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Managing HCV in Liver Transplant: Optimizing Success with New DAA Regimens

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Paul Kwo, MD

Professor of MedicineMedical Director, Liver TransplantationIndiana UniversityIndianapolis, IN

LI 1.2 Distribution of Adult Patients Waiting for a Liver Transplant

United States Organ Transplantation. SRTR & OPTN Annual Data Report, 2012.



LI 1.3 Characteristics of Adult Patients on Liver Transplant Waiting List:

December 31, 2002 & December 31, 2012


LI 4.9 Median MELD Score for Adult, Deceased Donor Liver Transplants, by DSA, 2012


Managing HCV in Liver Transplantation – Reframing the Paradigm in the Context of New HCV TherapiesMichael Abecassis, MD, MBA

J. Roscoe Miller Distinguished Professor

Departments of Surgery and Microbiology-Immunology

Founding Director, Comprehensive Transplant Center

Northwestern University Feinberg School of Medicine

Chicago, IL



Case Studies/Questions

• A 60-year-old woman 4 weeks status-post OLT for HCV cirrhosis; SVR pre-treatment; sudden elevation of LFTs (3X)– Biopsy versus empiric treatment of rejection?

Please Select Your Approach

1. Biopsy 2. Empiric treatment of rejection

Live Polling Results

82%

18%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Biopsy Empiric treatment ofrejection




• A 56-year-old man with cirrhosis complicated by HCC within Milan; HCV+ serologically but SVR.

• Liver offer: a 70-year-old, otherwise good donor, HCV-– Accept offer?

Would you accept a liver offer of a 70-year-old, otherwise good donor, HCV–?

1. Yes2. No


82%

18%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Yes No




• A 67-year-old man with NASH cirrhosis complicated by HCC just outside Milan; no living donor.

• Liver offer: a 40-year-old otherwise good donor, HCV+– Accept offer?

Would you accept a liver offer of a 40-year-old otherwise good donor, HCV+?

1. Yes

2. No


54%

46%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Yes No



Back in the Day…

• HCV as an important indication for transplantation– Natural history with and without Tx– DDLT versus LDLT– Waiting for the ‘next new drug’…

• HCV recurrence and outcomes– Impact on outcomes and need for retreatment– Tolerability of HCV therapies both before and after

treatment– Timing, efficacy, and effectiveness of HCV therapies– Use of HCV+ donors– Use of older donors (>40)

Today – ‘Where Tomorrow Begins…’

• Treatment options – ‘perfection is the enemy of good’ with respect to available organs

• Timing of treatment– ‘Before’ makes intuitive sense, but so does ‘after’

– Making our waitlists HCV- has disadvantaged HCV+/- recipients because we can no longer use HCV+ donors

• Management of post-Tx– Maintenance immunosuppression

– Biopsy vs empiric Rx for elevated LFTs

• Ethical concerns – should we allocate HCV+ organs to all HCV- recipients (including HCV+/-) just because we have an effective treatment?

• Cost

Questions for Tomorrow

• Should we develop criteria for who gets treated before and who gets treated after Tx?

• What about living donors who are HCV+/-?

• Will patients who meet criteria for Tx get better with HCV treatment?

• Will the risk of HCC remain the same even with effective treatment?



Closing Comments

• We should recognize and applaud the development of these HCV treatments that now cause us to ask these questions. Truly the only true ‘cure’, other than a vaccine, that I have witnessed in >25 years in practice.

• Thank you.

HCV Pharmacotherapy: Efficacy in the Pre- and Post-transplant Settings

Steven L. Flamm, MD

Chief, Liver Transplantation

Professor of Medicine and Surgery

Northwestern University Feinberg School of Medicine

Chicago, IL

Clinical Considerations in the Pre-transplant Setting

• Patients with decompensated cirrhosis have differential metabolism of drugs/metabolites that could affect efficacy and toxicity.

• Patients with decompensated disease are more susceptible to renal failure; this could cause differential metabolism of drugs/metabolites that could affect efficacy and toxicity.

• Treatment of patients may affect organ availability, as patients would NOT be eligible for HCV+ organs.

• Patients with decompensated disease may improve slightly, lowering the MELD score and thereby lowering priority for liver allocation.



HCV Management inDecompensated Cirrhosis

LDV/SOF + RBV: SVR12 in Genotype 1 or 4 with Decompensated Cirrhosis

LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks

SOLAR-1: GT 1 and 4[1.2]

100

80

60

40

20

0

SV

R12

(%

)

CTP B CTP C

87 89 86 90

26/ 30

24/ 27

19/ 22

18/ 20n/N =

100

80

60

40

20

0

SV

R12

(%

)

CTP B CTP C

8796

20/23

22/23

85

72

13/18

17/20n/N =

SOLAR-2: GT 1[3]

AE, adverse event; CTP, Child-Turcotte-Pugh; LDV, ledipasvir; RBV, ribavirin; SAE, serious adverse event; SOF, sofosbuvir.

Comparable efficacy between SOLAR-1 and SOLAR-2 studies

1. Charlton M, et al. Gastroenterology, 2015 [epub ahead of print]2. Flamm SL, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Abstract 239. 3. Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

LDV/SOF + RBV: Safety in AdvancedLiver Disease Pre OLT

• Treatment-related serious adverse events (SAEs) mostly related to RBV

• No deaths or D/C attributed to treatment with study drug (LDV/SOF)

Samuel D, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Poster P0774. SOLAR-1 and SOLAR-2

Safety Outcome, n (%) Pre-transplant CTP B + C (n = 215)

Grade 3/4 AE 51 (24)

SAE 61 (28)

Serious treatment-related AE 5 (2)

AE leading to discontinuation of LDV/SOF > 2 patients

HCCSepsis

9 (4)

2 (<1)2 (<1)

Death 10 (5)

Liver Transplantation 11 (5)



LDV/SOF + RBV: Change in MELD Score from Baseline to Follow-up Week 4 in CTP B or C Disease

*Missing FU-4: n = 24.

