Management of Viral Hepatitis in Patients with Renal Failure - PowerPoint PPT Presentation

HKASLD Nov. 16 2014 (Hong Kong) Management of Viral Hepatitis in Patients with Renal Failure Chun-Jen Liu, MD, PhD; Chen-Hua Liu, MD Hepatitis Research Center, and Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan

Outline • Prevalence and clinical impact of chronic viral hepatitis in patients with end-stage renal disease (ESRD) • Management of chronic hepatitis C in patients with ESRD • Management of chronic hepatitis B in patients with ESRD • Conclusions and perspectives

Prevalence of HCV Infection in Hemodialysis Patients (DOPPS) • Dialysis Outcomes and Practice Patterns Study (DOPPS): a large, prospective, observational study of HD patients in 12 countries that collects extensive data on enrollees, including hepatitis status and medications • Study design: 49,762 HD patients enrolled between 1996 and 2011 Overall prevalence: 9.5% (4,735 of 49,767 patients) 20 18 16.8 16.0 Prevalence of HCV (%) 16 14 12.9 12 10.5 10 8.6 8 5.9 6 4.8 4.7 4.7 4.7 4.6 3.3 4 2 0 UK CA SW GE AU NZ BE USA FR SP IT JP CA: Canada; SW: Sweden; GE: German; AU: Australia; NZ: New Zealand; BE: Belgium; FR: France; SP: Spain; IT: Italy; JP: Japan Goodkin DA, et al. Am J Nephrol 2013;38:405-12

Impact of HCV on Survival in Dialysis Patients • Study design: meta-analysis of 14 observation studies (cohort and case-control studies), involving 145,608 patients on long-term dialysis Estimates for adjusted relative risks (aRR) of all cause mortality and HCV among dialysis patients Fixed effects aRR Random effects aRR Study, n R i p – value (by Q test) (95% CI) (95% CI) All studies 14 1.32 (1.25-1.39) 1.35 (1.25-1.47) 0.39 0.08 Population-based studies 5 1.28 (1.21-1.36) 1.28 (1.21-1.36) 0.00 0.90 US studies 3 1.31 (1.09-1.58) 1.37 (1.05-1.78) 0.46 0.18 HD patients only 6 1.43 (1.23-1.65) 1.40 (1.12-1.76) 0.52 0.08 Cohort studies 11 1.33 (1.26-1.41) 1.37 (1.27-1.48) 0.37 0.12 Chronic HCV 13 1.33 (1.25-1.40) 1.35 (1.26-1.46) 0.32 0.14 Non-Australian studies 11 1.32 (1.24-1.40) 1.37 (1.24-1.52) 0.50 0.04 Estimates for adjusted relative risks (aRR) of disease-specific mortality and HCV among dialysis patients Fixed effects aRR Random effects aRR Study, n R i p – value (by Q test) (95% CI) (95% CI) Liver disease-related mortality 4 3.18 (2.08-4.84) 3.82 (1.82-7.61) 0.58 0.08 Cardiovascular mortality 3 1.26 (1.10-1.45) 1.26 (1.10-1.45) 0.00 0.73 Infectious disease-related mortality 2 1.53 (1.11-2.12) 1.53 (1.11-2.12) 0.00 0.85 R i : proportion of total variance due to between studies variance (assessment of heterogeneity) Fabrizi F, et al. J Viral Hepat 2012;19:601-7

Impact of HCV Infection on Kidney Transplantation Outcomes: Systemic Review • Systemic review: retrospective cohort study (n = 16), clinical trial (n = 2) for patient and/or graft survival Hazard ratio (95% CI), patient mortality Hazard ratio (95% CI), graft loss Einollahi B Einollahi B Luan FL Aroldi A Aroldi A Gentil Govantes MA Pereira BJ 1995 Pereira BJ 1995 Pereira BJ 1998 Pereira BJ 1998 Legender C Gentil MA Gentil MA Lee WC Lee WC Bruchfeld A Bretenfeldt MK Morales JM Bruchfeld A Mitwalli AH Morales JM Mahmoud IM Ingsathit A Lin HH Batty DS Overall 1.56 (1.22,2.004), p < 0.0001 Mahmoud IM Lin HH 0.199 1 8.36 Overall 1.69 (1.33,1.97), p < 0.0001 0.77061 1 14.4264 Rostami Z, et al. Hepat Mon 2011;11:247-54

Prevention and Treatment of HCV Infection Chronic HCV Infection (post renal and/or liver transplantation) Chronic HCV Infection (maintenance dialysis) Acute HCV Infection (maintenance dialysis) No HCV Infection (maintenance dialysis) -10~ -15 0 0.5 10 20 Years Universal precaution Periodic screening Therapeutic intervention Therapeutic intervention Observation

Anti-HCV therapy in patients with ESRD: Clinical settings and rationale of therapy On hemodialysis Renal transplant candidates • Individualized • Indicated in all – Risk & benefit – Regimen: – Life expectancy • Peg-IFN or IFN with or without low dose ribavirin – Candidacy for renal transplant (RBV) – Co-morbidities • Direct acting antiviral (DAA)- based regimen? – Improve post-transplant After renal transplantation outcomes • Decrease liver disease • IFN increases risk of acute progression rejection, and not indicated post- • Reduce HCV-related transplant extrahepatic complications

