慢性乙型肝炎治療

新進展此ppt下載后可自行編輯慢性乙肝的全球影響由于乙肝的高發病率和引起的肝損傷乙肝造成了亞洲地區嚴重的健康和經濟負擔21.WHOandCDCfactsheets,availableatand

2.Rosmawatietal.J.GastroenterolHepatol2004;19:958-96920億HBV感染者全球人口60億3-4億慢乙肝患者125-40%的患者死于肝硬化或肝癌75%的患者在亞洲環太平洋地區2乙型肝炎病毒基因型的地理分布Ahn

SH,et

al.JMedVirol.2010;82:1126-1134;KimBK,et

al.AntivirTher.2011;16:1169-1186A1A1A1A1A2A2A2A2A2A2A2A2A3B2B2B3C1C1B1C2C2DDDDDDDDDDDDB6B6B6B6A1F4F1F2HGF1HF2F2F3F1C4D4C3C1EC1C5B5B4D2D1D1D1EED3G慢性乙肝治療目標HBsAg的清除是理想的“治療終點”Short-TermLong-TermHBeAg(+)and(-)patientsHBeAg(+)patientsHBeAglossAnti-HBeseroconversionHBeAg(-)patientsHBeAglossAnti-HBsseroconversionHistologicimprovementReversaloffibrosisPreventcomplicationsProlongsurvivalHBVDNAundetectableALTnormalizationTreatmentinitiationTIME1.AhnSHetal.HepatolInt2010;4:386-3952.LiawY-F,etal.2008;2(3):263-2833.EASLJHepatol2009;50:227-242CHLCHCCPOTENTIALTOSTOPTHERAPYHBeAgseroconversion乙肝治療的兩種方式HBVReplicationLiverFunction乙肝治療方式大綱治療方案更新-以應答為指導的慢乙肝抗病毒治療：（1）聚乙二醇化干擾素（2）核苷類似物UDCA用于病毒性肝炎大綱治療方案更新

-以應答為指導的慢乙肝抗病毒治療：（1）聚乙二醇化干擾素UDCA用于病毒性肝炎PEGASYS0WEEKS48WEEKSInitiatetreatmentEndoftreatmentSustainedimmunecontrol大綱治療方案更新

-以應答為指導的慢乙肝抗病毒治療：（2）核苷類似物為什么對核苷類似物需要應答指導的治療（RGT）？耐藥性是慢性乙型肝炎管理的主要挑戰病毒載量升高1低基因屏障4,7-9抗病毒耐藥2次優治療方案或者不治療持續的肝臟炎癥和損傷1纖維化/肝硬化8，肝衰竭1肝癌9，死亡1抗病毒耐藥性一旦產生耐藥性，就會持續71.FungSK.et

al.AntivirTher.2004;9:1013-1026.2.LiawY-F,etal.NEnglJMed.2004;351:1521-1531.3.DienstagJ.et

al.N

EnglJMed.2008;359:1486-1500.4.ColonnoRJ.etal.Hepatology.2006;44:1656-1665.5.TenneyDJ.et

al.AntimicrobAgentsChemother.2004;48:3498-3507.6.Baraclude(entecavir)prescribinginformation.Princeton,NJ:Bristol-MyersSquibb.July2008.7.LokAS,etal.Hepatology.2007;45:507-539.8.ChenC-J,et

al.JAMA2006;295:65-73.拉米夫定難治性的隊列研究（HBeAg-和+）：阿德福韋酯耐藥的5年積累概率ADVr=rtA181Vonly(44.6%);rtA181Tonly(25.9%);rtA181V+T(2.7%);rtN236Tonly(7.1%);rtA181V/T+tN236T(19.7)N=320N=279N=164N=66N=25YearsLeeJM…Ahn

SH.AntiviralTherapy2010;15(2):235-241拉米夫定耐藥患者

對核酸類似物的部分病毒學應答64%BaselineHBVDNA7.37.27.49.59.17.67.47.37.36.91.LeeJM,AhnSHetal.AntivirTher.2009;14:705-12;2.RaptiIetal.Hepatol2007;45:307-313;3.ShermanMetal.Gastroenterology2006;130:2039-494.ChangTTetal.Gastroenterol2005;129:1189-12095.RyuHJ,AhnSHetal.JMedVirol2010;82(11):1835-426.Yatsujietal.J

