Patients with Cirrhosis: Managing the HCV Peri-Transplant ...1950 1960 1970 1980 1990 2000 2010 2020...

Patients with Cirrhosis: Managing the

HCV Peri-Transplant Patient Fred Poordad, MD Professor of Medicine

University of Texas Health Science Center

VP, Academic and Clinical Affairs

The Texas Liver Institute

San Antonio, TX

Disclosures

• Grant/Research support: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ZymoGenetics

• Speaker: Gilead, Kadmon, Janssen, Merck, Onyx/Bayer, Genentech, Salix and Vertex

• Consultant/Advisor: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen, Theravance and Vertex.

Hepatitis C is the Leading Cause for Liver Transplant in the US

Berg et al. Am J Transplant. 2009;9(part 2):907.

160,000

140,000

120,000

100,000

80,000

60,000

40,000

20,000

0

1950 1960 1970 1980 1990 2000 2010 2020 2030

Year

Hepatocellular cancer

Decompensated cirrhosis

Nu

mb

er

of

Ca

se

s

Curves indicate gender and age at time of initial HCV infection. Data are for the United States.

Davis et al. Gastroenterology. 2010;138:513.

Numbers of HCV Patients With Decompensated Cirrhosis

and HCC Are Expected to Peak in 2020 in the US

• Increasing prevalence of decompensated cirrhosis and HCC could increase number

of patients on liver transplant waiting list

Ba

se

20

10

co

st

($/p

ati

en

t/ye

ar)

Summary of Studies Reporting Incremental Cost by Sequela (In 2010 US $)a

Costs of Liver Transplant Much Higher Than Costs

of Less Advanced Sequelae for Hepatitis C

aStudies use a patient cohort model to estimate total cost using cost and transition probability for each sequela.

El Khoury et al. J Viral Hepat. 2012;19:153.

UK

$97,040 ($52,490-$164,390)

United States $201,110 ($173,760- $223,460)

Brazil

$64,170

Japan

$163,140 ($74,920-$299,690)

Australia

$132,040 ($127,920-$136,170)

Taiwan

$23,150 ($15,430-$30,860)

Canada

$113,280 ($61,490-$165,070)

New Zealand

$82,530

Spain

$253,460 ($132,260-$443,700)

The lowest transplantation costs have been reported in Taiwan and the highest in Western Europe

El Khoury et al. J Med Econ. 2012;15:887.

Costs of Liver Transplants Vary Around the World

Potential Transplant Need

Nu

mb

er

of

Pers

on

s

20,000

0 5 10 15 20 25 30

40,000

60,000

80,000

100,000

120,000

140,000

160,000

180,000

0

Year in Model

18,193 25,573 27,175 26,207 24,258 21,994

49,013

91,310

126,296

150,617

162,559 162,747

No treatment 25% 50% 75% treated All treated

Desai et al. The Liver Meeting 2013. Abstract 1427.

Widespread Use of Effective Therapy Could Significantly Reduce Need for Transplants

HCC

ESLD

Incidence rate ratioa for HCC: 1.118 (95% CI, 1.107–1.130); P<0.001

10

12

8

6

4

2

0 2003

Ad

juste

da I

R p

er

10

0,0

00

2004 2005 2006 2007 2008 2009 2010

aAdjusted for age and sex.

Fleming et al. The Liver Meeting 2013. Abstract 12.

Numbers of HCV Patients on Liver Transplant:

HCC Numbers Have Nearly Doubled Since 2007

• The number of HCV patients wait-listed for HCC has risen by 12% per year on average (from 623

in 2003 to 1379 in 2010, or from 2.1 to 4.6 per 100,000)

• In contrast, wait-listing due to end-stage liver disease (ESLD) has remained relatively stable over

the study period (0.7% rise, from 1451 to 1674, or from 4.8 to 5.6 per 100,000)

Pre-Transplant Therapy

pTVR12 SOF 400 mg + RBV 1000‒1200 mg (n=61)

• N=61 DDLT candidates with MELD exception for HCC

– Genotypes 1-4

– CPT ≤7 (43% CP=5)

