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1、Roadmap for Management of Patients with Chronic Hepatitis B (CHB) Prof. Xinxin Zhang Rui Jin Hospital Jiao Tong University,2,Introduction Presentation Objectives Data Review: Associations of HBV DNA with Outcomes i. Natural history studies ii. Impact of treatment Key role of HBV DNA in On-Treatment
2、Management i. Timing and magnitude of HBV DNA suppression On-Treatment Roadmap Concept Summary and Conclusions,Contents,3,Introduction Treatment challenges highlight need for new management approach,Treating hepatitis B virus (HBV) infection continues to be a challenge for physicians due to Complica
3、tions arising from chronic 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 exist To establish a new treatment paradigm, we
4、should ask Does long-term suppression 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
5、 CHB?,4,Presentation Objectives,To explore the association between persistent viraemia and hepatitis disease progression To assess the relationship between the degree of viral suppression and clinical outcome To assess the role of early and effective viral load reduction and the association with cli
6、nical outcomes* To review an on-treatment 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.
7、 Natural history studies,6,Correlation 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=
8、0.0001,HAI at baseline,Mommeja-Marin et al 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
9、,HBsAg-positive, untreated participants (n=3,653),Chen et al 2006,9,Evidence for Association Between HBV DNA and Clinical Outcomes,Natural history studies demonstrate Lower HBV DNA levels are associated with better underlying histology High HBV DNA may be an independent predictor for cirrhosis and H
10、CC Sustained suppression of HBV may reduce long-term risk of cirrhosis and HCC Hypothesis needs to be proven prospectively,Data Review: Associations of HBV DNA with Outcomes,ii. Impact of treatment,11,Consistent relationship in treated and untreated patients HBV DNA could be used as a marker of effi
11、cacy,Median HBV DNA level decrease from baseline, log10 copies/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
12、, peg-interferon alfa-2a, or both combined for 48 weeks,Patients with 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
13、Significantly Impacts Disease Progression,HBeAg-positive patients (n=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 an
14、d Profound HBV Suppression: a Critical Goal of Therapy,Outcomes,Primary goal of treatment,Delay in progression to cirrhosis and HCC Improved survival Reduced resistance Increased seroconversion Improved liver histology Normalised alanine aminotransferase (ALT) levels,Sustained suppression of HBV rep
15、lication to the lowest possible level,Fontana 2003; Gauthier et al 1999; Keeffe 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-nega
16、tive patients (n=176) treated with peg-interferon alfa-2a for 48 weeks,P0.001,Farci et 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=qua
17、ntification limit (polymerase chain reaction (PCR)-undetectable at 300 copies/mL by COBAS 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,300 3 log,34 log,4 log,QL,300 3
18、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 Suppression 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,400,400 3 log,35 log,5 log,400,400 3 log,35 log,5 l
19、og,153/195,28/34,47/118,6/15,240/247,20/21,32/38,1/4,BMS Entecavir AVDAC Briefing Document 2005,20,HBeAg 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 Respo
20、nse to Lamivudine Association with higher rates of HBeAg seroconversion,21,n=183,n=54,n=81,n=107,Seroconversion 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,
21、Preliminary data from locked database,22,47/159,8/34,14/117,2/15,Seroconversion at 48 weeks, %,HBV DNA at 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 Vira
22、l Suppression Correlates with Lower Risk of Resistance,Hadziyannis et al 2006; Yuen et al 2001,Patients with 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, %,HB
23、eAg-negative patients (n=125),HBV DNA level at week 48, copies/mL,24,HBeAg-negative patients,Patients with telbivudine resistance week 92, %,n=178,n=16,n=18,n=10,Di Bisceglie et al 2006,Early Viral Suppression with Telbivudine Association with resistance,Preliminary analysis of patients with viral r
24、ebound at week 92,HBV DNA level at week 24, copies/mL,300,3003 log10,3 log104 log10,5 log10,25,HBeAg-positive,HBeAg-negative,Goals of HBV therapy Prevent cirrhosis, liver failure and HCC Improve survival,Signpost,Signpost,Early Viral Suppression Can Be a Signpost for Future Therapeutic Response,Star
25、t Rx.,On-Treatment Roadmap Concept,27,Potential Foundation for Building a CHB Therapeutic Roadmap,On-treatnent early virological response monitoring Can help to identify suboptimal responders Provides opportunities to modify treatment to enhance antiviral efficacy Can help support individualised tre
