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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,HBV再激活的发生,Hepatitis B:Some Sobering Facts,350 million people chronically infected2 billion with evidence of past or present infectionCountry of origin is THE major risk factor,World Health Organization.Hepatitis B Fact Sheet.Centers for Disease Control and Preventio
2、n.CDC Health Information for International Travel 2012.New York:Oxford University Press;2012.,慢性乙肝病毒感染自然史,Yim HJ,et al.Hepatology.2006;43:S173-S181.,HBeAg+HBeAg-HBeAb+,Immune Clearance,Immunotolerance,ALT,HBV DNA,Mos-Yrs,Immune Control(Nonreplicative),HBsAg+HBsAg-HBsAb+,Infection,Mos-Yrs,5-30 Yrs,Yi
3、m HJ,et al.Hepatology.2006;43:S173-S181.,Immune Clearance,Immunotolerance,ALT,HBV DNA,Mos-Yrs,HBsAg+HBsAg-HBsAb+,Infection,Mos-Yrs,5-30 Yrs,慢性乙肝病毒感染自然史,Most Oncology Patients Normal ALT Low/undetectable HBV DNA HBsAg+and HBeAg-or HBsAg-,anti-HBc+,Immune Control(Nonreplicative),HBV能被清除吗?,Immune contr
4、olnot clearance“Resolved HBV”a misnomerstill HBV DNA in liver,cccDNA,Werle-Lapostolle B,et al.Gastroenterology.2004;126:1750-1758.,HBV能被清除吗?,Immune controlnot clearance“Resolved HBV”a misnomerstill HBV DNA in liver,cccDNA,Werle-Lapostolle B,et al.Gastroenterology.2004;126:1750-1758.,HBV能被清除吗?,Immune
5、 controlnot clearance“Resolved HBV”a misnomerstill HBV DNA in liver,cccDNA,Werle-Lapostolle B,et al.Gastroenterology.2004;126:1750-1758.,免疫抑制的后果,Immune control can be lostImmune-mediated liver damage with immune reconstitution,HIVSteroidsChemotx,cccDNA,Werle-Lapostolle B,et al.Gastroenterology.2004;
6、126:1750-1758.,免疫抑制的后果,Immune control can be lostImmune-mediated liver damage with immune reconstitution,HIVSteroidsChemotx,cccDNA,Werle-Lapostolle B,et al.Gastroenterology.2004;126:1750-1758.,HBV 再激活,5-30 Yrs,Mos-Yrs,Infection,Immunotolerance,Immune Clearance,HBeAg+HBeAg-HBeAb+,Mos-Yrs,ALT,HBV DNA,
7、HBeAg+,Hoofnagle JH.Hepatology.2009;49(5 suppl):S156-S165.,HBV 再激活,5-30 Yrs,Mos-Yrs,Infection,Immunotolerance,Immune Clearance,HBeAg+HBeAg-HBeAb+,Mos-Yrs,ALT,HBV DNA,HBeAg+,Immune Suppression,Hoofnagle JH.Hepatology.2009;49(5 suppl):S156-S165.,HBV 再激活,Infection,Immunotolerance,Immune Clearance,HBeAg
8、+HBeAg-HBeAb+,ALT,HBV DNA,HBeAg+,Immune Suppression,Immune Reconstitution,Hoofnagle JH.Hepatology.2009;49(5 suppl):S156-S165.,5-30 Yrs,Mos-Yrs,Mos-Yrs,HBV 再激活,定义非活动性或“痊愈”的HBV感染患者失去针对HBV的免疫控制 在免疫重建过程中和/或紧随着免疫重建，病毒复制的突然出现或增加临床表现可发生自亚临床到严重致死性肝炎等病变HBVDNA水平升高，可伴有或不伴有HBeAg的出现ALT升高（可为轻度或极其严重的升高）尽管已经采取抗病毒治疗
9、，仍可以进展至肝衰竭或死亡,Hoofnagle JH.Hepatology.2009;49(5 suppl):S156-S165.,已报道的能引起HBV再激活的药物,Yeo W,et al.Hepatology.2006;43:209-220.,未及时认识HBV再激活的后果,肝炎发作可以是严重的，甚至是致命的偶尔HBVDNA检测不到，主要是由于ALT升高时伴HBVDNA下降可导致误诊，但是最终可出现肝炎复发一旦ALT升高出现，病情可能就难以控制化疗中断肿瘤治疗结局不佳,Yeo W,et al.Hepatology.2006;43:209-220.,HBV再激活的概率:实体肿瘤,HBsAg（+）
