Welcome to the Singapore Hepatitis Conference 2016! Registration Fees only USD 150

Transcription

1 Welcome to the Singapore Hepatitis Conference 2016! Registration Fees only USD 150

2 NEW!! SHC Preceptorship Program For trainees, general physicians, specialists Present a difficult to manage case from your practice Additional half day training & EM workshops Registration, hotel and flights fully paid Limited places Apply through website:

3 Invited Faculty: One day HCV, One day HBV Teerha Piratvisuth Yock Young Dan Laurent Castera Bob Gish Pei Cher Chen Khin Maung Win Cristoph Sarrazin Norah Terrault Shamir Shah Kieron Lim Phil Newsome Rajender Reddy Rino Gani Soek Siam Tan Henry Chan Ed Gane

4 SHC-EASL 2015 Highlights Best of EASL Symposium: HCV Treatment options and current EASL guidelines Treatment options in Asia: A moving target DAA resistance do we need to worry? Real life DAA experience in Asia Special lecture: Moving towards perfectovir HBs antigen loss: An achievable treatment target? Optimising HBV treatment options Special Lecture: Future HBV Treatments

5 Current and Future Management of CHB 4 th ASEAN Perspectives in Liver Disease (APLD) Chiangmai Jan 20-23, 2016 Prof Seng Gee Lim Director of Hepatology, Dept of Gastroenterology and Hepatology National University Health System Singapore

6 Disclosures Advisory Board Bristol Myer Squibb Janssen MSD Gilead Roche Boehringer Ingelheim Achillion Novartis Speaker s Bureau GlaxoSmithKline Bristol Myer Squibb MSD Roche Boehinger Ingelheim Gilead Novartis

7 Goals of treatment APASL guidelines 2012 To permanently suppress HBV replication. The ultimate long-term goal is to achieve durable response to prevent hepatic decompensation, reduce or prevent progression to cirrhosis and/or HCC, and prolong survival AASLD guidelines 2009 To achieve sustained suppression of HBV replication and remission of liver disease. The ultimate goal is to prevent cirrhosis, hepatic failure and HCC. EASL guidelines 2012 To improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensated cirrhosis, end-stage liver disease, HCC and death. This goal can be achieved if HBV replication can be suppressed in a sustained manner. Liaw YF et al. Hepatol Int 2012; 6: Lok AS et al. Hepatol 2009; AASLD Practice Guidelines; EASL Jury, J Hepatol :

8 Can Chronic Hepatitis B be cured/eradicated? Current paradigm: chronicity is for life What is eradication? Occult HBV exists Residual cccdna after HBsAg loss Functional Cure HBsAg loss/seroconversion Absolute or complete cure Absence of cccdna in body Zeisel MB, et al. Gut 2015;epub ahead of print (state of the art ANRS workshop on HBV cure) Zoulim, Cold Spring Harb Perspect Med 2015;5:a021501

9 Cumulative propability (%) Is a Functional Cure possible? HBsAg Seroclearance in Asymptomatic Carriers: Long-Term Follow-Up N=1965 HBeAg(-) asymptomatic adult carriers The cumulative probabilities of HBsAg seroclearance were 8.1% after 10 yrs, 24.9% at 20 yrs and 44.7% at 25 yrs HBsAg seroclearance correlated positively with age at entry (P<0.0001) and sustained remission of hepatitis (P<0.0001) and marginally significantly with male sex (P=0.053) However, far from achieving this with patients on treatment Years after entry Chu & Liaw. Hepatology 2007;45: :

10 Improved survival and HCC in CHB patients with HBsAg seroclearance treated with NA Median FU = 6y, n=5409 Propensity matched scoring 1:4 Kim G-A, et al. Gut 2013;0:1 8.

11 Complex Management of Chronic Hepatitis B Screening Principles Identify patients Issues Screen pop.>2% Diagnosis Confirm HBsAg+ ~99% accuracy Case selection Select those at risk of disease progression 20-40% progress Treatment Monitoring stopping Which therapy? Monitor those on treatment Stopping rules PEG, NA or combo Short vs long term Tests & frequency Relapse or HBsAg seroclearance?