Pre/Post-transplantation (CTP B and C; n = 136)*

Ch

an

ge

in M

EL

D S

co

re

4

2

0

-2

-4

-6

-8

-10(-11)

(-17)

n = 18

(8)

**

*

SOLAR-2Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

Real-world Efficacy of SOF/SMV ± RBV & SOF/RBV Regimens in Cirrhosis Pts With MELD > 10

• HCV-Target Network: North America, Germany, Israel

Reddy RK, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract O007. HCV-TARGET

GT1 Naive GT 1Exp’d MELD 10-15 MELD 16-21 MELD > 21

100

80

60

40

20

0

SV

R12

(%

)

3/7 31/40 6/10

8/14 21/26 37/67 67/92 19/28

5573 6860

5768

7843

5/8 7/10 2/3

63 7067

0/1 6/6 1/1

100 100

n/N =

SOF + RBV (n = 102) SOF + SMV (n = 117) SOF + SMV + RBV (n = 34)

48/67

72

8/14 48/67 13/19

81

GT 2 GT 3

39

10/26

HCV-TARGET: SAEs, Death, Liver Transplantation

SOF/RBVN=88

SOF/SMVN=114

SOF/SMV/RBV N=32

Total N=234

Total patients with SAEs, N (%) 27 (31) 8 (7) 9 (26) 44 (17)

Hepatic decompensation* 10 (11) 2 (2) 4 (12) 16 (6)

Infections 0 2 (2) 1 (3) 10 (4)

Death 0 2 (2) 1 (3) 3 (1)

Unspecified 0 0 1 (3) 1 (0.4)

Hepatic Failure 0 1 (1) 0 (0) 1 (0.4)

Shock 0 1 (1) 0 1 (0.4)

Underwent OLT on treatment 4 (5) 3 (3) 5 (16) 12 (5)

Reddy RK, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract O007.

*Hepatic encephalopathy, variceal bleeding, hepatic failure, hepatic hydrothorax, bacterial peritonitis



Management of HCV in Decompensated Cirrhosis: Future Options

Treatment of Decompensated HCV Cirrhosis in Patients with Diverse Genotypes: 12 weeks Sofosbuvir and NS5A

Inhibitors With/Without Ribavirin

• Non-randomized observational cohort study of National Health Service of England (N = 467)

• Patients received 12 weeks SOF + LDV or DCV ± RBV at treating MD discretion (non-randomized)

Foster GR, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract O002.

DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat.

12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV

N =

100

80

60

40

20

0All GT1 GT3

SV

R1

2, %

(IT

T)

P<.05

59

43

70 71

252 28 172 15 164 21 45 5 61 7 114 7

80 71 74 73

86 81 82

60

Other GT

100

3

8589

27 13

• Treatment naïve or treatment experienced adults with any HCV genotype

• DAA failures allowed, except NS5A

• Child-Pugh score: A, B, or C• MELD scores 8-40• Hepatocellular carcinoma allowed

SOF + DCV + RBV for 12 Weeks in Patients With Genotype 1 HCV and Cirrhosis

Poordad F, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract LO8.

SV

R1

2, %

92 94

56

0

20

40

60

80

100

A B C

Child-Pugh class

All Genotypes

11/12 30/32 9/16

ALLY-1

76100

80 83100

0

20

40

60

80

100

1a 1b 2 3 4Genotype

SV

R1

2, %



European Compassionate Use Program (CUP): SOF + DCV ± RBV for 24 Weeks

• Treatment naïve or treatment experienced– CP Category: 57% CP A; 36% CP B; 6% CP C

– MELD Scores: >50% had MELD Scores ≥ 9 and < 15

• DCV dose determined by country; inclusion of RBV based on physician discretion

Welzel TM, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract P0772.

n/N =

100

80

60

40

20

0A B C

SV

R1

2, %

100 100 100

39/40

19/20

58/60

97 95 97 100 95 98

24/24

21/22

45/46

1/1 1/1 2/2

CP Score

24-wk DCV + SOF + RBV24-wk DCV + SOF All patients

Summary: Management of HCV in Decompensated Cirrhosis

• Patients with decompensated liver disease generally tolerate current regimens well, and SVR rates approach the rates observed in patients with compensated cirrhosis.

• The regimens are generally well tolerated in the decompensated population.

• New regimens will likely be available in the near future to add to our armamentarium for HCV.

– Note: Daclatasvir was approved on July 24, 2015 for use with sofosbuvirfor treatment of chronic HCV genotype 3 infection

• Ribavirin is still used in current regimens; it is reasonably well tolerated, but hemoglobin must be monitored carefully and renal dysfunction can be problematic.

AASLD/IDSA/IAS–USA: Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed June 10, 2015.Press Release. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455888.htm

HCV Management in the Post-transplant Setting



Clinical Considerations:Post-transplant Setting

• Post-liver transplantation patients with HCV recurrence may have an aggressive natural history with fibrosing cholestatic hepatitis or, more commonly, a relatively rapid progression to cirrhosis.

• The leading cause of mortality in the post-transplantation setting for HCV is recurrent HCV; hence, eradication of HCV in this population is very important.

• Post-liver transplantation patients are more susceptible to renal insufficiency; this could cause differential metabolism of drugs/ metabolites that could affect efficacy and toxicity – ribavirin may be problematic.

• Drug-drug interactions with immunosuppression agents (particularly calcineurin inhibitors) may affect dosing of anti-viral agents and the other agent.

Recommendations for Recurrent HCV Infection Post-liver Transplantation: HCV Genotype 1

AASLD/IDSA/IAS–USA: Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org.

Recommended regimen for treatment-naïve and -experienced patients with HCV genotype 1 or 4 infection in the allograft, including compensated cirrhosis

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) with weight-based RBV (1000 mg [<75 kg] to 1200 mg [≥75 kg]) for 12 weeks

Alternative regimen for treatment-naive patients with HCV genotype 1 or 4 infection in the allograft with compensated liver disease who are RBV intolerant or ineligible.

