Hepatitis B Virus therapy. Maria Buti Hospital Universitario Valle Hebron Barcelona Spain

Hepatitis B Virus therapy Maria Buti Hospital Universitario Valle Hebron Barcelona Spain

Disclosures Advisor: AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis Lecturer: Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis Clinical trials: Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Roche

Natural history of CHB Treatment indicated Immune tolerance Immune active Immune control HBeAg HBeAg or anti-hbe Anti-HBe HBV DNA log 10 IU/ml HBsAg log 10 IU/ml 5 4 3 2 ALT (U/L) 500 100 20 Janssen, et al. Gut 2012

Chronic hepatitis B infection Treatment not indicated Immune tolerant HBV HBV carrier state Treatment indicated Chronic hepatitis ALT elevated HBV DNA >2000 IU/mL Fibrosis Cirrhosis Decompensated cirrhosis Liaw Y-F, et al. Hepatol Int 2012;11:1636 45 ALT: alanine aminotransferase; HBV: hepatitis B virus

What can be achieved now In immune tolerant patients In patients with CHB and cirrhosis In decompensated patients CHB: chronic hepatitis B

Long-term follow-up of immune tolerant patients Consecutive immune tolerant patients HBsAg- and HBeAg- for > 6 months Normal ALT levels on 3 consecutive readings over 6 months HBV DNA >10 7 copies/ml 57 patients followed up for 5 years 84% of patients remained immune tolerant at Year 5 No HCC Patients (%) 35 30 25 20 15 10 5 0 F0 F1 F2 Baseline biopsy Biopsy at 5 years Hui CK, et al. Hepatology 2007;46:395 401 HBsAg: hepatitis B surface antigen; HBeAg: hepatitis B e antigen; HCC: hepatocellular carcinoma

What can be achieved now in immune tolerant patients? TDF and FTC/TDF in patients with normal ALT and high HBV DNA Phase 2, randomised, double-blind study in HBeAg-positive patients HBV DNA 10 8 copies/ml ALT ULN (N=126) Randomised to TDF for 192 weeks (n=64) Discontinued treatment before Week 192 (n=11; 17%) Randomised to FTC/TDF for 192 weeks (n=62) Discontinued treatment before Week 192 (n=8; 13%) Completed study through Week 192 (n=53; 83%) Completed study through Week 192 (n=54; 87%) Chan HL, et al. Gastroenterology 2014;146:1240 8 FTC/TDF and FTC are investigational agents and not licensed for use in CHB; TDF: tenofovir disoproxil fumarate; FTC: emtricitabine; UNL: upper normal limit

HBV DNA suppression in immune tolerant patients 100 FTC/TDF 76% 80 Patients (%) 60 40 20 TDF 55% 0 0 16 32 48 64 80 96 112 128 144 160 176 192 Study week 6% TDF patients and 2% TDF/FTC achieved HBeAg loss 5% TDF patients and 0% TDF/FTC achieved HBeAg seroconversion There were no cases of HBsAg loss/seroconversion No patients developed HCC or clinical events Chan HL, et al. Gastroenterology 2014;146:1240 8

What can be achieved now? In immune tolerant patients In patients with CHB and cirrhosis In decompensated patients

Chronic hepatitis B infection Treatment not indicated Immune tolerant HBV HBV carrier state Treatment indicated Chronic hepatitis ALT elevated HBV DNA >2000 IU/mL Fibrosis Cirrhosis Decompensated cirrhosis Liaw Y-F, et al. Hepatol Int 2012;11:1636 45

Approved Agents used to Treat HBV Tenofovir Telbivudine Entecavir Peginterferon alpha-2b Adefovir Lamivudine Interferon alpha-2a

Therapeutic strategies for chronic hepatitis B Short-term "curative" treatment IFN Follow-up (mo/yrs) On treatment response HBV DNA < 2000 IU/ml ALT < UNL (anti-hbe) HBsAg Loss Long-term "suppressive" treatment NUC HBV DNA undetectable by PCR (<10-15 IU) HBsAg loss Years

Therapeutic Strategies for Chronic Hepatitis B

Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients HBeAg-POSITIVE Patients: Week 72 Treatment Response P = 0.002 P = 0.006 P < 0.001 P = 0.02 P < 0.001 P < 0.001 Lau GKK, et. al. N Engl J Med. 2005;352:2682-95.

Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative Patients HBeAg-NEGATIVE Patients: Week 72 Treatment Response P=0.004 P=0.007 P=0.915 P=0.003 P=0.849 P=0.003 Marcellin P, et. al. N Engl J Med. 2004;351:1206-7.

Impact of (peg)-ifn therapy on CHB Safety profile well known Progression to cirrhosis prevented Clinical decompensation prevented HCC reduced (?) Improved patient survival Immune control status in 30% of patients

How can we improve PEG-IFN efficacy? pretreament predictors of response High ALT levels Low levels HBV DNA Genotype A Young people on-treatment predictors of response

Response-guided therapy (RGT) using HBsAg levels in Peg-IFN-treated patients: to identify non responders HBeAg-positive HBeAg-negative (geno D) Week 12: - No decline of HBsAg (A,D) - HBsAg >20,000 IU/mL (B,C) Week 12: - No decline in HBsAg + <2 log decline in HBV DNA Week 24: - HBsAg >20,000 IU/ml (A,B,C,D) * 97-100% Negative Predictive Values Sonneveld et al. Hepatology 2010 Piratvisuth et al. APASL 2010 Liaw et al. Hepatology 2011 Sonneveld et al., Hepatology 2013 Rijckborst et al. Hepatology 2010 Rijckborst / Lampertico et al. J Hepatol 2012

Response-guided therapy by HBsAg levels in Peg-IFN-treated patients: to identify non responders HBeAg-positive HBeAg-negative (geno D) Week 12: - No decline of HBsAg (A,D) - HBsAg >20,000 IU/mL (B,C) Week 12: - No decline in HBsAg + <2 log decline in HBV DNA Week 24: - HBsAg >20,000 IU/ml (A,B,C,D) * 97-100% Negative Predictive Values Sonneveld et al. Hepatology 2010 Piratvisuth et al. APASL 2010 Liaw et al. Hepatology 2011 Sonneveld et al., Hepatology 2013 Rijckborst et al. Hepatology 2010 Rijckborst / Lampertico et al. J Hepatol 2012

Therapeutic Strategies for Chronic Hepatitis B

High virological responses with long-term ETV or TDF ETV TDF Response HBeAg+ patients Year 5 1 HBeAgpatients Year 3 2,a HBeAg+ patients Year 8 3 HBeAgpatients Year 8 3 HBV DNA suppression b 94% (88/94) 95% (54/57) 98% (159/160) 99% (271/273) Resistance 1% (n=1) NR 0% 0% HBsAg loss (seroconversion) NR NR 12.9% (10.3%) 1.1% (<1) 1. Chang TT, et al. Hepatology 2010;51:422 30; 2. Shouval D, et al. Hepatology 2008; Poster 927; 3. Marcellin P, et al. AASLD 2014; Abstract 926 a ETV re-treatment (relapsed <6 months post-treatment in ETV-027 study); b TDF: HBV DNA <400 copies/ml, ETV: HBV DNA <300 copies/ml; ETV: entecavir; NR: not reported

CIBERHEP: Efficacy of TDF in Treatment naïve and Treatment Experienced patients Patients (N=370) from 48 Spanish centres treated for 12 295 weeks % Patients with VR, HBV DNA < 69 IU/mL 100 80 60 40 20 0 TN, N TE, N 74 74 84 82 86 85 100 100 Week 48 Week 96 Week 144 Week 192 23 19 HBeAg-positive 19 17 HBsAg loss: n=4 (1 HBsAg seroconversion) Viral suppression was similar between TN and TE patients, with HBeAg loss occurring more in TN patients Tabernero D. EASL 2014; Poster 1058 14 13 3 8 % Patients with VR, HBV DNA < 69 IU/mL 100 MDRD (ml/min/1.73m 2 ) 80 60 40 20 0 TN, N TE, N 210 180 150 120 90 60 30 0 91 94 88 HBeAg-negative 95 TN 100 100 100 91 Week 48 Week 96 Week 144 Week 192 65 48 50 40 26 33 13 25 0 48 96 144 192 Week TE TE: treatment experienced; TN: treatment naïve

