Outcomes for Patients with Hepatitis C Virus after Liver Transplantation in Korea

Jong Man Kim

doi:10.4285/jkstn.2016.30.4.155

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Kim: Outcomes for Patients with Hepatitis C Virus after Liver Transplantation in Korea

Review Article

J Korean Soc Transplant 2016;30(4):155-164.

Published online: 19 January 2016

DOI: https://doi.org/10.4285/jkstn.2016.30.4.155

Outcomes for Patients with Hepatitis C Virus after Liver Transplantation in Korea

Jong Man Kim, M.D.

Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Corresponding author: Jong Man Kim Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: 82-2-3410-1719, Fax: 82-2-3410-0040 E-mail: jongman94@hanmail.net

Received 25 August 2016 Accepted 25 August 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Hepatitis C virus (HCV)-related liver disease is the most common indication for liver transplantation (LT) in Western countries, whereas HCV LT is rare in Korea. We conducted a survey of HCV RNA-positive patients who underwent LT and investigated the prognostic factors for patient survival and the effects of immunosuppression. To accomplish this, we retrospectively reviewed the multicenter records of 192 HCV RNA-positive patients who underwent LT. The 1-, 3-, and 5-year overall survival rates were 78.8%, 75.3%, and 73.1%, respectively. Excluding cases of hospital mortality (n=23), 169 patients were evaluated. Most patients were genotype 1 (n=111, 65.7%) or genotype 2 (n=42, 24.9%). The proportion of living donors for LT (n=135, 79.9%) was higher than that of deceased donors (DDLT; n=34, 20.1%). The median donor and recipient ages were 32 and 56 years, respectively. Twenty-eight patients (16.6%) died during the observation period, while 75 underwent universal prophylaxis and 15 received preemptive therapy. HCV recurrence was detected in 97 patients. Recipients who were older than 60, received DDLT, used cyclosporine, or suffered acute rejection had lower rates of survival. Acute rejection was closely associated with a lack of induction therapy, cyclosporine use, and universal prophylaxis after transplantation. The careful avoidance of acute rejection in the post-transplant period through adequate use of tacrolimus is a preferable strategy that increases patient survival following liver transplantation.

Keywords: Hepacivirus, Hepatitis C, Immunosuppression, Tacrolimus, Graft rejection, Survival, Antiviral agents

REFERENCES

1). Mohd Hanafiah K., Groeger J., Flaxman AD., Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013. 57:1333–42.

2). European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol. 2011. 55:245–64.

3). Shin HR., Hwang SY., Nam CM. The prevalence of hepatitis C virus infection in Korea: pooled analysis. J Korean Med Sci. 2005. 20:985–8.

4). Kim SJ. Viral hepatitis surveillance system and statue of C hepatitis sentinel surveillance in Korea. Public Health Weekly Report, KCDC. 2012. 214–9.

5). Lee HW., Lee KW., Kim BW., Song GW., Han YS., Kwon CH, et al. Liver transplantation for hepatitis C virus-related liver disease in Korea. J Korean Soc Transplant. 2012. 26:269–76.

6). Balagopal A., Thomas DL., Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology. 2010. 139:1865–76.

7). Gane EJ., Naoumov NV., Qian KP., Mondelli MU., Maertens G., Portmann BC, et al. A longitudinal analysis of hepatitis C virus replication following liver transplantation. Gastroenterology. 1996. 110:167–77.

8). Howell J., Angus P., Gow P. Hepatitis C recurrence: the Achilles heel of liver transplantation. Transpl Infect Dis. 2014. 16:1–16.

9). Gane EJ., Portmann BC., Naoumov NV., Smith HM., Underhill JA., Donaldson PT, et al. Long-term outcome of hepatitis C infection after liver transplantation. N Engl J Med. 1996. 334:815–20.

10). Berenguer M., Prieto M., San Juan F., Rayón JM., Martinez F., Carrasco D, et al. Contribution of donor age to the recent decrease in patient survival among HCV-infected liver transplant recipients. Hepatology. 2002. 36:202–10.

11). Samonakis DN., Germani G., Burroughs AK. Immunosuppression and HCV recurrence after liver transplantation. J Hepatol. 2012. 56:973–83.

