3/14/2017

1

HCV Infection in the CKD and ESRD Patient: Who to

Treat and When

David Roth, MD

William W. Anderson Professor of Nephrology

University of Miami Miller School of Medicine

Miami, Florida

Disclosures

• Scientific Advisory Board: Merck; Abbvie; Bristol-Myers Squibb.

• Consultant: Merck and Co.

Objectives

� Review the clinical impact of HCV infection in patients with CKD and ESRD.

� Identify what effect HCV antiviral treatment has on outcomes in CKD and ESRD patients.

� Review the safety and efficacy of the second generation direct acting antiviral agents in patients with kidney disease

� Discuss the management of the HCV-infected kidney transplant candidate, the treatment of viremic kidney transplant recipients and the use of kidneys from HCV-positive organ donors .

3/14/2017

2

Case Presentation

� 61 y/o AA male with a history of T2D for 20 yrsand HTN first seen 5 years ago with CKD3 (eGFR45ml/min).

� Initial work-up: US with increased echogenicity but otherwise normal appearing kidneys, 2.5 gms of protein/24hr, U/A with protein and 2-5 RBC/hpfwith all serology, HBV, HIV, SPEP, and FLC negative except for HCV ELISA positive.

�The patient was lost to follow-up and presented recently with edema and poorly controlled HTN and an eGFR of 14 ml/min.

Case Presentation: Questions

What other testing to evaluate the positive HCV ELISA should have been done at initial presentation? Would antiviral treatment have been appropriate at that time?

1. If presenting today as he did 5 years ago, should this patient be treated with antiviral agents to eradicate his HCV infection?

2. Should the patient be referred for kidney transplantation, sent to see a hepatologist, both or neither at this time?

3. Should treatment for HCV be started now? Would post transplant DAA treatment be the best plan of care?

Case Presentation: Questions

1. What other testing to evaluate the positive HCV ELISA should have been done at initial presentation? Would antiviral treatment have been appropriate at that time?2. If presenting today as he did 5 years ago, should this patient be treated with antiviral agents to eradicate his HCV infection?3. Should the patient be referred for kidney transplantation, sent to see a hepatologist, both or neither at this time?4. Should treatment for HCV be started now? Would post transplant DAA treatment be the best plan of care?

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3

The “Lingo”

�SVR12- sustained viral response at 12 weeks after completing antiviral medication. Patients that test negative for virus at week 12 post therapy are considered cured of HCV. Patients with detectable virus after a SVR12 have been re-infected.

�DAA- direct acting antivirals. These are the new generation of HCV meds that followed the interferon era and target specific sites on the HCV genome.

�Genotype- there are at least 6 different genotypes of the virus with varying penetration globally.

�Liver injury- Stage 4 liver disease represents cirrhosis. Patients can have stage 0-4. Non-invasive tests are available that can obviate the need for a biopsy in many cases.

~2% ever infected with HCV1

3.5 million people living in the US with chronic HCV2

19,658 HCV-related deaths in 20142; may reach

36,000 deaths/year in 2030–20351

1. www.hepatitisc.uw.edu/pdf/screening-diagnosis/epidemiology-us/core-concept/all 2. www.cdc.gov/hepatitis/HCV/HCVfaq.htm

Groeger J, Flaxman AD, Wiersma ST. Hepatology. 2013;57(4):1333-42.

Global Variance in HCV Genotypes

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4

HCV as a Systemic Infection Affecting Multiple Organ Systems

10Gill K, et al. Hepatol Int. 2016;10(3):415-423.

Liver

Lymphatic

system

Primary HCV Association

Secondary HCV Association

CKD

Membranoproliferative

glomerulonephritis

Impaired glucose metabolism

(insulin resistance, diabetes)

Neurocognitive

impairment

Coronary artery disease

Cardiovascular disease

Hepatitis C Virus and Kidney Disease

� Patients with ESRD have a higher prevalence of HCV infection than the general population.

� The prevalence of anti-HCV sero-positivity amongst ESRD patients ranges from 5%-20% in developed countries and even higher in less developed regions of the world.

� HCV infection is directly involved in the pathogenesis of certain forms of immune-complex GN and cryoglobulinemia and is associated with a higher incidence of CKD and progression to ESRD.

