internationalstandardfornormalisationofexpression

ofHBVDNAconcentrations[30].SerumHBVDNA

levelsshouldbeexpresdinIU/mltoensurecompara-

bility;thesameassayshouldbeudinthesamepatient

toevaluateantiviralefficacy.(A1)

(3)Othercausofchronicliverdiashouldbesys-

tematicallylookedforincludingcoinfectionwithHDV,

HCVand/-morbidities,includingalcoholic,

autoimmune,metabolicliverdiawithsteatosisor

steato-hepatitisshouldbeassd.(A1)

(4)Aliverbiopsyisrecommendedfordeterminingthede-

greeofnecroinflammationandfibrosisinpatientswith

eitherincreadALTorHBVDNAlevels>2000IU/ml

(orboth)sincehepaticmorphologycanassistthe

decisiontostarttreatment.(A1)Biopsyisalsouful

forevaluatingotherpossiblecausofliverdiasuch

ghliverbiopsyis

aninvasiveprocedure,theriskofverecomplications

isverylow(1/4,000–10,000).Itisimportantthatthe

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

4EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx

sizeoftheneedlebiopsyspecimenbelargeenough

toprecilyanalythedegreeofliverinjuryand

fibrosis[31].(A1)Aliverbiopsyisusuallynotrequired

inpatientswithclinicalevidenceofcirrhosisorin

thoinwhomtreatmentisindicatedirrespectiveofthe

gradeofactivityorthestageoffibrosis.(A1)There

isgrowinginterestintheuofnon-invasivemethods,

includingrummarkersandtransientelastography,to

assshepaticfibrosistocomplementoravoidaliver

biopsy[32−36].

therapy

ThegoaloftherapyforhepatitisBistoimprovequality

oflifeandsurvivalbypreventingprogressionofthe

diatocirrhosis,decompensatedcirrhosis,end-stage

liverdia,alcanbeachieved

ifHBVreplicationcanbesuppresdinasustained

manner,theaccompanyingreductioninhistologicalactivity

ofchronichepatitislesningtheriskofcirrhosisand

decreasingtheriskofHCCinnon-cirrhoticpatients

andprobablyalso,buttoalesrextent,incirrhotic

patients[37].(B1)However,HBVinfectioncannotbe

completelyeradicatedduetothepersistenceofcovalently

clodcircularDNA(cccDNA)inthenucleusofinfected

hepatocytes.

-pointsoftherapy

TherapymustreduceHBVDNAtoaslowalevelas

possible,ideallybelowthelowerlimitofdetectionofreal-

timePCRassays(10−15IU/ml),toensureadegreeof

virologicalsuppressionthatwillthenleadtobiochemical

remission,histologicalimprovementandpreventionof

eronalphaornucleoside/nucleotide

analogue(NUC)therapy-inducedHBVDNAreductionto

ned

HBVDNAreductiontoundetectablelevelsisnecessaryto

increasthe

chanceofHBeroconversioninHBeAg-positivepatients

andthepossibilityofHBsAglossonthemidtolongtermin

-time

PCRisunavailable,HBVDNAshouldbemeasuredbythe

mostnsitiveassaypossible.

(1)InHBeAg-positiveandHBeAg-negativepatients,the

idealend-pointoftherapyissustainedHBsAgloss

associatedwithacompleteanddefinitiveremissionof

theactivityofchronichepatitisBandanimproved

long-termoutcome.(A1)

(2)InHBeAg-positivepatients,durableHBeroconver-

sionisasatisfactoryend-pointbecauithasbeen

showntobeassociatedwithimprovedprognosis.(A1)

(3)InHBeAg-positivepatientswhodonotachieveHBe

roconversion,andinHBeAg-negativepatients,a

maintainedundetectableHBVDNAlevelontreatment

withNUCsorasustainedundetectableHBVDNA

levelafterinterferontherapyisthenextmostdesirable

end-point.(A1)

finitionsofrespon

Twodifferenttypesofdrugscanbeudinthetreatmentof

CHB:interferonalphaandnucleoside/nucleotideanalogues

definitionofrespontoantiviraltherapyvariesaccording

tothetypeoftherapy.

(1)Oninterferonalphatherapy:

•Primarynon-responisdefinedaslessthan

1log

10

IU/mldecreainHBVDNAlevelfrom

balineat3monthsoftherapy.

•VirologicalresponisdefinedasanHBVDNA

concentrationoflessthan2000IU/mlat24weeks

oftherapy.

•SerologicalresponisdefinedbyHBeroconver-

sioninpatientswithHBeAg-positiveCHB.

(2)OnNUCtherapy:

•Primarynon-responisdefinedaslessthan

1log

10

IU/mldecreainHBVDNAlevelfrom

balineat3monthsoftherapy.

