Accepted Manuscript Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation Songfeng Yu, Jun Yu, Wei Zhang, Longyu Cheng, Yufu Ye, Lei Geng, zhiyong Yu, Sheng Yan, Lihua Wu, Weilin Wang, Shusen Zheng PII: DOI: Reference:

S0168-8278(14)00312-2 http://dx.doi.org/10.1016/j.jhep.2014.05.003 JHEPAT 5154

To appear in:

Journal of Hepatology

Received Date: Revised Date: Accepted Date:

7 January 2014 1 May 2014 5 May 2014

Please cite this article as: Yu, S., Yu, J., Zhang, W., Cheng, L., Ye, Y., Geng, L., Yu, z., Yan, S., Wu, L., Wang, W., Zheng, S., Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation, Journal of Hepatology (2014), doi: http://dx.doi.org/10.1016/j.jhep.2014.05.003

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Safe use of liver grafts from hepatitis B surface antigen positive donors in liver transplantation

Authors: Songfeng Yu1,2,3*, Jun Yu1,2,3*, Wei Zhang1,2,3, Longyu Cheng2,3, Yufu Ye1,2,3, Lei Geng1,2,3, zhiyong Yu 1,2,3, Sheng Yan1,2,3, Lihua Wu 2,3, Weilin Wang1,2,3, Shusen Zheng1,2,3,4

Department and institution: 1

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First

Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. 2

Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public

Health, Hangzhou, China. 3

Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, China.

4

Corresponding author

*

These authors contributed equally to this work.

Correspondence To: Prof. Shusen Zheng, E-mail: [email protected]. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. Tel: +86-571-87236601; Fax: +86-571-87236739;

Abbreviations: LTx, liver transplantation; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBIG, hepatitis B immunoglobulin; NAs, nucleotide analogues; HBcAb, hepatitis B core antibody; MELD, model for end stage liver disease; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; ALT, alanine transaminase; AST, aspartate aminotransferase; TB, total bilirubin; DB, direct 1

bilirubin; PT, prothrombin time

Conflict of interest: The authors declare that they have no conflict of interest with respect to this manuscript.

Funding: This study was supported by the Project of Education department of Zhejiang Province

(No.Y201330248),

the

National

S&T

Major

Project

(No.2012ZX10002017), and the Major Program of Science and Technology Bureau of Zhejiang Province (No.2009R50038).

2

Abstract: Background and Aims: Liver grafts from hepatitis B surface antigen (HBsAg) positive donors could have potential to increase the donor pool. However, knowledge is extremely limited in this setting because currently available data are mostly from case reports. We aimed to assess the outcomes and experiences of liver transplantation from HBsAg positive donors in a single center study. Methods: From January 2010 to February 2013, 42 adult patients underwent liver transplantation from HBsAg positive donors and 327 patients from HBsAg negative ones. The outcomes including complications and survival of two groups were compared and antiviral therapy retrospectively reviewed. Results: HBsAg positive liver grafts were more likely to be allocated to patients with hepatitis B (HBV)-related diseases. Post-transplant evaluation showed similar graft function regaining pace and no differences in complications such as primary nonfunction, acute rejection and biliary complications. Patient and graft survivals were comparable to that of HBsAg negative grafts. Furthermore, HBsAg persisted after transplant in all patients that received positive grafts. Donor HBV serum status determined that of recipient after transplantation. No HBV flare-ups were observed under antiviral therapy of oral nucleotide analogues, regardless of using hepatitis B immunoglobulin combination. Conclusions: Utilization of HBsAg positive liver grafts seems to not increase postoperative morbidity and mortality. Therefore it is a safe way to expand donor pool when no suitable donor is available. Our experience also suggests that hepatitis B immunoglobulin should be abandoned in recipients of HBsAg positive liver grafts, in whom HBV prophylaxis could be the only oral antiviral therapy. Key words: Liver transplantation; HBsAg positive donor; Marginal graft; Antiviral therapy 3

Introduction Liver transplantation (LTx) is currently the only curative option for patients with end-stage liver diseases. The disparity between the large amount of patients waiting for LTx and the limited available donor organs has become a worldwide problem. To overcome the donor shortage, many transplantation centers have expanded the criteria for transplant donors by utilizing so called “marginal grafts” that might have been discarded previously， including liver grafts from donors with evidence of viral infection[1]. The use of hepatitis C positive grafts has been demonstrated to have no deleterious effect when transplanted into hepatitis C patients[2, 3]. Hepatitis B virus (HBV) infection is a more global problem, and over 2 billion people worldwide have evidence of HBV infection[4]. A nationwide survey of HBV in the general Chinese population showed that approximately 7.2% were hepatitis B surface antigen (HBsAg) positive carriers[5]. Therefore, utilizing HBsAg positive donor grafts could largely increase the number of potential liver donors and benefit for expanding the donor pool, especially in high HBV prevalence areas such as Asia and Africa. It is well known that transplanting liver grafts from donors with past or present HBV infection results in a high risk of HBV transmission from donor to recipient. With the antiviral prophylaxis of hepatitis B immunoglobulin (HBIG) and nucleoside analogues (NAs), many studies have shown that using liver grafts from hepatitis B core antibody (HBcAb) positive donors, which indicating past HBV infection, does not affect graft or patient survival[6-8]. One recent paper argued that the outcome of using such grafts was less favorable than previously thought, particularly when allocated to HBsAg negative recipients without appropriate prophylaxis[9]. Yet others believed that these grafts could even be safely used in HBV naïve recipients without an increase in mortality or graft loss while demanding lifelong prophylaxis[10]. However, experience is extremely limited for liver grafts from HBsAg positive carriers without significant liver diseases. Data from the literature shows that most available studies in this setting of LTx are single center cases or case series reports[11-17]. Two recent reports 4

including ours reviewed the outcome of a small number of patients who received HBsAg positive liver grafts based on the US national database[18, 19]. Although results of these studies were encouraging, the small number of patients in limited studies was not sufficient to draw a firm conclusion. Furthermore, the optimal regimen of antiviral prophylaxis after LTx with such grafts is still not well defined. Herein, we report our results with a promising outcome of LTx patients by using HBsAg positive liver grafts in a single transplantation center in China. In addition, we also evaluated the role of HBIG in post transplant antiviral prophylaxis for such grafts.

Patients and methods From January 2010 to February 2013, 42 adult patients underwent LTx from HBsAg positive donors at our center. All grafts were procured from donors after cardiac death. We declared that no donor organs were obtained from executed prisoners. The outcomes of those 42 recipients were reviewed in this study. As controls, 327 patients who received liver grafts from HBsAg negative deceased donors during the same time period were also enrolled. All patients receiving HBsAg positive liver grafts were informed of the possible risks and potential poor prognosis before transplantation. Ethical approval of each transplant was obtained from the Committee of Ethics in Biomedical Research of Zhejiang University, and in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. Written informed consent was obtained from all participants. Evaluation and allocation of HBsAg positive liver grafts Pre-transplant evaluation of liver graft focused on liver function, serovirological tests and liver biopsy at the site of explant. HBsAg positive graft was used only when documented a normal liver function, a fibrosis Ishak score