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

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

HKASLD

• Nov. 16 2014 (Hong Kong)

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)

3.3 4.6 4.7 4.7 4.7 4.8 5.9 8.6 10.5 12.9 16.0 16.8

2 4 6 8 10 12 14 16 18 20

UK CA SW GE AU NZ BE USA FR SP IT JP

Prevalence of HCV (%) Goodkin DA, et al. Am J Nephrol 2013;38:405-12

• 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)

CA: Canada; SW: Sweden; GE: German; AU: Australia; NZ: New Zealand; BE: Belgium; FR: France; SP: Spain; IT: Italy; JP: Japan

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 Fabrizi F, et al. J Viral Hepat 2012;19:601-7

Estimates for adjusted relative risks (aRR) of all cause mortality and HCV among dialysis patients Study, n Fixed effects aRR (95% CI) Random effects aRR (95% CI) Ri p – value (by Q test)

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 Study, n Fixed effects aRR (95% CI) Random effects aRR (95% CI) Ri p – value (by Q test)

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

Ri: proportion of total variance due to between studies variance (assessment of heterogeneity)

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

Rostami Z, et al. Hepat Mon 2011;11:247-54

Hazard ratio (95% CI), patient mortality

Einollahi B Luan FL Aroldi A Pereira BJ 1995 Pereira BJ 1998 Legender C Gentil MA Lee WC Bretenfeldt MK Bruchfeld A Morales JM Ingsathit A Batty DS Mahmoud IM Lin HH Overall

1.69 (1.33,1.97), p < 0.0001

0.77061 1 14.4264

Hazard ratio (95% CI), graft loss

Einollahi B Aroldi A Gentil Govantes MA Pereira BJ 1995 Pereira BJ 1998 Gentil MA Lee WC Bruchfeld A Morales JM Mitwalli AH Mahmoud IM Lin HH Overall

1.56 (1.22,2.004), p < 0.0001

0.199 1 8.36

Prevention and Treatment of HCV Infection

• 10~ -15 0 0.5 10 20 Years

Acute HCV Infection (maintenance dialysis) Chronic HCV Infection (maintenance dialysis) Chronic HCV Infection (post renal and/or liver transplantation) No HCV Infection (maintenance dialysis) Universal precaution Periodic screening Therapeutic intervention Therapeutic intervention Observation

Anti-HCV therapy in patients with ESRD: Clinical settings and rationale of therapy

On hemodialysis

• Individualized

– Risk & benefit – Life expectancy – Candidacy for renal transplant – Co-morbidities

Renal transplant candidates

• Indicated in all

– Regimen:

• Peg-IFN or IFN with or

without low dose ribavirin (RBV)

• Direct acting antiviral (DAA)-

based regimen?

– Improve post-transplant

• utcomes
• Decrease liver disease

progression

• Reduce HCV-related

extrahepatic complications

After renal transplantation

• IFN increases risk of acute

rejection, and not indicated post- transplant

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

33 33 39 41 31 37 33 26 27 28 23 19 30 17

20 40 60 80 100

SVR Withdrawal

Conventional or Pegylated IFN-α Monotherapy for Dialysis Patients with Chronic Hepatitis C

Meta-analysis

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 Patients (%)

Conventional IFN-α (1-6 MU three times/week) for 8-48 weeks Pegylated IFN-α (2a: 135-180 μg/week; 2b: 0.5-1.0 μg/kg/week) for 24-48 weeks

Study Design for Treatment-Naïve Dialysis Chronic Hepatitis C Patients with Peginterferon or Interferonα-2a

Clinical trial number: NCT00172809

• 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

Dialysis patients with chronic hepatitis C (n = 50) Peg-IFN α-2a 135 μg/week (n = 25) IFN α-2a 3 MU/three times per week (n =25) Follow-up Follow-up 0 4 12 24 48 Weeks (RVR) (EVR) (ETVR) (SVR)

Primary efficacy endpoint: SVR rate Primary safety endpoint: treatment-related withdrawal rate Liu CH, et al. Gut 2008;57:525-30

60 44 92 88 92 60 48 20

20 40 60 80 100

RVR EVR ETVR SVR

Pegylated IFN Standard IFN

Standard versus Pegylated Interferon α Monotherapy for Dialysis Patients with Chronic Hepatitis C

