抗病毒治疗ppt课件.ppt

艾滋病抗病毒治疗 中国疾病预防控制中心性病艾滋病预防控制中心治疗与关怀室赵燕 HIV感染的自然史抗病毒治疗药物药品及作用机理治疗目的抗病毒治疗前准备治疗时机 方案治疗效果依从性耐药 ARTARVHAARTNNRTINRTIPIAdherenceIRISDR 临床表现 HIV感染的自然史 急性期无症状期 临床潜伏期 临床期 艾滋病期 急性HIV感染期 50 70 以上的患者在感染后2周到2个月出现 主要表现为传染性单核细胞增多症样表现通常在2 4周内自行缓解 无症状期 临床潜伏期 5 15 的无症状期患者在2 3年发展为艾滋病称快速进展者 5 的无症状期患者可以维持正常免疫12年以上称长期存活者 一般6 10年 AIDS期 此期具有以下基本特点体质性疾病严重的细胞免疫缺陷发生各种病原感染 多脏器多系统的性机会性感染发生各种机会性肿瘤 诊断标准 艾滋病期 原因不明的38 以上持续不规则发热 1个月 慢性腹泻次数多于3次 日 1个月 6个月之内体重下降10 以上 反复发作的口腔白念珠菌感染 反复发作的单纯疱疹病毒感染或带状疱疹病毒感染 肺孢子虫肺炎 反复发生的细菌性肺炎 活动性结核或非结核分枝杆菌病 诊断标准 深部真菌感染 中枢神经系统占位性病变 中青年人出现痴呆 活动性巨细胞病毒感染 弓形虫脑病 青霉菌感染 反复发生的败血症 皮肤黏膜或内脏的卡波氏肉瘤 淋巴瘤 17 CD4小于200 l HIV AIDS实验室诊断 诊断性检测 初筛实验 IFA ELISA 1985确认实验 Westernblot 预后判定性检测 T细胞亚群检测 流式细胞仪技术HIVRNA检测 HIV耐药检测 表型耐药 细胞培养技术基因型耐药 序列测定 杂交技术 RT Provirus Proteins RNA DNA RNA DNA DNA RT Viralprotease Reversetranscriptase RNA RNA DNA DNA DNA Fusionandentry HIVLifeCycle RT Provirus Proteins RNA RNA RT Viralmaturation Reversetranscriptase RNA RNA DNA DNA DNA Currentantiretroviraltargetsandagents ZDV ddI ddC d4T 3TC ABC TDF FTCDLV NVP EFV TMC125 R278 SQVRTVIDVNFVAPVLPVFOSATZTPVTMC114BCVPL 100 Fusion Integration Viralprotease PA 457 MK 0518GS 9137 T 20TRI 1144 Entryinhibitors MaravirocVicrivirocTNX 355 TimelineofARVDevelopment AIDS1streported Eliza WB bloodscreeningprogram ZDV ddI ddC d4T 3TC SAQ RTV IDV NVP NFV DLV COM SAQ gc EFV ABC APV ViralloadAmplicor1 0 1981 1984 1994 1992 1991 1985 1987 1995 1996 1997 1999 1998 2000 2001 2002 2003 2005 HIVisolated ResistanceTestingTruGene Amplicor1 5 NEJM Pallelaetal LPV r ddI EC TZV TDF EFV 600 3TC 300 ENFNFV 625ATVFTCFPV EPV ABCTDF FTCTPV CurrentAntiretroviralMedications NRTIAbacavirABCDidanosineDDIEmtricitabineFTCLamivudine3TCStavudineD4TZidovudineZDVTenofovirTDFNNRTIDelavirdineDLVEfavirenzEFVNevirapineNVP PIAmprenavirAPVAtazanavirATVDarunavirDRVFosamprenavirFPVIndinavirIDVLopinavirLPVNelfinavirNFVRitonavirRTVSaquinavirSQVhardgelHGCtabletINVTipranavirTPVFusionInhibitorEnfuvirtideT 20 目前我国所有的抗病毒药物 核苷类 DDI D4T 3TC AZT ABC TDF 非核苷类 EFV NVP蛋白酶 IDV ATV LPV RTV NewAntiretroviralsinDevelopment NRTIs NtRTIsAmdoxovir DAPD Apricitabine AVX754 CompoundXDexelvucitabine D d4FC Racivir FTC SN1212ProteaseinhibitorsBrecanavir GW640385 Darunavir TMC114 P 1946 EntryinhibitorsBMS 488043MaravirocNB 2 NB 64PRO140TNX 355VicrivirocKRH 3955KRH 3140TRI 999TRI 1144 NNRTIsBILR355BSCSICDAPY DATAEtravirine TMC125 TMC120 microbicide TMC278UC781IntegraseinhibitorsGS 9137MK 0518MaturationinhibitorsPA 457 J