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1、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,Inflammation persistante,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？,The Antiretroviral Th
2、erapy 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,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,#823Pillay D,et al.14th CROI,Los Angeles 2007,#642,CD4 COUNT,VIRAL LOAD,VIROLOGIC FAILURE,IMMUNOLOGIC FAILURE,CLINI
3、CAL FAILURE,DRUG RESISTANCE,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,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,Zhan
4、g Fujie et al.Clin Infect Dis.2010,病毒学失败的原因,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.,2,11,20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
5、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,不同种类药物的基因屏障数量,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
6、 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_log10 or rebound before week 32Late VF:Failure to suppress to 200 copies/mL or rebound after week 32Time to regimen completionVF OR treatment-lim
7、iting toxicity or intolerance,as assessed by the site investigator,to any regimen component,ARV-naveHIV RNA 2000 c/mLAny 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 20
8、06,#THLB0204.,96 Weeks,*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 200
9、8;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 NNRTIs1/3 failing EFV+2NRTI regimen also develop resistance to the NRTIsOf the patients failing a LPV/r+2NRTI regimen,none developed major PI mutat
10、ions,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,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,99-12DDI+3TC,01-8双肽芝+IDV,00-3DDI+3TC+IDV,03-12D4T+NVP+IDV,04-8双肽芝+IDV,04-123TC+EFV+IDV,05-83TC+NVP+IDV,08-33TC+EFV+L
11、PV/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,d4T,3TC,Nevirapine,NRTIs: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
12、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,Cohort 1Treatment-nave patients（first-line drug）N=500,Cohort 3Patients switch to second-line drug due to first-line dr
13、ug therapeutic failure N=100,Drug resistancetest,21,Institutions participated in the project of the“11th five-year plan”,Shanghai Public Health Center,Fuzhou Infectious Desease Hospital,Zhengzhou Infectious Disease Hospital,The Fourth Military Medical University,Tangdu Hospital,Shenzhen Donghu Hospi
14、tal,Yunnan AIDS Center,Guangzhou 8th People Hospital,PUMCHBeijing Youan HospitalBeijing Ditan Hospital,22,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=9
15、4),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)V
16、L400 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 en
17、dpoint(ITT),Patient genotype resistance analyses at baseline(n=91),Patient genotype resistance analyses at baseline(n=91),Patients genotype drug resistance at baseline,12例病人未完成2年研究的原因分析,Except at 4-week,cd4 t counts at other visit point are significant different from baseline both in ITT(blue)and in
18、 PP(red)(p0.05),CD4+T cell counts,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,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
19、),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,The virological response according baseline drug resistance,药物不良反应（98例次）,ITT分析,PP分析,ITT分析,PP分析,ITT分析,PP分析,肾脏功能分析（
20、ITT）,aValues are expressed as median(interquartile range)or number(percentage).beGFR=175(Serum creatinine(mg/dL)-1.234(age(years)-0.179(0.79 if female).cCRcl（ml/min）=(140-age(years)weight(kg)(0.85 if female)/(72Scr(mg/dl),肾脏功能分析（PP）N=66,aValues are expressed as median(interquartile range)or number(p
21、ercentage).beGFR=175(Serum creatinine(mg/dL)-1.234(age(years)-0.179(0.79 if female).cCRcl（ml/min）=(140-age(years)weight(kg)(0.85 if female)/(72Scr(mg/dl),Resistance and LPV concentration in Viral failure patients during 3TC/DF/LPVr treatment(n=17),病毒学失败与Lopinavir血药浓度,总结,3TC/TDF/LPVr(even only remain
22、ing LPVr monotherapy)was efficace for 1st line treated faileure patientsScond line ARV was good tolerenceAdherence is key factor for HIV treatment,and TDM might be useful for improving adherence,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）,抗病毒治疗的局限性,Distributio
23、n 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 Death Among Mortalite 2000 and 2005 surveys,France,-Primar
24、y 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.,2000,2005,-Deaths with non-AIDS defining illnesses,Distribution of Causes of Death Among Mortalite 2000 and 2005 surve
25、ys,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.,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
26、续性的适宜治疗方案,综合治疗模式,CD4+T细胞计数,CD4+T细胞计数,血浆病毒载量,血浆病毒载量,免疫重建,49,长期治疗后免疫功能重建障碍,免疫重建障碍（约20%）,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
27、,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 sa
28、me 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
29、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,20
30、11,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,51,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(/mm3),CD4+T 细胞计数增加量(/mm3),CD4增加与胸腺新生亚群(CD31%)显著正相关,52,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：,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
31、,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,免疫重建障碍的治疗策略应当是促进胸腺功能恢复,55,病毒储存库在哪里?,HIV储存库和Sanctuaires,研究结果,艾滋患者泪液研究入选2011年度国内十大医学新闻,58,Shacker T.Nature Med 2010;16:373-4,强化的抗病毒治疗,Published by AAAS,D.D.Richman et al.,Science 323,1304-1307(2009),唤醒病毒储存库促进细胞增殖,Thank you,