Daily fixed-dose combination of ledipasvir (90 mg)/sofosbuvir (400 mg) for 24 weeks

Alternative regimen for patients with HCV genotype 1 in the allograft, including compensated cirrhosis.

Daily sofosbuvir (400 mg) plus simeprevir (150 mg) with or without weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 kg]) for 12 weeks

Alternative regimen for patients with HCV genotype 1 in the allograft, including early (Metavir fibrosis stage F0-F2) recurrence.

Daily fixed-dose combination of paritaprevir (150 mg)/ritonavir (100 mg)/ombitasvir (25 mg) plus twice-daily dosed dasabuvir (250 mg) and weight-based RBV (1000 mg [<75 kg] to 1200 mg [>75 mg]) for 24 weeks

Prevention of Post-transplant HCV

• Entry criteria– DDLT candidates with HCV and HCC meeting MILAN criteria

– MELD <22 and HCC-weighted MELD ≥22

– CTP ≤7

• Enrollment at 16 sites across 8 UNOS regions and 2 international sites

• 61 patients enrolled

• Original protocol: 24 weeks of treatment or until LT

– Amendment: extend treatment duration to 48 weeks or LT

Curry M, et al. Gastroenterology. 2015;148:100-107.

0 12 24-48Week

pTVR12SOF 400 mg + RBV 1000‒1200 mg(n=61)



Prevention of Post-transplant HCV: On-treatment Viral Response

Curry M, et al. Presented at AASLD; November 1-5, 2013; Washington, DC. Abstract 213.

-6

-5

-4

-3

-2

-1

0BL 1 2 3 4 8

Me

an

Ch

an

ge

in

H

CV

RN

A ±

SD

(lo

g1

0IU

/mL

)

Study Week

HCV RNA Change from Baseline (n=61)

91 93

0

20

40

60

80

100

≥12 Week Treatment

Any Treatment

Pa

tie

nts

(%

)

HCV RNA <LLOQ Before Transplant

30/33 41/44

Prevention of Post-transplant HCV: Post-transplant Virologic Response

93

64

0

20

40

60

80

100

Transplant pTVR12

Vir

al R

esp

on

se R

ate

(%)

Subjects with HCV RNA <LLOQ (%)

41/44*

*3 subjects were >LLOQ at transplant.†1 subject has not reached pTVR12, 1 subject LTFU at Week 8 post-transplant.

25/39*†

Curry M, et al. Presented at AASLD; November 1-5, 2013; Washington, DC. Abstract 213.

PTV/OMB/DSB + RBV: Genotype 1 Patients After Liver Transplantation

• PTV/OMB/DSB: co-formulated paritaprevir/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID

• RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol

Kwo PY, et al. N Engl J Med. 2014;371(25):2375-2382.

Day 0 Week 24

SVR12

To Week 72

PTV/OMB/DSB + RBV

(n=34)

CORAL-I



PTV/OMB/DSB + RBV: SVR Rates in Genotype 1 Liver Transplant Patients

• No patient had breakthrough

• One patient had a relapse (post-treatment day 3)

– At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline

Kwo PY, et al. N Engl J Med. 2014;371(25):2375-2382.

100% 97% 97% 97%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

EOTR SVR4 SVR12 SVR24

CORAL-I

34/34 33/34 33/34 33/34

LDV/SOF + RBV: Genotype 1 and 4 With Advanced Liver Disease

Week 0 Week 12 Week 36Week 24

LDV/SOF + RBV

LDV/SOF + RBV

SVR12

SVR12

SOLAR-1

• Treatment naïve or experienced

• CTP Class B

• CTP Class C

• Post liver transplantation

SOLAR-2

• Treatment naïve or experienced

• CTP Class B

• CTP Class C

• Post liver transplantation

SOLAR-1 and SOLAR-2Charlton M, et al. Gastroenterology, 2015 [epub ahead of print]Reddy RT, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Abstract 8.Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

SVR12 Rates in OLT PatientsReceiving LDV/SOF + RBV

• In the 24-week arm, 8 patients with CTP B and 1 patient with CTP C have not reached the follow-up week 12 visit

• MELD scores improved from baseline through follow-up Week 4 in 15/48 patients with CTP A and 8/41 patients with CTP B disease

Charlton M, et al. Gastroenterology, 2015 [epub ahead of print]Reddy RT, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Abstract 8.

100

80

60

40

20

0F0-F3 CTP A CTP B CTP C

12 weeks LDV/SOF + RBV24 weeks LDV/SOF + RBV

96 98 96 9683

606785

SV

R12

(%

)

53/55 55/56 25/26 24/25 22/26 15/18 3/5 2/3n/N =

SOLAR-1



Overall Tx ExperiencedYes No

094/104

90%

52/60 42/44

87%95%

51/58

88%

27/28

96%

59/67 35/37

88%

19/21 8/10

Post-transplant HCV RNA Outcomes for SOF + SMV ± RBV: Genotype 1 Interim Analysis

95% 90%80%

SV

R %

20

40

60

80

100

HCV-TARGETO'Leary J, et al. Presented at: American Transplant Congress; May 2-6, 2015. Abstract 1048.

Genotype1a 1b

CirrhoticYes No

MELD< 10 ≥ 10

Clinical Considerations in Patients with Renal Impairment

Dose Adjustments in Chronic Kidney Disease

Creatinine Clearance PEG-IFN alfa 2a, μg/wk PEG-IFN alfa 2b, μg/kg/wk Ribavirin Daily

> 50 mL/min 180 1.5 1000-1200 mg/day

30-50 mL/min 180 1.125Alternating doses,

200 mg and 400 mg every other day

Less than 30 mL/min 135 0.75 200 mg/day

Hemodialysis 135 0.75 200 mg/day

AASLD/IDSA/IAS–USA: Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed June 10, 2015. See prescribing information: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

Creatinine Clearance

Sofosbuvir SimeprevirLedipasvir/ sofosbuvir

PTV/OMB/DSB

60-89 (Mild) 400 mg 150 mg 90 mg/400 mg 75/50/12.5 mg + 250 mg

30-59 (Moderate) 400 mg 150 mg 90 mg/400 mg 75/50/12.5 mg + 250 mg

15-29 (Severe) No data 150 mg No data 75/50/12.5 mg + 250 mg

<15 (Kidney failure/dialysis)

No data No data No data 75/50/12.5 mg + 250 mg



Summary

• Treatment of patients with current regimens post-liver transplantation is now possible, with very high expected SVR rates.

