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 1 IU/ml HBsAg log 1 IU/ml 5 4 3 2 ALT (U/L) 5 1 2 Janssen, et al. Gut 212

Chronic hepatitis B infection Treatment not indicated Immune tolerant HBV HBV carrier state Treatment indicated Chronic hepatitis ALT elevated HBV DNA >2 IU/mL Fibrosis Cirrhosis Decompensated cirrhosis Liaw Y-F, et al. Hepatol Int 212;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 >1 7 copies/ml 57 patients followed up for 5 years 84% of patients remained immune tolerant at Year 5 No HCC Patients (%) 35 3 25 2 15 1 5 F F1 F2 Baseline biopsy Biopsy at 5 years Hui CK, et al. Hepatology 27;46:395 41 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 1 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 214;146:124 8 LQ2 FTC/TDF and FTC are investigational agents and not licensed for use in CHB; TDF: tenofovir disoproxil fumarate; FTC: emtricitabine; UNL: upper normal limit

Dia 7 LQ2 CHECK JOURNAL INFO Liesje Quine; 2-6-214

HBV DNA suppression in immune tolerant patients 1 FTC/TDF 76% 8 Patients (%) 6 4 2 TDF 55% 16 32 48 64 8 96 112 128 144 16 176 192 Study week 6% TDF patients and 2% TDF/FTC achieved HBeAg loss 5% TDF patients and % 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 214;146:124 8

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

Timeline for FDA-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 < 2 IU/ml ALT < UNL (anti-hbe) HBsAg Loss Long-term "suppressive" treatment NUC HBV DNA undetectable by PCR (<1-15 IU) HBsAg loss Years

How to achieve sustained immune control?

Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients HBeAg-POSITIVE Patients: Week 72 Treatment Response P =.2 P =.6 P <.1 P =.2 P <.1 P <.1 Lau GKK, et. al. N Engl J Med. 25;352:2682-95.

Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Negative Patients HBeAg-NEGATIVE Patients: Week 72 Treatment Response P=.4 P=.7 P=.915 P=.3 P=.849 P=.3 Marcellin P, et. al. N Engl J Med. 24;351:126-7.

Impact of (peg)-ifn therapy on CHB Safety profile well known Progression to cirrhosis prevented Clinical decompensation prevented HCC reduced (?) Improved patient survival Sustained virological and serological response as immuno control status in 3% 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 >2, IU/mL (B,C) Week 12: - No decline in HBsAg + <2 log decline in HBV DNA Week 24: - HBsAg >2, IU/ml (A,B,C,D) * 97-1% Negative Predictive Values Sonneveld et al. Hepatology 21 Piratvisuth et al. APASL 21 Liaw et al. Hepatology 211 Sonneveld et al., Hepatology 213 Rijckborst et al. Hepatology 21 Rijckborst / Lampertico et al. J Hepatol 212

How to achieve sustained immune control?

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 7 3 HBeAgpatients Year 7 3 HBV DNA suppression b 94% (88/94) 95% (54/57) 99% (159/16) 99% (271/273) Resistance 1% (n=1) NR % % HBsAg loss (seroconversion) NR NR 12% (1%) <1% (<1) 1. Chang TT, et al. Hepatology 21;51:422 3; 2. Shouval D, et al. Hepatology 28; Poster 927; 3. Marcellin P, et al. AASLD 213; Abstract 926 a ETV re-treatment (relapsed <6 months post-treatment in ETV-27 study); b TDF: HBV DNA <4 copies/ml, ETV: HBV DNA <3 copies/ml; ETV: entecavir; NR: not reported

CIBERHEP: long-term efficacy of TDF in TN and TE patients Patients (N=37) from 48 Spanish centres treated for 12 295 weeks % Patients with VR, HBV DNA < 69 IU/mL 1 8 6 4 2 TN, N TE, N 74 74 HBeAg-positive 1 1 84 82 86 85 Week 48 Week 96 Week 144 Week 192 23 19 19 17 14 13 3 8 % Patients with VR, HBV DNA < 69 IU/mL 1 8 6 4 2 TN, N TE, N 91 94 88 HBeAg-negative 95 TN 1 1 1 91 Week 48 Week 96 Week 144 Week 192 65 48 5 4 26 33 13 25 TE 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 214; Poster 158 MDRD (ml/min/1.73m 2 ) 21 18 15 12 9 6 3 48 96 144 192 Week 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 (%) 1% 8% 6% 4% 2% % 91% Age <65 (n=392) W48 W96 W144 95% 95% 1% 95% 93% n=268 n=252 n=233 n=4 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 12 1 8 6 4 2 99 98 99 97 97 95 95 94 77 71 71 71 Overall population (N=44) Age <65 years (n=392) Age 65 years (n=48) Baseline Week 48 Week 96 Week 144 Causse X. EASL 214; Poster 162 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 214)

Histological changes during long-term ETV treatment N=57; 4 patients with cirrhosis Median interval 6 years (range 3 7 years) 6 6 Number of patients 5 4 3 2 1 Knodell Necroinflammatory Score Missing 1 14 7 9 4 6 3 Number of patients 5 4 3 2 1 Ishak Fibrosis Score Missing 6 5 4 3 2 1 Baseline Week 48 Year 6 Baseline Week 48 Year 6 Chang TT, et al. Hepatology 21;52:886 93

