干扰素核苷类似物讲稿.ppt
干扰素核苷类似物第一页,讲稿共二十八页哦Peginterferon as First-Line Treatment in HBeAg-Positive Patients Robert P.Perrillo,MDAssociate Director,HepatologyCoordinator,Liver Fellowship ProgramHepatology Division Baylor University Medical CenterDallas,Texas第二页,讲稿共二十八页哦Magnitude of HBV DNA Decline Does Not Predict HBeAg Outcome Fried M,et al.EASL 2005.Abstract 488.Mean HBV DNA Reduction(log10 copies/mL)Week 48 HBV DNA Reduction(On treatment)HBeAg Seroconversion 24 Weeks Posttreatment-8-6-4-202-4.5-5.8 Percentage of PatientsPegIFN alfa-2aLAM32P .0119020406080100PegIFN alfa-2aLAM第三页,讲稿共二十八页哦HBeAg+patients received pegIFN alfa-2a 180 ug/week,pegIFN+LAM 100 mg/day or LAM for 48 weeks(N=814)24-week off-treatment follow-upHBeAg Seroconversion Rates Over Time With PeginterferonLau GK,et al.N Engl J Med.2005;352:2682-2695.27242032271901020304050PegIFN(n=271)PegIFN+LAM(n=271)LAM(n=272)HBeAg Seroconversion(%)End of treatment(Week 48)Off-treatment follow-up(Week 72)P .001P=.023第四页,讲稿共二十八页哦Loss of HBsAg,HBeAg Seroconversion After 1 Year of TreatmentPegIFN LAMTBVETVADV3-5001222-2717232112010203040Data from individual studies,not direct comparisons(different populations,baseline values)Lau G,et al.N Engl J Med.2005;352:2682-2695.Janssen H,et al.Lancet.2005;365:123-129.Dienstag J,et al.N Engl J Med.1999;341:1256-1263.Baraclude package insert.Tyzeka package insert.Hepsera package insert.Chang TT,et al.N Engl J Med.2006;354:1001-1010.Perrillo RP,et al.N Engl J Med.1990;323:295-301.Lok AS,et al.Gastroenterology.1987;92:1839-1843.HBeAg Seroconversion(%)HBsAg loss(%)0UntreatedHBeAg seroconversionHBsAg loss10第五页,讲稿共二十八页哦P 2-3 x ULNHBV genotype A or BAbsence of cirrhosisNucleos(t)ide analogue best in the following patient groupsAdult of any ageBaseline HBV DNA 2 x 108 IU/mL Baseline ALT 5 x ULNAny HBV genotypeCirrhosis with or without decompensationHBsAg(+)chemotherapy patientProper Patient Selection Is KeyPerrillo RP.Hepatology.2006;43:S182-S193.第十二页,讲稿共二十八页哦ConclusionsIFN has dual antiviral and immunomodulatory rolePotential for HBsAg clearance should not be disputed,diminished,or dismissed,particularly in HBeAg+diseaseResponses are durable and clinical benefits continue after discontinuation of treatmentNo resistance observedMore costly initially,but cost equivalent to oral therapies at 2-3 years第十三页,讲稿共二十八页哦Nucleos(t)ide Analogues as First-Line Treatment in HBeAg-Positive Patients Jules L.Dienstag,MDHarvard Medical SchoolGastrointestinal UnitMassachusetts General HospitalBoston,Massachusetts第十四页,讲稿共二十八页哦 100,00010,000-99,999HBV DNA Associated With Increased Risk of HCC and CirrhosisREVEAL:Long-term follow-up of untreated HBsAg positive individuals in TaiwanBaseline HBV DNA(copies/mL)Patients(%)Cumulative Incidence of HCC at Year 13 Follow-up1(N=3653)504030201001.31.43.612.214.9Cumulative Incidence of Cirrhosis at Year 13 Follow-up2(N=3582)4.55.99.823.536.2 300300-9991000-9999 300300-999910,000-99,999100,000-999,999 1 million1.Chen CJ,et al.JAMA.2006;295:65-73.2.Iloeje UH,et al.Gastroenterology.2006;130:678-686.第十五页,讲稿共二十八页哦REVEAL:Persistent HBV DNA Associated With Increased HCC Risk*Cox proportional hazards models.Risk is relative to 104 copies/mL at entry/not tested at follow-up.Data adjusted for sex,age,cigarette smoking,and alcohol consumption.Adjusted Hazard Ratio*for HCC(95%CI)Low 104Mid 104-105High 105HBV DNA(copies/mL)High 105High 105High 105DNA at entry:DNA at follow-up:10.17.33.80481216n=146120537Chen CJ,et al.JAMA.2006;295:65-73.第十六页,讲稿共二十八页哦Reversal of Fibrosis With Long-termNucleos(t)ide Analogue TherapyPaired biopsies from before,after 3 years of lamivudine(N=63)HAI necroinflammatory scores56%improved by 2 points33%had no change11%had worsening(YMDD mutations blunted the response)Fibrosis63%(12/19)had improvement in bridging fibrosis by 173%(8/11)had improvement in cirrhosis(score 4 3)Only 2%(1/52)had progression to cirrhosis and 9%(3/34)to bridging fibrosisall with YMDD mutationsDienstag J,et al.Gastroenterology.2003;124:105-117.