hcv treatment: before or after liver...

HCV TREATMENT:

BEFORE OR AFTER LIVER

TRANSPLANTATION?

The XI International Conference «White Nights of Hepatology 2017» EASL

Saint Petersburg , June 8 - 9 2017

Elena N. Bessonova Ph.D Sverdlovsk Regional Hepatological Center

SBHCE «Sverdlovsk Regional Clinical Hospital №1»

Ekaterinburg, Russia

INTRODUCTION

• HCV infection is the leading indication for liver transplantation throughout the world1

• Approximately 5,000 liver transplantations are performed annually in the USA, with 40% due to HCV-related cirrhosis2 in adults

• Patients who undergo liver transplantation with detectable HCV RNA levels will inevitably experience graft infection3

• Recurrence of HCV accounts for the majority of post-liver transplant deaths and for two-thirds of graft rejections4

• HCV-positive transplant recipients have a shorter survival than other recipients4

• Cirrhosis related to HCV occurs in 20–30% of transplant patients within 5 years of receiving liver graft5

1. Charlton M, et al. Liver Transpl 2004;10:1120–30

2. Wiesner RH, et al. Liver Transpl 2003;9:S1–9; 3. Garcia-Retortillo M, et al. Hepatology 2002;35:680–7

4. Berenguer M, et al. Heptology 2000;32:673–84; 5. Berenguer M. Curr Opin Organ Transplant 2005;10:81–89

73

86 85 83 83

92

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

HBV

HCV

Alcohol

years

Surv

ival (

%)

81

67 69

64 59

83 80 77

72 69

Cholestatic/AIH

70 72

HCV

Recipients with HCV have lower 5 year survival

Forman LM, et al. Gastroenterology. 2002;122:889-896.

Cryptogenic

After Liver Transplantation survival

Liver

Transplantation

Waiting List

Patients with

HCV

HCV Treatment

HCV infection

recurrence After

Liver

Transplantation

HCV TREATMENT

BEFORE LIVER TRANSPLANTATION

The aim of HCV infection treatment in decompensated cirrhosis before liver transplantation

To prevent HCV recurrence

New DAAs with remarkable results

can be used in decompensated

patients To improve the

patient status and to

achieve delisting from LT

waiting list

ELITA Cohort Expansion Study

EASL 2017 Delisting of liver transplant candidates with chronic HCV infection after viral eradication and outcome after

delisting. A European cohort study. L.S. Belli, M. Berenguer, P. Cortesi, M. Strazzabosco, G. Perricone et al.

Regimen: SOF+RBV (46%)

SOF+DCV or LDV+SOF (54%) 12 weeks.

142 liver transplantation candidates, age: 37-71, 69% male, without HCC

69

58

15

MELD level at the DAA start

<16

16-20

>201

66

75

Child-Pugh at the start of DAA

A

B

C

ELITA Cohort Expansion Study

• DAA therapy improves liver function in patients with HCV infection and decompensated cirrhosis

• 1 in 5 (38 out of 142) liver transplantation candidates with chronic HCV infection

was delisted due to clinical improvement after DAA therapy • Low incidence of liver complications: 3 in 38 patients (1 redecompensated and relisted, 1 – TIPS for refractory ascitis, 1 – died with following

diagnosis of HCC)

2017 EASL

Ruiz-Chavez I. Liver Transplant. 2015

Antviral treatment sofosbuvir and ribavirin

Parameter Day 1 Week 4 Week

8

Week

12

Week

16

Week 24 Week12 after

treatment

Prothrombin time (seconds) 1,58 1,76 1,65 1,58 1,58 1,67 1,60

Albumin (g/l) 23,6 24,2 25,6 28,2 29,7 28,9 31,6

Total bilirubin (µmol/l) 53 48 65 56 49 48 21

Aspartate aminotransferase

(IU/l)

138 48 39 40 37 35 32

Alanine aminotransferase

(IU/l)

72 31 30 26 21 21 25

HCV RNA (IU/ml) 53 50 < 12 < 12 < 12 < 12 < 12

Ascites

Yes, refractory

Yes, refractory

Yes, treated

Yes, treated

No, treated

No, untreated

No, untreated

Hepatic encephalopathy Yes Yes No No No No No

Child-Pugh score C12 C12 C10 B9 B7 B7 A6

Model for end-stage liver

disease score

16 17 17 16 16 16 12

DAA Suitable in Patients With Cirrhosis

CTP-A CTP-B CTP-C

Suitable if

Renal

Impairment

Sofosbuvir Yes Yes

Yes

Not if CrCl

< 30 mL/min

Simeprevir Yes No No Not if CrCl

< 15 mL/min

Asunaprevir Yes No No Unknown

ABT-450/RTV Yes No No Unknown

Ledipasvir Yes Yes Yes Unknown

Ombitasvir Yes No

(as combo)

No

(as combo)

Unknown

Daclatasvir Yes Yes Yes Yes

Dasabuvir Yes No No Unknown

Bifano M, et al. AASLD 2011. Abstract 1362. Garimella K, et al. Clinical Pharm 2014. Abstract P43. Sofosbuvir [package

insert]. Simeprevir [package insert]. Khatri A, et al. AASLD 2012. Abstract 758. German, et al. AASLD 2013. Abstract 467.

