Optimizing current therapy in CHB M. J. Sonneveld, MD PhD MSc

Transcription

1 Optimizing current therapy in CHB M. J. Sonneveld, MD PhD MSc Erasmus MC University Medical Center Rotterdam The Netherlands

2 Disclosures I have received speakers fees and research support from Roche, BMS, Merck and Innogenetics

3 Hepatitis B: treatment options Peginterferon Nucleos(t)ide analogues

4 PEG-IFN Treatment options Off-treatment sustained response: peginterferon HBeAg seroconversion Low HBV DNA undetectable HBV DNA HBsAg loss Treatment maintained response: direct antivirals Nucleos(t)ide analogue Undetectable HBV DNA during therapy HBsAg loss years

5 Question 1 Does treatment with NUCs eliminate the risk of HCC?

6 Nearly all patients achieve undetectable HBV DNA during ETV therapy 243 NUC naïve patients treated with ETV HBeAg-negative 89% 99% 90% 60 HBeAg-positive Nearly all patients achieved undetectable HBV DNA % Time (weeks) Zoutendijk et al. Hepatology 2011; Arends & Sonneveld, Gut 2015

7 Disease progression (% patients) Lamivudine Reduces Cirrhosis Progression Study of 651 HBeAg-positive or HBeAg-negative patients randomly assigned to receive lamivudine (LAM) or placebo Placebo p=0.001 Lamivudine Time (months) Liaw, NEJM 2004

8 Lim, Gastroenterology 2014; Cumulative probability of HCC High risk of HCC in cirrhosis with ETV or LAM ETV LAM Log rank test: P= % Years since NUC initiation 6

9 Cumulative probability of HCC HBV DNA suppression alone does not annihilate the risk of HCC Annual HCC rate No cirrhosis 0.5% Cirrhosis 4% 0.40 Log rank test: P<0.001 Dec. cirrhosis 6% % 23.8% 20.9% % % 2.5% 1.2% 2.5% % Years since NUC initiation Papatheodoridis, JHEP 2015; Arends & Sonneveld, Gut 2015

10 HBsAg levels predict the risk of HCC in (untreated) HBeAg-negative patients with low HBV DNA ERADICATE-B (2688 HBV Carrier) Risiko for HCC (per 100,000 person years) HBV DNA IU/ml HBV DNA IU/ml HBV DNA IU/ml HBV DNA IU/ml HBV DNA <200 IU/ml HBV DNA <2000 IU/ml and HBsAg 1000 IU/ml 5x elevated risk HBV DNA <2000 IU/ml and HBsAg <1000 IU/ml Tseng, Kao et al. Gastroenterology 2012; Chan HL. Gastroenterology 2012

11 HBsAg clearance remains essential despite HBV DNA suppression in NUC treated patients Kim, Gut 2013

12 Question 2 Is stopping NUC therapy feasible in HBsAg-positive patients?

13 Long-term therapy required before HBsAg loss in NUC treated patients 0 HBsAg -1-2 Baseline VR VR+1 VR+2 HBV DNA HBeAg-positive HBeAg-negative HBeAg-positive High ALT Years to HBsAg loss* 36.4 [9.6; 98.3] 38.9 [1.3; 80.5] 19.5 [7.3; 99.9] Zoutendijk et al. AASLD 2010; Zoutendijk et al. JID 2011

14 Outcome after NUC discontinuation 100 HBeAg positive % % 60% 56% 30% 46% 40% 36% Lee Pan Chi Cai % 6% 10% 0% Relapse SVR HBsAg loss Lee HW, et al. Hepatology 2010; 51: Pan X, et al. PLoS ONE 2013; 8: e68568 Chi H, et al. Aliment Pharmacol Ther. 2015; 41:867:76 Cai W, et al. J Clin Virol. 2010;48:22-6