Liu CH, et al. Gut 2008;57:525-30 Drop out rates: standard and pegylated IFN (20 vs. 0%, p = 0.02) Response rate (%)

p = 0.03

Standard or Pegylated IFN-α plus Low Dose RBV for Dialysis Patients with CHC (Meta-analysis)

Fabrizi F, et al. J Viral Hepat 2011;18:e263-9 Liu CH, et al. Gut 2009;58:314-6

Random effects model SVR estimate (95% CI) p value (by χsquare) 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)

• 10 studies (patient number: 151) from 1998-2010: HCV dialysis patients treated with IFN ( 3 MU

tiw) or Peg-IFN (alfa-2a 135 μg/week or alfa-2b 50 μg/week)+ low dose RBV (170 mg/day to 200 mg tiw)

Authors Patients stopping antiviral therapy n (%) Reasons for withdrawal 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)

Carriero et al.

10/14 (71) Anemia (3), loss of FU (2), depression (1), infection (2), angina (1), hip fracture (1)

Hakim et al.

10/15 (67) Fatigue (2), poor compliance (4), anemia (1), loss of FU (1), hematuria (1), non response (1)

Liu et al.

6/35 (17) Optic neuritis (2), interstitial pneumonia (1), anemia (3)

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)

Dialysis HCV-1 patients (n = 205) Peg-IFN α-2a 135 μg/week + Ribavirin 200 mg/qd (n = 103) Peg-IFN α-2a 135 μg/week (n =102) Follow-up Follow-up 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

1:1 randomization; blocks of 4

Liu CH, et al. Ann Intern Med 2013;159:729-38

Virologic Responses: HELPER-1 Trial

Variable Peginterferon + ribavirin (N = 103), n/N (%) Peginterferon (N =102), n/N (%) RR (95% CI) P value*

On-treatment virologic response RVR

53/103 (51) 37/102 (36) 1.42 (1.03-1.95) 0.035

EVR

94/103 (91) 95/102 (93) 0.98 (0.90-1.06) 0.80

ETVR

90/103 (87) 86/102 (84) 1.04 (0.93-1.16) 0.55

Virologic outcome SVR†

66/103 (64) 34/102 (33) 1.92 (1.41-2.62) < 0.001 SVR sensitivity (best scenario) 72/103 (70) 34/102 (33) 2.10 (1.55-2.84) < 0.001 SVR sensitivity (worst scenario) 66/103 (64) 37/102 (36) 1.77 (1.32-2.37) < 0.001

Non-SVR

37/103 (36) 68/102 (67)

• Relapse

20/103 (19) 51/102 (50)

• No-response

7/103 (7) 8/102 (8)

• Viral breakthrough

3/103 (3) 6/102 (6)

• Undetermined‡

7/103 (7) 3/102 (3)

• * P values were obtained by either chi-square test or Fisher’s exact test.

† Patients who were lost to 24-week follow-up, were null-responsive to treatment, or had viral breakthrough or relapsed after treatment were considered failure to achieve SVR. ‡ Combination therapy: 6 patients who lost to 24-week post-treatment follow-up (undetectable HCV RNA at week 48 and adverse events) and 1 patient who completed 24-week post-treatment follow-up (adverse events and detectable HCV RNA at the time of treatment discontinuation). Monotherapy: 3 patients who lost to 24-week post-treatment follow-up (undetectable HCV RNA at week 48 and adverse events).

Liu CH, et al. Ann Intern Med 2013;159:729-38

Subgroup Analyses of Prespecified Factors for SVR: HELPER-1 Trial

Variable Peginterferon + ribavirin (N = 103), n/N (%) Peginterferon (N = 102), n/N (%) RR (95% CI) P value for interaction*

Baseline viral load

0.83

< 800,000 IU/mL

44/54 (81) 27/53 (51) 1.60 (1.19-2.14)

≥ 800,000 IU/mL

22/49 (45) 7/49 (14) 3.14 (1.48-6.67)

IL-28B rs8099917 genotype

NA

TT

61/87 (70) 34/85 (40) 1.75 (1.31-2.35)

GT and GG

5/16 (31) 0/17 (0) NA†

Sex

0.86

Female

32/42 (76) 19/40 (48) 1.60 (1.11-2.32)

Male

34/61 (56) 15/62 (24) 2.30 (1.41-3.78)

