1. 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

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

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

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) Marcellin et al, AASLD 2008 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

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 Moucari et al, Hepatology 2009 SVR REL SVR (N=12): HBV DNA < 70 cp/ml at week 48 and 72 REL (n=18): HBV DNA < 70 at week 48

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. Months HBV-DNA (log cp/ml) ALT 206 60 25 40 426 182 40 41 LLQ LAM 100 mg/day 55 year old, HBeAg neg – (May 2003 – May 2005) 024681012141618202224 ADV 10 mg/day L180M and M204V

11. Months HBV-DNA (log cp/ml) ALT 206 60 25 40 426 182 40 41 LLQ LAM 100 mg/day 55 year old, HBeAg neg - May 2003 – May 2005 024681012141618202224 ADV 10 mg/day L180M and M204V

12. Responses on NUC Therapy Primary non-response Less than 1 log 10 IU/mL decrease in HBV DNA level from baseline at 3 months of therapy Virological response Undetectable HBV DNA by real-time PCR assay (<10-15 IU/mL) within 48 weeks of therapy Partial virological response Decrease of HBV DNA of more than 1 log 10 IU/mL but detectable HBV DNA by real-time PCR at 24 or 48 weeks of therapy (according to drug potency and genetic barrier to resistance) Virological breakthrough Confirmed increase in HBV DNA level of more than 1 log 10 IU/mL compared to the nadir HBV resistance to NUCs Selection of HBV variants with amino acid substitutions that confer reduced susceptibility to the administered NUC(s) EASL CPG HBV, J Hepatol 2009, in press

13. 0% 20% 40% 60% 80% 100% Patients with detectable HBV DNA by PCR, % 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. Baseline HBV DNA Week 24 LAM 1 68% 9.5 55% LDT 1 9.5 87% ADV 2 8.9 33% 9.6 ETV 3,4 24% 8.6 TDF 2 29% 20% Week 48 37% 10% 7% 7.66.97.07.77.4 HBeAg-positive HBeAg-negative Partial Virological Response to NUC

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. Case study #3 42 year old male from Greece with moderate HBeAg negative CHB ALTHBV DNA

17. Case Study #3 ALTHBV DNA

18. Case study #3 ALTHBV DNA

19. 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 Months Follow-up Median ALT 0 20 40 60 80 100 246121822 Hadziyannis S. et al, AASLD 2006

20. HBV-DNA levels during follow-up in sustained biochemical responders after stopping ADV treatment 0% 21% 79% 33% 17% 50% 43% 14% 43% 44% 31% 25% 33% 34% 30% 40% 30% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 126121822 FOLLOW-UP MONTH >10,000 copies/mL Detectable <10,000 copies/mL HBV-DNA not detectable 100% 0 70% of patients <10,000c/mL 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 ?