VIREAL study: high rates of virological response, regardless of age Subgroup (n=48) of elderly patients ( 65 years) Patients with HBV DNA <69IU/mL (%) 100% 80% 60% 40% 20% 0% 91% Age <65 (n=392) W48 W96 W144 95% 95% 100% 95% 93% n=268 n=252 n=233 n=40 n=29 n=26 Age 65 (n=48) Mean egfr by CKD-EPI (ml/min per 1.73 m 2 ) Incidence of comorbidities in elderly patients: 35% hypertension 17% diabetes 58% F3 F4 (METAVIR) at baseline 120 100 80 60 40 20 0 99 98 99 97 97 95 95 94 77 71 71 71 Overall population (N=440) Age <65 years (n=392) Age 65 years (n=48) Baseline Week 48 Week 96 Week 144 Causse X. EASL 2014; Poster 1062 TDF has not been studied in patients >65 years. As elderly patients are more likely to have decreased renal function, caution is required in these patients (Viread SmPC, March 2014)

Liver fibrosis regression and cirrhosis reversal over 5 years of treatment with TDF N=348 had biopsies at baseline and Year 5 (96 with cirrhosis) Patients (%) 100 80 60 40 20 P<0.001 P<0.001 Ishak Fibrosis Score Missing 6 5 4 3 2 1 0 3 2 1 0-1 -2-3 -4-5 Δ Ishak Fibrosis Score over 5 years in patients with cirrhosis 74% (71/96) had reversal of cirrhosis n=15 n=41 n=14 n=1 n=24 n=1 0 Baseline Year 1 Year 5 Marcellin P, et al. Lancet 2013;381:468 75 Histologically evaluable patients in the long-term histology cohort

Characteristics of patients shown to be associated with reversal of cirrhosis with TDF Characteristic Mean BMI at baseline, kg/m 2 (SD) No cirrhosis at Year 5 (n=71) Cirrhosis at Year 5 (n=25) P value 25.7 (3.7) 29.0 (4.4) 0.0007 BMI (kg/m 2 ) at baseline, % <0.001 Normal (<25) 41 12 Overweight (25 <30) 49 48 Obese ( 30) 10 40 Diabetes at baseline, % 1 24 0.001 Normal ALT on treatment, % 87 58 0.007 Marcellin P, et al. Lancet 2013;381:468 75 BMI: body mass index; SD: standard deviation

Japanese cohorts: significantly reduced HCC incidence with ETV compared with controls in cirrhotic patients Control ETV LAM Cumulative HCC rate (%) 50 40 30 20 10 0 No cirrhosis Log-rank test: P=0.440 1.6% 0% 3.6% 2.5% Cumulative HCC rate (%) 50 40 30 20 10 0 Cirrhotics Log-rank test: HCC ETV vs LAM: P=0.043 ETV vs control: P<0.001 LAM vs control: P=0.019 11.4% 4.8% 2.6% 20.9% 12.2% 4.3% 28.5% 19.7% 7.0% Control 38.9% 22.2% 7.0% ETV LAM No. at risk ETV Control 0 1 2 3 4 5 6 Treatment duration (years) 237 23 237 23 192 201 132 181 66 169 27 143 No. at risk ETV LAM Control 0 1 2 3 4 5 Treatment duration (years) 79 49 85 79 49 85 72 41 76 53 35 65 35 32 64 17 29 47 6 Hosaka T, et al. Hepatology 2013;58:98 107 LAM: lamivudine

Lower risk of death/transplantation with ETV than with LAM Death or transplantation HCC Estimated cumulative incidence of death or transplantation (%) 100 80 60 40 20 0 P<0.001 20 16 12 8 4 0 LAM ETV 0 1 2 3 4 5 6 Estimated cumulative incidence of HCC (%) 100 80 60 40 20 0 P=0.95 20 16 12 8 4 0 ETV LAM 0 1 2 3 4 5 6 No. at risk LAM ETV 0 1 2 3 4 5 6 Years after starting treatment 1792 1778 1792 1777 1740 1436 1660 966 1601 563 1531 224 1389 21 No. at risk LAM ETV 0 1 2 3 4 5 6 Years after starting treatment 1792 1777 1699 1792 1777 1384 1585 911 1496 511 1409 200 1262 19 Lim Y-S, et al. Gastroenterology 2014:doi: 10.1053/j.gastro.2014.02.033

When to stop NA therapy? EASL 2012 guidelines HBeAg positive A) Confirmed anti-hbe seroconversion (and undetectable HBV DNA) after at least 12 months of consolidation* B) Confirmed HBsAg loss and anti-hbs seroconversion HBeAg negative Confirmed HBsAg loss and anti-hbs seroconversion Cirrhotics Confirmed HBsAg loss and anti-hbs seroconversion Adapted from EASL Clinical Practice Guidelines. J Hepatol 2012;57:167 85 *A proportion of patients who discontinue nucleos(t)ide analogue (NA) therapy after anti-hbe seroconversion may require retreatment, since they fail to sustain their serological and/or virological response; HBeAg: hepatitis B e antigen; HBsAg: hepatitis B surface antigen

Off-therapy durability of response to ETV in HBeAg-negative CHB from Taiwan 95 patients (39 cirrhotic) treated with ETV for 24 (13 59) months Stopping rule: undetectable HBV DNA on 3 occasions at least 6 months apart Response after treatment discontinuation compared with LAM or LdT from historical data Cumulative relapse rates in Year 1: Virological relapse: 58% Clinical relapse: 45% No good predictors of relapse Off therapy cumulative relapse (%) 100 80 60 40 20 0 P=0.027 LAM or LdT ETV 0 90 180 270 360 Time to relapse (days) Jeng WJ, et al. Hepatology 2013;58:1888 96

qhbsag predicts HBsAg loss and HBV relapse after LAM discontinuation in HBeAg -ve HBV DNA relapse* HBsAg loss 100 HBsAg 200 1000 IU/mL 100 Cumulative incidence of HBV relapse 80 60 40 20 0 0 52 104 156 208 260 312 364 Duration of follow-up (weeks) No. at risk HBsAg (IU/mL) >1000 200 1000 <200 HBsAg >1000 IU/mL P<0.001 HBsAg <200 IU/mL 39 19 10 8 7 5 2 1 36 19 9 7 4 3 3 1 30 29 28 25 20 16 10 9 Cumulative incidence of HBsAg loss 80 60 40 20 <120 120 1000 >1000 0 P<0.001 HBsAg <120 IU/mL HBsAg 120 1000 IU/mL HBsAg >1000 IU/mL 0 52 104 156 208 260 312 364 Duration of follow-up (weeks) No. at risk HBsAg (IU/mL) 24 20 19 14 9 8 4 4 42 31 24 20 16 10 8 4 39 35 26 21 17 14 8 2 Chen CH, et al. J Hepatol 2014; doi.org/10.1016/j.jhep.2014.04.029 (epub ahead of print) *Defined as serum HBV DNA >2,000 IU/mL in 2 measurements at least 3 months apart

Stopping TDF After Long-Term Virologic Suppression in HBeAg-Negative CHB FINITE CHB, a randomized study in non cirrhotic HBeAg-ve patients with 4 yrs TDF therapy and undetectable HBV DNA Randomized N=45 Withdrew consent n=3 TDF-Stop n=21 TDF-Continue n=21 Week 48 TDF-Restart n=3 Week 48 TDF-Stop n=18 Week 48 TDF-Continue n=21 86% of TDF-Stop subjects did not restart TDF by Week 48 Berg, EASL, 2015, O119 32

FINITE CHB study 48 weeks outcome after therapy discontinuation TDF-Stop: HBsAg loss, HBV DNA, ALT, TDF-Restart 5% 10% 52% 48% 57% 5% 24% 38% 19% 10% 10% 10% 14% Berg, EASL, 2015, O119 33

