美国肝病协会抗乙肝防治指南英文原版.docx

美国肝病协会抗乙肝防治指南英文原版.docx

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美国肝病协会抗乙肝防治指南英文原版

55thAnnualMeetingoftheAmericanAssociationfortheStudyofLiverDiseases

ViralLiverDiseaseCME

October29,2004-November2,2004,Boston,Massachusetts

DevelopmentsintheManagementofHepatitisB

Introduction

HepatitisBvirus（HBV）isamajorhealthcareproblemaroundtheworld.Itisestimatedthat350-400millionpeoplearechronicallyinfected.[1,2]PatientswithchronichepatitisBareatincreasedriskforprogressiontocirrhosisandend-stageliverdiseaseandforthedevelopmentofhepatocellularcarcinoma（HCC）,includingpatientswhoareasymptomatic.InterferonhasbeenusedtotreathepatitisBsincethemid-1980s.Theefficacyofpegylatedinterferonisnowbeingactivelyinvestigated.ThedevelopmentandavailabilityofnucleosideandnucleotideanalogueshasgreatlyalteredthemanagementofpatientswithchronichepatitisB.Unfortunately,theincreaseduseofthesedrugs,particularlywhenusedasmonotherapy,hasproducedmutationsthatconferviralresistance,muchaswhatwasseeninthemanagementofHIV.Investigatorshavesoughttodefinethesemutationsandtoexaminetheroleofcombinationtherapytoimprovevirologicresponseandreduceviralresistance.

HepatitisBandtheRiskofDevelopingHCC

ItisknownthatpatientswithchronichepatitisBwhoarehepatitisBeantigen（HBeAg）-positiveareatgreatestriskforboththeprogressionofliverdiseaseandthedevelopmentofHCC.[3]Whatthisimplies,butwhathasn'tbeenclearlyshown,isthattheHBVviralloadalsocorrelateswithdiseaseprogressionandtheriskofHCC.Chenandcolleagues[4]lookedatthisissueintheir10-year,prospectivecohortstudyof3464patientsfoundtobehepatitisBsurfaceantigen（HBsAg）-positiveatscreeningbetween1992and1993.Tenyearslater,2354ofthesepatientshadeithersufficientbaselineserumsamplesoradequatefollow-upinformationtoallowthemtobeincludedinamortalityanalysis;1681patientshadbothsufficientbaselineserumsamplesandwerewillingtoundergorescreeningwithphysicalexamination,laboratorytests,andliverultrasound.Allofthepatientswereplacedin1of3viralloadcategoriesonthebasisoftheirviralloadsatthetimeofentry:

undetected（<1.6x103copies/mL）,lowtiter（<105copies/mLbut>/=1.6x103copies/mL）,andhightiter（>/=105copies/mL）.Liverdiseasewascharacterizedasnormal,mild,moderate,orsevereonthebasisofadaptedDionysoscriteria.HCCwasdiagnosedbythepresenceofa>2-cmmassonultrasoundandanalpha-fetoproteinlevel>400ng/mL.

Thepatientsinthehigh-titervirusgroupatentrywerefoundtobeatastatisticallysignificantgreaterriskformortalityfromprogressiveliverdiseaseorHCCthanpatientswithloworundetectableviralloads.Althoughitdidnotreachstatisticalsignificance,lowviralloadalsoappearedtobeassociatedwithanincreasedriskofmortalityfromprogressiveliverdiseaseorHCCwhencomparedwithpatientswithanundetectableviralload.

ThisstudyhaspotentiallysignificantimplicationsforthemanagementofpatientswithchronichepatitisB.ThereiscontroversyregardingwhetherpatientsintheimmunotolerantstageofHBVinfection（patientswithhighlevelsofHBVDNA,normalaminotransferases,andlittletononecroinflammatoryactivityonliverbiopsy）shouldbetreated.ThisstudybyChenandcolleagues[4]providesadditionalweighttotheargumentthatperhapsthesepatientswouldbenefitfrombeingtreatedandhighlightstheneedforatrialtobedesignedtolookatthisspecificquestion.Theendpointsofsuchastudy,theprogressionofliverdiseaseandthedevelopmentofHCC,wouldtakemanyyearstoassessandwillrequiretheenrollmentoflargenumbersofpatients.Inaddition,thestudywouldneedtousemultipleanti-HBVagentstopreventthedevelopmentofviralresistance.Hopefully,studies,suchasthisonebyChenandcolleagues,[4]willprovidetheimpetusforsuchfutureinvestigation.

PreventionofHepatitisB

TheuseofpassiveandactiveimmunitytoreducetheriskofverticaltransmissionofhepatitisBiswellacceptedinclinicalpractice.[5]HepatitisBimmunoglobulin（HBIg）,givenatthetimeofbirthincombinationwith3dosesoftherecombinanthepatitisBvaccinegivenoverthefirst6monthsoflife,hasproventobeasmuchas95%effectiveinpreventingverticaltransmission.[6]However,theriskofverticaltransmissionofhepatitisBincreasesasthemother'sviralloadincreases.Inoneseriesofmotherswithhighviralloads（definedasHBVDNA>/=1.2x109copies/mL）,thisriskwasashighas28%.[7]Itstandstoreasonthatifthemother'sviralloadcouldbereducedatthetimeofbirth,theriskofverticaltransmissioncouldalsobereduced.ThisisexactlywhatXuandcolleagues[8]examinedwithawell-structured,multicenter,randomized,double-blind,placebo-controlledstudycarriedoutatcentersinChinaandthePhilippines.

