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HEPATITIS WEB STUDY HEPATITIS C ONLINE

Last Updated: July 6, 2015

Treatment of Hepatitis C in Patients with Renal Insufficiency

Robert G. Gish MDProfessor Consultant, Stanford University Medical CenterSenior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, Arizona(Adjunct) Clinical Professor of Medicine, University of Nevada, Las VegasVice-Chair Executive Committee, and Steering Committee Member, National Viral Hepatitis Roundtable

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Robert Gish, MD: Relevant Disclosures To HCV

• Consulting Board: Bristol-Myers Squibb, Gilead, Merck & Co., Janssen, Abbvie

• Honoraria for Promotional Talks: Bristol-Myers Squibb, Gilead Sciences, Merck & Co., AbbVie, Janssen

Hepatitisweb study

Hepatitisweb study

• Background and Staging of Renal Disease

• Treatment with Interferon-Based Regimens

• Treatment with Direct-Acting Antiviral Agents

• Hepatitis C and Renal Transplantation

• Summary

Treatment of Hepatitis C in Patients with Renal Insufficiency

Hepatitisweb study

Hepatitisweb study

Background and Staging Renal DiseaseTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY

Hepatitisweb study

Hepatitis C Treatment Issues Related to Renal Disease

• Hepatitis C may be associated with or cause renal disease

• Treatment of hepatitis C and renal disease

(1) Treatment in patients with chronic renal insufficiency

(2) Treatment to prevent HCV causing renal disease

(3) Treatment post renal transplant for renal function and graft survival

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Epidemiology of HCV in Patients on Hemodialysis (HD)

• In US, estimated HCV prevalence of 8% - (approximately 400,000 persons on HD)

• HCV prevalence 5X greater in HD patients than in general US population

• Risk factors for HCV infection among hemodialysis patients:- Number of years on dialysis- Number of blood product transfusions- Injection drug use- History of organ transplantation

Source: Finelli L, et al. Semi Dial. 2005;18:52-61.

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Natural History of HCV Infection in Hemodialysis Patients

Impact of Hepatitis C Infection on Hemodialysis Patients:

• Increased overall risk of mortality

• Increased risk of cirrhosis

• Increased incidence of hepatocellular cancer

Source: Fabrizi F, et al. J Viral Hepat. 2007;14:697-703.

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Hepatitis C and Renal DiseaseHepatitis C as a Cause of Renal Disease

• HCV infection in patients with advanced liver failure increases risk for renal disease

• Chronic HCV infection associated with increased risk for renal cell carcinoma

• Chronic HCV infection accelerated renal disease in HIV-infected patients

Source: (1) Ozkok A, et al. Gastroenterol. 2014;20:7544-54. (2) Gordon SC, et al. Cancer Epidemiol Biomarkers Prev. 2010;19:1066-73.(3) Peters L, et al. AIDS. 2012;26:1917-26.

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Hepatitis C and Renal DiseaseHCV as a Cause of Renal Disease: Immune Complex Disorders

• HCV-associated immune complex disorders that cause renal disease Mixed Cryoglobulinemia: +RF as a screening test; reflex to qualitative or

quantitative cryoglobulin (type II cryoglobulins)

Glomerulonephritis (Membranoproliferative [MPGN] is the most common)

Polyarteritis nodosa

• Uncommon HCV-associated immune complex disorders that cause renal disease

Focal segmental glomerular sclerosis

Proliferative glomerulonephritis

Membranous glomerulonephritis

Fibrillary and immunotactoid glomerulopathies

Source: (1) Ozkok A, et al. Gastroenterol. 2014;20:7544-54. (2) Gordon SC, et al. Cancer Epidemiol Biomarkers Prev. 2010;19:1066-73.(3) Peters L, et al. AIDS. 2012;26:1917-26.

Hepatitisweb studySource: NKF KDOQI Clinical Practice Guidelines for Chronic Kidney Disease

Stages of Chronic Kidney Disease

CKD Stage Description GFR (mL/min/1.73 m2)

1 Kidney Damage with Normal or ↑ GFR >90

2 Kidney Damage with Mild ↓ GFR 60-89

3 Moderate ↓ GFR 30-59

4 Severe ↓ GFR 15-29

5 Kidney Failure <15 (or dialysis)

Hepatitisweb study

Hepatitisweb study

Experience with Interferon-Based TherapiesTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY

Hepatitisweb studySource: Russo MW, et al. Am J Gastroenterol. 2003;98:1610-5.