FINITE CHB. HBsAg levels between Patients who TDF stopped and those who TDF continued Week 48 HBsAg log 10 Reduction (Individual Patients) TDF-Stop (n=21) TDF-Continue (n=20) HBsAg loss HBsAg loss * HBsAg Log 10 Reduction: Median 0.283 Mean 0.773 HBsAg loss n=2 HBsAg Log 10 Reduction: Median 0.088 Mean 0.109 HBsAg loss n=0 * TDF-Restart * * -1 1 3 5 HBsAg (log 10 reduction) -1 1 3 5 HBsAg (log 10 reduction) Stopping TDF was associated with a more profound decline in HBsAg levels compared to continuous TDF Berg, EASL, 2015, O119 34

HBsAg Clearance After Addition of PegIFN for 48 Weeks in HBeAg-Negative CHB Patients on NUCs ANRS-HB06 PEGAN Study Multicenter, randomized, controlled study in 183 patients with documented undetectable HBV DNA while on NUCs for at least 1 year Wk 0 Wk 48 Wk 96 Wk 144 HBeAgundetectable HBV DNA on NUCs (n=183) NUC alone NUC + PegIFN NUC alone (n=90) (n=93) NUCs Alone N=93 PegIFN + NUCs N=90 P-value HBsAg loss (Week 48, %) 0 (0) 7 (8) 0.0057 HBsAg loss (Week 96, %) (1 endpoint) 3 (3) 7 (8) 0.1521 HBs seroconversion (Week 96, %) 1 (1) 6 (7) 0.0465 Patients receiving add-on PegIFN experienced higher HBsAg loss than NUC monotherapy at W48, but without statistical difference at W96 Bourliere, EASL, 2015, O112 35

HBsAg loss with TDF plus PEG in chronic hepatitis B (CHB): Results of a global randomized controlled trial at week 72 Week 1 2 0 48 72 120 6 4 HBsAg Loss HBeAg Loss n=186 TDF + PEG 9% 29% n=184 n=185 TDF+PEG TDF TDF 2.8% 25% 0% 15% n=185 PEG Start TDF during follow-up if prespecified safety criteria met 2.8% 25% ¾ from Asian No cirrhosis and bridging fibrosis were excluded Marcellin P, et al. AASLD 2014

Baseline and On-Treatment Predictors of HBsAg Loss at Week 72 Univariate P-value Multivariate P-value Hazard ratio Multivariate Genotype A vs B 0.024 <0.001 7.32 Genotype A vs C <0.001 <0.001 16.76 Baseline Predictors Genotype A vs D 0.004 0.007 8.64 Arm A vs B 0.030 0.017 3.78 Arm A vs C 0.018 0.070 15.68 Arm A vs D 0.031 0.014 4.19 HBsAg decrease > 1 log 10 IU/mL by Week 12 (yes vs no) <0.001 <0.001 17.8 On-Treatment Predictors HBsAb > 10 miu/ml at Week 12 (yes vs no) 0.138 0.003 9.97 ALT > 400 U/L (males) or >300 U/L (females) during first 12 weeks (yes vs no) <0.001 0.031 2.85 Arm A: PegIFN+TDF x 48 weeks Arm B: PegIFN+TDF x 16 weeks, TDF x 32 weeks Arm C: TDF x 120 weeks Arm D: pegifn x 48 weeks Chan, EASL, 2015, O117 37

Study 149.-On-Treatment Predictors of HBsAg Loss at Week 72 TDF + PegIFN 48 wk HBsAg decline from baseline > 1 log 10 at Week 12 Sensitivity Specificity Positive Predictive Value Negative Predictive Value 71% 92% 43% 97% High negative predictive values are seen among patients treated with TDF + PegIFN combination if they have: HBsAg decline < 1 log 10 IU/mL at Week 12 Chan, EASL, 2015, O117 38

What can be achieved now? High rates of virological response with low/no risk of resistance Histological improvement Stop progression of disease (decompensation) and reduced liver transplant Reduced risk of HCC?