APRI score

0.95

< 0.8

45/67 (67) 25/69 (36) 1.85 (1.30-2.64)

≥ 0.8

21/36 (58) 9/33 (27) 2.14 (1.15-3.98)

Week 4 viral response

0.51

RVR

47/53 (89) 23/37 (62) 1.43 (1.09-1.87)

non-RVR

19/50 (38) 11/65 (17) 2.25 (1.18-4.28)

RR: relative risk; CI: confidence interval; NA: not assessed; IL28B: interleukin 28B; APRI: aspartate transaminase to platelet ratio index; RVR: rapid virologic response. * The interaction for the pre-specific factors was compared by stratified Mantel-Haenszel test. † P = 0.018 by Fisher’s exact test.

Liu CH, et al. Ann Intern Med 2013;159:729-38

Adverse Events in Treated Patients: HELPER-1 Trial*

Variable Peginterferon + ribavirin (N = 103) Peginterferon (N =102)

Serious AEs All† 5 (5) 4 (4) Death 1 (1) 0 (0) Treatment-related 4 (4) 3 (3) Treatment withdrawal due to AEs 7 (7) 4 (4) Dose reduction to AEs 85 (83) 45 (44) Peginterferon 40 (39) 45 (44) Ribavirin 74 (72)

• Emergent blood transfusion‡

1 (1) 1 (1) Constitutional AEs Flu-like symptoms 26 (25) 28 (28) Fatigue 60 (58) 53 (52) Headache 29 (28) 28 (28) Insomnia 35 (34) 38 (37) Irritability 11 (11) 10 (10) Depression 14 (14) 12 (12) Anorexia 25 (24) 21 (21) Diarrhea 11 (11) 10 (10) Constipation 9 (9) 9 (9) Cough 13 (13) 10 (10) Dermatitis 23 (22) 20 (20) Injection site reaction 14 (14) 13 (13) Hair loss/alopecia 27 (26) 22 (22)

Variable Peginterferon + ribavirin (N = 103) Peginterferon (N =102)

Laboratory AEs§ Anemia║ 74 (72) 6 (6) 8.0-8.4 g/dL 42 (41) 6 (6) 7.5-7.9 g/dL 21 (20) 0 (0) 7.0-7.4 g/dL 8 (8) 0 (0) < 7.0 g/dL 3 (3) 0 (0) Neutropenia 15(15) 13 (13) 0.500-0.749 x 109 /L 12 (12) 11 (11) < 0.500 x 109 /L 3 (3) 2 (2) Thrombocytopenia 9 (9) 11 (11) 25-49 x 109 /L 9 (9) 11 (11) < 25 x 109 /L 0 (0) 0 (0)

AE = adverse event. * Values are numbers (percentages). † Peginterferon + ribavirin arm: one death interferon-induced Stevens-Johnson syndrome at week 20 of therapy; the other 4 serious AEs were pneumonia in one (week 10), peritonitis in one (week 12), anemia induced fainting in one (week 16), and hepatocellular carcinoma in one (week 24); the first 4 serious AEs were considered treatment-related. Peginterferon arm: pneumonia in 2 (week 12 and 20, respectively), Salmonella gastroenteritis in 1 (week 8), and duodenal ulcer bleeding in 1 (week 36); the first 3 serious AEs were considered treatment-related. ‡ Packed erythrocyte transfusion of 12 units for one patient in the combination therapy group (anemia-induced fainting) and 8 units for the other one patient in the monotherapy group (duodenal ulcer bleeding). § The grading of the laboratory AEs was shown for patients with the on-treatment nadir level. ║Mean epoetin beta dosages (SD): 13,946 (6,449) IU/week vs. 5,833 (1,169) IU/week, P = 0.006, and .mean duration of epoetin beta (SD): 29 (9) weeks vs. 18 (7) weeks, P = 0.004.

Liu CH, et al. Ann Intern Med 2013;159:729-38

Hemoglobin Levels during the Study: HELPER-1 Trial

Significant group differences for hemoglobin levels at week 8 of treatment (P < 0.001) and at week 4 post-treatment follow- up (P < 0.001). Tx: treatment, FU: follow-up. * The on-treatment hemoglobin levels for patients who prematurely discontinued treatment due to AEs, null-response or viral breakthrough were assessed until the last on-treatment visit. The off-therapy hemoglobin levels for patients who were lost to complete follow-up were assessed until the last off-therapy visit.