• Drug-drug interactions must be accounted for, particularly with protease inhibitors and calcineurin inhibitors.

• Renal insufficiency must also be accounted for, with appropriate dose modifications of anti-viral medications implemented.

Case Presentation:IFN-free Therapy in the Pre-transplant Setting

Paul Kwo, MD

Professor of Medicine

Medical Director, Liver Transplantation

Indiana University

Indianapolis, IN

Case Presentation

• A 64-year-old white male with hepatitis C genotype 1a presents to your transplant clinic with decompensated cirrhosis.

• He was recently hospitalized for spontaneous bacterial peritonitis.

• Ascites is moderately controlled with diuretics.• Encephalopathy is controlled with lactulose.• Varices have been banded.



Case Presentation

• Medications: lactulose, rifaximin, furosemide, spironolactone, trimethoprim sulfamethoxazole

• Exam: – BP: 90/60 mm Hg, pulse: 84, R: 18, temp: 37°

– HEENT: mild icterus

– Lungs : clear

– Cor: RRR, soft systolic murmur

– Abd: moderate ascites, splenomegaly

– Ext: muscle wasting, spider angiomata

– Neuro: asterixis

Database

• Hgb: 10.6 g/dL, Platelets: 55,000/mm3, WBC: 2.1 x 109/L

• TB: 3.3 mg/dL, AST: 58 IU/L, ALT: 31 IU/L• INR 1.7, Cr 1.4 mg/dL (MELD 20)• Blood group A, hepatitis C viral load 400,000

IU/mL• MRI: small nodular liver, mild ascites, patent

vessels, intra-abdominal varices

Please Select Your Approach

1. Evaluate and list for transplant with the plan to treat him post-transplantation

2. Follow patient closely3. Initiate ledipasvir/sofosbuvir with 600 mg

RBV for 12 weeks4. Initiate sofosbuvir/RBV for up to 48 weeks5. Not sure




38%

5%

52%

3% 2%0%

10%20%30%40%50%60%70%80%90%

100%

Evaluate/list fortransplant and

treat post-transplant

Follow patientclosely

Initiate LDV/SOFw/ 600 mg RBV

for 12 wks

InitiateSOF/RBV for up

to 48 wks

Not sure

Case Presentation: Discussion

Safety and Tolerability of HCV Pharmacotherapy:Focus on Drug-drug InteractionsMichael R. Charlton, MD, FRCP


Medical Director of Hepatology and Liver Transplantation

Intermountain Medical Center

Salt Lake City, UT



Safety

Paritaprevir + RTV + Ombitasvir + Dasabuvir + RBV in LT Recipients With Recurrent HCV Genotype 1 Infection

Phase 2 single-arm trial of 3D regimen for 24 weeks in 34 adult liver transplant recipients with recurrent HCV GT1 infection, fibrosis stage ≤F2, excluding post-transplant treatment experience

• Adjusted doses of TAC: 0.5 mg/week or 0.2 mg every 3 days

• Adjusted dose of CYA: 1/5th daily dose

* 4 patients experienced a TAC level > 15 ng/mL (15.7–34.0 ng/mL); All 4 patients had TAC dosing errors; 2 patients had associated creatinine increases (1.8 and 1.4 mg/dL), which normalized when dosing was corrected.

0

2

4

6

8

10

12

14

16

Tacr

olim

us C

once

ntra

tion

(ng/

mL)

*Pre-Rx on-Rx

SVR12 of 96%

Kwo P, et al. N Engl J Med. 2014;371:2375-2382.

Results: Overall Safety Summary3D Regimen

Symptom N, (%)

AEs 33 (97%)

Serious AEs 2 (6%)

Treatment discontinuation due to AE 1 (3%)

Fatigue 17 (50%)

Headache 15 (44%)

Anemia 10 (29%)

Grade 2 Anemia (Hb ≥ 8, <10 g/dL) 9 (26%)

Grade 3 Anemia (Hb < 8 g/dL) 1 (3%)

Kwo P, et al. N Engl J Med. 2014;371:2375-2382.

No on-treatment rejection

CORAL-I



Results: Overall Safety SummaryGT 1 or 4: Post-transplant F0–F3, CTP A, B, C

Charlton M, et al. Gastroenterology, 2015 [epub ahead of print].

F0-F3 CTP A CTP B CTP C

Patients, n (%)12 Wkn=55

24 Wkn=56

12 Wkn=26

24 Wkn=25

12 Wkn=26

24 Wkn=26

12 Wkn=5

24 Wkn=4

AEs 55 (100) 55 (98) 25 (96) 24 (96) 25 (96) 26 (100) 5 (100) 4 (100)

Grade 3‒4 AEs 15 (27) 14 (25) 4 (15) 7 (28) 6 (23) 9 (35) 1 (20) 1 (25)

Serious AEs 6 (11) 12 (21) 3 (12) 4 (16) 5 (19) 11 (42) 1 (20) 4 (100)

Serious and related AEs

2 (4) 1 (2) 2 (8) 2 (8) 0 1 (4) 0 0

Treatment DC due to AE

0 2 (4) 1 (4) 0 0 3 (12) 0 0

Treatment emergent Death

0 0 1 (4) 0 1 (4) 2 (8) 0 0

AE’s leading to DC: shortness of breath, hemoperitoneum, thoracic aorta aneurysm dissection, seizure, elevated ALT/AST, dyspnea

Overall Safety Summary*Results SOLAR-1 and -2 Combined

Charlton MR, et al. Presented at: DDW; May 17-19, 2015; Washington, DC. Oral Presentation 226.

