Lei Geng， Bing-Yi Lin， Tian Shen， Hua Guo， Yu-Fu Ye and Shu-Sen Zheng Hangzhou， China

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Anti-virus prophylaxis withdrawal may be feasible in liver transplant recipients whose serum HBeAg and HBV DNA are negative

Lei Geng， Bing-Yi Lin， Tian Shen， Hua Guo， Yu-Fu Ye and Shu-Sen Zheng Hangzhou， China

ABSTRACT:Anti-virus prophylactic therapy may be not necessary for the prevention of hepatitis B virus （HBV） recurrence after HBV-related liver transplantation （LT）. However，studies on completely stopping the hepatitis B immune globulin （HBIG） and nucleos（t）ide analogs （NUC） after LT are few. The aim of the current study was to evaluate the safety of antivirus prophylaxis withdrawal in liver recipients whose serum hepatitis B e antigen （HBeAg） and HBV DNA are negative. We analyzed 190 patients undergone LT for HBV-related liver disease from 2006 to 2012 and found that 10 patients completely stopped the HBIG and NUC due to poor compliance. These patients were liver biopsied and checked monthly with serum HBV markers， HBV DNA and liver function. Among the 10 patients， 9 did not show the signs of HBV recurrence after a mean follow-up of 51.6 months （range 20-73） after withdrawal of the HBIG and NUC. The average time from LT to the withdrawal of the anti-virus drug was 23.8 （13-42） months；one patient showed hepatitis B surface antigen-positive and detectable HBV DNA after stopping anti-virus drugs and this patient was successfully treated with entecavir. Our data suggested that complete withdrawal of anti-virus prophylaxis was safe and feasible for patients whose serum HBeAg and HBV DNA were negative at the time of LT.

（Hepatobiliary Pancreat Dis Int 2016；15:316-318）

KEY WORDS:anti-virus prophylaxis withdrawal；HBeAg；HBV DNA；liver transplantation

Author Affiliations: Division of Hepatobiliary and Pancreatic Surgery，Department of Surgery， First Affiliated Hospital， Zhejiang University School of Medicine， Hangzhou 310003， China （Geng L， Shen T， Guo H，Ye YF and Zheng SS）； Key Laboratory of Combined Multi-organ Transplantation， Ministry of Public Health， Key Laboratory of Organ Transplantation and Collaborative Innovation Center for Diagnosis Treatment of Infectious Diseases， Hangzhou 310003， China （Geng L， Lin BY， Shen T，Guo H， Ye YF and Zheng SS）

? 2016， Hepatobiliary Pancreat Dis Int. All rights reserved.

Published online April 20， 2016.

Introduction

Patients with chronic hepatitis B virus （HBV） infection are HBV-specific immunotolerance， the recurrence of HBV after liver transplantation （LT） is as high as 80% in the absence of effective prophylaxis and life-long anti-virus prophylaxis is currently advocated.［1］The standard therapy for preventing HBV reinfection of the allograft is the combination of hepatitis B immune globulin （HBIG） and nucleos（t）ide analogs （NUC） therapy after LT. This combination prevents HBV recurrence in most of the liver recipients.［2］However， the major drawbacks of long-term use of HBIG are high cost and monthly titer test.［3］With the availability of new higher antiviral potency of NUC such as entecavir and tenofovir，HBIG-free regimen has recently been implemented with encouraging results. Nevertheless， drug-resistance is a principal disadvantage of life-long NUC administration.［3， 4］

It is widely accepted that the risk of HBV recurrence after LT is directly proportional to the level of viral replication prior to transplantation. The recipients with seronegative for hepatitis B e antigen （HBeAg） and undetectable HBV DNA have the lowest rate of recurrence after LT.［5， 6］This indicates that indefinite discontinuation of anti-virus prophylaxis is feasible for patients with low risk of recurrence. Lenci et al［7］found that 83% of HBeAg and HBV DNA negative liver recipients did not show HBV recurrence with a 2-year follow-up. However，this notion needs further validation.

The current study was to further validate the safety and feasibility of anti-virus prophylaxis withdrawal in liver recipients whose serum HBeAg and HBV DNA were negative at the time of LT.

Methods

A total of 190 patients who had undergone LT for HBV-related liver disease from 2006 to 2012 were enrolled in this analysis in LT Center， First Affiliated Hospital， Zhejiang University School of Medicine. Hepatocellular carcinoma patients were excluded from the study. Ten patients were found to completely stop the HBIG and NUC after LT because of poor compliance. These patients were liver biopsied and checked monthly with serum HBV markers including hepatitis B surface antigen （HBsAg），HBeAg， hepatitis B core antibody （HBcAb）， HBV DNA and liver function. Serum and liver tissue HBV DNA was detected by real-time PCR. HBV recurrence was defined as serum HBsAg positive and detectable HBV DNA.