15 Outcome after NUC discontinuation % 91% HBeAg negative % 44% 45% 55% 50% 55% 39% Hadziyannis Patwardhan Chi Seto Jeng % 3% 12% Relapse SVR HBsAg loss 0% Hadziyannis SJ, et al. Gastroenterology 2012; 143: Patwardhan VR, et al. Aliment Pharmacol Ther. 2014; Chi H, et al. Aliment Pharmacol Ther. 2015; 41:867:76 Seto WK, et al. Gut 2015;64: Jeng WJ, et al. Hepatology. 2013;58:

16 Increasing rates of HBsAg loss after NUC discontinuation in HBeAg-negative genotype D patients with long-term viral suppression under ADV Hadziyannis, Gastroenterology 2013

17 Sustained response among HBeAg-negative Caucasians who discontinue TDF HBV DNA (log 10 IU/mL) 1:1 Randomizatio n Wk 0 Wk 48 Wk 144 CHB patients HBeAg-negative 4 years TDF therapy TDF-Stop N=21 TDF-Continue N=21 Primary endpoint: HBsAg loss by Week 144 Berg, EASL 2015 Patients requiring TDF re-initiation (n=3) Time TDF was restarted HBV DNA became detectable in 21/21 (100%) of TDF-Stop subjects HBV DNA up to W48: Median: 5.32 log 10 IU/mL Min: 4.41 log 10 IU/mL Max: 8.50 log 10 IU/mL At W48* 89% (16/18) HBV DNA < IU/mL 78% (14/18) HBV DNA < IU/mL * TDF-Restart excluded

18 FINITE CHB: Stopping TDF after long-term viral suppression in HBeAg-negative CHB: week 48 interim results Patients (%) HBsAg loss HBV DNA <2000, ALT <2 x ULN Week 12 Week 24 Week 48 HBV DNA <2000, ALT >2 x ULN HBV DNA >2000, ALT <2 x ULN HBV DNA >2000, ALT >2 x ULN TDF-Restart Berg T. et al abstract #O119

19 Question 3 What is the use of qhbsag with PEG-IFN therapy?

20 High HBsAg level at week 12 is associated with low rates of response to PEG-IFN in HBeAg-positive CHB Percentage of patients 60 HBsAg level p<0.001 <1500 IU/mL (n=165) ,000 IU/mL (n=392) >20,000 IU/mL (n=222) p< HBeAg loss with HBV DNA <2,000 IU/mL HBsAg loss Sonneveld, Hepatology 2013

21 High HBsAg level at week 12 is associated with low rates of response to PEG-IFN in HBeAg-positive CHB Percentage of patients 60 HBsAg level p<0.001 <1500 IU/mL (n=165) ,000 IU/mL (n=392) >20,000 IU/mL (n=222) p< HBeAg loss with HBV DNA <2,000 IU/mL HBsAg loss Sonneveld, Hepatology 2013

22 HBsAg based management algorithm for HBeAgpositive patients on PEG-IFN therapy HBeAg-positive patient Geno A Geno B Geno C Geno D Sonneveld, Hepatology 2013

23 HBsAg based management algorithm for HBeAgpositive patients on PEG-IFN therapy HBeAg-positive patient Geno A Geno B Geno C Geno D WEEK 12 No decline NPV: 100% >20,000 IU/mL NPV: 92% >20,000 IU/mL NPV: 98% No decline NPV: 97% Sonneveld, Hepatology 2013

24 HBsAg based management algorithm for HBeAgpositive patients on PEG-IFN therapy HBeAg-positive patient Geno A Geno B Geno C Geno D WEEK 12 No decline NPV: 100% >20,000 IU/mL NPV: 92% >20,000 IU/mL NPV: 98% No decline NPV: 97% or or or or WEEK 24 >20,000 IU/mL NPV: 96% >20,000 IU/mL NPV: 100% >20,000 IU/mL NPV: 100% >20,000 IU/mL NPV: 100% Sonneveld, Hepatology 2013