第十七页,讲稿共二十八页哦Lau G,et al.N Engl J Med.2005;352:2682-2695.PegIFN alfa-2a vs LAM vs Combination at 48 Weeks in HBeAg+Patients020406080100End of Treatment(Week 48)PegIFN 180 g(n=271)PegIFN+LAM(n=271)LAM 100 mg(n=272)272420HBV DNA 105 copies/mLALTNormalHBeAgLossHBeAgSeroconversion302722528662394662Patients(%)HBsAg seroconversion 0%in all 3 armsHBV DNA 400 copies/mL256940第十八页,讲稿共二十八页哦PegIFN alfa-2a vs LAM vs Combination at 48 Weeks in HBeAg(+)Patients-5.8-4.5-7.2HBV DNA Reduction at Week 48Mean log10 HBV DNA reduction-8.0-7.0-6.0-5.0-4.0-3.0-2.0-1.00.01.0PegIFN 180 g(n=271)PegIFN+LAM(n=271)LAM 100 mg(n=272)Lau G,et al.N Engl J Med.2005;352:2682-2695.第十九页,讲稿共二十八页哦PegIFN alfa-2a vs LAM vs Combination:Off-Treatment Follow-up-2.0-2.4-2.6HBV DNA Reduction at Week 72(24 Weeks Off-Treatment)Follow-upLau G,et al.N Engl J Med.2005;352:2682-2695.Mean log10 HBV DNA reduction-8.0-7.0-6.0-5.0-4.0-3.0-2.0-1.00.01.0PegIFN 180 g(n=271)PegIFN+LAM(n=271)LAM 100 mg(n=272)第二十页,讲稿共二十八页哦Limitations of PegIFN StudiesAssessing the impact of LAM 6 months after discontinuation subjects LAM to a new standard for a nucleoside,usually not stopped at 48 weeksIn this trial,ALT 2 x ULN for entry for majorityIn this Asian cohort,2 potential candidates were excluded for every participant includedOnly lamivudine has been studied as a comparatorLamivudine has inferior antiviral effects compared with other nucleos(t)ide analogues第二十一页,讲稿共二十八页哦Telbivudine“vs”Entecavir“vs”Lamivudine in Chronic Hepatitis BMean HBV DNA Reduction(log10 copies/mL)-6.5-5.5TBV vs LAM52 WeeksTBV*22%LAM 46%ETV 1%Resistance at 2 Years-8.00-6.00-4.00-2.000.00ETV vs LAM48 Weeks-6.9-5.4*Week 92 dataLai C,et al.AASLD 2005.Abstract LB1.Lai C,et al.AASLD 2006.Abstract 91.Baraclude package insert.Colonno RJ,et al.EASL 2007.Abstract 781.第二十二页,讲稿共二十八页哦Patients(%)PegIFN alfa-2aTelbivudineWeek 52Week 76(On Treatment)Week 48Week 72(Off Treatment)Lau G,et al.N Engl J Med.2005;352:2682-2695.Lai CL,et al.AASLD 2005.Abstract LB01.27320204060801002233HBeAg Seroconversion Rates at 1 Year,24-Week Follow-up第二十三页,讲稿共二十八页哦HBeAg Seroconversion After Extended Nucleos(t)ide Analogue Therapy1.Leung N.J Gastroenterol Hepatol.2002;17:409-414.2.Lai C,et al.AASLD 2006.Abstract 91.3.Chang TT,et al.N Engl J Med.2006;354:1001-1010.4.Gish R,et al.AASLD 2005.Abstract 992.5.Chang TT,et al.AASLD 2006.Abstract 109.Patients With HBeAg Seroconversion(%)LAM1ETV3-5 TBV22222212940473031020406080Year 1 Year 2Year 3Year 410039第二十四页,讲稿共二十八页哦0Rates of Resistance in Nucleos(t)ide-Naive PatientsLai CL,et al.Clin Infect Dis.2003;36:687-696.Lok AS,et al.Gastroenterology.2003;125:1714-1722.Hepsera package insert.Foster City,Calif:Gilead Sciences;2006.Colonno R,et al.EASL 2007.Abstract 781.Lai CL,et al.Gastroenterology.2005;129:528-536.Lai CL,et al.AASLD 2006.Abstract 91.2355716546Year12345Patients(%)8040602010003111930 1 1 1 1522*9*?LamivudineAdefovirEntecavirTelbivudine,all patientsTelbivudine,HBeAg-positive patientsTelbivudine,HBeAg-negative patients*Week 92第二十五页,讲稿共二十八页哦Adverse Effects of PegIFN Therapy1.Hadziyannis S,et al.Ann Intern Med.2004;140:346-355.2.Fried M,et al.N Engl J Med.2002;347:975-982.3.Zeuzem S,et al.Gastroenterol.2004;127:1724-1732.4.Marcellin P,et al.N Engl J Med.2004;351:1206-1217.020406080100D/CDose ReductionFeverFatigueMyalgiasRigorsDepressionHBV4HCV3HCV2HCV1第二十六页,讲稿共二十八页哦TDF vs ADV at 48 Weeks in HBeAg+Chronic Hepatitis BHeathcote EJ,et al.AASLD 2007.Abstract LB6.Histology 2 HAIHBV DNA 300 c/mLHBeAgSero-conversionCompositeHistol+VirolPatients(%)7468741267122118TDF(n=176)ADV(n=90)HBsAgLoss30P .001020406080100P .001P=.018第二十七页,讲稿共二十八页哦Median HBV DNA Reduction in HBeAg+Chronic Hepatitis B*Data from individual reports,not direct comparisons(different populations,baseline values,HBV DNA assays).-7-6-5-4-3-2-10Log10 Decrease HBV DNA-3.5-4.5-4.8-5.5-6.2-6.5-6.9-5.1PegIFNNucleos(t)ide AnaloguesLau GK,et al.N Engl J Med.2005;352:2682-2695.Baraclude package insert.Tyzeka package insert.Hepsera package insert.Marcellin P,et al.N Engl J Med.2003;348:808-816.Yoo BC,et al.AASLD 2005.Abstract 186.第二十八页,讲稿共二十八页哦