艾滋病抗病毒失败研究进展课件

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, Agents: LA Update on HIV/AIDS,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, Agents: LA Update on HIV/AIDS,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, and Using Antiretrovirals for Multiclass-Experienced Patients,Cliquez et modifiez le titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,le,meilleur,de la CROI 2007,Click to edit Master title style,Click to edit Master text styles,second level,third level,fourth level,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, Agents: LA Update on HIV/AIDS,Cliquez et modifiez le titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,le,meilleur,de la CROI 2007,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, Agents: LA Update on HIV/AIDS,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, Protease Inhibitors, New Treatment Goals,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, Agents: LA Update on HIV/AIDS,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style Click to edit Master title style,Cliquez et modifiez le titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,le,meilleur,de la CROI 2007,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, Annual Update 2006,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level, and Durability of Recommended Regimens for First-Line Therapy,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Cliquez et modifiez le titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,Click to edit Master title style,Click to edit Master text styles,second level,third level,fourth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Cliquez et modifiez le titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Cliquez et modifiez le titre,Cliquez pour modifier les styles du texte du masque,Deuxime niveau,Troisime niveau,Quatrime niveau,Cinquime niveau,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,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,*,*,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,*,*,艾滋病抗病毒失败研究进展,艾滋病抗病毒失败研究进展艾滋病抗病毒失败研究进展,艾滋病抗病毒失败研究进展艾滋病抗病毒失败研究进展艾滋病抗病毒,1,HIV,感染：目前我们所知道的,HAART,治疗：过去,15,年的最大进展,（,HIV-RNA 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,抗病毒治疗的成功和限制性 6大类，25种药物,3,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,Inflammation persistante,抗病毒治疗的局限性,费用 抗病毒治疗的局限性,4,可持续性长期抗病毒治疗,:,我们需要什么？,The Antiretroviral Therapy Cohort Collaboration. CID 2010,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,可持续性长期抗病毒治疗:我们需要什么？The Antire,5,病毒学失败所导致的严重后果,6,Murri R,et al. JAIDS,. 2006;41:23-30.,Losina E,et al, 15th CROI,2008, #823,Pillay D,et al. 14th CROI, Los Angeles 2007, #642,CD4 COUNT,VIRAL LOAD,VIROLOGIC FAILURE,IMMUNOLOGIC FAILURE,CLINICAL FAILURE,DRUG RESISTANCE,病毒学失败所导致的严重后果6Murri R, et al.,6,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,7,Murri R,et al. JAIDS,. 