25 Low HBsAg level at week 12 is associated with high rates of response to PEG-IFN in HBeAg-positive CHB Percentage of patients 60 HBsAg level p<0.001 <1500 IU/mL (n=165) ,000 IU/mL (n=392) >20,000 IU/mL (n=222) p< HBeAg loss with HBV DNA <2,000 IU/mL HBsAg loss Sonneveld, Hepatology 2013

26 Low HBsAg level at week 12 is associated with high rates of response to PEG-IFN in HBeAg-positive CHB Percentage of patients 60 HBsAg level p<0.001 <1500 IU/mL (n=165) ,000 IU/mL (n=392) >20,000 IU/mL (n=222) p< HBeAg loss with HBV DNA <2,000 IU/mL HBsAg loss Sonneveld, Hepatology 2013

27 Percentage of patients with a response Response with 24 or 48 weeks according to HBsAg level at week 12 Treatment Duration 24 weeks 48 weeks <1,500 1,500 20,000 >20, p= p= p= <1500 (n=148) (n=298) >20000 (n=147) 1 4 Sonneveld, EASL 2015

28 Percentage of patients with a response Response with 24 or 48 weeks according to HBsAg level at week 12 stratified by HBV genotype p=0.207 <1,500 Treatment Duration 24 weeks 48 weeks 40 p= ,500 20, P=0.005 p= Geno B (n=72) Geno C (n=73) Geno B (n=123) Geno C (n=166) Sonneveld, EASL 2015

29 An algorithm for the management of HBeAg-positive genotype B or C patients treated with PEG-IFN HBeAg positive patient with genotype B or C HBsAg week 12 <1,500 1,500-20,000 >20,000 Genotype B Genotype C 24 weeks Rx 48 weeks Rx 48 weeks Rx Stop Sonneveld, EASL 2015

30 An algorithm for the management of HBeAg-positive genotype B or C patients treated with PEG-IFN HBeAg positive patient with genotype B or C HBsAg week 12 <1,500 1,500-20,000 >20,000 Genotype B Genotype C 24 weeks Rx 48 weeks Rx 48 weeks Rx Stop Sonneveld, EASL 2015

31 An algorithm for the management of HBeAg-positive genotype B or C patients treated with PEG-IFN HBeAg positive patient with genotype B or C HBsAg week 12 <1,500 1,500-20,000 >20,000 Genotype B Genotype C 24 weeks Rx 48 weeks Rx 48 weeks Rx Stop Sonneveld, EASL 2015

32 An algorithm for the management of HBeAg-positive genotype B or C patients treated with PEG-IFN HBeAg positive patient with genotype B or C HBsAg week 12 <1,500 1,500-20,000 >20,000 Genotype B Genotype C 24 weeks Rx 48 weeks Rx 48 weeks Rx Stop Sonneveld, EASL 2015

33 An algorithm for the management of HBeAg-positive genotype B or C patients treated with PEG-IFN HBeAg positive patient with genotype B or C HBsAg week 12 <1,500 1,500-20,000 >20,000 Genotype B Genotype C 24 weeks Rx 48 weeks Rx 48 weeks Rx Stop Sonneveld, EASL 2015

34 An algorithm for the management of HBeAg-positive genotype B or C patients treated with PEG-IFN HBeAg positive patient with genotype B or C HBsAg week 12 <1,500 1,500-20,000 >20,000 Genotype B Genotype C 24 weeks Rx 48 weeks Rx 48 weeks Rx Stop Sonneveld, EASL 2015

35 An algorithm for the management of HBeAg-positive genotype B or C patients treated with PEG-IFN HBeAg positive patient with genotype B or C HBsAg week 12 <1,500 1,500-20,000 >20,000 Genotype B Genotype C 24 weeks Rx 48 weeks Rx 48 weeks Rx Stop Sonneveld, EASL 2015

36 Question 4 Does therapy prolongation increase response rates to PEG-IFN?

37 HBeAg seroconversion PEG-IFN alfa-2a for 48 weeks yields highest response rates N=136 PEG-IFN alfa-2a 180 µg Follow-up 40 36% N=136 N=136 PEG-IFN alfa-2a 90 µg 0 48 PEG-IFN 180 µ Follow-up Follow-up % 23% 26% N=140 PEG-IFN 90 µg Follow-up / /24 90 / /48 Liaw, Hepatology 2012