12). Everson GT., Trotter J., Forman L., Kugelmas M., Halprin A., Fey B, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology. 2005. 42:255–62.

13). Singal AK., Guturu P., Hmoud B., Kuo YF., Salameh H., Wiesner RH. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation. 2013. 95:755–60.

14). Adam R., Karam V., Delvart V., O'Grady J., Mirza D., Klempnauer J, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol. 2012. 57:675–88.

15). Akamatsu N., Sugawara Y., Kokudo N., Eguchi S., Fujiwara T., Ohdan H, et al. Outcomes of living donor liver transplantation for hepatitis C virus-positive recipients in Japan: results of a nationwide survey. Transpl Int. 2014. 27:767–74.

16). Charlton M., Seaberg E., Wiesner R., Everhart J., Zetterman R., Lake J, et al. Predictors of patient and graft survival following liver transplantation for hepatitis C. Hepatology. 1998. 28:823–30.

17). Shackel NA., Jamias J., Rahman W., Prakoso E., Strasser SI., Koorey DJ, et al. Early high peak hepatitis C viral load levels independently predict hepatitis C-related liver failure post-liver transplantation. Liver Transpl. 2009. 15:709–18.

18). Roche B., Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int. 2012. 32(Suppl 1):120–8.

19). Chalasani N., Manzarbeitia C., Ferenci P., Vogel W., Fontana RJ., Voigt M, et al. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology. 2005. 41:289–98.

20). Bzowej N., Nelson DR., Terrault NA., Everson GT., Teng LL., Prabhakar A, et al. PHOENIX: A randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl. 2011. 17:528–38.

21). Guillouche P., Féray C. Systematic review: antiviral therapy of recurrent hepatitis C after liver transplantation. Aliment Pharmacol Ther. 2011. 33:163–74.

22). Berenguer M., Rayón JM., Prieto M., Aguilera V., Nicolás D., Ortiz V, et al. Are posttransplantation protocol liver biopsies useful in the long term? Liver Transpl. 2001. 7:790–6.

23). Berenguer M., Palau A., Aguilera V., Rayón JM., Juan FS., Prieto M. Clinical benefits of antiviral therapy in patients with recurrent hepatitis C following liver transplantation. Am J Transplant. 2008. 8:679–87.

24). Fukuhara T., Taketomi A., Motomura T., Okano S., Ninomiya A., Abe T, et al. Variants in IL28B in liver recipients and donors correlate with response to peginterferon and ribavirin therapy for recurrent hepatitis C. Gastroenterology. 2010. 139:1577–85. 1585 e1-3.

25). Watashi K., Hijikata M., Hosaka M., Yamaji M., Shimotohno K. Cyclosporin A suppresses replication of hepatitis C virus genome in cultured hepatocytes. Hepatology. 2003. 38:1282–8.

26). Carrión JA., Navasa M., García-Retortillo M., García-Pagan JC., Crespo G., Bruguera M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology. 2007. 132:1746–56.

27). Rabie R., Mumtaz K., Renner EL. Efficacy of antiviral therapy for hepatitis C after liver transplantation with cyclosporine and tacrolimus: a systematic review and meta-analysis. Liver Transpl. 2013. 19:36–48.

28). ReViS-TC Study Group. Cyclosporine a-based immunosuppression reduces relapse rate after antiviral therapy in transplanted patients with hepatitis C virus infection: a large multicenter cohort study. Transplantation. 2011. 92:334–40.

29). Martin P., Busuttil RW., Goldstein RM., Crippin JS., Klintmalm GB., Fitzsimmons WE, et al. Impact of tacrolimus versus cyclosporine in hepatitis C virus-infected liver transplant recipients on recurrent hepatitis: a prospective, randomized trial. Liver Transpl. 2004. 10:1258–62.

30). Berenguer M., Royuela A., Zamora J. Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis. Liver Transpl. 2007. 13:21–9.

31). Watt KD., Dierkhising R., Heimbach JK., Charlton MR. Impact of sirolimus and tacrolimus on mortality and graft loss in liver transplant recipients with or without hepatitis C virus: an analysis of the Scientific Registry of Transplant Recipients Database. Liver Transpl. 2012. 18:1029–36.

