爱滋病11.ppt

Human Immunodeficiency Virus/AIDS获得性免疫缺陷综合症(爱 滋 病)吉林大学第一医院感染科25 years of AIDS9In 1991-1993,HIV prevalence in young pregnant women in Uganda and in young men in Thailand begins to decrease,the first major downturns in the epidemic in developing countries 10 Highly Active Antiretroviral Treatment launched11 Scientists develop the first treatment regimen to reduce mother-to-child transmission of HIV12 UNAIDS is created13 Brazil becomes the first developing country to provide antiretroviral therapy through its public health system14 The UN General Assembly Special Session on HIV/AIDS.Global Fund to fight AIDS,Tuberculosis and Malaria launched15 WHO and UNAIDS launch the 3 x 5 initiative with the goal of reaching 3 million people in developing world with ART by 200516 Global Coalition on Women and AIDS launched40302010050352515545Million198019851990199520002005123 456891112131415167101 First cases of unusual immune deficiency are identified among gay men in USA,and a new deadly disease noticed2Acquired Immune Deficiency Syndrome(AIDS)is defined for the first time3 The Human Immune Deficiency Virus(HIV)is identified as the cause of AIDS4 In Africa,a heterosexual AIDS epidemic is revealed5 The first HIV antibody test becomes6 Global Network of People living with HIV/AIDS(GNP+)(then International Steering Committee of People Living with HIV/AIDS)founded7 The World Health Organisation launches the Global Programme on AIDS8 The first therapy for AIDS zidovudine,or AZT-is approved for use in the USAPeople People living living with with HIVHIVChildren Children orphaned orphaned by AIDS in by AIDS in sub-sub-Saharan Saharan AfricaAfrica1.1nHuman Immunodeficiency VirusHuman Immunodeficiency VirusnAcquired Immunodeficiency syndrome first described in 1981nHIV-1 isolated in 1984,and HIV-2 in 1986nBelong to the lentivirus subfamily of the retroviridaenEnveloped RNA virus,120nm in diameternHIV-2 shares 40%nucleotide homology with HIV-1nGenome consists of 9200 nucleotides(HIV-1):ngag core proteins-p15,p17 and p24npol-p16(protease),p31(integrase/endonuclease)nenv-gp160(gp120:outer membrane part,gp41:transmembrane part)nOther regulatory genes ie.tat,rev,nef,vif,vpr and vpu HIV particlesHIV-1全长全长9181 bp两端为长末端重复序列两端为长末端重复序列（LTR）中间有中间有9个开放性读框个开放性读框HIV基因组基因组六个调控基因：六个调控基因：六个调控基因：六个调控基因：反式激活基因（反式激活基因（tat）病毒蛋白调节因子（病毒蛋白调节因子（rev）病毒感染因子（病毒感染因子（vif）负调节子（负调节子（nef）病毒蛋白病毒蛋白R基因（基因（vpr）U基因和基因和X基因（基因（vpu,vpx）三个结构基因三个结构基因三个结构基因三个结构基因 ：群抗原基因（群抗原基因（gag）多聚酶基因（多聚酶基因（pol）包膜蛋白基因包膜蛋白基因（env）Gene and their products of HIVGene proteins function/propertyGag p24 corePol RT polymeraseEnv gp120 envelopeTat trans-activator transcriptionRev regulator of expression of virion proteins Nef negative regulatory factor Vpu viral protein UVif virion infec proteinVpr viral protein R Sensitivity for HIVnFever:56 30n 25%alcoholn0.2%natrihypochlorousnBleaching powdern EpedemiologyA global view of HIV infectionA global view of HIV infection38.6 million people 33.446.0 million living with HIV,20052.4Cumulative AIDS cases world-wide:1998Reported cases(n=1,987,217)Adjusted for under reporting(n=13 million)Oceania 0.5%Europe 10.6%USA 34.8%Americas*5%Asia 7%USA 5%Europe 2%Oceania 10000No.of HIV infectionsBACKGROUNDBased Number of Reported CasesInfection sourcenPatient and asymptomatic carriernBloodnSemen nSecretion of uterus and cuntnOther body fluid Transmit approach 1.Sexual transmission-male homosexuals and constitute the largest risk group in N.America and Western Europe.In developing countries,heterosexual spread constitute the most important means of transmission.2.Blood/blood products-IV drug abusers represent the second largest AIDS patient groups in the US and Europe.Haemophiliacs were one of the first risk groups to be identified:they were infected through contaminated factor VIII.3.Vertical transmission-the transmission rate from mother to the newborn varies from around 15%in Western Europe to up to 50%in Africa.Vertical transmission may occur transplacentally route,perinatally during the birth process,or postnatally through breast milk.易感人群 n人群普遍易感。HIV的感染与人类的行为密切相关，男性同性恋者、静脉药物依赖者、与HIV携带者经常有性接触者、以及经常输血者如血友病人都属于高危险群体。nHI V PathogenesisReplicationnThe first step of infection is the binding of gp120 to the CD4 receptor of the cell,which is followed by penetration and uncoating.nThe RNA genome is then reverse transcribed into a DNA provirus which is integrated into the cell genome.nThis is followed by the synthesis and maturation of virus progeny.nHIV需借助于易感细胞表面的受体进入细胞，包括第一受体（CD4，主要受体）和第二受体（CCR5和CXCR4等辅助受体）。根据HIV对辅助受体利用的特性将HIV分为X4和R5毒株。R5型病毒通常只利用CCR5受体，而X4型病毒常常同时利用CXCR4、CCR5和CCR3受体，有时还利用CCR2b受体。