*Between first dose and 30 days post-dose.

Patients, n (%)

Post-transplant

TotalN=659

F0-F3 + CTP An=330

CTP B + Cn=114

Any AE 316 (96) 109 (96) 633 (96)

Grade 3 or 4 AE 76 (23) 33 (29) 160 (24)

SAE 49 (15) 34 (30) 144 (22)

Serious treatment-related AE 10 (3) 4 (4) 19 (3)

AE leading to d/c of LDV/SOF 5 (2) 5 (4) 19 (3)

Death 4 (1) 6 (5) 20 (3)

Rejection episode 1 0 1

Graft loss 1 0 2

Liver transplantation 0 0 11

Combined SOLAR-1 and -2 Treatment-emergent Serious Adverse Events


Results

SAEs were mostly due to progression of decompensated liver disease.

Patients, n (%)Pre-transplant Post-transplant

TotalN=659

CTP B + Cn=215

F0-F3 + CTP An=330

CTP B + Cn=114

Any SAE 61 (28) 49 (15) 34 (30) 144 (22)

Anemia 4 (2) 7 (2) 3 (3) 14 (2)

Hepatic encephalopathy 10 (5) 1 (<1) 2 (2) 13 (2)

Renal failure acute 3 (1) 3 (1) 4 (4) 10 (2)

Sepsis 4 (2) 0 4 (4) 8 (1)

Ascites 4 (2) 0 2 (2) 6 (1)

Gastric variceal hemorrhage 4 (2) 1 (<1) 1 (1) 6 (1)

Diarrhea 1 (<1) 3 (1) 1 (1) 5 (1)

Pneumonia 4 (2) 0 1 (1) 5 (1)



Laboratory Values Over the First 12 Weeks of Treatment and Follow-up Week 4

Median creatinine remained at baseline levels during and after treatment


Conclusions: Safety

• 3D/RBV x 24 weeks and LDV/SOF/RBV x 12 weeks can be used safely and with high efficacy in mild fibrosis stages (F0-2) of recurrence.

• LDV/SOF/RBV x 12 weeks can be used safely and with high efficacy in moderate and severe stages of recurrence.

Drug-Drug Interactions



LDV/SOF: Metabolism

Cornpropst M, et al. Presented at: EASL; April 18-22, 2012; Barcelona, Spain. Abstract 1101; Kirby B, et al. Presented at: International Workshop on Clinical Pharmacology of Hepatitis Therapy; June 26-27, 2013; Cambridge, MA. Poster O22;HARVONI (ledipasvir and sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences; October 2014. SOVALDI (sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences; December 2013.

Sofosbuvir: 80% of dose excreted in urine (most as 007) - 007 t1/2 is 27 hours

– HD: 12-20 fold increase in 007 AUC

Ledipasvir: Primarily eliminated in feces (>70%)– Limited (<2.0%) urinary excretion– No changes in exposure with GFR <30

AUC (% increase) compared to GFR >80

Mild Moderate Severe

SOF 61% 107% 171%

331007 55% 85% 451%

AUC (% increase) when GFR <30

PAR RTV OMB DAS

Cmax 66%

AUC 45% 114% 50%

3D Regimen: Metabolism

• All components: hepatic metabolism– <2% excreted in urine

VIEKIRA PAK (ombitasvir, paritaprevir and ritonavir + dasabuvir) tablets [package insert]. North Chicago, IL: AbbVie Inc.; December 2014.

OMB:Ombitasvir, PAR: Paritaprevir, RTV: Ritonavir, DAS: Dasabuvir

Transporter-mediated Interactions

Like enzymes, transporter expression can be induced and transporter function can be inhibited.

Hepatocyte

OATP1B1 P-gp, MRP2, BCRP, BSEP



DAAs as Victims

Dick TB, et al. Hepatology. 2015. [Epub ahead of print]

(Other drugs affect DAA metabolism or transport)

MedicationDaclatasvir Ledipasvir Sofosbuvir Simeprevir

Cmax AUC Cmax AUC Cmax AUC Cmax AUC

Cyclosporine 4% 40% ND ND 154% 353% 374% 481%

Tacrolimus 7% 5% ND ND 3% 13% 79% 85%

DAAs as Culprits

Dick TB, et al. Hepatology. 2015. [Epub ahead of print]

MedicationCyclosporine Tacrolimus Sirolimus Everolimus

Cmax AUC Cmax AUC Cmax AUC Cmax AUC

Ribavirin

Ledipasvir ND ND ND ND ND ND

Sofosbuvir 27% 9% ND ND ND ND

Simeprevir 16% 19% 24% 17% ND ND ND ND

Daclatasvir 4% 3% 5% ND ND ND ND

3D Regimen 1% 482% 299% 5613% Expected increase in both Cmax and AUC.

Expected increase in both Cmax and AUC.

HCV infection inhibits cytochrome P450 through direct and indirect mechanisms. SVR leads to lower CNI levels and risk of ACR.

Effect of Proton Pump Inhibition and Juices on Gastric pH

• Gastric PH is very variable in patients who have PPI administration and giving a drug at the same time as a PPI, you'll still have a gastric pH of about 4

Abu-Sneineh A, et al. Aliment Pharmacol Ther. 2010;32(8):1023-1030.



Effect of Proton Pump Inhibition (PPI) and Juices on Gastric pH

3.3

2.3

33.37 3.38

2

3.4 3.3 3.22.93

3.3

0

0.5

1

1.5

2

2.5

3

3.5

4

pH

US Food and Drug Administration. Omeprazole Magnesium Tablets October 20, 2000. Document #NDA No. 21-229. http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3650b1a_11.pdf.

3.3

2.3

33.37 3.38

2

3.4 3.3 3.22.93

3.3

0

0.5

1

1.5

2

2.5

3

3.5

4

pH

US Food and Drug Administration. Omeprazole Magnesium Tablets October 20, 2000. Document #NDA No. 21-229. http://www.fda.gov/ohrms/dockets/ac/00/backgrd/3650b1a_11.pdf.