•Virologicalresponisdefinedasundetectable

HBVDNAbyreal-timePCRassaywithin48weeks

oftherapy.

•Partialvirologicalresponisdefinedasade-

creainHBVDNAofmorethan1log

10

IU/ml

butdetectableHBVDNAbyreal-timePCRassay.

Apartialvirologicalresponshouldbeassd

tomodifytherapyat24weeksoftreatmentfor

moderatelypotentdrugsordrugswithalowgenetic

barriertoresistance(lamivudineandtelbivudine)

andat48weeksoftreatmentforhighlypotent

drugs,drugswithahighergeneticbarrierto

resistanceordrugswithalateemergenceof

resistance(entecavir,adefovirandtenofovir).

•Virologicalbreakthroughisdefinedasacon-

firmedincreainHBVDNAlevelofmorethan

1log

10

IU/mlcomparedtothenadir(lowestvalue)

HBVDNAlevelontherapy;itusuallyprecedes

abiochemicalbreakthrough,characterizedbyan

ncausof

virologicalbreakthroughonNUCtherapyarepoor

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx5

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

HBeroconversionUndetectableHBVDNANormalALT

30%

22%

24%

22%

26%

21%

24%

39%

21%

67%

60%

74%

39%

66%

48%

68%

77%

69%

fHBeroconversion,undetectableHBVDNAandnormalALTatoneyearoftherapywithpegylatedinterferonalpha-2a(PEG-IFN),

lamivudine(LAM),adefovir(ADV),entecavir(ETV),telbivudine(LdT)andtenofovir(TDF)inHBeAg-positivepatientswithCHBinrandomized

rialsuddifferentHBVDNAassaysandtheywerenothead-to-headcomparisonsforallthedrugs.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

UndetectableHBVDNANormalALT

63%

72%

51%

90%

88%

91%

38%

74%

72%

78%

74%

77%

fundetectableHBVDNAandnormalALTatoneyearoftherapywithpegylatedinterferonalpha-2a(PEG-IFN),lamivudine(LAM),

adefovir(ADV),entecavir(ETV),telbivudine(LdT)andtenofovir(TDF)

trialsuddifferentHBVDNAassaysandtheywerenothead-to-headcomparisonsforallthedrugs.

adherencetotherapyandlectionofdrug-resistant

HBVvariants(resistance).(A1)

•HBVresistancetoNUCsischaracterizedbylec-

tionofHBVvariantswithaminoacidsubstitutions

thatconferreducedsusceptibilitytotheadminis-

teredNUC(s).Resistancemayresultinprimary

treatmentfailureorvirologicalbreakthroughon

therapy.(A1)

sofcurrenttherapies

Sevendrugsarenowavailableforthetreatmentofchronic

hepatitisB:theyincludeconventionalinterferonalpha,

rHBV

therapybelongtothreeclass:L-nucleosides(lamivudine,

telbivudine,andemtricitabine),deoxyguanosineanalogues

(entecavir)andacyclicnucleosidephosphonates(adefovir

andtenofovir).Lamivudine,adefovir,entecavir,telbivudine

andtenofovirhavebeenapprovedinEuropeforHBVtreat-

ment,andthecombinationoftenofovirandemtricitabine

inonetablethasbeenlicendforthetreatmentofHIV

infection.

Theefficacyofthedrugshasbeenassdin

randomizedcontrolledtrialsatoneyear(twoyearswith

telbivudine).Longer-termresults(upto5years)are

availableforlamivudine,adefovir,entecavir,telbivudine

s1and2show

trialsuddifferentHBVDNAassaysandtheywerenot

head-to-headcomparisonsforallthedrugs.

(1)InHBeAg-positivepatients,virologicalresponrates

atoneyear(definedvariouslyinthedifferenttrials

anddifferentlyfromtheprentguidelines)were24%,

36−39%,21%,67%,60%and74%withpegylated

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

6EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx

interferonalpha-2a/2b,lamivudine,adefovir,entecavir,

telbivudineandtenofovir,respectively(Fig.1)[38−44].

HBeroconversionrateswereoftheorderof30%

withconventionalandpegylatedinterferonalphaand

approximately20%oconversion

ratesincreawithcontinuedNUCstreatment,butare

affectedifresistanceoccurs.(B1)LossofHBsAgrates

afteroneyearwere3−4%withpegylatedinterferon

alpha,0%withlamivudine,adefovir,entecavir,and

telbivudine,and3%withtenofovir.

