Treatment Of HCV in CKD Patients Prof. Hussein EL-Fishawy MNDU 8

2. 4/22/2011 ICVH Baltimore 2011
Discovery of Hepatitis C

5. Seroprevalence of Hepatitis C:
170 to 200 Million Worldwide
Americas
12-15 M
Africa
30-40M Australia
.2 M
Western Pacific
60 M
Western Europe
5 M
Eastern Europe
10 M
Southeast Asia
30-35 M
1. World Health Organization. Wkly Epidemiol Rec. 2000;75:17-28.
2. Edlin B et al. AASLD; November 11-15; 2005 San Francisco, California. Oral Presentation #44.
3. Fontanet A. Annual Report of Emerging Diseases for Year 2005. Accessed 03/13/06 at
http://www.pasteur.fr/recherche/RAR/RAR2005/Epimal-en.html
United States
5M
Highest Prevalence:
Egypt-5M
(45% adults >40y)
Highest impact in the world
Serological prevalence of 13.9–15.5% (14.7%)
Positive nucleic acid test in 7.0–12.2% (9.8%)
90% of patients is (GT- 4), difficult to treat

6. HCV and Renal disease
HCV infection may lead to renal disease or be associated
with renal disease
 Membranoproliferative glomerulonephritis (MPGN)
 Mixed cryoglobulinemia (type II cryoglobulins)
 Membranous GN
 Polyarteritis nodosa
NB: Crescentic glomerulonephritis may be
superimposed on any of these glomerular lesions
Ana Maria Sandri et al., Nephron Clin Pract 2011;119:c121–
c130

7. HCV and Renal disease
 Less common
 Focal segmental glomerular sclerosis
 Poliferative glomerulonephritis
 Mesangial proliferative GN
 Focal segmental and necrotizing GN
 IgA nephropathy
 Post infectious GN
 Fibrillary glomerulopathies
 Immunotactoid glomerulopathies
 Amyloidosis
 Interstitial nephritis
 Thrombotic microangiopathy (Renal transplantation)
 Acute and chronic transplant glomerulopathy
Ana Maria Sandri et al., Nephron Clin Pract 2011;119:c121–
c130

8. Increased Mortality
 Chronic HCV is associated with a 8- to 12-year
reduction in overall life expectancy and
reduced quality of life1
 Chronic HCV patients have significantly higher
mortality rate
 HR 1.53; (95% CI, 1.13-2.07)2
 HR 1.37; (95% CI, 1.31-1.47)3
 Death rate 12-fold higher than general
population4
1 Ryder SD, et al. J Hepatology, 2007; 3 Butt AA, et al. Hepatology, 2009
2 Uto H, et al. Hepatology, 2009; 4 Mahajan R, et al. Clin Infect Dis 2014

9. 35
30
25
20
15
10
5
0
Chronic HCV Infection
Increases Mortality
*P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA
detectable vs. undetectable. †P<0.001 for comparison among all 3 groups and
P=0.002 for HCV RNA detectable vs. undetectable
Lee MH, et al. J Infect Dis 2012;206:469–77
Follow-up
(Years)
20
18
16
14
12
10
2
0
8
6
4
Follow-up
(Years)
12
10
8
6
4
2
0
All causes(n=2,394)
Liver cancer
(n=115)
Extrahepatic diseases
(n=2,199)
Cumulativemortality(%)
Follow-up
(Years)
30.1%*
12.8%
12.4%
10.4%*
1.6%
0.3%
19.8%†
12.2%
11.0%
Anti-HCV+, HCV RNA detectable Anti-HCV+, HCV RNA undetectable Anti-HCV-
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
• 23 820 adults, Taiwan
• 1095 anti-HCV positive
• 760 (69%) HCV-RNA detectable
HCV+, RNA+
HCV+, RNA-
HCV-