Gastric production falls by 96% on 60 mg/day of omeprazole It takes 3-5 days for gastric acid secretion to return to normal after discontinuation of PPI. Requires generation of new proton pumps.

Effect of Proton Pump Inhibition (PPI) and Juices on Gastric pH

Conclusions:Acid Suppression

• Stop PPIs and transfer to H2 receptor agonists when possible– PPIs often started at LTx for reasons that do

not persist (eg, MMF)

• If the patient must use a PPI, 20 mg/day equivalent of omeprazole, give with cranberry juice at same time as PPI



Renal Failure

What Do the Package Labels SayAbout Renal Impairment?

Drug/Regimen Label Language

SOF No dose adjustment for mild-moderate renal disease.

No dose recommendation can be given for eGFR <30 mL/min/1.73m2 or ESRD. Accumulation of SOF metabolite (GS-331007) up to 20x expected. Safety and efficacy not established.

LDV/SOF Same as SOF alone.

SMV No dose adjustment necessary for mild, moderate, or severe renal impairment. Not studied in patients with GFR <30 or on dialysis.

3D + RBV No dose adjustment necessary for mild, moderate, or severe renal impairment. Not studied in patients on dialysis.

RBV Moderate (30-50 mL/min): 200 mg/400 mg alternating QODSevere or HD (<30 mL/min): 200 mg QD

See individual prescribing information at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

Can SOF Be Used Effectively and Safely in Advanced Renal Disease?

• Pilot study of SOF/RBV in those with severe renal impairment (eGFR<30) or on HD– 10 non-cirrhotic GT1 or 3 subjects

Study Design

Gane EJ, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Poster 966.

Week 0 24 24

SOF 200 mg QD + RBVSOF 200 mg QD + RBVSVR12

SVR12

0 0 24 0 24

SVR12

SVR12

SOF 400 mg QD + RBV

SOF 200 mg QD + RBVSOF 200 mg QD + RBV

SOF 400 mg QD + RBV

Part 1n=20

Part 2n=20

QD: once daily; SVR12: sustained virologic response at post-treatment week 12.



SOF and 007 Plasma Exposures

Gane EJ, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Poster 966.

Label Be Damned – Real-world Experience with SOF/SMV in ESRD

• Miami: 16 patients – GFR <15 or HD

– 42% naïve, 58% cirrhotic

– SOF 200 mg QD + SMV 150 mg QD; no RBV 3 patients: SOF 400 mg QOD

with SMV

• Texas: 11 patients – GFR <30 or HD

– 82% naïve, 47% cirrhosis

– SOF 400 mg QD + SMV 150 mg QD; no RBV

– 88% on HD

Czul F, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Poster P0878.Nazario HE, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Poster P0802.

88100

9080

0

20

40

60

80

100

U Miami Texas

SVR12

1a

1b

16 11 5

SV

R12

(%)

11

3D + RBV in Treatment-naïve Patients With ESRD

20 patients enrolled; SVR4 data on 10100% SVR4

8/13 genotype 1a with RBV dose interruption

Pockros PJ, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Oral Presentation LO1.

Ombitasvir/ParitaprevirRitonavir + Dasabuvir

Ombitasvir/ParitaprevirRitonavir + Dasabuvir + RBV



Grazoprevir/Elbasvir in ESRD

• GZR/EBR: both <1% renal elimination

– No dose adjustment needed

• 81% CKD stage 5 (GFR <15 or HD)

94% SVR12

Roth D, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Poster LP02.

GZR: HCV NS3/4A inhibitorEBR: HCV NS5A inhibitor

Conclusions:Post-transplant Renal Insufficiency

• In patients with recurrent HCV post transplantation and GFR > 30 mL/min, prescribe normally for DAAs

• In patients with recurrent HCV post transplantation and GFR ≤ 30 mL/min:– Consider 3D, if compensated liver disease

– Use SOF-based regimens with caution

• For RBV in moderate (GFR 30-50 mL/min): 200 mg/400 mg alternating QOD

• For RBV in severe or HD (<30 mL/min): 200 mg QD

Case Presentation:IFN-free Therapy in the Post-transplant Setting

Paul Kwo, MD



Indiana University

Indianapolis, IN



Case Presentation

• A 61-year-old African-American woman with hepatitis C genotype 1b is seen in the post-transplant clinic

• She was transplanted for HCV cirrhosis with a 3.5 cm hepatoma

• Her postoperative course was unremarkable

• She returns for 6-month visit

Case Presentation

• Medications: Tacrolimus 1 mg BID, trimethoprim sulfamethoxazole, metoprolol 50 mg BID

• Exam: BP: 130/60 mm Hg, pulse: 64, R: 18, temp: 36°

• HEENT: Normal• Lungs : Clear• Cor: RRR• Abdominal: Subcostal scar – well healed

Database

• Hgb: 11.2 g/dL, Platelets 155,000/mm3, WBC: 2.9 x 109/L

• TB: 1.8mg/dL, AST: 98 IU/L, ALT: 131 IU/L• INR: 1.0, Cr: 1.4 mg/dL• Hepatitis C viral load > 170,000,000 IU/mL• CT: Transplanted liver, mild residual

splenomegaly, no varices, no recurrent hepatoma



Please Select Your Next Step

1. Staging liver biopsy and treat if > F2 fibrosis

2. Elastography and treat if > 9 kPa3. See patient back at 1 year4. Initiate therapy for hepatitis C5. Not sure


13% 12%

1%

73%

1%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Staging liverbiopsy - treat

if >F2

Elastography -treat if >9 kPa

See patientin 1 year

Initiate Tx forHCV

Not sure




Please Select Your Therapy of Choice

1. Sofosbuvir 400 mg + ribavirin 1000-1200 mg daily

2. Ledipasvir / sofosbuvir for 24 weeks

3. Ledipasvir / sofosbuvir / ribavirin 600 mg for 12 weeks

4. Ombitasvir, paritaprevir, ritonavir / dasabuvir / ribavirin 600 mg for 24 weeks

5. Something else


8%

21%

56%

15%

0%0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

SOF 400 mg/RBV 1000-1200

mg daily

LDV/SOF 24weeks

LDV/SOF/RBV600 mg

for 12 weeks

OMB/PTV/rDSB/RBV 600

mg for 24 weeks

Something else




What if…

• Her hemoglobin was 9 g/dL?