Hepatol2008;48:923-931.預防抗病毒耐藥性

應對策略一線治療二線治療預防耐藥

使用強效抗病毒藥物治療伊始即避免耐藥‘添加’第二種藥物治療或耐藥發生時，更換藥物PreemptiveSwitchRGT

withpotentantiviraldrugsorCombinationtheapyLocarnini

S,et

al.Antiver

Ther2004;9:679-693;KeefeEB,et

al.Clin

Gastroenterol

Hepatol2008;6:1315-1341.Switch

ToENT(STENT)

StudyHBVDNAlevles.Drug-resistantmutations.HBeAg

status,Liverbiochemistry服用拉米夫定100mg至少6個月篩選隨機分組每日一次，服用96周每日一次，服用96周RGTN=72N=36N=36HBeAg+HBVDNA≥60IU/mlbyPCRYonseiUniversityCollegeofMedicinePusanNationalUniversitySchoolofMedicineYeungnamUniversityCollegeofMedicineKyungpookNationalUniversityCollegeofMedicineKoreaUniversityCollegeofMedicineAhnSHetal.APASL2010.AASLD2011.4W12W24W36W48W60W72W84W96WAprospectiverandomized

trial迅速從LAM轉換到ETV

能夠增強抗病毒的效果P<0.001WeeksInStudyNo.evaluatedETV36363636363636363434LAM36363635322724191611HeoJ…Ahn

SH.AntiviralTherapy2012InPress不同藥物的RGT策略不同EASL定義的部分病毒學應答（PVR）

-乙肝病毒DNA下降超過1Log10IU/ml,但在24周時（LAM,LdT）或48周

時（ADV，ETV,TDF）,通過實時定量PCR仍然能檢出TheflowofpatientsaccordingtotreatmentresponseApracticalmanagementguidelineintreatment-naivePatientswithCHBreceivingETVChonYE,…AhnSH.AntiviralTherapy2011Totalpatients(baseline)PVR:HBVDNA>35IU/mlatweek48FavorableVR:HBVDNA<35IU/mlatweek48VR:HBVDNAnegative(<12IU/ml)atweek96NonVR:HBVDNApositive(>12IU/ml)atweek96

N=175

(100%)N=41(23.4%)N=13476.6%)N=35(20.6%)N=139(79.4%)Week12ResponderassessmentResponder(>1log10declineinHBVDNA

)Primanynon-responder(>1log10declineinHBVDNA)Week48ResponderassessmentCompliant-identifyHBVresistantmutations-AddorswitchtopotentdrugNon-compliantCounselonadherenceFavorablevirologic

response(HBV

DNA<35IU/ml)Partialvirological

Response(HBVDNA<35IU/ml)ContinueETVtherapywithRegularmonitoringCompliantNon-compliantCounselonadherenceBaselinelowviralload(BaselineHBVDNA<1.77E+08IU/ml)Baselinelowviralload(BaselineHBVDNA<1.77E+08IU/mlContinueETVtherapywithRegularmonitoringAddorswitchtopotentdrug乙肝病毒的發現BarushSBlumberg,M.D.,Ph.D.TheNobelPrizeinPhysiologyandMedicine1976

NIH:Doublediffusioninagargel(Ouchterlony)methodtodetectantibodiesinmultiplytransfusedpatients.Au-antigenfromhemophiliacs(Mt.SinaiHospitalinNewYork)“WhydidprecipitinbandhasdevelopedbetweentheserumofhemophiliaPatientsinNYandthatofanaboriginefromAustralia?”AssociationbetweenAuandacutehepatitis(AnnIntMed1967;66:924-931)SubsequentstudyfoundtheAustralianAntigentobethe

HBsantigen.HBsAg定量/HBVDNA定量HBsAg定量和HBVDNA

定量提供了互補信息HBsAg定量是對HBVDNA定量的一個補充！HBVVirionpreS1Peg-interferonHBsAg=MarkerofImmunologicalresponseHBc3.2kbDNAOralantiviralagents(NAs)HBVDNA=MarkerofVirusreplicationLeeJM,Ahn

SH.WorldJGastroenterol2011B;runetto

Editorial.J

Hepatol2010降低HBsAg水平

PEG-IFN比恩替卡韋療效更佳InHBeAg(+)patientsHBVDNAdeclineHBeAgdeclineWeekPEG-IFN(N=61)ETV(N=33)-2.2-4.5Reijndersetal.J

