Long-term safety and effectiveness of withdrawal of HBIG and/or nucleos(t)ide analogues in recipients undergoing hepatitis B immune reconstitution after liver transplantation
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摘要:
目的 探讨乙型病毒性肝炎（乙肝）相关疾病肝移植受者接种乙肝疫苗成功后长期停用乙型肝炎免疫球蛋白（HBIG）和（或）核苷（酸）类似物（NAs）预防乙型肝炎病毒（HBV）再感染的安全性及有效性。 方法 回顾性分析76例接种乙肝疫苗后成功重建乙肝主动免疫的肝移植受者的基本资料，分析疫苗接种及应答情况、应答者停用HBIG和（或）NAs的随访结果、停用HBIG和（或）NAs后HBV再感染情况。 结果 肝移植术后至开始接种乙肝疫苗的时间间隔为26（20，40）个月。接种疫苗至应答时间为15（8，27）个月。初始76例受者全部停用HBIG，36例受者停用HBIG和NAs。随访期间，76例停用HBIG受者中12例恢复使用HBIG，36例停用HBIG和NAs者中16例恢复使用NAs。HBIG和NAs停用时间分别为135（98，150）个月与133（34，149）个月。16例应答者未接种过加强针，36例应答者定期接种加强针，第1次接种加强针的时间距离停用HBIG的间隔时间为44（11，87）个月，未接种加强针和接种加强针的应答者一般资料比较差异均无统计学意义（均为P>0.05）。截止至随访日，9例受者失访，5例HBV再感染，3例受者死亡，1例受者移植物丢失并进行二次肝移植。5例HBV再感染受者中4例发生病毒变异。再感染者与未感染者是否停用NAs、移植前乙型肝炎e抗原（HBeAg）是否为阳性差异有统计学意义（均为P＜0.05）。 结论 乙肝相关疾病肝移植术后乙肝主动免疫重建成功的受者长期停用HBIG是可行和安全的，但能否同时停用NAs还需要进一步研究。 Abstract:Objective To investigate the long-term safety and effectiveness of withdrawal of hepatitis B immuneglobulin (HBIG) and nucleos(t)ide analogues (NAs) to prevent hepatitis B virus (HBV) reinfection in liver transplant recipients with hepatitis B-related diseases after successful vaccination. Methods Baseline data of 76 liver transplant recipients undergoing hepatitis B immune reconstitution after receiving hepatitis B vaccines were retrospectively analyzed. The vaccination and response, the follow-up results of respondents with HBIG and/or NAs withdrawal, and the reinfection of HBV after withdrawal of HBIG and/or NAs were analyzed. Results The time interval from liver transplantation to hepatitis B vaccination was 26 (20, 40) months. The time interval from vaccination to response was 15 (8,27) months. Initially, 76 recipients withdrew HBIG, and 36 recipients withdrew HBIG and NAs. During the follow-up, 12 of 76 recipients who withdrew HBIG resumed use of HBIG, and 16 of 36 recipients who withdrew HBIG and NAs resumed use of NAs. The withdrawal time of HBIG and NAs was 135 (98,150) and 133 (34,149) months, respectively. Sixteen respondents did not receive booster, and 36 respondents received boosters on a regular basis. The time interval between the first boosters and HBIG withdrawal was 44 (11,87) months. No significant differences were observed in baseline data between the respondents with and without boosters (all P>0.05). During the follow-up, 9 recipients were lost to follow-up, 5 were re-infected with HBV, 3 died, and 1 recipient developed graft loss and underwent secondary liver transplantation. Among 5 recipients re-infected with HBV, 4 cases had virus mutation. Significant differences were found between re-infected and uninfected patients regarding withdrawal of NAs and hepatitis B e antigen (HBeAg) positive before transplantation (both P<0.05). Conclusions Long-term withdrawal of HBIG is feasible and safe for recipients with successful hepatitis B immune reconstitution after liver transplantation for hepatitis B-related diseases. Nevertheless, whether antiviral drugs can be simultaneously withdrawn remains to be validated. -
