修回日期: 2016-01-11
接受日期: 2016-01-19
在线出版日期: 2016-03-08
合并乙型肝炎病毒(hepatitis B virus, HBV)感染的恶性肿瘤患者接受化疗后HBV再激活的发生率较高, HBV再激活是致命性的, 因此认识HBV再激活现象并了解其防治原则非常重要. 目前对HBV再激活的相关研究很多, 但数据分散, 本文就合并HBV感染的恶性肿瘤患者接受化疗相关HBV再激活的预防和治疗进展作一综述, 旨在对恶性肿瘤患者在化疗之前进行常规筛查及治疗, 有效避免HBV再激活的发生, 提高患者生存质量.
核心提示: 本文就恶性肿瘤患者化疗相关HBV再激活的预防和治疗作一综述, 阐述多种恶性肿瘤化疗相关HBV再激活的现状, 强调积极的乙型肝炎病毒学筛查和个性化抗病毒治疗的重要性, 对临床工作有一定的指导意义.
引文著录: 杨彩霞, 赖维菊, 唐映梅. 恶性肿瘤患者化疗相关HBV再激活的防治进展. 世界华人消化杂志 2016; 24(7): 1048-1053
Revised: January 11, 2016
Accepted: January 19, 2016
Published online: March 8, 2016
It is believed that malignant tumor patients with hepatitis B virus (HBV) infection show a higher incidence of reactivation of HBV after receiving chemotherapy, which is fatal, suggesting that awareness of HBV reactivation and the principles of prevention and treatment is important. There are many studies on HBV reactivation, however, the data are scattered. Here, we summarize the current understanding of the prevention and treatment of HBV reactivation in malignant tumor patients with HBV after receiving chemotherapy, aiming at providing routine screening and treatment for these patients which protect them against reactivation of HBV and improve the quality of life of patients.
- Citation: Yang CX, Lai WJ, Tang YM. Progress in prevention and treatment of HBV reactivation associated with chemotherapy in malignant tumor patients. Shijie Huaren Xiaohua Zazhi 2016; 24(7): 1048-1053
- URL: https://www.wjgnet.com/1009-3079/full/v24/i7/1048.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v24.i7.1048
恶性肿瘤是严重威胁人类健康的一个公共卫生问题. 目前我国肿瘤负担不断增加, 据统计, 截至2011年我国恶性肿瘤发病率为21.2%, 死亡率为12.69%[1]. 值得注意的是, 肿瘤患者的发病率及死亡率与乙型肝炎病毒(hepatitis B virus, HBV)感染关系密切[2], HBV感染可能在恶性肿瘤的发展过程中有一定作用[3]. 我国HBV感染人数众多, 2006年全国乙型肝炎血清流行病学调查发现, 年龄1-59岁人群乙型肝炎表面抗原(hepatitis B surface antigen, HBsAg)携带率为7.18%[4,5]. 据报道, 我国恶性肿瘤合并HBV感染患者数目庞大, 患者接受化疗后HBV再激活发生率偏高, 一旦出现HBV再激活, 将导致进一步治疗难以实施, 甚至危及生命. 因此, 为了避免HBV再激活, 有效延长恶性肿瘤患者的生命, 临床医生应对恶性肿瘤患者接受化疗前的常规HBV筛查引起重视并给予及时处理. 下面将对合并HBV感染的恶性肿瘤患者HBV再激活的预防和治疗进展作一综述.
早期HBV再激活被定义为在化疗和/或免疫抑制治疗过程中, 或紧随其后发生的HBV DNA升高10倍以上或其绝对值>109拷贝/mL[6-8]. 但在2013年《中国淋巴瘤合并HBV感染患者管理专家共识》中对HBV再激活有了明确定义: 对于HBsAg阳性患者, 符合下列任一条件可定义为HBV再激活: (1)血清HBV DNA由不可测变为可测或超过基线水平≥1 log10; (2)乙型肝炎e抗原(hepatitis B e antigen, HBeAg)阴性患者血清HBeAg转阳; 对于HBsAg阴性/抗-HBc阳性患者, 符合下列任一条件也可定义为HBV再激活: (1)血清HBsAg转阳; (2)血清HBV DNA由不可测变为可测[9].
