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George LAU

George LAU. Hepatitis B e antigen positive patients: Why do I treat my patient with pegylated interferon? 2nd Hepatitis Paris conference. George KK Lau, M.D. The University of Hong Kong. What do we want to achieve in treating HBeAg+ CHB patients?. HBeAg loss. HBeAg seroconversion.

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George LAU

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  1. George LAU

  2. Hepatitis B e antigen positive patients: Why do I treat my patient with pegylated interferon? 2nd Hepatitis Paris conference George KK Lau, M.D. The University of Hong Kong

  3. What do we want to achieve in treating HBeAg+ CHB patients? HBeAg loss HBeAg seroconversion Disease remission (↓ HBV DNA; ↓ ALT) HBsAg loss/seroconversion Prevention of HCC and cirrhosis Increased survival Hoofnagle et al. Ann Intern Med 1981; Fattovich et al. Hepatology 1986; Di Bisceglie et al. Gastroenterology 1987; Niederau et al. NEJM 1996; Chu et al. Gastroenterology 2002; van Zonneveld et al. Hepatology 2004

  4. Why is serological clearance of HBeAgHBsAg important? Study of HBV progression and HCC in 11,893 men in Taiwan HBsAgHBeAgALTRelative Risk -- -- normal 1 (23/71,105 person-yr) ---- elevated 5.4 +-- normal 10.3 + -- elevated 29.3 + + normal 61.3 + + elevated 109 Yang et al., NEJM 2002

  5. Registered treatment of chronic hepatitis B-2007

  6. Peginterferon- trials on HBeAg positive CHB Hui et al Semin Liv Disease 2006

  7. PEGASYS in CHB: Phase III Study Designs HBeAg-positive CHB – ITT population: n=814 End of Treatment 48 weeks End of Follow-up 72 weeks Randomised PEGASYS 180 g qw + oral placebo qd 24 week follow-up PEGASYS 180 g qw + lamivudine 100 mg qd Lamivudine 100 mg qd 0 24 48 72 Study weeks Lau et al. NEJM 2005

  8. HBeAg Seroconversion Rates at End of Follow-up On-treatment Follow-up P<0.001 10 32% P=0.023 27% -2.0 8 -2.6 Mean HBV DNA (log10 copies/mL) -2.4 19% 6 -4.5* -5.8* 4 -7.2* n=271 n=271 n=272 2 PEGASYS PEGASYS + LAM LAM 0 6 12 18 24 30 36 42 48 54 60 66 72 HBV DNA Levels Over Time plus HBeAg Seroconversion at End of Follow-up 12 Study week *all numbers shown are log10 reduction from baseline

  9. HBV DNA Suppression in Patients Achieving HBeAg Seroconversion 12 On-treatment Follow-up 10 8 patients with HBeAg seroconversion maintained DNA levels <10,000 cp/mL Mean HBV DNA (log10 copies/mL) 6 10,000 cp/mL 4 3.3 2 0 0 6 12 18 24 30 36 42 48 54 60 66 72 Study week Fried et al. EASL 2005

  10. Incidence of Hepatocellular Carcinoma (HCC) by HBV DNA Level 14.89 12.17 Cumulative Incidence of HCC (%)* 3.57 1.30 1.37 105–106 <104 PCR negative 104–105 ≥106 Level of HBV DNA (cp/mL) *at the end of the 19th year of follow-up Chen et al. JAMA 2006

  11. End of Treatment HBeAg seroconversion in Relation to Extent of HBV DNA Suppression (%) HBeAg seroconversion at end of treatment (%) ETV LAM LAM Peg-2a + LAM Peg-2a Peg-2b Peg-2b + LAM No 354 355 272 271 271 136 130 69% 38% 40% 69% 25% 10% 33% DNA <400cp/ml Lau NEJM 2005 Chang NEJM 2006 Janssen Lancet 2005

  12. Serological clearance of HBsAg with current treatment (~1 yr) Spontaneous HBsAg clearance in Chinese-0.1-0.8%/yr *HBeAg loss 1Lai et al NEJM 1998, 2Marcellin et al NEJM 2003, 3Poynard et al. J Hepatol 2004, 4Chang et al. Hepatology 2004, 5Lau et al. NEJM 2005, 6 Lau et al Gastroenterology 2002