Hepatology2010WeekETV(N=33)PEG-IFN(N=61)-0.38-0.94qHBsAg的基線水平能預示

恩替卡韋的完全病毒學應答ForVR(HBV

DNA<60copies/ml),baselinelogqHBeAglevel:3.98IU/ml(sensitivity,86.8%;specificity,78.9%)(sensitivity,75.0%;specificity,89.8%)MonthP<0.005HBeAg(+)LeeJM,Ahn

SH…ParkJY.Hepatology2011;53(5):1486-93AqHBsAg水平的快速下降能預示

恩替卡韋治療期間，

HBsAg轉陰ForSerologicResponse(HBeAglossat24months),thereductionoflogqHBeAg:1.00PEIU/mlat6months(sensitivity,75.0%;specificity,89.8%)P<0.05MonthLeeJM,Ahn

SH…ParkJY.Hepatology2011;53(5):1486-93B何時停用核苷類藥物？Predictionofoff-treatmentdurability乙肝治療停用核苷類藥物的原則CHBTreatmentGuidelinesEASL1(April2009)AASLD*2(Nov2009)APASL3(Feb2012)HBeAg+veHBeAgSeroconversionwith6-12monthsofconsolidation+undetectableDNAHBeAgSeroconversionwith6monthsofconsolidation+undetectableDNAHBeAgSeroconversion+undetectableDNAfor12monthsHBeAg-veHBeAgSeroconversionConteinueuntilHBeAgclearanceConsiderifDNAundetectable3times6monthsapartEASLguidelinesstateadurableresponsecanbeexpectedin80%OfHBeAg+vepatients1*AASLDrecommendationsonfinitetreatmentdifferforeachNUCtherapy

1.EASLClinicalPractics

Guidelines.J

Hepatol2009;50:227-242.2.LokA.et

al.Hepatology2009;50(3):1-363.LiawYF,et

al.HepatolInt.2008;2:263-283HBsAg下降可預測HBsAg

的轉陰N=266patienttreatedwithtenofovir(or

adefovir-tenofovir)for2years.HBeAglevelsduringtreatmentHBVDNAlevelsduringtreatmentWeeksofstudyWeeksofstudyHealthcoteetal.EASLandAASLD2009.N=266overallN=16clearedHBsAg監測HBsAg

水平能指導

HBsAg陰性的慢性乙肝患者拉米夫定的停藥時間53HBeAg-CHBonlamivudineforameanof19mo.Attheendoflamivudine

treatementSR-12:HBVDNA≤200IU/ml,atmonth12post-treatmentChanHLetal.Hepatol

Int2011;5:abstPPO5-102HBsAgreduction

No.ofPatientsNo.ofSR-12

By>1LogTo≤100IU/MLYesYes

55YesNoNoYes84NoNo400UDCA的發展歷史中國黑熊膽汁的主要組成成分：被用于傳統中藥；HydrophilicFrom~In1927,firstisolationofUDCA~In1954,developmentofsyntheticmethod~In1957,作為利膽劑首次上市1975年，UDCA被報道用于膽固醇性結石的溶解主要治療領域是包括PBC在內的膽汁淤積性肝病

~USFDA批準用于PBC的唯一藥物

~收錄于“2009版AASLD，EASL指南”在Japan,Korea

增加了丙肝的適應癥

Shodaetal.,JBiochem.,1927;7:505-17Iwasakietal.,ZPhysiol.Chem.,1936;244:181-93Makinoetal.,J.Gastroenterol.Hepatol.,1998;13:659-64Makinoetal.,Jpn.J.Gastroenterol.,1975;72:690-702Leuschneretal.Dig.Dis.Sci.,1985;30:642-9UDCA:作用機制3種主要的作用機制

1.保護膽管細胞對抗膽汁酸毒性

2.刺激膽汁分泌

3.保護肝細胞拮抗膽汁酸引起的凋亡GustavPaumgartner,Clin.Liver.Dis.,2004;8:67-81UDCAStimulationofbiliarysecretionUDCAUDCAStimulationofdetoxificationInhibitionofapoptosisHEPATOCYTEBileacidsApoptosisNecrosisBileacidsMetabolitesUDCAProtectionofcholangiocytesCHOLANGIOCYTEUDCA對急性病毒性肝炎的療效

-

UDCA改善肝臟炎性反應-Source:Jan

Gslskyetal.,J

Clin

Gastroentroentrol1999;28(3):249-253N=40N=38P=0.037TherapyperiodFollow-upperiodTime(month)UDCA

能延緩乙肝

由急性到慢性的病程進展Source:Jan

Gsl