TRANSPLANTATIONSZENTRUM

What’s new in viral hepatitis – including EASL coverage

Thomas Berg Clinic and Policlinic for Gastroenterology, Hepatology, Infectiology and Pneumology University Clinic Leipzig

© Universitätsklinikum Leipzig What‘s new in viral hepatitis • News in HCV – Real-world experience with DAAs, a special emphasis on HCV type 3 – Resistance still an issue? – How to treat HCV-induced HCC and DAA-associated HCC risk – Long-term HCC risk and surveillance strategies after cure

• News in HBV infection – Differences between ETV vs TDF – Cure strategies with current regimens – timing matters? – A finite approach to cure? – The race for cure in HBV – new agents in development Real World VEL/SOF Integrated analysis of 12 clinical practice cohorts n=5.541 Patients, 73% caucasian, 21% cirrhosis

Mangia A et al., EASL 2019; GS-03 Real World VEL/SOF Integrated analysis of 12 clinical practice cohorts

Mangia A et al., EASL 2019; GS-03 / (G/P) – Italian „real-world“ effectiveness

N=738 (89%) were treated for only 8 weeks

D'Ambrosio R et al. J Hepatol. 2019;000 70: 379 DAA effectiveness GT3 HCV infection in England: high response rates regardless of degree of fibrosis, but RBV improves response in cirrhosis Regimen n SVR12, % P value Comparison 1 (SVR12 in GT 3 patients with moderate fibrosis) GLE/PIB (8 weeks) 92 96.6 0.793 SOF/VEL (12 weeks) 214 97.1 Comparison 2 (SVR12 in GT 3 patients with compensated cirrhosis) Comparator SOF/VEL + RBV (12 weeks) 196 98.0 regimen SOF/VEL 218 91.6 0.005* SOF + DCV + RBV 868 92.2 0.002* GLE/PIB (12 weeks) 167 96.4 NS†

*vs SOF/VEL + RBV (12 weeks); †vs all other regimens. Drysdale K, et al. ILC 2019; LB-08 How to best treat HCV type 3 with cirrhosis? The role of in the treatment of HCV type 3 with cirrhosis: A randomized trial Esteban R et al. Gastroenterology 2018;155:1120

000 The importance of baseline resistance (RAS) Esteban R et al. Gastroenterology 2018;155:1120

000 Pre-therapeutic assessment – HCV genotype and resistance

However, …

EASL CPG J Hepatol 2018, EASL homepage Rare HCV types in the WHO African region – Impact on treatment response?

Childs K et al. EASL 2019; PS-181; J Hepatol 2019, epub Rare HCV types in the WHO African region

Childs K et al. EASL 2019; PS-181; J Hepatol 2019, epub Rare HCV types in the WHO African region – Impact on treatment response?

Childs K et al. EASL 2019; PS-181; J Hepatol 2019, epub Suboptimal SVR rates in African patients with atypical HCV subtypes 1: implications for global elimination of ?

SOF/LDV, PrOD, GZR/EBR

Childs K et al. EASL 2019; PS-181; J Hepatol 2019, epub Re-Treatment for patients who failed a DAA-based regimen SOF/VEL/VOX – Rescue treatment of choice (EASL CPG)

Foster GR et al. Hepatology 2016; 64 (Suppl) Abstract (AASLD 2016) Real-world experience: 2nd line treatment for DAA failures // (VOX/VEL/SOF)

TRIO USA Scotland Navigatore French ATU German DHC-R N=173 (N=12) (N=179) (N=46) (N=110) + Ribavirin 4% 0% 22% 20% 4% GT1 131 5 103 15 71 GT2 4 18 4 GT3 30 7 42 18 34 GT4-5 6 16 9 5 preTx V/S,G/E,3D, NS5A+SOF, SOF+PI, SOF+NS5A, SOF+PI, SOF+NS5A, SOF+X PI+NS5A3D, SOF+NS5A, 2D/3D, PI+NS5A 3D, PI+NS5A PI+NS5A, 3D Cirrhosis 43% 31% 45% 100% 27% Non-SVR n=2 n=1 n=4 n=2 n=0