– Median MELD =8 (8-14)

– CrCl ≥60 mL/min

– Rx-naïve (25%) or experienced (75%)

– Absence of HIV or HBV

Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation

SOF + RBV to Prevent HCV Recurrence Post-LT

• On-treatment HCV RNA suppression was rapid and similar to other patient populations on SOF

regimens

• Treatment with SOF + RBV was generally safe and well tolerated

Vir

al

Resp

on

se

Rate

(%

)

*3 subjects were >LLOQ at transplant †1 subject has not reached pTVR12, 1 subject lost to follow up at Week 8 post transplant


Virological Response

SOF + RBV to Prevent HCV Recurrence Post-Transplant

Analysis of Post-Transplant Recurrence in GT 1–4

Days HCV RNA Continuously TND Prior to Transplant

No Recurrence (n=29) Recurrence (n=10)

Median days TND

• No recurrence: 99

• Recurrence: 5.5

p <0.001*

No recurrence in 24/25 (96%) of

patients who maintained HCV RNA

TND >28 days

28

*Wilcoxon rank sum test.


SOF + RBV

n=25

Observation

n=25

Male, n (%) 18 (72) 20 (80)

Median age, y (range) 56 (43‒69) 55 (44‒69)

BMI ≥30 kg/m2, n (%) 8 (32) 7 (28)

Mean HCV RNA, log10 IU/mL (range) 6.1 (4.4‒7.0) 6.1 (3.8‒6.9)

GT, n (%)

1a 10 (40) 9 (36)

1b 9 (36) 6 (24)

2 2 (8) 1 (4)

3 2 (8) 8 (32)

4 2 (8) 1 (4)

IL28B non-CC, n (%) 22 (88) 18 (72)

Prior HCV treatment, n (%) 17 (68) 23 (92)

Mean HVPG mmHg, n (range) 16.9 (9‒29) 16.2 (7‒27)

HVPG >12 mmHg, n (%) 19 (76) 20 (80)

SOF 400 mg + RBV

1000‒1200 mg

SVR12

Observation SOF 400 mg + RBV

1000‒1200 mg

SVR12

Arm 1

n=25

Arm 2

n=25

Wk 0 Wk 24 Wk 48 Wk 96 Wk 72

Preliminary results

Afdhal N, EASL, 2014, O68

SOF+RBV for Chronic HCV with Cirrhosis and Portal HTN

± Decompensation

• Randomized, open-label, safety and efficacy study of SOF+RBV for 48

weeks compared to observation for 6 months in patients with HCV cirrhosis

and portal HTN (CTP 5–9)

HC

V R

NA

< L

LO

Q (

%)

Week *1 patient was a non-responder at Week 8.


Virologic Response

Ascites Hepatic Encephalopathy

Patients, n

SOF + RBV

n=25

Observation

n=25

SOF + RBV

n=25

Observation

n=25

Baseline 6 9 5 2

Week 12 5 8 3 3

Week 24 0 7 0 4

Platelets (103/µL) Albumin (g/dL)

SOF+RBV Observation 24 weeks

ALT (U/L)

CTP A CTP B

p=0.003

p=NS

p=0.001 p=0.001


Laboratory and Clinical Event Changes

Post Transplant Therapy

SOF Compassionate Use Program SOF+RBV±PEG

n=104

Severe acute hepatitis/early recurrence (<12 months from liver transplant with typical

biochemical and histological findings) n=48

Post transplant compensated and decompensated cirrhosis [liver biopsy

(F4) or clinical decompensation] n=56

Completed 24-48 weeks treatment

N=72

Death N=13

Liver transplant n=12

Discon due to AE n=7

Forns, et al. EASL 2014

Sofosbuvir Compassionate Use Program: Patient Disposition

Demographics Overall

(n=104)

Male, n (%) 76 (73)

Median age, y (range) 55 (16-76)

Median HCV RNA, log10 IU/mL (range) 8.4 (1.3-8.9)

GT, n

1/1a/1b 8/29/51

2/3/4 1/7/8

Median bilirubin, mg/dL (range) 3.1 (0.4-45)

