艾滋病抗病毒失败研究进展

艾滋病抗病毒治疗失败研究进展HIV感染：目前我们所知道的HAART治疗：过去15年的最大进展（HIV-RNA50cp的HIV感染者，预期寿命超过30-40年甚至更长!!)只要药物有效、病人依从性好、未出现耐药，HAART存在长期效力可应用的药物种类增加:6大药物种类：超过20种化合物抗病毒治疗的成功和限制性•6大类，25种药物•艾滋病的病死率显著下降•药物的毒副作用，耐药，费用费用终身用药耐药毒副作用持续存在的免疫激活组织对药物的屏障Inflammationpersistante抗病毒治疗的局限性可持续性长期抗病毒治疗:我们需要什么？TheAntiretroviralTherapyCohortCollaboration.CID2010重要脏器并发导致的非艾滋死亡耐药引起的治疗失败和死亡艾滋病引起的死亡安全有效的抗病毒治疗方案可持续性的适宜治疗方案综合治疗模式病毒学失败所导致的严重后果6MurriR,etal.JAIDS.2006;41:23-30.LosinaEetal,15thCROI2008,#823PillayD,etal.14thCROI,LosAngeles2007,#642CD4COUNTVIRALLOADVIROLOGICFAILUREIMMUNOLOGICFAILURECLINICALFAILUREDRUGRESISTANCE临床失败只是冰山的一角病毒学失败导致免疫学失败导致临床失败7MurriR,etal.JAIDS.2006;41:23-30.LosinaEetal,15thCROI2008,#823临床失败免疫学失败病毒学失败Treatmentduration(months)ViralLoad(copies/ml)*Total400400-10001000-50005000-30000300006-11,N(%)179(82.1)6(2.8)9(4.1)8(3.7)16(7.3)21812-23,N(%)303(72.8)23(5.5)20(4.8)29(7.0)41(9.9)416≥24,N(%)352(66.8)18(3.4)54(10.3)40(7.6)63(12.0)527抗病毒治疗后病毒学失败与治疗时间的关系*Treatmentfailuredefinedas≥400copies/ml;at6-11,12-23,and≥24-monthstreatment,observedfailurewas17.9%,27.2%,and33.2%,respectivelyMaY,ZhangFujieetal.ClinInfectDis.2010病毒学失败的原因原因例子依从性差忘记服药，藏匿药物病毒耐药之前使用过ART，传播的耐药性不正确的药物使用Nelfinavir没有餐中服用药物储存不正确Ritonavir受热吸收差GI功能药物药物相互作用NVP或PI和利福平,草药毒性GI，神经系统毒性依从性和HIV病毒抑制之间的关系*886名未治HIV病人系列;CD4500x106cells/L或血浆病毒载量5000copies/mL.†名HIV病人前瞻性观察性研究‡MEMS,药物事件监测系统1.Low-BeerSetal.JAIDS.2000;23:360-361.Letter.2.PatersonDLetal.AnnInternMed.2000;133:21-30.21120例NVP耐药患者血药浓度监测耐药患者NVP谷浓度监测024681012Followm1m3m6m12NVPCtroughμg/ml70%曾低于3.0μg/ml，90%曾低于3.9μg/ml。耐药患者服药依从性差是导致血药浓度低和耐药的重要因素增加EC50药物特点和耐药屏障突变增加EC50低波谷EC50高波谷高波谷NRTI每个突变改变少但是药物浓度低非核苷类药物浓度高但是每个突变改变大增强PI每个突变改变小而且药物水平高DrugClassGBNNRTI/NRTI1-2整合酶抑制剂1-2CCR5抑制剂1-2融合抑制剂1-增强的蛋白酶抑制剂3–8不同种类药物的基因屏障数量LPV/rSGC533/133mgBID+EFV600mgQD(n=250)EFV600mgQD+3TC+d4TXRorTDForZDV(n=250)LPV/rSGC400/100mgBID+3TC+d4TXRorTDForZDV(n=253)AComparisonofThreeStrategiesinARV-NaïvePatients(A5142)PrimaryEndpoints*:Tocompare,pairwisebetweenarms:Timetovirologicfailure(VF)•EarlyVF:Lackofsuppressionby1_log10orreboundbeforeweek32•LateVF:Failuretosuppressto200copies/mLorreboundafterweek32Timetoregimencompletion•VFORtreatment-limitingtoxicityorintolerance,asassessedbythesiteinvestigator,toanyregimencomponent•ARV-naïve•HIVRNA2000c/mL•AnyCD4+countMulticenterRandomizedOpen-labelScreening*Multiplebetween-armcomparisonsandinterimanalysesàAdjustedsignificancelevel=0.016.RiddlerSA,etal.XVIIAC,Toronto2006,#THLB0204.96WeeksLPV/r+EFVLPV/r+2NRTIEFV+2NRTIObservedVF,n739460GenotypeAssays,n567846NRTIMutationsDetected,%11%19%30%NNRTIMutationsDetected,n(%)66%3%44%MajorPIMutations*4%00Mutationsin2Classes7%1%26%*Definedas30N,32I,33F,46I,47A/V,48V,50L/V,76V,82A/F/L/S/T,84V,88Sor90M.HaubrichRH,etal.XVIIHDRW,Barbados2007,#57.ResistanceProfileandImplicationsRiddlerS,HaubrickR,DiRienzoG,etal.Class-sparingregimensforinitialtreatmentofHIV-1infection.NEnglJMed2008;358:2095-2106.