Results

All of the 10 patients received routinely prophylactic therapy consisting of 400-800 IU HBIG monthly intramuscular injection to maintain the antibody titer over 100 IU/L and lamivudine （LAM） 100 mg per day. Tacrolimus （FK506） was used as immunosuppressant. Mycophenolate-mofetil （MMF） was also used in 4 patients. The FK506 concentration was lower than 3 ng/mL when stopping anti-virus drugs. They did not experience acute rejection， biliary complication， arterial hypertension，hypercholesterolemia， diabetes mellitus or renal function deterioration during the study. Donor’s serum viral markers of HBV were negative.

Nine patients did not exhibit the signs of HBV recurrence after a mean follow-up of 51.6 months （range 20-73） after stopping HBIG and NUC. HBV DNA was undetectable in the serum and liver sample. The average time between LT and anti-virus drug withdrawal was 23.8 months （range 13-42）. A final biopsy showed no pathological findings. The patients average age was 46.67 years， seven of them were female； they were HBsAg positive， HBeAg negative and undetectable HBV DNA at the time of LT （Table）.

A 50-year-old woman became HBsAg-positive with detectable HBV DNA after stopping anti-virus drugs. Her HBsAg and HBeAg were positive and serum HBV DNA level was 3×106IU/mL at the time of LT. At the eighth month after stopping anti-virus drugs， she exhibited serological signs of HBV recurrence with abnormal liver graft function. Her serum HBV DNA was 4×105IU/mL. Sequencing analysis of the entire HBV genome showed that she had LAM resistant mutations （M204V+L180M）. She was successfully treated with entecavir and her serum HBV DNA was undetectable after 5 months.

Table. Characteristics of patients successfully stopping anti-HBV drugs

Discussion

Because of the high cost and drug-resistance of the combined use of HBIG and NUC， studies on modification of treatment including NUC monotherapy， HBsAg vaccination and even complete withdrawal of prophylaxis havebeen conducted in liver recipients.［4， 7， 8］Most importantly，the withdrawal of anti-virus prophylactic treatment may represent an ultimate feasible strategy.［9］Lenci et al［7］first reported complete prophylaxis withdrawal in 30 patients and a successful rate of 83.3% in 2011. From then on， no study provided data supporting the complete prophylaxis withdrawal. We analyzed the 190 patients and found that 10 patients stopped anti-virus therapy due to poor compliance， and 9 of them did not exhibit HBV recurrence after a follow-up for 20-73 months.

It is critical to identify clinical parameters associated with a high likelihood of successful withdrawal of antivirus drugs. It is widely accepted that pre-transplant virus replication status is the most HBV recurrent related factor. In patients with pre-transplant negative HBeAg and HBV DNA， the risk of HBV recurrence is very low.［5， 6］Lenci et al showed that 25 of the 30 patients with pre-transplant negative HBeAg and HBV DNA did not have HBV recurrence. Our analysis showed that 9 patients with HBeAg negative and undetectable HBV DNA at the time of LT did not have HBV recurrence after antivirus prophylaxis withdrawal. The current protocol of stopping HBIG and NUC administration was to wean the HBIG and NUC prophylaxis gradually.［7］Our analysis supports the viewpoint that post-transplant complete anti-virus prophylaxis withdrawal is feasible in patients with low risk of HBV recurrence. Furthermore， the time of follow-up in our study was 20-73 months which was longer than that of Lenci et al study，［7］indicating that anti-virus prophylaxis withdrawal is safe. Besides of the character of HBeAg and HBV DNA negative at the time of LT， 9 patients maintained lower tacrolimus concentrations （＜3 ng/mL）. This may provide more valuable information on how to select patients.

One patient in our analysis showed positive HBeAg and detective HBV DNA at LT and this patient experienced HBV recurrence which was successfully treated with entecavir. HBV DNA became undetectable after 5 months， which implied that the recurrence of HBV could be easily managed.［10］

In conclusion， our study provided the facts that stopping life-long and expensive prophylaxis in patients with low risk of recurrence after LT is practical， but further large-scale studies are needed.

Contributors: GL and ZSS proposed the study. ST collected the data. LBY and GH analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. ZSS is the guarantor.

Funding: This study was supported by grants from the National Natural Science Foundation of China （81373160 and 81400673），and Zhejiang Provincial Natural Science Foundation of China （LQ15H030003 and LY14H160022）.

Ethical approval: The study was approved by the Ethics committee of First Affiliated Hospital， Zhejiang University School of Medicine.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

References

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Received December 22， 2015

Accepted after revision March 30， 2016

Corresponding Author:Shu-Sen Zheng， MD， PhD， FACS， Division of Hepatobiliary and Pancreatic Surgery， Department of Surgery， First Affiliated Hospital， Zhejiang University School of Medicine， Hangzhou 310003， China （Tel: +86-571-87236570； Fax: +86-571-87236628； Email: zyzss@zju.edu.cn）

doi:10.1016/S1499-3872（16）60087-5