The Essential Steps in the Life Cycle of HIV-1.HIV PathogenesisnThe profound immunosuppression seen in AIDS is due to the depletion of T4 helper lymphocytes.nIn the immediate period following exposure,HIV is present at a high level in the blood(as detected by HIV Antigen and HIV-RNA assays).nIt then settles down to a certain low level(set-point)during the incubation period.During the incubation period,there is a massive turnover of CD4 cells,whereby CD4 cells killed by HIV are replaced efficiently.nEventually,the immune system succumbs and AIDS develop when killed CD4 cells can no longer be replaced(witnessed by high HIV-RNA,HIV-antigen,and low CD4 counts).HIV PathogenesisnCD4+T淋巴细胞受损方式 1.病毒直接损伤 2.非感染细胞受累 3.HIV感染干细胞 4.免疫损伤HIV Pathogenesisn单核-巨噬细胞功能异常nB淋巴细胞损伤的异常表现nNK细胞损伤的异常表现nHIV感染后的免疫应答nClinical Features临床表现临床表现（一）（一）急性感染期急性感染期（二）无症状期（二）无症状期（三）持续性淋巴结肿大综合征（三）持续性淋巴结肿大综合征（四）艾滋病期（四）艾滋病期急性感染期急性感染期n60%60%的的HIVHIV感染者出现该期表现。一般在感染后感染者出现该期表现。一般在感染后2 2周左右周左右出现出现;n发热、头痛、乏力、皮疹、淋巴结肿大、末捎神经炎发热、头痛、乏力、皮疹、淋巴结肿大、末捎神经炎;n实验室检查发现肝功异常，血象改变（贫血，血小板实验室检查发现肝功异常，血象改变（贫血，血小板减少）减少）;n急性感染的早期急性感染的早期HIVHIV抗体不能被测及抗体不能被测及(抗体窗口期抗体窗口期).).急性感染期急性感染期 进行进行HIVHIV抗体检查并定期复查。有条件的话，抗体检查并定期复查。有条件的话，应同时进行下列检查：应同时进行下列检查：（1 1）HIV P24HIV P24抗原测定；抗原测定；（2 2）HIVHIV病毒测定；病毒测定；（3 3）T T淋巴细胞亚群测定淋巴细胞亚群测定。无症状期无症状期n没有任何临床症状，但潜伏期不是静止期，更没有任何临床症状，但潜伏期不是静止期，更不是安全期，病毒在持续繁殖，是主要的传染不是安全期，病毒在持续繁殖，是主要的传染源源;nHIVHIV抗体阳性抗体阳性;nT T淋巴细胞亚群检查显示淋巴细胞亚群检查显示，T4/T8比例倒置，T4淋巴细胞持续缓慢的减少，但一般仍大于350/mm3.持续性淋巴结肿大综合征持续性淋巴结肿大综合征 主要表现主要表现n除腹股沟淋巴结肿大外除腹股沟淋巴结肿大外,全身其它部位两处或全身其它部位两处或两处以上淋巴结肿大两处以上淋巴结肿大,其特点使直径在其特点使直径在1 1厘米以厘米以上上.质地柔韧质地柔韧,无压痛无压痛,无拈连能自由活动无拈连能自由活动.爱滋病n体质性疾病n神经系统症状n机会性感染n继发性肿瘤n其他疾病艾滋病期艾滋病期n严重的细胞免疫功能低下严重的细胞免疫功能低下 (CD(CD4 4+T+T 细胞数多低于细胞数多低于200/200/mmmm3 3)n各种机会性感染和肿瘤。各种机会性感染和肿瘤。n如如不不给给予予有有效效的的抗抗病病毒毒治治疗疗，几几乎乎100%100%的的病病人人在两年内死亡。在两年内死亡。艾滋病期的的常见病原学艾滋病期的的常见病原学n细菌：肺炎球菌，流杆杆菌细菌：肺炎球菌，流杆杆菌n病毒：病毒：CMVCMV，单疱病毒单疱病毒,EBV,EBVn原虫：原虫：PCPC，弓型体弓型体,隐孢子虫隐孢子虫n真菌：隐球菌，白念菌，青霉菌真菌：隐球菌，白念菌，青霉菌n分枝杆菌：结核，分枝杆菌：结核，MAICMAICn肿瘤：卡波济肉瘤肿瘤：卡波济肉瘤,淋巴瘤淋巴瘤艾滋病期的临床表现艾滋病期的临床表现n皮肤、黏膜皮肤、黏膜n肺、支气管肺、支气管n神经系统神经系统 n消化系统消化系统n血液系统血液系统艾滋病期的皮肤粘膜病变艾滋病期的皮肤粘膜病变n90%90%的病人受累的病人受累;n常见的临床表现常见的临床表现:口腔和外阴的念珠菌感染口腔和外阴的念珠菌感染;皮肤和粘膜的单庖皮肤和粘膜的单庖/带庖感染带庖感染;卡波济肉瘤卡波济肉瘤;皮肤搔痒和脂溢性皮肤搔痒和脂溢性;其它其它.艾滋病期的呼吸系统病变艾滋病期的呼吸系统病变n80%80%的病人受累的病人受累;n常见的临床表现常见的临床表现:PCPPCP;TB/MAIC TB/MAIC;细菌性细菌性;卡波济肉瘤卡波济肉瘤;真菌性真菌性 其它其它.艾滋病期的神经系统病变艾滋病期的神经系统病变n35-80%35-80%的病人受累的病人受累;n常见的临床表现常见的临床表现:n(一一)占位性占位性 弓型虫脑炎弓型虫脑炎(法法30%,30%,美美15%);15%);淋巴瘤淋巴瘤 LEMP LEMP(多灶性进展性白质病变多灶性进展性白质病变)n(二二)非占位性非占位性 隐球菌隐球菌 TB TB CMV CMV HIV HIV脑病脑病艾滋病期的消化系统病变艾滋病期的消化系统病变n50%50%的病人受累的病人受累;n常见的临床表现常见的临床表现:1.1.