Liu CH, et al. Ann Intern Med 2013;159:729-38

Peginterferon α-2a ± Low Dose Ribavirin for Treatment- Naïve Hemodialysis HCV-2 Patients: HELPER-2 Trial

• HELPER-2: Hemodialysis Low Dose Peginterferon and Ribavirin for HCV-2 Patients
• Randomized, multicenter, open-label trial, 2-arm parallel, active control trial (n = 172) in

8 academic centers in Taiwan (2007-2012)

Dialysis HCV-2 patients (n = 172) Peg-IFN α-2a 135 μg/week + Ribavirin 200 mg/qd (n = 86) Peg-IFN α-2a 135 μg/week (n =86) Follow-up Follow-up 0 4 12 24 48 Weeks (RVR) (EVR) (ETVR) (SVR)

Primary efficacy endpoint: SVR rate Primary safety endpoint: adverse event (AE)-related withdrawal rate Clinical trial number: NCT00491244

1:1 randomization; blocks of 4

Liu CH, et al. Gut 2014 Apr 19 [Epub ahead of print]

Virologic Responses: HELPER-2

Variable Peginterferon + ribavirin (N = 86), n/N (%) Peginterferon (N =86), n/N (%) RR (95% CI) P value*

On-treatment virologic response RVR 55/86 (64) 54/86 (63) 1.02 (0.81-1.28) 0.99 EVR 80/86 (93) 82/86 (95) 0.98 (0.91-1.05) 0.75 ETVR 76/86 (88) 77/86 (90) 0.99 (0.89-1.10) 0.99 Virologic outcome SVR† 64/86 (74) 38/86 (44) 1.68 (1.29-2.20) < 0.001 SVR sensitivity (best scenario) 67/86 (78) 38/86 (44) 1.76 (1.34-2.29) < 0.001 SVR sensitivity (worst scenario) 64/86 (74) 41/86 (48) 1.56 (1.21-2.01) 0.001 Non-SVR 22/86 (26) 48/86 (56)

• Relapse

9/86 (10) 36/86 (42)

• Null-response

6/86 (7) 4/86 (5)

• Viral breakthrough

4/86 (5) 5/86 (6)

• Undetermined‡

3/86 (3) 3/86 (3)

• * P values were obtained by either chi-square test or Fisher’s exact test.

† Patients who were lost to 24-week follow-up, were null-responsive to treatment, or had viral breakthrough or relapsed after treatment were considered failure to achieve SVR. ‡ Combination therapy: 3 patients who lost to 24-week post-treatment follow-up (undetectable HCV RNA at week 24 in 1 and adverse events in 2). Monotherapy: 3 patients who lost to 24-week post-treatment follow-up (undetectable HCV RNA at week 24 in 2 and adverse events in 1).

Liu CH, et al. Gut 2014 Apr 19 [Epub ahead of print]

Variable (n) Peginterferon + ribavirin (N = 86) , n/N (%) Peginterferon (N = 86), n/N (%) RR (95% CI) P value for interaction* Baseline viral load 0.001 < 800,000 IU/mL 27/37 (73) 27/41 (66) 1.11 (0.83-1.45) ≥ 800,000 IU/mL 37/49 (76) 11/45 (24) 3.08 (1.80-5.29) IL-28B rs8099917 genotype 0.56 TT 53/68 (78) 32/70 (46) 1.70 (1.28-2.27) GT and GG 11/18 (61) 6/16 (38) 1.63 (0.78-3.39) Sex 0.42 Female 27/34 (79) 21/36 (58) 1.36 (0.98-1.88) Male 37/52 (71) 17/50 (34) 2.09 (1.37-3.20) APRI score 0.74 < 0.8 47/62 (76) 27/61 (44) 1.71 (1.25-2.35) ≥ 0.8 17/24 (71) 11/25 (44) 1.61 (0.97-2.68) Week 4 virologic response 0.167 RVR 53/55 (96) 34/54 (63) 1.53 (1.24-1.89) non-RVR 11/31 (35) 4/32 (13) 2.84 (1.01-7.97)

Subgroup Analyses of Pre-Specified Factors: HELPER-2

Liu CH, et al. Gut 2014 Apr 19 [Epub ahead of print]