26、atment maps Has the potential to improve long-term outcomes,Response markers act as signposts for clinical management,28,Unresolved questions What 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
27、 therapy?,? ?,Expert panel convened to evaluate evidence and develop treatment recommendations,Report of an International Workshop: Roadmap for Management of Patients Receiving Oral Therapy for Chronic Hepatitis B Keeffe EB et al. Clinical Gastroenterology and Hepatology 2007,Proposed New Treatment
28、Algorithm for CHB Recent expert panel and Roadmap publication,Keeffe et al 2007,29,Start treatment,1 log 10 copies/mL decrease from baseline: primary response,Roadmap Concept Management algorithm according to 12-week virologic response,Continue,1log10 copies/mL decrease from baseline: primary failur
29、e,Non-compliant,Compliant,Counsel,Change Tx,Week 12: assessment for primary non-response,Keeffe et al 2007,30,Start treatment,Roadmap Concept On-treatment 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,
30、Week 12: assessment for primary non-response,Week 24: early predictors of efficacy,Keeffe et al 2007,Defined as 300 copies/mL,31,Roadmap Concept Management algorithm for complete response at 24 weeks,Complete response PCR negative,Continue Monitor 6-monthly,Definition of complete response: PCR negat
31、ive (300 copies/mL) Interval for monitoring can be prolonged to every 6 months In patients with more advanced disease, monitoring every 3 months or more frequently,Week 24: early predictors of efficacy,Keeffe et al 2007,Defined as 300 copies/mL,32,Roadmap Concept Management algorithm for partial res
32、ponse at 24 weeks,Week 24: early predictors of efficacy,Keeffe et al 2007,Partial response 602000 IU/mL or 30010,000 copies/mL,Add another drug without cross- resistance or continue Monitor 3-monthly,33,Inadequate response 2000 IU/mL or 10,000 copies/mL,Adapt regimen,Complete response,Partial respon
33、se,Inadequate response,Roadmap Concept Management algorithm for inadequate response at 24 weeks,Week 24: early predictors of efficacy,Keeffe et al 2007,Defined as 300 copies/mL,34,HBV Roadmap Proposal: Monitoring,Monitor every 3 months If patient achieves complete response by 48 weeks, follow monito
34、ring 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 months If patient shows an increase or plateauing of viral level, they should be treated based on roadmap recommendation for inad
35、equate or non-responder In patients with more advanced disease, more frequent monitoring may be indicated,Keeffe et al 2007,35,Summary and Conclusions Importance of early monitoring of virologic response to therapy,Early and sustained viral suppression has been associated with prevention of disease
36、progression HBV DNA is a critical signpost in the on-treatment management of CHB On-treatment management offers opportunities to optimise treatment response Essential to identify suboptimal responses Modify management to enhance antiviral efficacy Potential to improve long-term outcomes,How should t
37、he roadmap be applied to telbivudine?,37,Conclusion from Report of an International Workshop: Roadmap for Management of Patients Receiving Oral Therapy for Chronic Hepatitis B,Early monitoring of the virologic response to therapy in chronic hepatitis B treated with oral nucleos(t)ides is essential U
38、se 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, Gane E, Jacobson IM, Lim SG, Naoumov NN, Marcellin P, Piratvisuth T, Zoulim F. Clin Gastroenterol Hepatol. In p
39、ress.,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 Telbivudine,Early Virologic Response Efficacy at Week 24,PCR Negative (300 copies/mL),HBV DNA 3
40、00 copies/mL to 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 by Week 24: Telbivudine vs. Lamivudine,Di Bisceglie A, et al. Presented at AASLD 2006
41、,HBeAg Positive,HBeAg Negative,*,*,* P 0.05,40,Telbivudine Is A Good Option for Therapy for HBeAg-Positive Patients,49% of Telbivudine Treated Patients Achieve PCR Negativity (300 copies/mL) at Week 24,86% PCR Negative Week 104,49% Seroconversion Week 104,2% Resistance Week 92,Baseline ALT 2 x ULN N
42、=558,85% ALT Normalization Week 104,41,Telbivudine Is A Good Option for Therapy for HBeAg-Negative Patients,80% of Telbivudine Treated Patients Achieve PCR Negativity (300 copies/mL) at Week 24,88% PCR Negative Week 104 N=78/86,2% Resistance at 92 weeks,49% Seroconversion Week 104,All telbivudine-tr
43、eated HBeAg-Negative Patients N=588,42,Start Telbivudine,Early Virologic Response Efficacy at Week 24,HBV DNA PCR Negative (300 copies/mL),HBV DNA 30010,000 copies/mL,HBV DNA 10，000 copies/mL,Maintain Telbivudine Week 52 - Monitor HBV DNA closely,How May the HBV Treatment Roadmap be Applied to Telbi
44、vudine Treatment?,If PCR Negative Maintain 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. Clin Gastroenterol Hepatol. In press.,4
45、3,Start Telbivudine,Early Virologic Response Efficacy at Week 24,PCR Negative (300 copies/mL),HBV DNA 30010,000 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!,