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.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
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