Adverse Events, Dose Reduction and Treatment Discontinuation: HELPER-2*

Variable Peginterferon + ribavirin (N = 86) Peginterferon (N = 86)

Serious AEs All† 3 (3) 3 (3) Death 0 (0) 0 (0) Treatment-related 3 (3) 3 (3) Treatment withdrawal due to AEs‡ 5 (6) 3 (3) Dose reduction to AEs 70 (81) 33 (38) Peginterferon 31 (36) 33 (38) Ribavirin 60 (70)

• Emergent blood transfusion§

1 (1) 0 (0) Constitutional AEs Flu-like symptoms 21 (24) 22 (25) Fatigue 46 (54) 44 (51) Headache 22 (26) 20 (23) Insomnia 27 (31) 28 (32) Irritability 10 (12) 9 (11) Depression 11 (13) 11 (13) Anorexia 19 (22) 17 (20) Diarrhea 11 (13) 10 (12) Constipation 7 (8) 6 (7) Cough 13 (15) 10 (12) Dermatitis 20 (23) 18 (21) Injection site reaction 13 (15) 14 (16) Hair loss/alopecia 20 (23) 21 (24)

Variable Peginterferon + ribavirin (N = 86) Peginterferon (N = 86)

Laboratory AEs¶ Anemia║ 60 (70) 7 (8) 8.0-8.4 g/dL 34 (40) 6 (7) 7.5-7.9 g/dL 15 (18) 1 (1) 7.0-7.4 g/dL 8 (9) 0 (0) < 7.0 g/dL 3 (3) 0 (0) Neutropenia 15 (17) 13 (15) 0.500-0.749 x 109 /L 12 (14) 10 (12) < 0.500 x 109 /L 3 (3) 3 (3) Thrombocytopenia 10 (12) 10 (12) 25-49 x 109 /L 9 (10) 10 (12) < 25 x 109 /L 1 (1) 0 (0)

AE = adverse event. * Values are numbers (percentages). † Combination therapy: anemia with postural dizziness in one (treatment week 12), intractable diarrhea in one (treatment week 16), pneumonia in one (treatment week 20). Monotherapy: pneumonia in one (treatment week 12), biliary tree infection in one (treatment week 16), and major depression in one (treatment week 20). All serious AEs were considered treatment-related. ‡ Including 3 patients in each group with SAE; another two patients in the combination therapy group stopped treatment at treatment week 20 due to fatigue and insomnia, respectively. § Packed erythrocyte transfusion of 8 units for one patient receiving combination therapy due to anemia with postural dizziness at treatment week 12 of therapy (hemoglobin level was 6.8 g/dL at time of transfusion). ¶ The grading of the laboratory AEs was shown for patients with the on-treatment nadir level. ║Anemia was defined as a nadir hemoglobin level < 8.5 g/dL. Mean epoetin beta dosages (SD): 13,417 (7,219) versus 6,667 (2,581) IU per week, P = 0.027, and mean duration of epoetin beta (SD): 10 (5) versus 7 (3) weeks, P = 0.065, for patients receiving combination therapy and monotherapy, respectively.

Liu CH, et al. Gut 2014 Apr 19 [Epub ahead of print]

Mean (95% CI) Hemoglobin Levels: HELPER-2

Significant group differences for mean haemoglobin levels from week 8 of treatment (P <0.001) until week 4 post-treatment follow-up (P=0.006) Tx: treatment; FU: follow-up

Liu CH, et al. Gut 2014 Apr 19 [Epub ahead of print]

Dosage Modification for Impaired Renal Function [Peginterferon α -2a & Peginterferon α -2b]

Ccr Peg-IFN alfa-2a, μg/wk Peg-IFN alfa-2b, μg/kg/wk Ribavirin Daily

30-50 mL/min 180 1.125 Alternating doses, 200 mg and 400 mg every other day Less than 30 mL/min 135 0.75 200 mg/day Hemodialysis 135 0.75 200 mg/day

FDA, Peginterferon alfa-2a and peginterferon alfa-2b package insert

Long-Term Survival in Hemodialysis Patients with HCV Infection with/without Antiviral Treatment (DOPPS)