Interferon Monotherapy for HD Patients with Chronic HCVAnalysis of the Literature on Efficacy (SVR)

Pooled SVR

CasanovasChan

FernandezPol

DegosIzopet

Campistol

Raptopoulou-Gigi

0

10

20

30

40

50

60

70

80

33

20

27

21 20 19

56 58

68

SV

R (

%)

Analysis of 8 Studies Using INF-alfa 2b Monotherapy 3 million units 3x/week

Hepatitisweb studySource: Fabrizi F, et al. J Viral Hepat. 2014;21:314-24.

Peginterferon + Ribavirin for HCV in Hemodialysis PatientsMeta-Analysis of the Literature on Efficacy

All Studies Cohort Studies Controlled Studies Peg-IFN alfa-2a Peg-IFN alfa-2b0

20

40

60

80

100

6054

86

5763

Su

mm

ary

Es

tim

ate

s f

or

SV

R R

ate

s Analysis of 11 Studies (287 patients) Using PEG alfa-2a/PEG alfa-2b + RBV

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

PEG-IFN +/- Low-dose RBV (200 mg/day) in HCV GT1 on Hemodialysis

HELPER-1 Trial: Study Regimens

• Virologic Responses

Peginterferon alfa-2a + Ribavirin

Peginterferon alfa-2a

48 720

Drug Dosing

Peginterferon alfa-2a 135 µg 1x/weekLow-dose Ribavirin: 200 mg once daily

SVR24

SVR24N = 102

N = 103

N = 94

N = 91

Week

Hepatitisweb study

PEG-IFN +/- Low-dose RBV (200 mg/day) in HCV GT1 on Hemodialysis

HELPER-1 Trial: Results

Virologic Responses

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

RVR ETVR SVR240

20

40

60

80

100

51

87

64

36

84

33

Peginterferon + RibavirinPeginterferon

Vir

olo

gic

Re

sp

on

se

(%

)

Drug DosingPeginterferon alfa-2a: 135 µg once weeklyRibavirin: 200 mg daily

66/103 34/10290/103 86/10253/103 37/102

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Controversies with Ribavirin Use in Advanced Renal Disease

• Not recommended with eGFR < 50 ml/min/1.73 m2 in:- Package inserts for Rebetol, Ribasphere- KDIGO 2008 guidelines- 2009 AASLD guidelines

• Permitted with eGFR < 50 ml/min/1.73 m2 (with dose reduction) in:- Package insert for CoPegus - 2014 AASLD/IDSA/IAS-USA guidelines

Hepatitisweb study

Hepatitisweb study

Experience with Direct-Acting Antiviral AgentsTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY

Hepatitisweb study

Treatment of Hepatitis C in Patients with Renal DiseasePossible Options using Direct Acting Antiviral Agents

• Sofosbuvir plus Ribavirin

• Simeprevir plus Sofosbuvir

• Ombitasvir-Paritaprevir-Ritonavir plus Dasabuvir (genotype 1)

• Ledipasvir-Sofosbuvir (pangenotypic)

• Sofosbuvir plus Daclatasvir*

*Daclatasvir was not FDA approved in United States as of July 1, 2015

Hepatitisweb studySource: Sofosbuvir Prescribing Information, Gilead Sciences.

Sofosbuvir PharmacokineticsHCV-Negative Patients with Renal Impairment

Sofosbuvir Pharmacokinetics in HCV-Negative Patients with Renal Impairment

Patient Renal Impairment Sofosbuvir AUC* GS-3310007 AUC*

Following Single 400 mg dose of sofosbuvir

eGFR ≥50 and < 80 mL/min/1.73 m2 61% 55%

eGFR ≥30 and < 50 mL/min/1.73 m2 107% 88%

eGFR <30 mL/min/1.73 m2 171% 451%

ESRD requiring hemodialysis

Dosed 1 hour before hemodialysis

Dosed 1 hour after hemodialysis

28%

60%

1280%

2070%

*AUC given relative to subjects with normal renal function

Hepatitisweb study

Simeprevir PharmacokineticsSevere Renal Impairment versus Healthy Subjects

Linear Mean Plasma Concentration-Time Profiles

Source: Janssen Products

9,000

8,000

7,000

6,000

5,000

4,000

3,000

2,000

1,000

00 4 8 12 16 20 24

Time, Hours

Subjects with severe renal impairment (n=8)Matched healthy subjects (n=8)

Sim

epre

vir

Pla

sma

Con

cent

ratio

n, n

g/m

L

Bars represent standard deviation

Hepatitisweb studySource: Saxena V, et al. 50th EASL. 2015; Abstract LP08.

Sofosbuvir-Containing Regimens including Patients with Renal Disease

HCV-TARGET Trial: Study Features

HCV-Target and Patients with Renal Disease: Features

Design: Longitudinal, cohort study with sofosbuvir-containing regimens, including patients with renal disease

Setting: 56 centers in US, Germany, and Canada

Entry Criteria - Chronic HCV treated with sofosbuvir-containing regimen- HCV genotype 1-6- Age 18 or older- Treatment naïve and treatment experienced- Includes patients with baseline renal insufficiency- Includes patients with cirrhosis

Primary End-Points- Efficacy (SVR12), safety

Hepatitisweb study

Sofosbuvir-Containing Regimens in Patients with Renal Disease HCV -TARGET

HCV TARGET: SVR12, by Baseline eGFR

Source: Saxena V, et al. 50th EASL. 2015; Abstract LP08.

≤ 30 31-45 46-60 > 600

20

40

60

80

100

8881

8981

Estimated Glomerular Filtration Rate (eGFR)

Pat

ien

ts w

ith

SV

R 1

2 (%

)

15/17 39/48 125/140 1128/1393

Hepatitisweb study

Sofosbuvir-Containing Regimens including Patients with Renal Disease HCV-TARGET Trial: Result

HCV-TARGET Trial: SVR12 Results by Baseline eGFR and Regimen

Source: Saxena V, et al. 50th EASL. 2015; Abstract LP08.

≤30 30-45 46-60 >600

20

40

60

80

100100

33

93

81

100

8084

73

80 80

9187

100 100

92

79

SOF/PEG/RBV SOF/RBV SOF/SMV SOF/SMV/RBV

Estimated GFR mL/min/1.73 m2

Pa

tie

nts

wit

h S

VR

12

(%

)

1/1 2/24/4 8/10 1/3 9/98/10 20/25 13/14 12/1338/45 62/68188/232

135/171

292/400

480/552

Abbreviations: SOF = sofosbuvir; PEG = peginterferon; RBV = ribavirin; SMV = simeprevir

Hepatitisweb studySource: Pockros PJ, et al. 50th EASL. 2015; Abstract L01.

Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal Disease

RUBY-I: Study Design

RUBY-I: Features

Design: Phase 3b, randomized, open-label trial evaluating safety and efficacy of 3D (ombitasvir-paritaprevir-ritonavir and dasabuvir) with or without ribavirin for 12 weeks in treatment-naïve patients with chronic HCV GT1 and advanced kidney disease

Setting: 9 sites in United States

Entry Criteria - Adults with chronic HCV genotype 1 infection- Chronic kidney disease stage 4 or 5 (eGFR <30 mL/min/1.73 m2) +/- HD- Plasma HCV RNA greater than 1,000 IU/mL- Absence of cirrhosis- Absence of coinfection with HBV or HIV- Baseline Hb ≥10 g/dL

Primary End-Point: SVR12

Hepatitisweb studySource: Pockros PJ, et al. 50th EASL. 2015; Abstract L01.

Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal Disease

RUBY-I: Regimens

GT 1an = 13

Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir + Ribavirin

SVR12

Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir

SVR12

Week 0 2412

Drug DosingOmbitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) + Dasabuvir: 250 mg twice dailyRibavirin for patients not on hemodialysis: 200 mg once dailyRibavirin for patients on hemodialysis: 200 mg given 4 hours before each hemodialysis session

GT 1bn = 7

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Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal DiseaseRUBY-I: Baseline Results

RUBY-I: SVR 12 Rates*

Source: Pockros PJ, et al. 50th EASL. 2015; Abstract L01.

