Shinshu Med J, 67⑹：417～423, 2019

Interferon-free Anti-hepatitis C Virus Treatment forLong-term Liver Transplantation Recipients with
Failed Interferon Therapy
Kiyotaka Hosoda, Yuichi Masuda＊, Atsuyoshi Mita and Akira Kobayashi
First Department of Surgery, Shinshu University school of Medicine

Background : Recurrent hepatitis and cirrhosis due to hepatitis C virus (HCV) infection is a major cause of graft
loss in liver transplant (LT) patients. Although interferon (IFN)-based therapy has been used in patients withrecurrent hepatitis C after LT, the safety and efficacy of treatment remains unclear. IFN-free regimens withdirect-acting antiviral agents (DAAs) against HCV showed excellent results in terms of sustained virologicalresponse (SVR) in non-LT patients. Recently, the efficacy of DAAs for LT patients has been reported. However,drug-drug interactions, the increasing risk of hepatocellular carcinoma (HCC), and the existence of drugresistant gene variants require investigation in LT patients.
Method : This study included patients with recurrent hepatitis C after LT who failed IFN therapy and received
IFN-free therapy. Medical records were reviewed retrospectively.
Results : Seven recipients were included. The median duration from LT to DAA treatment was 124 (34-181)
months. HCV genotype was 1b in 6 patients and 2a in 1 patient. The Child-Pugh classification at IFN-freetherapy was A in 6 patients and B in 1 patient. DAAs were used as follows : daclatasvir and asunaprevir in 3
patients, ledipasvir and sofosbuvir in 3, and sofosbuvir and ribavirin in 1. In all patients, sustained virologic
response at week 24 was achieved without significant adverse events. No evidence of HCC has been observed.
Conclusion : HCV can be eradicated with interferon-free therapy in LT recipients with failed IFN therapy.
Shinshu Med J 67 : 417―423, 2019
(Received for publication March 28, 2019 ; accepted in revised form July 4, 2019)
Key words : direct-acting antiviral agents, interferon, liver transplantation, hepatitis C virus
Some direct-acting antiviral agents (DAAs) have

Ⅰ Introduction

been approved and high sustained virological re­

Liver transplant (LT) recipients with hepatitis Csponse (SVR) rates in non-LT HCV patients treatedvirus (HCV) have a risk of recurrent hepatitis C. Liverwith DAAs have been reported3）-7）. Historically, DAAs

cirrhosis (LC) due to the recurrence of HCV is a major

have been used with IFN, (peg-IFN＋RBV＋tela­cause of graft loss after LT. Interferon (IFN)-based therapy

previr [TVR]/ simeprevir [SMV]). These regimens(IFN or peg-IFN with/without ribavirin [RBV]) has

have been used in LT patients, and improved SVR

been administered for recurrent hepatitis C afterrates have been observed. However, the frequency1）
2）.

of adverse events with these regimens remains

LT recipients frequently discontinued these treat­high8）-10）. Recent IFN-free DAA regimens, including

ments due to the relatively high incidence of compli­

combinations of daclatasvir (DCV) and asunaprevir

cations and an increased risk of rejection.

(ASV)3）4）, sofosbuvir (SOF) and ledipasvir (LDV)5）6）,

LT, and a response rate of 30-40 ％ was reported＊Corresponding author : Yuichi MasudaFirst Department of Surgery, Shinshu University School ofMedicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
E-mail : khosoda@shinshu-u.ac.jp

No. 6, 2019

and SOF and RBV7） reportedly have greater safetyand efficacy. The regimens resulted in high rates of
SVR in LT patients11）, and even remained high inpatients with failed IFN therapy. Meanwhile, DAA417

Hosoda・Masuda・Mita et al.

resistant HCV, drug interactions, and higher rates of12）

HCC have also been reported .

obtained prior to treatment. Calcineurin inhibitors
were administered in all patients, with tacrolimus

Herein, we report our long-term experience with 7in 5, and cyclosporine in 2. Mycophenolate mofetil

cases of IFN-free treatment after failed IFN therapy

was used in combination with a calcineurin inhibitorin LT recipients.