38 Cumulative HBeAg loss (%) Prolongation of therapy may increase response rates to PEG-IFN N=49 HBeAg-positive patients treated for 96 weeks Week 48: HBeAg loss = 37% (18/49) Week 96: HBeAg loss increased to 53% (26/49); HBsAg cleared in 10% (5/49) % 30% 35% 37% 51% 53% Weeks of Peginterferon alfa 2a treatment Wu. APASL 2008

39 Extending PEG-IFN in HBeAg-negative disease reduces relapse: PegBeLiver study 96% genotype D 40 HBV DNA <2000 IU/mL HBsAg clearance N=51 PEGASYS 180 Follow-up 30 29% N=52 PEGASYS 180 PEGASYS Study weeks Follow-up % 6% Duration of therapy (weeks) Extending therapy can increase response rate in genotype D patients 0 0% Lampertico et al. GUT 2013

40 Question 5 Does treatment prolongation increase response rates to PEG-IFN in patients meeting a stopping-rule?

41 Response-guided PEGASYS therapy in patients with HBeAg-positive CHB A PEGASYS Follow-up treatment free HBeAgpositive Randomization PEGASYS (180 μg/week) Early response* Non-early response B C D Definition of early response*: HBsAg <1500 IU/mL and HBV DNA <10 5 copies/ml PEGASYS PEGASYS PEGASYS plus Adefovir 10 mg/d Follow-up treatment free Follow-up treatment free Follow-up treatment free Study Weeks Abstract: P1067 Hou J. et al. EASL 2013

42 RGT study: prolonging PEG-IFN or adding ADV does not increase response in patients with high HBsAg at week 24 Hou, EASL 2014

43 NPV 100% with PARC stopping-rule in patients treated for 96 weeks in PEG-B-Liver Includes PEG-B-Liver 96 weeks arm Validation trials HBV genotype D N=91 No N=60 (66%) Yes N=31 (34%) No Yes No Yes N=17 N=43 N=14 N=17 (19%) (47%) (15%) (19%) 0/17 12/43 6/14 7/17 (0%) (28%) (43%) (41%)

44 Question 6 Is there a role for de novo combination of IFN and NUCS?

45 HBeAg loss (%) PEG-IFN vs PEG-IFN + Lam for HBeAg(+) CHB: HBeAg loss PEG-IFN (n=136) PEG-IFN + Lam (n=130) PEG-IFN + lamivudine PEG-IFN + placebo Lamivudine P= % P= % 35% % 30 29% 30 27% 30% 22% 28% % weeks end of therapy 78 weeks end of follow-up 0 48 weeks end of therapy 72 weeks end of follow-up Janssen et al. Lancet 2005 Lau et al. NEJM 2005

46 PEG-IFN ± TDF for HBeAg(+) and HBeAg(-) Patients: Gilead 0149 (N=740) Week n=186 TDF + PEG n=184 TDF+PEG TDF n=185 TDF n=185 PEG Start TDF during follow-up if prespecified safety criteria met Marcellin, AASLD 2014 Oral #193

47 Mean Change From Baseline(log 10 IU/mL) PEG-IFN ± TDF for HBeAg(+) and HBeAg(-) Patients: HBsAg decline (n=740) Study Week 60% of patients HBeAg (+) at start treatment ,2-0,4-0,6 TDF 120 wk TDF+PEG 16 wk TDF 32 wk -0.3 log -0.5 log p<.001 p<.001-0,8 PEG 48 wk -0.8 log p= ,2 TDF + PEG 48 wk -1.1 log -1,4 3 patients who were re-treated at Week 48 were excluded from Week 48 calculations. Marcellin, AASLD 2014 Oral #193

