Successful Management of Graft Reinfection of HCV Genotype 2 in Living Donor Liver Transplantation from a Hepatitis B Core Antibody-Positive Donor with Sofosbuvir and Ribavirin.

Direct-acting antivirals (DAAs) are relatively safe and highly effective for the eradication of hepatitis C virus (HCV) in liver transplant recipients. In this case study, we present a female with a graft reinfected with HCV genotype 2 who was treated with a combination of sofosbuvir and ribavirin after living donor liver transplantation (LDLT). Because the graft was from a hepatitis B core antibody-positive donor, passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG) and entecavir were also provided to prevent hepatitis B virus (HBV) reactivation. It became clear that the combination of sofosbuvir and ribavirin promptly led to a sustained virologic response and that this combination was safe to treat graft reinfection with HCV genotype 2 after LDLT. Adverse events caused by DAAs were not observed, except for slight anemia. HBIG and entecavir were useful in the prevention of HBV reactivation. In conclusion, the present case indicated that DAA treatment for graft reinfection with HCV is safe and effective in LDLT from hepatitis B core antibody-positive donors.

Introduction

Hepatitis C virus (HCV) infection is a leading cause of end-stage liver disease and hepatocellular carcinoma [1, 2]. HCV-related liver disease is the most common indication for orthotopic liver transplantation in the USA and Northern Europe and for living donor liver transplantation (LDLT) in Japan [3, 4, 5]. Unfortunately, liver transplantation is not a cure for HCV infection, and the occurrence of graft reinfection with HCV is universal, leading to progression of liver fibrosis and occasionally to graft loss at rates higher than in transplant patients not infected with HCV [5, 6].

In Japan, because of long-standing legal difficulties associated with cadaveric donation [7], LDLT is the main type of liver transplantation for end-stage liver disease. Infection with HCV is of negative predictive value in LDLT [8]. The sustained virologic response (SVR) rate was ∼40% in donors of LDLT treated with pegylated interferon (peginterferon) plus ribavirin [9], although adverse events were commonly observed even in nontransplanted patients receiving this treatment [10]. Akamatsu et al. [9] reported that the dose reduction rate and the discontinuation rate of peginterferon plus ribavirin treatment was 40 and 42%, respectively.

Recent progress in the development of direct-acting antivirals (DAAs) against HCV has made it possible to eradicate HCV effectively and to shorten the treatment duration compared to the previous standard of care, i.e. peginterferon plus ribavirin [10]. Treatment with the HCV NS5B polymerase inhibitor sofosbuvir plus ribavirin for 12 weeks was shown to lead to high rates of SVR (∼97%) in Japanese patients infected with chronic HCV genotype 2 [11].

Asian-Pacific countries, including Japan, account for ∼50% of all chronic hepatitis B virus (HBV) infection globally [12]. Given the prevalence of HBV, LDLT from hepatitis B core antibody-positive donors to recipients was occasionally performed with passive immunization with hyperimmune hepatitis B immunoglobulin (HBIG) plus nucleos(t)ide analogs [13].

Here, we report on an LDLT recipient who was reinfected with HCV genotype 2a after receiving a graft from a hepatitis B core antibody-positive donor. HCV genotype 2a was eradicated by a 12-week treatment with sofosbuvir plus ribavirin with HBIG plus entecavir, one of the nucleos(t)ide analogs, for the successful prevention of HBV reappearance.

Case Report

A 66-year-old Japanese woman developed liver failure due to cirrhosis and HCV genotype 2a infection. She was a treatment-naïve patient, but her IL28B rs8099917 was a favorable genotype (TT). Two years prior to LDLT, she has been diagnosed with liver cirrhosis due to HCV infection without liver biopsy. She had been infected with HCV after having received a blood transfusion during childbirth at the age of 30 years. At LDLT, she had peripheral edema with a MELD (Model for End-Stage Liver Disease) score of 12. LDLT with a right liver graft from a hepatitis B core antibody-positive donor was performed in February 2015.

Five months after LDLT, the HCV RNA level was 5.8 log IU/ml, and she was diagnosed with graft reinfection with HCV genotype 2a. Combination treatment with 400 mg daily of sofosbuvir and 400 mg daily of ribavirin was commenced. Her height, body weight, and body mass index were 1.56 m, 50 kg, and 20.5, respectively. She abstained from consumption of alcohol. Her laboratory data before treatment are shown in table 1. The HCV RNA level before treatment was 5.8 log IU/ml. After LDLT, she received triple immunosuppressive therapy consisting of tacrolimus (3 mg daily), mycophenolate mofetil, and basiliximab with passive immunization with HBIG and 0.5 mg daily of entecavir.