� HCV-infected kidney transplant recipients have had enormous unmet medical need which is just now being addressed with DAA agents.

HCV Involvement in Kidney Disease

12

HCV as a cause of CKD:

• HCV is a significant cause of some forms of

glomerulonephritis +/- MCS.

• HCV-infected CKD patients progress more

rapidly into ESRD.

• Population-based studies have found an

association between HCV positivity and

markers of CKD, such as albuminuria or

proteinuria.

HCV as a consequence of CKD

treatment:

• Blood transfusions

• Nosocomial transmission in dialysis

units

• Transmission by kidney grafts

Much higher prevalence of HCV infection in CKD and transplant patients than

in the general population. Opportunities to treat are now available.

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5

Hepatitis C Virus Infection Increases the Risk for CKD

Fabrizi, et al. Dig Dis Sci 2015;60:3801

HR 1.43 ( 95% CI 1.23;1.63)

CKD and CVD Outcomes in a Large US Database

• Truven Health MarketScan Database (2008-2014)

• HCV (+) (n=72,213) group with propensity-matched HCV (-) cohort (n=216,639)

0

20

40

60

80

100

120

CKD CVD

Positive Negative

Nu

mb

er/

10

,00

0 p

ati

en

t y

rs.

Hazards Ratio 95% CI

CKD outcome 2.2 2.01, 2.38

CVD event 1.91 1.85, 1.97

Park, et al. AASLD 2016, Abstract #785

Association of HCV with the Incidence and Progression of Chronic Kidney Disease

Outcome RR/HR 95% CI

Mortality 2.17 2.13-2.21

Onset of eGFR < 60 ml/min/1.73m2 1.15 1.12-1.17

Slope of eGFR loss > 5ml/min/1.73m2 1.22 1.19-1.26

Development of ESRD 1.98 1.81-2.16

• Cohort study of > 100,000 HCV (+) and > 920,000 HCV (-) US Veterans.

• Associations examined in adjusted Cox models using a propensity-matched cohort for sensitivity analysis.

Molnar, et al. Hepatology. 2015;61:1495-1502

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6

Impact of IFN-based Treatment on the Incidence of CKD

Chen Y-C, Medicine 2015;94(32):e1334

n= 3,679 untreated patients

n = 919 with > 3 mo IFN-based therapy

HR=0.42; p=0.03

Untreated

Treated

Cu

mu

lati

ve

in

cid

en

ce,

%

Modified log rank, p=0.008

Follow up, year

Impact of HCV Treatment on CKD Progression

• Kaiser-Permanente: HCV-infected patients (n=2,452) treated between 2004-2014.

• CKD defined by eGFR<60 ml/min on 2 measurements > 90 d apart.

• SVR24 achieved in 61.6% using IFN-based and 1st generation DAAs.

0

1

2

3

SVR24 No SVR

1.12

2.33

De

clin

e i

n G

FR

(m

l/m

in/y

r)

Patients achieving SVR:

HR for ESRD=0.05 (0.01, 0.33)

Rodriguez, et al,. AASLD 2016, Abstract 1946.

Hsu, et al. Gut 2015;64:495

Untreated

Treated

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7

Summary Estimates for All-Cause Mortality Among ESRD Patients:

Impact of HCV Infection

Fixed effects aRR P-value

All studies 14 1.32 (1.25; 1.39) 1.35 (1.25; 1.47) 0.08

Population-based

studies 5 1.28 (1.21; 1.36) 1.28 (1.21; 1.36) 0.90

US studies 3 1.31 (1.09; 1.58) 1.37 (1.05; 1.78) 0.18

HD patients only 6 1.43 (1.23; 1.65) 1.40 (1.12; 1.76) 0.08

Cohort studies 11 1.33 (1.26; 1.41) 1.37 (1.27; 1.48) 0.12

Chronic HCV 13 1.33 (1.25; 1.40) 1.35 (1.26; 1.46) 0.14

Non-Australian studies 11 1.32 (1.24; 1.40) 1.37 (1.24; 1.52) 0.04

Fabrizi, et al. J Viral Hep. 2012;19:601

Random effects aRR

2

Impact of Treatment on Mortality in

HCV-Infected Taiwanese ESRD Patients

Treated

Untreated

ESRD pts. matched 4:1 to HCV cohort

n=134n=2,097

HR 2.62 (95% CI 1.24-5.55)