32). Berenguer M., Prieto M., Córdoba J., Rayón JM., Carrasco D., Olaso V, et al. Early development of chronic active hepatitis in recurrent hepatitis C virus infection after liver transplantation: association with treatment of rejection. J Hepatol. 1998. 28:756–63.

Fig. 1.

Patient survival rates. The 1-, 3-, and 5-year patient survival rates are 78.8%, 75.3%, and 73.1%, respectively.

Fig. 2.

Patient survival according to recipient age, donor type, calcineurin inhibitor, and biopsy-proven acute rejection. Abbreviations: LDLT, living donor liver transplantation; DDLT, deceased donor liver transplantation; BPAR, biopsy-proven acute rejection.

Fig. 3.

Patient survival according to SVR. Patient survival in patients with SVR was higher than in patients without SVR, but there was no statistically significant difference in patient survival between the two groups. Abbreviations: SVR, sustained viral response.

Table 1.

The causes of graft failure and mortality

Variable	＜1 Year	＞1 Year
Graft failure	18	12
Chronic rejection	8	2
Graft dysfunction	2	0
HCC recurrence	1	0
HCV recurrence	4	6
Hepatic failure	3	4
Mortality (hospital mortality/ no hospital mortality)	38	12
Chronic rejection	2 (1/1)	1
Graft dysfunction	2 (2/0)	0
HCC recurrence	3 (0/3)	1
HCV recurrence	4 (0/4)	2
Hepatic failure	6 (5/1)	3
Infection	17 (10/7)	4
Cerebrovascular accident	1 (1/0)	1
Bronchial hemorrhage	1 (0/1)	0
Gastrointestinal bleeding	1 (1/0)	0
Stress-induced	1 (1/0)	0
cardiomyopathy

Abbreviations: HCC, hepatocellular carcinoma; HCV, hepatitis C virus.

Table 2.

Baseline characteristics

Characteristic	Value
Gender
Male	118 (69.8)
Female	51 (30.2)
Recipient age ＜60 years	117 (69.2)
HCV genotype
Unknown	9 (5.3)
Type 1	111 (65.7)
Type 2	42 (24.9)
Type 3	4 (2.4)
Type 6	3 (1.8)
Coexistence of hepatitis B virus	21 (12.4)
Coexistence of hepatocellular carcinoma	77 (45.6)
HCV-RNA level at transplantation (IU/mL)	133,568
	(12∼26,000,000)
MELD score	16 (6∼50)
Type of liver transplantation
Deceased donor	34 (79.9)
Living donor	135 (20.1)
Donor age ≥30 years old	100 (59.2)
Donor gender
Male	123 (72.8)
Female	46 (27.2)
Graft type
Whole liver	33 (19.5)
Right Lobe	125 (74.0)
Left lobe	10 (5.9)
Split	1 (0.6)
Induction agent
None	64 (37.9)
Basiliximab	105 (62.1)
Calcineurin inhibitor
None	3 (1.8)
Cyclosporin	88 (52.1)
Tacrolimus	78 (46.2)
MMF	105 (62.1)

Data are presented as number (%) or median (range). Abbreviations: HCV, hepatitis C virus; MELD, model for end-stage liver disease; MMF, mycophenolate mofetil.

Table 3.

Risk factors for patient survival

Univariate	Odds ratio	95% Confidence interval	P-value
Recipient gender (female)	0.880	0.387∼2.001	0.761
Recipient age ≥60 years	2.410	1.133∼5.128	0.018
Genotype
Type 1	1.392	0.185∼10.486	0.748
Type 2	2.100	0.265∼16.614	0.482
Pre-transplant antiviral treatment	2.048	0.897∼4.680	0.089
HCV RNA level	1.000	1.000∼1.000	0.023
Coexistence of hepatitis B virus	0.500	0.119∼2.110	0.346
Coexistenceof Hepatocellular carcinoma	0.828	0.390∼1.755	0.622
MELD score	0.990	0.941∼1.042	0.703
Deceased donor liver transplantation	2.475	1.119∼5.495	0.020
Donor age ≥30 years	3.214	1.216∼8.493	0.019
Donor gender (female)	0.889	0.376∼2.103	0.789
Cold ischemic time	1.000	0.997∼1.002	0.858
Warm ischemic time	1.005	0.994∼1.016	0.404
Induction agent (Basiliximab)	0.643	0.302∼1.369	0.252
Use of cyclosporin	2.475	1.089∼5.618	0.025
MMF	0.879	0.411∼1.881	0.740
Universal prophylaxis	1.421	0.668∼3.024	0.362
Preemptive treatment	0.663	0.154∼2.862	0.582
HCV recurrence	1.113	0.529∼2.344	0.778
Biopsy-proven acute rejection	4.013	1.909∼8.436	＜0.001
Multivariate
Recipient age ≥60	2.277	1.014∼5.113	0.046
Deceased donor liver transplantation	2.398	1.041∼5.525	0.040
Use of cyclosporin	5.870	1.276∼11.909	0.029
Biopsy-proven acute rejection	4.338	1.884∼9.990	0.001

