Progress in complete withdrawal of anti-hepatitis B drugs among HBV related liver transplantation recipients

doi:10.3877/cma.j.issn.1674-3903.2026.04.018

Abstract

Abstract:

Recent studies have demonstrated that complete discontinuation anti-HBV therapy (hepatitis B immunoglobulin + nucleoside analogues) may be safe and feasible in selected HBV-related liver transplantation recipients under rigorous scientific monitoring. Currently, clinically available predictive and evaluative markers mainly include HBV DNA, HBsAg, HBV cccDNA, HBV RNA, HBcrAg and HBcAb. The advent of novel markers and advances in detection assays may facilitate the identification and screening of candidates eligible for complete discontinuation of anti-HBV drugs after liver transplantation, further supporting scientific management after liver transplantation. This review elaborates on research progress regarding complete withdrawal of anti-hepatitis-B agents among HBV-related liver transplantation recipients, as well as relevant predictive and evaluative biomarkers to inform individualized postoperative clinical management.

Key words: Liver transplantation, Hepatitis B virus, HBV reinfection, HBV recurrence, Prophylaxis, Withdrawal

Lijun Wang, Wei Rao. Progress in complete withdrawal of anti-hepatitis B drugs among HBV related liver transplantation recipients[J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(04): 326-332.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhyzzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-3903.2026.04.018

