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1、乙型肝炎病毒再激活: 一个能够预防的问题南昌大学第一附属医院张伦理1 1HBV再激活的发生2 2Hepatitis B: Some Sobering Factsn n350 million people chronically infected350 million people chronically infectedn n2 billion with evidence of 2 billion with evidence of past or present infectionpast or present infectionn nCountry of origin is THE majo
2、r risk factorCountry of origin is THE major risk factorWorld Health Organization. Hepatitis B Fact Sheet. Centers for Disease Control and Prevention. CDC Health Information for International Travel 2012. New York: Oxford University Press; 2012.Prevalence of HBsAgHigh 8%Intermediate 2% to 7%Low 3 10H
3、BV DNA 3 105 5 copies/mLcopies/mL Elevated if HBeAg Elevated if HBeAg positivepositiven n人口统计人口统计 Men womenMen womenYeo W, et al. Hepatology. 2006;43:209-220.1919单纯抗HBc阳性的意义n n表明曾暴露于表明曾暴露于HBVHBVn n通常保持终身，但也可以数年后消失通常保持终身，但也可以数年后消失n n如果确实没有如果确实没有HBVHBV危险因素，可以是假阳性危险因素，可以是假阳性 n n目前尚无治疗指南目前尚无治疗指南n n再激活的风
4、险再激活的风险 对大多数标准的实体肿瘤患者，风险较低对大多数标准的实体肿瘤患者，风险较低 如果存在肝硬化应考虑预先治疗如果存在肝硬化应考虑预先治疗 如果采用下列治疗方案应考虑预先治疗如果采用下列治疗方案应考虑预先治疗n nRituximabRituximabn nBone marrow/stem cell transplantationBone marrow/stem cell transplantationManzano-Alonso ML, et al. World J Gastroenterol. 2011;17:1531-1537.2020其他因素引起HBV再激活Roche B, et
5、 al. Liver Int. 2011;31(suppl 1):104-110. ImmunomodulatoryTherapy Anti-TNF (infliximab, adalimumab, etanercept)Antimetabolite(methotrexate)Purine Analogues(azathioprine/6mp) Steroids(prednisone, budesonide) Other(rituximab, cyclosporine) 2121Rituximab: 一特殊的问题n n抗抗CD20CD20单克隆抗体单克隆抗体 (B-cell marker)(B
6、-cell marker)n n减少减少B-cell B-cell 的数量和抗体水平的数量和抗体水平n n作为作为 CHOP-R, EPOCH-R CHOP-R, EPOCH-R方案的一部分，常被使用方案的一部分，常被使用n n增加增加HBVHBV再激活的风险，包括再激活的风险，包括 HBsAg HBsAg（- -）的病人）的病人n n逆转学清转换逆转学清转换: : 由于免疫控制的丧失，原先由于免疫控制的丧失，原先HBsAgHBsAg阴性的阴性的病人可以再次出现病人可以再次出现HBsAgHBsAg阳性阳性Yeo W, et al. Hepatology. 2006;43:209-220. Pa
7、pamichalis P, et al. Clin Res Hepatol Gastroenterol. 2012;36:84-93.2222采用Rituximab治疗的 HBsAg（-）患者的HBV再激活n nPatients with diffuse large B-cell lymphoma Patients with diffuse large B-cell lymphoma HBsAg-negative, anti-HBcpositive individuals treated HBsAg-negative, anti-HBcpositive individuals treated
8、with CHOP or CHOP-Rwith CHOP or CHOP-RHBV ReverseSeroconversionHBV-RelatedDeathYeo W, et al. J Clin Oncol. 2009;27:605-611.Risk of reactivation with rituximab significant in anti-HBc positive40302010024005Proportion of Anti-HBc Positive, HBsAg-Negative Patients (%)CHOP (n = 25)CHOP-R (n = 21)2323与Ri
9、tuximab 相关的HBV 再激活: 典型的迟发且严重n n逆转逆转HBVHBV血清转换血清转换11 Among 5 patients who reactivated, 1 during fifth cycle of Among 5 patients who reactivated, 1 during fifth cycle of chemotherapy; 3 median of 98 days AFTER last rituximab chemotherapy; 3 median of 98 days AFTER last rituximab cycle; can occur early
10、 as wellcycle; can occur early as well Median peak ALT: 809 U/L (362-3499)Median peak ALT: 809 U/L (362-3499) Median peak bilirubin: 65 mol/L (19-249) Median peak bilirubin: 65 mol/L (19-249) n n已报道的其他情况已报道的其他情况 Including instances of liver failure and liver-related Including instances of liver fail
11、ure and liver-related deathsdeathsYeo W, et al. J Clin Oncol. 2009;27:605-611.Risk Factors for reactivation1.Men women (almost all cases)2.Anti-HBs negative (or low titer)3.? increased age ( 50 yrs)2424接受Rituximab治疗的抗HBc阳性患者的处理n n无共识且资料有限无共识且资料有限n n选择选择 化疗前开始抗病毒治疗化疗前开始抗病毒治疗 化疗后密切监测化疗后密切监测HBVDNAHBVDN
12、A，若出现阳性即开始抗病毒，若出现阳性即开始抗病毒治疗治疗 化疗后密切监测化疗后密切监测HBsAgHBsAg，若出现阳性即开始抗病毒治，若出现阳性即开始抗病毒治疗疗 化疗后密切监测化疗后密切监测HBsAg HBsAg 和和HBVDNAHBVDNA，若出现阳性即开，若出现阳性即开始抗病毒治疗始抗病毒治疗2525骨髓抑制增加再激活的风险n n再激活几率显著升高再激活几率显著升高 (HBsAg positive)(HBsAg positive) Up to 54%Up to 54%11 need preemptive antiviral therapy! need preemptive antivi