免疫功能低下是HBV再激活的关键因素[10]. 恶性肿瘤患者使用化疗药物均有不同程度的免疫抑制作用, 相关文献报道[11,12], HBV再激活患者临床表现不一, 大部分患者再激活后仅表现为病毒携带状态, 没有临床症状; 部分患者表现为轻、中、重度肝炎, 轻者无症状或有典型的肝炎症状: 疲乏、黄疸、腹水和肝性脑病, 重者可能出现急性肝衰竭, 甚至死亡[13]. 虽然有部分患者可自行恢复, 但死亡率仍然为5%-40%[14].
血液系统恶性肿瘤患者发生HBV再激活的风险高, 大约有40%左右的患者体内HBV会被再次激活[15], HBsAg阳性是发生HBV再激活的高危因素[16]. 研究[17]发现在HBsAg阳性的血液系统肿瘤患者中HBV再激活发生率高38%, 在非霍奇金淋巴瘤患者中高达48%[18]. 潘儒艳等[19]发现HBsAg阳性非霍奇金淋巴瘤患者化疗后可能出现HBV再激活. 有学者报道[20,21]淋巴瘤的患者发生再激活的风险较大, 主要是因为疾病本身导致免疫系统严重受损以及使用药物对免疫系统影响更大.
HBV再激活主要见于HBsAg阳性患者, 但也见于HBsAg阴性而抗-HBc阳性或抗-HBs阴性患者[22,23]. 法国一项研究报道在HBsAg阴性等84例血液系统肿瘤患者中, 超过8%发生了HBV再激活[22]. 研究[24]发现HBsAg阴性或乙型肝炎核心抗体(hepatitis B core antibody, HBcAb)阳性的非霍奇金淋巴瘤患者化疗后HBV再激活概率较HBsAg阳性低, 但也不应忽视. 近期Gu等[25]报道HBsAg阴性多发性骨髓瘤患者在长春新碱、阿霉素和地塞米松联合化疗后出现HBsAb水平急剧下降, 7 mo后HBsAb阴性, 提示抗肿瘤化学制剂引起HBsAb水平减低, 这一观点得到其他学者的支持[26].
高病毒载量也是发生HBV再激活最重要的危险因素[15]. Zhong等[27]对抗肿瘤药物化疗后患者HBV再激活组和HBV未激活组HBV DNA进行定量检测, 发现再激活组HBV DNA载量明显高于未激活组. 因此, 对于高危人群要重视血清HBV DNA和HBsAg水平.
目前对于HBV慢性感染者或隐匿性感染者化疗前的预防性处理及HBV再激活后处理措施没有严格指南, 世界各国组织机构、专家意见不统一, 但根据美国肝病研究学会(American Association for the Study of Liver Diseases, AASLD)[34]、欧洲肝脏研究协会(European Association for the Study of the Liver, EASL)[35]、亚太肝脏研究学会(Asia Pacific liver Research Institute, APASL)[36]、日本厚生劳动省(Ministry of Health, Labour, and Welfare, MHLW)[37], 中华医学会肝病学分会等权威机构的推荐意见及部分相关研究数据总结出以下措施.
预防并减少HBV的感染与传播远比治疗有意义. 对于乙型肝炎高危人群包括乙型肝炎高发地区、家庭中有HBV感染患者或者与乙型肝炎感染患者有性接触、乙型肝炎患者的后代、吸毒者等加强宣教, 并采取有效措施如乙型肝炎疫苗主动或被动免疫减少HBV传播.
所有患者在行化疗之前需完成HBV学相关筛查[38,39], 这有利于评估患者化疗后发生HBV再激活的风险程度. 其次, 在恶性肿瘤患者化疗过程中, HBV学的监测能及时发现HBV再激活迹象, 帮助临床医生迅速采取有效治疗措施、控制患者病情、改善预后具有积极作用.
根据2015年最新《慢性乙型肝炎防治指南》[40], 对HBsAg阳性的化疗患者, 即使HBV DNA低于检测下限且丙氨酸转氨酶(alanine aminotransferase, ALT)正常, 也应当在化疗前2-4 wk开始预防性抗病毒治疗, 直至化疗结束后半年, 具体停药时间需依据患者病情.
