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 infection – 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 Glecaprevir/Pibrentasvir (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 ribavirin 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 Hepatitis C? 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 Voxilaprevir/Velpatasvir/Sofosbuvir (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 Ledipasvir ± 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 Hepatitis B 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 m Therapy c/ 0.0 0 1 g o HBsAg (l e Partial Cure Anti-HBc n -1.0 aseli b m -2.0 +/- Anti-HBsAb o r f e Functional Cure ng a -3.0 h c HBV DNA -4.0 Sterilizing Cure HBV DNA HBV Time Complete Cure LIVER cccDNA X Lok et al.