https://zhyzzz.cma-cmc.com.cn/EN/Y2026/V20/I04/326

Figures/Tables 1

References 55

1	Terrault NA, Bzowej NH, Chang KM, et al; American Association for the Study of Liver Diseases. AASLD guidelines for treatment of chronic hepatitis B[J]. Hepatology, 2016, 63(1): 261-283.
2	中国肝移植注册中心. 2018年中国肝脏移植医疗质量报告[R]. 杭州：中国肝移植注册中心，2019.
3	Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection[J]. Nat Rev Dis Primers, 2018, 4: 18035.
4	Wong GLH, Gane E, Lok ASF. How to achieve functional cure of HBV: stopping NUCs, adding interferon or new drug development？[J]. J Hepatol, 2022, 76(6): 1249-1262.
5	Lenci I, Milana M, Grassi G, et al. Hepatitis B virus recurrence after liver transplantation: an old tale or a clear and present danger? [J]. World J Gastroenterol, 2020, 26(18): 2166-2176.
6	Cholongitas E, Papatheodoridis GV. High genetic barrier nucleos(t)ide analogue(s) for prophylaxis from hepatitis B virus recurrence after liver transplantation: a systematic review [J]. Am J Transplant, 2013, 13(2): 353-362.
7	Roche B, Samuel D. HBV prophylaxis after liver transplantation: close to the full success but at the price of long-term prophylaxis adapted to the risk of HBV recurrence [J]. Hepatol Int, 2023, 17(5): 1072-1074.
8	Fung J, Cheung C, Chan SC, et al. Entecavir monotherapy is effective in suppressing hepatitis B virus after liver transplantation [J]. Gastroenterology, 2011, 141(4): 1212-1219.
9	Fung J, Chan SC, Cheung C, et al. Oral nucleoside/nucleotide analogs without hepatitis B immune globulin after liver transplantation for hepatitis B [J]. Am J Gastroenterol, 2013, 108(6): 942-928.
10	Fung J, Wong T, Chok K, et al. Long-term outcomes of entecavir monotherapy for chronic hepatitis B after liver transplantation: results up to 8 years [J]. Hepatology, 2017, 66(4): 1036-1044.
11	Muthiah MD, Tan EY, Chua SHM, et al. Nucleoside analog monotherapy for prophylaxis in hepatitis B liver transplant patients is safe and efficacious [J]. Hepatol Int, 2020, 14(1): 57-69.
12	姜晓青，解曼，张群，等. 替诺福韦单一用药预防肝移植术后乙肝复发的疗效分析 [J/CD]. 实用器官移植电子杂志，2021, 9(2): 139-145.
13	Lenci I, Tisone G, Di Paolo D, et al. Safety of complete and sustained prophylaxis withdrawal in patients liver-transplanted for HBV-related cirrhosis at low risk of HBV recurrence [J]. J Hepatol, 2011, 55(3): 587-593.
14	Lenci I, Baiocchi L, Tariciotti L, et al. Complete hepatitis B virus prophylaxis withdrawal in hepatitis B surface antigen-positive liver transplant recipients after longterm minimal immunosuppression [J]. Liver Transpl, 2016, 22(9): 1205-1213.
15	Duan BW, Tian LT, Lin DD, et al. Long-term consequences of stopping HBIG and/or nucleotide analogues in liver transplant recipients administered hepatitis B vaccination to prevent HBV reinfection [J]. J Viral Hepat, 2019, 26(Suppl 1): 85-89.
16	Xie M, Zang YJ, Zhang B, et al. Successful withdrawal of antiviral treatment in two HBV-related liver transplant recipients after hepatitis B vaccination with long-term follow-up [J]. Hepatobiliary Pancreat Dis Int, 2021, 20(6): 595-597.
17	Geng L, Lin BY, Shen T, et al. Anti-virus prophylaxis withdrawal may be feasible in liver transplant recipients whose serum HBeAg and HBV DNA are negative [J]. Hepatobiliary Pancreat Dis Int, 2016, 15(3): 316-318.
18	Duvoux C, Belli LS, Fung J, et al. 2020 position statement and recommendations of the European Liver and Intestine Transplantation Association (ELITA): management of hepatitis B virus-related infection before and after liver transplantation [J]. Aliment Pharmacol Ther, 2021, 54(5): 583-605.
19	中华医学会肝病学分会，中华医学会感染病学分会. 慢性乙型肝炎防治指南(2022年版)[J]. 中华肝脏病杂志，2022, 30(12): 1309-1331.
20	刘明琛，杨兴雯，彭思雯，等. 核苷(酸)类药物对慢性乙型肝炎患者血清HBV DNA和RNA定量检测的影响 [J]. 中华实验和临床病毒学杂志，2021, 35(3): 305-311.
21	Otsuka M, Koike K. Should level of HBV RNA be used to determine when patients should stop treatment with nucleos(t)ide analogues [J]. Clin Gastroenterol Hepatol, 2020, 18(3): 551-552.
22	Wong DK, Yuen MF, Ngai VW, et al. One-year entecavir or lamivudine therapy results in reduction of hepatitis B virus intrahepatic covalently closed circular DNA levels [J]. Antivir Ther, 2006, 11(7): 909-916.
23	张长坤，高杰，汪洋，等. 乙型肝炎病毒背景肝移植患者术后长期抗乙型肝炎病毒治疗的策略研究[J]. 中华普通外科杂志，2023, 38(6): 435-440.
24	Izumi T, Toshima T, Itoh S, et al. Novel protocol for prevention from hepatitis B reactivation following living-donor liver transplantation[J]. Hepatol Res, 2024. [Epub ahead of print]
25	Yuen MF, Lim SG, Plesniak R, et al. Efficacy and safety of bepirovirsen in chronic hepatitis B infection [J]. N Engl J Med, 2022, 387(21): 1957-1968.
26	Nasir M, Wu GY. Prevention of HBV recurrence after liver transplant: a review [J]. J Clin Transl Hepatol, 2020, 8(2): 150-160.
27	中华医学会器官移植学分会，中华医学会肝病学分会. 中国肝移植乙型肝炎防治指南(2016版) [J]. 中华肝脏病杂志，2016, 12(24): 885-891.
28	Orfanidou A, Papatheodoridis GV, Cholongitas E. Antiviral prophylaxis against hepatitis B recurrence after liver transplantation: current concepts[J]. Liver Int, 2021, 41(7): 1448-1461.
29	Duan BW, Lu SC, Lai W, et al. The detection of (total and ccc) HBV DNA in liver transplant recipients with hepatitis B vaccine against HBV reinfection [J]. Hum Vaccin Immunother, 2015, 11(10): 2490-2494.
30	鲁凤民，于乐成，高林，等. HBeAg阴性慢性乙型肝炎患者停药后HBsAg可阴转：停药-治愈策略或许正在来临[J]. 中华医学杂志，2022, 102(40): 3160-3166.
31	Lau KCK, Osiowy C, Giles E, et al. Deep sequencing shows low-level oncogenic hepatitis B virus variants persists post-liver transplant despite potent anti-HBV prophylaxis [J]. J Viral Hepat, 2018, 25(6): 724-732.
32	Faria LC, Gigou M, Roque-Afonso AM, et al. Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation[J]. Gastroenterology, 2008, 134(7)：1890-1899; quiz 2155.
33	Yuen MF, Chen DS, Dusheiko GM, et al. Hepatitis B virus infection[J]. Nat Rev Dis Primers, 2018, 4: 18035.
34	Leung RH, Hui RW, Mak LY, et al. ALT to qHBsAg ratio predicts long-term HBsAg seroclearance after entecavir cessation in Chinese patients with chronic hepatitis B[J]. J Hepatol, 2024, 81(2): 218-226.
35	Roche B, Roque-Afonso AM, Nevens F, et al. Rational basis for optimizing short and long-term hepatitis B virus prophylaxis post liver transplantation: role of hepatitis B immune globulin [J]. Transplantation, 2015, 99(7): 1321-1334.
36	Roche B, Samuel D. Withdrawal of posttransplant hepatitis B virus prophylaxis: a blind test [J]. Liver Transpl, 2016, 22(9): 1183-1185.
37	Matsuzaki T, Tatsuki I, Otani M, et al. Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation [J]. J Gastroenterol Hepatol, 2013, 28(7): 1217-1222.
38	中华医学会肝病学分会基础医学与实验诊断协作组. 乙型肝炎病毒标志物临床应用专家共识[J]. 中华肝脏病杂志，2023, 31(4): 389-400.
39	中华医学会感染病学分会，中华医学会肝病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 中华肝脏病杂志，2019, 27(12): 938-961.
40	Cornberg M, Lok A SF, Terrault NA, et al. Guidance for design and endpoints of clinical trials in chronic hepatitis B - Report from the 2019 EASL-AASLD HBV Treatment Endpoints Conference[J]. Hepatol, 2020, 72(3)：539-557.
41	European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67(2)：370-398.
42	Xia M, Chi H, Wu Y, et al. Serum hepatitis B virus RNA level is associated with biochemical relapse in patients with chronic hepatitis B infection who discontinue nucleos(t)ide analogue treatment [J]. Aliment Pharmacol Ther, 2021, 54(5): 709-714.
43	Papatheodoridi M, Papachristou E, Moschidis Z, et al. Significance of serum HBV RNA in non-cirrhotic HBeAg-negative chronic hepatitis B patients who discontinue effective antiviral therapy [J]. J Viral Hepat, 2022, 29(11): 948-957.
44	Seto WK, Liu KS, Mak LY, et al. Role of serum HBV RNA and hepatitis B surface antigen levels in identifying Asian patients with chronic hepatitis B suitable for entecavir cessation [J]. Gut, 2021, 70(4): 775-783.
45	Liu Y, Xue J, Liao W, et al. Serum HBV RNA dynamic and drug withdrawal predictor value in patients with chronic HBV infection on long-term nucleos(t)ide analogue (NA) therapy [J]. J Clin Gastroenterol, 2020, 54(8): e73-e82.
46	Fan R, Zhou B, Xu M, et al. Association between negative results from tests for HBV DNA and RNA and durability of response after discontinuation of nucles(t)ide analogue therapy [J]. Clin Gastroenterol Hepatol, 2020, 18(3): 719-727.e7.
47	Inoue T, Matsui T, Tanaka Y. Novel strategies for the early diagnosis of hepatitis B virus reactivation [J]. Hepatol Res, 2021, 51(10): 1033-1043.
48	Testoni B, Lebosse F, Scholtes C, et al. Serum hepatitis B core-related antigen (HBcrAg) correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients [J]. J Hepatol, 2019, 70(4): 615-625.
49	Hagiwara S, Kusumoto S, Inoue T, et al. Management of hepatitis B virus (HBV) reactivation in patients with resolved HBV infection based on a highly sensitive HB core-related antigen assay [J]. Hepatol Res, 2022, 52(9): 745-753.
50	中华医学会感染病学分会，中华医学会肝病学分会. 慢性乙型肝炎临床治愈(功能性治愈)专家共识[J]. 中华肝脏病杂志，2019, 27(8): 594-603.
51	Caviglia GP, Abate ML, Tandoi F, et al. Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: a new tool to detect occult infection [J]. J Hepatol, 2018, 69(2): 301-307.
52	Fan R, Sun J, Yuan Q, et al. Baseline quantitative hepatitis B core antibody titre alone strongly predicts HBeAg seroconversion across chronic hepatitis B patients treated with peginterferon or nucleos(t)ide analogues [J]. Gut, 2016, 65(2): 313-320.
53	Lou B, Ma G, Lv F, et al. Baseline quantitative hepatitis B core antibody titer is a predictor for hepatitis B virus infection recurrence after orthotopic liver transplantation [J]. Front Immunol, 2021, 12: 710528.
54	Chi H, Li Z, Hansen BE, et al. Serum level of antibodies against hepatitis B core protein is associated with clinical relapse after discontinuation of nucleos(t)ide analogue therapy [J]. Clin Gastroenterol Hepatol, 2019, 17(1): 182-191.e1.
55	Lazarevic I, Banko A, Miljanovic D, et al. Clinical utility of quantitative HBV core antibodies for solving diagnostic dilemmas [J]. Viruses, 2023, 15(2)：373.