Bacon et al., THU-116; Boyle et al., THU-121; Hezode et al., THU-142; Vermehren et al., THU-188 Characteristics of patients with relapse after SOF/VEL/VOX triple rescue treatment

Sarrazin C et al. J Hepatol 2018 Aug 0008 [Epub] Resistance-guided retreatment of HCV patients failing NS5A inhibitors in real world

• How to use resistance data in order to individualize re-treatment of DAA failure in countries with limited access to new DAA combinations

Pérés AB et al. J Hepatol 2019; epub High efficacy of Resistance-guided retreatment of HCV patients failing NS5A inhibitors in real world

Failure of Sofosbuvir ± Ribavirin

Pérés AB et al. J Hepatol 2019; epub High efficacy of Resistance-guided retreatment of HCV patients failing NS5A inhibitors in real world

• The study provides evidence on how to use resistance data in order to achieve SVR rates of 90% in countries with limited access to new DAA combinations

• If no NS5A RASs is found: SOF+NS5A inhibitor + RBV • If HCV type 3 and only Y93H: SOF+Velpatasvir + RBV for 24 weeks • If both NS5A and NS3 RASs: retreat with a SOF-based three-drug regimen + RBV

Pérés AB et al. J Hepatol 2019; epub How to best manage patients with HCV-induced HCC?

• Treat the tumor first? • Risk of HCC recurrence after DAA? SVR rates to DAA therapy in patients with chronic hepatitis C and HCC

A systematic review and meta-analysis

Ji F et al. J Hepatol 2019; 71: 473 Incidence of HCC in HCV-associated cirrhosis according to different treatment strategies

Llovet JM and Villanueva A. Nat Rev Gastroenterol Hepatol 2016 HCC incidence – DAA- versus IFNa-based treatment Nahon P et al. Gastroenterology 2018 Jul 18 [Epub] HCC incidence – DAA- versus IFNa-based treatment weighed according to the disease severity Nahon P et al. Gastroenterology 2018 Jul 18 [Epub]

000 HCC risk after DAA treatment – post hoc image analysis (water-only DIXON MRI)

Scott RA et al. Gastroenterology 2018; 154: 1846 Time association between hepatitis C therapy and HCC emergence in cirrhosis: Relevance of non-characterized nodules

Marino Z et al. J Hepatol 2019; 70: 874 DAAs after successful treatment of early HCC (BCLC 0/A) improve survival in HCV-cirrhotic patients

Cabibbo G et al. J Hepatol 2019; 71: 265 DAAs after successful treatment of early HCC (BCLC 0/A) improve survival in HCV-cirrhotic patients

• The improvement in survival seems to be caused by a reduction in hepatic decompensation • DAAs did not impact on HCC recurrence

Cabibbo G et al. J Hepatol 2019; 71: 265 Factors influencing the 5-year survival in curatively treated HCC Cabibbo et al, J Hepatol. 2017;67:65-71

No event within 1 year after complete Early HCC recurrence as first event radiological response

Early hepatic decompensation as first event AGA Clinical Practice Update on Interaction Between Oral Direct-Acting Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review

1. The presence of active HCC is associated with a small but statistically significant decrease in sustained virologic response with DAA therapy

2. Patients with HCC who are eligible for potentially curative therapy with liver resection or ablation should defer DAA therapy until after HCC treatment is completed.

3. There are insufficient data evaluating benefits and cost-effectiveness of DAA therapy in patients with active intermediate or advanced HCC. Decisions regarding DAA treatment in these patients should be considered in light of HCC tumor burden, degree of liver dysfunction, life expectancy, and patient preferences.