(2)InHBeAg-negativepatients,virologicalresponrates

atoneyear(definedvariouslyinthedifferenttrialsand

differentlyfromtheprentguidelines)were63%,72%,

51%,90%,88%and91%withpegylatedinterferon

alpha-2a,lamivudine,adefovir,entecavir,telbivudine

andtenofovir,respectively(Fig.2)[41,45−49].Lossof

HBsAgratesafteroneyearwere3%withpegylated

interferonalphaand0%withlamivudine,adefovir,

entecavir,telbivudineortenofovir.

tionsfortreatment

Theindicationsfortreatmentaregenerallythesamefor

badmainlyonthecombinationofthreecriteria:

•SerumHBVDNAlevels.

•Serumaminotransferalevels.

•Histologicalgradeandstage.

Patientsshouldbeconsideredfortreatmentwhen

HBVDNAlevelsareabove2000IU/ml(imately

10,000copies/ml)and/ortherumALTlevelsareabove

theupperlimitofnormal(ULN)forthelaboratory,and

liverbiopsy(ornon-invasivemarkerswhenvalidatedin

HBV-infectedpatients)showsmoderatetovereactive

necroinflammationand/orfibrosisusingastandardid

scoringsystem(forexampleatleastgradeA2orstageF2

byMETAVIRscoring).(A1)Indicationsfortreatmentmust

alsotakeintoaccountage,healthstatus,andavailabilityof

anti-viralagentsinindividualcountries.

Thefollowingspecialgroupsofpatientsshouldbe

considered:

•Immunotolerantpatients:mostpatientsunder30years

ofagewithpersistentlynormalALTlevelsandahigh

HBVDNAlevel(usuallyabove107IU/ml),withoutany

suspicionofliverdiaandwithoutafamilyhistoryof

HCCorcirrhosisdonotrequireimmediateliverbiopsy

-upismandatory.(B1)

•PatientswithmildCHB:patientswithslightlyelevated

ALT(lessthan2timesULN)andmildhistological

lesions(lessthanA2F2withMETAVIRscoring)may

-upismandatory.(B1)

•Patientswithcompensatedcirrhosisanddetectable

HBVDNAmaybeconsideredfortreatmenteven

ifALTlevelsarenormaland/orHBVDNAlev-

elsarebelow2000IU/ml(imately10,000

copies/ml).(B1)

•Patientswithdecompensatedcirrhosisrequireurgent

ndprofoundviralsup-

pressionandefficaciouspreventionofresistanceare

ficantclinical

improvementcanbeassociatedwithcontrolofviral

replication,butpatientswithveryadvancedliverdia

maynotalwaysbenefitiftreatedatthislatestageand

shouldbeconsideredforlivertransplantation.(A1)

torsofrespon

Certaingeneralbalineandon-treatmentpredictorsof

subquentresponhavebeenidentifitorsof

responfortheexistingantiviraltherapiesatvarioustime

pointsvaryfordifferentagents.

(1)Forinterferonalpha-badtreatment:

•Pre-treatmentfactorspredictiveofHBeroconver-

sionarelowviralload(HBVDNAbelow107IU/ml

or7log

10

IU/ml),highrumALTlevels(above

3timesULN),andhighactivityscoresonliver

biopsy(atleastA2)[50−52].(B2)

•Duringtreatment,anHBVDNAdecreatoless

than20,000IU/mlat12weeksisassociatedwith

a50%chanceofHBeroconversioninHBeAg-

positivepatientsandwitha50%chanceofsus-

tainedresponinHBeAg-negativepatients[53,

54].

•Duringtreatment,HBeAgdecreaatweek24may

predictHBeroconversion[54,55].(B2)

•Furtherstudiesareneededtodeterminetheroleof

HBsAgquantitationtopredictsustainedvirological

responandHBsAgloss.

•HBVgenotypeAandBhavebeenshowntobe

associatedwithabetterrespontointerferonalpha

thangenotypesCandD[56].However,theHBV

genotypehasapoorindividualpredictivevalueand

currently,genotypealoneshouldnotoverridethe

choiceoftreatment.(B2)

(2)ForNUCstreatment:

•Pre-treatmentfactorspredictiveofHBeroconver-

sionarelowviralload(HBVDNAbelow107IU/ml

or7log

10

IU/ml),highrumALTlevels(above

3timesULN),highactivityscoresonliverbiopsy

(atleastA2)[52].