念珠菌食道炎念珠菌食道炎;2.2.HSV-1HSV-1感染感染;3.3.CMVCMV感染感染4.4.MAICMAIC感染感染;5.5.卡波济肉瘤卡波济肉瘤;6.6.沙门氏菌感染沙门氏菌感染.Opportunistic InfectionsProtozoalpneumocystis carinii(now thought to be a fungi),toxoplasmosis,crytosporidosisFungalcandidiasis,crytococcosishistoplasmosis,coccidiodomycosisBacterialMycobacterium avium complex atypical mycobacterial diseasesalmonella septicaemiamultiple or recurrent pyogenic bacterial infectionViralCMV,HSV,VZV,JCV Opportunistic infection in AIDSOpportunistic TumoursnThe most frequent opportunistic tumour,Kaposis sarcoma,is observed in 20%of patients with AIDS.nKS is observed mostly in homosexuals and its relative incidence is declining.It is now associated with a human herpes virus 8(HHV-8).nMalignant lymphomas are also frequently seen in AIDS patients.Kaposis Sarcoma口腔白念珠感染 毛状白斑HIV/AIDS：传染性软疣HIV/AIDS：尖锐湿疣 水痘水痘-带状疱疹病毒（带状疱疹病毒（VZV）感染感染PCP弓型虫脑病HIV/AIDS：脑淋巴瘤Laboratory DiagnosisnHIV/AIDS的实验室检测方法包括1.HIV抗体、2.病毒载量、3.CD4+T淋巴细胞、4.P24抗原检测等。ELISA for HIV antibodyMicroplate ELISA for HIV antibody:coloured wells indicate reactivityWestern blot for HIV antibodynThere are different criteria for the interpretation of HIV Western blot results e.g.CDC,WHO,American Red Cross.nThe most important antibodies are those against the envelope glycoproteins gp120,gp160,and gp41np24 antibody is usually present but may be absent in the later stages of HIV infectionHIV1/2抗体检测nHIV1/2抗体筛查检测方法（ELISA）。但随着自愿咨询检测（VCT）工作的开展，也可采用快速检测。HIV抗体确认试验常用的方法是免疫印迹法（WB）。n筛查试验呈阴性反应可出具HIV1/2抗体阴性报告。筛查试验呈阳性反应，不能出具阳性报告，只可出具“HIV抗体待复查”报告。经确认试验HIV-1（或HIV-2）抗体阳性者，出具HIV-1（或HIV-2）抗体阳性确认报告，并按规定做好咨询、保密和报告工作。病毒载量测定n病毒载量一般用血浆中每毫升HIV RNA的拷贝数（c/ml）来表示。n病毒载量测定常用方法有逆转录PCR系统（RT-PCR）、核酸序列依赖性扩增(NASBA NucliSens)技术、分枝DNA信号放大系统（bDNA）。不同病毒载量试验n病毒载量测定的临床意义包括预测疾病进程、提供开始抗病毒治疗依据、评估治疗效果、指导治疗方案调整，也可作为HIV感染早期诊断的参考指标。CD4+T淋巴细胞检测nCD4+T淋巴细胞是HIV感染最主要的靶细胞，HIV感染人体后，出现CD4+T淋巴细胞进行性减少，CD4+/CD8+T细胞比值倒置现象，细胞免疫功能受损。n目前常用的CD4+T淋巴细胞亚群检测方法为流式细胞术，可以直接获得CD4+T淋巴细胞数绝对值，或通过白细胞分类计数后换算为CD4+T淋巴细胞绝对数。nCD4+T淋巴细胞计数的临床意义是：了解机体的免疫状态和病程进展、确定疾病分期和治疗时机、判断治疗效果和HIV感染者的临床合并症。nCD4+T淋巴细胞计数的检测间隔时间：一般建议对于CD4+T淋巴细胞数 350/mm3的HIV无症状感染者，每年应检测一次；对于CD4+T淋巴细胞数200350/mm3之间且尚未开始AVT的HIV/AIDS病人，应每半年检测一次；对于已接受ART的病人在治疗的第一年内应每三个月进行一次CD4+T淋巴细胞数检测，治疗一年以上且病情稳定的病人可改为每半年检测一次。