in 4. Corticosteroids were not administrated to any

Patients and methods :patients. During the course of DAA treatment, theAmong 46 patients who received LT for HCVlevels of serum AST and ALT decreased or remain­disease in our institute, recipients who failed IFN

ed within normal limits in all cases. The serum

therapy and received IFN-free therapy were select­

HCV-RNA levels were 1.2-7.0 logIU/ml (median :ed and included in this study. The medical records

5.2 logIU/ml) before the treatment, and decreased

were retrospectively analyzed. This study protocol

to undetectable levels within 2-9 weeks (median : 3

was approved by the Shinshu University Hospital

weeks), and sustained virologic response at week 24

Ethics Committee.

(SVR24) was achieved in all cases. Occurrence of HCC
ⅡResults

Seven LT recipients with failed IFN therapy treat­
ed with DAAs were included in this study. The
median age at LT was 53 years old (range : 43-65
years old). All of them underwent living donor trans­

was not observed during this study period. The detailsof each clinical course are shown in Table 1-3. The
clinical course of IFN-free therapy in one representa­
tive case (Case 1) is shown in Fig. 1.
ⅢDiscussion

plantation, including one case of re-transplantation.

After LT for HCV-related cirrhosis, most patientsHCV genotype was 1b in 6 patients and 2a in 1 pa­

experience recurrence of hepatitis13）. In our institu­

tient. Drug resistance-associated variants (NS3 D168tion, 46 patients received LT due to HCV infection.

or NS5A L31 or Y93 variants) were detected in 4 pa­

Forty-five of the 46 experienced recurrence of hepa­

tients. In all cases, liver biopsy specimens weretitis. Among these, 36 were previously treated withtaken at the time of IFN therapy, and recurrent hep­

IFN-based therapy. SVR was achieved in only 12

atitis was diagnosed. All patients were previouslywith IFN-based therapy. Two were treated withtreated with IFN, IFN with RBV, or peg-IFN with

DAAs with IFN and achieved SVR. Four were not

RBV after LT. The median duration of IFN-basedable to start DAAs due to their physical condition,therapy was 69 weeks (range : 1-274 weeks). IFN-and 11 had died. Seven recipients were treated withbased therapy discontinuation was due to depression,

IFN-free DAA therapy, and were reviewed in thisheart failure, retinopathy, rejection, or non-respond­

study. A recipient in whom HCV was eradicateder status. All patients remained positive for serumwith IFN-based therapy before LT had no episodes

HCV-RNA regardless of therapy.

of recurrent hepatitis. It is known that insufficientPatients started treatment with IFN-free regi­

HCV therapy will lead to much earlier development

mens at 2 to 15 years after LT (median : 12 years).

of cirrhosis in LT patients, and is associated with aThe median age at initiation of IFN-free therapy

poor prognosis. Liver cirrhosis accounts for above

was 64 years old (range : 55-70 years). Three were

50 ％ of graft loss or death in HCV LT recipients14）15）.

treated with DCV and ASV, 3 with LDV and SOF,

Because of the clinical course, LC recipients withand 1 with SOF and RBV. Child-Pugh classification

HCV had a worse prognosis than LC recipients withat the beginning of the therapy was class A in 6,

other etiologies. Only 2.5 ％ of patients achieved SVR

and class B in 1. Since the use of DAAs for patientswith IFN monotherapy1）, and 24-45 ％ of those achieved

with Child-Pugh B was considered an off-label indi­

SVR with peg-IFN and RBV.2） Not only antiviral

cation in Japan, institutional review board approv­

effects but also multiple side effects, such as heart

al and informed consent from the patients werefailure, retinopathy, depression, cytopenia, and graft

418

Shinshu Med Jl. 67

IFN-free therapy for long-term LT recipients
Table 1The details of patients’ characteristics treated with daclatasvir and asunaprevir.
Case 1†¶Case 2