Hsu, Yueh-Han; et al. Medicine. 2015;94(47):e2113

HCV Treatment in Dialysis Patients

• DOPPS 1-4: 1996–2011; DOPPS 5: 2012-2015

• IFN and ribavirin in DOPPS 1-4; DAAs used in some of the DOPPS 5 patients

Goodkin DA et al. Am J Nephrol. 2013;38:405-412; Goodkin CJASN 2016, doi: 10.2215/CJN.07940716

0123456789

10

HCV +, total Received anti-HCV rx Received anti-HCV rx,

on waitlist for KT

4,735/49,762

48/4,589

23/617

9.5%

7.5%

2%

%

3.7%

5,751/76,689

21/1013

1%

DOPPS 1-4

DOPPS 5

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8

Evolution of HCV Therapies

Webster DP et al. Lancet. 2015;385:1124-1135.

Su

sta

ine

d v

iro

log

ica

l re

spo

nse

ra

te (

%) 100

75

25

50

0

1990

Year

7–10%

1998

25%

2001

40–50%

2011

60–70%

2014

>90%

Peginterferon

+ ribavirin

+ PI

Peginterferon

+ ribavirin

Interferon +

ribavirin Interferon

Direct-Acting

Antivirals

PI = protease inhibitor

C E1p

7NS2 NS3 NS4A NS5A NS5BE2 NS4B

5’ NTR 3’ NTR

NS3/4A inhibitors

Protease inhibitorsSimeprevir

Paritaprevir

Grazoprevir

DirectDirectDirectDirect----Acting AntiviralsActing AntiviralsActing AntiviralsActing Antivirals

Serine

protease

RNA helicase

RNA polymerase

RNA replicationEnvelope

glycoproteins

Capsid

protein

Ion

channel

Transmembrane

protein

NS3

Cofactor

Membrane

reorganization

Phosphoprotein

Regulator of

replication and

viral assembly

NS5A inhibitorsDaclatasvir

Ledipasvir

Ombitasvir

Elbasvir

Velpatasvir

NS5B inhibitors

Polymerase inhibitors

Sofosbuvir

Dasabuvir

Structural proteins Non-structural proteins

NTR = non-translated region; NS = non-structural protein.

Translation

HCV NS proteins

NS2

Polyprotein processing

NS3

NS4B

NS5A NS5B

HCV RNA

Fusion and uncoating

RNA replication

NS5A

CypA

NS5B

NS2

NS3

NS4B

Viral assembly

Transport and release

Potential Therapeutic Targets in the HCV Lifecycle

3/14/2017

9

Translation

HCV NS proteins

NS2

Polyprotein processing

NS3

NS4B

NS5A NS5B

HCV RNA

Fusion and uncoating

RNA replication

NS5A

CypA

NS5B

NS2

NS3

NS4B

Viral assembly

Transport and release

NS3/4A protease

inhibitors

NS5A

inhibitors

NS5B polymerase

inhibitors

NS5A

inhibitors

Potential Therapeutic Targets in the HCV Lifecycle

Does the level of kidney function

affect treatment choices in

HCV-infected CKD patients?

Direct-Acting Antiviral Drug Choices in Patients With Kidney Disease

Sofosbuvir (Sovaldi®) prescribing information (PI); ledipasvir/sofosbuvir (Harvoni®) PI; elbasvir/grazoprevir (Zepatier™) PI; daclatasvir (Daklinza™) PI; simeprevir (Olysio®) PI; paritaprevir/ritonavir/ombitasvir, dasabuvir (Viekira Pak) PI.