12 Not all patients are recommended for therapy Treatment Indicated Chronic hepatitis (inflammation) Significant fibrosis Cirrhosis Decompensated cirrhosis immunosuppression Treatment not indicated Chronic carriers (HBV DNA <10 4 IU/ml) without significant fibrosis/cirrhosis *Recommended by guidelines

13 Approved Treatments available Strategy 1 Nucleos(t)ides Lamivudine Adefovir Telbivudine Entecavir* Tenofovir* Strategy 2 Immunomodulators Standard interferon Peg-interferon* *Recommended by guidelines

14 Predictable outcomes Nucleos(t)ides Excellent viral suppression HBeAg seroconversion 20-25% HBsAg loss <1% Immunomodulators Suboptimal viral suppression HBeAg seroconversion 30-35% HBsAg loss 3-5%

15 Liaw YF et al. Hepatol Int 2012; 6: Lok AS et al. Hepatol 2009; AASLD Practice Guidelines; EASL Jury, J Hepatol : Current CHB Treatment Strategy Not for: Decompensated cirrhosis ACLF Stopping Rule Treatment indicated Short Term X Fixed Duration IFN Short Term NA Based on fixed duration HBeAg seroconversion Long Term NA HBsAg clearance

16 Therapeutic Signposts for Chronic Hepatitis B HBeAg positive CHB signposts Goals of Tx Start Rx Reduce serum HBV DNA Normal ALT HBeAg loss AntI-HBe Seroconversion qhbsag HBsAg Loss/SC Prevent Cirrhosis Liver failure HCC HBeAg negative CHB ~?% Improve survival Start Rx Reduce serum HBV DNA Normal ALT PCR negative qhbsag HBsAg Loss/SC Liver inflammation and fibrosis Adapted from Naumov, EASL 2006

17 Nucleos(t)ide Analogues

18 Recommendations on NAs AASLD 2009 Treatment can be initiated with any of the approved treatments but entecavir and tenofovir are preferred (I) EASL 2012 Entecavir and Tenofovir have high barriers to resistance and can be confidently used as first line therapies (A1). The other 3 agents may only be used if high barrier drugs are not available or inappropriate (A1) APASL 2012 Entecavir or tenofovir is the preferred nucleos(t)ide.

19 Long Tern NA Cumulattive HBeAg seroconversion Sustained viral suppression Normalisation of LFTs Regression of liver cirrhosis Salvage of liver decompensation Reduction in HBV flares Very low rates of HBsAg seroclearance

20 Poor HBsAg clearance rate in Asian HBV patients on treatment Study n Median FU Treatment HBsAg clearance Seto et al, JGH y ETV 0.45% Kim et al, Gut y LAM or ETV 2% Wong et al, Hepatol y pegifna2a 2.4% Marcellin et al, Gastro * 36m pegifna2a 9.3% *genotype B & C analysis Seto, J Gastro Hep 2014;29: Kim, Gut Oct 25. doi: /gutjnl Wong, Hepatology, 2010;51: Marcellin, Gastroenterology 2009;136:

21 Duration of PEG increases response rate

22 HBeAg seroconversion Extending PEG-IFN α-2b to 48 weeks improves response in HBeAg(+) patients Patients recruited from 25 centers in China, Malaysia, Taiwan, and Singapore in prospective, randomized control trial 40 P=0.001 N=224 PEG-IFN alfa-2b 1.5 µg/kg Follow-up 30 30% 0 48 N=221 PEG-IFN 1.5µg Follow-up % 16% N=225 PEG-IFN 1.0µg Follow-up / / /48 PEG-IFN α-2b 1.5 ug/kg for 48 wks is superior to PEG-IFN α-2b for 24 wks Fan et al. AASLD 2010

23 HBeAg seroconversion 48w superior to 24w confirmed in NEPTUNE study N=136 PEG-IFN alfa-2a 180 µg Follow-up 40 36% N=136 PEG-IFN alfa-2a 90 µg Follow-up 30 23% 26% 0 48 N=136 PEG-IFN 180µ Follow-up % N=140 PEG-IFN 90µg Follow-up µg 180µg 90µg 180µg 24w 24w 48w 48w Use PEG-IFN α-2a 180 ug for 48 wks Liaw et al. AASLD 2010

24 PegBeLiver: Extension of PegIFN alfa-2a to 2 Yrs in HBeAg-Negative HBV Randomized 2:2:1 Wk 48 Wk 96 PegIFN alfa-2a 180 µg/wk (n = 51) 1-yr FU HBeAg-negative pts with chronic HBV infection PegIFN alfa-2a 180 µg/wk (n = 52) PegIFN alfa-2a 135 µg/wk 1-yr FU (N = 128) PegIFN alfa-2a 180 µg/wk + LAM 100 mg/day* (n = 25) 92% to 96% of patients had GT D HBV PegIFN alfa-2a 135 µg/wk *PegIFN/LAM arm included for exploratory analysis of combination therapy; this arm not included in statistical calculations for study design. Lampertico P, et al. EASL Abstract yr FU

25 HBeAg-Negative Pts (%) PegBeLiver: Virologic and Serologic Response With Extended PegIFN wk pegifn 96-wk pegifn P = P = EOT 12-Mo Post-Tx EOT 12-Mo Post-Tx EOT 12-Mo Post-Tx HBV DNA < 2000 IU/mL HBsAg Loss HBsAg 10 IU/mL No apparent benefit of adding LAM to pegifn during year 1 Lampertico P, et al. EASL Abstract 98. Figure used with permission.