Prognostic testsOnce a diagnosis of HIV infection had been made,it is important to monitor the patient at regularly for signs of disease progression and response to antiviral chemotherapy.HIV Antigen tests-they were widely used as prognostic assays.It was soon apparent that detection of HIV p24 antigen was not as good as serial CD4 counts.The use of HIV p24 antigen assays for prognosis has now been superseded by HIV-RNA assays.HIV viral load-HIV viral load in serum may be measured by assays which detect HIV-RNA e.g.RT-PCR,NASBA,or bDNA.HIV viral load has now been established as having good prognostic value,and in monitoring response to antiviral chemotherapy.诊诊 断断nHIVHIV感染的确诊感染的确诊nAIDSAIDS的诊断的诊断HIVHIV感染的确诊感染的确诊 两次两次ELISAELISA初筛试验阳性，经蛋白初筛试验阳性，经蛋白印迹试验确认后方可确诊印迹试验确认后方可确诊HIVHIV感染。感染。WHO 1993WHO 1993年的诊断标准年的诊断标准 按临床表现可分为按临床表现可分为A A、B B、C C三类。三类。结合结合T4T4淋巴细胞计数，又可进一步分为淋巴细胞计数，又可进一步分为A1A1、A2A2、A3A3、B1B1、B2B2、B3B3、C1C1、C2C2、C3C3九个等级。九个等级。A3A3、B3B3和所有的和所有的C C期病人为艾滋病病人。期病人为艾滋病病人。HIV/AIDSHIV/AIDS的诊断标准（的诊断标准（19931993年）年）A A 组：组：无症状无症状HIVHIV 感染；感染；长期淋巴结肿大；长期淋巴结肿大；急性感染期。急性感染期。B B 组：组：除除 A A 组和组和C C 组以外的组以外的HIVHIV 感染者。感染者。C C 组组 艾滋病艾滋病 A A 组：组：无症状无症状HIVHIV 感染；感染；长期淋巴结肿大；长期淋巴结肿大；急性感染期。急性感染期。B B 组：组：除除 A A 组和组和C C 组以外的组以外的HIVHIV 感染者。感染者。C C 组组 艾滋病艾滋病 高危人群：性乱者和性病患者，静脉高危人群：性乱者和性病患者，静脉 吸吸毒毒者者，输输血血（19961996年以前）；年以前）；原因未明的长期发热原因未明的长期发热原因不明的消瘦原因不明的消瘦原因不明的腹泻原因不明的腹泻原因不明的淋巴结大原因不明的淋巴结大原因不明的皮疹原因不明的皮疹原因不明的视力下降或视野改变原因不明的视力下降或视野改变无原因出现各种神经系统病变无原因出现各种神经系统病变无明显原因出现各种机会性感染无明显原因出现各种机会性感染如何发现如何发现HIV/AIDSTreatmentn抗病毒治疗n免疫治疗n并发症的治疗n支持及对症治疗n预防性治疗抗抗HIVHIV药物作用机理药物作用机理Anti-Retroviral AgentsnNucleoside analogue reverse transcriptase inhibitors e.g.AZT,ddI,lamivudinenNon-nucleoside analoque reverse transcriptase,inhibitors e.g.Nevirapine nProtease Inhibitors e.g.Indinavir,RitonavirnHAART(highly active anti-retroviral therapy)regimens normally comprise 2 nucleoside reverse transcriptase inhibitors and a protease inhibitor.e.g.AZT,lamivudine and indinavir.Since the use of HAART,mortality from HIV has declined dramatically in the developed world.（二）开始抗逆转录病毒治疗的指征和时机n1成人及青少年开始抗逆转录病毒治疗的指征和时机n临床分期CD4细胞计数（个/mm3）推荐意见n急性感染期无论CD4细胞计数为多少考虑治疗n无症状感染期 350/mm3，无论血浆病毒载量的值为多少定期复查，暂不治疗n200350/mm3之间定期复查，出现以下情况之一即进行治疗：n1）CD4细胞计数1年内下降大于30%；n2）血浆病毒载量 100，000/mLn3）患者迫切要求治疗，且保证有良好的依从性。n艾滋病期无论CD4细胞计数为多少进行治疗抗病毒治疗时机抗病毒治疗时机(2004(2004年年)n有有HIV/AIDSHIV/AIDS的明确症状；的明确症状；nCD4CD4细胞计数细胞计数 200/mm200/mm3 3；nCD4CD4细细胞胞计计数数200-350/200-350/mmmm3 3，但但快快速速减减少少者者.Three kinds of anti-HIV drugsNuceoside analog reverse transcriptase inhibitorsAZT,ddi,ddc,3TCd4T(StavudineNon-Nuceoside analog reverse transcriptase inhibitors NavirapinedelavidineProtease inhibitorsSaquinavir,indinavirNalfinavir,ritonavir1.