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Professor George KK Lau The University of Hong Kong Hong Kong SAR, China

HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated interferon. Professor George KK Lau The University of Hong Kong Hong Kong SAR, China. Positivity for HBeAg is Associated with an Increased Risk of HCC – Taiwanese Data. 12 10 8 6 4 2 0. HBsAg+, HBeAg+.

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Professor George KK Lau The University of Hong Kong Hong Kong SAR, China

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  1. HBeAg-positive chronic hepatitis B:whydoI treatmy patientswithpegylated interferon Professor George KK Lau The University of Hong Kong Hong Kong SAR, China

  2. Positivity for HBeAg is Associated withan Increased Risk of HCC – Taiwanese Data 12 10 8 6 4 2 0 HBsAg+, HBeAg+ Percent cumulative incidence HBsAg+, HBeAg– HBsAg–, HBeAg– 0 1 2 3 4 5 6 7 8 9 10 Year Yang et al. NEJM 2002

  3. Spontaneous HBeAg Seroconversion Confers Favorable Long-term Outcomes Hsu. Hepatology 2007.

  4. Timing is important: earlier seroconversion is associated with reduced risk of cirrhosis 35 30 25 20 15 10 5 0 Hazard ratio* = 3.4(95% CI 1.4–8.2) % of patients with cirrhosis <30 30-39 40-49 ≥50 Age of HBeAg seroconversion (years) Longitudinal study of 240 patients with normal ALT at baseline * Hazard ratio for progression to cirrhosis for each decade without HBeAg seroconversion Chu & Liaw 2007

  5. Long-term Outcome of IFN Treatment inHBeAg-positive CHB: 11-year Follow-up Follow-up: mean 11 years (median 6.6 years; range: 1.1 to 16.5 years) *p vs control Lin et al. EASL 2005 and J Hepatol 2007

  6. Meta-analysis: Effect of IFN treatment on HCC Twelve studies (n = 2742) enrolling patients treated by IFN vs. control showed that the risk of HCC after treatment was reduced by 34% (RR:0.66, 95% CI: 0.48–0.89). Sung et al Aliment Pharmacol Ther 2008

  7. Favourable long-term outcome following HBeAg seroconversion HBeAg loss HBeAg seroconversion Disease remission HBsAg loss/seroconversion Prevention of HCC Increased survival Hoofnagle Ann Intern Med 1981; Fattovich Hepatology 1986;Di Bisceglie Gastroenterology 1987;Niederau NEJM 1996; Chu Gastroenterology 2002; van Zonneveld Hepatology 2004

  8. Registered treatment of CHB-2009

  9. What are the response rates with longer-term treatment with NAs? NAs on-treatment PEGASYSoff-treatment 24wk 48wk LdT ADV ETV LAM 48 48 HBeAg response (%) 39 36 32 32 31 30 29 25 22 21 21 12 1 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 1 2 3 4 5 Years of treatment

  10. of resistance (%) Cumulative incidence Resistance Profiles of antiviral agents Genotypic resistance to adefovir2 Genotypic resistance to lamivudine1 100 100 HBeAg(+) HBeAg(-) 80 80 71 65 55 60 60 46 Prevalence of resistance (%) of resistance (%) Cumulative probability 40 40 29 23 18 20 20 11 3 0 0 0 1 2 3 4 5 1 2 3 4 5 Year of treatment Year of treatment Viral rebound with genotypic resistance to entecavir5 100 100 Viral rebound with genotypic resistance to telbivudine3,4 HBeAg(+) and (-) patients Nucleoside naive Lamivudine refractory 80 80 HBeAg(+) HBeAg(-) 60 60 Cumulative Probability of Resistance (%) 40 40 22 16 15 10 20 20 9 4 3 <1 <1 <1 <1 <1 0 0 1 2 3 4 5 1 2 3 4 5 Year of treatment Year of treatment 1. Lok AS, et al. Gastroenterology. 2003;125:1714-22. 2. Borroto-Esoda K. J Hepatol. 2006;44(suppl 2):S179-80 (Poster 483). 3. Standrigg DN, et al. J Hepatol. 2006;44(suppl 2):S191 (Poster 514). 4. Lai CL, et al. Hepatology. 2006;44(4 suppl 1):222A (Oral 91). 5. Colonno et al. J Hepatol 2007;46(suppl 1):S293 (oral 781).