Case 3

IFN -free therapy

DCV ＋ASV#DCV＋ASV

DCV＋ASV

Child-Pugh classification at start of IFN-free therapy

AAAHCV genotype

1b1b1bAge at IFN-free therapy

5966

60

13y11m15y1m

TacTac‡Time from LT to IFN-free therapy

8y5m
Tac

Immunosuppressive agent at start of IFN-free therapy††＋MMF‡‡

AST pre/post IFN-free therapy (IU/mL)

43/14

24/26

49/27

ALT pre/post IFN-free therapy (IU/mL)

82/10

22/23

43/23

Age at LT (years)

51

53

45

LT modality

LDLT§§LDLT

LDLTTime from LT to liver biopsy (weeks)372

5New Inuyama Classification

A1/F0A1/F1

A2/F2＋RBV

Peg-IFN＋RBV

IFN

Duration of IFN-based therapy (weeks)

20182

1

Cause of discontinuation of IFN therapy

retinopathy

heart failure

depression

Drug resistance-associated variants

noNS3 D168T
NS5A Y93H

NS5A Y93H

7.0

6.3

6.1

693

Duration from attainment of SVR|| (months)

30

30

11Occurrence of HCC

nonono| ||Peg-IFN

Previous therapy¶¶Serum HCV-RNA levels before the treatment (log10 IU/ml)§Duration from institution of DAAs

to undetected HCV RNA(weeks)† : interferon ‡ : liver transplantation § : direct-acting antiviral agents || : sustained virological response¶ : daclatasvir # : asunaprevir †† : tacrolimus ‡‡ : mycophenolate mofetil§§ : living donor liver transplantation |||| : pegylated interferon ¶¶ : ribavirin

rejection have been reported16）. Some patients had toimprovements in viral response rates using DAAs

discontinue IFN therapy because of adverse effects.

with IFN. However, the adverse events caused by IFN

Therefore, a safe and effective strategy for HCV

were still significant. Recently, combination DAA

therapy after LT has been needed.

therapy without IFN was reported to have a＞90 ％DAAs have been introduced in recent years. Regi­

SVR rate in non-LT patients3）4）. These regimens

mens have included TVR or SMV, which are NS3/

were also used in LT patients. The SVR rate in LT

4A protease inhibitors, in combination with IFN. Com­patients was 93.1 ％ with DCV＋ASV and 100 ％ withpared with peg-IFN-only regimens, the response

SOF＋LDV11）. Mutation in HCV genes is known torates were much improved in non-LT patients withdecrease SVR. NS3 D168 variants in a SMV/ASV

use of DAAs. In LT patients, the reported SVRregimen and NS5A L31 or Y93 in a DCV/ASV regimen

7）, and thehave been of concern. In a DCV/ASV regimen, theserate with SMV was 80 ％10）. There were significant

variants were associated with poor response rates,rates with TVR regimens were 67 ％No. 6, 2019419

Hosoda・Masuda・Mita et al.
Table 2The details of patients’ characteristics treated with sofosbuvir and ledipasvir.
Case 4†‡

Case 5

Case 6

IFN-free therapy

SOF ＋LDVSOF＋LDVSOF＋LDVChild-Pugh classification at start of IFN-free therapy

ABA

HCV genotype

1b1b1bAge at IFN-free therapy

64

70

55

Time from LT to IFN-free therapy

6y5m

12y8m

12y9m

§

Immunosuppressive agent at start of IFN-free therapy

Tac＋MMF

CyA ＋MMF

CyA＋MMF

AST pre/post IFN-free therapy (IU/mL)

21/18

54/50

32/23

ALT pre/post IFN-free therapy (IU/mL)

9/9

39/36

24/14

Age at LT (years)

58

58

43

LT modality

LDLT

LDLT

① LDLT② DDLT||Time from LT to liver biopsy (weeks)

1026

21

New Inuyama Classification

A1/F0

A2/F4

A2/F0

Previous therapy

Peg-IFN＋RBV

IFN＋RBV

Peg-IFN＋RBV

Duration of IFN-based therapy (weeks)

