How to optimize the management of my HBeAg negative patients? 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

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 ?

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

Peg-IFN α-2a in HBeAg-neg CHB Sustained response after 4 years of FUP PEGASYS +/– LAM (N=230) 27 LAM (N=85) 24 P=0.042 18 Patients (%) 16 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 Modified ITT analysis, missing data = non response Marcellin et al, EASL 2008

Patients with HBsAg clearance (%) 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 = 14.6 (95% CI 5.5 – 38.5) P<0.0001 RR = 22.8 (95% CI 8 – 649) P<0.0001 52% Patients with HBsAg clearance (%) 42% 3% 2% 11/26 5/172 12/23 4/171 >2 log IU/mL <2 log IU/mL <10 IU/mL >10 IU/mL Brunetto et al. EASL 2008

HBsAg levels ≤1500 IU/mL (n=61) HBsAg levels >1500 IU/mL 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

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

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

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 ?

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 2 4 6 8 10 12 14 16 18 20 22 24 Months

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 2 4 6 8 10 12 14 16 18 20 22 24 Months

Responses on NUC Therapy Primary non-response Less than 1 log10 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 log10 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 log10 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

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% At week 24, 45% of telbivudine HBeAg-positive patients had nondetectable HBV DNA (vs 32% of HBeAg-positive lamivudine patients). Of these patients, the seroconversion rate for telbivudine was 46% at 104 weeks. The seroconversion rate for all patients receiving telbivudine was 30% at 104 weeks. Di Bisceglie AM, et al. Telbivudine GLOBE trial: maximal early HBV suppression is predictive of optimal two-year efficacy in nucleoside-treated hepatitis B patients. Hepatology. 2006;44(4 suppl 1):230A. Abstract 112. 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

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 ?

Case study #3 42 year old male from Greece with moderate HBeAg negative CHB 12,545,500 265,500 40 80 120 160 200 SCR 3 6 9 12 OL2 OL5 OL8 OL11 OL14 OL17 OL20 OL23 OL26 OL29 OL32 OL35 Fup2 Fup5 Fup8 Fup11 Fup14 Fup17 Fup20 Fup23 Months ALT/AST (IU/L) 1,E+01 1,E+02 1,E+03 1,E+04 1,E+05 1,E+06 1,E+07 1,E+08 Logs HBV-DNA ADV 10mg/day ALT HBV DNA

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

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

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 Months Follow-up Median ALT 20 40 60 80 100 2 4 6 12 18 22 ULN Hadziyannis S. et al, AASLD 2006

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

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 ?