•Duringtreatmentwithlamivudine,adefoviror

telbivudine,avirologicalresponat24or48

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx7

Table2

MainrespectiveadvantagesanddisadvantagesofpegylatedinterferonalphaandNUCsinthetreatmentofCHB

PegylatedinterferonalphaNUCs

AdvantagesFiniteduration

Abnceofresistance

HigherratesofHBeandHBsroconversion

Potentantiviraleffect

Goodtolerance

Oraladministration

DisadvantagesModerateantiviraleffect

Poortolerance

Subcutaneousinjections

Indefiniteduration

Riskofresistance

LowerratesofHBeandHBsroconversion

weeks(undetectableHBVDNAinareal-timePCR

assay)isassociatedwithalowerincidenceof

resistance,ovedchanceofmaintained

virologicalrespon,andHBeroconversionin

HBeAg-positivepatients[41,46,57].(B1)

•HBVgenotypedoesnotinfluencetheresponto

anyNUC.

entstrategies:how-to-treat

Themaintheoreticaladvantagesofinterferonalpha(con-

ventionalorpegylated)aretheabnceofresistanceand

thepotentialforimmune-mediatedcontainmentofHBV

infectionwithanopportunitytoobtainasustainedvirolog-

icalresponoff-treatmentandachanceofHBsAglossin

patientswhoachieveandmaintainundetectableHBVDNA.

Frequentsideeffectsandsubcutaneousinjectionarethe

eron

alphaiscontraindicatedinpatientswithdecompensated

HBV-relatedcirrhosisorautoimmunediaandintho

withuncontrolledveredepressionorpsychosis.(A1)

EntecavirandtenofovirarepotentHBVinhibitorsand

theyhaveahighbarriertoresistance[38,58,59].Thusthey

canbeconfidentlyudasfirst-linemonotherapies.(A1)

Theroleofmonotherapywithentecavirortenofovircould

bemodifiedifhigherratesofresistancebecomeapparent

withlongertreatmentduration.

Adefovirismoreexpensivethantenofovir,isless

efficacious,andengendershigherratesofresistance.(A1)

TelbivudineisapotentinhibitorofHBVbut,dueto

alowgeneticbarriertoresistance,ahighincidence

ofresistancehasbeenobrvedinpatientswithhigh

balinelevelsofreplicationandinthowithdetectable

HBVDNAafter24weeksoftherapy[41].(A1)Lamivudine

isaninexpensiveagent,butengendersveryhighratesof

resistancewithmonotherapy[60,61].(A1)

Severaltreatmentoptionxistforindividualpatients,

makingrationalchoicesforfirst-andcond-linetreatment

sometimesdiffiferenttreatmentstrategiesare

applicableinbothHBeAg-positiveandHBeAg-negative

CHBpatients:treatmentoffinitedurationwithpegylated

interferonalphaorNUCsandlong-termtreatmentwith

NUCs.

(1)Treatmentoffinitedurationwithpegylatedinterferon

rategyisintendedtoachievea

sustainedvirologicalresponoff-treatment.(A1)

•Finite-durationtreatmentwithpegylatedinterferon

alpha:a48-weekcourofpegylatedinterferon

alphaismainlyrecommendedforHBeAg-positive

patientswiththebestchanceofHBerocon-

lsobeudforHBeAg-negative

patientswhohavethebestchanceofasustained

groups,thearepa-

tientswithhighbalineALT(>3timesULN)and

HBVDNAlessthan2×106IU/ml(approximately

107copies/ml)or6.3log

10

IU/

informationabouttheadvantages,adverevents

andinconveniencesofpegylatedinterferonalpha

versusNUCs(Table2)shouldbeprovidedsothe

patientcanparticipateinthedecision.(B2)

Thecombinationofpegylatedinterferonalpha

withlamivudineshowedahigheron-treatment

responbutdidnotshowahigherrateofsustained

slimitedinformationonthe

efficacyandsafetyofcombinationofpegylated

interferonalphawithotherNUCsandprentlythis

typeofcombinationisnotrecommended.

•Finite-durationtreatmentwithNUCsisachievable

forHBeAg-positivepatientswhodevelopHBe

r,durationis

unpredictablepriortotherapyasitdependsonwhen

oconversion

ismorefrequentinpatientswithhighbaline

ALT(>3timesULN)andHBVDNAlessthan

2×106IU/ml(approximately107copies/ml)or

6.3log

10

IU/mlatbaline.(A1)Anattemptat

finitetreatmentshoulduthemostpotentagents

withthehighestbarriertoresistance(entecavir

ortenofovir)torapidlyreducelevelsofviremia

toundetectablelevelsandavoidreboundsdue

toHBVresistance.(A1)Telbivudinemightbe

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

8EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx

udinpatientswithgoodpredictorsofrespon

(HBVDNA<2×106IU/ml,imately107

copies/ml,or6.3log

10

IU/mlatbaline)withveri-

ficationofHBVDNAsuppressionbelowdetection

e

roconversionoccursonNUC,treatmentshould

beprolongedforanadditional6to(preferentially)