表 1 未接种加强针和接种加强针的应答者临床资料比较
Table 1. Comparison of the clinical data between respondents who did not receive boosters and those who received boosters
项目 未接种加强针（n=16） 接种加强针（n=36） P值 年龄（$\overline {{x}}\pm s $，岁） 62±10 61±10 0.785 性别男[n（%）] 9（56） 27（75） 0.176 原发病[n（%）] 0.109 失代偿期肝硬化 7（44） 13（36） 肝衰竭 6（38） 6（17） 原发性肝癌 3（19） 17（47） 肝移植到疫苗接种时间[M（P25，P75），月] 25（18，37） 26（20，44） 0.918 停用HBIG到停用NAs间隔时间[M（P25，P75），月] 5.7（3.3，9.8） 2.8（1.0，6.5） 0.871 HBIG停药持续时间[M（P25，P75），月] 141（125，144） 145（122，166） 0.159 NAs停药持续时间[M（P25，P75），月] 130（33，136） 153（59，169） 0.279 抗-HBs滴度①[M（P25，P75），IU/L] 179（128，911） 184（116，291） 0.300 抗病毒药①[n（%）] 0.350 替比夫定 1（6） 1（3） 恩替卡韦 3（19） 14（39） 替诺福韦 6（38） 8（22） 恩替卡韦+替诺福韦 0 1（3） 恩替卡韦+替比夫定 0 1（3） 免疫抑制方案①[n（%）] 0.416 他克莫司 6（38） 18（50） 他克莫司+吗替麦考酚酯 5（31） 11（31） 他克莫司+西罗莫司 2（13） 2（6） 吗替麦考酚酯 3（19） 1（3） 他克莫司+吗替麦考酚酯+西罗莫司 0 1（3） 吗替麦考酚酯+西罗莫司 0 1（3） 环孢素 0 1（3） 停用过NAs[n（%）] 8（50） 18（50） 0.618 注：①为随访截止日情况。 
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表 2 HBV再感染者与未感染者的资料对比
Table 2. Comparison of data of responders with HBV reinfection and those without reinfection
项目 再感染（n=5）① 未感染（n=58） P值 年龄（$\overline {{x}}\pm s $，岁） 67±7 63±10 0.345 性别男[n（%）] 5 41（71） 0.312b 原发病[n（%）] 0.188b 失代偿期肝硬化 1 23（40） 肝衰竭 3 9（16） 原发性肝癌 1 26（45） 肝移植前HBeAg阳性[n（%）] 5 24（41） 0.017b 接种期间免疫抑制剂方案[n（%）] 0.498b 他克莫司 4 22（38） 他克莫司+吗替麦考酚酯 1 24（41） 他克莫司+西罗莫司 0 9（16） 他克莫司+吗替麦考酚酯+西罗莫司 0 2（4） 环孢素 0 1（2） 肝移植后抗病毒药[n（%）] 0.761b 拉米夫定 1 21（36） 恩替卡韦 2 23（40） 阿德福韦酯 2 12（21） 替比夫定 0 2（4） 肝移植到接种疫苗时间[M（P25，P75），月] 22（20，53） 26（19，38） 0.889 接种疫苗到判定成功时间[M（P25，P75），月] 21（13，45） 14（6，23） 0.127 停用过NAs[n（%）] 5 26（45） 0.024b 停用HBIG时抗-HBs滴度[M（P25，P75），IU/L] 421（305，478） 228（170，423） 0.109 停用NAs时抗-HBs滴度[M（P25，P75），IU/L] 421（182，779） 440（150，644） 0.946 注：①因为合计例数较少，不统计百分率。b为Fisher精确检验。
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表 3 5例应答者停用HBIG及NAs后HBV再感染特点
Table 3. Characteristics of HBV reinfection after HBIG and NAs withdraw in 5 responders
例序 性别 年龄（岁） 肝移植前乙肝标记物 肝移植前HBV DNA（IU/L） 接种疫苗后抗-HBs（IU/L） HBV再感染时乙肝标记物 HBV再感染时HBV DNA（IU/L） HBV再感染时ALT②（U/L） HBV再感染时AST（U/L） 停药至HBV 再感染复发时间（月） HBV再感染后NAs HBsAg基因型 HBsAg逃逸
突变血清学转换 1 男 60 1,3,5①
阳性2.97×109 133
（50，1 000）1,2,3,4,5阳性 2.92×103 36 23 23 恩替卡韦+富马酸替诺
福韦B2 G145R 是 2 男 75 1,3,5
阳性未知 359
（132，1 000）1,2,3,5
阳性5.23×106 18 24 24 阿德福韦酯+恩替卡韦 C1 P120LPQR,
G145R, P120PQ,
M133
MT否 3 男 72 1,3,5
阳性1.00×104 199
（105，1 000）1,2,4,5
阳性1.59×102 59 33 6 恩替卡韦 C2 无 是 4 男 60 1,3,5
阳性2.00×107 196
（103，782)1,2,3,5
阳性2.00×102 28 24 16 恩替卡韦 B2 N236T,
Q129R,
G145R是 5 男 65 1,3,5
阳性4.27×105 214
（80，568）1,2,3,5
阳性8.60×104 35 28 71 恩替卡韦+富马酸替诺
福韦未知 G145R 否 注：①1为HBsAg，2为抗-HBs，3为HBeAg，4为乙型肝炎e抗体（抗-HBe），5为乙型肝炎核心抗体（抗-HBc）。
②ALT为丙氨酸转氨酶。
③AST为天冬氨酸转氨酶。
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