Abbreviations: HCV, hepatitis C virus; MELD, model for end-stage liver disease; MMF, mycophenolate mofetil.

Table 4.

Antiviral treatment in pre- and post-transplant

Variable	Value
Pre-transplant antiviral treatment	30 (17.8)
Regimen of pre-transplant antiviral treatments
IFN	6
IFN and RBV	15
RBV	8
Unknown	2
Universal prophylaxis	75 (44.4)
Preemptive treatment	15 (8.9)
Post-transplant antiviral treatment
No treatment	81 (47.9)
IFN	4 (2.4)
IFN and RBV	74 (43.8)
RBV	9 (5.3)
Unknown	1 (0.6)
First protocol biopsy
None	138 (81.7)
＜3 months	11 (6.5)
3∼6 months	8 (4.7)
6∼12 months	5 (3.0)
≥1 year	7 (4.1)
Interval of HCV RNA examination
None	2 (1.2)
Every visits	103 (60.9)
＜3 months	32 (18.9)
3∼6 months	14 (8.3)
6∼12 months	8 (4.7)
≥1 year	10 (5.9)
HCV recurrence	97 (57.4)
HCV recurrence based on pathology	37
HCV recurrence based on HCV RNA	52
HCV recurrence based on LFT	41
SVR
Non-response	24
SVR achieved	64
Not assessed	9

Data are presented as number (%). Abbreviations: IFN, interferon; RBV, ribavirin; HCV RNA, hepatitis C virus ribonucleic acid LFT, liver function test; SVR, sustained viral response.

Table 5.

Comparison of patients with and without biopsy-proven acute rejection

	No BPAR (n=130)	BPAR (n=39)	P-value
Gender (male)	89 (68.5)	29 (74.4)	0.554
Recipient age ≥60	42 (32.3)	10 (25.6)	0.553
HCV genotype			0.585
Unknown	8 (6.2)	1 (2.6)
Type 1	86 (66.2)	25 (64.1)
Type 2	30 (23.1)	12 (30.8)
Type 3	4 (3.1)	0 (0)
Type 6	2 (1.5)	1 (2.6)
Coexistence of HBV	17 (13.1)	4 (10.3)	0.786
Coexistence of HCC	62 (47.7)	15 (38.5)	0.362
LDLT	105 (80.8)	32 (82.1)	0.858
Donor age ≥30	77 (59.2)	23 (59.0)	0.977
Donor gender (male)	91 (70.0)	32 (82.1)	0.156
HCV RNA	156,885 (12∼26,000,000)	63,493 (120∼62,000,000)	0.077
MELD score	16 (6∼50)	15 (9∼40)	0.685
Cold ischemic time	81 (8∼1437)	84 (27∼463)	0.670
Basiliximab induction	92 (70.8)	13 (33.3)	＜0.001
Main immunosuppression			＜0.001
None	3 (2.3)	0 (0)
Cyclosporin	55 (42.3)	33 (84.6)
Tacrolimus	72 (55.4)	6 (15.4)
MMF	84 (64.6)	21 (53.8)	0.260
Universal prophylaxis	47 (36.2)	28 (71.8)	＜0.001
Preemptive treatment	11 (8.5)	4 (10.3)	0.751
Follow-up duration (mo)	38.5 (1∼151)	27 (1∼157)	0.019

Data are presented as number (%) or median (range). Abbreviations: BPAR, biopsy-proven acute rejection; HCV, hepatitis C virus; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; MELD, model for end-stage liver disease; MMF, mycophenolate mofetil.

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