10、的 乳腺癌患者接受化疗HBV相关的急性肝炎发生率:21%1即使严密监测HBVDNA,仍有高达41%的HBV 再激活发生2HBV DNA 在ALT高峰期可检测不到其他实体瘤的资料有限,Of those who flare2:35%chemotherapy interruption 35%premature termination of chemotherapy,1.Kim MK,et al.Korean J Intern Med.2007;22:237-243.2.Yeo W,et al.J Med Virol.2003;70:553-561.,血液系统恶性病变:更大的风险,HBV Reacti
11、vation,Jaundice,NonfatalLiver Failure,Death,100 patients with NHL undergoing CHOP;27 HBsAg positive,Lok AS,et al.Gastroenterology.1991;100:182-188.,HBsAg Patients(%),100,80,60,40,20,0,48,22,4,4,HBV再激活的危险因素,恶性肿瘤NHL:40%to 58%of HBsAg positiveBreast cancer:up to 41%of HBsAg positive化疗Prednisone,蒽环类抗生素,
12、rituximab increased risk“Potency of immunosuppression”,HBV DNAHBV DNA 3 105 copies/mLElevated if HBeAg positive人口统计Men women,Yeo W,et al.Hepatology.2006;43:209-220.,单纯抗HBc阳性的意义,表明曾暴露于HBV通常保持终身，但也可以数年后消失如果确实没有HBV危险因素，可以是假阳性 目前尚无治疗指南再激活的风险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采用下列治疗方案应考虑预先治疗RituximabBone
13、marrow/stem cell transplantation,Manzano-Alonso ML,et al.World J Gastroenterol.2011;17:1531-1537.,其他因素引起HBV再激活,Roche B,et al.Liver Int.2011;31(suppl 1):104-110.,ImmunomodulatoryTherapy,Anti-TNF(infliximab,adalimumab,etanercept),Antimetabolite(methotrexate),Purine Analogues(azathioprine/6mp),Steroids
14、(prednisone,budesonide),Other(rituximab,cyclosporine),Rituximab:一特殊的问题,抗CD20单克隆抗体(B-cell marker)减少B-cell 的数量和抗体水平作为 CHOP-R,EPOCH-R方案的一部分，常被使用增加HBV再激活的风险，包括 HBsAg（-）的病人逆转学清转换:由于免疫控制的丧失，原先HBsAg阴性的病人可以再次出现HBsAg阳性,Yeo W,et al.Hepatology.2006;43:209-220.Papamichalis P,et al.Clin Res Hepatol Gastroenterol
15、.2012;36:84-93.,采用Rituximab治疗的 HBsAg（-）患者的HBV再激活,Patients with diffuse large B-cell lymphoma HBsAg-negative,anti-HBcpositive individuals treated with CHOP or CHOP-R,HBV ReverseSeroconversion,HBV-RelatedDeath,Yeo W,et al.J Clin Oncol.2009;27:605-611.,Risk of reactivation with rituximab significant in
16、 anti-HBc positive,40,30,20,10,0,24,0,0,5,Proportion of Anti-HBc Positive,HBsAg-Negative Patients(%),CHOP(n=25)CHOP-R(n=21),与Rituximab 相关的HBV 再激活:典型的迟发且严重,逆转HBV血清转换1Among 5 patients who reactivated,1 during fifth cycle of chemotherapy;3 median of 98 days AFTER last rituximab cycle;can occur early as
17、 wellMedian peak ALT:809 U/L(362-3499)Median peak bilirubin:65 mol/L(19-249)已报道的其他情况Including instances of liver failure and liver-related deaths,Yeo W,et al.J Clin Oncol.2009;27:605-611.,Risk Factors for reactivationMen women(almost all cases)Anti-HBs negative(or low titer)?increased age(50 yrs),接受
18、Rituximab治疗的抗HBc阳性患者的处理,无共识且资料有限选择化疗前开始抗病毒治疗化疗后密切监测HBVDNA，若出现阳性即开始抗病毒治疗化疗后密切监测HBsAg，若出现阳性即开始抗病毒治疗化疗后密切监测HBsAg 和HBVDNA，若出现阳性即开始抗病毒治疗,骨髓抑制增加再激活的风险,再激活几率显著升高(HBsAg positive)Up to 54%1 need preemptive antiviral therapy!Long-term complications:cirrhosis in 10%2如果仅抗HBc阳性者，血清转换被逆转现象常见【3】Up to 50%become HBs