26 NA and PEG: combination, add-on or sequential therapy?

27 Peginterferon alfa 2a for CHB: Patients (%) HBeAg (+) disease During PEG treatment HBeAg SC ALT Normal HBV DNA HBeAg SC ALT Normal HBV DNA <400 c/ml <400 c/ml Week 48 (EOT) Week 72 p=0.02; *p=0.006 vs LAM; **p=0.002 vs LAM ***p<0.001 vs LAM *** 32 After PEG treatment ** 41 * 39 PegIFN (n=271) PegIFN + LAM (n=271) LAM (n=272) 28 *** 14 *** 14 Lau et al, N Engl J Med 2005; 352:

28 Peginterferon alfa 2a for CHB: Patients (%) HBeAg (-) disease During PEG treatment ALT Normal HBV DNA <400 c/ml * 59 ** ALT Normal Week 48 (EOT) Week 72 *p=0.004 vs LAM; **p=0.003 vs LAM ***p<0.001 vs LAM After PEG treatment *** 19 PegIFN (n=177) PegIFN + LAM (n=179) LAM (n=181) *** 20 7 HBV DNA <400 c/ml Marcellin et al, N Engl J Med 2004; 351:

29 PEG vs PEG+LAM post-treatment responses Li, BMC Infect Dis. 2011; 11: 165.

30 Which NA to combine?

31 HBeAg seroconversion at end of FU PEG PEG + LAM PEG PEG + ADV Kim, J Viral Hepat May 13: epub ahead of print

32 TDF vs PEG IFN vs Combination 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

33 Mean Change From Baseline(log 10 IU/mL) TDF vs PEG IFN vs Combination Change in Serum HBsAg Levels Study Week TDF 120 wk -0.3 log -0.6 TDF+PEG 16 wk TDF 32 wk -0.5 log p< PEG 48 wk -0.8 log p< p= TDF + PEG 48 wk -1.1 log patients who were re-treated at Week 48 were excluded from Week 48 calculations. Error bars represent 95% confidence intervals. Marcellin et al. AASLD 2014

34 Patients with HBsAg Loss, Kaplan-Meier Estimate (%) TDF vs PEG IFN vs Combination HBsAg Loss through week weeks TDF + PEG 48 wk 9.0% PEG 48 wk TDF + PEG 16 wk TDF 32 wk TDF 120 wk 72 weeks 2.8% 2.8% 0% p=0.003 p< 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 Marcellin et al. AASLD 2014

35 Study 149 Conclusions Best treatment responses for HBsAg loss HBV genotype A TDF + PegIFN for 48 weeks Best predictor for HBsAg loss : HBsAg decline >1 log 10 IU/mL at Week 12 Future research to identify patient subpopulations who may derive the most benefit from combination therapy is warranted Chan, EASL, 2015, O117 Marcellin, APASL, 2015, Oral #1993 Marcellin, AASLD, 2014, Oral #193 37

36 Switch or Add PEG?

37 Switching from long-term ETV to Peg-IFN alfa-2a in patients with HBeAg-positive chronic hepatitis B (the OSST study, J of Hepatology accepted) Randomised, multicentre, open-label study Aims to determine whether HBeAg-positive patients with HBV DNA suppression maintained on ETV can achieve HBeAg seroconversion or HBsAg loss by switching to Peg-IFN alfa-2a Primary endpoint: HBeAg seroconversion at end of treatment (week 48) Secondary endpoint: HBsAg loss at week 48 ETV 0.5 mg QD for ~9 36 months (n=200) HBV DNA 1000 copies/ml Arm A Switch to Peg-IFN alfa-2a 180 μg/week (n=100) ETV 0.5 mg QD Follow-up HBeAg <100 PEIU/mL Arm B ETV 0.5 mg QD (n=100) Time (weeks) PEIU = validated with in-house reference standards obtained from Paul Ehrlich Institute Ning Q, et al. J Hepatol 2014;21(4):

38 Response rates at week 48 (%) Response rates at week 48 of treatment with Peg-IFN alfa-2a: ITT population Peg-IFN alfa-2a + ETV results in significantly greater serological and virological response rates at week 48 than ETV monotherapy p< Peg-IFN alfa-2a (n=97) ETV (n=100) n/n HBV DNA <1000 copies/ml p= HBeAg seroconversion p=0.0014* /97 90/100 15/97 6/100 9/97 4/97 HBsAg loss p=0.0569* HBsAg seroconversion *Fisher Exact test, other p values are using Chi-Squared Test Updated data from time of abstract submission ITT = intention-to-treat Ning Q, et al. J Hepatol 2014;21(4):