12months;adurablerespon(persistenceofanti-

HBeantibodiesoff-treatment)canbeexpectedin

80%ofthepatients.(B1)

(2)rategyis

necessaryforpatientswhocannotachieveasustained

virologicalresponoff-treatmentandrequireextended

therapy,Ag-positivepatientswhodonot

developHBeroconversionandinHBeAg-negative

rategyisalsorecommendedinpatients

withcirrhosisirrespectiveofHBeAgstatusorHBe

roconversionontreatment.(A1)

Themostpotentdrugswiththeoptimalresistance

profile,virorentecavir,shouldbeudas

first-linemonotherapies.(A1)Itisoptimaltomaintain

HBVDNAsuppressiontoundetectableHBVDNAin

real-timePCR,whateverthedrugud.(B1)Thelong-

termeffects,safetyandtolerabilityofentecavirand

tenofovir(fivetotenyears)arestillunknown.

Thereareasyetnodatatoindicateanadvantage

ofdenovocombinationtreatmentwithNUCsinnaive

patientsreceivingeitherentecavirortenofovir.(C1)

pertsrec-

ommendadenovocombinationtherapyapproach

topreventpotentialresistanceinpatientswitha

highlikelihoodofdevelopingresistance(highbaline

HBVDNAlevels)orinwhomtheoccurrenceof

viralresistancewouldbelife-threateningduetothe

underlyingcondition(cirrhosis).However,thelong-

termsafetyofthecombinationofNUCs,andin

particularofthecombinationofentecavirandtenofovir

isunknownandthisapproachiscostly.(B2)Tenofovir

pluslamivudine,ortenofovirplumtricitabinein

onetablet,maybeconsidereddenovoforthe

patients.(C1)

entfailure

Itisimportanttodistinguishbetweenprimarynon-respon

(lessthan1log

10

dropofHBVDNAat12weeks),partial

virologicalrespon(detectableHBVDNAonreal-time

PCRassayduringcontinuoustherapy)andvirological

breakthroughduetoantiviraldrugresistance[29,62].

(1)ynon-responems

tobemorefrequentwithadefovir(approximately

10−20%)thanwithotherNUCsbecauofsuboptimal

switchtotenofovirorentecaviris

recommended.(B1)Primarynon-responisrarely

obrvedwithlamivudine,telbivudine,entecaviror

entswithprimarynon-respon,itis

pliant

patientwithaprimarynon-respon,identificationof

possibleHBVresistancemutationscanformulatea

rescuestrategythatmustreasonablybebadonan

earlychangetoamorepotentdrugthatisactiveagainst

theresistantHBVvariant.(B1)

(2)lvirologicalrespon

entsreceiving

lamivudine,adefovirortelbivudinewithapartial

virologicalresponatweek24,twostrategiescan

beud:changetoamorepotentdrug(entecaviror

tenofovir)oradditionofamorepotentdrugthatdoes

notsharecross-resistance(addtenofovirtolamivudine

ortelbivudine,oraddentecavirtoadefovir).(A1)In

patientsreceivingentecavirortenofovirwithapartial

virologicalresponatweek48,someexpertswould

suggestaddingtheotherdruginordertoprevent

resistanceinthelongterm.(C1)Thelong-termsafety

oftenofovirandentecavirincombinationishowever

unknown.

(3)gicalbreakthroughin

ofresistanceatupto5yearsofadministration

-

tanceisassociatedwithpriortreatmentwithNUCs

(i.e.,lamuvidine,adefovir,telbivudine,emtricitabine)

or,intreatment-naivepatients,withhighbaline

HBVDNAlevels,aslowdeclineinHBVDNAand

-

tanceshouldbeidentifiedaarlyaspossiblebefore

clinicalbreakthrough(increadALT)bymeansof

HBVDNAmonitoring,andifpossibleidentification

ofthepatternofresistancemutationsshouldbeud

,clinicaland

virologicalstudieshavedemonstratedthebenefitof

anearlytreatmentadaptation,assoonasviralload

increas[52,63].(A1)

Incaofresistance,anappropriaterescuetherapy

shouldbeinitiatedwiththemosteffectiveantiviraleffect

andtheminimalrisktoinducemultipledrug-resistant

ore,adding-onaconddrugwithoutcross-

resistanceistheonlyeffi3shows

cross-resistancedataforthemostfrequentresistantHBV

variants[64].Thesafetyofsomecombinationsinthe

longtermisunknown.