19、Ag positive use preemptive antivirals May occur very late捐献者的HBV状态非常重要1,4If natural immunity(anti-HBs,anti-HBc):may clear HBsAgIf vaccinated(anti-HBs):possibly some protection,1.Lau GK,et al.Bone Marrow Transplant.1997;19:795-799.2.Hui CK,et al.Blood.2005;106:464-469.3.Onozawa M,et al.Transplantatio
20、n.2005;79:616-619.4.Lau GK,et al.J Infect Dis.1998;178:1585-1591.,类固醇增加HBV再激活发生的风险,50 patients with NHL who were HBsAg positive randomized to epirubicin,cyclophosphamide and etoposide(ACE)prednisolone(P),Cheng AL,et al.Hepatology.2003;37:1320-1328.,HBV Reactivation,Jaundice,Survivalat 4 Yrs,ALT 10 x
21、 ULN,CompleteRemission,*,*P.05,Prednisolone increased risk and severity of HBV reactivationbut trend toward improved NHL outcome,HBsAg Patients(%),100,80,60,40,20,0,38,73*,13,44*,4,28*,35,46,36,68,ACE,PACE,HBV再激活的治疗和预防,采用化疗/免疫调节剂治疗患者的管理,HBV DNA,HBV DNA,*Caveats:If concern about monitoring err on sid
22、e of treatmentHigh risk:anti-HBs negative older men consider up-front treatment,Screen all patientsHBsAg,anti-HBc,anti-HBs,预先使用拉米夫定可减少HBV再激活的风险,HBsAg-positive patients with lymphoma treated with high-dose chemotherapy randomized to“preemptive”vs“on-demand”lamivudine,On-demand LAM(if HBV DNA increase
23、d),Survival Free From Hepatitis Due to HBV Reactivation,Lau GK,et al.Gastroenterology.2003;125:1742-1749.,Preemptive LAM,100,75,50,25,0,0,10,20,30,40,Wk,P=.002 by log-rank test,Pts at Risk,nPreemptive LAMOn-demand LAM,1515,1213,1010,94,62,预先抗病毒治疗的价值,HBsAg-positive patients with NHL treated with CHOP
24、 randomized to“preemptive”vs“on-demand”lamivudine,Hsu C,et al.Hepatology.2008;47:844-853.,On-demand group:start LAM if ALT 1.5 x ULN Preemptive group:start LAM on Day 1 of CHOP,Preemptive antivirals decrease HBV reactivation,HBV Reactivation and Hepatitis Flare,HBV Reactivationand Jaundice,HBV React
25、ivation and ALT 10 x ULN,Death(After ChemoTx),100,80,60,40,20,0,HBsAg Patients(%),48,8,36,0,20,0,0,8,如何选择抗病毒治疗方案与监测,治疗方案的选择受 HBV DNA 水平的影响HBV DNA 2000 IU/mL:entecavir or tenofovir治疗方案的选择受治疗时间长短的影响 12 mos:entecavir or tenofovir HBV DNA and ALT 应该每3个月检测一次,EASL.J Hepatol.2009;50:227-242.Lok AS,et al.He
26、patology.2009;50:661-662.,抗病毒治疗的时间,什么时间开始Ideally before or together with chemotherapyDo not delay start of chemotherapy 什么时间停止If baseline HBV DNA 2000 IU/mL:high risk of withdrawal flareContinue therapy as for chronic HBV infectionIf baseline HBV DNA 2000 IU/mL6-12 mos after end of chemotherapy每月检测HBVDNA和ALT监测停药后肝炎是否复发,EASL.J Hepatol.2009;50:227-242.Lok AS,et al.Hepatology.2009;50:661-662.,总结,HBV再激活的诱因较多HBsAg 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HBsAg筛选如果HBsAg阳性，化疗或其他免疫调节治疗后，HBV再激活易于发生单纯抗HBc阳性者，在使用Rituximab和骨髓或干细胞移植时，有可能发生HBV再激活，应该在治疗过程中严密监测HBV-DNA和HBsAg有效地抗乙肝病毒治疗可以预防HBV再激活，但是必须尽早开始。应在化疗前或同时进行！,Thanks,