2006;41:23-30.,Losina E,et al, 15th CROI,2008, #823,临床失败,免疫学失败,病毒学失败,临床失败只是冰山的一角 病毒学失败 导致 免疫学失败7M,7,Treatment duration,(months),Viral Load (copies/ml)*,Total,30000,6-11, N (%),179 (82.1),6 (2.8),9 (4.1),8 (3.7),16 (7.3),218,12-23, 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,*,Treatment failure defined as 400 copies/ml; at 6-11, 12-23, and 24-months treatment, observed failure was 17.9%, 27.2%, and 33.2%, respectively,Ma Y, Zhang Fujie et al.,Clin Infect Dis.,2010,Treatment durationViral Load (,8,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,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,9,依从性和HIV病毒抑制之间的关系,*,886,名未治,HIV,病人系列,;,CD4 5000 copies/mL.,名,HIV,病人前瞻性观察性研究,MEMS,药物事件监测系统,1. Low-Beer S et al.,JAIDS,. 2000;23:360-361. Letter.,2. Paterson DL et al.,Ann Intern Med,. 2000;133:21-30.,2,依从性和HIV病毒抑制之间的关系*886名未治HIV病人系列,10,11,20,例,NVP,耐药患者血药浓度监测,耐药患者,NVP,谷浓度监测,70%,曾低于,3.0g /ml,，,90%,曾低于,3.9g /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,1120例NVP耐药患者血药浓度监测耐药患者NVP谷浓度监测,11,增加,EC,50,药物特点和耐药屏障,突变增加,EC,50,低波谷,EC,50,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,增加 EC50药物特点和耐药屏障突变增加EC50低波谷EC5,12,Drug Class,GB,NNRTI/NRTI,1-2,整合酶抑制剂,1-2,CCR5,抑制剂,1-2,融合抑制剂,1-,增强的蛋白酶抑制剂,38,不同种类药物的基因屏障数量,Drug ClassGBNNRTI/NRTI1-2整合酶抑制,13,LPV/r SGC 533/133 mg BID,+ EFV 600 mg QD,(n=250),EFV 600 mg QD,+ 3TC + d4T XR or TDF or ZDV,(n=250),LPV/r SGC 400/100 mg BID,+ 3TC + d4T XR or TDF or ZDV,(n=253),A Comparison of Three Strategies in ARV-Nave Patients (A5142),Primary Endpoints*:,To compare, pairwise between arms,:,Time to virologic failure (VF),Early VF: Lack of suppression by 1_log,10,or rebound before week 32,Late VF: Failure to suppress to 2000 c/mL,Any CD4+ count,Multicenter Randomized Open-label,Screening,*,Multiple between-arm comparisons and interim analyses Adjusted significance level = 0.016.,Riddler SA, et al.,XVI IAC, Toronto 2006, #THLB0204.,96 Weeks,LPV/r SGC 533/133 mg BID EFV 6,14,LPV/r + EFV,LPV/r + 2NRTI,EFV + 2NRTI,Observed VF, n,73,94,60,Genotype Assays, n,56,78,46,NRTI Mutations Detected, %,11%,19%,30%,NNRTI Mutations Detected, n (%),66%,3%,44%,Major PI Mutations*,4%,0,0,Mutations in 2 Classes,7%,1%,26%,*,Defined as 30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V, 76V, 82A/F/L/S/T, 84V, 88S or 90M.,Haubrich RH, et al.,XVI IHDRW, Barbados 2007, #57.,Resistance Profile and Implications,Riddler S, Haubrick R, DiRienzo G, et al. Class-sparing regimens for initial treatment of HIV-1 infection.,N Engl J Med,2008;358:2095-2106.,Almost half failing EFV + 2NRTI regimen develop resistance to the EFV with a mutation that confers cross-resistance to all other approved NNRTIs,1/3 failing EFV + 2NRTI regimen also develop resistance to the NRTIs,Of the patients failing a LPV/r + 2NRTI regimen, none developed major PI mutations,LPV/r + EFVLPV/r + 2NRTIEFV +,15,治疗失败之后的耐药,时间,病毒载量,阈值,Adapted from Gallant, 2007,M184V,CD4,病毒学失败,免疫学失败,临床表现,K103N,TAM 1,TAM 2,TAM 3,AZT/3TC/EFV,二线方案,?,3TC/LPV/r,TAM 4,治疗失败之后的耐药时间病毒载量阈值Adapted from,16,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,99-12,DDI+3TC,01-8,双肽芝,+IDV,00-3,DDI+3TC+IDV,03-12,D4T+NVP+IDV,04-8,双肽芝,+IDV,04-12,3TC+EFV+IDV,05-8,3TC+NVP+IDV,08-3,3TC+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,16,万之间波动,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,多重耐药患者LLE抗病毒治疗一览表,17,d4T, 3TC, Nevirapine,NRTIs: ABC, AZT, ddI, d4T,TDF,ABC, AZT, ddI, d4T,TDF,NNRTIs:,无,无,PIs:,所有,所有,NRTIs:,无,AZT,NNRTIs:,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,d4T, 3TC, NevirapineNRTIs: AB,18,二线治疗在中国,：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）？,二线治疗在中国：我们不知道的？,19,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,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艾,20,研究设计,Cohort 1,Treatment-nave patients,（,first-line drug,）,N=500,Cohort 3,Patients switch to second-line drug due to first-line drug therapeutic failure,N=100,Drug resistance,test,21,Hepatic toxicity,anaphylactic reaction,gastrointestinal complications,other,Cohort 2,Patients under long-term HAART (followed up in 10,th,five-year plan),N=60,Clinical efficacy,Viral load,CD4,Adverse events,Effective concentration,monitoring,Mechanisms and treatment of immune reconstitution failure,Cardiovascular disease,lipodystrophy,研究设计 Cohort 1Cohort 3Drug resi,21,Institutions participated in the project of the “11,th,five-year plan”,Shanghai Public Health Center,Fuzhou Infectious Desease Hospital,Zhengzhou Infectious Disease Hospital,The Fourth Military Medical University, Tangdu Hospital,Shenzhen Donghu Hospital,Yunnan AIDS Center,Guangzhou 8,th,People Hospital,PUMCH,Beijing Youan Hospital,Beijing Ditan Hospital,22,Institutions participated in t,22,艾滋病抗病毒失败研究进展课件,23,Lost follow-up at 96 weeks (n=12),Death (n=3),SAE withdrawal (n=2),Unknown missing (n=7),Enrolled subjects to receive second-line treatment,(n=120),Patients included in the study received 3TCTDFLPVr (N=94),Baseline plasma HIV RNA was evaluated via pol gene sequencing (N=94),Genotypic drug resistance analysis was successfully performed (N=91),Nested RT-PCR failure (n=3),No genotypic mutation found in pol gene (n=7),Genotypic mutation sites found in pol gene against NRTIs and NNRTIs (n=84),Excluded (n=22),VL400 cps/ml (n=21),withdrawal (n=1),Total 77 Virological positive response patients at endpoint (ITT),Genotypic drug resistance analysis was successfully performed (N=17),Patients taking 3TCTDFLPVr for 2 year (N=82),Total 17 virological failure patients including 8 VL non-respondent and 9 VL rebound at endpoint (ITT),Lost follow-up at 96 weeks (n,24,Patient genotype resistance analyses at baseline (n=91),Genotype resistance,Subjects,Total,n=91,3TC,High,TDF high,0,17,34,TDF intermediate,9,TDF low,8,Intermediate,TDF high,1,5,TDF intermediate,4,TDF low,0,Low,TDF high,0,12,TDF intermediate,12,TDF low,0,3TC,High,26,32,Intermediate,6,Low,0,TDF,High,0,7,Intermediate,6,Low,1,LPVr,High,0,3,Intermediate,0,Low,3,NNRTIs,High/intermediate,71,71,/,Susceptible,7,7,Patient genotype resistance an,25,Patient genotype resistance analyses at baseline (n=91),Patients genotype drug resistance at baseline,Patient genotype resistance an,26,4W,8W,12W,24W,36W,48W,72W,96W,原因,NO.1,1,SAE,NO.2,1,SAE,NO.3,1,DIED,NO.4,1,DIED,NO.5,1,DIED,NO.6,1,UNKNOWN,NO.7,1,UNKNOWN,NO.8,1,UNKNOWN,NO.9,1,UNKNOWN,NO.10,1,UNKNOWN,NO.11,1,UNKNOWN,NO.12,1,UNKNOWN,汇总,1,3,1,1,2,0,3,1,12,12,例病人未完成,2,年研究的原因分析,4W8W12W24W36W48W72W96W原因NO.1,27,Except at 4-week, cd4 t counts at other