Kirby R, et al. Clinical Pharm 2013. Abstract PO20.

Studies on PK/PD in Patients With Renal and Hepatic Impairment

•AASLD/IDSA Guidance for Pts With Decompensated Cirrhosis

Refer to experienced HCV practitioner

(ideally liver transplant center)

Avoid BOC, GZR/EBV, IFN, PTV/RTV/OBV + DSV, SIM, TVR, or monotherapy with RBV or DAA

AASLD/IDSA Guidelines. February 2016

*Initial dose of 600 mg/day, increased as tolerated.

Population RBV Eligible RBV Ineligible

SOF + DCV SOF/LDV SOF + DCV SOF/LDV

GT1/4 12 wks +

low-dose RBV*

12 wks + low-dose RBV*

24 wks 24 wks

GT1/4, SOF failure

Not recommended

24 wks + low-dose RBV*

Not recommended

Not recommended

Treatment with DAA before liver transplantation

Patients with decompensated cirrhosis without HCC awaiting liver

transplantation and MELD score <18-20 can be treated prior to liver

transplantation

Patients with decompensated cirrhosis and an indication for liver

transplantation with a MELD score ≥18-20 should be transpanted first

and treated after LT

Treatment is not recommended in patients with limited life expectancy

due to non-liver-related comorbidities.

Protease inhibitors should not be used in patients with Child-Pugh B or C

decompensated cirrhosis

EASL 2017 recommendations

Decompensated cirrhosis before liver transplantation

Low MELD score

<18 - 20

Improvement and probably delisting

High MELD score >20

Treatment Post lT

Those delisted due to

improvement, do they still will

need LT in the future?

Patients with decompensated cirrhosis without HCC awaiting LT EASL Clinical Recommendations 2017

genotype MELD <18 - 20 MELD ≥18 - 20

1 – 4, 6 SOF + LDV + RIB 12 weeks

SOF + VEL+ RIB 12 weeks

SOF + DAC+ RIB 12 weeks

RIB (start at 600 mg and adjusted depending on weight

and tolerance)

SHOULD

BE

TRANSPLANTED

FIRST 2 SOF + VEL+ RIB

12 weeks


3 SOF + VEL+ RIB 24 weeks


HCV TREATMENT

AFTER LIVER TRANSPLANTATION

Impact of Post-Transplantation HCV Infection

Recurrent HCV infection is the leading cause of graft failure in recipients of liver transplant.

Infection of the graft occurs nearly universally in patients with untreated HCV infection who

receive liver transplantation.

Reinfection occurs as soon as reperfusion of the allograft takes place in the operating

room, and viral titers have been detected to reach pre-transplantation levels within 72

hours.

Until recently, attempts to prevent or treat HCV recurrence have been limited by poor

tolerability and responses to interferon-based antiviral therapy.

The availability of highly effective and safe all-oral DAAs will improve the ability to treat

HCV recurrence in liver transplantation.

Fagiuoli S, Ravasio R, Lucà MG, World J Gastroenterol. 2015

HCV RECURRENCE OUTCOMES

In 5 years post-LT, 30% of LT patients have graft cirrhosis

LT

Death Retransplantation

Patient HCV RNA+

after LT

Adapted from Mc Caughan

20%

70%

10%

Asymptomatic

hepatitis

Fibrosing

cholestatic

hepatitis

Chronic

Hepatitis

Cirrhosis Acute Hepatitis

Chronic

hepatitis

Pre- and posttransplanation factors associated with rapid cirrhosis progression

Gane EJ, et al. Liver Transpl 2008;14:S36–44

Recipient

• HLA

• gender

• DM

• Crioglobulinemia

Immunosupresion

• Steroids bolus

Viral

• GT

• High HCV level

Co Infection

• CMV

• HIV

• HBV

HCV

recurrence

Surgical

• ↑CIT

• ↑WIT

• Preservation injury

Donor

• age

• steatosis

ALLY-1 Multicenter, prospective, open-label, phase 3 study

Regime: DCV: 60 mg , SOF: 400 mg ,

RBV: 600 mg, adjusted to 1000 mg/day based on hemoglobin levels and

renal function

- Treatment-naive or experienced, - HCV genotypes 1-6, - RNA >104 IU/ml, - compensated and decompensated cirrhosis

(60 patients) or received liver transplant ≥3 months prior to screening

- 53 patients: 72 % male, - age 22-82

Poordad F, et al. Hepatology. 2016;63:1493-505.

ALLY-1

SVR-12 results for post-liver transplant

Poordad F, et al. Hepatology. 2016;63:1493-505.