39 PEGAN Study: Design randomization Ptimary endpoint W-6 W0 W48 W96 W144 PEGIFN α2a 180 µg/wk N=185 CHB patients HBeAg negative N=92 N=90* NUC treatment N=93 N=93 Randomized, controlled, open-label study (N=185). Stratified by HBsAg titer (<2.25 log IU/ml or 2.25log IU/ml) Key inclusion criteria HBeAg negative Undetectable HBV DNA with NUC for at least 1 year Stable NUC regimens for at least 3 months (no Telbivudine) No decompensated cirrhosis Patients in the PEGIFN group were monitored monthly during the first 48 weeks, then every 3 months. Treatment discontinuation was allowed if HBsAg loss was sustained for 24 weeks. 26/07/2013 EASL 2015 / April Vienna 41

40 Results: ITT analysis NA PEG+NA 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% p= p=ns 8% 8% 3% 0% week 48 week 96 M. Bouliere EASL 2015

41 HBV Treatment Strategies Therapeutic targets Block T-cell responses Recovery of HBV-specific T-cell responses 1 1 Viraemia Viral particles cause (re)infection Humoral responses Robust anti-envelope neutralizing responses 2 2 Antigen load (HBe, HBs) Subviral particles overhaul host immune system Innate immunity Suppression through cytokine- and APCmediated mechanisms 3 3 cccdna Master template causes persistence Boost

42 New Therapeutic Agents for HBV Nucleoside Analogues Mechanism Company Status MIV-210 Inhibits viral DNA polymerase Medivir/Daewoong South Korea Phase IIdiscontinued 2013 Amdoxovir (DAPD) Inhibits viral DNA polymerase RFS Pharm LLC Tucker, GA Discontinued Besifovir (LB80380) Inhibits viral DNA polymerase lldong Pharma, S. Korea Phase III (Clinical trials no: NCT ) Tenofovir Alafenamide (TAF) Inhibits viral DNA polymerase Gilead Sciences, Foster City, USA Phase III Non-nucleoside antivirals Mechanism Company Status Myrcludex B Entry Inhibition Hepatera, Russia Phase IIA HAP Compound Bay REP 9AC Inhibits viral nucleocapsid HBsAg Release Inhibitor AiCuris, Germany REPLICor Inc. Montreal, Quebec Novira Therapeutics, NVR-1221 Capsid inhibitor Doylestown, PA Adapted from: Probably discontinued Phase I Phase 1B

43 New Therapeutic Agents for HBV Non-nucleoside antivirals Mechanism Company Status ARC-520 BSBI-25 TKM-HBV Non-Interferon Immune Enhancers GS-4774 CYT107 (Interleukin-7) DV-601 RNAi gene silencer cccdna inhibitor RNAi gene silencer Arrowhead Research, Pasadena, CA Baruch S. Blumberg Intsitute, Doylestown, PA Tekmira, Vancouver, CA Phase IIa Preclinical Preclinical Mechanism Company Status Therapeutic Vaccine Immunemodulator HBV surface and core antigens Gilead Sciences with Globe Immune Louisville, CO Cytheris, Paris, France Dynavax, Berkeley, CA Phase II Phase I/IIa Phase Ib HBV Core Antigen Vaccine Therapeutic HBV vaccine Emergent Europe, U.K. Phase I Gilead Sciences, GS-9620 TLR7 agonist Foster City, USA Adapted from: Phase II

44 Conclusions The goal of CHB therapy is moving from control towards cure NAs with high barrier to resistance, and PEG are a recommended first line therapy and can be used for a wide spectrum of CHB patients The short term strategy relies on HBeAg seroconversion Generally refers to PEG NA may behave differently eg TELB, although limited by resistance Long term therapy leads to predictable outcomes of HBV DNA suppression, ALT normalisation, improvement in fibrosis & cirrhosis Long term NA can lead to HBsAg seroclearance in few patients Combination therapy with PEG and TDF, switching from NA to PEG, and add-on PEG therapy are promising strategies However, these strategies are only able to achieve limited HBsAg seroclearance and we will need new classes of antiviral agents in order to achieve this

45 NEW!! SHC Preceptorship Program For trainees, general physicians, specialists Present a difficult to manage case from your practice Additional half day training & EM workshops Registration, hotel and flights fully paid Limited places Apply through website: