Transcript PPTX

HEPATITIS WEB STUDY
HEPATITIS C ONLINE
Treatment of Hepatitis C in Patients with Renal Insufficiency
Robert G. Gish MD
Professor Consultant, Stanford University Medical Center
Senior Medical Director, St Josephs Hospital and Medical Center, Liver Program, Phoenix, Arizona
(Adjunct) Clinical Professor of Medicine, University of Nevada, Las Vegas
Vice-Chair Executive Committee, and Steering Committee Member, National Viral Hepatitis Roundtable
Last Updated: July 6, 2015
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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
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Treatment of Hepatitis C in Patients with Renal Insufficiency
• Background and Staging of Renal Disease
• Treatment with Interferon-Based Regimens
• Treatment with Direct-Acting Antiviral Agents
• Hepatitis C and Renal Transplantation
• Summary
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TREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
Background and Staging Renal Disease
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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 Disease
Hepatitis 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 Disease
HCV 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.
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Stages of Chronic Kidney Disease
CKD Stage
Description
GFR (mL/min/1.73 m2)
1
Kidney Damage with Normal or ↑ GFR
2
Kidney Damage with Mild ↓ GFR
60-89
3
Moderate ↓ GFR
30-59
4
Severe ↓ GFR
15-29
5
Kidney Failure
<15 (or dialysis)
>90
Source: NKF KDOQI Clinical Practice Guidelines for Chronic Kidney Disease
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TREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
Experience with Interferon-Based Therapies
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Interferon Monotherapy for HD Patients with Chronic HCV
Analysis of the Literature on Efficacy (SVR)
80
Analysis of 8 Studies Using INF-alfa 2b Monotherapy 3 million units 3x/week
68
70
SVR (%)
60
56
58
50
40
33
27
30
20
20
21
20
19
10
0
Source: Russo MW, et al. Am J Gastroenterol. 2003;98:1610-5.
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Peginterferon + Ribavirin for HCV in Hemodialysis Patients
Meta-Analysis of the Literature on Efficacy
Summary Estimates for SVR Rates
100
Analysis of 11 Studies (287 patients) Using PEG alfa-2a/PEG alfa-2b + RBV
86
80
60
63
60
57
54
40
20
0
All Studies
Cohort Studies
Controlled Studies Peg-IFN alfa-2a
Source: Fabrizi F, et al. J Viral Hepat. 2014;21:314-24.
Peg-IFN alfa-2b
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PEG-IFN +/- Low-dose RBV (200 mg/day) in HCV GT1 on Hemodialysis
HELPER-1 Trial: Study Regimens
0
Week
• Virologic
Responses
48
72
N = 103
Peginterferon alfa-2a + Ribavirin
SVR24
N = 94
N = 102
Peginterferon alfa-2a
SVR24
N = 91
Drug Dosing
Peginterferon alfa-2a 135 µg 1x/week
Low-dose Ribavirin: 200 mg once daily
Source: Liu CH, et al. Ann Intern Med. 2013;159:729-38.
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PEG-IFN +/- Low-dose RBV (200 mg/day) in HCV GT1 on Hemodialysis
HELPER-1 Trial: Results
Virologic Responses
100
Virologic Response (%)
87
84
80
Peginterferon + Ribavirin
Peginterferon
64
60
51
36
40
33
20
0
53/103 37/102
90/103 86/102
66/103 34/102
RVR
ETVR
SVR24
Drug Dosing
Peginterferon alfa-2a: 135 µg once weekly
Ribavirin: 200 mg daily
Source: Liu CH, et al. Ann Intern Med. 2013;159:729-38.
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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
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TREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
Experience with Direct-Acting Antiviral Agents
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Treatment of Hepatitis C in Patients with Renal Disease
Possible 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
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Sofosbuvir Pharmacokinetics
HCV-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%
Dosed 1 hour before hemodialysis
28%
1280%
Dosed 1 hour after hemodialysis
60%
2070%
ESRD requiring hemodialysis
*AUC given relative to subjects with normal renal function
Source: Sofosbuvir Prescribing Information, Gilead Sciences.
