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1、Roadmap for Management of Patients with Chronic Hepatitis B(CHB)Prof.Xinxin ZhangRui Jin HospitalJiao Tong University,2,IntroductionPresentation ObjectivesData Review:Associations of HBV DNA with Outcomesi.Natural history studiesii.Impact of treatmentKey role of HBV DNA in On-Treatment Managementi.T
2、iming and magnitude of HBV DNA suppressionOn-Treatment Roadmap ConceptSummary and Conclusions,Contents,3,IntroductionTreatment challenges highlight need for new management approach,Treating hepatitis B virus(HBV)infection continues to be a challenge for physicians due toComplications arising from ch
3、ronic HBV(CHB)The increasing number of available therapeutic options Treatment guidelines recognize the importance of monitoring and evaluation of treatment response;however,a standard on-treatment management approach does not existTo establish a new treatment paradigm,we should askDoes long-term su
4、ppression of HBV replication achieve the goals of treatment in CHB?Can the degree of on-treatment viral suppression predict outcomes?Does profound,early viral suppression at week 24 predict clinical outcomes?Can a Roadmap concept help achieve the goals of treatment in CHB?,4,Presentation Objectives,
5、To explore the association between persistent viraemia and hepatitis disease progressionTo assess the relationship between the degree of viral suppression and clinical outcomeTo assess the role of early and effective viral load reduction and the association with clinical outcomes*To review an on-tre
6、atment management strategy the roadmap concept that may offer a valuable opportunity for enhanced treatment response,*For safety information on the products referred to,please refer to the Product Information.,Data Review:Associations of HBV DNA with Outcomes,i.Natural history studies,6,Correlation
7、Between HBV DNA and Histologic Activity Index(HAI)in Untreated Patients,Review of 26 prospective clinical trials found a statistically significant correlation between viral load level and histological grading,Baseline HBV DNA level,log10 copies/mL,r=0.78;P=0.0001,HAI at baseline,Mommeja-Marin et al
8、2003,7,Cirrhosis:Association with Baseline HBV DNA Taiwan natural history study,Iloeje et al 2006,8,Hepatocellular Carcinoma(HCC)Association with baseline HBV DNA:Taiwan natural history study,Cumulative incidence of HCC,%,HBV DNA at baseline,copies/mL,HBsAg-positive,untreated participants(n=3,653),C
9、hen et al 2006,9,Evidence for Association Between HBV DNA and Clinical Outcomes,Natural history studies demonstrateLower HBV DNA levels are associated with better underlying histologyHigh HBV DNA may be an independent predictor for cirrhosis and HCCSustained suppression of HBV may reduce long-term r
10、isk of cirrhosis and HCCHypothesis needs to be proven prospectively,Data Review:Associations of HBV DNA with Outcomes,ii.Impact of treatment,11,Consistent relationship in treated and untreated patientsHBV DNA could be used as a marker of efficacy,Median HBV DNA level decrease from baseline,log10 cop
11、ies/mL,HAI improvement from baseline,Mommeja-Marin et al 2003,Correlation Between HBV DNA and Histologic Activity Index(HAI)in Treated Patients,12,P0.001,HBV DNA at week 72,copies/mL,HBeAg-negative patients(n=537)treated with lamivudine,peg-interferon alfa-2a,or both combined for 48 weeks,Patients w
12、ith histological response at week 72,%,Marcellin et al 2004,Viral Suppression at Week 72 is Associated with Histologic Improvement,105/329,116/208,13,Months,13%,21%,5%,Liaw 2005,Patients with disease progression,%,Viral Suppression Significantly Impacts Disease Progression,HBeAg-positive patients(n=
13、651)treated with lamivudine or placebo,14,Viral Suppression Improves Outcomes Studies reporting associations with outcomes,0,Key Role of HBV DNA in On-Treatment Management,i.Timing and magnitude of HBV DNA suppression,16,Rapid and Profound HBV Suppression:a Critical Goal of Therapy,Outcomes,Primary
14、goal of treatment,Delay in progression to cirrhosis and HCC Improved survivalReduced resistanceIncreased seroconversion Improved liver histology Normalised alanine aminotransferase(ALT)levels,Sustained suppression of HBV replication to the lowest possible level,Fontana 2003;Gauthier et al 1999;Keeff
15、e et al 2006;Liaw et al 2004;Liaw et al 2005;Mommeja-Marin et al 2003;Niederau et al 1996;Yuen et al 2001,17,Patients with HBV DNA 20,000 copies/mL at 72 weeks(%),Serum HBV DNA level at 12 weeks,copies/mL,HBeAg-negative patients(n=176)treated with peg-interferon alfa-2a for 48 weeks,P0.001,Farci et
