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

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Presentation on theme: "1 Roadmap for Management of Patients with Chronic Hepatitis B (CHB) Prof. Xinxin Zhang Rui Jin Hospital Jiao Tong University."— Presentation transcript:

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

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

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?

4 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.

5 5 Data Review: Associations of HBV DNA with Outcomes i. Natural history studies

6 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

7 7 2.5 1.4 1.0 5.6 6.5 P<0.001 (log-rank test) Multivariate adjusted hazard ratio 0 10 20 30 40 012345678910111213 Year of follow-up Cumulative incidence of cirrhosis, % >1,000,000 10,000–999,999 1000–9999 300–999 <300 HBV DNA at entry, copies/mL: Cirrhosis: Association with Baseline HBV DNA Taiwan natural history study Iloeje et al 2006

8 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 <300300–10 3 10 3 –10 4 10 4 –10 6 >10 6

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

10 10 Data Review: Associations of HBV DNA with Outcomes ii. Impact of treatment

11 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<0.000003 12345 –2 –1 0 1 2 3 4 5 Mommeja-Marin et al 2003 Correlation Between HBV DNA and Histologic Activity Index (HAI) in Treated Patients

12 12 P<0.001 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 with histological response at week 72, % Marcellin et al 2004 Viral Suppression at Week 72 is Associated with Histologic Improvement 105/329116/208

13 13 Months 0 5 10 15 20 25 061218243036 13% 21% 5% Liaw 2005 Patients with disease progression, % Viral Suppression Significantly Impacts Disease Progression Lamivudine – Wild type Lamivudine – YMDDm Placebo HBeAg-positive patients (n=651) treated with lamivudine or placebo

14 14 Viral Suppression Improves Outcomes Studies reporting associations with outcomes OutcomeCitation(s) Improved clinical outcomes after response to interferon alfa (HBeAg+ or HBeAg-) – Niederau et al 1996 – Papatheodoridis et al 2001 – van Zonneveld et al 2004 – Lin et al 2005 Improved clinical outcomes with lamivudine long-term viral suppression – DiMarco et al 2004 – Liaw et al 2004 – Papatheodoridis et al 2005 Decreased clinical events, improved Child-Pugh scores, decreased HCC in patients with advanced liver disease treated with lamivudine – Liaw et al 2004 Improved virological, biochemical, and clinical parameters in lamivudine-resistant patients with decompensated cirrhosis treated with adefovir – Schiff et al 2004

15 15 Key Role of HBV DNA in On-Treatment Management i. Timing and magnitude of HBV DNA suppression

16 16 Rapid and 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 replication 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 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 P<0.001 Farci et al 2005 Viral Suppression with Peg-Interferon alfa-2a Association with subsequent HBV DNA response

18 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 ® 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 3–4 log >4 log ≤QL 300– 3 log 3–4 log >4 log Telbivudine Lamivudine 20314657638379107165 1781571820162410 20

19 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 3–5 log >5 log ≤400 400– 3 log 3–5 log >5 log 153/19528/3447/1186/15 240/24720/2132/381/4 BMS Entecavir AVDAC Briefing Document 2005

20 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 <10 4 (n=12) 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 21 n=183n=54n=81n=107 Seroconversion at 2 years, % Serum HBV DNA level at 24 weeks, log 10 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 22 47/1598/3414/1172/15 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 23 Profound, Early Viral 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 1/123/2313/4176/118 Patients with ADV resistance at week 192, % HBeAg-negative patients (n=125) HBV DNA level at week 48, copies/mL

24 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 ≤300 300–3 log 10 3 log 10 –4 log 10 >5 log 10

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.

26 26 On-Treatment Roadmap Concept

27 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

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

29 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 failure Non-compliantCompliant CounselChange Tx Week 12: assessment for primary non-response Keeffe et al 2007

30 30 Start treatment Roadmap Concept On-treatment responses Complete response PCR negative † Partial response ≥60–<2000 IU/mL or ≥300–<10,000 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 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 <300 copies/mL

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–<2000 IU/mL or ≥300–<10,000 copies/mL Add another drug without cross- resistance or continue Monitor 3-monthly

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 <300 copies/mL

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

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

36 36 How should the roadmap be applied to telbivudine?

37 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.

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 (<300 copies/mL) (<300 copies/mL) HBV DNA 300 copies/mL to 10 , 000 copies/mL HBV DNA > 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?

39 39 Viral Load Achieved by Week 24: Telbivudine vs. Lamivudine Di Bisceglie A, et al. Presented at AASLD 2006 <QLQL-3 Log3-4 Log>4 Log HBeAg Positive HBeAg Negative * * * P < 0.05

40 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 at Week 24 86% PCR Negative PCR Negative Week 104 49%Seroconversion 2% Resistance Week 92 Baseline ALT ≥ 2 x ULN N=558 85% ALT Normalization ALT Normalization Week 104

41 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 at Week 24 88% PCR Negative Week 104 N=78/86 2% Resistance at 92 weeks 49%Seroconversion Week 104 All telbivudine-treated HBeAg-Negative Patients N=588

42 42 Start Telbivudine Early Virologic Response Efficacy at Week 24 HBV DNA PCR Negative (<300 copies/mL) HBV DNA ≥300–<10,000 copies/mL HBV DNA > 10 , 000 copies/mL > 10 , 000 copies/mL Maintain Telbivudine Week 52 - Monitor HBV DNA closely How May the HBV Treatment Roadmap be Applied to Telbivudine 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.

43 43 Start Telbivudine Early Virologic Response Efficacy at Week 24 PCR Negative (<300 copies/mL) (<300 copies/mL) HBV DNA ≥300–<10,000 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.

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