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Simeprevir Pharmacokinetics
Severe Renal Impairment versus Healthy Subjects
Linear Mean Plasma Concentration-Time Profiles
Subjects with severe renal impairment (n=8)
Matched healthy subjects (n=8)
9,000
Simeprevir Plasma
Concentration, ng/mL
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
0
Bars represent standard deviation
Source: Janssen Products
4
8
12
16
20
24
Time, Hours
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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
Source: Saxena V, et al. 50th EASL. 2015; Abstract LP08.
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Sofosbuvir-Containing Regimens in Patients with Renal
Disease HCV -TARGET
HCV TARGET: SVR12, by Baseline eGFR
Patients with SVR 12 (%)
100
80
89
88
81
81
60
40
20
0
15/17
39/48
125/140
1128/1393
≤ 30
31-45
46-60
> 60
Estimated Glomerular Filtration Rate (eGFR)
Source: Saxena V, et al. 50th EASL. 2015; Abstract LP08.
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Sofosbuvir-Containing Regimens including Patients with Renal Disease
HCV-TARGET Trial: Result
HCV-TARGET Trial: SVR12 Results by Baseline eGFR and Regimen
SOF/PEG/RBV
Patients with SVR 12 (%)
100
100
100
100
SOF/RBV
SOF/SMV/RBV
100
93
80
SOF/SMV
91
92
84
80
80
80
87
81
79
73
60
40
33
20
1/1
0
4/4
8/10
≤30
2/2
1/3
8/10
20/25
9/9
13/14 38/45 62/68 12/13
30-45
46-60
188/
232
292/
400
480/
552
135/
171
>60
Estimated GFR mL/min/1.73 m2
Abbreviations: SOF = sofosbuvir; PEG = peginterferon; RBV = ribavirin; SMV = simeprevir
Source: Saxena V, et al. 50th EASL. 2015; Abstract LP08.
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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
Source: Pockros PJ, et al. 50th EASL. 2015; Abstract L01.
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Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal Disease
RUBY-I: Regimens
Week 0
12
24
GT 1a
n = 13
Ombitasvir-Paritaprevir-Ritonavir
and Dasabuvir + Ribavirin
SVR12
GT 1b
n=7
Ombitasvir-Paritaprevir-Ritonavir
and Dasabuvir
SVR12
Drug Dosing
Ombitasvir-Paritaprevir-Ritonavir (25/150/100 mg once daily) + Dasabuvir: 250 mg twice daily
Ribavirin for patients not on hemodialysis: 200 mg once daily
Ribavirin for patients on hemodialysis: 200 mg given 4 hours before each hemodialysis session
Source: Pockros PJ, et al. 50th EASL. 2015; Abstract L01.
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Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal Disease
RUBY-I: Baseline Results
RUBY-I: SVR 12 Rates*
GT1a: 3D + RBV
Virologic Response
100
100
100
100
100
100
2/2 85/88
9/9
1/1
91/91 2/2
GT1b: 3D
80
60
40
20
12/12
0
EOT
SVR4
0/0
SVR12
3D = Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir; RBV = ribavirin; EOT = end of treatment
Source: Pockros PJ, et al. 50th EASL. 2015; Abstract L01.
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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
Source: AASLD/IDSA/IAS-USA (www.hcvguidelines.org). Viewed June 26, 2015
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TREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
HCV and Renal Transplantation
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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
Relative Risk of Death
6
5
Above red line = higher death risk with Renal Transplant
Below red line = higher death risk with Dialysis
4.75
4
3
2
1.76
1
0
0.31
0 to 3 months
3 to 6 months
7 months to 4 years
Source: Pereira BJG, et al. Kidney Int. 1998;53:1374-81.
0.84
Longer than 4 years
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Hepatitis C and Renal Disease
Rationale 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)
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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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TREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
Summary and Recommendations
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Treatment of Hepatitis C in Patients with Renal Insufficiency
Summary 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
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