What if…

• She had genotype 2 infection?

What if…

• She had genotype 3 infection?



Fibrosing Cholestatic Hepatitis C

• What if she presented at month 6 with ascites and bilirubin of 17 mg/dL, alkaline phosphatase of 400 IU/mL with liver biopsy showing fibrosing cholestatic hepatitis?

• If she cleared virus and was still further decompensated, would you evaluate for repeat transplant?

HCV and Nonhepatic Solid Organ Transplant: Focus on Renal, Heart, and Lung Transplant

Paul Y Kwo, MD



Gastroenterology/Hepatology Division

Indiana University School of Medicine

HCV and Renal Disease

• HCV infection may lead to renal disease or be associated with renal disease

• Mixed cryoglobulinemia (type II cryoglobulins, or + RF)• Membranoproliferative glomerulonephritis (MPGN)• Polyarteritis nodosa

• Less common– Focal segmental glomerular sclerosis – Proliferative glomerulonephritis– Membranous GN – Fibrillary and immunotactoid glomerulopathies

• Diabetes (direct link to HCV) and hypertension common in HCV infection

Fabrizi F, et al. Expert Opin Pharmacother. 2015;16(12):1815-27.



Dose Adjustments in Chronic Kidney Disease

AASLD/IDSA/IAS–USA: Recommendations for testing, managing, and treating hepatitis C. http://www.hcvguidelines.org. Accessed June 10, 2015.See prescribing information: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

Creatinine Clearance PEG-IFN alfa 2a, μg/wk PEG-IFN alfa 2b, μg/kg/wk Ribavirin Daily

> 50 mL/min 180 1.5 1000-1200 mg/day

30-50 mL/min 180 1.125Alternating doses,

200 mg and 400 mg every other day

Less than 30 mL/min 135 0.75 200 mg/day

Hemodialysis 135 0.75 200 mg/day

Creatinine Clearance

Sofosbuvir SimeprevirLedipasvir/ sofosbuvir

PTV/OMB/DSB

60-89 (Mild) 400 mg 150 mg 90 mg/400 mg 75/50/12.5 mg + 250 mg

30-59 (Moderate) 400 mg 150 mg 90 mg/400 mg 75/50/12.5 mg + 250 mg

15-29 (Severe) No data 150 mg No data 75/50/12.5 mg + 250 mg

<15 (Kidney failure/dialysis)

No data No data No data 75/50/12.5 mg + 250 mg

No dosage adjustment of daclatasvir is required for patients with any degree of renal impairment.

Total Kidney Transplants

SRTR Report 2012. Am J Transplant. 2014;14 Suppl 1:5-192. Reprinted with permission.

All

Deceased Donor

Living Donor

20

15

10

5

098 00 02 04 06 08 10 12

Year

Tra

nspl

ants

(in

Tho

usan

ds)

Adult Kidney Donor-recipient Hepatitis C Serology Matching, 2008–2012

SRTR Report 2012. Am J Transplant. 2014;14 Suppl 1:5-192.

Deceased Donor Living Donor

Recipient Neg. Pos. Unk. Total Neg. Pos. Unk. Total

Negative 90.5 0.2 0.0 90.7 87.3 0.2 6.8 94.2

Positive 4.3 2.0 0.0 6.3 2.1 0.0 0.2 2.3

Unknown 2.9 0.1 0.0 3.0 2.1 0.0 1.4 3.5

Total 97.7 2.3 0.0 100 91.5 0.2 8.3 100



Shorter Waiting Times for HCV+ Patients Who Accept HCV+ Donor Kidney

Waitlist times for patients accepting HCV+ grafts was 318 days(for R+/D+ patients) versus 613 days (R−/D−) or 570 days (R+/D−)

Scalea JR, et al. Transplantation. 2015;99:1192-1196. Reprinted with permission.

n=195, R+D+

n=1418, R-D-

n=66, R+D-R+D+ vs R+D-, P≤.001R-D- vs R+D-, P=.005R+D+ vs R-D-, P=.06

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

Post Transplant Years

Dea

th C

enso

red

Gra

ft S

urvi

val

0 1 2 3 4 5 6 7 8 9 10

Graft Survival (death-censored)

Renal Transplant Patients

• Renal transplantation is associated with a 68% reduction in long-term mortality compared to remaining on the waiting list

• Lower rate of hepatic fibrosis progression post renal transplant than prior to renal transplant (mean change in fibrosis 0.28±0.64 vs 0.04±0.26 per year (P=.08)

Roth D, et al. J Am Soc Nephrol. 2011:22:1152-1160. Reprinted with permission.

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Months Since Listing

Cu

mu

lativ

e H

aza

rd

0 12 24 36 48 60 72 84 96 108 120

Transplant Occurred During the Past 6 Months(N=110, 9 Deaths, P=.02 vs PretransplantPretransplant (N=175, 28 DeathsTransplant Occurred Greater than 6 Months Ago(N=95, 27 Deaths, P=.01 vs Pretransplant

HCV infection is associated with lower graft and recipient survival

Graft Survival

Patient Survival

Graft and Recipient Survival

HCV: Virologic Status of Renal Transplant Recipients

Gentil MA, et al. Nephrol Dial Transplant. 1999;14:2455-2460. Reprinted with permission.

100

90

80

70

60

50

40

30

20

10

0

Survival Time (Years)0 1 2 3 4 5 6 7 8 9 10

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5 6 7 8 9 10

Log-rank P=.007 Log-rank P=.006

HCV+-

HCV+-



Total Heart Transplants: 2012

SRTR 2012 Annual report. Am J Transplant. 2014;14 Suppl 1:13-38. Reprinted with permission.