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx9

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

24%

38%

49%

67%

70%

0%

3%

11%

18%

29%

0.5%

1.2%

1.2%

1.2%

4%

22%

0%

LAMADVETVLdTTDF

0.2%

0%

Year1

Year2

Year3

Year4

Year5

tiveincidenceofHBVresistancetolamivudine(LAM),adefovir(ADV),entecavir(ETV),telbivudine(LdT)andtenofovir(TDF)in

hodofcalculation,eref.[29].Thetrialsincludeddifferentpopulations,uddifferent

exclusioncriteriaanddifferentfollow-upendpoints.

Table3

Cross-resistancedataforthemostfrequentresistantHBVvariants.

Theamino-acidsubstitutionprofilesareshownintheleftcolumn

andthelevelofsusceptibilityisgivenforeachdrug:S(nsitive),

I(intermediate/reducedsusceptibility),R(resistant)[64].

HBVvariantLevelofsusceptibility

L

a

mi

v

u

d

i

n

e

T

e

l

b

i

v

u

d

i

n

e

E

n

t

e

c

a

v

i

r

A

d

e

f

o

v

i

r

T

e

n

o

f

o

v

i

r

Wild-typeSSSSS

M204IRRI/RSS

L180M+M204VRRISS

A181T/VISSRS

N236TSSSRI

L180M+M204V/I±I169T±V173L±M250VRRRSS

L180M+M204V/I±T184G±S202I/GRRRSS

•Lamivudineresistance:addtenofovir(addadefovirif

tenofovirnotyetavailable).(B1)

•Adefovirresistance:itisrecommendedtoswitchto

tenofovirifavailableandaddaconddrugwithout

236Tsubstitutionisprent,

addlamivudine,entecavirortelbivudineorswitchto

tenofovirplumtricitabine(inonetablet).(C1)If

anA181T/Vsubstitutionisprent,addentecavir(the

safetyofthetenofovir–entecavircombinationisun-

known)orswitchtotenofovirplumtricitabine.(B1)

•Telbivudineresistance:addtenofovir(addadefovirif

tenofovirnotyetavailable).Thelong-termsafetyof

thecombinationsisunknown.(C1)

•Entecavirresistance:Addtenofovir(thesafetyofthis

combinationisunknown).(C1)

•Tenofovirresistance:resistancetotenofovirhasnotbeen

commendedthatgenotyping

andphenotypingbedonebyanexpertlaboratory

todeterminethecross-resistanceprofivir,

telbivudine,lamivudineoremtricitabinecouldbeadded

(thesafetyofthecombinationsisunknown).(B1)

onitortreatmentandstoppingpoints

therapywithpegylatedinterferonalpha

Inpatientstreatedwithpegylatedinterferonalpha,full

bloodcountsandrumALTlevelsshouldbemonitored

BVDNAlevelshouldbeassdat

weeks12and24toverifyprimaryrespon.

•InHBeAg-positivepatients,HBeAgandanti-HBe

antibodiesshouldbecheckedatweeks24and48

oconversion

togetherwithALTnormalizationandrumHBVDNA

below2000IU/ml(approximately10,000copies/ml),

i.e.3.3log

10

IU/ml,isthedesiredoutcome.(A1)Un-

detectablerumHBVDNAbyreal-timePCRduring

follow-upistheoptimaloutcomesinceitisasso-

-

positivepatientswhodevelopHBeroconversionwith

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

10EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx

pegylatedinterferonorNUCsrequirelongfollow-up

becauofthepossibilityofHBeroreversionor

houldbe

checkedat6-monthintervalsafterHBeroconversion

tativeHBsAg

ofaprimary

non-respon,etoachievea1log

10

reduction

frombalineat12weeks,interferontreatmentshould

bestoppedandreplacedbyaNUC.(B1)

•HBeAg-negativepatientsshouldbesimilarlymonitored

forefficacyandsafetythrough48weeksoftreatment.

AvirologicalresponwithHBVDNA<2000IU/ml

(approximately10,000copies/ml),i.e.3.3log

10

IU/ml,

isgenerallyassociatedwithremissionoftheliver

ctableHBVDNAinreal-timePCRis

theidealdesiredoff-treatmentsustainedresponwith

ahighprobabilityofHBsAglossinthelongerterm.

HBsAgshouldbecheckedat6-monthintervalsif

HBVDNAisundetectable.(B1)

Allpatientstreatedwithpegylatedinterferonalpha

shouldbemonitoredfortheknownadvereffectsof

interferon.

treatmentwithNUCsinHBeAg-positive

patients

TheobjectiveoffinitetreatmentwithNUCsisHBe

shouldbemeasuredevery12

suppressiontoundetectablelevelsin

real-timePCRandsubquentHBeroconversionis

associatedwithbiochemicalandhistologicalrespons.