Drug Primary Metabolic

Pathway

Recommendations from

Package Insert and AASLD Guidelines

Sofosbuvir Renal Insufficient data for CrCl < 30 ml/min

Ledipasvir Hepatic Data not available for CrCl < 30 ml/min

Velpatasvir Hepatic Data not available for CrCl < 30 ml/min

Grazoprevir Hepatic No restrictions in CKD or ESRD

Elbasvir Hepatic No restrictions in CKD or ESRD

Daclatasvir Hepatic No restrictions

Simeprevir Hepatic Limited data for ESRD/HD

Paritaprevir/r Hepatic

No dose adjustments necessary for CKD or

ESRD/HD. Use Ribavirin with cautionOmbitasvir Hepatic

Dasabuvir Hepatic

3/14/2017

10

Studies Providing Data on DAAs in HCV-Infected

ESRD Patients

• RUBY-1(Cohort 1 and 2) • RUBY-2• C-SURFER• EXPEDITION- IV

OBV/PTV/r + DSV

Open label

≥ 18 years old

Genotype 1

Treatment-naïve

CKD 4 (n=6) or 5 (n=14)

(all on dialysis)

No cirrhosis**

No HBV or HIV co-infection

RUBY-I Study: Ombitasvir/Paritaprevir/ritonavir + Dasabuvir + RBV for HCV Genotype 1 Patients with CKD

SVR12

OBV/PTV/r + DSV + RBV

n = 7

Genotype 1a

Genotype 1b

n = 13

Pockros PJ. Gastroenterology 2016;150:1590-8

DesignW12

� SVR12: 18/20 patients (90%)

� SVR12 in 11/13 (85%) genotype 1a patients

� 9/13 genotype 1a patients had to interrupt ribavirin treatment due to anemia- 4 required EPO.

Results

RUBY-I Study, Cohort 2: Ombitasvir/paritaprevir/ritonavir + Dasabuvir± RBV for HCV Genotype 1 with Renal Impairment

Vierling JM. AASLD 2016, Abs. 886

3/14/2017

11

RUBY-I Study, Cohort 2: Ombitasvir/paritaprevir/ritonavir + Dasabuvir± RBV for HCV Genotype 1 with Renal Impairment

Vierling JM. AASLD 2016, Abs. 886

9

Open label

≥ 18 years

Chronic HCV infection

Genotype 1a or 4

Treatment-naïve

Stage 4 or 5 chronic kidney disease

with eGFR (MDRD) < 30 ml/min/1.73m2

(dialysis permitted)

No cirrhosis

No HBV or HIV co-infection

RUBY-II Study: Ombitasvir/paritaprevir/ritonavir + Dasabuvir for HCV Genotype 1a or 4 with Stage 4/5/5D CKD

SVR12

N = 5

Genotype 1a

Genotype 4

N = 13

Gane E. AASLD 2016, Abs. 935

W12

OBV/PTV/r + DSV

OBV/PTV/r

SVR12, %ITTmITT

100100

80 *100

Genotype 4 (N = 5)

OBV/PTV/rGenotype 1a (N = 13)

OBV/PTV/r + DSV

C-SURFER: Grazoprevir + Elbasvir in HCV Genotype 1 Patients with CKD 4/5/5D

• Objective

• SVR12 (HCV RNA < 15 IU/ml) in immediate + PK groups:

• 45% historical response rate to IFN-based regimens used

Roth D et al. Lancet. 2015;386:1537-1545.

N = 111 GZR + EBR(Immediate treatment)

Placebo

GZR + EBR (Intensive PK)

N = 113

N = 11

GZR/EBR(Deferred treatment)

W12 W16 W28

≥ 18 years

Genotype 1

CKD stage 4/5 ± hemodialysis

Treatment naïve or failures

with IFN-based regimens;

Compensated cirrhosis allowed

No HBV or HIV co-infection

Open label

Randomization

1 : 1

Double blind

3/14/2017

12

0

25

50

75

100

99.1

(95.3-100)94.3

(88.5-97.7)

116 122

Modified

Full analysis SetFull analysis

Set

SVR12 (HCV RNA < 15 IU/ml), % (95% CI), mITT

%

Primary analysis

100

(94.1-100)

61

98.2

(90.3-100)

55

97.6

(87.1-99.9)

41

100

(95.2-100)

75

1a 1b NoYes

DiabetesGenotype

* Genotype 1b, non cirrhotic, CKD stage 5, NS5A RAV at baseline : L31M, at failure : L31M + Y93H

Modified full analysis set excluded patients who

died or discontinued for reasons unrelated to

treatment

Relapse 1* 1

Discontinuation unrelatedto treatment 0 6

Roth D. Lancet 2015; Oct 6; 386:1537-45

C-SURFER: SVR12 Rates

Single arm

Open label

≥ 18 years

HCV genotypes 1 to 6

eGFR (MDRD) < 30 mL/min

with CKD4 and 5 (HD)