Singal AG et al. AGA Clinical Practice Update. Gastroenterology 2019; 156: 2149 AGA Clinical Practice Update on Interaction Between Oral Direct-Acting Antivirals for Chronic Hepatitis C Infection and Hepatocellular Carcinoma: Expert Review

4. There are no conclusive data that DAA therapy is associated with increased or decreased risk, differential time to recurrence, or aggressiveness of recurrent HCC in patients with complete response to HCC therapy.

5. DAA therapy should not be withheld from patients with complete response to HCC therapy; however, DAA therapy can be deferred 4–6 months to confirm response to HCC therapy.

Singal AG et al. AGA Clinical Practice Update. Gastroenterology 2019; 156: 2149 Post-treatment follow-up of patients who achieve SVR HCC risk and SVR

SVR and HCC risk HCC risk after SVR – importance of cirrhosis

Janjua NZ et al J Hepatol 2017; 66: 504 HCV-induced epigenetic changes associated with HCC risk persist after SVR

Hamdane N and Jühling F et al. Gastroenterology 2019;156:2313–2329 Post-treatment follow-up of patients who achieve SVR

EASL CPG J Hepatol 2018, EASL homepage HCC risk after SVR – the need for individualized prognostic models HCC incidence according to treatment response and individual risk factors Calvaruso V et al. Gastroenterology 2018;155:411–421

000 Individualized HCC risk prediction

Ioannou GN et al. J Hepatol. 2018; 69:000 1088 Individualized HCC risk prediction

www.hccrisk.com

Ioannou GN et al. J Hepatol. 2018; 69:000 1088 virus (HBV) - Infection Entecavir or Tenofovir

When it comes to HCC prevention – are all HBV antivirals the same? Are there differences between TDF and ETV regarding HCC risk?

J Choi et al., JAMA Oncol. 2019 Jan 1;5(1):30-36 Are there differences between TDF and ETV regarding HCC risk?

Kim et al. J Hepatol 2019; Apr 436 epub Tenofovir treatment has lower risk of hepatocellular carcinoma than entecavir treatment in patients with chronic hepatitis B • 29,350 CHB patients (mean age 52.9 ± 13.2 years; 63.7% male) • 1,309 (4.5%) and 28,041 (95.5%) first received TDF and ETV, respectively • At a median 3.6 years FU, 8 (0.6%) TDF and 1,386 (4.9%) ETV-treated patients developed HCC

HCC risk analysis Univariate analysis† Multivariable analysis† Parameters SHR 95% CI Adjusted SHR 95% CI ETV TDF vs ETV 0.15 0.07–0.29 0.32 0.16–0.65 Age 1.06 1.06–1.06 1.05 1.04–1.05 Male sex 2.17 1.90–2.47 2.42 2.11–2.76 Cirrhosis 5.73 5.16–6.36 2.30 2.01–2.64 Platelet* 0.35 0.31–0.40 0.54 0.49–0.60 Albumin 0.91 0.91–0.92 0.97 0.97–0.98 TDF ALT* 0.81 0.77–0.84 0.87 0.83–0.91 Total bilirubin* 1.48 1.41–1.56 – – HBeAg+‡ 0.82 0.73–0.93 1.44 1.26–1.65

TCF Yip et al., ILC 2019; LB-03 Definition of HBV Cure when anti-HBc titers go to zero ) SERUML +1.0 Follow-up

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h c HBV DNA -4.0 Sterilizing Cure HBV DNA HBV Time Complete Cure LIVER cccDNA X Lok et al. Hepatitis B Cure: From Discovery to Regulatory Approval; Hepatology 2017 Functional cure with current regimens

000 HBsAg loss rates after current treatment regimens

Schinazi RF et al. Liver Int 2018; 38 (Suppl.1):000 102 HBsAg Loss in HBeAg+ Patients under TDF treatment 8 years follow-up Year 1 2 3 4 5 6 7 8

12.9% (n=28)