StudieshavesuggestedthatNUCtherapycanbestopped24

to48weeksafterHBeroconversion.(B1)HBsAgshould

becheckedat6-monthintervalsafterHBeroconversion.

HBsAglossishoweverrarelyobrvedafterNUCtherapy.

-termtherapywithNUCs

HBVDNAlevelsshouldbemonitoredatweek12to

ascertainvirologicalresponandthenevery12to24

reductiontoundetectablelevelsbyreal-

timePCR(10–15IU/ml)shouldideallybe

monitoringisthus

criticaltodetecttreatmentfailure.(A1)InHBeAg-positive

patients,HBeAgandsubquentlyanti-HBeantibodies

onceHBeAgisnegativeshouldbemeasuredatintervals

of6to12months.

NUCsareclearedbythekidneys,andappropriate

dosingadjustmentsarerecommendedforpatientswith

reducedcreatinineclearance.(A1)Drugconcentrationsare

comparableinpatientswithvaryingdegreesofhepatic

-

erbationsofhepatitisBmayoccurandrequiremore

intensivemonitoring(monthlyinthefirstthreemonths)

etofcomplicationsin

thepatientsrequiresurgentmanagement.(B1)Renal

impairmenthasrarelybeenreportedinpatientswithHIV

infectionreceivinganti-HBVdrugs,orinpatientsreceiving

nephrotoxicdrugsandtreatedwithtenofoviroradefovir

10mg/dayandappropriatemonitoringfornephrotoxicity

anddoadjustmentsisnecessary.

Decreasinbonemineraldensityhaverarelybeenre-

portedinHIV-positivepatientstreatedwithtenofovir.(B2)

-termmonitoringforcar-

hyhasrarely

beenreportedinCHBpatientstreatedwithtelbivudine.

Peripheralneuropathyhasbeenobrvedinpatientstreated

withpegylatedinterferonandtelbivudine;thiscombination

shouldbeavoided.(B1)

entofpatientswithvereliverdia

entofpatientswithcirrhosis

Treatmentofpatientswithcirrhosisshouldnotbebad

onALTlevels,asthemaybenormalinadvanced

eronalphaincreastheriskofpsis

anddecompensationinpatientswithadvancedcirrhosis.

However,interferoncanbeudforthetreatmentofwell

compensatedcirrhosis[65].(A1)TheuofpotentNUCs

withverylowriskofresistance,virorentecavir,

isparticularlyrelevantinthisgroupofpatients.(B1)Clo

monitoringofHBVDNAlevelsisimportantandresistance

mustbepreventedbyaddingaconddrugwithoutcross-

resistanceifHBVDNAisnotundetectableatweek48of

vudinehastobeprescribed(becauoflocal

policy),itshouldbeudincombinationwithadefoviror

preferablytenofovir.(B1)

Hepaticdecompensationmayoccurwithexacerbationsof

diathatmustbedistinguishedfromnon-complianceand

resistance[40].Thuspatientswithcirrhosisrequirelong-

termtherapy,withcarefulmonitoringforresistanceand

flalstudiesindicatethatprolongedandadequate

suppressionofHBVDNAmaystabilizepatientsanddelay

orevenobviateneedfortransplantation[37,66].(B1)Partial

regressionoffibrosishasbeenreported.

entofpatientswithdecompensated

cirrhosis

Patientswithdecompensatedcirrhosisshouldbetreated

inspecializedliverunits,astheapplicationofantiviral

therapyiscomplex,andthepatientsmaybecandidates

-stageliverdiashould

entisindicated

evenifHBVDNAlevelislowinordertoprevent

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx11

NUCswithgoodresistance

profiles(entecavirortenofovir)r,

therearelittledataforthesafetyoftheagentsin

decompensatedcirrhosis.(B1)Patientsmayshowslow

clinicalimprovementoveraperiodof3−r

somepatientswithadvancedhepaticdiawithahigh

Child–PughorMELDscoremayhaveprogresdbeyond

thepointofnoreturn,andmaynotbenefit,thusrequiring

transplantationifpossible[67].Inthatsituation,treatment

withNUCswilldecreatheriskofHBVrecurrenceinthe

graft.

tionofrecurrenthepatitisBafterliver

transplantation

RecurrentHBVinfectioninthetransplantedliverhas

-transplanttherapy

withapotentNUCwithahighbarriertoresistanceis

recommendedforallHBsAg-positivepatientsundergo-

inglivertransplantationforHBV-relatedend-stageliver

diaorHCC,toachievethelowestpossiblelevelof

HBVDNAbeforetransplantation[68−70].(A1)Todate,

lamivudineand/oradefovirhavebeengivenpost-transplant

incombinationwithhepatitisBimmunoglobulin(HBIg).