Treatment-naïve or treatment-

experienced

Compensated cirrhosis allowed

No HBV or HIV co-infection

N = 104SVR12

GLE/PIB

Gane E. AASLD 2016, Abs. LB-11

W12

‒ GLE/PIB : 100/40 mg 3 tablets QD

� Objective– SVR12 (HCV RNA < 15 IU/mL)

Expedition-IV: Treatment of HCV-Infected CKD Patients with Glecaprevir and Pibrentasvir

• Glecaprevir (NS3/4A inhibitor) and pibrentasvir (NS5A inhibitor) have minimal renal clearance.

• CKD 4: 13%; CKD 5: 87%; 82% HD

Expedition-IV: Treatment of HCV-Infected CKD Patients with Pangenotypic Agents

• 42%TE, 19% comp cirrhosis

• GT1-52%; GT2-16%; GT3-11%; GT4-19%;

GT5 and 6-1%

0

10

20

30

40

50

60

70

80

90

100

SV

R1

2,

%

Relapse 0

Failure 0

Discontinued 1

LTFU 1

ITT

mITT= 100% SVR12

98

Gane, et al. AASLD, 2016

3/14/2017

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Arth Rheum 1991;34:1606

Kidney Disease Associated with HCV Infection

B-cell Syndromes in HCV-Infected Patients

Adapted from Soriano, et al. Antiviral Ther 2016;21:1-8

B cell

HCV

replication

Antibody

disorders

Mixed

Cryoglobulinaemia/

Glomerulonephritis

Monoclonal

gammopathies

B-cell

proliferation

Non-Hodgkins

lymphomas

CD81

E2

Dammacco et al. Clin Exp Med 2016;16:233

Immune-Complex Mediated Injury in HCV-Related Vasculitis

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Glomerular Disease in Patients with Chronic HCV Inf ection

Kupin CJASN doi:10.2215/CJN.04320416

Sofosbuvir plus Ribavirin for HCV-Associated Cryoblobulinaemia Vasculitis:

The VASCUVALDIC Study

• Open label, prospective study of patients (n=24) with HCV-cryoglobulinaemic vasculitis with skin, joint, renal, peripheral nerve, central neurological, GI, pulmonary and/or cardiac involvement and active HCV viremia.

• Sofosbuvir (400 mg/d) and ribavirin (200-1400 mg/d) x 24 wks.

• Primary efficacy end point: complete clinical response of the vasculitis at the end of treatment defined by improvement of all of the affected organs and the absence of a clinical relapse.

• Renal improvement: proteinuria < 300 mg/24h, disappearance of hematuria and > 20% improvement of GFR at week 24.

Saadoun, et al Ann Rheum Dis 2016; 75: 1777-82

VASCUVALDIC Study: Clinical and Virologic Outcomes

Variable CR PRVirological

responseCryoglobulin (g/L)

Baseline 0.35 (0.16-0.83)

Week 24 21/24 (87.5%) 3/24 (12.5%) 22/24 (91.7%) 0.15 (0.05-0.45)

EOT, wk. 12 20/23 (86.9%) 17/23 (74%) 0 (0-0.37)

Virological

failure2

Relapse 1 4

Saadoun, et al Ann Rheum Dis 2016; 75: 1777-82

CR- complete clinical response; PR- partial response

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Proposed Therapeutic Algorithm for HCV-Related Cryoglobulinemic Vasculitis

Dammacco F, Sansonno D. N Engl J Med 2013;369:1035-1045

Kidney Transplantation in the HCV-Infected Patient

What are the Concerns?

1) Effect of immunosuppression on viral replication2) Impact of HCV infection on:

-Patient/graft survival

-Underlying/progressive liver injury

-Extrahepatic effects

-HIV co-infection

3) Use of kidneys from HCV+ donors

The Case for Pre and Post Kidney Transplant HCV Therapy

• Cure is probable and durable

• Likely to reduce the risk of:• progressive liver injury• post-transplant GN• new onset diabetes

• Avoid drug-drug interactions with IS post transplant

Favoring Post

• Can use HCV+ donor kidney

• Shorter wait time

• Less dialysis vintage

• Improved eGFR of the KTR allows for greater therapeutic options.