Table 1

Laboratory findings before the commencement of the combination treatment with sofosbuvir and ribavirin in the present case

Item	Value	Item	Value
AST	74 IU/l	WBC	2,500/µl
ALT	61 IU/l	RBC	362 × 104/µl
LDH	223 IU/l	Hemoglobin	12.2 g/dl
ALP	525 IU/l	Hematocrit	35.6%
γ-GTP	40 IU/l	Platelets	12.1 × 104/µl
T.BIL	0.5 mg/dl	PT	120%
D.BIL	0.1 mg/dl	PT-INR	0.96
TP	6.5 g/dl	Anti-HCV	positive
Alb	4.0 g/dl	HCV RNA	5.8 log IU/ml
T.CHO	156 mg/dl	HCV genotype	2a
UA	6.0 mg/dl	HBsAg	negative
UN	23 mg/dl	Anti-HBs	positive
Cre	1.12 mg/dl	HBV DNA	negative
eGFR	38.1 ml/min/1.73 m2	Anti-HIV	negative

AST = Aspartate aminotransferase; ALT = alanine transaminase; LDH = lactate dehydrogenase; ALP = alkaline phosphatase; γ-GTP = γ-glutamyltransferase; T.BIL = total bilirubin; D.BIL = direct bilirubin; TP = total protein; Alb = albumin; T.CHO = total cholesterol; UA = uric acid; UN = urea nitrogen; Cre = creatinine; eGFR = estimated glomerular filtration rate; WBC = white blood cell count; RBC = red blood cell count; PT = prothrombin time; PT-INR = PT international normalized ratio; anti-HCV = anti-hepatitis C virus antibody; HBsAg = hepatitis B virus surface antigen; anti-HBs = anti-hepatitis B virus surface antibody; anti-HIV = anti-human immunodeficiency virus antibody.

Four weeks after initiating the combination treatment with sofosbuvir and ribavirin, HCV RNA levels were undetectable. She completed this treatment for 12 weeks and achieved SVR at 24 weeks following the termination of this treatment (SVR24) (fig. 1). There was no evidence of HBV reactivation.

Fig. 1

Clinical course of the patient in the present study. SVR4, SVR8, SVR12, and SVR24 denote SVRs at 4, 8, 12 and 24 weeks, respectively. ALT = Alanine transaminase; Cre = creatinine; Hb = hemoglobin; LDLT = living donor liver transplantation; R = ribavirin; SOF = sofosbuvir.

Because her hemoglobin level was 12.2 g/dl before the commencement of this treatment, an oral iron preparation was also started. After 2 months of treatment, her hemoglobin level fell to 10.8 mg/dl. Then, the dose of ribavirin was decreased to 200 mg daily, and her hemoglobin level improved to 12.8 g/dl (fig. 1). During this period of treatment, she did not develop evidence of bone marrow suppression, such as observed in peginterferon-plus-ribavirin treatment. No serious adverse events were observed. During treatment, the trough level of tacrolimus remained stable.

Discussion

We presented a female patient with living donor-related graft reinfection with HCV genotype 2a who was treated with a combination of sofosbuvir and ribavirin for 12 weeks. Although several DAAs have drug-drug interactions, no changes in this patient's drug protocol, which included immunosuppressants and combination treatment of sofosbuvir plus ribavirin, were necessary in this case.

Treatment of HCV infection after liver transplantation is a challenge. Peginterferon plus ribavirin with or without DAAs may be attempted, but the use of peginterferon is restricted by severe side effects and inadequate efficacy [5]. In addition, interferon has an immune-mediated cytotoxicity, occasionally causing allograft dysfunction [14]. Interferon-free therapy is a viable treatment option and improves treatment efficacy [15, 16, 17, 18, 19, 20]. This case suggests that DAAs are well tolerated and effective for the eradication of HCV from post-liver transplantation patients.

In the present case of LDLT, graft reinfection with HCV genotype 2 was treated with a combination of sofosbuvir plus ribavirin. The patient achieved SVR24, although she had anemia as an adverse event, and anti-HCV treatment was continued without blood transfusion. Curry et al. [17] reported that common adverse events of combination treatment with sofosbuvir and ribavirin were fatigue (in 38% of patients), headache (23%), and anemia (21%) after liver transplantation. Charlton et al. [18] reported that the most common adverse events were fatigue (30%), diarrhea (28%), headache (25%), and anemia (20%) during a 24-week combination treatment course of sofosbuvir plus ribavirin after liver transplantation.

In the present study, the patient received a liver graft from a hepatitis B core antibody-positive donor, and, in general, HBV from these donors is transmitted to recipients at a high rate [13]. Therefore, passive immunization with HBIG plus treatment with entecavir were provided to prevent HBV reactivation. Curing HCV infection with DAAs in HBV/HCV coinfection and monitoring for HBV reactivation should be performed [21], because DAAs against HCV do not have any effect on HBV replication, unlike interferon. In the present case, the patient was treated with HBIG and entecavir, and there was no evidence of HBV reactivation.

Recently, more effective regimens with DAAs against HCV have been reported [22, 23]. These regimens may make it possible to shorten the duration of treatment and to make it easier to achieve SVR. The use of interferon-free regimens is possible for the eradication of HCV in post-LDLT patients with grafts from hepatitis B core antibody-positive donors, as was demonstrated by our patient, who was successfully treated with HBIG and entecavir to prevent HBV reactivation. In conclusion, 12-week treatment with sofosbuvir plus ribavirin is relatively safe and highly effective for the eradication of HCV genotype 2 in LDLT patients.

Statement of Ethics

The authors have no ethical conflicts to disclosure.

Disclosure Statement

Tatsuo Kanda and Osamu Yokosuka received lecture fees from Gilead Sciences. The other authors declare that there is no conflict of interest regarding the publication of this manuscript.