TDF-TDF (Kaplan-Meier-ITT analysis)

ADV-TDF Cumulative Probability Function Estimate Function Probability Cumulative

Weeks on Study • Baseline predictors for HBsAg loss (multivariate)1

– Caucasian race, genotype A or D, ≤4 years of HBV infection, HBsAg level (log10 IU/mL) Marcellin P et al. J Hep 2014 HBsAg Loss in HBeAg+ Patients under TDF treatment 8 years follow-up Year 1 2 3 4 5 6 7 8

12.9% (n=28)

TDF-TDF (Kaplan-Meier-ITT analysis)

ADV-TDF 8 years follow-up in HBeAg-negative patients under TDF treatment:

 1% HBsAg loss Cumulative Probability Function Estimate Function Probability Cumulative

Weeks on Study • Baseline predictors for HBsAg loss (multivariate)1

– Caucasian race, genotype A or D, ≤4 years of HBV infection, HBsAg level (log10 IU/mL) Marcellin P et al. J Hep 2014 Increasing functional cure with current HBV agents? Combination treatments suppressing both HBV replication and cccDNA transcritption may trigger significant HBeAg and HBsAg decline

Thimme R and Dandri M. J Hepatol 2013; 58:205 Increasing functional cure with current HBV agents

De-novo PEG-IFN combination NA

Add-on PEG-IFN PEG-IFN NA

PEG-IFN Switch NA

NA = nucleos(t)ide analogue “Add-on” PEG-IFN in NA-treated HBeAg-negative patients A RCT multicenter study from France

HBsAg levels

NA alone (n=93)

NA + PEG-IFN → NA (n=90)

*p<0.05. †p<0.01. ‡p<0.001

Bourliere M et al . Lancet Gastroenterol Hepatol 2017 Add-on of peg to a stable nucleoside regimen (PEGAN ANRS study)

HBsAg loss (ITT analysis)

PEG-IFN add-on NA alone p

Week 48 7/90 (8%) 0/93 (0%) 0.006

Week 144 9/90 (10%) 4/93 (4%) 0.11

Bourliere M et al . Lancet Gastroenterol Hepatol 2017 Add-on of peg interferon to a stable nucleoside regimen (PEGAN ANRS study)

HBsAg loss (ITT analysis)

• 20% had early discontinuationPEG-IFN add of -PEGon -IFNa (inNA 41% alone due to SAEs) p • Grade 3 (29%) and 4 (21%) adverse events were more frequent in the PEGWeek-IFNa48 plus NA than in 7/90the NA(8%)-alone group 0/93(3% (0%)grade 3; 6% grade0.006 4)

Week 144 9/90 (10%) 4/93 (4%) 0.11

Safety: AE were more frequent in the PEG+NUC vs NUC (Grade 3: 29% vs 3%; Grade 4: 21% vs 6%) Bourliere M et al . Lancet Gastroenterol Hepatol 2017 Summary of PEG-IFN + NA combination strategies

• The combination of PEG with NAs has a strong biological rationale

• Three different strategies have been assessed (de-novo combo, switch to, add-on)

• Most studies showed a faster HBsAg decline in the PEG-IFN + NA combinations vs NA alone

……but HBsAg rebounds occur, and only few patients cleared HBsAg

• No clear benefit of extending PEG-IFN + NA combinations beyond week 48

• Heterogeneous patient populations make between studies comparisons difficult Antiviral strategies in HBV infection – timing matters (?)

Timing of therapeutic interventions during the chronic course of HBV infection

Early (< 2 years) Middle (10 years) Late (> 20 years)

Treatment response

HBeAg/HBsAg loss/Stability of the response

Prevention of complications

Chance for finite therapy Timing matters?

