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3 rd Paris Hepatitis Conference January, 20th 2009

3 rd Paris Hepatitis Conference January, 20th 2009. How to optimize the management of my HBeAg negative patients?. Pietro Lampertico 1st Gastroenterology Unit Fondazione Policlinico, Mangiagalli e Regina Elena University of Milan Milan - Italy. Case study 1. 35 year old male from Italy

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3 rd Paris Hepatitis Conference January, 20th 2009

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  1. 3rd Paris Hepatitis Conference January, 20th 2009 How to optimize the management of my HBeAg negative patients? Pietro Lampertico 1st Gastroenterology Unit Fondazione Policlinico, Mangiagalli e Regina Elena University of Milan Milan - Italy

  2. Case study 1 • 35 year old male from Italy • LB: mild chronic hepatitis B (Ishak 6+2) • HBeAg negative • ALT: 75 IU • HBV DNA 6.0 log IU/ml • No signs of liver cirrhosis, no previous anti-HBV therapy, no concomitant medications/diseases • How would you manage this patient ?

  3. Case study 1 • PEGIFN alpha 2a, 180 ug/week for 48 weeks • HBV DNA clearance (week 24) • ALT normalization (week 30) • No significant side effects • Biochemical and virological response through week 48 • PEG IFN withdrawal at week 48 • HBV DNA and ALT relapse during follow-up

  4. Peg-IFN α-2a in HBeAg-neg CHBSustained response after 4 years of FUP PEGASYS +/– LAM (N=230) 27 LAM (N=85) 24 P=0.042 18 16 Patients (%) 17 P=0.021 11 7 2 ALT normal <20,000 cp/mL ~4,000 IU/mL <400 cp/mL <~100 IU/mL Cleared HBsAg ModifiedITT analysis, missing data = non response Marcellin et al, EASL 2008

  5. Predictive value of HBsAg reduction/level at week 48 for HBsAg clearance at 3 years HBsAg reduction from BL to week 48 HBsAg level at week 48 RR = 22.8 (95% CI 8 – 649) P<0.0001 RR = 14.6 (95% CI 5.5 – 38.5) P<0.0001 52% Patients withHBsAg clearance (%) 42% 2% 3% 12/23 4/171 11/26 5/172 >10 IU/mL <10 IU/mL >2 log IU/mL <2 logIU/mL Brunetto et al. EASL 2008

  6. Sustained response rates to PEG-IFN according to qHBsAg at week 12 on treatment in 156 patients HBsAg levels ≤1500 IU/mL (n=61) HBsAg levels >1500 IU/mL (n=95) An HBsAg cut-off of 1500 IU/mL at week 12 resulted in a PPV of 39%, 31% and 23% for achieving HBV DNA levels ≤10,000 copies/mL, ≤400 copies/mL and HBsAg clearance 4 years post treatment. The corresponding NPV were 88%, 92% and 96%, respectively Marcellin et al, AASLD 2008

  7. 48-wk PEG alpha 2a for HBeAg-neg patients: kinetics of HBV DNA and qHBsAg in SVR* and REL HBV DNA levels HBsAg levels REL REL SVR SVR SVR (N=12): HBV DNA < 70 cp/ml at week 48 and 72 REL (n=18): HBV DNA < 70 at week 48 Moucari et al, Hepatology 2009

  8. 48-wk PEG apha 2a for HBeAg-neg patients: serum HBsAg levels at week 12 and 24 Moucari et al, Hepatology 2009

  9. Case study #1 - Discussion • How many HBeAg negative patients do you treat with PEG? • Do you treat only high ALT, low HBV DNA and non-D pts? • Endpoint: HBV DNA < 2000 U or PCR undetectable ? • Stopping rules for PEG on therapy? • Do you check for HBsAg titers ? • Do you rescue all patients with detectable HBV DNA ? • Do you treat with PEG patients with compensated cirrhosis ?