SOLAR-1 randomized, prospective, multicenter trial

Regimen: LDV-SOF(90/400 mg), RBV: weight-based (1000 mg/day if < 75 kg or 1200

mg/day if ≥ 75 kg), Child Class B, C: started at 600 mg/day and

escalated up to maximum of 1200 mg/day.

12 weeks LDV+SOF+RBV, 24 weeks LDV+SOF

- 223 adults, - HCV GT 1,4, - naïve and experienced, - Child A,B,C, more than 3 months from transplant, - without HCC

Reddy KR, al. 65th AASLD. 2014: Abstract 8

SOLAR-1 SVR12

Fatigue, anemia, headache and nausea were the most common adverse events, and serious adverse events were rare.

Reddy KR, al. 65th AASLD. 2014: Abstract 8

CORAL-1 open-label, single-arm trial

Regimen: 3D: Ombitasvir-Paritaprevir-Ritonavir- (25/150/100 mg once

daily) + Dasabuvir: 250 mg twice daily. Ribavirin

(RBV): dosing managed - most patients received 600-

800 mg/day 24 weeks

- 34 patients - HCV GT1, - transplant at least 12 months prior, - treatment-naïve or treated with PEG-IFN+RBV, - age 18-70, - F0-F2, - receiving tacrolimus or cyclosporine.

Kwo PY, et al. N Engl J Med. 2014;371:2375-82.

CORAL-1 Results

No episodes of rejection

5 patients received EPO and no blood transfusions.

Adjustment of doses tacrolimus: reduction 0,2 mg every 3 days.

Adjustment of doses cyclosporine: reduction of 20 % pretreatment dose.

Kwo PY, et al. N Engl J Med.

2014;371:2375-82.

Estimated study completion date: 05.2018

Regimen:

For 1b: Grazoprevir 100 mg/day + Elbasvir 50 mg/day for 12 weeks

For 1a, 4: Grazoprevir 100 mg/day + Elbasvir 50 mg/day + Ribavirin

1200 mg/day for 16 weeks

- age 18-78, - previous liver transplantation (more than 6

month), - genotype 1 and 4, - positive HCV-RNA, viral load ≥104 UI/mL, - immunosuppression with tacrolimus

and/or mycophenolate (Prednisone use is allowed at low dose ≤10 mg/d),

- treatment naïve or treatment experienced

EGRADICATE

HCV DAAs and Immunosuppressives Drug–Drug Interactions

Drug DDI With CNIs

Yes No

Protease

inhibitors

Simeprevir CsA + Tac +

ABT-450/RTV +

Nucleoside Sofosbuvir +

Nonnucleoside Dasabuvir +

NS5A Ledipasvir +

Daclatasvir +

Ombitasvir + (in combo) +

Tischer S, et al. J Hepatol. 2014;60:872-884.

Calcineurin Inhibitor Dosing With ABT-450/RTV/Dasabuvir + Ombitasivr

• Phase I study: dosing tacrolimus or cyclosporine with the 3 DAA regimen compared with either alone resulted in:

• 7-fold increase in tacrolimus half-life

• 3-fold increase in cyclosporine half-life

• Based on these findings, recommended dosing during 3 DAA treatment:

• Tacrolimus 0.5 mg once weekly or 0.2 mg every 3 days

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

Kwo P, et al. EASL 2014. Abstract O114.

Patients with post-transplant recurrence of HCV without cirrhosis and cirrhosis Child-Pugh A,B,C

EASL Clinical Recommendations 2017

genotype All genotypes

1 – 4, 6 SOF + LDV + RIB - 12 weeks

SOF + DAC+ RIB - 12 weeks

RIB (adjusted depending on weight, for decompensated

cirrhosis rib start from 600 mg)

No need for immunosuppressive drugs dose adjustments (except everolimus)

SOF + VEL+ RIB

12 weeks

24 weeks in genotype 3

and decompensated

cirrhosis

(after the results of

ongoing studies

presented)

2 SOF + DAC+ RIB - 12 weeks


cirrhosis rib start from 600 mg )


3 SOF + DAC+ RIB - 24 weeks


cirrhosis rib start from 600 mg )


Post-transplant recurrence of HCV Summary

All patients with post-transplant recurrence of HCV infection

should be considered for antiviral therapy

Treatment should be initiated as early as possible when recipient

is stabilized (optimal after 3 months post transplant)

Cholestatic hepatitis or the presence of portal hypertension one

year after transplantation predict rapid disease progression and

graft loss and is indication for immediate antiviral treatment

Guidelines of Treatments Hepatities C, EASL 2016

Conclusion

In the liver transplantation settings the patient must be treated before or after transplantation. The decision should be individualized depending of the disease progression HCV infected LT candidates or recipients of the graft should be prioritized in all antiviral treatment programs Using of protease inhibitors in sever decompensated patient are not recommended New DAAs with good safety and tolerability profile are coming and HCV recurrence after LT probably will not be a problem any more

hcv treatment: before or after liver...

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