10. 35
30
25
20
15
10
5
0
Chronic HCV Infection Increases
Mortality from Hepatic Diseases
*P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA detectable vs.
undetectable. †P<0.001 for comparison among all 3 groups and P=0.002 for HCV RNA
detectable vs. undetectable
Lee MH, et al. J Infect Dis 2012;206:469–77
Follow-up
(Years)
20
18
16
14
12
10
2
0
8
6
4
Follow-up
(Years)
12
10
8
6
4
2
0
All causes
(n=2,394)
Liver cancer
(n=115)
Extrahepatic diseases
(n=2,199)
Follow-up
(Years)
30.1%*
12.8%
12.4%
10.4%*
1.6%
0.3%
19.8%†
12.2%
11.0%
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
HCV+, RNA+
HCV+, RNA-
HCV-
Cumulativemortality(%)

11. Chronic HCV Infection Increases
Mortality from Extra Hepatic Diseases
*P<0.001 for comparison among all 3 groups and P<0.001 for HCV RNA detectable
vs. undetectable. †P<0.001 for comparison among all 3 groups and P=0.002 for
HCV RNA detectable vs. undetectable
Lee MH, et al. J Infect Dis 2012;206:469–77
Follow-up
(Years)
20
18
16
14
12
10
2
0
8
6
4
Extrahepatic
diseases
(n=2,199)
Cumulativemortality(%)
19.8%†
12.2%
11.0%
0 2 4 6 8 10 12 14 16 18 20
HCV+, RNA+
HCV+, RNA-
HCV-

12. Chronic HCV Infection Increases
Mortality from both Hepatic and
Extra Hepatic Diseases
 Compared with anti-HCV negative individuals, anti-HCV positive
individuals had higher mortality
 Higher mortality in individuals with detectable HCV RNA vs. those
with undetectable HCV RNA
CI: confidence interval
Lee MH, et al. J Infect Dis 2012;206:469–77
Hazard ratio [95% CI]
All causes 1.89 [1.66–2.15]
Hepatic diseases
Extra hepatic diseases
Cardiovascular diseases
Nephritis
Esophageal cancer
Prostate cancer
Thyroid cancer
12.48 [9.34–16.66]
1.35 [1.15–1.57]
1.50 [1.10–2.03]
2.77 [1.49–5.15]
4.08 [1.38–12.08]
4.19 [1.18–14.94]
8.22 [1.36–49.66]

13. Patrice Cacoub et al., annrheumdis-2013-203883

14. Prevalence of HCV Infection in
Dialysis Patients
 60 to 100 % in Egypt
 8 to 36 % in North America
 1 to 54 % in Europe
 17 to 51% in Asia
 1.2 to 10% in New Zealand and Australia

15. HCV infecton in ESKD patients
 HCV in Hemodialysis patients:
 8% (of 400,000 on HD) in USA
 5 times greater than general US population
 2.6%-23% (mean 13.5%) In industrialized populations
 Number of years on dialysis independent risk factor
for HCV infection
 HCV: Natural History
 HCV infection independently associated with
increased mortality in hemodialysis patients
 Increased rates of cirrhosis and hepatocellular cancer
http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/

17. Impact of HCV on Survival of HD Patients
Espinosa et al Nephrol Dial Transplant 2001;16:1669-74.
 175 patients
 57 anti HCV-positive
 Independent predictors of survival
 baseline age (RR 1.04)
 diabetic aetiology (3.6)
 transplantation during f-up (0.66)
 HCV-positivity (1.62)
 Kaplan-Meier survival
 52% at 8 years for HCV-negative
 32% at 8years for HCV-positive
 Causes of death similar
 except 4 HCV-pos died of liver
disease (vs 0 HCV-negs)
Confirmed in meta-analysis. Fabrizi et al Aliment Pharmacol Ther 2004;20:1271-7.

