抗病毒治疗.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,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,临床分期,症状编号,临,床,期,1,、无症状,2,、持续性全身淋巴结肿大,临,床,期,1,、不明原因的中度体重下降,(,原体重的,10%),2,、不明原因的慢性腹泻,1,个月,3,、不明原因的长期发热,(37.6C,，间歇性或持续性,1,个月,),4,、口腔念珠菌病（鹅口疮）,5,、口腔毛状粘膜白斑,6,、肺结核,7,、严重的细菌感染,(,如肺炎,脓胸,脓毒性肌炎,骨或关节感染,脑膜炎或菌血症,),8,、急性坏死性溃疡性口炎,牙龈炎或牙周炎,9,、不明原因的贫血,(8 g/dl),嗜中性粒细胞减少,(0.5 10,9,/L),或慢性血小板减少,(1,个月或内脏感染,),5,、食管念珠菌病（或气管、支气管、肺念珠菌病）,6,、肺外结核,7,、卡波西肉瘤,8,、巨细胞病毒感染,(,视网膜炎或其他脏器的感染,),9,、弓型虫脑病,10,、,HIV,脑病,11,、肺外隐球菌病包括脑膜炎,12,、播散性非典型分支杆菌感染,13,、进行性多灶性脑白质病,14,、慢性隐孢子虫病,(,伴有腹泻,),15,、慢性等孢子球虫病,16,、播散性霉菌病,(,球胞子菌或组织胞浆菌病,),17,、复发性非伤寒沙门菌败血症,18,、淋巴瘤,(,脑或,B,细胞非霍奇金,),或其它,HIV,相关实体瘤,19,、侵入性宫颈癌,20,、非典型播散性利什曼病,21,、,HIV,相关性肾病或,HIV,相关性心肌病,HIV/AIDS,实验室诊断,诊断性检测,初筛实验：,IFA,、,ELISA:1985,确认实验：,Western blot,预后判定性检测,T,细胞亚群检测：流式细胞仪技术,HIV RNA,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,Viral protease,Reversetranscriptase,RNA,RNA,DNA,DNA,DNA,(Fusion and entry),HIV Life Cycle,RT,Provirus,Proteins,RNA,RNA,RT,Viral maturation,Reversetranscriptase,RNA,RNA,DNA,DNA,DNA,Current antiretroviral targets and agents,ZDV,ddI,ddC,d4T,3TC,ABC,TDF,FTC,DLV,NVP,EFV,TMC125,R278,SQV,RTV,IDV,NFV,APV,LPV,FOS,ATZ,TPV,TMC114,BCV,PL-100,Fusion,Integration,Viral protease,PA-457,MK-0518,GS-9137,T-20,TRI-1144,Entry inhibitors,Maraviroc,Vicriviroc,TNX-355,Timeline of ARV Development,AIDS 1,st,reported,Eliza,WB,blood screening program,ZDV,ddI,ddC,d4T,3TC,SAQ,RTV,IDV,NVP,NFV,DLV,COM,SAQ-gc,EFV,ABC,APV,Viral load Amplicor 1.0,1981,1984,1994,1992,1991,1985,1987,1995,1996,1997,1999,1998,2000,2001,2002,2003,2005,HIV isolated,Resistance Testing TruGene,Amplicor 1.5,NEJM,Pallela et al.,LPV/r,ddI-EC,TZV,TDF,EFV-600,3TC-300,ENF,NFV-625,ATV,FTC,FPV,EPV-ABC,TDF-FTC,TPV,Current Antiretroviral Medications,NRTI,AbacavirABC,Didanosine DDI,EmtricitabineFTC,Lamivudine3TC,StavudineD4T,ZidovudineZDV,TenofovirTDF,NNRTI,DelavirdineDLV,EfavirenzEFV,NevirapineNVP,PI,AmprenavirAPV,AtazanavirATV,DarunavirDRV,FosamprenavirFPV,IndinavirIDV,LopinavirLPV,NelfinavirNFV,RitonavirRTV,Saquinavir SQV,hard gelHGC,tabletINV,TipranavirTPV,Fusion Inhibitor,EnfuvirtideT-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,New Antiretrovirals in Development,NRTIs/NtRTIs,Amdoxovir(DAPD),Apricitabine(AVX754),Compound X,Dexelvucitabine(D-d4FC),Racivir(,FTC),SN1212,Protease inhibitors,Brecanavir(GW640385),Darunavir(TMC114),P-1946,Entry inhibitors,BMS-488043,Maraviroc,NB-2,NB-64,PRO140,TNX-355,Vicriviroc,KRH-3955,KRH-3140,TRI-999,TRI-1144,NNRTIs,BILR 355 BS,CSIC,DAPY/DATA,Etravirine(TMC125),TMC120(microbicide),TMC278,UC781,Integrase inhibitors,GS-9137,MK-0518,Maturation inhibitors,PA-457,J.Gallant CCO 2005,AIDS-related Mortality in the USA,1995199619971998199920002001,Year,Deaths per 100 person-years,Therapy with a PI(%of patient-days),Deaths,Use of PIs,Palella et al.8th CROI,2001,40,35,30,25,20,15,10,5,0,100,75,50,25,0,1994,1995,1996,1997,Use of protease inhibitors,AIDS Deaths,0,10,20,30,40,Deaths per 100 Person-Years,0,20,40,60,80,100,Therapy with a Protease Inhibitor,(%of patient-days),Impact of Protease Inhibitors on AIDS Mortality,Palella F.et al.,New Engl J Med 1998;338:853-860,HAART Impacted on AIDS progression and/or death