•AlmosthalffailingEFV+2NRTIregimendevelopresistancetotheEFVwithamutationthatconferscross-resistancetoallotherapprovedNNRTIs•1/3failingEFV+2NRTIregimenalsodevelopresistancetotheNRTIs•OfthepatientsfailingaLPV/r+2NRTIregimen,nonedevelopedmajorPImutations治疗失败之后的耐药时间病毒载量阈值AdaptedfromGallant,2007M184VCD4病毒学失败免疫学失败临床表现K103NTAM1TAM2TAM3AZT/3TC/EFV二线方案?3TC/LPV/rTAM4多重耐药患者LLE抗病毒治疗一览表耐药检测：仅TDF敏感、DRV为低耐，其余均为中、高度耐药0100200300400500600Oct-99Apr-00Oct-00Apr-01Oct-01Apr-02Oct-02Apr-03Oct-03Apr-04Oct-04Apr-05Oct-05Apr-06Oct-06Apr-07Oct-07Apr-08Oct-08Apr-09Oct-09Apr-10020000400006000080000100000120000CD4VL99-12DDI+3TC01-8双肽芝+IDV00-3DDI+3TC+IDV03-12D4T+NVP+IDV04-8双肽芝+IDV04-123TC+EFV+IDV05-83TC+NVP+IDV08-33TC+EFV+LPV/r拟更换方案为DRV+TDF+RAL+LPV/r体重增加，体力恢复低热，乏力，体重下降体重增加，血小板开始下降，在1~6万之间波动需要用LPV/r，但购买不到进入国家免费治疗血小板恢复正常13.7万d4T,3TC,NevirapineNRTIs:ABC,AZT,ddI,d4T,TDFABC,AZT,ddI,d4T,TDFNNRTIs:无无PIs:所有所有NRTIs:无AZTNNRTIs:无无PIs:所有所有临床失败(晚期病毒失败)早期病毒失败可选的治疗选择治疗失败的策略TDF,3TC,Nevirapine二线治疗在中国：我们不知道的？•病毒学失败病人的耐药发生率？•二线治疗的效果如何？•影响治疗效果的因素？•二线药物的不良反应（TDF的肾毒性）？艾滋病和病毒性肝炎等重大传染病防治项目成人艾滋病患者抗病毒治疗和免疫重建课题责任单位：中国医学科学院北京协和医院课题负责人：李太生课题编号:2008ZX10001-006课题起止年限：2008年10月—2010年12月艾滋病和病毒性肝炎等重大传染病防治项目研究设计Cohort1Treatment-naïvepatients（first-linedrug）N=500Cohort3Patientsswitchtosecond-linedrugduetofirst-linedrugtherapeuticfailureN=100Drugresistancetest21HepatictoxicityanaphylacticreactiongastrointestinalcomplicationsotherCohort2Patientsunderlong-termHAART(followedupin10thfive-yearplan)N=60ClinicalefficacyViralloadCD4AdverseeventsEffectiveconcentrationmonitoringMechanismsandtreatmentofimmunereconstitutionfailureCardiovasculardiseaselipodystrophyInstitutionsparticipatedintheprojectofthe“11thfive-yearplan”ShanghaiPublicHealthCenterFuzhouInfectiousDeseaseHospitalZhengzhouInfectiousDiseaseHospitalTheFourthMilitaryMedicalUniversity,TangduHospitalShenzhenDonghuHospitalYunnanAIDSCenterGuangzhou8thPeopleHospitalPUMCHBeijingYouanHospitalBeijingDitanHospital22Table1.Baselinepatientcharacteristics(n=94)Age(median)yrs43Gender(male/female)55/39Married66Infectionroutepaidplasmadonation64bloodtransfusion9sex14otherorunknown7Educationprimaryandmiddleschool65otherorunknown29Emplo