Thisregimenhasreducedtheriskofgraftinfectionto

lessthan10%.Adefovirhasbeensuccessfullyaddedfor

rcoursandlowerdosof

HBIgandotherformsofprophylaxis,includingadefovir

incombinationwithlamivudineandentecavir,arebeing

ficacyandsafetydatawithnewer,morepotent

NUCswithlowerratesofresistance,virand

tenofovir,havenotbeenpublishedbuttheagentsshould

beconsidered,asprofoundsuppressionandlowratesof

resistanceareadvantageous.(B1)Antiviraltherapyfor

prophylaxisofrecurrenthepatitisBprobablyrequireslife-

longcontinuationoftreatment.(B1)

entinspecialpatientgroups

-infectedpatients

HIV-positivepatientswithCHBareatincreadriskof

cirrhosis[71−76].TreatmentofHIVmayleadtoflaresof

icationsfor

therapyarethesameasinHIV-negativepatients,bad

onHBVDNAlevels,rumALTlevelsandhistological

lesions[77].InagreementwithrecentHIVguidelines,itis

recommendedthatmostcoinfectedpatientsbesimultane-

ouslytreatedforbothHIVandHBVdenovo[78].Tenofovir

andemtricitabine(FTC)together,plusathirdagentactive

againstHIV,areindicated[79].(A1)Inasmallnumber

ofpatients,HBVmayhavetobetreatedbeforeHIV;

adefovirandtelbivudine,whicharenotproventobeactive

againstHIV,dine,entecavirand

tenofovirhaveactivityagainstbothHIVandHBVandare

contraindicatedassingleagentsforhepatitisBincoinfected

patients.(A1)However,ifthedrugswithalowbarrierto

resistancedonotreachthegoalofundetectableHBVDNA,

treatmentofHIVinfectionshouldbeenvisaged.

-infectedpatients

Activeco-infectionwithHDVisconfirmedbytheprence

ofdetectableHDVRNA,immuno-histochemicalstaining

forHDVantigen,eronalpha

(conventionalorpegylated)istheonlydrugeffectiveon

HDVreplication[80−85].Theefficacyofinterferonalpha

therapyshouldbeassdat24weeksbymeasuring

anoneyearoftherapymay

benecessary,butisofunprovenefficacy[86].(B2)A

proportionofpatientsbecomeHDVRNA-negativeoreven

HBsAg-negative,withaccompanyingimprovementinhis-

otherapydoesnotappeartoimpactHDV

replicationandrelateddia.

-infectedpatients

HBVDNAlevelisoftenloworisundetectableand

HCVisresponsiblefortheactivityofchronichepatitis

inmostpatients,tients

shouldreceivepegylatedinterferonalphawithribavirin

asforHCV[87].(B1)Sustainedvirologicalrespon

(SVR)ratesforHCVarebroadlycomparablewithHCV

monoinfectedpatients[88−91].Thereisapotentialriskof

HBVreactivationduringorafterclearanceofHCVthat

mustthenbetreatedwithNUCs.(B1)

everehepatitis

Morethan95−99%ofadultswithacuteHBVinfectionwill

recoverspontaneouslyandroconverttoanti-HBswithout

r,somepatientswithfulminant

hepatitisorvereprotractedsubacutehepaticnecrosismay

benefitforsuchastrategy

maybefoundinasmallnumberofreportswithlamivudine

buttheefficacyisunproven.(B1)Asforchronichepatitis,

morepotentdrugswithalowbarriertoresistance,i.e.

entecavirortenofovir,ationof

r,continuationofanti-

viraltherapyforatleast3monthsafterroconversionto

anti-HBsoratleast6monthsafterHBeroconversion

withoutHBsAglossisrecommended.(B2)Sometimes,the

distinctionbetweentrueacutehepatitisBandreactivation

ofchronichepatitisBmaybedifficultandmayrequire

r,inbothcasNUCtreatmentisthe

treatmentofchoice[92−94].

Pleacitethisarticleinpressas:

inicalPracticeGuidelines:ol50(2009),

doi:10.1016/.2008.10.001

ArticleinPress

12EuropeanAssociationfortheStudyoftheLiver/JournalofHepatology50(2009)xxx–xxx

en

ChronichepatitisBcausbenigndiainmostchildren.

Onlyconventionalinterferonalpha,lamivudineandadefovir

havebeenevaluatedforsafetyandefficacycomparableto

adults[95−98].ThereareongoingstudiesofotherNUCsin

childrentobetterdefinetreatmentstrategiesforchildren.

careworkers

Healthcareworkers,especiallysurgeons,involvedinexpo-

sure-proneprocedureswhoareHBsAg-positivewithHBV

DNA