Goodkin DA, et al. Am J Nephrol 2013;38:405-12

• 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: 4,074 HD patients with HCV infection with sufficient data for the analysis; 43 patients

received antiviral treatment Hazard ratio (HR) with 95% CI 0.47 (0.17-1.26) [treated (n = 43) versus untreated (n = 4,031)]

based on Cox regression adjusted for propensity for treatment, stratified by country, and accounting for facility clustering

Drop-out Rate

Risk difference, random model, bilateral CI, 95% for trials, 0% for MA

Thervet Harihara Rostaing 1955 Magnone Ozgur Yasumura 1997 Hanafusa 1998 Durlik 1998 Tokumoto 1999 Baid 2003 Tang 2003 Shu 2004 Total Heterogeneity (p = 0.0014)

Antiviral Therapy of Hepatitis C-related Liver Diseases in Renal Transplant Patients: Meta-Analysis

• Systemic review of 12 clinical trials (102 patients)

SVR

Risk difference, random model, bilateral CI, 95% for trials, 0% for MA

Rostaing 1955 Yasumura 1997 Hanafusa 1998 Durlik 1998 Tokumoto 1999 Baid 2003 Tang 2003 Shu 2004 Total Heterogeneity (p = 0.08)

• 0.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
• 0.2 0.0 0.2 0.4 0.6 0.8 1.0

0.18 [0.07-0.29] 0.35 [0.2-0.5]

Fabrizi F, et al. Aliment Pharmacol Ther 2006;24:1413-22

Core E1 E2 P 7 NS2 NS3 NS4A NS4B NS5A NS5B

Novel Therapeutic Targets for HCV Under Investigation

5– –3

Telaprevir Boceprevir RG7227 (Danoprevir) TMC435 (Simeprevir) MK-7009 (Vaniprevir) MK-5172 BI201335 (Faldaprevir) BMS-650032 (Asunaprevir) ABT-450 GS-9256 BMS790052 (Daclatasvir) GS-5885 (Ledipasvir) MK-8742 PPI461 PPI668 Active site (nucleosides) RG-7128 (Mericitabine) GS-7977 (Sofosbuvir) IDX184 Non- nucleosides GS-9190 (Tegobuvir) BI207127 (Deleobuvir) TMC647055 Filibuvir (PF-00868554) VX-222 GS-9669 BMS791325 ANA598 (Setrobuvir) ABT-072 ABT-333 NNI-site 1 NNI-site 1 NNI-site 1 NNI-site 2 NNI-site 2 NNI-site 2 NNI-site 1 & 2 NNI-site 3 NNI-site 3 NNI-site 4

NA3/4A Protease inhibitors NS5B Polymerase inhibitors Host-targeted Antivirals

Debio025 (Alisporivir) SCY-635 Miravirsen (SPC3649) ITX-5061 ANA773 (TLR-7)

NS5A inhibitors NS4B inhibitors

Clemizole

Telaprevir with Adjusted Dose of Ribavirin in Treatment- Naïve HCV-1 Hemodialysis Patients: TARGET-C

• Design: pilot study to evaluate the efficacy and safety of Peg-FN alfa-2a 135 μg/week + RBV (200-400

mg/day) + TVR in RGT in ESRD patients with HCV-1 infection (May 2011-Nov 2012)

• Patients (n = 36): male/female (26/10); genotype 1a/1b (41%/58%); IL28B CC/CT/TT (27%/27%/44%);

Black/Asian/Hispanic/White (64%/11%/17%/8%); Fibrosis F2/F3/F4 (14%/72%/14%)

• Primary efficacy endpoint: SVR24

Basu P, et al. EASL 48th Annual Meeting, Amsterdam, Netherland, 2013 Placebo + Peg-IFN α-2a 135 µg qw + RBV 400 mg/day TVR 750 mg q8h + Peg-IFN α-2a 135 µg qw + Placebo TVR 750 mg q8h + Peg-IFN α-2a 135 µg qw + RBV 200 mg/day Peg-IFN α-2a 135 µg qw + RBV 400 mg/day Peg-IFN α-2a 135 µg qw + RBV 400 mg/day

0 4 12 24 36 48 Weeks

T12/PR24* (n = 12) T12/P12 + PR24 (n = 12) PR48 (n = 12)

* RBV 200 mg/day for the first 12 weeks Viral load tested at weeks 0, 1, 2, 4, 12,24, 36, 48, 60, 72