85/88 91/91

3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin; EOT = end of treatment

EOT SVR4 SVR120

20

40

60

80

100100 100 100100 100

0/0

GT1a: 3D + RBV GT1b: 3D

Vir

olo

gic

Re

sp

on

se

12/12 2/2 9/9 1/1 2/2

Hepatitisweb studySource: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed June 26, 2015

AASLD/IDSA/IAS-USA 2015 HCV Treatment Recommendations

Recommendations for Patients with Renal Impairment

AASLD/IDSA Recommendations for Patients with Renal Impairment*

Dosage adjustments for patients with mild to moderate renal impairment (CrCl 30 mL/min-80 mL/min)

Sofosbuvir: no dosage adjustment required

Simeprevir: no dosage adjustment required

Ledipasvir-sofosbuvir: no dosage adjustment required

Ombitasvir-paritaprevir-ritonavir + dasabuvir: no dosage adjustment required

Dosage adjustments for patients with severe renal impairment(CrCl <30 mL/min or ESRD)

Treatment can be contemplated after consultation with an expert, because safety and efficacy data are not available for these patients.

*Recommendations for patients with renal impairment, including severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease requiring hemodialysis or peritoneal dialysis

Hepatitisweb study

Hepatitisweb study

HCV and Renal TransplantationTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY

Hepatitisweb study

Impact of HCV on Outcome of Renal Transplantation

• HCV increases glomerulonephritis in transplanted kidney

• HCV reduces renal allograft survival

• HCV decreases long-term patient survival

HCV infection is not a contraindication to renal transplantation unless portal hypertension is present or there is decompensated liver disease since patient survival with RT is better than with dialysis

Source: Baid-Agrawal S, et al. Am J Transplant. 2014. August [Epub ahead of print]

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Relative Risk of Death among Patients Undergoing Renal Transplantation versus those who Remained on Dialysis

Relative Risk of Death (all causes): Transplanted versus Dialysis

Source: Pereira BJG, et al. Kidney Int. 1998;53:1374-81.

0 to 3 months 3 to 6 months 7 months to 4 years Longer than 4 years0

1

2

3

4

5

6

4.75

1.76

0.31

0.84

Re

lati

ve

Ris

k o

f D

ea

th

Above red line = higher death risk with Renal TransplantBelow red line = higher death risk with Dialysis

Hepatitisweb study

Hepatitis C and Renal DiseaseRationale for HCV Treatment in Renal Transplant Candidate

• Eradicate HCV as immunologic stimulus to B-cells to decrease immune complex formation and impact vasculitis or glomerulonephritis

• Decrease extrahepatic HCV-related complications

• Prevent HCV-related post-transplant complications- Interaction with HCV immune complexes and calcineurin inhibitor related renal toxicity

• HCV-related liver disease may accelerate with post-transplant immunosuppression

• Post-transplant treatment extremely difficult due to risk of graft rejection from interferon (historical)

Hepatitisweb study

Treatment of HCV after Renal Transplantation

• Interferon-based therapy relatively contraindicated because

of risk of allograft rejection and loss

• Post-transplant interferon/ribavirin recommended only for

- Fibrosing cholestatic hepatitis

IF daclatasvir compassionate use not available

- Life-threatening vasculitis

• Interferon-free regimens will provide new options

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Treatment of HCV Post-Renal Transplant

• Renal function less problematic depending on:

- Use, dose, & blood levels of calcineurin inhibitor (cyclosporine, tacrolimus)

- Improvement in GFR with graft recovery

- History of rejection and residual renal damage

• Address drug-drug interactions per medication & drug class

• Higher HCV RNA levels due to immunosuppression may impact SVR

rates

• No effective therapy yet published in controlled trials

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Hepatitisweb study

Summary and RecommendationsTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY

Hepatitisweb study

Treatment of Hepatitis C in Patients with Renal InsufficiencySummary Points

• Renal disease severity should guide treatment decisions

• Interferon- and Peginterferon-based Rx of historical importance only

• Maximize EPO use when using ribavirin in this patient population

• First-generation HCV protease inhibitors not recommended

• No dose adjustments with DAAs if GFR ≥ 30 mL/min

• Limited data with DAAs in patients with GFR <30 mL/min

• Obtain expert consultation if GFR <30 mL/min, especially HD patients

• Renal transplant candidates should receive HCV treatment with DAAs- Either before or after transplantation, depending on clinical scenario