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HBV再激活的发生HepatitisB:SomeSoberingFacts350millionpeoplechronicallyinfected2billionwithevidenceofpastorpresentinfectionCountryoforiginisTHEmajorriskfactorWorldHealthOrganization.HepatitisBFactSheet.CentersforDiseaseControlandPrevention.CDCHealthInformationforInternationalTravel2012.NewYork:OxfordUniversityPress;2012.PrevalenceofHBsAgHigh≥8%Intermediate2%to7%Low<2%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.ImmuneClearanceImmunotoleranceALTHBVDNAMos-YrsHBsAg+ HBsAg-HBsAb+InfectionMos-Yrs5-30Yrs慢性乙肝病毒感染自然史MostOncologyPatientsNormalALTLow/undetectableHBVDNAHBsAg+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ImmunecontrolcanbelostImmune-mediatedliverdamagewithimmunereconstitutionHIVSteroidsChemotxTcellTcellTcellcccDNAWerle-LapostolleB,etal.Gastroenterology.2004;126:1750-1758.免疫抑制的后果ImmunecontrolcanbelostImmune-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%ofHBsAgpositiveBreastcancer:upto41%ofHBsAgpositive化疗Prednisone,蒽环类抗生素,rituximabincreasedrisk“Potencyofimmunosuppression”HBVDNAHBVDNA>3×105copies/mLElevatedifHBeAgpositive人口统计Men>womenYeoW,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RituximabBonemarrow/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.Immunomodulatory

TherapyAnti-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-celllymphomaHBsAg-negative,anti-HBc–positiveindividualstreatedwithCHOPorCHOP-RHBVReverseSeroconversionHBV-RelatedDeathYeoW,etal.JClinOncol.2009;27:605-611.Riskofreactivationwithrituximabsignificantinanti-HBcpositive40302010024005Proportionof

Anti-HBcPositive,

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[1]Among5patientswhoreactivated,1duringfifthcycleofchemotherapy;3medianof98daysAFTERlastrituximabcycle;canoccurearlyaswellMedianpeakALT: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.RiskFactorsforreactivationMen>>women(almostallcases)Anti-HBsnegative(orlowtiter)?increasedage(>50yrs)接受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(HBsAgpositive)Upto54%[1]

→needpreemptiveantiviraltherapy!Long-termcomplications:cirrhosisin10%[2]如果仅抗HBc阳性者，血清转换被逆转现象常见【3】Upto50%becomeHBsAgpositive→usepreemptiveantivirals

Mayoccurverylate捐献者的HBV状态非常重要[1,4]Ifnaturalimmunity(anti-HBs,anti-HBc):mayclearHBsAgIfvaccinated(anti-HBs):possiblysomeprotection1.LauGK,etal.BoneMarrowTransplant.1997;19:795-799.2.HuiCK,etal.Blood.2005;106:464-469.

3.OnozawaM,etal.Transplantation.2005;79:616-619.4.LauGK,etal.JInfectDis.1998;178:1585-1591.类固醇增加HBV再激活发生的风险50patientswithNHLwhowereHBsAgpositiverandomizedtoepirubicin,cyclophosphamideandetoposide(ACE)±prednisolone(P)ChengAL,etal.Hepatology.2003;37:1320-1328.HBVReactivationJaundiceSurvivalat4YrsALT>10xULNCompleteRemission**P<.05PrednisoloneincreasedriskandseverityofHBVreactivationbuttrendtowardimprovedNHLoutcomeHBsAgPatients(%)1008060402003873*1344*428*35463668ACEPACEHBV再激活的治疗和预防Watchforwithdrawalflares采用化疗/免疫调节剂治疗患者的管理HBsAg+HBsAg-,anti-HBc+HBVDNAHBVDNALAMx6-12mosposttherapyETV/TDFuntilHBV

endpointsPositivePositiveNegativeTestHBsAgqmoHBVDNAq3mosUntil6-12mosposttherapy*Caveats:IfconcernaboutmonitoringerronsideoftreatmentHighrisk:anti-HBsnegativeoldermenconsiderup-fronttreatment<2000IU/mL≥2000IU/mLScreenallpatientsHBsAg,anti-HBc,anti-HBs预先使用拉米夫定可减少HBV再激活的风险HBsAg-positivepatientswithlymphomatreatedwithhigh-dosechemotherapyrandomizedto“preemptive”vs“on-demand”lamivudineOn-demandLAM(ifHBVDNAincreased)SurvivalFreeFromHepatitisDuetoHBVReactivationLauGK,etal.Gastroenterology.2003;125:1742-1749.PreemptiveLAM1007550250010203040WkP=.002bylog-ranktestPtsatRisk,n

PreemptiveLAMOn-demandLAM15

1512

1310

109

46

2预先抗病毒治疗的价值HBsAg-positivepatientswithNHLtreatedwithCHOPrandomizedto“preemptive”vs“on-demand”lamivudineHsuC,etal.Hepatology.2008;47:844-853.On-demandgroup:startLAMifALT>1.5xULNPreemptivegroup:startLAMonDay1ofCHOPPreemptiveantiviralsdecreaseHBVreactivationHBVReactivation

andHepatitisFlareHBVReactivation

andJaundiceHBVReactivation

andALT>10xULNDeath(AfterChemoTx)100806040200HBsAgPatients(%)4883602