48 Mean Change From Baseline(log 10 IU/mL) PEG-IFN ± TDF for HBeAg(+) and HBeAg(-) Patients: HBsAg decline (n=740) Study Week 60% of patients HBeAg (+) at start treatment 0-0, ,4 Arm TDF retreatment -0,6-0,8-1 PEG+TDF (54%) PEG+TDF 16/ (54%) PEG mono (61%) -1,2-1,4 3 patients who were re-treated at Week 48 were excluded from Week 48 calculations. Marcellin, AASLD 2014 Oral #193

49 HBeAg loss (%) PEG-IFN ± TDF for HBeAg(+) Patients: comparable HBeAg loss rates P=NS for PEG+TDF vs PEG mono Week 48 Week ,6 25, ,8 25,5 13,2 14,7 10 8,3 0 PEG+TDF 48 PEG +TDF 16/32 PEG TDF Marcellin, AASLD 2014 Oral #193

50 HBsAg loss (%) PEG-IFN ± TDF for HBeAg(-) and HBeAg(+) Patients: HBsAg loss not sustained Week 48 Week 72 P=NS across the arms Marcellin, AASLD 2014 Oral #193 7,3 6,8 2,3 1,1-7 patients had HBsAg seroreversion on or after Week 48 (4 [TDF + PEG 48 wk], 3 [TDF + PEG 16 wk TDF 32 wk]) - 5/7 had 1 week of therapy after HBsAg loss 2,8 2,8 PEG+TDF 48 PEG +TDF PEG TDF 16/32 N=186 N=184 N=185 N=185 Primary end-point = K-L estimate (??) 65% (11/17) of patients HBeAg(+) at start treatment 0 0

51 Question 7 Is there a role for PEG-IFN add-on to NUCs?

52 ARES study: 24 weeks PEG-IFN add-on for HBeAg(+) CHB Randomisation 1:1 Responders stop treatment at week 72 PEG-IFN 180µg/week yes ETV 0.5mg/day Follow-up ETV 0.5mg/day N=85 48 no ETV 0.5mg/day 0 ETV 0.5mg/day 24 N=90 Response? yes ETV 0.5mg/day Responders stop treatment at week 72 Follow-up ETV 0.5mg/day Major criteria: Adults with HBeAg-positive CHB, compensated liver disease, ALT >1.3 x ULN No treatment with lamivudine or telbivudine for more than 6 months 48 no ETV 0.5mg/day Brouwer, Xie, Sonneveld et al, Hepatology 2015

53 Adding PEG-IFN to ETV increases HBsAg and HBeAg decline HBV DNA decline (log IU/mL) ETV P<0.001 ETV +PEG-IFN Weeks HBeAg decline (log IU/mL) ETV ETV +PEG-IFN P< Weeks HBsAg decline (log IU/mL) ETV ETV +PEG-IFN P< Weeks Sonneveld et al, AASLD 2012

54 PEG-IFN add-on induces sustained ETV PEG-IFN add-on immune control in HBeAg + 81% Continue ETV therapy 19% 21% 79% Stop Rx Immune control* ETV monotherapy 90% Continue ETV therapy 75% 10% 25% Stop Rx Immune control* * HBeAg negative, normal serum ALT and HBV DNA <2000 IU/mL Brouwer, Xie, Sonneveld et al, Hepatology 2015

55 Chi H. et al, AASLD 2014 abstract #1882 PEGON study: PEG-IFN add-on for 48 weeks to long-term NA therapy in HBeAg(+) CHB More HBsAg and HBeAg response in add-on arm 40 p=0.14 Response rate (%) /38 12/36 2/38 6/36 0 7/36 HBeAg loss & HBV DNA <200 IU/mL p= HBeAg seroconversion & HBV DNA <200 IU/mL p= HBsAg decline >1 log IU/mL qhbsag decline (log IU/ml) -0.0 NA monotherapy p= PEG-IFN add-on Treatment week Interim analysis. Number of patients analyzed at week 48: 74/82