Median albumin, g/dL (range) 3.1 (1.3-12.2)

Median INR (range) 1.3 (0.8-4.5)

Median ALT, IU/L (range) 71 (8-1162)

Median platelets, x103/µL (range) 78 (19-340)

Median MELD (range) 15 (6-43)

Median months from LT to treatment (range) 17 (1-262) Forns, et al. EASL 2014

Results: Baseline Characteristics

Patients were excluded from this analysis if received a liver transplant (n=8 at EOT; n=12 at SVR12)


Results: Overall Virologic Response

81/93 53/85

0

20

40

60

80

100

EOT SVR12

Lost to follow-up

Death

HCV RNA>LLOQ

HCV RNA <LLOQ

53/85 81/93

Pati

en

ts (

%)

8/93

4/93

15/85

13/85

4/85

Results: Overall Virologic Response


• All patients who received ≥1 dose of SOF are included

21 21

100

80

60

40

20

0

Improved* Stable Worsened/Deceased

60/104 22/104 22/104

Pati

en

ts (

%)

*Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-

related laboratory values.


62

Results: Clinical Outcomes

12

10

8

6

4

2

0

Baseline EOT FU Wk12

0

0.5

1

1.5

2


5

4

3

2

1

0


Bil

iru

bin

(mg

/dL

)

Alb

um

in (

g/L

)

INR

25

20

15

10

5

0

Baseline EOT FU Wk12 M

EL

D


Results: Laboratory Tests (Median and Interquartile Ranges)

0 24 Study Week

SOF 400 mg + RBV 400–1200 mg SVR 12 TN & TE with

recurrent HCV N=40

Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels

Samuel D, EASL, 2014, P1232

SOF+RBV for Established Recurrent HCV Post-Liver Transplant

Study inclusion criteria

– Liver transplant ≥ 6 months and ≤ 150 months

– CTP ≤ 7 and MELD ≤ 17

Exclusion: Prednisone >5 mg/day

Key baseline characteristics

– 55% GT1a, 28% GT1b, 15% GT3, 3% GT4

– 88% treatment experienced (23% PI/PEG/RBV failures)

– 40% F4 cirrhotic

40/40 40/40 29/40 28/40 28/40


Virologic Response

• Relapse was not influenced by RBV dose or exposure

• No TAC or CsA toxicities or drug interactions were observed - 4 patients increased TAC dosing due to

improved liver function

Adverse Events, n (%)

SOF + RBV,

N=40

SAEs* 6 (15)

AEs that led to D/C of study treatment† 2 (5)

AEs in ≥ 15% of patients

Fatigue 12 (30)

Diarrhea 11 (28)

Headache 10 (25)

Arthralgia 9 (23)

Nausea 8 (20)

Anemia 8 (20)

Cough 7 (18)

Grade 3 and 4 Lab Abnormalities, n (%)

SOF + RBV,

N=40

Overall Grade 3 11 (28)

Overall Grade 4 11 (28)

Lymphocytes (5 G3; 9 G4) 13 (33)

Hemoglobin (G3) 8 (20)

Hyperglycemia (3 G3; 1 G4) 4 (10)

White blood cell count (G3) 3 (8)

Hyperbilirubinemia (G4) 1 (3)

Lipase (G4) 1 (3)

Neutrophils (G3) 1 (3)

AST (G3) 1 (3)

Adverse Events and Lab Abnormalities

*All SAEs assessed as unrelated to SOF: ascites, pyrexia (2 cases), jaundice, pneumonia, urinary tract infection, hemarthrosis,

osteoporotic fracture, confusion, hallucination; †Recurrence of hepatocellular carcinoma and pneumonia.

AST, aspartate aminotransferase; DC, discontinuation; G, grade; SAE, serious adverse event.