18. liver fibrosis score
(degree of scarring)
0
6
3
years10 20 30 60
cirrhosis
HCV-pos
(median time 38 years)cirrhosis

19. liver fibrosis score
(degree of scarring)
0
6
3
years10 20 30 60
cirrhosis
?
end-stage
renal disease
Impact of HCV on Cirrhosis in HD

20. liver fibrosis score
(degree of scarring)
0
6
3
years10 20 30 60
cirrhosis
end-stage
renal disease
?
immune
suppression

23. 20
27
21 20
56 58
68
33
0
20
40
60
80
100
SVR (%)
Casanovas
Chan
Fernandez Pol
Degos
Izopet
Cam
pistol
Raptopoulou-Gigi
Pooled
SVR
Interferon monotherapy 3 MU TIW
19
IFN In Dialysis Patients:
Meta-analysis
Russo et al, Am J Gastro July 2003
Studies using IFN 3 MU tiw

24. SVR and Reduced Risk of All-Cause Mortality
US VA Study: Treatment with Pegylated Interferon/Ribavirin
Backus L, et al. Clin Gastroenterol Hepatol. 2011
CumulativeMortality
0 1 2 3 4 5 6
0.00
0.05
0.10
0.15
0.20
0.25
0.30
P (log-rank) < 0.0001
No SVR
SVR
HCV Genotype 1
Years
Genotype N SVR Hazard Ratio for Death with
SVR
P-value
1 12,166 35% 0.70 < 0.0001
2 2904 72% 0.64 0.006
3 1794 62% 0.51 0.0002

26. “Grading the evidence for
hepatitis C therapies:
Can we do better than a C”

27. 2002
IFN
RBV
2011
IFN RBV
DAA
Association
of DAA
(direct acting agents)
Trends in anti-HCV therapies
2014

28. Simple Regimen
Short duration
simple,
straightforward
stopping rules
What Are the Key Elements of an
Ideal HCV Regimen?
Pan-Genotypic
Regimen can be used
across all genotypes
Highly Effective
High efficacy in
traditionally challenging
populations (ie, poor
IFN sensitivity, cirrhosis)
Safe and Tolerable
Few or easily
manageable adverse
effects
All Oral
PegIFN/RBV replaced
with alternate backbone
with low chance of
resistance
Not Eliminated by
the Kidney
Easy Dosing
Once daily, low pill burden

30. PEG IFN/RBV/TVR in hemodialysis
patients with HCV infection
30
24 weeks
48 weeks
PEG 135/TVR/RBV400mg 12 weeks+ 12 weeks PR
PEG135 /TVR/RBV200mg 12 weeks+ 36 weeks PR
N=18
N=17
SVR 24 weeks 13/18 (72%)
SVR 48 weeks 11/17 (65%)
Anemia, RBV dose reduction, EPO required
Protease inhibitors can be used safely in dialysis patient
Basu Journal of Hepatology, Volume 58, Supplement 1, April 2013, Pages S30–S31 #67

31. From: SaxenaV. ILC 2015, #LP08
The HCV-TARGET cohort

32. From: SaxenaV. ILC 2015, #LP08

33. Safety and efficacy of sofosbuvir-containing regimens in
hepatitis C-infected patients with impaired renal function
Saxena V, et al. Liver International 2016;Feb.29
Safety outcomes by baseline renal function in RBV-free regimen (SOF/SMV)
a Outcome abstracted from HCV TARGET database as reported by investigators; includes test terms of acute kidney failure, acute
kidney injury, renal insufficiency, renal failure, azotemia, acute renal failure, acute renal failure, anuric renal failure and impaired renal
function.
b The patient with eGFR ≤45 who died was a liver transplant recipient with baseline MELD of 26 who died from worsening renal failure
and hepatic decompensation.
Bold text signifies statistically significant differences.
Safety outcome All patients, N = 718 eGFR ≤45, N = 39 eGFR >45, N = 679 P-value
arly treatment discontinuation, n (%) 37 (5) 3 (8) 34 (5) 0.45
Early treatment discontinuation because of
AE, n (%)
21 (3) 3 (8) 18 (3) 0.10
Common AEs, n (%)
Fatigue 76 (25) 9 (23) 167 (25) 1.00
Headache 112 (16) 4 (11) 108 (16) 0.50
Nausea 92 (13) 5 (13) 87 (13) 1.00
Anaemia AE, n (%) 121 (17) 12 (31) 109 (16) 0.03
Required transfusion(s) 9 (1) 3 (8) 6 (1) 0.01
Erythropoietin stimulating drug started on
treatment, n (%)
0 (0) 0 (0) 0 (0) 1.00
Worsening renal functiona, n (%) 13 (2) 4 (10) 9 (1) 0.004
Any serious AEs, n (%) 41 (6) 7 (18) 34 (5) 0.005
Cardiac serious AEs, n (%) 2 (<0.5) 0 (0) 2 (<0.5) 0.73
Death, n (%) 6 (1) 1 (3)b 5 (1) 0.28