56 HBsAg titer log 10 (IU/ml) 48 wk PEG-IFN add-on therapy to long-term NA in HBeAg negative patients: the PEGAN study RCT in 185 HBeAg negative patients with undetectable HBV DNA 1 year (no telbivudine); randomized 1:1 to add-on vs NA NA treatment discontinuation only in case of HBsAg loss 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0-0,5-1,0-1,5-2,0-2,5 HBsAg loss: NA Alone N=3 (3%) PEGIFN + NA N=7 (8%) W0 W12 W24 W36 W48 W60 W72 W84 W96 P=0.152 Bourliere M. et al EASL 2015 abstract #O112 Weeks

57 Conclusions

58 Conclusions NUC therapy does not eliminate the risk of HCC HBsAg clearance remains essential despite HBV DNA suppression NUC discontinuation results in relapse in around 50% of patient A subset, particularly genotype D caucasians, may achieve HBsAg loss HBsAg levels during IFN identify non-responders and can identify patients eligible for a reduced therapy duration with maintanance of response rates

59 Conclusions PEG-IFN prolongation can increase response rates, but is pointless in patients who meet an early HBsAg based stopping-rule PEG-IFN add-on to NUCs may increase HBsAg decline and may allow therapy discontinuation in some patients who remain HBeAg-positive during NUC therapy PEG-IFN add-on in HBeAg-negative patients increases HBsAg decline but yields limited HBsAg loss rates

60

61 Optimizing the use of PEG-IFN in CHB Select the right patients at baseline HBeAg-positive: Based on HBV genotype, HBV DNA, ALT (soon: EPIC-B predictor) HBeAg-negative: No clear baseline predictors Response-guided therapy using on-treatment factors HBeAg-positive: Discontinue if HBsAg >20,000 IU/mL at week 24 HBeAg-negative: Discontinue if no HBsAg decline and no HBV DNA decline >2log at week 12

62 Increasing the chance of finite therapy with PEG-IFN Prolongation of PEG-IFN therapy

63 HBeAg seroconversion PEG-IFN alfa-2a for 48 weeks yields highest response rates N=136 PEG-IFN alfa-2a 180 µg Follow-up 40 36% N=136 N=136 PEG-IFN alfa-2a 90 µg 0 48 PEG-IFN 180 µ Follow-up Follow-up % 23% 26% N=140 PEG-IFN 90 µg Follow-up / /24 90 / /48

64 Increasing the chance of finite therapy with PEG-IFN Combined PEG-IFN with a NUC

65 Mean log HBV DNA (geq/ml) One year of PEG-IFN induces HBeAg clearance in one third of patients 9 On-therapy HBV DNA suppression HBeAg Seroconversion Rates at End of Follow-up 8 7 PEG-IFN -2b (n=136) 29% 29% PEG-IFN -2b + LAM (n=130) Janssen et al. Lancet 2005 Week n=136 n=130 PEG- IFN -2b PEG- IFN -2b + LAM

66 A randomized trial of PEG-IFN plus TDF Week n=186 TDF + PEG n=184 TDF+PEG TDF n=185 TDF n=185 PEG Start TDF during follow-up if prespecified safety criteria met Randomized, controlled, open-label study (N=740) Stratified by screening HBeAg status and HBV genotype Inclusion criteria HBeAg+ and HBV DNA 20,000 IU/mL; HBeAg- and HBV DNA 2,000 IU/mL ALT >54 and 400 U/L (men); ALT >36 and 300 U/L (women) No bridging fibrosis or cirrhosis on liver biopsy or by transient elastography 66

67 High rates of HBsAg clearance with PEG- Patients with HBsAg Loss, Kaplan-Meier Estimate (%) IFN plus TDF weeks 72 weeks 7.3% TDF + PEG 48 wk 2.8% PEG 48 wk 2.8% TDF + PEG 16 wk TDF 32 wk 0% TDF 120 wk Week 7 patients had HBsAg seroreversion on or after Week 48 (4 [TDF + PEG 48 wk], 3 [TDF + PEG 16 wk TDF 32 wk]) 5/7 had 1 week of therapy after HBsAg loss