一线推荐方案：AZT（或d4T）+3TC+EFV（或NVP）2替代方案（1）AZT（或d4T）+3TC+IDV（2）ddI+d4T+EFV（或NVP）（3）AZT+ddI+EFV（或NVP）3.特殊人群的ARVTreatmentnZidovudine(AZT)was the first anti-viral agent shown to have beneficial effect against HIV infection.However,after prolonged use,AZT-resistant strains rapidly appears which limits the effect of AZT.nCombination therapy has now been shown to be effective,especially for trials involving multiple agents including protease inhibitors.(HAART-highly active anti-retroviral therapy)nThe rationale for this approach is that by combining drugs that are synergistic,non-cross-resistant and no overlapping toxicity,it may be possible to reduce toxicity,improve efficacy and prevent resistance from arising.Proventive TreatmentOT Test（+）者 异烟肼治疗1月CD4细胞0。2*109/L 戊烷脒/CoSMZ（预防肺孢子虫 肺炎）Treatment for complicate of AIDSn卡氏肺孢子虫肺炎：戊烷米，COSMZn卡氏肉瘤：AZT，IFN，博来酶素等n隐孢子虫感染：螺旋酶素nCMV：更昔洛韦n隐球菌脑膜炎：氟康唑PreventionnThe risk of contracting HIV increases with the number of sexual partners.A change in the lifestyle would obviously reduce the risk.nThe spread of HIV through blood transfusion and blood products had virtually been eliminated since the introduction of blood donor screening in many countries.nAZT had been shown to be effective in preventing transmission of HIV from the mother to the fetus.The incidence of HIV infection in the baby was reduced by two-thirds.nThe management of health care workers exposed to HIV through inoculation accidents is controversial.Anti-viral prophylaxis had been shown to be of some benefit but it is uncertain what is the optimal regimen.nVaccines are being developed at present but progress is hampered by the high variability of HIV.Clinical trials for several vaccines are in progress.暴露程度分级（1）一级暴露：暴露源为体液或者含有体液、血液的医疗器械、物品；暴露类型为暴露源沾染了不完整的皮肤或粘膜，但暴露量小且暴露时间较短。（2）二级暴露：暴露源为体液或者含有体液、血液的医疗器械、物品；暴露类型为暴露源沾染了不完整的皮肤或粘膜，暴露量大且暴露时间较长；或暴露类型为暴露源刺伤或割伤皮肤，但损伤程度较轻，为表皮肤擦伤或针刺伤（非大型空心针或深部穿刺针）。（3）三级暴露：暴露源为体液或含有体液、血液的医疗器械、物品；暴露类型为暴露源刺伤或割伤皮肤，但损伤程度较重，为深部伤口或割伤物有明显可视的血液。职业暴露后的处理原则（1）用肥皂液和流动的清水清洗被污染局部；（2）污染眼部等粘膜时，应用大量生理盐水反复对粘膜进行冲洗；（3）存在伤口时，应轻柔挤压伤处，尽可能挤出损伤处的血液，再用肥皂液和流动的清水冲洗伤口；（4）用75%的酒精或0.5%碘伏对伤口局部进行消毒、包扎处理 职业暴露后预防性抗逆转录病毒治疗方案 常用药物组合 基本用药方案 AZT+3TC 首选组合 ddI+d4T d4T+3TCn强化用药方案 AZT+3TC+IDV首选组合 基本用药方案+EFV（耐PI）基本用药方案+ABC2n开始治疗的时间及疗程 在发生职业暴露后尽可能在最短的时间内（尽可能在2小时内）进行预防性用药，最好不超过24小时，但即使超过24小时，也建议实施预防性用药。n 基本用药方案和强化用药方案的疗程均为连续服用28天