16、al 2005,Viral Suppression with Peg-Interferon alfa-2a Association with subsequent HBV DNA response,18,Profound,Early Viral Suppression Week 24 viral load and 2-year outcomes with telbivudine and lamivudine,QL=quantification limit(polymerase chain reaction(PCR)-undetectable at 300 copies/mL by COBAS
17、Amplicor)Preliminary data from locked database,Di Bisceglie et al 2006,HBV DNA at week 24,copies/mL,PCR-negative at 2 years,%,HBeAg-positive(n=921),HBeAg-negative(n=446),QL,3003 log,34 log,4 log,QL,3003 log,34 log,4 log,203,146,57,63,83,79,107,165,178,157,18,20,16,24,10,20,19,Profound,Early Viral Su
18、ppression Week 24 viral load and 1-year outcomes with entecavir,HBV DNA at week 24,copies/mL,PCR-negative at week 48,%,HBeAg-positive,HBeAg-negative,400,4003 log,35 log,5 log,400,4003 log,35 log,5 log,153/195,28/34,47/118,6/15,240/247,20/21,32/38,1/4,BMS Entecavir AVDAC Briefing Document 2005,20,HBe
19、Ag seroconversion occurred only in this group,Weeks,Median HBV DNA,log10 copies/mL,Potential assessment of early virological response to predict outcome,Gauthier et al 1999,Magnitude of Viral Response to Lamivudine Association with higher rates of HBeAg seroconversion,21,n=183,n=54,n=81,n=107,Seroco
20、nversion at 2 years,%,Serum HBV DNA level at 24 weeks,log10 copies/mL,Early Viral Suppression with Telbivudine Association with 2-year HBeAg seroconversion,HBeAg-positive patients,Han et al 2007,Preliminary data from locked database,22,47/159,8/34,14/117,2/15,Seroconversion at 48 weeks,%,HBV DNA at
21、24 weeks,copies/mL,HBeAg-positive patients,BMS Entecavir AVDAC Briefing Document 2005,Early Viral Suppression with Entecavir Association with 1-year HBeAg seroconversion,23,Profound,Early Viral Suppression Correlates with Lower Risk of Resistance,Hadziyannis et al 2006;Yuen et al 2001,Patients with
22、lamivudine resistance,%,HBeAg-positive patients(n=159),median 30 months follow up,HBV DNA level at week 24,copies/mL,1/12,3/23,13/41,76/118,Patients with ADV resistance at week 192,%,HBeAg-negative patients(n=125),HBV DNA level at week 48,copies/mL,24,HBeAg-negative patients,Patients with telbivudin
23、e resistance week 92,%,n=178,n=16,n=18,n=10,Di Bisceglie et al 2006,Early Viral Suppression with TelbivudineAssociation with resistance,Preliminary analysis of patients with viral rebound at week 92,HBV DNA level at week 24,copies/mL,300,3003 log10,3 log104 log10,5 log10,25,HBeAg-positive,HBeAg-nega
24、tive,Goals of HBV therapyPrevent cirrhosis,liver failure and HCCImprove survival,Signpost,Signpost,Early Viral Suppression Can Be a Signpost for Future Therapeutic Response,StartRx.,On-Treatment Roadmap Concept,27,Potential Foundation for Building a CHB Therapeutic Roadmap,On-treatnent early virolog
25、ical response monitoringCan help to identify suboptimal respondersProvides opportunities to modify treatment to enhance antiviral efficacyCan help support individualised treatment mapsHas the potential to improve long-termoutcomes,Response markers act as signposts for clinical management,28,Unresolv
26、ed questionsWhat Is the best on-treatment marker?When Is the best timing for decision points?What Cut-off level for on-treatment decisions?Which Type of initial/add-on therapy?,?,Expert panel convened to evaluate evidence and develop treatment recommendations,Report of an International Workshop:Road
27、map for Management of Patients Receiving Oral Therapy for Chronic Hepatitis BKeeffe EB et al.Clinical Gastroenterology and Hepatology 2007,Proposed New Treatment Algorithm for CHBRecent expert panel and Roadmap publication,Keeffe et al 2007,29,Start treatment,1 log 10 copies/mLdecrease from baseline
28、:primary response,Roadmap ConceptManagement algorithm according to 12-week virologic response,Continue,1log10 copies/mLdecrease from baseline:primary failure,Non-compliant,Compliant,Counsel,Change Tx,Week 12:assessment for primary non-response,Keeffe et al 2007,30,Start treatment,Roadmap ConceptOn-t
29、reatment responses,Complete response PCR negative,Partial response 602000 IU/mL or 30010,000 copies/mL,Inadequate response 2000 IU/mL or 10,000 copies/mL,Week 12:assessment for primary non-response,Week 24:early predictors of efficacy,Keeffe et al 2007,Defined as 300 copies/mL,31,Roadmap ConceptMana
30、gement algorithm for complete response at 24 weeks,Complete response PCR negative,ContinueMonitor 6-monthly,Definition of complete response:PCR negative(300 copies/mL)Interval for monitoring can be prolonged to every 6 monthsIn patients with more advanced disease,monitoring every 3 months or more fr