34. Safety and efficacy of sofosbuvir-containing
regimens in hepatitis C-infected patients with
impaired renal function
Saxena V, et al. Liver International 2016;Feb.29
SVR12 rates with 95% confidence intervals by treatment regimen in total cohort and by baseline renal function. eGFR,
estimated glomerular filtration rate; PEG, peg-interferon; RBV, ribavirin; SMV, simeprevir; SOF, sofosbuvir; SVR12,
sustained virologic response at 12 weeks.

35. Sofosbuvir-Containing Regimens Have Been Linked
to Worsening of Renal Function in HCV-TARGET
1. Saxena V et al. Liver International 2016: ISSN1478-3223

36. Safety and efficacy of sofosbuvir-containing
regimens in hepatitis C-infected patients with
impaired renal function
Saxena V, et al. Liver International 2016;Feb.29
On treatment eGFR trend among patients with baseline eGFR ≤45 who experienced worsening renal function. One
patient with baseline eGFR <45 and worsening renal failure was excluded from this figure because of lack of longitudinal
eGFR submitted.

37. A small US study

39. Sofosbuvir
• Sofosbuvir extensively metabolized in the liver to form active
nucleoside analogue triphosphate GS-461203
• Dephosphorylation results in the formation of inactive nucleoside
metabolite GS-331007
• GS-331007 accounts for
• >90% of systemic drug exposure
• renal elimination

44. The Austrian experience

45. RUBY-1

47. RUBY-1

50. Pharmacokinetics: DCV-TRIO

52. Efficacy and safety of daclatasvir and asunaprevir
combination therapy in chronic hemodialysis patients with
chronic hepatitis C
Suda G, et al. J Gastroenterol 2016;Jan 14
Mean changes in hepatitis C virus (HCV) RNA during treatment in all patients, patients with resistance-associated variants
(RAVs) in NS5A, or patients with liver cirrhosis
34 HD patients treated for 24 weeks with Daclatasvir 60 mg/d + Asunapevir 100
mg bid Only ONE patient relapsed (he had a NS3 D168E-resistant strain)

53. Efficacy and safety of daclatasvir and asunaprevir
combination therapy in chronic hemodialysis patients with
chronic hepatitis C
Suda G, et al. J Gastroenterol 2016;Jan 14
Changes in biochemistry, tumor, and
fibrosis markers during and after
daclatasvir and asunaprevir combination
therapy;
a alanine transaminase (n = 21),
b serum albumin (n = 21),
c alpha-fetoprotein (n = 20),
d hyaluronic acid (n = 16).
EOT, end of treatment ; post. 12 wk, 12 weeks
post-treatment completion; ALT, alanine
Transaminase ; AFP, alpha-fetoprotein.
Paired Mann–Whitney U test, **p0.05, *p0.01

54. C-SURFER
[Grazoprevir + Elbasvir]

57. HCV Treatment Options
Expected in the Near Future

58. What about NS5a inhibitor?
Ledipasvir
 Pan-genotypic
 Ledipasvir is likely to be approved this year
 Excellent safety profile, no anemia
 Ledipasvir : Primarily excreted (>98%) unchanged
in the feces, with little renal excretion
 No data yet in dialysis patients
Kirby B, Mathias A, Yang C, et al. Metabolism and excretion of ledipasvir (GS-5885) in humans
[abstract O_20]. 8th International Workshop on Clinical Pharmacology of Hepatitis Therapy, June
26-27, 2013, Cambridge, MA.
http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/02/WC500160499.pdf