Very early treatment initiation Early treatment in the HBeAg-positive chronic infection (immune-tolerant) phase

N=69 (median age 7, range 1-16 years)

Zhu S et al. J Hepatol 2018; 68: 1123 Early treatment in the HBeAg-positive chronic infection (immune-tolerant) phase

Zhu S et al. J Hepatol 2018; 68: 1123 Early treatment in the HBeAg-positive chronic infection (immune-tolerant) phase

Control Group HBeAg seroconversion: 4.4% HBsAg loss: 0%

Zhu S et al. J Hepatol 2018; 68: 1123 Very early treatment in infants with the HBeAg-positive chronic hepatitis B

N=18 (median age 8 months, range 6-11 months) Cumulative HBsAg loss 83%

N=11 (median age 12 months, range 12-24 months) Cumulative HBsAg loss 36%

Zhu S et al. J Hepatol 2019; in press

Stopping NUCs: Summary of studies on off-therapy HBsAg losses

Study N Tx duration HBsAg loss Incidence

Chan 53 27 mo 11/53 23% - 5 yrs

Hadziyannis 33 4-5 yrs 13/33 39% - 3 yrs

Chen 105 93 wks 30% - 6 yrs

Patwardhan 33 5.3 yrs ? 30% - 6 yrs

Hung 73 30 mo 20/73 46% - 6 yrs

Yao 119 151 wks 44/119 55% - 6 yrs

Berg 21 (42) >4 yrs 4/21 19% - 144 wks

Jeng 691 156 wks 42/691 13% - 6 yrs

Papatheodoridis 57 5.3 yrs 12/57 25% 1.5 yrs

Courtesy F. Zoulim EASL PCG 2018; adapted from Jeng WJ et al. Hepatology 2018;68:425 The first prospective randomized trial evaluating finite treatment duration for HBeAg-negative chronic hepatitis B (FINITE study)

Berg T et al. J Hepatol 2017, 67(5):918-924 NA discontinuation frequently results in virologic and biochemical flares that runs through different phases

Treatment phase Lag-phase Reactivation phase Consolidation phase Long-term outcome phase (> 3 years) (variable ( 3 months) ( 12 months) <1-12 months)

Nucleos(t)ide Analog (NA)

HBV DNA

?

Limit of HBV DNA detection

TIME

Lampertico P and Berg T. Hepatology 2018; 68: 397 NA discontinuation frequently results in virologic and biochemical flares that runs through different phases

Treatment phase Lag-phase Reactivation phase Consolidation phase Long-term outcome phase (> 3 years) (variable ( 3 months) ( 12 months) <1-12 months) Outcome categories A-D

Nucleos(t)ide Analog (NA) A) HBsAg loss ( 20% after 2-3 years of follow- HBV DNA up) B) Sustained virologic response (true „healthy carrier“ state) ± HBsAg level decline  20-30% C) Indeterminate state not fulfilling immediate re-treatment criteria ( 10-20%) D) Chronic hepatitis B requiring Limit of HBV DNA detection re-treatment ( 40%)

TIME

Lampertico P and Berg T. Hepatology 2018; 68: 397 HBV-specific T cell responses after stopping NA

Rinker F et al. J Hepatol 2018; 69: 584 Current and future HBV virological targets for treatment and cure

Revill P et al. Lancet Gastroenterol Hepatol 2019: 4: 545, correction000 The Race - Direct-acting antivirals for HBV in development

Xia Y and Liang J Gastroenterology 2019; 156:311000-324 The Race - Agents that targets host factors in development

Xia Y and Liang J Gastroenterology 2019; 156:311000-324 Capsid inhibitors CpAMs/CAMs (capsid assembly inhibitors)

Figure from Yang L et al. ACS Infect Dis 2019;000 5: 713 Types and structures of HBV capsid inhibitors

(SBA) (HAPs)

Interference with pgRNA Abnormal assembly packaging (aggregated and (immature and abnormal capsid empty capsids) structures)

Xia Y and Liang J Gastroenterology 2019; 156:311-324; Figure adapted from Wynne et al. Mol Cell 1099;000 3: 771 Abnormal HBV capsid particle formation after treatment with different CpAMs in HepAD38 cells (electron microscopy)