  10. 0 2 4 6 8 10 12 14 16 18 20 22 24 55 year old, HBeAg neg – (May 2003 – May 2005) ALT 206 60 25 40 426 182 40 41 LAM 100 mg/day ADV 10 mg/day L180M and M204V HBV-DNA (log cp/ml) LLQ Months

  11. 0 2 4 6 8 10 12 14 16 18 20 22 24 55 year old, HBeAg neg - May 2003 – May 2005 ALT 206 60 25 40 426 182 40 41 LAM 100 mg/day ADV 10 mg/day L180M and M204V HBV-DNA (log cp/ml) LLQ Months

  12. Responses on NUC Therapy EASL CPG HBV, J Hepatol 2009, in press

  13. Partial Virological Response to NUC Week 24 Week 48 100% 87% 80% 68% HBeAg-positive HBeAg-negative 60% 55% Patients with detectable HBV DNA by PCR, % 40% 37% 33% 29% 24% 20% 20% 10% 7% 0% LAM1 LDT1 ADV2 ETV3,4 TDF2 Baseline HBV DNA 9.5 7.4 9.5 7.7 8.9 7.0 9.6 7.6 8.6 6.9 1) Lai C-L et al. NEJM 2007;357:2576-88; 2) Marcellin P et al, NEJM 2008;359:2442-55; 3) Chang T-T, et al. NEJM 2006;354:1001-10; 4) Lai C-L et al. NEJM 2006;354:1011-20.

  14. Partial Virological Response • Check for compliance • Patients receiving LAM, ADV or LDT with a partial virological response at week 24: • Either change to a more potent drug (TDF or ETV) • Or add a more potent drug that does not share cross-resistance • Patients receiving TDF or ETV with a partial virological response at week 48: • Add the other drug in order to prevent resistance in the long term EASL CPG HBV, J Hepatol 2009, in press

  15. Case study #2 - Discussion • How do you manage Partial Virological Responders (PVR) ? • Do you follow EASL guidelines ? • Do you rescue PVR with LAM, LDT at week 24 ? • Do you rescue PVR with ADV, ETV, TDF at week 48 ? • How do you rescue: switch vs add on ?

  16. ADV 10mg/day 200 1,E+08 12,545,500 1,E+07 160 1,E+06 120 1,E+05 265,500 ALT/AST (IU/L) Logs HBV-DNA 1,E+04 80 1,E+03 40 1,E+02 0 1,E+01 3 6 9 12 OL2 OL5 OL8 SCR Fup2 Fup5 Fup8 OL29 OL32 OL17 OL20 OL23 OL26 OL35 OL11 OL14 Fup14 Fup17 Fup23 Fup11 Fup20 Months Case study #342 year old male from Greece with moderate HBeAg negative CHB ALT HBV DNA

  17. ADV 10mg/day 200 1,E+08 12,545,500 1,E+07 160 1,E+06 120 1,E+05 265,500 ALT/AST (IU/L) Logs HBV-DNA 1,E+04 80 1,E+03 40 1,E+02 0 1,E+01 3 6 9 12 OL2 OL5 OL8 SCR Fup2 Fup5 Fup8 OL29 OL32 OL17 OL20 OL23 OL26 OL35 OL11 OL14 Fup14 Fup17 Fup23 Fup11 Fup20 Months Case Study #3 ALT HBV DNA

  18. ADV 10mg/day 200 1,E+08 12,545,500 1,E+07 160 1,E+06 120 1,E+05 265,500 ALT/AST (IU/L) Logs HBV-DNA 1,E+04 80 1,E+03 40 1,E+02 0 1,E+01 3 6 9 12 OL2 OL5 OL8 SCR Fup2 Fup5 Fup8 OL29 OL32 OL17 OL20 OL23 OL26 OL35 OL11 OL14 Fup14 Fup17 Fup23 Fup11 Fup20 Months Case study #3 ALT HBV DNA

  19. 100 80 60 Median ALT 40 20 0 2 4 6 12 18 22 Months Follow-up Median ALT levels (IU/L) during 22 months of follow-up after stopping 4 or 5 yrs of ADV therapy. Results among patients in sustained biochemical remission ULN Hadziyannis S. et al, AASLD 2006

  20. HBV-DNA levels during follow-up in sustained biochemical responders after stopping ADV treatment >10,000 copies/mL 100% 90% 25% 30% Detectable <10,000 copies/mL 34% 43% 80% 50% 70% HBV-DNA not detectable 100% 79% 31% 60% 70% of patients <10,000 c/mL 14% 40% 33% 50% 17% 40% 30% 44% 43% 20% 33% 33% 30% 21% 10% 0% 0% 0 1 2 6 12 18 22 FOLLOW-UP MONTH Hadziyannis S. et al, AASLD 2006

  21. Case study #3 - Discussion • Stopping rules for HBeAg negative CHB on NUCs ? • Do you follow EASL guidelines ? • Would you stop a NUC in a 5 year long-term responder ? • How frequent do you monitor HBV DNA on therapy ? • Side effects on long term NUC therapy ?

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