68 Chi H. et al, AASLD 2014 abstract #1882 PEGON study: PEG-IFN add-on for 48 weeks to long-term NA therapy in HBeAg(+) CHB ETV or TDF for at least 1 year before randomization Randomization Long-term nucleos(t)ide analogue 48 weeks of peginterferon alfa-2b Nucleos(t)ide analogue Nucleos(t)ide analogue Nucleos(t)ide analogue Off-treatment follow-up Nucleos(t)ide analogue Nucleos(t)ide analogue Off-treatment follow-up Nucleos(t)ide analogue Interim analysis N=74/82

69 Chi H. et al, AASLD 2014 abstract #1882 PEGON study: PEG-IFN add-on for 48 weeks to long-term NA therapy in HBeAg(+) CHB More HBsAg and HBeAg response in add-on arm 40 p=0.14 Response rate (%) /38 12/36 2/38 6/36 0 7/36 HBeAg loss & HBV DNA <200 IU/mL p= HBeAg seroconversion & HBV DNA <200 IU/mL p= HBsAg decline >1 log IU/mL qhbsag decline (log IU/ml) -0.0 NA monotherapy p= PEG-IFN add-on Treatment week Interim analysis. Number of patients analyzed at week 48: 74/82

70 Patients (%) HERMES study: Single arm, 48 weeks PEG-IFN add-on to long-term NA therapy in HBeAg(-) CHB Interim analysis at week 24 N=70 39 Week 0 Week 12 Week HBsAg <1000 HBsAg <500 Lampertico, AASLD 2014 LB #31 All patients were infected with HBV genotype D

71 HBsAg loss (%) PEGAN study: 48 weeks PEG-IFN add-on to long-term NA therapy in HBeAg(-) CHB Preliminary results at week 48 N=178 Week 48 8 P= HBsAg clearance at week 48 according to HBsAg titer at randomization HBsAg titer at randomization (UI/ml) Analogue(s) Alone (N=93) PEGIFN + Analogue(s) (N=90) <100 1/11 (9%) 2/9 (22%) /17 3/19 (16%) /10 1/10 (10%) /54 1/52 (2%) 0 PEG-IFN add-on N=85 NA mono N=93 Bourliere, AASLD 2014 abstract #1863

72 HBsAg titer log 10 (IU/ml) 48 wk PEG-IFN add-on therapy to long-term NA in HBeAg negative patients: the PEGAN study RCT in 185 HBeAg negative patients with undetectable HBV DNA 1 year (no telbivudine); randomized 1:1 to add-on vs NA NA treatment discontinuation only in case of HBsAg loss 3,5 3,0 2,5 2,0 1,5 1,0 0,5 0,0-0,5-1,0-1,5-2,0-2,5 HBsAg loss: NA Alone N=3 (3%) PEGIFN + NA N=7 (8%) W0 W12 W24 W36 W48 W60 W72 W84 W96 P=0.152 Bourliere M. et al abstract #O112 Weeks

73 Flare slideset

74 Relationship between timing of flare and presence PC and/or BCP mutants Before week 24 WT PC/BCP mutants Week WT PC/BCP mutants Off-treatment WT PC/BCP mutants Percentage of patients in group Sonneveld, CID 2012

75 Higher probability of response in patients with host induced flares Host Virus Indeterminate 70 P= P< P< HBeAg loss Combined response HBsAg loss Sonneveld, CID 2012

76 ALT Host induced flare: ALT peak precedes HBV DNA, HBeAg and HBsAg decline HBeAg Anti-HBe HBsAg Anti-HBs HBV DNA / HBeAg / HBsAg ALT HBVDNA HBeAg HBsAg Sonneveld, CID 2012

77 ALT Virus induced flare: ALT peak after HBV DNA, HBeAg and HBsAg peak HBeAg Anti-HBe HBsAg Anti-HBs HBV DNA / HBeAg / HBsAg ALT HBVDNA HBeAg HBsAg Sonneveld, CID 2012