Day 0 Week 24

SVR12

To Week 72

3D + RBV (N=34)

Kwo, et al. EASL 2014

ABT-450/r/ABT-267 + ABT-333 + Ribavirin in Liver Transplant Recipients With Recurrent HCV

• 3D: co-formulated ABT-450/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


Calcineurin Inhibitor (CNI) Dosing With 3D Regimen

• A phase 1 drug-drug interaction study demonstrated that dosing tacrolimus

(TAC) or cyclosporine (CYA) with the 3D regimen compared to either alone

resulted in a

– 7-fold increase in TAC half-life

– 3-fold increase in CYA half-life

• Based on these findings, recommended dosing during 3D treatment was

– TAC

• 0.5 mg once weekly or

• 0.2 mg every 3 days

– CYA

• 1/5 of the daily pre-3D treatment dose given once daily


Eligibility Criteria

• 18 to 70 years of age, inclusive

• HCV GT1 infection

• Liver transplantation due to HCV infection >12 months before screening

• Treatment-naïve after transplantation

– PegIFN/RBV treatment prior to transplantation was permitted

• Screening liver biopsy-confirmed Metavir score <F2

• No history of steroid-resistant rejection

• Receiving a stable TAC- or CYA-based immunosuppressant regimen

– Prednisone use permitted at doses ≤5 mg/day

– Use of mTOR inhibitors not permitted

3D + RBV (N=34)

Mean time since transplantation, months 47.9

Male (%) 79.4

Black/white race (%) 11.8 / 85.3

Hispanic or Latino ethnicity (%) 17.6

Mean age (years) 59.6

Mean BMI (kg/m2) 29.7

Fibrosis stage (%)

F0-F1/F2 53 / 47

IL28B non-CC (%) 76.5

HCV subtype (%)

GT1a/GT1b 85.3 / 14.7

Mean HCV RNA (log10 IU/mL) 6.6

Immunosuppressive medication (%)

Tacrolimus/cyclosporine 85.3 / 14.7

Mean creatinine clearance (mL/min) 90.5

Mean creatinine (mg/dL) 1.1

Mean ALT/AST/GGT (U/L) 78.9 / 63.9 / 170.3

Baseline Patient Characteristics


No patient had breakthrough; One patient had a relapse (post-treatment day 3)


Preliminary Efficacy Results %

Pati

en

ts

34/34

97.0%

34/34

96.2%

32/33 25/26

SVR4 SVR12 RVR (Week 4)

EOTR (Week 24)

100% 100%

Adverse Events Occurring in >15% of Patients

Event, n (%)

3D + RBV (N=34)

Any AE 33 (97.1)

Headache 15 (44.1)

Fatigue 14 (41.2)

Cough 10 (29.4)

Insomnia 9 (26.5)

Asthenia 8 (23.5)

Diarrhea 8 (23.5)

Nausea 8 (23.5)

Rash 7 (20.6)

Anemia 6 (17.6)

Dizziness 6 (17.6)

Muscle spasms 6 (17.6)

Pyrexia 6 (17.6) Kwo, et al. EASL 2014

• No episodes of acute or chronic

rejection

• 1 patient discontinued study drug due to

AEs (moderate rash, memory

impairment, and anxiety) after week 18

– Patient achieved SVR12

• 2 patients had serious AEs

– Hypotension and tachycardia associated

with initiation of tamsulosin after elective

surgery

– Moderate peripheral edema and pain in

extremity in a diabetic patient with history of

peripheral edema

Event, n (%)

3D + RBV

(N=34)

<LLN-10.0 g/dL (Grade 1) 12 (35.3)

<10.0-8.0 g/dL (Grade 2) 8 (23.5)

<8.0-6.5 g/dL (Grade 3) 1 (2.9)

<6.5 g/dL (Grade 4) 0

• 5 patients received erythropoietin at investigator discretion

• No patient underwent transfusion

• No patient discontinued study drugs due to anemia


Hemoglobin Effect

RBV total daily dose (mg), n (%)

Baseline

(N=34)

End of Treatment

(N=34)

400 3 (8.8) 4 (11.8)

600 to 800 19 (55.9) 25 (73.5)

1000 to 1200 12 (35.3) 5 (14.7)

• 600 to 800 mg daily was the most frequent RBV dosage

both at baseline and end of treatment

3D + RBV


Ribavirin Dose Modifications

• Ctrough levels were comparable pre-

treatment and on-treatment

• TAC dose was 0.5 to 1.0 mg at 1-2

week intervals for most patients

• 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

Pre-Treatment On-Treatment

(Treatment Weeks 1-4)

