EASL乙肝诊治指南英文.docx

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EASL乙肝诊治指南英文

JournalofHepatology50（2009）227–242

EASLClinicalPracticeGuidelines:

ManagementofchronichepatitisB

EuropeanAssociationfortheStudyoftheLiver*

Keywords:

HepatitisBvirus;EASLguidelines;Treatment;Interferonalpha;Nucleoside/nucleotideanalogues

1.Introduction

OurunderstandingofthenaturalhistoryofhepatitisB

virus（HBV）infectionandthepotentialfortherapyofthe

resultantdiseasehasimproved.Severalnewandeffective

antiviralagentshavebeenevaluatedandlicensedsincethe

EASLInternationalConsensusConferenceonhepatitisB

heldin2002[1].TheobjectiveoftheseEASLClinical

PracticeGuidelines（CPGs）istoupdaterecommendations

fortheoptimalmanagementofchronichepatitisB

（CHB）.TheCPGsdonotfocusonpreventionandvaccination.

Severaldifficultiesremaininformulatingtreatments

forCHB;thusareasofuncertaintyexist.Atthe

presenttimeclinicians,patientsandpublichealthauthorities

mustcontinuetomakechoicesonthebasisofevidence

thatisnotfullymatured.

2.Context

2.1.

Epidemiology

and

public

health

burden

Approximatelyonethirdoftheworld’spopulation

hasserologicalevidenceofpastorpresentinfectionwith

HBVand350millionpeoplearechronicallyinfected.

Thespectrumofdiseaseandnaturalhistoryofchronic

HBVinfectionisdiverseandvariable,rangingfroma

lowviremicinactivecarrierstatetoprogressivechronic

hepatitis,whichmayevolvetocirrhosisandhepatocellular

carcinoma（HCC）.HBV-relatedendstageliverdis

*

EASLoffice,7ruedesBattoirs,CH1205Geneva,Switzerland.

Tel.:

+41228070360;fax:

+41223280724.

E-mail

address:

easloffice@easloffice.eu

easeorHCCareresponsibleforover1milliondeaths

peryearandcurrentlyrepresent5–10%ofcasesofliver

transplantation[2–5].Hostandviralfactors,aswellas

coinfectionwithotherviruses,inparticularhepatitisC

virus（HCV）,hepatitisDvirus（HDV）,orhumanimmunodeficiency

virus（HIV）togetherwithotherco-morbidities

includingalcoholabuseandoverweight,can

affectthenaturalcourseofHBVinfectionaswellas

theefficacyofantiviralstrategies.

CHBmaypresenteitherashepatitisBeantigen

（HBeAg）-positiveorHBeAg-negativeCHB.HBeAgpositive

CHBisduetoso-called‘‘wildtype”

HBV.It

typicallyrepresentstheearlyphaseofchronicHBV

infection.HBeAg-negativeCHBisduetoreplication

ofnaturallyoccurringHBVvariantswithnucleotide

substitutionsintheprecoreand/orbasiccorepromoter

regionsofthegenomeandrepresentsalaterphaseof

chronicHBVinfection.TheprevalenceoftheHBeAgnegative

formofthediseasehasbeenincreasingover

thelastdecadeasaresultofHBV-infectedpopulation

agingandrepresentsthemajorityofcasesinmany

areas,includingEurope[6–8].

MorbidityandmortalityinCHBarelinkedtopersistence

ofviralreplicationandevolutiontocirrhosisor

HCC.LongitudinalstudiesofpatientswithCHBindicate

that,afterdiagnosis,the5-yearcumulativeincidence

ofdevelopingcirrhosisrangesfrom8to20%.

The5-yearcumulativeincidenceofhepaticdecompensation

isapproximately20%withthe5-yearprobabilityof

Contributors:

ClinicalPracticeGuidelinesPanel:

PatrickMarcellin,

GeoffreyDusheiko,FabienZoulim,RafaelEsteban,StefanosHadziyannis,

PietroLampertico,MichaelManns,DanielShouval,Cihan

Yurdaydin;Reviewers:

AntonioCraxi,XavierForns,DariusMoradpour,

Jean-MichelPawlotsky,JoergPetersen,HeinerWedemeyer.

0168-8278/$34.00

.

2009

Published

by

Elsevier

B.V.

on

behalf

of

the

European

Association

for

the

Study

of

the

Liver.

doi:

10.1016/j.jhep.2008.10.001

European

Association

for

the

Study

of

the

Liver

/

Journal

of

Hepatology

50

（2009）

227–242

survivalbeingapproximately80–86%inpatientswith

compensatedcirrhosis[4,9–13].Patientswithdecompensated

cirrhosishaveapoorprognosiswitha14–35%

probabilityofsurvivalat5years.Theworldwideincidence

ofHCChasincreased,mostlyduetoHBVand

HCVinfections;presentlyitconstitutesthefifthmost

commoncancer,representingaround5%ofallcancers.

TheannualincidenceofHBV-relatedHCCinpatients

withCHBishigh,rangingfrom2%to5%whencirrhosis

isestablished[13].However,theincidenceofHBV-

relatedHCCappearstovarygeographicallyandcorrelates

withtheunderlyingstageofliverdisease.

Populationmovementsandmigrationarecurrently

changingtheprevalenceandincidenceofthediseasein

severallowendemicitycountriesinEuropeandelsewhere.

Substantialhealthcareresourceswillberequired

forcontroloftheworldwideburdenofdisease.

2.2.

