乙型肝炎病毒再激活

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HepatitisB:SomeSoberingFacts350millionpeoplechronicallyinfected2billionwithevidenceofpastorpresentinfectionCountryoforiginisTHEmajorriskfactorWorldHealthOrganization.HepatitisBFactSheet.CentersforDiseaseControlandPrevention.CDCHealthInformationforInternationalTravel2012.NewYork:OxfordUniversityPress;2012.PrevalenceofHBsAgHigh≥8%Intermediate2%to7%Low2%慢性乙肝病毒感染自然史YimHJ,etal.Hepatology.2006;43:S173-S181.HBeAg+HBeAg-HBeAb+ImmuneClearanceImmunotoleranceALTHBVDNAMos-YrsImmuneControl(Nonreplicative)HBsAg+HBsAg-HBsAb+InfectionMos-Yrs5-30YrsYimHJ,etal.Hepatology.2006;43:S173-S181.HBeAg+HBeAg-HBeAb+ImmuneClearanceImmunotoleranceALTHBVDNAMos-YrsHBsAg+HBsAg-HBsAb+InfectionMos-Yrs5-30Yrs慢性乙肝病毒感染自然史MostOncologyPatientsNormalALTLow/undetectableHBVDNAHBsAg+andHBeAg-orHBsAg-,anti-HBc+ImmuneControl(Nonreplicative)HBV能被清除吗?Immunecontrol—notclearance“ResolvedHBV”amisnomer—stillHBVDNAinlivercccDNAWerle-LapostolleB,etal.Gastroenterology.2004;126:1750-1758.HBV能被清除吗?Immunecontrol—notclearance“ResolvedHBV”amisnomer—stillHBVDNAinlivercccDNAWerle-LapostolleB,etal.Gastroenterology.2004;126:1750-1758.HBV能被清除吗?Immunecontrol—notclearance“ResolvedHBV”amisnomer—stillHBVDNAinliverTcellTcellTcellcccDNAWerle-LapostolleB,etal.Gastroenterology.2004;126:1750-1758.免疫抑制的后果ImmunecontrolcanbelostImmune-mediatedliverdamagewithimmunereconstitutionHIVSteroidsChemotxTcellTcellTcellcccDNAWerle-LapostolleB,etal.Gastroenterology.2004;126:1750-1758.免疫抑制的后果ImmunecontrolcanbelostImmune-mediatedliverdamagewithimmunereconstitutionHIVSteroidsChemotxTcellTcellTcellcccDNAWerle-LapostolleB,etal.Gastroenterology.2004;126:1750-1758.HBV再激活5-30YrsMos-YrsInfectionImmunotoleranceImmuneClearanceHBeAg+HBeAg-HBeAb+Mos-YrsALTHBVDNAHBeAg+HoofnagleJH.Hepatology.2009;49(5suppl):S156-S165.HBV再激活5-30YrsMos-YrsInfectionImmunotoleranceImmuneClearanceHBeAg+HBeAg-HBeAb+Mos-YrsALTHBVDNAHBeAg+ImmuneSuppressionHoofnagleJH.Hepatology.2009;49(5suppl):S156-S165.HBV再激活InfectionImmunotoleranceImmuneClearanceHBeAg+HBeAg-HBeAb+ALTHBVDNAHBeAg+ImmuneSuppressionImmuneReconstitutionHoofnagleJH.Hepatology.2009;49(5suppl):S156-S165.5-30YrsMos-YrsMos-YrsHBV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，仍可以进展至肝衰竭或死亡HoofnagleJH.Hepatology.2009;49(5suppl):S156-S165.已报道的能引起HBV再激活的药物YeoW,etal.Hepatology.2006;43:209-220.ClassAgents皮质激素类地塞米松,甲强龙,强的松龙抗肿瘤抗生素放线菌素D,博来霉素,柔红霉素,阿霉素,表柔比星,丝裂霉素植物生物碱长春花碱,长春新碱烷化剂卡铂,苯丁酸氮芥,顺氯氨铂,环磷酰胺,异环磷酰胺抗代谢物氮尿苷,阿糖胞苷,氟尿嘧啶,吉西他滨,巯基嘌呤,氨甲喋呤,硫鸟嘌呤单克隆抗体类抗CD52单抗,利妥昔单抗其他天冬酰胺酶,多西他赛,依托泊苷,氟达拉滨,叶醛酸,干扰素,丙卡巴肼未及时认识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YeoW,etal.Hepatology.2006;43:209-220.HBV再激活的概率:实体肿瘤HBsAg（+）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[2]•HBVDNA在ALT高峰期可检测不到•其他实体瘤的资料有限Ofthosewhoflare[2]:35%chemotherapyinterruption35%prematureterminationofchemotherapy1.KimMK,etal.KoreanJInternMed.2007;22:237-243.2.YeoW,etal.JMedVirol.2003;70:553-561.血液系统恶性病变:更大的风险HBVReactivationJaundiceNonfatalLiverFailureDeath100patientswithNHLundergoingCHOP;27HBsAgpositiveLokAS,etal.Gastroenterology.1991;100:182-188.HBsAgPatients(%)100806040200482244HBV再激活的危险因素恶性肿瘤•NHL:40%to58%ofHBsAgpositive•Breastcancer:upto41%ofHBsAgpositive化疗•Prednisone,•蒽环类抗生素,•rituximabincreasedrisk•“Potencyofimmunosuppression”HBVDNA•HBVDNA3×105copies/mL•ElevatedifHBeAgpositive人口统计•MenwomenYeoW,etal.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RituximabBonemarrow/stemcelltransplantationManzano-AlonsoML,etal.WorldJGastroenterol.2011;17:1531-1537.其他因素引起HBV再激活RocheB,etal.LiverInt.2011;31(suppl1):104-110.ImmunomodulatoryTherapyAnti-TNF(infliximab,adalimumab,etanercept)Antimetabolite(methotrexate)PurineAnalogues(azathioprine/6mp)Steroids(prednisone,budesonide)Other(rituximab,cyclosporine)Rituximab:一特殊的问题抗CD20单克隆抗体(B-cellmarker)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YeoW,etal.Hepatology.2006;43:209-220.PapamichalisP,etal.ClinResHepatolGastroenterol.2012;36:84-93.采用Rituximab治疗的HBsAg（-）患者的HBV再激活PatientswithdiffuselargeB-celllymphoma•HBsAg-negative,anti-HBc–positiveindividualstreatedwithCHOPorCHOP-RHBVReverseSeroconversionHBV-RelatedDeathYeoW,etal.JClinOncol.2009;27:605-611.Riskofreactivationwithrituximabsignificantinanti-HBcpositive40302010024005ProportionofAnti-HBcPositive,HBsAg-NegativePatients(%)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[1]•Among5patientswhoreactivated,1duringfifthcycleofchemotherapy;3medianof98daysAFTERlastrituximabcycle;canoccurearlyaswell•MedianpeakALT:809U/L(362-3499)•Medianpeakbilirubin:65µmol/L(19-249)已报道的其他情况•Includinginstancesofliverfailureandliver-relateddeathsYeoW,etal.JClinOncol.2009;27:605-611.RiskFactorsforreactivation1.Menwomen(almostallcases)2.Anti-HBsnegative