Abnormal assembly with aggregated and abnormal capsid structures)

Huber AW et al. ACS Infect Dis 2019;000 5: 750 Influence of the capsid assembly modulator NVR 3-778 on viral replication in HBeAg+ patients with chronic HBV infection

Yuen MF et al. Gastroenterology (2019), doi: https://doi.org/10.1053/j.gastro.2018.12.023 RNA interference siRNA

000 siRNA vs. reverse transcriptase inhibitors (NUCs) mode of action for the treatment of chronic HBV

siRNA hybridize with viral mRNA, and the resulting double-stranded RNA is degraded

Courtesy Xu Z et al. Poster THU-213/EASL_ILC 2016 Short-term RNA interference therapy in chronic hepatitis B using JNJ-3989 brings majority of patients to HBsAg <100 IU/ml threshold

Mean HBsAg reductions from baseline

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o L - 2 . 5 NADIR HBsAg 0 1 2 3 4 5 6 7 8 Threshold N Percent M o n t h s ≤100 IU/ml 35 of 40 88% ≤10 IU/ml 17 of 40 43%

Yuen MF et al. ILC 2019; PS-080 HBsAg release inhibitors (Nucleic acid polymers, NAPs)

000 REP 401 on-treatment HBsAg response

Serum HBsAg Serum anti-HBs Serum HBV DNA

Standard of care only < 1 log reduction in HBsAg HBsAg > 1 log reduction but > 1 IU/mL HBsAg < 1 IU/mL

Bazinet M et al. HBV EASL AASLD Endpoint Meeting, London 2019 ALT flares in nearly all patients early after start of REP2139/2165

Transaminase flares occur in 38/40 patients Appear to be immune-mediated: Timing correlated with antiviral response Strength correlated with HBsAg response All self-resolving either during therapy or follow-up Liver function is continually normal throughout

Correlated with the establishment functional control

Standard of care only < 1 log reduction in HBsAg HBsAg > 1 log reduction but > 1 IU/mL HBsAg < 1 IU/mL

Bazinet M et al. HBV EASL AASSLD Endpoint Meeting, London 2019 HBV entry inhibitors

000 Bulevirtide (Myrcludex B) ± Peg-IFNa-2a in patients with chronic HBV/HDV co-infection (Phase 2)

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➢ Phase 3 study started

Wedemeyer H et al. EASL ILC 2019; GS-13 Excellent safety and effectiveness of myrcludex-B monotherapy administered for 48 weeks in HDV-related compensated cirrhosis

Loglio A et al. J Hepatol 2019, epub Overview of new immunotherapeutic approaches for HBV

Martinez M et al. J Viral Hepatol 2019; doi:10.1111/jvh.13090000 Potential combination strategies to achieve HBV cure

Alonso S et al. BMC Gastroenterology 2017; 17:168 Immunotherapy in chronic HBV infection • New immune therapies, currently in the pipeline, are supported by strong scientific rational but their efficacy in the real-world setting remains to be seen • The risk of inducing severe liver inflammation has so far restricted direct clinical testing • We probably also need better criteria of CHB patient selection for the different immunotherapeutic approaches

000 Possible therapeutic concepts adapted to immunological phases

Lang J et al. Hepatol Intern 2019; 00013: 113 Anti-PD1 (immune checkpoint) blockade with nivolumab w/wo therapeutic vaccine in virally suppressed paitents

Gane E et al. J Hepatol 2019, epub Anti-PD1 (immune checkpoint) blockade with nivolumab w/wo therapeutic vaccine in virally suppressed paitents

Gane E et al. J Hepatol 2019, epub Anti-PD1 (immune checkpoint) blockade with nivolumab w/wo therapeutic vaccine in virally suppressed paitents

Gane E et al. J Hepatol 2019, epub