1609274

Cause of discontinuation of IFN therapy

retinopathy

rejection

depression,
infection

Drug resistance-associated variants

undetectable

NS5A L31M
NS5A Y93H

NS3 Q80L
NS5A Y93H

Serum HCV-RNA levels before the treatment (log10 IU/ml)

3.1

3.9

5.1

Duration from institution of DAAs to undetected HCV RNA(weeks)

222

Duration from attainment of SVR (months)

181325

Occurrence of HCC

nonono† : sofosbuvir‡ : ledipasvir§ : cyclosporine|| : deceased donor liver transplantationand only 40 ％ of patients with these variants could3）

cases, an SOF＋RBV regimen was used. SVR wasachieve SVR . The SOF/LDV regimen can evenachieved in all patients in this study, and levels of

attain a high rate of SVR in these patients17）. In ourserum HCV have remained undetectable. Occult

institution, anti-HCV therapy has been initiated inHCV cases in HCV LT recipients treated withrecipients with recurrent HCV hepatitis diagnosedDAAs have been reported. In LT patients, thepathologically. The anti-HCV therapy regimen

serum levels of HCV and liver functions should beconsisted of IFN with or without RBV and DAAs

carefully monitored, even in cases that achieved

until 2014, and IFN-free regimens with DAAs wereSVR18）.

started in 2015. SOF and LDV were used in recent

DAAs are metabolized by CYP3A, and cause drugcases. Prior to the approval of SOF/LDV regimen ininteractions between DAAs and immunosuppressive

Japan, patients without L31 or Y93 variants wereagents, such as tacrolimus and cyclosporine. The pa­

treated with DCV/ASV, and with those variants

tients in this study were long-term recipients of LT,

were followed closely without DAAs. In genotype 2and used less immunosuppressive medication ; no420

Shinshu Med Jl. 67

IFN-free therapy for long-term LT recipients
Table 3The details of patients’ characteristics treated with sofosbuvir and ribavirin.
Case 7

IFN-free therapy

SOF＋RBV

Child-Pugh classification at start of IFN-free therapy

AHCV genotype2aAge at IFN-free therapy

68Time from LT to IFN-free therapy

2y10m

Immunosuppressive agent at start of IFN-free therapy

Tac

AST pre/post IFN-free therapy (IU/mL)

80/35

ALT pre/post IFN-free therapy (IU/mL)

34/33

Age at LT (years)

65

LT modality

LDLTTime from LT to liver biopsy (weeks)

69

New Inuyama Classification

A2/F1

Previous therapy

Peg-IFN＋RBV

Duration of IFN-based therapy (weeks)

69

Cause of discontinuation of IFN therapy

non-responder
statusDrug resistance-associated variants

undetectable

Serum HCV-RNA levels before the treatment (log10 IU/ml)1.2

Duration from institution of DAAs to undetected HCV RNA(weeks)

8Duration from attainment of SVR (months)

26

Occurrence of HCC

nopatients had difficulty controlling blood levels of cal­lower in SVR patients. In the present study, at least

cineurin inhibitors. In addition, DAA treatment wasin the short term (10 to 30 months after SVR), there

completed without severe adverse events except in

was no evidence of HCC recurrence.

1 of the 7 cases with slight elevation of liver enzymes

Ⅳ Conclusionand serum bilirubin level in this study.
Recently, the risk of HCC recurrence after DAA12）All HCV recipients achieved SVR24 with IFN-freetreatment has been reported . IFN-based therapy

DAA treatment. DAA treatment for LT recipientswas thought to have a positive effect on the anti-was used safely with monitoring of liver function

cancer immune system. However, Li et al. reported

tests. HCV can be eradicated with interferon-freethat DAA treatment was not associated with a high­

DAA therapy without significant adverse events in19）

er incidence of HCC . They also noted that regard­

long-term LT patients following failure of IFN ther­less of DAA or IFN use, the incidence of HCC wasapy.

No. 6, 2019421

Hosoda・Masuda・Mita et al.

Fig. 1

Clinical course of IFN-free therapy in one representative case (Case 1)

Interrupted line at upper left of figure represents period of IFN-based therapy, andinverted triangle denotes start of IFN-free therapy.

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