干扰素核苷类似物.ppt

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1、干扰素核苷类似物现在学习的是第1页，共28页Peginterferon as First-Line Treatment in HBeAg-Positive Patients Robert P.Perrillo,MDAssociate Director,HepatologyCoordinator,Liver Fellowship ProgramHepatology Division Baylor University Medical CenterDallas,Texas现在学习的是第2页，共28页Magnitude of HBV DNA Decline Does Not Predict HBeA

2、g 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现在学习的是第3页，共28页HBeAg+patients receive

3、d 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

4、 treatment(Week 48)Off-treatment follow-up(Week 72)P .001P=.023现在学习的是第4页，共28页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.

5、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.Gastroenterolo

6、gy.1987;92:1839-1843.HBeAg Seroconversion(%)HBsAg loss(%)0UntreatedHBeAg seroconversionHBsAg loss10现在学习的是第5页，共28页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 gen

7、otypeCirrhosis with or without decompensationHBsAg(+)chemotherapy patientProper Patient Selection Is KeyPerrillo RP.Hepatology.2006;43:S182-S193.现在学习的是第12页，共28页ConclusionsIFN has dual antiviral and immunomodulatory rolePotential for HBsAg clearance should not be disputed,diminished,or dismissed,part

8、icularly 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现在学习的是第13页，共28页Nucleos(t)ide Analogues as First-Line Treatment in HBeAg-Positive Patients Jule

9、s L.Dienstag,MDHarvard Medical SchoolGastrointestinal UnitMassachusetts General HospitalBoston,Massachusetts现在学习的是第14页，共28页 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(copi

10、es/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,

11、et al.Gastroenterology.2006;130:678-686.现在学习的是第15页，共28页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 R

12、atio*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.现在学习的是第16页，共28页Reversal of Fibrosis With Long-termNucleos(t)ide Analogue TherapyPaired biopsies from before,after 3 years

13、 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

14、)to bridging fibrosisall with YMDD mutationsDienstag J,et al.Gastroenterology.2003;124:105-117.现在学习的是第17页，共28页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

15、 mg(n=272)272420HBV DNA 105 copies/mLALTNormalHBeAgLossHBeAgSeroconversion302722528662394662Patients(%)HBsAg seroconversion 0%in all 3 armsHBV DNA 400 copies/mL256940现在学习的是第18页，共28页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

16、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.现在学习的是第19页，共28页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-up

17、Lau 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)现在学习的是第20页，共28页Limitations of PegIFN StudiesAssessing the impact of LAM 6 months after discontinuation subjects LAM to a new standard for

18、 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

19、)ide analogues现在学习的是第21页，共28页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

20、,et al.AASLD 2006.Abstract 91.Baraclude package insert.Colonno RJ,et al.EASL 2007.Abstract 781.现在学习的是第22页，共28页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 LB01.273202040608010

21、02233HBeAg Seroconversion Rates at 1 Year,24-Week Follow-up现在学习的是第23页，共28页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 200

22、5.Abstract 992.5.Chang TT,et al.AASLD 2006.Abstract 109.Patients With HBeAg Seroconversion(%)LAM1ETV3-5 TBV222 22212940473031020406080Year 1 Year 2Year 3Year 410039现在学习的是第24页，共28页0Rates of Resistance in Nucleos(t)ide-Naive PatientsLai CL,et al.Clin Infect Dis.2003;36:687-696.Lok AS,et al.Gastroenter

23、ology.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*?LamivudineAdefovirEntecavir

24、Telbivudine,all patientsTelbivudine,HBeAg-positive patientsTelbivudine,HBeAg-negative patients*Week 92现在学习的是第25页，共28页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.

25、4.Marcellin P,et al.N Engl J Med.2004;351:1206-1217.020406080100D/CDose ReductionFeverFatigueMyalgiasRigorsDepressionHBV4HCV3HCV2HCV1现在学习的是第26页，共28页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-conversionComposi

26、teHistol+VirolPatients(%)7468741267122118TDF(n=176)ADV(n=90)HBsAgLoss30P .001020406080100P .001P=.018现在学习的是第27页，共28页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.现在学习的是第28页，共28页