59. ASTRAL-1, -2, -3, -4 Trials: Sofosbuvir/
Velpatasvir FDC ± RBV in GT1-6 HCV
 Multicenter, randomized phase III trials in Tx-naive and Tx-experienced pts
ASTRAL-1[1]:
GT 1, 2, 4, 5, or 6 HCV
(N = 740)
Sofosbuvir/Velpatasvir (n = 624)
Placebo QD (n = 116)
12 wks
All pts
followed
for SVR12,
primary
endpoint
ASTRAL-2[2]:
GT2 HCV
(N = 266)
ASTRAL-3[3]:
GT3 HCV
(N = 552)
Sofosbuvir/Velpatasvir (n = 134)
Sofosbuvir + RBV (n = 132)
Sofosbuvir/Velpatasvir (n = 277)
Sofosbuvir + RBV (n = 275)
Sofosbuvir/Velpatasvir (n = 90)
Sofosbuvir/Velpatasvir + RBV (n = 87)
Sofosbuvir/Velpatasvir (n = 90)
24 wks
ASTRAL-4[4]:
GT1-6 HCV and
CTP B cirrhosis
(N = 267)
1. Feld JJ, et al. AASLD 2015. Abstract LB-2. 2. Sulkowski MS, et al. AASLD 2015.
Abstract 205. 3. Mangia A, et al. AASLD 2015. Abstract 249. 4. Charlton MR, et al.
AASLD 2015. Abstract LB-13.
Sofosbuvir/velpatasvir 400/100 mg QD

60. 100
ASTRAL-2 Open-Label Trial: SVR12,
Safety With Sofosbuvir/Velpatasvir in
GT2 HCV
 No impact of BL NS5A RAVs on SVR rates
 Safety profile similar to ASTRAL-1
All Pts No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis
n/N =
P = .018
(superiority)
99
SVR12(%)
Treatment Naive Treatment Experienced
SOF/VEL 12 wks
80
60
40
20
0
94
133/
134
124/
132
99/
100
92/
96
15/
15
14/
15
15/
15
13/
16
4/
4
4/
4
10010010099 96 100 93 81
SOF + RBV 12 wks
Sulkowski MS, et al. AASLD 2015. Abstract 205. Reproduced with
permission. Foster GR, et al. N Engl J Med. 2015;[Epub ahead of print].

61. 100
ASTRAL-3 Open-Label Trial: SVR12,
Safety With Sofosbuvir/Velpatasvir in
GT3 HCV
Mangia A, et al. AASLD 2015. Abstract 249. Reproduced with permission.
Foster GR, et al. N Engl J Med. 2015;[Epub ahead of print].
n/N =
SVR12(%)
80
60
40
20
0
264/
277
221/
275
191/
197
163/
187
73/
80
55/
83
200/
206
176/
204
64/
71
45/
71
95
80
63
909797
87
91
66
86
All Pts No Yes Naive Experienced
Cirrhosis
P < .001
(superiority)
SOF/VEL 12 wks
SOF + RBV 24 wks
Treatment History

62. ASTRAL-4: Sofosbuvir/Velpatasvir in
Decompensated Cirrhosis
 Open-label trial; HCC and liver transplantation excluded
 In pts with BL MELD > 15, SVR12, score improved in 84%, worsened in 8%;
in pts with BL MELD < 15, SVR12, score improved in 52%, worsened in 27%
 AEs consistent with advanced liver disease and RBV toxicity
Charlton MR, et al. AASLD 2015. Abstract LB-13.
Curry MP, et al. N Engl J Med. 2015;[Epub ahead of print].
All Pts 1 3
HCV Genotype
n/N =
SVR12(%)
SOF/VEL 12 wks SOF/VEL + RBV 12 wks SOF/VEL 24 wks
2, 4, and 6
100
80
60
40
20
0
83
94
86 88
96 92
50
85
50
100 100
86
75/
90
82/
87
77/
90
60/
68
65/
68
65/
71
7/
14
11/
13
6/
12
8/
8
6/
6
6/
7