visit point are significant different from baseline both in ITT (blue) and in PP(red) (p0.05),CD4+T,cell counts,Except at 4-week, cd4 t counts,28,Increasing cd4 t counts at other visit point are significant different from 4-week-point both in ITT (blue) and in PP(red) (p0.05),Increasing CD4T,counts,Increasing cd4 t counts at oth,29,治疗,2,年,VL,水平（中位数）,VLs at each visit point are significant different from baseline both in ITT (blue) and in PP(red) (p0.05),治疗2年VL水平（中位数）VLs at each visit,30,治疗,2,年,VL,下降的水平,Decreasing VLs at other visit point are significant different from at 4-week-point both in ITT (blue) and in PP(red) (p0.05),治疗2年VL下降的水平Decreasing VLs at o,31,治疗,2,年病毒抑制率分析,按照,VL40,和,400cps/ml,进行分组分析,蓝色为,ITT,分析，红色为,PP,分析,治疗2年病毒抑制率分析按照VL40和0.05,0.05,0.05,The virological response accor,33,药物不良反应（,98,例次）,Drug-related Adverse Events,Totol,Grade I,Grade II,Grade III,Grade IV,Hepatotoxicity,（,%,）,23,（,23.5,）,11,（,11.2,）,10,（,10.2,）,2,（,2.1,）,0,Rash,（,%,）,14,（,14.3,）,8,（,8.2,）,4,（,4.1,）,2,（,2.1,）,0,Gastrointestinal disorders(%),27,（,27.6,）,17,（,17.3,）,10,（,10.2,）,0,0,Anemia(%),0,0,0,0,0,Neutropenia(%),0,0,0,0,0,lipodystrophy(%),0,0,0,0,0,muscle weakness,2,（,2.1,）,0,2,（,2.1,）,0,0,headache,1,（,1.0,）,0,1,（,1.0,）,0,0,Hearing loss,1,（,1.0,）,0,1,（,1.0,）,0,0,hyperlipoidemia,2,（,2.1,）,2,（,2.1,）,0,0,0,药物不良反应（98例次）Drug-related Adver,34,ITT,分析,PP,分析,ITT分析PP分析,35,ITT,分析,PP,分析,ITT分析PP分析,36,ITT,分析,PP,分析,ITT分析PP分析,37,肾脏功能分析（,ITT,）,a,Values are expressed as,median (interquartile range),or number (percentage).,b,eGFR = 175,(Serum creatinine (mg/dL),-1.234,(age (years),-0.179,(0.79 if female).,c,CRcl,（,ml/min,）,=(140-age(years),weight(kg),(0.85 if female)/(72,Scr (mg/dl),肾脏功能分析（ITT）aValues are express,38,肾脏功能分析（,PP,）,N=66,a,Values are expressed as,median (interquartile range),or number (percentage).,b,eGFR = 175,(Serum creatinine (mg/dL),-1.234,(age (years),-0.179,(0.79 if female).,c,CRcl,（,ml/min,）,=(140-age(years),weight(kg),(0.85 if female)/(72,Scr (mg/dl),肾脏功能分析（PP）N=66aValues are expr,39,Resistance and LPV concentration in Viral failure patients during 3TC/DF/LPVr treatment (n=17),Resistance and LPV concentrati,40,病毒学失败与,Lopinavir,血药浓度,病毒学失败与Lopinavir血药浓度,41,总结,3TC/TDF/LPVr (even only remaining LPVr monotherapy) was efficace for 1st line treated faileure patients,Scond line ARV was good tolerence,Adherence is key factor for HIV treatment , and TDM might be useful for improving adherence,总结3TC/TDF/LPVr (even only rema,42,艾滋病治疗研究的热点,长期成功抗病毒治疗后艾滋病死亡原因和机制,(,非艾滋病直接死亡和异常免疫激活）,免疫重建障碍（重建不全）的机制和治疗,根治艾滋病的策略（清除病毒储存库）,艾滋病治疗研究的热点长期成功抗病毒治疗后艾滋病死亡原因和机制,43,抗病毒治疗的局限性,骨密度降低,Prvalence accrue d,ostoporose ou d,ostopnie au niveau vertbral, des hanches ou des bras: 63% des patients,肾脏问题,30% des patients VIH ont des anomalies de la fonction rnale,心血管病变,中枢神经,Chez plus de la moiti des patients,恶性肿瘤,Risque accr de cancers non SIDA:,anus, vagin, foie, poumons, colon, rein.,Augmentation de 75% du risque d,infarctus,aigu,疲劳综合征,Risque accr par 3-14 fois chez VIH; corrl au taux de CD4,治疗,10,年以上,治疗,10-15,年以上,治疗,10,年以上,治疗,15,年以上,抗病毒治疗的局限性骨密度降低Prvalence accr,44,Distribution of Causes of Death Among HOPS Patients, US,Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study, J AIDS, 2006;43:2734.,-,-Primary or secondary cause,Distribution of Causes of Deat,45,Distribution of Causes of Death Among Mortalite 2000 and 2005 surveys, France,-,-Primary or secondary cause,Changes in Causes of Death Among Adults Infected by HIV Between 2000 and 2005: The Mortalite 2000 and 2005 Surveys (ANRS EN19 and Mortavic), J AIDS, 2008;48:590598.,Distribution of Causes of Deat,46,2000,2005,-Deaths with non-AIDS defining illnesses,Distribution of Causes of Death Among Mortalite 2000 and 2005 surveys, France,Changes in Causes of Death Among Adults Infected by HIV Between 2000 and 2005: The Mortalite 2000 and 2005 Surveys (ANRS EN19 and Mortavic), J AIDS, 2008;48:590598.,20002005-Deaths with non,47,可持续性长期抗病毒治疗,:,我们需要什么？,The Antiretroviral Therapy Cohort Collaboration. CID 2010,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,可持续性长期抗病毒治疗:我们需要什么？The Antire,48,CD4+T,细胞计数,CD4+T,细胞计数,血浆病毒载量,血浆病毒载量,0,50,100,150,200,250,300,350,400,0,3,6,9,12,15,18,21,24,27,30,0,1,2,3,4,5,0,50,100,150,200,250,300,350,400,0,3,6,9,12,15,18,21,24,27,30,0,1,2,3,4,5,抗病毒治疗时间,(,月,),CD4+T,细胞计数,(/mm,3,),病毒载量,log,10,拷贝,/ml,免疫重建,长期治疗后免疫功能重建障碍,免疫重建障碍（约,20%,）,49,CD4+T细胞计数CD4+T细胞计数血浆病毒载量血浆病毒载量,同时选取年龄、性别相匹配的健康对照组患者,17,人,50,Flow Chart of Method,Since 2003, 55 pts under regular follow,up in PUMCH, AIDS research center,were recruited, signed informed consent form.,Patients were regularly followed up at 1, 3,6, 9, 12, 18, 24, 30, 36 months after HAART,Record clinical manifestation, test serum,viral load, analysis the fresh subset of T,lymphocyte, freeze PBMC for later use.,After effective HAART, patients who maintained,serum viral load 50 copies/ml for more than,1 year were allocated into corresponding group.,At the same time, 17 healthy volunteers with,matching age and gender were also recruited,as healthy control group.,Grouping criteria:,The increase of CD4+ T,lymphocytes was less than 20% of their basic,level or CD4+ T cell count200/ul,Yes: immune,non-responder(INR),n=17,No:,Immune responder (IR) pick 13,Thaw PBMC and test:,1.Nave CD4+ T lymphocyte percentage,(CD4+CD45RA+CD31+/CD4+),2.Apoptosis CD4+ T lymphocyte percentage,(CD4+AnnexinV+PI-/CD4+),3.Regulatory T lymphocyte percentage,(CD4+CD25+FoxP3+/CD4+),4.Memory CD4+ T lymphocyte percentage,Early (CD27+CCR7+), middle (CD27+CCR7-),and late (CD27-CCR7-),Taisheng LI, et al. CID, 2011,同时选取年龄、性别相匹配的健康对照组患者17人50Flow,50,纯真表型,CD4+T,细胞,记忆表型,CD4+T,细胞,免疫重建障碍的纯真,/,记忆亚群的动力学变化,0,40,80,120,160,0,6,12,18,24,30,36,0,40,80,120,160,0,6,12,18,24,30,36,免疫重建障碍,免疫重建,免疫重建障碍,免疫重建,抗病毒治疗时间（月）,抗病毒治疗时间（月）,CD4+T,细胞计数增加量,(/mm,3,),CD4+T,细胞计数增加量,(/mm,3,),51,纯真表型CD4+T细胞记忆表型CD4+T细胞免疫重建障碍的纯,CD4,增加与胸腺新生亚群,(CD31%),显著正相关,Taisheng Li, et al.,Clinical Infectious Diseases,.,2011.,N(t),：某一时刻,CD4+T,细胞计数,B,：,CD4+T,细胞增加的理论最大值（常数）,e,：自然底数,：重建指数,数学模型：,52,CD4增加与胸腺新生亚群(CD31%)显著正相关Taishe,免疫学无应答组患者,CD4+T,淋巴细胞无显著增长的主要原因在于胸腺功能的衰竭,艾滋病期,免疫学无应答,免疫学应答,胸腺新生能力,凋亡比例,T,稳态维持,Taisheng LI, et al. CID, 2011,免疫学无应答组患者CD4+T淋巴细胞无显著增长的主要原因在于,53,免疫学无应答组患者,CD4+T,淋巴细胞无显著增长的主要原因在于胸腺功能的衰竭,艾滋病期,免疫学无应答,免疫学应答,胸腺新生能