慢性乙型肝炎患者管理（英文版）

1 Roadmap for Management of Patients with Chronic Hepatitis B (CHB) Prof. Xinxin Zhang Rui Jin Hospital Jiao Tong University 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 2 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? 3 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. 4 5 Data Review: Associations of HBV DNA with Outcomes i. Natural history studies 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 246810120 0 2 4 6 8 10 12 Baseline HBV DNA level, log10 copies/mL r=0.78; P=0.0001 HAI at baseline Mommeja-Marin et al 2003 6 2.5 1.4 1.0 5.6 6.5 P1,000,000 10,000999,999 10009999 300999 106 8 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 9 10 Data Review: Associations of HBV DNA with Outcomes ii. Impact of treatment Consistent relationship in treated and untreated patients HBV DNA could be used as a marker of efficacy Median HBV DNA level decrease from baseline, log10 copies/mL HAI improvement from baseline r=0.96; P4 logQL 300 3 log 34 log 4 log Telbivudine Lamivudine 203 14657638379107 165 178 1571820162410 20 18 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 log400 400 3 log 35 log 5 log 153/19528/3447/1186/15240/24720/2132/381/4 BMS Entecavir AVDAC Briefing Document 2005 19 HBeAg seroconversion occurred only in this group 4 6 8 10 2 Baseline81624324048566472 Weeks Median HBV DNA, log10 copies/mL Median 104 (n=11) Median 5 log10 24 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 Signpost Early Viral Suppression Can Be a Signpost for Future Therapeutic Response Start Rx. 25 26 On-Treatment Roadmap Concept 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 27 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 28 Start treatment 1 log 10 copies/mL decrease from baseline: primary response Roadmap Concept Management algorithm according to 12-week virologic response Continue 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 10 10，000 copies/mL000 copies/mL Assessment of Primary Response at week 12 Maintain TelbivudineMaintain Telbivudine How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment? 38 39 Viral Load Achieved by Week 24: Telbivudine vs. Lamivudine Di Bisceglie A, et al. Presented at AASLD 2006 4 Log HBeAg Positive HBeAg Positive HBeAg Negative HBeAg Negative * * * P 10 10，000 copies/mL000 copies/mL Maintain Telbivudine Week 52 - Monitor HBV DNA closely How May the HBV Treatment Roadmap be Applied to Telbivudine Treatment? If PCR NegativeIf PCR Negative Maintain Telbivudine MonotherapyMaintain Telbivudine Monotherapy If PCR Positive revise treatm