31、equently,Week 24:early predictors of efficacy,Keeffe et al 2007,Defined as 300 copies/mL,32,Roadmap ConceptManagement algorithm for partial response at 24 weeks,Week 24:early predictors of efficacy,Keeffe et al 2007,Partial response602000 IU/mL or 30010,000 copies/mL,Add another drugwithout cross-re
32、sistance or continueMonitor 3-monthly,33,Inadequate response2000 IU/mL or 10,000 copies/mL,Adapt regimen,Complete response,Partial response,Inadequate response,Roadmap ConceptManagement algorithm for inadequate response at 24 weeks,Week 24:early predictors of efficacy,Keeffe et al 2007,Defined as 30
33、0 copies/mL,34,HBV Roadmap Proposal:Monitoring,Monitor every 3 monthsIf patient achieves complete response by 48 weeks,follow monitoring recommendation(6-monthly)If patient shows continuous decline up to 48 weeks,but still has higher viral load than a complete responder,continue to monitor every 3 m
34、onthsIf patient shows an increase or plateauing of viral level,they should be treated based on roadmap recommendation for inadequate or non-responderIn patients with more advanced disease,more frequent monitoring may be indicated,Keeffe et al 2007,35,Summary and ConclusionsImportance of early monito
35、ring of virologic response to therapy,Early and sustained viral suppression has been associated with prevention of disease progressionHBV DNA is a critical signpost in the on-treatment management of CHBOn-treatment management offers opportunities to optimise treatment responseEssential to identify s
36、uboptimal responsesModify management to enhance antiviral efficacy Potential to improve long-termoutcomes,How should the roadmap be applied to telbivudine?,37,Conclusion fromReport of an International Workshop:Roadmap for Management of Patients Receiving Oral Therapy for Chronic Hepatitis B,Early mo
37、nitoring of the virologic response to therapy in chronic hepatitis B treated with oral nucleos(t)ides is essentialUse of this roadmap should permit improved individualized on-treatment management designed to enhance long-term patient outcomes,1.Keeffe EB,Zeuzem S,Koff RS,Dieterich DT,Esteban-Mur R,G
38、ane E,Jacobson IM,Lim SG,Naoumov NN,Marcellin P,Piratvisuth T,Zoulim F.Clin Gastroenterol Hepatol.In press.,38,Adapted form:Keeffe EB,Zeuzem S,Koff RS,Dieterich DT,Esteban-Mur R,Gane E,Jacobson IM,Lim SG,Naoumov NN,Marcellin P,Piratvisuth T,Zoulim F.Clin Gastroenterol Hepatol.In press.,Start Telbivu
39、dine,Early Virologic Response Efficacy at Week 24,PCR Negative(300 copies/mL),HBV DNA300 copies/mLto 10，000 copies/mL,HBV DNA 10，000 copies/mL,Assessment of Primary Response at week 12,Maintain Telbivudine,How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment?,39,Viral Load Achieved
40、by Week 24:Telbivudine vs.Lamivudine,Di Bisceglie A,et al.Presented at AASLD 2006,HBeAg Positive,HBeAg Negative,*,*,*P 0.05,40,Telbivudine Is A Good Option for Therapy for HBeAg-Positive Patients,49%of Telbivudine Treated PatientsAchieve PCR Negativity(300 copies/mL)at Week 24,86%PCR Negative Week 1
41、04,49%Seroconversion Week 104,2%ResistanceWeek 92,BaselineALT 2 x ULNN=558,85%ALT Normalization Week 104,41,Telbivudine Is A Good Option for Therapy for HBeAg-Negative Patients,80%of Telbivudine Treated PatientsAchieve PCR Negativity(300 copies/mL)at Week 24,88%PCR Negative Week 104N=78/86,2%Resista
42、nce at 92 weeks,49%Seroconversion Week 104,All telbivudine-treatedHBeAg-Negative PatientsN=588,42,Start Telbivudine,Early Virologic Response Efficacy at Week 24,HBV DNAPCR Negative(300 copies/mL),HBV DNA30010,000 copies/mL,HBV DNA 10，000 copies/mL,Maintain Telbivudine Week 52-Monitor HBV DNA closely
43、,How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment?,If PCR NegativeMaintain Telbivudine Monotherapy,If PCR Positive revise treatment strategy,Adapted form:Keeffe EB,Zeuzem S,Koff RS,Dieterich DT,Esteban-Mur R,Gane E,Jacobson IM,Lim SG,Naoumov NN,Marcellin P,Piratvisuth T,Zoulim F
44、.Clin Gastroenterol Hepatol.In press.,43,Start Telbivudine,Early Virologic Response Efficacy at Week 24,PCR Negative(300 copies/mL),HBV DNA30010,000 copies/mL,HBV DNA 10,000 copies/mL,Assessment of Primary Response at week 12,How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment?,Revise treatment strategy,Adapted form:Keeffe EB,Zeuzem S,Koff RS,Dieterich DT,Esteban-Mur R,Gane E,Jacobson IM,Lim SG,Naoumov NN,Marcellin P,Piratvisuth T,Zoulim F.Clin Gastroenterol Hepatol.In press.,44,Thank you for your attention!,