文献	例数(例)	停药指标	原发病	肝移植后抗HBV方案	停药时移植时间(月)	随访时间(月)	HBV再感染(例)	HBV再治疗	HBsAb血清学转变	预后
Lenci等^[13,14]	30^*	移植肝内HBV DNA和cccDNA均阴性，且肝移植前HBeAg(－)，肝移植后HBV DNA(－)	29例肝硬化、4例HCC	28例HBIG＋LAM，2例HBIG＋LAM＋ADV	>36	77±5.8	6^a	3例(1例HBIG＋LAM、2例TDF)	3例(复发组)＋15例(未复发组)	良好
Duan等^[15]	36	乙肝疫苗应答者[HBsAb滴度440(102.3~1 000)IU/L]	－	ETV/LAM/ADV＋HBIG	>18	64(2~132)	4^b	4例(2例ETV、1例ETV＋TDF、1例ADV＋ETV)	2例	良好
Xie等^[16]	2	HBV DNA阴性乙肝疫苗应答者(HBsAb滴度>100 IU/L)	慢加急性肝衰竭、肝硬化	HBIG＋LAM、ETV＋HBIG	46、60	128、82	0	－	－	良好
Geng等^[17]	10	自行停药(9例肝移植前HBV DNA、HBeAg和cccDNA均阴性)	非HCC	HBIG＋LAM	23.8(13~42)	48(8~73)	1^c	1例(ETV)	－	良好