MotherschronicallyinfectedwithhepatitisB（HBsAg-positive）andwithhighHBVviralloads（definedasaserumHBVDNA>1000mEq/mL）wereenrolled.Onehundredfourteenmotherscompletedthestudy;56mothersreceivedlamivudine,100mgaday,beginningatthe32ndweekofgestationandcontinuinguntil4weekspostpartum.Thecontrolgroupofmothers（n=59）receivedplacebo.Alloftheinfantsreceivedstandardprophylaxis（HBIgwithin24hoursofbirthandvaccinationwiththerecombinantHBVvaccine;3injectionsoverthefirst6monthsoflife）.TheprimaryendpointofthestudywasHBsAgpositivityintheinfantsat1year.SecondaryendpointswerehepatitisBsurfaceantibody（HBsAb）positivityandHBVDNApositivityintheinfantsat1year.

Notsurprisingly,themotherstreatedwithlamivudineweremorelikely（98%）tohaveareductionintheirviralloadsto<1000mEq/mLthanthecontrols（31%）.Thisreductioninviralloadtranslatedintoimprovedoutcomesfortheinfantsofmothersreceivinglamivudine.TheyhadalowerlikelihoodofbeingHBsAg-positiveat1yearofage（18%vs39%;P=.014）ortobeviremic（20%vs46%;P=.003）.InfantsalsohadagreaterchanceofbeingHBsAb-positiveat1yearofage（84%vs61%;P=.008）.Therewasnodifferenceseeninadverseeventsbetweenthetreatmentandcontrolgroupsineitherthemothersortheinfants.

Althoughthisstudyhadsomeissueswithpatientdropout,itnonethelessstronglysuggeststhattheuseoflamivudineinthethirdtrimesterofpregnancyinmotherswithhighHBVviralloadsiseffectiveinreducingtheriskofverticaltransmissionbeyondwhatcanbeachievedwithpassiveandactiveimmunization.Inaddition,thistherapyissafeforboththemotherandtheinfant.Whileweawaitadditionaltrials,lamivudine*shouldbeconsideredforuseinthethirdtrimesterinthosemothersinfectedwithchronichepatitisBatgreatestriskforpassingtheinfectionontotheirinfants--ie,thosewithhighviralloads.

NewandOldTherapiesforHepatitisB

Entecavir,acarbocyclicanalogueof2'-deoxyguanosine,isapotentandselectiveinhibitorofHBVpolymerase.Rosmawatiandcolleagues[9]reportedtheresultsofaphase3trialcomparingentecavir,.5mgaday,withlamivudine,100mgaday,for48weeksinpatientswithHBeAg-positivechronichepatitisB.Theinvestigatorschosetopayparticularattentiontothosepatientswithlow-baselinealanineaminotransferase（ALT）levels,definedas<2.6timestheupperlimitofnormal.Thereasonforthisfocuswasapreviouslycompletedphase2trialthatsuggestedthatentecavirmaybeaseffectiveinpatientswithlow-baselineALTasinthosewithmoreelevatedALT.Thiswasofinterestbecausepatientswithnormalornear-normalALTlevelsatbaselinerespondlesswelltointerferonorlamivudinethandopatientswithelevatedALT.Theinvestigatorsdidnotexplainwhythethresholdvalueof2.6timestheupperlimitofnormalwaschosenforthisparticularanalysis.TheresultsshowedthatinthosepatientswithabaselineALT<2.6timestheupperlimitofnormal,entecavirproducedameanlogreductionintheHBVDNAof6.79at48weekscomparedwitha4.85logreductionforlamivudine（P<.0001）.InthosepatientswithabaselineALTof>/=2.6timestheupperlimitofnormal,entecavirproducedameanlogreductionintheHBVDNAof7.18at48weekscomparedwitha6.15logreductionforlamivudine（P<.0001）.EntecavirwasmuchmorelikelytosuppresstheHBVDNAto<400copies/mLbypolymerasechainreactionatweek48.NodatawereprovidedonHBeAglossorseroconversion.

Inaphase1/2clinicaltrial,clevudine,anL-nucleoside,wasshowntohavepotentanti-HBVactivityovera12-weekperiod.Leeandcolleagues[10]examinedthesafetyandantiviralactivityofclevudine,30mgaday,in21patientswithHBeAg-positivechronichepatitisBover24weeksat7sitesinSouthKorea.TheresultsshowninTable1suggestthatclevudinehasexcellentanti-HBVactivitywithincreasedbenefitat24weekscomparedwith12weeks.Therewasnoviralbreakthroughreported.

Table1.ViralSuppressionandNormalizationofALT

EndPoint

Week12

Week24

LogreductioninHBVDNA

4.05

4.64

HBVDNA<4700copies/mL

59%

82%

HBVDNA<400copies/mL

24%

59%

NormalizationofALT

47%

76%

HBeAgloss

12%

24%

ALT=alanineaminotransferase;HBeAg=hepatitisBeantigen

Marcellinandcolleagues[11]reportedthe144-weekdatainalong-termstudyofadefovir,10mgaday,inpatientswithHBeAg-positivechronichepatitisB.Eighty-fourpatientswerefollowedthroughthe144weeks.ThesepatientsenjoyedincreasingratesofHBeAgseroconversion（12%at48weeks,29%at96weeks,and43%at144weeks）,HBVDNAsuppressiondefinedas<1000copies/mL（28%at48weeks,45%at96weeks,and56%at144w