in Hong Kong,Wong,et al,CID,2004,N=303,N=278,1984-1996,1997-mid 2003,HAART era,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,Goals of Therapy&Tools to Achieve Goals,Improvement of quality of life,Reduction of HIV-related morbidity and mortality,Restoration and/or preservation of immunologic function,Maximal and durable suppression of viral load,Selection of ARV regimen,Preservation of future treatment options,Rational sequencing of therapy,Maximizing adherence,Use of resistance testing in selected clinical settings,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,组 织,急性感染,有症状,无症状,CD4,无症状：病毒载量,DHHS,是,是,100,000,IAS-USA,是,是,50,000-100,000,英国,是,是,200:,是,200-350:,可能,“,高病毒载量”,中国,？,是,200:,是,200-350,：可能,？,巴西,否,是,100,000,Initial Treatment:Preferred Components,*Avoid in pregnant women and women with significant pregnancy potential.,*Emtricitabine can be used in place of lamivudine and vice versa.,Efavirenz*,OR,Atazanavir+ritonavir,Fosamprenavir+ritonavir(BID),Lopinavir/ritonavir(BID),NNRTI Option,PI Options,Tenofovir+emtricitabine*,Zidovudine+lamivudine*,+,NRTI Options,Initial Treatment:Alternative Components,*Nevirapine should not be initiated in women with CD4 counts 250 cells/mm3 or men with CD4 counts 400 cells/mm3,*Atazanavir must be boosted with ritonavir if used in combination with tenofovir,Nevirapine*,OR,Atazanavir*,Fosamprenavir,Fosamprenavir+ritonavir(1x/day),Lopinavir/ritonavir(1x/day),NNRTI Option,PI Options,Abacavir+lamivudine,Didanosine+(emtricitabine or lamivudine),NRTI Options,Initial Treatment:Other Possible Options,Abacavir+lamivudine+zidovudine,Nelfinavir,Saquinavir(ritonavir-boosted),Stavudine+lamivudine,Inferior virologic efficacy,Inferior virologic efficacy,Inferior to lopinavir/ritonavir,Significant toxicities,Rationale,ARV drugs or regimens,These are considered acceptable but inferior to preferred or alternative components.They may be used in special circumstances.,Antiretroviral Components in Initial Therapy:NNRTIs,ADVANTAGES,Less dyslipidemia and fat maldistribution than in PI-based regimens,PI options preserved for future use,DISADVANTAGES,Resistance-single mutation,Cross-resistance among NNRTIs,Rash;hepatotoxicity,Potential drug interactions(CYP450),Antiretroviral Components in Initial Therapy:PIs,ADVANTAGES,Longest prospective data,NNRTI options preserved for future use,DISADVANTAGES,Metabolic complications(fat maldistribution,dyslipidemia,insulin resistance),Greater potential for drug interactions(CYP450),especially with ritonavir,Antiretroviral Components in Initial Therapy:NRTIs,ADVANTAGES,Established backbone of combination therapy,Minimal drug interactions,PI and NNRTI preserved for future use,DISADVANTAGES,Lactic acidosis and hepatic steatosis reported with most NRTIs(rare),Triple NRTI regimens show inferior virologic response compared with efavirenz-and indinavir-based regimens*,*Triple NRTI regimen of abacavir+lamivudine+zidovudine to be used only when a preferred or alternative NNRTI-or PI-based regimen cannot or should not be used as first-line therapy.,98%,61%,Week,LPV/r+d4T+3TC in treatment-na,ve adults HIV-1 RNA 400(50)copies/mL through Week 360,N:1008672 63 62,Murphy