GallantCCO2005 AIDS relatedMortalityintheUSA 1995199619971998199920002001 Year Deathsper100person years TherapywithaPI ofpatient days Deaths UseofPIs Palellaetal 8thCROI 2001 4035302520151050 1007550250 ImpactofProteaseInhibitorsonAIDSMortality PalellaF etal NewEnglJMed1998 338 853 860 HAARTImpactedonAIDSprogressionand ordeathinHongKong WongetalCID2004 N 303 N 278 1984 1996 1997 mid2003 HAARTera Pre HAART 抗逆转录病毒治疗的目的 抑制病毒的复制病毒载量最大程度的下降免疫重建防止耐药的出现存活疾病进展传染性 GoalsofTherapy ToolstoAchieveGoals ImprovementofqualityoflifeReductionofHIV relatedmorbidityandmortalityRestorationand orpreservationofimmunologicfunctionMaximalanddurablesuppressionofviralload SelectionofARVregimenPreservationoffuturetreatmentoptionsRationalsequencingoftherapyMaximizingadherenceUseofresistancetestinginselectedclinicalsettings 推迟治疗的潜在益处避免药物治疗带来的对于生活质量的负面影响及药物毒副反应 保留治疗选择推迟药物耐药的发生患者有更多时间充分理解治疗需求减少总的服药时间有机会等待效力更强 毒副反应更少的药物及更好药物组合的出现推迟治疗的潜在风险由于没有及时接受治疗对免疫系统造成不可逆转的损害增加进展为艾滋病的可能性由于没有接受治疗 增加了传播HIV的危险 InitialTreatment PreferredComponents Avoidinpregnantwomenandwomenwithsignificantpregnancypotential Emtricitabinecanbeusedinplaceoflamivudineandviceversa OR NNRTIOption PIOptions Tenofovir emtricitabine Zidovudine lamivudine NRTIOptions InitialTreatment AlternativeComponents NevirapineshouldnotbeinitiatedinwomenwithCD4counts 250cells mm3ormenwithCD4counts 400cells mm3 Atazanavirmustbeboostedwithritonavirifusedincombinationwithtenofovir OR NNRTIOption PIOptions Abacavir lamivudineDidanosine emtricitabineorlamivudine NRTIOptions InitialTreatment OtherPossibleOptions Rationale ARVdrugsorregimens Theseareconsideredacceptablebutinferiortopreferredoralternativecomponents Theymaybeusedinspecialcircumstances AntiretroviralComponentsinInitialTherapy NNRTIs ADVANTAGESLessdyslipidemiaandfatmaldistributionthaninPI basedregimensPIoptionspreservedforfutureuse DISADVANTAGESResistance singlemutationCross resistanceamongNNRTIsRash hepatotoxicityPotentialdruginteractions CYP450 AntiretroviralComponentsinInitialTherapy PIs ADVANTAGESLongestprospectivedataNNRTIoptionspreservedforfutureuse DISADVANTAGESMetaboliccomplications fatmaldistribution dyslipidemia insulinresistance Greaterpotentialfordruginteractions CYP450 especiallywithritonavir AntiretroviralComponentsinInitialTherapy NRTIs ADVANTAGESEstablishedbackboneofcombinationtherapyMinimaldruginteractionsPIandNNRTIpreservedforfutureuse DISADVANTAGESLacticacidosisandhepaticsteatosisreportedwithmostNRTIs rare