  11. Peginterferon alfa-2b (12KD) in HBeAg-positive CHB Patients with HBeAg-positive CHB were randomised using a 1:1 ratio ITT population: n=266 End of Treatment (52 weeks) End of Follow-up (78 weeks) Peginterferon alfa-2b (12KD) 100 g qw* + oral placebo 26 week follow-up Peginterferon alfa-2b (12KD) 100 g qw*+ lamivudine 100 mg od 0 52 78 Study weeks * PEG-IFN-2b (12KD) dose reduced to 50 g qwafter 32 weeks Off-label Product Use Janssen et al Lancet 2005

  12. HBeAg Loss Peginterferon alfa-2b (12KD) + placebo Peginterferon alfa-2b (12KD) + lamivudine P=0.01 P=0.91 44% 36% 35% Patients (%) 29% End of Follow-up (Week 78) End of Treatment (Week 52) Janssen et al Lancet 2005 Relapse at wk 78 : 5/40 (13%) Vs 22/57 (39%), p=0.005 Janssen et al Gut 2007

  13. Long-Term Follow-Up of Peginterferon and Lamivudine Combination Treatment in HBeAg-Positive CHB Chan LY Hepatology 2005

  14. HBeAg Seroconversion* in Asian Patients(6 Months Post-treatment) Overall population: HBeAg seroconversion 32% in PEGASYS monotherapy arm P=0.005 NS P=0.02 31% 29% Patients (%) 19% n=238 n=238 n=232 PEGASYS + placebo PEGASYS + lamivudine Lamivudine *HBeAg loss and presence of anti-HBe ABs

  15. 42% Overall response 14% of initial non-responders developed a late response 6–12 months post-treatment 86% of initial responders maintained response after 1 year 14/103 59/69 HBeAg Seroconversion Long-term Roll-over Study: 1 Year Analysis • 173 patients from the PEGASYS mono therapy arm entered the long-term study (63% of original study): 69 responders and 103 non responders 50 40 32% 30 Patients (%) 20 10 87/271 0 Initial study1 24 weeks post-treatment Long-term study2 48 weeks post-treatment 1. Lau et al. N Engl J Med 2005; 2. Lau et al. EASL 2006

  16. HBsAg need to be cleared before the development of cirrhosis *only in those with HCV/HDV co-infection 1Fattovich et al Am J Gastro 1998; 2Liaw et al Gastroenterology 2002

  17. Immunosuppressed Advanced liver disease IFN/PEG-IFN non-responders Immunocompetent Compensated liver disease Younger patients NA-failures/resistant High ALT Low HBV DNA Liver lesions Who should be treated with what? Direct antivirals Interferon-based Patient/physician preference Consider risk of drug resistance Length of treatment Side effects NA treatment should not be prescribed until the PATIENT understands that they CANNOT be stopped abruptly for any reason

  18. NAs Long-term maintenance (years) Risk of resistance, and cross-resistance – monitor closely Use in combination? Prescribe responsibly PEGASYS Short-term, finite duration (48 wks) Long-term benefit in ~1/3 pts HBsAg seroconversion achievable No resistance Prior exposure to NAs not a barrier to tx Optimising response in HBeAg-positive CHB through immune control ! For patients who do not respond or for whom IFN contraindicatedwe need to know how to use NAs appropriately

  19. Summary: Treatment Algorithm to Improve Clinical Outcomes Survival 1st choice Aiming for sustained remission Using a treatment of finite duration eg pegylated or conventional IFN 2nd choice Maintained remission Using a treatment of indefinite duration eg nucleos(t)ide analogues Sustainedremission no* yes *or IFN contraindicated / not tolerated Lau GK, Marion P Hepatol Int 2008

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