干扰素核苷类似物讲稿.ppt

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1、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 Ou

2、tcome 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 pegI

3、FN 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 treat

4、ment(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

5、: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;

6、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 genotypeCirrh

7、osis 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

8、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,M

9、DHarvard 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(%

10、)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.Gastroente

11、rology.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

12、)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)

13、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 fibrosi

14、sall 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 DN

15、A 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.

16、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.2

17、005;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 st

18、opped 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

19、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

20、.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 Rate

21、s 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

22、.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

23、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 patientsTelbivudi

24、ne,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.2

25、004;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(%)7468741267

26、122118TDF(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