TripleNRTIregimensshowinferiorvirologicresponsecomparedwithefavirenz andindinavir basedregimens TripleNRTIregimenofabacavir lamivudine zidovudinetobeusedonlywhenapreferredoralternativeNNRTI orPI basedregimencannotorshouldnotbeusedasfirst linetherapy 98 61 Week LPV r d4T 3TCintreatment na veadultsHIV 1RNA 400 50 copies mLthroughWeek360 N 10086726362 MurphyR etal 10thEACS Dublin Ireland November2005 P7 9 3Study720 95 59 HIVRNA 400 50 copies mlonKaletra d4T 3TC Week MeanchangeinCD4CellCountThrough7years 501cells mm3 n 60 MurphyR etal 10thEACS Dublin Ireland November2005 P7 9 3Study720 Meanabsolutevalueatyear7 776cells mm3 SubjectswithValuesatWeek360 n 15 n 12 n 11 n 11 n 11 BartlettJA etal AIDS 2006 Inpress 65 VL 50疗效药物 48周 在48周VL 50百分比 BoostedPI NNRTI 40 COMBINE NVP ZDV 3TC 2NN NVPBID d4T 3TC ZODIAC EFV ABCQD 3TC M98 863 LPV RTV d4T 3TC ZODIAC EFV ABC 3TC CNA30024 EFV ZDV 3TC 2NN NVPQD d4T 3TC 2NN EFV d4T 3TC CNA30024 EFV ABC 3TC M02 418 LPV RTV FTC TDFQD FTC301 EFV FTC ddIQD DMP266 043 EFV D4T 3TC CLASS EFV ABC 3TC ANRS12 04 EFV ddI 3TC M97 720 LPV RTV d4T 3TC Dart1 EFV ddIEC 3TC GS903 EFV d4T 3TC GS903 EFV TDF 3TC ANRS091 EFV ddI FTC 50 60 70 80 90 100 30 Treatment ExperiencedPatients ARVTreatmentFailure Causesoftreatmentfailureinclude Patientfactors CD4nadir VL comorbidities etc SuboptimaladherenceARVtoxicityandintolerancePharmacokineticproblemsSuboptimaldrugpotencyViralresistance ImmuneReconstitutionInflammatorySyndrome IRIS Lipoatrophy fatloss ARV的毒性包括 线粒体的毒性代谢异常肝脏毒性超敏反应不同药物的副作用 0 Time days DrugConcentration IC50 2 4 6 8 10 12 14 16 NNRTI NRTIs HowtostopARV Definitions GenotypeVirusnucleotidesequencefromwhichaprotein saminoacidscanbededucedMutationsreportedaschangeinthededucedaminoacidsequence e g Met184ValSpecificmutationsconferphenotypicresistanceThephenotypeisalwaysderivedfromthegenotypePhenotypeRelativegrowthofthevirusinthepresenceofdifferentdrugconcentrationsUsuallyreportedasthedrugconcentrationthatinhibitsvirusreplicationby50 IC50 orthefoldincreaseinIC50 ClinicalcharacteristicsPrimaryHIVinfectionEstablishedHIVinfectionFirstregimenfailureMultipleregimenfailuresPregnancy RecommendationConsidertestingConsidertestingRecommendtestingRecommendtestingRecommendtesting RationaleDetecttransmissionofdrug resistantvirus modifytherapytooptimizeresponseandmaintainHIV specificimmuneresponsesDetectpriortransmissionofdrug resistantHIValthoughthismaynotalwaysbepossiblewithcurrenttestsDocumentdrug s towhichthereisresista