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1 Roadmap for Management of Patients with Chronic Hepatitis B (CHB) Prof. Xinxin Zhang Rui Jin...

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  • Slide 1
  • 1 Roadmap for Management of Patients with Chronic Hepatitis B (CHB) Prof. Xinxin Zhang Rui Jin Hospital Jiao Tong University
  • Slide 2
  • 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 Management i. Timing and magnitude of HBV DNA suppression On-Treatment Roadmap Concept Summary and Conclusions Contents
  • Slide 3
  • 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 Complications 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 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 CHB?
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  • 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 clinical 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.
  • Slide 5
  • 5 Data Review: Associations of HBV DNA with Outcomes i. Natural history studies
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  • 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 24681012 0 0 2 4 6 8 10 12 Baseline HBV DNA level, log 10 copies/mL r=0.78; P=0.0001 HAI at baseline Mommeja-Marin et al 2003
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  • 7 2.5 1.4 1.0 5.6 6.5 P1,000,000 10,000999,999 10009999 300999
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  • 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) Chen et al 2006 10 6
  • Slide 9
  • 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 HCC Sustained suppression of HBV may reduce long-term risk of cirrhosis and HCC Hypothesis needs to be proven prospectively
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  • 10 Data Review: Associations of HBV DNA with Outcomes ii. Impact of treatment
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  • 11 Consistent relationship in treated and untreated patients HBV DNA could be used as a marker of efficacy Median HBV DNA level decrease from baseline, log 10 copies/mL HAI improvement from baseline r=0.96; P
  • 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-positiveHBeAg-negative 400 400 3 log 35 log >5 log 400 400 3 log 35 log >5 log 153/19528/3447/1186/15 240/24720/2132/381/4 BMS Entecavir AVDAC Briefing Document 2005
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  • 20 HBeAg seroconversion occurred only in this group 4 6 8 10 2 Baseline 81624324048566472 Weeks Median HBV DNA, log 10 copies/mL Median >10 4 (n=11) Median
  • 24 HBeAg-negative patients Patients with telbivudine resistance week 92, % n=178 n=16n=18n=10 Di Bisceglie et al 2006 Early Viral Suppression with Telbivudine Association with resistance Preliminary analysis of patients with viral rebound at week 92 HBV DNA level at week 24, copies/mL 300 3003 log 10 3 log 10 4 log 10 >5 log 10
  • Slide 25
  • 25 HBeAg loss Liver inflammation and fibrosis HBeAg-positive HBeAg-negative Reduce serum HBV DNA Normal ALT PCR negative Anti-HBeAg sero- conversion HBsAg loss Reduce serum HBV DNA Normal ALT PCR negative HBsAg loss Goals of HBV therapy a) Prevent cirrhosis, liver failure and HCC b) Improve survival Signpost Early Viral Suppression Can Be a Signpost for Future Therapeutic Response Start Rx.
  • Slide 26
  • 26 On-Treatment Roadmap Concept
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  • 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 treatment maps Has the potential to improve long-term outcomes Response markers act as signposts for clinical management Chosen therapy is effective and well tolerated Additional interventions required
  • Slide 28
  • 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 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 Algorithm for CHB Recent expert panel and Roadmap publication Keeffe et al 2007
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  • 29 Start treatment 1 log 10 copies/mL decrease from baseline: primary response Roadmap Concept Management algorithm according to 12-week virologic response Continue
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  • 30 Start treatment Roadmap Concept On-treatment responses Complete response PCR negative Partial response 602000 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
  • Slide 31
  • 31 Roadmap Concept Management algorithm for complete response at 24 weeks Complete response PCR negative Continue Monitor 6-monthly Definition of complete response: PCR negative (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
  • Slide 32
  • 32 Roadmap Concept Management algorithm for partial response at 24 weeks Week 24: early predictors of efficacy Keeffe et al 2007 Partial response 60
  • Slide 33
  • 33 Inadequate response 2000 IU/mL or 10,000 copies/mL Adapt regimen Complete responsePartial responseInadequate response Roadmap Concept Management algorithm for inadequate response at 24 weeks Week 24: early predictors of efficacy Keeffe et al 2007 Defined as
  • Slide 34
  • 34 HBV Roadmap Proposal: Monitoring Monitor every 3 months If 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 months If patient shows an increase or plateauing of viral level, they should be treated based on roadmap recommendation for inadequate or non-responder In patients with more advanced disease, more frequent monitoring may be indicated Keeffe et al 2007
  • Slide 35
  • 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 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
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  • 36 How should the roadmap be applied to telbivudine?
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  • 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 Use 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 press.
  • Slide 38
  • 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 ( 10 000 copies/mL > 10 000 copies/mL Assessment of Primary Response at week 12 Maintain Telbivudine How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment?
  • Slide 39
  • 39 Viral Load Achieved by Week 24: Telbivudine vs. Lamiv

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