  13. On-therapy Response to Long-term Nucleos(t)ide Analog Therapy in HBeAg-positive CHB Lamivudine1 Adefovir2 43% Patients with HBeAg seroconversion (%) 35% 29% 28% 23% 17% 16% 12% NA NA Years NA = not available 1. Lok et al Gastroenterology 2004; 2. Marcellin et al AASLD 2004

  14. Identified Mutations Associated with Drug Resistance Pol/RT RNaseH spacer Terminal protein 1 349 692 845 a.a. 183 (rt1) (rt 344) YMDD GVGLSPFLLA I(G) II(F) A B C D E V173L L180M M204I/V LAM1/ FTC2 ADV 3 N236T A181V ETV *4 T184A/G/I/S S202G/I M250V LdT5 M204I 3 Qi X, et al. J Hepatol 2004, 40 (suppl 1): 20-21 4 Tenney et al. AAC. 2004:48:3498-507 5 Lai CL, et al. Hepatology 2003; 38: 262A 6 Soriano V et al, AASLD 2004 * All ETV resistance require background YMDD mutations 1 Allen MI, et al. Hepatology 1998; 27:1670-1677 2 Gilead data on file

  15. Long-Term Safety of Lamivudine in HBeAg Positive CHBHepatitis Flares • Hepatitis flares(ALT >3 x ULN) more frequent in patients with lamivudine resistance (P < .005) • Hepatitis flares increased with duration of lamivudine resistance (P < .001) 3–5 x ULN 5–10 x ULN n = 998 100 75 50 25 0 >10 x ULN % of Patients with Hepatitis Flare Not <1 1–2 2–3 3–4 >4 detected Duration of Lamivudine-ResistantMutations (Years) Lok ASF, et al. Gastroenterology. 2003;125:1714.

  16. HBeAg Relapse Following Lamivudine and IFN Cumulative rate of relapse in patients who had achieved HBeAg seroconversion by end of treatment 100 90 80 70 LAM 60 Cumulative % relapse of HBeAg seroconversion 54% 50 40 IFN 32% 30 20 10 0 26 52 78 104 130 156 Time (weeks) after the end of therapy van Nunen et al. Gut 2003

  17. Adverse Events experienced in Chronic HBeAg+ patients * AEs with an incidence of >10% in one treatment arm during treatment and up to 8 weeks post-therapy

  18. Long-term Follow-up Study: 1-year Analysis Initial study* Long-term study PEGASYS 180 μg qw + placebo qd PEGASYS 180 μg qw + 100 mg lam qd ** Lamivudine 100 mg qd 48 weeks EOT (week 48) 6 monthspost EOT (week 72) 12 monthspost-EOT (week 96) 5 years post-EOT * Lau et al. NEJM 2005; Marcellin et al. NEJM 2004 **1-year analysis of patients from initial study who completed 6-month follow-up

  19. HBeAg Seroconversion: 40% of Asian Patients Achieved Sustained Responses 1 year Post-treatment • Over 80% of patients with responses 6 months post-treatment sustained these responses 1 year post-treatment Entered long-term study Initial study 40% Late responders 39% 31% (83%) Patients achieving HBeAg seroconversion (%) Sustained responders n=238 n=58/150 n=60/150 Week 48 Week 72 Week 96 Time point Lau et al. Shanghai Hong Kong Liver Congress 2006

  20. HBV DNA Levels 1 Year Post-treatment According to Type of Response HBV DNA 1 year post-treatment (copies/ml) No HBeAg Seroconversion (n=67) Sustained HBeAg Seroconversion (n=53) Late HBeAg Seroconversion (n=13)

  21. Long-term follow-up on CHB patients with active hepatitis or advance fibrosis/cirrhosis Rx with IFN-based therapy Lau GK. J Hepatol 2007

  22. Pros and cons of available treatment options

  23. Significant* Baseline Predictors of Response 24 Weeks Post-treatment *P<0.05 by MV analysis; **ALT normalisation and HBV DNA <20,000 cp/mL Roche data on file

  24. HBsAg-seroconversion by Genotype PEG-IFN α-2b 1 PEG-IFN α-2a 2 24 24 22% 21 21 18 18 15% 15 15 Percentage of patients (%) Percentage of patients (%) 12 12 8% 9 9 5% 6 6 2% 3 3 0% 0% 0% 0 0 B n=12 C n=21 D n=51 B n=76 C n=162 D n=9 A n=47 A n=23 HBV genotype HBV genotype 1 Flink, Am J Gastroenterol 2006; 2 Hadziyannis, EASL 2005

  25. 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

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