文献	例数(例)	停药指标	原发病	肝移植后抗HBV方案	停药时移植时间(月)	随访时间(月)	HBV再感染(例)	HBV再治疗	HBsAb血清学转变	预后
Lenci等^[13,14]	30^*	移植肝内HBV DNA和cccDNA均阴性，且肝移植前HBeAg(－)，肝移植后HBV DNA(－)	29例肝硬化、4例HCC	28例HBIG＋LAM，2例HBIG＋LAM＋ADV	>36	77±5.8	6^a	3例(1例HBIG＋LAM、2例TDF)	3例(复发组)＋15例(未复发组)	良好
Duan等^[15]	36	乙肝疫苗应答者[HBsAb滴度440(102.3~1 000)IU/L]	－	ETV/LAM/ADV＋HBIG	>18	64(2~132)	4^b	4例(2例ETV、1例ETV＋TDF、1例ADV＋ETV)	2例	良好
Xie等^[16]	2	HBV DNA阴性乙肝疫苗应答者(HBsAb滴度>100 IU/L)	慢加急性肝衰竭、肝硬化	HBIG＋LAM、ETV＋HBIG	46、60	128、82	0	－	－	良好
Geng等^[17]	10	自行停药(9例肝移植前HBV DNA、HBeAg和cccDNA均阴性)	非HCC	HBIG＋LAM	23.8(13~42)	48(8~73)	1^c	1例(ETV)	－	良好