Regimen and Duration Drugs • Interferon α monotherapy • Pegylated interferon α monotherapy • Interferon α + ribavirin therapy • Pegylated interferon α + ribavirin therapy Duration • 24 weeks • 48 weeks

Conventional or Pegylated IFN- α Monotherapy for Dialysis Patients with Chronic Hepatitis C Meta-analysis SVR 100 Withdrawal 80 Patients (%) 60 41 39 37 40 33 33 33 31 30 28 27 26 23 19 17 20 0 Conventional IFN- α (1-6 MU three times/week) for 8-48 weeks Pegylated IFN- α (2a: 135-180 μ g/week; 2b: 0.5-1.0 μ g/kg/week) for 24-48 weeks Fabrizi F, et al. Aliment Pharmacol Ther 2003;18:1071-81 Russo MW, et al. Am J Gastroenterol 2003;98:1610-5 Fabrizi F, et al. J Viral Hepat 2008:15:79-88 Gordon CE, et al. Am J Kidney Dis 2008;51:263-77 Fabrizi F. et al. J Med Virol 2010;82:768-75

Study Design for Treatment-Naïve Dialysis Chronic Hepatitis C Patients with Peginterferon or Interferon α -2a • Study design: multicenter, open-label, randomized, active controlled study (n = 50) • Outpatient visit (hemogram, liver panel, and adverse events): weeks 1,2,4,6,8,12 and then monthly till the end of follow-up Peg- IFN α -2a 135 μ g/week Follow-up (n = 25) Dialysis patients with chronic hepatitis C (n = 50) IFN α -2a 3 MU/three times per week Follow-up (n =25) 0 4 12 24 48 Weeks (RVR) (EVR) (ETVR) (SVR) Primary efficacy endpoint: SVR rate Primary safety endpoint: treatment-related withdrawal rate Clinical trial number: NCT00172809 Liu CH, et al. Gut 2008;57:525-30

Standard versus Pegylated Interferon α Monotherapy for Dialysis Patients with Chronic Hepatitis C Pegylated IFN Standard IFN 100 92 92 88 80 p = 0.03 Response rate (%) 60 60 60 48 44 40 20 20 0 RVR EVR ETVR SVR Drop out rates: standard and pegylated IFN (20 vs. 0%, p = 0.02) Liu CH, et al. Gut 2008;57:525-30

Standard or Pegylated IFN- α plus Low Dose RBV for Dialysis Patients with CHC (Meta-analysis) • 10 studies (patient number: 151) from 1998-2010: HCV dialysis patients treated with IFN ( 3 MU tiw) or Peg-IFN (alfa-2a 135 μ g/week or alfa-2b 50 μ g/week)+ low dose RBV (170 mg/day to 200 mg tiw) Random effects model SVR estimate (95% CI) p value (by χ square) All studies (n = 10) 0.56 (0.28-0.84) 0.0000 (328.04) Peg-IFN α + RBV (n = 8) 0.60 (0.28-0.93) 0.0000 (312.41) Peg-IFN α -2a + RBV (n = 7) 0.62 (0.27-0.96) 0.0000 (312.30) European studies (n = 4) 0.60 (0.19-1.02) 0.0000 (33.42) Naïve patients (n = 9) 0.56 (0.25-0.87) 0.0000 (329.10) Cohort studies (n = 9) 0.51 (0.22-0.80) 0.0000 (176.42) Patients stopping antiviral Authors Reasons for withdrawal therapy n (%) Bruchfeld et al. 2/6 (33) Anemia (1), heart failure (1) Bruchfeld et al. 2/6 (33) Depression (1), heart failure (1) Rendina et al. 4/35 (11) Anemia (1), dermatitis (1), loss of FU (2) Anemia (3), loss of FU (2), depression (1), infection (2), angina (1), hip fracture Carriero et al. 10/14 (71) (1) Fatigue (2), poor compliance (4), anemia (1), loss of FU (1), hematuria (1), non Hakim et al. 10/15 (67) response (1) Liu et al. 6/35 (17) Optic neuritis (2), interstitial pneumonia (1), anemia (3) Fabrizi F, et al. J Viral Hepat 2011;18:e263-9 Liu CH, et al. Gut 2009;58:314-6

Peginterferon α -2a ± Low Dose Ribavirin for Treatment- Naïve Hemodialysis HCV-1Patients: HELPER-1 Trial • HELPER-1: Hemodialysis Low Dose Peginterferon and Ribavirin for HCV-1 Patients • Randomized, multicenter, open-label trial, 2-arm parallel, active control trial (n=205) in 8 academic centers in Taiwan (2007-2011) 1:1 randomization; blocks of 4 Peg-IFN α -2a 135 μ g/week + Ribavirin 200 mg/qd Follow-up (n = 103) Dialysis HCV-1 patients (n = 205) Peg- IFN α - 2a 135 μg/week Follow-up (n =102) 0 4 12 24 48 72 Weeks (RVR) (EVR) (ETVR) (SVR) Primary efficacy endpoint: SVR rate Primary safety endpoint: adverse event (AE)-related withdrawal rate Clinical trial number: NCT00491244 Liu CH, et al. Ann Intern Med 2013;159:729-38