R.et al.,10,th,EACS,Dublin,Ireland,November 2005,#P7.9/3 Study 720,(95%),(59%),HIV RNA 65%VL 50,疗效药物,(48,周,),在,48,周,VL 50,百分比,Boosted PI,NNRTI,40,COMBINE(NVP+ZDV/3TC),2NN(NVP BID+d4T+3TC),ZODIAC(EFV+ABC QD+3TC),M98-863(LPV/RTV+d4T+3TC),ZODIAC(EFV+ABC+3TC),CNA30024(EFV+ZDV+3TC),2NN(NVP QD+d4T+3TC),2NN(EFV+d4T+3TC),CNA30024(EFV+ABC+3TC),M02-418(LPV/RTV+FTC+TDF QD),FTC301(EFV+FTC+ddI QD),DMP266-043(EFV+D4T+3TC),CLASS(EFV+ABC+3TC),ANRS 12-04(EFV+ddI+3TC),M97-720(LPV/RTV+d 4T+3TC),Dart 1(EFV+ddI EC+3TC),GS903(EFV+d4T+3TC),GS903(EFV+TDF+3TC),ANRS 091(EFV+ddI+FTC),50,60,70,80,90,100,30,Treatment-Experienced Patients:ARV Treatment Failure,Causes of treatment failure include:,Patient factors(CD4 nadir,VL,comorbidities,etc),Suboptimal adherence,ARV toxicity and intolerance,Pharmacokinetic problems,Suboptimal drug potency,Viral resistance,Immune Reconstitution Inflammatory Syndrome(IRIS),Lipoatrophy(fat loss),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),Drug Concentration,IC50,2,4,6,8,10,12,14,16,-NNRTI,-NRTIs,How to stop ARV,Definitions,Genotype,Virus nucleotide sequence from which a protein,samino acids can be deduced,Mutations reported as change in the deduced amino acid sequence,e.g.,Met184Val,Specific mutations confer phenotypic resistance,The phenotype is always derived from the genotype,Phenotype,Relative growth of the virus in the presenceof different drug concentrations,Usually reported as the drug concentration that inhibits virus replication by 50%(IC50),or the fold increase in IC50,Clinical characteristics,Primary HIV infection,Established HIV infection,First regimen failure,Multiple regimen failures,Pregnancy,Recommendation,Consider testing,Consider testing,Recommend testing,Recommend testing,Recommend testing,Rationale,Detect transmission of drug-,resistant virus;modify therapy to,optimize response and maintain,HIV-specific immune responses,Detect prior transmission of drug-,resistant HIV although this may,not always be possible with,current tests,Document drug(s)to which there,is resistance,Optimize the number of active,drugs in the next regimen;,exclude drugs to which response,is unlikely,Optimize maternal treatment and,prophylaxis for the neonate,IAS-USA Recommendations for Use of HIV Drug Resistance Assays,Hirsch.JAMA 2000;283:2417.,CDC:Prevalence of Drug-Resistant HIV Among Newly Diagnosed Patients,1.Bennett D,et al.CROI 2002.Abstract 372.,2.Bennett D,et al.CROI 2005.Abstract 674.,Prevalence of Drug Resistance(%),1998,1,(n=257),1999,1,(n=239),2000,1,(n=299),2003-2004,2,(n=787),Any drug,5.5,8.8,10.7,14.5,NRTI,5.1,7.1,7.7,7.1,NNRTI,0.4,2.1,1.7,8.4,PI,0,0.8,3.0,2.8,2 drug class,0,1.3,1.3,3.1,未来新药,Bevirimat,PIs,NNRTI,NRTI,Maturation inhibitors,Maraviroc,GS-9137,TMC278,Etravirine,Apricitabine,Brecanavir,Integrase inhibitors,Entry inhibitors,(anti-gp120,CCR5),CXCR4 inhibitors,MK-0518,TNX-355,2006,2007,2008,2009,2010,Vicriviroc,后面内容直接删除就行,资料可以编辑修改使用,资料可以编辑修改使用,主要经营：网络软件设计、图文设计制作、发布广告等,公司秉着以优质的服务对待每一位客户，做到让客户满意！,致力于数据挖掘，合同简历、论文写作、,PPT,设计、计划书、策划案、学习课件、各类模板等方方面面，打造全网一站式需求,感谢您的观看和下载,The user can demonstrate on a projector or computer,or print the presentation and make it into a film to be used in a wider field,