[1]	Xun Liu, Liang Bi, Ren Lang, Anshi Wu. Analysis of risk factors for early mortality after orthotopic liver transplantation [J]. Chinese Archives of General Surgery(Electronic Edition), 2026, 20(03): 150-156.
[2]	Gongjie Ye, Shi Zheng, Yiru Weng, Zhouzhou Dong. The value of NMF standard in selecting the timing of renal replacement therapy for patients with acute kidney injury after liver transplantation [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(04): 260-267.
[3]	Branch of Organ Transplantation, Chinese Medical Association, Branch of Organ Transplant Physicians, Chinese Medical Doctor Association, Environmental Oncology Committee of China Anti Cancer Association. Clinical practice guideline for diagnosis and treatment of de novo malignancy in adult liver transplantation recipient (2026 edition) [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(03): 145-157.
[4]	Changjiang Zhang, Ruolin Wu, Zhixiang He, Lingbao Kong, Minhui Huang, Heng Ge, Hongchuan Zhao. Recurrence of hepatitis B and its influencing factors after liver transplantation [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(03): 168-173.
[5]	Jing Yang, Huafen Wang, Fangyan Lu, Li Dong, Lei Lan. The impact of preoperative nutritional status on early postoperative clinical outcomes in pediatric liver transplantation [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(03): 174-179.
[6]	Luojiaoya Lin, Shilong Xie, Ying Chen, Wei Zhang, Fangyan Lu. Liver transplantation for liver failure in pregnancy: two case reports and literature review [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(03): 193-196.
[7]	Shuo Wang, Qinfen Xie, Wu Gu, Li Zhuang, Zhuoyi Wang, Shusen Zheng, Zhe Yang. Extracorporeal membrane oxygenation-assisted liver transplantation for liver failure complicated by malignant arrhythmia and cardiogenic shock: a case report [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(03): 197-200.
[8]	Qinfen Xie, Shuo Wang, Yu Yang, Shusen Zheng. Timing and prognostic factors of liver transplantation in acute-on-chronic liver failure [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(03): 201-210.
[9]	Jinyan Chen, Zhu Li, Xiao Xu, Di Lu. Multidimensional intervention and rehabilitation strategies for sarcopenia in liver transplant recipients [J]. Chinese Journal of Transplantation(Electronic Edition), 2026, 20(03): 215-221.
[10]	Zuyu Wang, Xiaoan Liu, Hanxuan Wang, Shaocheng Lyu, Ren Lang. Influencing factors and prediction model construction for refractory hypersplenism after liver transplantation for benign end-stage liver diseases [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2026, 15(04): 606-611.
[11]	Wanqi Lin, Fangfei Ren, Weihang Zhong, Qing Yang, Ling Ma, Haili Chen, Sha Xiang, Mengjiao Chen, Liping Zhu, Xinnian He, Xianling Zhang. Application and efficacy of prospective interventional strategies based on multi-dimensional evaluation in perioperative period of liver transplantation for liver cancer [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2026, 15(04): 612-618.
[12]	Yu Ding, Qian Lin, Zhi Wang, Wenrui Wu, Kelin Zhang, Haixuan Zhao. Construction of a simplified scoring model for the risk of early postoperative infection after liver transplantation and its hierarchical nursing strategies [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2026, 15(04): 619-626.
[13]	Jianliang Yang, Ailing Zhang, Xiaoming Wang, Tianxing Dai, Feng Yuan, Canhua Zhu, Lan Lan, Hanyu Yang, Guoying Wang. Clinical application of fast-track anesthesia with early tracheal extubation after liver transplantation [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2026, 15(03): 398-404.
[14]	Xiaoyong Ye, Lin Zhou. Progress in application of tolerant dendritic cells in immune tolerance of liver transplantation [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2026, 15(03): 420-425.
[15]	·Maimaiti Maiwulanjiang, ·Tulading Aliya, ·Tuxun Tuerhongjiang. Immunosuppression strategy for ABO-incompatible liver transplantation [J]. Chinese Journal of Hepatic Surgery(Electronic Edition), 2026, 15(02): 152-159.

Please choose a citation manager

Content to export