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 (%) 1 8 6 4 2 P<.1 P<.1 Ishak Fibrosis Score Missing 6 5 4 3 2 1 3 2 1-1 -2-3 -4-5 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 Baseline Year 1 Year 5 Marcellin P, et al. Lancet 213;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 No cirrhosis at Year 5 (n=71) Cirrhosis at Year 5 (n=25) P value Mean BMI at baseline, 25.7 (3.7) 29. (4.4).7 kg/m 2 (SD) BMI (kg/m 2 ) at baseline, % <.1 Normal (<25) 41 12 Overweight (25 <3) 49 48 Obese ( 3) 1 4 Diabetes at baseline, % 1 24.1 Normal ALT on treatment, % 87 58.7 Marcellin P, et al. Lancet 213;381:468 75 BMI: body mass index; SD: standard deviation

Long-term therapy with TDF decreased the incidence of HCC vs predicted risk 7-year long-term follow-up from pivotal TDF studies compared with predicted rate of HCC using the REACH-B model 24% (152/634 were cirrhotic at baseline) Of the 14 patients with HCC, 6 had cirrhosis at baseline Validated in both cirrhotic and non-cirrhotic patients 3 Cumulative no. of HCC cases 25 2 15 1 5 Predicted Observed Progressive divergence after 3.3 years* *Standardised incidence ratio between observed and predicted was statistically significant at 5.5-year follow-up (.45; CI:.227.99) P<.5 48 96 Kim WR, et al. EASL 213; Oral 43 144 192 Week 24 288 336 REACH-B is a risk calculator developed in non-cirrhotic patients only and therefore may underestimate the risk in cirrhotic patients

Japanese cohorts: significantly reduced HCC incidence with ETV compared with controls in cirrhotic patients Control ETV LAM Cumulative HCC rate (%) 5 4 3 2 1 No cirrhosis Log-rank test: P=.44 1.6% % 3.6% 2.5% Cumulative HCC rate (%) 5 4 3 2 1 Cirrhotics Log-rank test: HCC ETV vs LAM: P=.43 ETV vs control: P<.1 LAM vs control: P=.19 11.4% 4.8% 2.6% 2.9% 12.2% 4.3% 28.5% 19.7% 7.% Control 38.9% 22.2% 7.% ETV LAM No. at risk ETV Control 1 2 3 4 5 6 Treatment duration (years) 237 23 237 23 192 21 132 181 66 169 27 143 No. at risk ETV LAM Control 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 213;58:98 17 LAM: lamivudine

When to stop NA therapy? EASL 212 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 212;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 8 6 4 2 Off therapy cumulative relapse (%)1 P=.27 LAM or LdT ETV 9 18 27 36 Time to relapse (days) Jeng WJ, et al. Hepatology 213;58:1888 96

qhbsag predicts HBsAg loss and HBV relapse after LAM discontinuation in HBeAg -ve HBV DNA relapse* HBsAg loss 1 HBsAg 2 1 IU/mL 1 Cumulative incidence of HBV relapse 8 6 4 2 52 14 156 28 26 312 364 Duration of follow-up (weeks) No. at risk HBsAg (IU/mL) >1 2 1 <2 HBsAg >1 IU/mL P<.1 HBsAg <2 IU/mL 39 19 1 8 7 5 2 1 36 19 9 7 4 3 3 1 3 29 28 25 2 16 1 9 Cumulative incidence of HBsAg loss 8 6 4 2 <12 12 1 >1 P<.1 HBsAg <12 IU/mL HBsAg 12 1 IU/mL HBsAg >1 IU/mL 52 14 156 28 26 312 364 Duration of follow-up (weeks) No. at risk HBsAg (IU/mL) 24 2 19 14 9 8 4 4 42 31 24 2 16 1 8 4 39 35 26 21 17 14 8 2 Chen CH, et al. J Hepatol 214; doi.org/1.116/j.jhep.214.4.29 (epub ahead of print) *Defined as serum HBV DNA >2, IU/mL in 2 measurements at least 3 months apart

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

ETV and TDF are well tolerated in patients with decompensated liver disease Phase 2 study in patients with CHB and decompensated liver disease randomised to TDF, TDF/FTC, ETV Median CTP score: 7 Baseline MELD score: 11., 13. and 1.5 for TDF, TDF/FTC or ETV, respectively Primary endpoint was safety and all treatments were well tolerated Secondary analysis demonstrated efficacy of these treatments in patients with decompensated liver disease Median change in MELD score at Week 48: -2 21% of TDF and 27% of TDF/FTCtreated patients achieved HBeAg (no ETV-treated patients) Patients with HBV DNA <4 copies/ml TDF (n=45) ETV (n=22) 1 8 6 4 2 51 47 5 TDF/FTC (n=45) 71 88 73 Week 12 Week 48 Liaw Y-F, et al. Hepatology 211;53:62 72 FTC is an investigational agent and not licensed for use in CHB; CTP: Child Turcotte Pugh; MELD: model of end-stage liver disease

Decline in the need for liver transplantation for ESLD secondary to HBV in the USA Number of patients 5 45 4 35 3 25 2 15 End-stage cirrhosis HCC Acute liver failure LAM approval 1 5 1985 199 1995 2 25 Year Kim WR, et al. Hepatology 29;49:S28 S34 ESLD: end-stage liver disease

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?