对HBsAg阴性、抗-HBc阳性者, 如化疗药物为抗-CD20、抗-TNF或大剂量糖皮质激素, 可酌情予以预防性抗病毒[41,42]; 如未进行抗病毒治疗, 则密切监测患者血清HBV学标志, 一旦提示HBV DNA水平变化和HBsAg阳性, 应及时加用抗病毒药物, 并在化疗结束后, 继续应用核苷酸类似物治疗至少6 mo.
抗病毒药物分别有干扰素-α和核苷酸类似物. 现供临床使用的干扰素-α有两种: 普通干扰素-α和聚乙二醇干扰素-α, 具有抗病毒和抗肿瘤的双重作用[43]. 理论上讲, 干扰素-α能较好地用于恶性肿瘤患者化疗相关性HBV再激活的防治, 但其骨髓抑制及加重肝损害等不良作用, 限制了其临床应用.
核苷酸类似物的安全性、耐受性更好, 治疗作用更为确切, 常用的有拉米夫定、阿福韦酯、替诺福韦酯、替比夫定、恩替卡韦.以往最常选用的是拉米夫定, 但针对化疗相关性HBV再激活患者建议优先选用强效低耐药的恩替卡韦或替诺福韦酯[44]. Chen等[45]学者发现实体肿瘤患者化疗前, HBV DNA水平均>2000 IU/mL、HBeAg患者, 预防HBV再激活恩替卡韦效果优于拉米夫定, 而HBV DNA水平<2000 IU/mL患者两种药效相同. 淋巴瘤患者化疗过程中同时使用恩替卡韦和拉米夫定预防HBV再激活[44,46-48], 发现恩替卡韦效果明显优于拉米夫定[47]. 但随着治疗时间的延长, 使用核苷酸类似物可能出现耐药激活或者停药激活.
恶性肿瘤是我国以及全球重要的公共健康问题, 据统计, 我国肿瘤总体5年生存率仅为30.9%[49]. 随着肿瘤发病率的不断提高以及在临床上广泛的使用细胞毒性化疗药物对肿瘤进行治疗, 携带HBV的肿瘤化疗患者的人数也在不断的增加, HBV感染、血清HBsAg阳性、抗-HBc阳性等肿瘤患者化疗过程中或治疗之后HBV再激活风险高, 而预防性使用抗病毒治疗则可有效防止HBV再激活[50]. 对于肿瘤患者而言, 预防比治疗更重要; 一旦有HBV再激活表现, 须延迟或者停止用药, 以减少HBV复制[51], 避免发生严重的肝衰竭, 甚至死亡. 但这往往不能即刻显效, 因此临床医生在对患者进行肿瘤治疗前预防HBV再激活显得尤其重要, 患者化疗前应常规筛查HBV, 避免出现HBV再激活[52], 提高治疗效率.
恶性肿瘤的发病率近年呈上升趋势, 同时, 乙型肝炎病毒(hepatitis B virus, HBV)感染人群普遍. 合并HBV感染的肿瘤患者基数大. 而此类患者接受化疗可能出现HBV再激活, 如未能及时有效控制HBV再激活将影响进一步治疗.
蒋益, 主任医师, 温州医科大学附属第二医院消化内科; 王晓娣, 主任医师, 中日友好医院消化内科; 魏继福, 研究员, 江苏省人民医院
国内外相关新近文献建议, 依据患者病情, 在抗病毒药物干预时间以及药物的选择上个性化, 对预防HBV再激活是有效的.
目前国内外均有防治化疗相关性HBV再激活的报道. 相关新近文献推荐积极全面的HBV学筛查和个性化抗病毒治疗.
本文结合新近文献, 探讨多种常见恶性肿瘤患者化疗相关HBV再激活的预防及治疗经验.
本文就恶性肿瘤患者化疗相关HBV再激活的预防及治疗作了综述, 对临床工作有一定指导意义.
HBV再激活: 指曾伴发慢性乙型肝炎的恶性肿瘤患者、携带HBV的恶性肿瘤患者或者既往感染HBV的恶性肿瘤患者在接受化疗后出现HBV复制活跃及HBV感染加重, 诱发肝损伤、出现肝衰竭, 甚至危及患者生命的现象.
本文作者综述关于恶性肿瘤患者化疗相关HBV再激活的预防及治疗进展, 关注特殊患者抗病毒治疗, 对临床肿瘤患者化疗中防止HBV再激活有一定的指导意义.
编辑: 郭鹏 电编: 都珍珍
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