13、ral therapy! Long-term complications: cirrhosis in 10%Long-term complications: cirrhosis in 10%22n n如果仅抗如果仅抗HBcHBc阳性者，血清转换被逆转现象常见阳性者，血清转换被逆转现象常见【3 3】 Up to 50% become HBsAg positive Up to 50% become HBsAg positive use preemptive use preemptive antiviralsantivirals May occur very lateMay occur very l
14、aten n捐献者的捐献者的HBVHBV状态非常重要状态非常重要1,41,4 If natural immunity (anti-HBs, anti-HBc): may clear If natural immunity (anti-HBs, anti-HBc): may clear HBsAgHBsAg If vaccinated (anti-HBs): possibly some protectionIf vaccinated (anti-HBs): possibly some protection1. Lau GK, et al. Bone Marrow Transplant. 1997
15、;19:795-799. 2. Hui CK, et al. Blood. 2005;106:464-469. 3. Onozawa M, et al. Transplantation. 2005;79:616-619. 4. Lau GK, et al. J Infect Dis. 1998;178:1585-1591.2626类固醇增加HBV再激活发生的风险n n50 patients with NHL who were HBsAg positive randomized to 50 patients with NHL who were HBsAg positive randomized
16、to epirubicin, cyclophosphamide and etoposide (ACE) epirubicin, cyclophosphamide and etoposide (ACE) prednisolone prednisolone (P)(P)Cheng AL, et al. Hepatology. 2003;37:1320-1328.HBV ReactivationJaundiceSurvivalat 4 YrsALT 10 x ULNCompleteRemission* *P .05Prednisolone increased risk and severity of
17、 HBV reactivationbut trend toward improved NHL outcomeHBsAg Patients (%)1008060402003873*1344*428*35463668ACEPACE2727HBV再激活的治疗和预防2828Watch for withdrawal flares采用化疗/免疫调节剂治疗患者的管理HBsAg+HBsAg-, anti-HBc+HBV DNAHBV DNALAM x 6-12 mosposttherapyETV/TDF until HBV endpointsPositivePositiveNegativeTest HBsAg
18、 q moHBV DNA q 3 mosUntil 6-12 mos posttherapy*Caveats: If concern about monitoring err on side of treatmentHigh risk: anti-HBs negative older men consider up-front treatment 1.5 x ULN Preemptive group: start LAM on Day 1 of CHOP Preemptive antivirals decrease HBV reactivationHBV Reactivation and He
19、patitis FlareHBV Reactivationand JaundiceHBV Reactivation and ALT 10 x ULNDeath(After ChemoTx)100806040200HBsAg Patients (%)488360200083131如何选择抗病毒治疗方案与监测n n治疗方案的选择受治疗方案的选择受 HBV DNA HBV DNA 水平的影响水平的影响 HBV DNA 2000 IU/mL: any therapy can be used HBV DNA 2000 IU/mL: entecavir or tenofovirHBV DNA 2000 I
20、U/mL: entecavir or tenofovirn n治疗方案的选择受治疗时间长短的影响治疗方案的选择受治疗时间长短的影响 12 mos: entecavir or tenofovir 12 mos: entecavir or tenofovir n nHBV DNA and ALT HBV DNA and ALT 应该每应该每3 3个月检测一次个月检测一次EASL. J Hepatol. 2009;50:227-242. Lok AS, et al. Hepatology. 2009;50:661-662.3232抗病毒治疗的时间n n什么时间开始什么时间开始 Ideally bef
21、ore or together with chemotherapyIdeally before or together with chemotherapy Do not delay start of chemotherapyDo not delay start of chemotherapyn n 什么时间停止什么时间停止 If baseline HBV DNA 2000 IU/mL: high risk of If baseline HBV DNA 2000 IU/mL: high risk of withdrawal flarewithdrawal flaren nContinue the
22、rapy as for chronic HBV infectionContinue therapy as for chronic HBV infection If baseline HBV DNA 2000 IU/mLIf baseline HBV DNA 2000 IU/mLn n6-12 mos after end of chemotherapy6-12 mos after end of chemotherapyn n每月检测每月检测HBVDNAHBVDNA和和ALTALT监测停药后肝炎是否复监测停药后肝炎是否复发发EASL. J Hepatol. 2009;50:227-242. Lok
23、 AS, et al. Hepatology. 2009;50:661-662.3333总结n nHBVHBV再激活的诱因较多再激活的诱因较多n nHBsAg HBsAg 检测便宜，应该在需化疗或免疫调节治疗检测便宜，应该在需化疗或免疫调节治疗的病人中广泛开展的病人中广泛开展HBsAgHBsAg筛选筛选n n如果如果HBsAgHBsAg阳性，化疗或其他免疫调节治疗后，阳性，化疗或其他免疫调节治疗后，HBVHBV再激活易于发生再激活易于发生n n单纯抗单纯抗HBcHBc阳性者，在使用阳性者，在使用RituximabRituximab和骨髓或干和骨髓或干细胞移植时，有可能发生细胞移植时，有可能发生HBVHBV再激活，应该在治再激活，应该在治疗过程中严密监测疗过程中严密监测HBV-DNAHBV-DNA和和HBsAgHBsAgn n有效地抗乙肝病毒治疗可以预防有效地抗乙肝病毒治疗可以预防HBVHBV再激活，再激活，但但但但是是是是必须尽早开始。应在化疗前或同时进行！必须尽早开始。应在化疗前或同时进行！必须尽早开始。应在化疗前或同时进行！必须尽早开始。应在化疗前或同时进行！3434 Thanks3535个人观点供参考，欢迎讨论