2,500

2,000

1,500

1,000

500

0

98 00 02 04 06 08 10 12

Year

Tra

nspl

ants

Heart Transplant

• SRTR database review 1993-2007

• 443 HCV-positive and 20,244 HCV-negative heart recipients

• Mortality rates were higher among HCV-positive heart transplant recipients at 1 year, 5 years, 10 years, and 15 years post-transplantation

Lee I, et al. J Heart Lung Transplant. 2011;30:1266 –1274.

Total Lung Transplants

SRTR 2012 Annual report. Am J Transplant. 2014;14 Suppl 1:39-65. Reprinted with permission.

Single

All Lung (Including HL)

Bilateral

2,000

1,500

1,000

500

0

98 00 02 04 06 08 10 12

Year

Tra

nsp

lan

ts

98 00 02 04 06 08 10 12

Year

Retransplant

First Transplant



Lung Transplants

• UNOS database 1987-2011

• 289 HCV-positive recipients

• Survival was significantlylower in HCV-positiveindividuals(median survival:3.8 vs 5.1 years;P=.005)

Englum BR, et al. J Heart Lung Transplant. 2014:53;S182-S183. Reprinted with permission.

1.0

0.8

0.6

0.4

0.2

0.0

Years

Sur

viva

l Pro

babi

lity

0 2 4 6 8 10

HCV- RecipientHCV+ Recipient

HCV – Recipient 16380 9194 5919 3647 2156 1155HCV+ Recipient 289 158 93 50 24 9

Kaplan-Meier Survival Curves for HCV+vs. HCV- Lung Transplant Recipients

What About our Current Therapies?

Drug-Drug Interactions

TAC CYA Sirolimus Everolimus MMF AZA

Ribavirin

Sofosbuvir

Ledipasvir P P

Simeprevir Contraindicated P P

Paritaprevir/Ombitasvir/Dasabuvir

YReduce TAC

to 0.5 weekly

YReduce CYA to

1/5th of dose

P Contraindicated P

Daclatasvir P

Liverpool HEP iChart.

= No clinically significant interaction or no interaction expectedY= Interaction, adjustment requiredP = Potential interaction, monitor/adjust drug level



PTV/OMB/DSB + RBV: SVR Rates in Genotype 1 Liver Transplant Patients

• No patient had breakthrough

• 1 patient had a relapse (post-treatment day 3)

– At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in

NS5A, and G554S+G557R in NS5B, none of which were present at baseline

Kwo PY, et al. N Engl J Med. 2014;371:2375-2382.

100% 97% 97% 97%

0%

20%

40%

60%

80%

100%

EOTR SVR4 SVR12 SVR24

CORAL-I

34/34 33/34 33/34 33/34

PEARL-III: SVR12 and Virologic Failure Rates With 3D Regimen + RBV in HCV Genotype 1b

Ferenci P, et al. Presented at EASL; London, England; April 9-13, 2014. Abst. P1299.

0

20

40

60

80

100

Pa

tient

s (%

)

3D Regimen ± RBV

No RBV(n=209)

With RBV(n=210)

99%

0.5%

99%

SVR12

0%

No RBV(n=209)

With RBV(n=210)

Virologic Failure

SOLAR-1 and SOLAR-2: Genotype 1 and 4 With Advanced Liver Disease

Reddy RT, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Abstract 8.Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

Week 0 Week 12 Week 36Week 24

LDV/SOF + RBV

LDV/SOF + RBV

SVR12

SVR12

SOLAR-1Treatment naïve or experiencedCTP Class BCTP Class CPost liver transplantation

SOLAR-2Treatment naïve or experiencedCTP Class BCTP Class CPost liver transplantation



SOLAR-1: SVR12 Rates in OLT Patients Receiving LDV/SOF + RBV

Reddy RT, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Abstract 8.

• In the 24-week arm, 8 patients with CTP B and 1 patient with CTP C have not reached the follow-up week 12 visit

• MELD scores improved from baseline through follow-up Week 4 in 15/48 patients with CTP A and 8/41 patients with CTP B disease

100

80

60

40

20

0F0-F3 CTP A CTP B CTP C

12 weeks LDV/SOF + RBV24 weeks LDV/SOF + RBV

96 98 96 9683 60

6785

SV

R12

(%

)

53/55

55/56

25/26

24/25

22/26

15/18

3/5

2/3n/N =

Sofosbuvir (SOF) +Daclatasvir (DCV) +RBV 600 mg 12 weeks

aHCV RNA < LLOQ(25 IU/mL); error bars reflect 95% confidence intervals.

SV

R12

, %a

Genotype 1 Primary Endpoint

All Patients

94 95

0

20

40

60

80

100

Follow-upDCV 60 mg QD +SOF 400 mg QD + RBV

Week 0 Week 24SVR12a

Week36

Week 12

Post-liver transplant

N = 53

Poordad F, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract LO8.

Preliminary DataPost Renal Transplant

• Retrospective chart review of all kidney transplant recipients treated with DAAs from September 2013 – November 2014 at Indiana University with follow up data up to April 30, 2015– Sofosbuvir (SOF) + Ribavirin (RBV) = 4

– SOF + Simeprevir (SMV) = 6

– SOF + SMV + RBV = 1

– SOF + Ledipasvir (LDV) = 1

• All receiving tacrolimus based immunosuppression

• 11/12 achieved SVR

• No change in Cr levels or tacrolimus levels

Sharfuddin, et al. Presented at: ATC; Philadelphia, PA; May 5, 2015. Abstract 3034.



Hepatitis C and Nonhepatic Solid Organ Transplant

• There are all-oral DAA therapies for heart, lung, and kidney recipients

• Must be aware of drug-drug interactions

• Dose adjust for GFR

• Genotype 1, 4: SOF/LDV±RBV, SOF/DCV±RBV, PTV/OMB/DSB/RBV, SOF/SMV±RBV

• Genotype 2, 3: SOF/RBV, SOF/DCV±RBV

Documents

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