In Favor of Pre

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Control of Viral Replication Improves Patient and Graft Survival Post Kidney Transplantation

0

10

20

30

40

50

60

70

80

90

Patient Graft

10 year outcomes

Viral neg Viral pos Negative

• French cohort, 1993-2010

• Viral control: SVR or spontaneous clearance

• HCV infected, n=1109

• Non-infected pts., n=30,602

Fontaine, et al. AASLD, 2016

%

Treatment of Hepatitis C in Renal Transplant Recipients with Direct Acting Antiviral Agents

Sawinski D et al. Am J Transplant. 2016; 16:1588

HC

V v

ira

l lo

ad

, lo

g c

op

ies/

mL

Weeks after DAA start

8

7

6

5

4

3

2

1

00 2 4 6 8 10 12 14

pt 1

pt 2

pt 3

pt 4

pt 5

pt 6

pt 7

pt 8

pt 9

pt 10

pt 11

pt 12

pt 13

pt 14

pt 15

pt 16

pt 17

pt 18

pt 19

pt 20

Case series of patients who were 1–4 years post-transplant (n=20)88% genotype 1; 60% failed IFN; 45% had HCV+ donor

• 12 weeks follow-up, SVR12 100%• DAA started mean 888 days post transplant• Tacrolimus levels decreased at end of therapy. 45% dose increased

LDV/SOF

W12

> 18 years old

Kidney transplant ≥ 6 months

Genotype 1 or 4

Treatment-naïve or experienced

Compensated cirrhosis allowed *

Hb ≥ 10 g/dl, platelet > 50 x 103/mm3,

CrCl ≥ 40 ml/min

* Metavir F4 or Ishak ≥ 5 or Fibroscan > 12.5 kPa or Fibrotest > 0.75 and APRI > 2

Design

� Objective– SVR12 (HCV RNA < 15 IU/ml), with 95% CI, by ITT

Randomisation

1 : 1

n = 57

n = 57

LDV/SOF in Kidney Transplant Recipients

LDV/SOF

W24

Colombo M, EASL 2016, Abs. GS13 ; J Hepatol 2016;64:S183

SVR12

SVR12

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SVR12, % (ITT)

� Baseline NS5A RAVs (15% cutoff) present in 19% of patients: SVR12 of 100%

with or without baseline RAVS

0

20

40

60

80

100 100

57

Overall

57

100

51

100

53

100

Genotype 1

6

100

4

Genotype 4

100%

LDV/SOF 12 weeks LDV/SOF 24 weeks

N=

Colombo M, Ann. Intern Med 2016, 15 Nov, Epub ahead of print

LDV/SOF in Kidney Transplant Recipients

Important Considerations When Treating Kidney Transplant Recipients with DAAs

� Drug-drug interactions: CNIs and mTORi are substrates of CYP3A4/5 and drug transporter P-glycoprotein (P-gp).

� The ideal time to initiate DAA treatment post kidney transplant has not been established.

� Sofosbuvir is not approved for use in patients with eGFR< 30 ml/min/1.73m2. Imperative to assess the status of allograft function before starting treatment.

� Possible impact of viral eradication on CNI metabolism.

� Activation of quiescent hepatitis B virus infection

Summary

Clinical Parameter HCV Impact Will antiviral treatment matter

Cause of chronic kidney disease

Increases rate of CKD progression

Increases mortality in ESRD pts.

Increases morbidity in KTR

Transmissible in dialysis clinics

Likely

Likely

Possibly

Probably

Yes

3/14/2017

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Case Presentation: Questions

1. What other testing to evaluate the positive HCV ELISA should have been done at initial presentation? Would antiviral treatment have been appropriate at that time?

HCV PCR for viremia. Back then we had IFN- not well tolerated with little data in the CKD area. 2. If presenting today as he did 5 years ago, should this patient be treated with antiviral agents to eradicate his HCV infection?Data on slowing progression of CKD is intriguing- likely yes.3. Should the patient be referred for kidney transplantation, sent to see a hepatologist, both or neither at this time?Yes and yes.4. Should treatment for HCV be started now? Would post transplant DAA treatment be the best plan of care? Depends on if LRD is available. If not would hold off and try for HCV positive donor organ.

Thank you!Thank you!Thank you!Thank you!