64. 3’UTR5’UTR Core E1 E2 NS2 NS4BNS3 NS5A NS5B
p7
Telaprevir
Boceprevir
Simeprevir
Asunaprevir
Paritaprevir
Grazoprevir
Daclatasvir
Ledipasvir
Ombitasvir
Elbasvir
GS-5816
Sofosbuvir
VX-135
IDX21437
ACH-3422
Dasabuvir
Beclabuvir
NS5B
NUC Inhibitors
NS3
Protease Inhibitors
NS5A
Replication Complex
Inhibitors
Ribavirin
NS5B
Non-NUC
Inhibitors
PolymeraseProtease
....previr (PI)
....asvir (NS5A)
....buvir (Pol)
How do I know which kind of DAA?

65. Do we really have to be
cornered?
BEFORE AFTER
To have to
treat our
patients with
all the
drawbacks
Not be able
to treat our
patient

67. Evaluation For Treatment
Stage of liver
disease
Estimated
GFR
Nature and
Severity of
Extrahepatic
Manifestations
Chronic drug
administration
Previous antiviral
treatment with
interferon or direct
anti-viral agents
Nature and stage
of CKD
Presence of
Co-morbid
Conditions

68. Evaluation For Treatment
Stage of liver
disease
Fibrosis stage
Compensation
of hepatocellular
function
Fib4 calculation
fibroscans
Child scores
MELD scores

69. Evaluation For Treatment
Nature and stage
of CKD
Regular HDx KTx
Infected wih
HCV
Waiting
For KTx De-novo HCV
persisting
for over 12 weeks
Proteinuria
MCGN

70. Evaluation For Treatment
Nature and
Severity of
Extrahepatic
Manifestations
Cryoglobulinemic vasculitis with
end-organ manifestations
(joints, peripheral nerves, skin,
kidneys, lungs, , eyes, gut, brain etc.)

71. Evaluation For Treatment
Presence of
Co-morbid
Conditions
Co-infection with HBV, HIV
Other co-morbid conditions

72. Evaluation For Treatment
Chronic drug
administration
Drug compatibility checker for
identifying potential drug-drug
interactions

73. Evaluation For Treatment
Previous antiviral
treatment with
interferon or direct
anti-viral agents

74. H. EL-Fishawy, M. Hassaballa, G.
Saady, R. Barsoum, et al. 2016

75. H. EL-Fishawy, M. Hassaballa, G.
Saady, R. Barsoum, et al. 2016

76. Guideline 2 :
Treatment of HCV infection in
patients with CKD
(Kidney International, 2008, 73, Suppl 109)

77. • 2.1.2 It is suggested that the decision to treat is
based on the potential benefits and risks of therapy,
including life expectancy, candidacy for kidney
transplantation, and comorbidities (weak).
• 2.1.6 It is suggested that antiviral therapy be considered
for patients with HCV-related GN (weak).
Guideline 2.1: Evaluation of HCV-infected CKD
patients for antiviral treatment
(Kidney International, 2008, 73, Suppl 109)

83. 83

84. Guideline
All patents with HCV infection
should be treated

90. H. EL-Fishawy, M. Hassaballa, G.
Saady, R. Barsoum, et al. 2016

92. Abstract ERA-EDTA London 2015

94. Components of Non Invasive Tests

101. Proceed
Change to
alternate
YES
Change
DAA
regimen
NO
Adjust dose;
proceed
with
monitoring
NO
Alternates available?
Check for alternates
with the help of a specialist if necessary
YES
Stop co-medication
N
O
Use with caution
Contraindicated
Is the co-medication
absolutely
necessary?
Proceed
NO
Selecting the Correct Medications to Avoid DDIs
Check for potential interaction
with DAA regimen
Summary of Product Characteristics
www.hep-druginteractions.org
Identify all co-medications
including physician-prescribed, self-
prescribed, herbal, recreational*
*including grapefruit, which is a strong inhibitor of CYP3A4