Natural

history

ChronichepatitisBisadynamicprocess.Thenatural

historyofCHBcanbeschematicallydividedintofive

phases,whicharenotnecessarilysequential.

（1）The‘‘immunetolerant”

phaseischaracterizedby

HBeAgpositivity,highlevelsofHBVreplication

（reflectedbyhighlevelsofserumHBVDNA）,normal

orlowlevelsofaminotransferases,mildorno

livernecroinflammationandnoorslowprogression

offibrosis[3,5].Duringthisphase,therate

ofspontaneousHBeAglossisverylow.Thisfirst

phaseismorefrequentandmoreprolongedinsubjects

infectedperinatallyorinthefirstyearsoflife.

Becauseofhighlevelsofviremia,thesepatientsare

highlycontagious.

（2）The‘‘immunereactivephase”

ischaracterizedby

HBeAgpositivity,alowerlevelofreplication（as

reflectedbylowerserumHBVDNAlevels）,

increasedorfluctuatinglevelsofaminotransferases,

moderateorseverelivernecroinflammation

andmorerapidprogressionoffibrosiscompared

tothepreviousphase[3,5].Itmaylastforseveral

weekstoseveralyears.Inaddition,therateof

spontaneousHBeAglossisenhanced.Thisphase

mayoccurafterseveralyearsofimmunetolerance

andismorefrequentlyreachedinsubjectsinfected

duringadulthood.

（3）The‘‘inactiveHBVcarrierstate”

mayfollowseroconversion

fromHBeAgtoanti-HBeantibodies.It

ischaracterizedbyveryloworundetectableserum

HBVDNAlevelsandnormalaminotransferases.

Asaresultofimmunologicalcontroloftheinfection,

thisstateconfersafavourablelong-termoutcome

withaverylowriskofcirrhosisorHCCin

themajorityofpatients.HBsAglossandseroconversion

toanti-HBsantibodiesmayoccurspontaneously

in1–3%ofcasesperyear,usuallyafter

severalyearswithpersistentlyundetectableHBV

DNA[14].

（4）‘‘HBeAg-negative

CHB”

mayfollowseroconversion

fromHBeAgtoanti-HBeantibodiesduring

theimmunereactivephaseandrepresentsalater

phaseinthenaturalhistoryofCHB.Itischaracterized

byperiodicreactivationwithapatternof

fluctuatinglevelsofHBVDNAandaminotransferases

andactivehepatitis.Thesepatientsare

HBeAg-negative,andharbourHBVvariantswith

nucleotidesubstitutionsintheprecoreand/orthe

basalcorepromoterregionsunabletoexpressor

expressinglowlevelsofHBeAg.HBeAg-negative

CHBisassociatedwithlowratesofprolonged

spontaneousdiseaseremission.Itisimportant

andsometimesdifficulttodistinguishtrueinactive

HBVcarriersfrompatientswithactiveHBeAgnegative

CHBinwhomphasesofspontaneous

remissionmayoccur.Theformerpatientshavea

goodprognosiswithaverylowriskofcomplications,

whilethelatterpatientshaveactiveliverdisease

withahighriskofprogressiontoadvanced

hepaticfibrosis,cirrhosisandsubsequentcomplications

suchasdecompensatedcirrhosisand

HCC.Acarefulassessmentofthepatientisneeded

andaminimalfollow-upofoneyearwithserum

alanineaminotransferase（ALT）andHBVDNA

levelsevery3monthsusuallyallowsdetectionof

fluctuationsofactivityinpatientswithactive

HBeAg-negativeCHB[15].

（5）Inthe‘‘HBsAg-negativephase”

afterHBsAgloss,

low-levelHBVreplicationmaypersistwithdetectable

HBVDNAintheliver[16].Generally,HBV

DNAisnotdetectableintheserumwhileanti-

HBcantibodieswithorwithoutanti-HBsare

detectable.HBsAglossisassociatedwithimprovement

oftheoutcomewithreducedriskofcirrhosis,

decompensationandHCC.Theclinicalrelevance

ofoccultHBVinfection（detectableHBVDNA

intheliverwithlow-level[<200internationalunits

（IU）/ml]HBVDNAinblood）isunclear[16].

Immunosuppressionmayleadtoreactivationin

thesepatients[17,18].

3.Methodology

TheseEASLCPGshavebeendevelopedbyaCPG

PanelofexpertschosenbytheEASLGoverningBoard;

therecommendationswerepeer-reviewedbyexternal

expertreviewersandapprovedbytheEASLGoverning

Board.TheCPGshavebeenbasedasfaraspossibleon

evidencefromexistingpublications,and,ifevidencewas

unavailable,theexperts’personalexperienceandopinion.

Manuscriptsandabstractsofimportantmeetings

European

Association

for

the

Study

of

the

Liver

/

Journal

of

Hepatology

50

（2009）

227–242

publishedpriortoAugust2008havebeenevaluated.erantphasehavepersistentlynormalALTlevelsanda

TheevidenceandrecommendationsintheseguidelinesproportionofpatientswithHBeAg-negativeCHBmay

havebeengradedaccordingtotheGradingofRecom-haveintermittentlynormalALTlevels.Therefore

mendationsAssessmentDevelopmentandEvaluationappropriate,longitudinallong-termfollow-upiscrucial.

（GRADE）system.Thestrengthofrecommendations

thusreflectsthequalityofunderlyingevidence.The

（1）Theassessmentoftheseverityoftheliverdisease

principlesoftheGRADEs