treatment of hepatitis c in patients with renal...
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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 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
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
• 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
Background and Staging Renal DiseaseTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
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
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.
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.
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.
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.
Source: 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)
Experience with Interferon-Based TherapiesTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
Source: Russo MW, et al. Am J Gastroenterol. 2003;98:1610-5.
Interferon Monotherapy for HD Patients with Chronic HCV
Analysis of the Literature on Efficacy (SVR)
33
20
27
21 20 19
5658
68
0
10
20
30
40
50
60
70
80
SV
R (
%)
Analysis of 8 Studies Using INF-alfa 2b Monotherapy 3 million units 3x/week
Source: Fabrizi F, et al. J Viral Hepat. 2014;21:314-24.
Peginterferon + Ribavirin for HCV in Hemodialysis Patients
Meta-Analysis of the Literature on Efficacy
6054
86
5763
0
20
40
60
80
100
All Studies Cohort Studies Controlled Studies Peg-IFN alfa-2a Peg-IFN alfa-2b
Su
mm
ary
Esti
mate
s f
or
SV
R R
ate
s Analysis of 11 Studies (287 patients) Using PEG alfa-2a/PEG alfa-2b + RBV
Source: 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/week
Low-dose Ribavirin: 200 mg once daily
SVR24
SVR24N = 102
N = 103
N = 94
N = 91
Week
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.
51
87
64
36
84
33
0
20
40
60
80
100
RVR ETVR SVR24
Vir
olo
gic
Resp
on
se (
%)
Peginterferon + Ribavirin
Peginterferon
Drug DosingPeginterferon alfa-2a: 135 µg once weeklyRibavirin: 200 mg daily
66/103 34/10290/103 86/10253/103 37/102
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
Experience with Direct-Acting Antiviral AgentsTREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
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
Source: Sofosbuvir Prescribing Information, Gilead Sciences.
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 m261% 55%
eGFR ≥30 and < 50 mL/min/1.73 m2107% 88%
eGFR <30 mL/min/1.73 m2171% 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
Simeprevir Pharmacokinetics
Severe 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
0
0 4 8 12 16 20 24
Time, Hours
Subjects with severe renal impairment (n=8)
Matched healthy subjects (n=8)
Sim
epre
vir
Pla
sm
a
Co
nce
ntr
atio
n,
ng
/mL
Bars represent standard deviation
Source: 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
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.
8881
89
81
0
20
40
60
80
100
≤ 30 31-45 46-60 > 60
Pati
en
ts w
ith
SV
R 1
2 (
%)
Estimated Glomerular Filtration Rate (eGFR)
15/17 39/48 125/140 1128/1393
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.
100
33
93
81
100
8084
73
80 80
9187
100 100
92
79
0
20
40
60
80
100
≤30 30-45 46-60 >60
Pa
tie
nts
wit
h S
VR
12
(%
)
Estimated GFR mL/min/1.73 m2
SOF/PEG/RBV SOF/RBV SOF/SMV SOF/SMV/RBV
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
Source: 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
Source: Pockros PJ, et al. 50th EASL. 2015; Abstract L01.
Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal Disease
RUBY-I: Regimens
GT 1a
n = 13
Ombitasvir-Paritaprevir-Ritonavir
and Dasabuvir + RibavirinSVR12
Ombitasvir-Paritaprevir-Ritonavir
and DasabuvirSVR12
Week 0 2412
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
GT 1b
n = 7
Ombitasvir-Paritaprevir-Ritonavir and Dasabuvir in GT1 & Renal Disease
RUBY-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
100 100 100100 100
0/00
20
40
60
80
100
EOT SVR4 SVR12
Vir
olo
gic
Resp
on
se
GT1a: 3D + RBV GT1b: 3D
12/12 2/2 9/9 1/1 2/2
Source: 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
HCV and Renal Transplantation
TREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
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]
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.
4.75
1.76
0.310.84
0
1
2
3
4
5
6
0 to 3 months 3 to 6 months 7 months to 4 years Longer than 4 years
Rela
tive R
isk o
f D
eath
Above red line = higher death risk with Renal Transplant
Below red line = higher death risk with Dialysis
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)
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
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
Summary and Recommendations
TREATMENT OF HCV IN PATIENTS WITH RENAL INSUFFICIENCY
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