Ta

cro

lim

us

Co

nc

en

tra

tio

n (

ng

/mL

)

16

14

12

10

8

6

4

2

0


Pre-Treatment and On-Treatment Tacrolimus Ctrough Concentrations

• CYA levels were

maintained within the

desired range with the

recommended dosing

regimen (N=5 patients)

• On-treatment CYA dose

was 1/5 of the pre-

treatment dose in these

patients

Pre-Treatment On-Treatment

Cyc

los

po

rin

e

Co

nc

en

tra

tio

n (

ng

/mL

)

200

150

100

50


Pre-Treatment and On-Treatment Cyclosporine Ctrough Concentrations

Future Therapies

HC

V R

NA

<L

LO

Q

Pa

tie

nts

, %

Patients Achieving SVR12

14

16

15

15 12

14

14

14 41

41

39

41

15

15 14

14

21

21

19

20

GT2/3 GT1a/1b

Treatment-naive;

24 wk of treatment Treatment-naive;

12 wk of treatment

Prior PI failures;

24 wk of treatment

Sulkowski et al. N Engl J Med. 2014;370:211.

DCV+SOF: A1 444-040 Study Shows High SVR Rates in Multiple Genotypes

• Safety Highlights

– DCV + SOF has an acceptable tolerability profile

• Only 2/211 (<1%) patients receiving SOF + DCV with and without RBV discontinued therapy due to adverse events

• The most common adverse events were fatigue (29%-50%), headache (16%-38%), and nausea (10%-32%), which were mild-to- moderate

LI SOF

+DCV

DCV

+SOF

DCV

+SOF

+RBV

LI SOF

+DCV

DCV

+SOF

DCV

+SOF

+RBV

DCV

+SOF

DCV

+SOF

+RBV

DCV +SOF DCV +SOF

+RBV

Pre-transplant (n=60)

Post-transplant (n=50)

DCV 60 mg QD + SOF

400 mg QD

24-wk follow-up DCV 60 mg QD +

SOF 400 mg QD

Therapy up to 12 wk

Study Week 24 0 12 36

3 mo – 12 y

SVR12

24-wk follow-up

OR Transplant 24-wk follow-up

AI444-215.

www.ClinicalTrials.gov/ct2/show/NCT02032875.

DCV + SOF: ALLY 1 Cirrhosis and Post-Transplant Study Design

• Objective: Assess the efficacy and safety of DCV 60 mg QD + SOF 400 mg

QD in treatment-naive or -experienced GT1–6 patients with advanced liver

disease awaiting liver transplantation, or with recurrent HCV post-transplant

• Primary end point: SVR12

• Objective: Assess the effect of DCV + SMV on the pharmacokinetics of cyclosporine

and tacrolimus and the efficacy and safety of DCV + SMV + RBV in post–orthotopic

liver transplantation participants with recurrent HCV genotype 1b infection

• Primary end point: SVR12

• Inclusion criteria – Liver transplant between 6 months and 10 years prior to screening visit

– Screening HCV RNA level >10,000 IU/mL

– No post–orthotopic liver transplant anti-HCV treatment

– Receiving stable immunosuppressant therapy with cyclosporine or tacrolimus for >3 months prior to the screening visit

Week 24 SVR12

Part 1: DCV + SMV + RBV Follow-up

Part 2: DCV + SMV + RBV Follow-up

Recurrent HCV

GT 1b (n=40)

Metavir Score

F1-F2

F1-F4

SMV = simeprevir.

NCT01938625; http://clinicaltrials.gov/ct2/show/study/NCT01938625.

Study Design of DCV + SMV + RBV

Conclusion

• Peri-transplant patients are an important group of

HCV patients, although small in numbers overall

• Eradication in this population will “free up” organs

for other liver indications

• IFN no longer has an indication in this population

• Multiple all oral therapies appear effective

Patients with Cirrhosis: Managing the HCV Peri-Transplant ...1950 1960 1970 1980 1990 2000 2010 2020...

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