Telaprevir with Adjusted Dose of Ribavirin in Treatment-Naïve HCV-1 Hemodialysis Patients: TARGET-C (Efficacy & Safety)

33 41 50 50 25 25 25 33 63 42 33 25

20 40 60 80 100

Week 1 Week 2 (vRVR) Week 4 (RVR) Week 12 (EVR)

T12/PR24 T12/P12 + PR24 PR48

Patients with undetectable HCV RNA (%)

67 63 25 25 50 50

20 40 60 80 100

ETVR SVR T12/PR24 T12/P12 + PR24 PR48

Patients with undetectable HCV RNA (%)

* 1 patients with relapse: Black with GT1a (T12/PR24); no relapse (T12/P12 + PR24); 1 patients with viral breakthrough: Black with GT1a (PR48)

* Increased incidence of select AEs in TVR arms

• vs. Peg-IFN/RBV:
• Anemia (54% vs 33%)
• Neutropenia (50% vs 33%)
• Thrombocytopenia (37% vs 25%)
• Rash (42% vs 17%)
• Anorectal dysfunction (33% vs 0%)
• Dysgeusia (42% vs 17%)

Basu P, et al. EASL 48th Annual Meeting, Amsterdam, Netherland, 2013

Direct Acting Antiviral Agents for Hemodialysis Patients with HCV Infection

Pharmaceutical Company Direct Acting Antiviral Agents (DAA)

Gilead Sofosbuvir Ledipasvir

Not recommended in patients with severe renal impairment or requiring hemodialysis

• Bristol-Myers-Squibb

Asunaprevir Daclatasvir BMS-791325

No dosage adjustment No dosage adjustment

• Abbvie

ABT-450/r Ombitasvir Dasabuvir

No dosage adjustment No dosage adjustment No dosage adjustment

Merck Sharp & Dohme MK-5172 MK-8742

• Johnson & Johnson

Simeprevir

Summary

• HCV infection is prevalent in patients with end-stage renal disease (ESRD) on

maintenance dialysis

• The long-term prognosis of ESRD patients with chronic HCV infection is poor, either
• n maintenance dialysis or post-transplant stage.
• Treatment of chronic HCV infection by IFN-based monotherapy is relatively poor

(SVR:30-40%).

• Adding of low-dose ribavirin to IFN may increased the SVR rates.
• Randomized controlled-trial of chronic HCV-1 and HCV-2 hemodialysis patients have

proved the beneficial effect of combination therapy over monotherapy; safety profiles are acceptable

• The use of direct-acting antiviral agents (DAAs), IFN-free or IFN-containing regiment,

with a short duration of therapy (12-24 weeks) may show promise in the near future.

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

Anti-HBV therapy in patients with ESRD: General assessments

• Clinical indications of treatment

– Upper limit of serum ALT needs to be adjusted downward

• Real goals of treatment

– Viral – Hepatic – Renal

• Dose reduction and adverse effects

Anti-HBV therapy in patients with ESRD: Clinical settings and treatment considerations

Setting Considerations

ERSD without hemodialysis Adjust dose and monitor renal safety. Entecavir is the preferred agent in naïve patients; tenofovir is preferred if LAM or TBV experienced. ESRD on hemodialysis Among patients not candidates for renal transplantation, treatment should be reserved for active or fibrotic liver disease. Renal transplant candidate All HBsAg+ve candidates must be treated with NUC before renal transplantation. KDIGO (2009) recommended prophylaxis with ETV, TDF or LAM. Renal transplant recipients with HBV reactivation IFN therapy is contraindicated. Salvage NUC therapy is less effective than prophylactic NUC therapy.

Anti-HBV therapy in patients with ESRD: Selection and concerns of agents

IFN

• Poorly tolerated
• Relatively low efficacy
• Risk of acute rejection of

kidney transplant

• Co-morbidities

Nucleos(t)ide analogue (NUC)

• Potency: ETV, TDF, TBV
• Genetic barrier: ETV, TDF
• Renal safety concern: ADV,

TDF

• LAM or TBV experienced:

TDF

• Dose reduction

Pipili et al. Kidney Int 2013;84:880

Dose adjustment of NUCs according to CrCl

Pipili et al. Kidney Int 2013; APT 2014

Proposed algorithm for management of HBV in patients with renal failure

Pipili et al. Aliment Pharmacol Ther 2014;39:35-46

Thank You for Your Attention