1、艾滋病抗病毒治疗艾滋病抗病毒治疗失败研究进展失败研究进展HIV 感染：目前我们所知道的感染：目前我们所知道的HAART治疗：过去治疗：过去15年的最大进展年的最大进展（HIV-RNA 6大类，大类，25种药物种药物 艾滋病的病死率显著下降艾滋病的病死率显著下降 药物的毒副作用，耐药，费用药物的毒副作用，耐药，费用费用费用终身用药终身用药耐药耐药毒副作用毒副作用持续存在的免疫激活持续存在的免疫激活组织对药物的屏障组织对药物的屏障 Inflammation persistante抗病毒治疗的局限性抗病毒治疗的局限性可持续性长期抗病毒治疗可持续性长期抗病毒治疗:我们需要什么？我们需要什么？The A
2、ntiretroviral Therapy Cohort Collaboration.CID 2010重要脏器并发导重要脏器并发导致的非艾滋死亡致的非艾滋死亡耐药引起的治疗耐药引起的治疗失败和死亡失败和死亡艾滋病引起的死艾滋病引起的死亡亡安全有效的抗病安全有效的抗病毒治疗方案毒治疗方案可持续性的适宜可持续性的适宜治疗方案治疗方案综合治疗模式综合治疗模式6Murri R,et al.JAIDS.2006;41:23-30.Losina E et al,15th CROI 2008,#823Pillay D,et al.14th CROI,Los Angeles 2007,#642CD4 COUN
3、TVIRAL LOADVIROLOGIC FAILUREIMMUNOLOGIC FAILURECLINICAL FAILUREDRUG RESISTANCE病毒学失败病毒学失败 导致 免疫学失败免疫学失败导致 临床失败临床失败7Murri R,et al.JAIDS.2006;41:23-30.Losina E et al,15th CROI 2008,#823临床失败临床失败免疫学失败免疫学失败病毒学失败病毒学失败Treatment Treatment durationduration(months)(months)Viral Load(copies/ml)Viral Load(copies
4、/ml)*TotalTotal40030000300006-11,N(%)6-11,N(%)179(82.1)179(82.1)6(2.8)6(2.8)9(4.1)9(4.1)8(3.7)8(3.7)16(7.3)16(7.3)218 21812-23,N(%)12-23,N(%)303(72.8)303(72.8)23(5.5)23(5.5)20(4.8)20(4.8)29(7.0)29(7.0)41(9.9)41(9.9)416 41624,N(%)24,N(%)352(66.8)352(66.8)18(3.4)18(3.4)54(10.3)54(10.3)40(7.6)40(7.6)63
5、(12.0)63(12.0)527 527抗病毒治疗后病毒学失败与治疗时间的关系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%,respectivelyMa Y,Zhang Fujie et al.Clin Infect Dis.2010病毒学失败的原因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N
6、elfinavir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;133:21-30.21120例例NVP耐药患者血药浓度监测耐药患者血药浓度监测耐药患者NVP谷浓度监测 024681012F
7、ollowm1m3m6m12NVPCtrough g/ml70%曾低于曾低于3.0g/ml，90%曾低于曾低于3.9g/ml。耐药患者服药依从性差耐药患者服药依从性差是导致血药浓度低和耐是导致血药浓度低和耐药的重要因素药的重要因素增加 EC50药物特点和耐药屏障药物特点和耐药屏障EC50低波谷EC50高波谷高波谷Drug ClassGBNNRTI/NRTI1-2整合酶抑制剂整合酶抑制剂1-2CCR5 抑制剂抑制剂1-2融合抑制剂融合抑制剂1-增强的蛋白酶抑制剂增强的蛋白酶抑制剂38不同种类药物的基因屏障数量不同种类药物的基因屏障数量LPV/r SGC 533/133 mg BID+EFV 60
8、0 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_log10 or r
9、ebound before week 32Late VF:Failure to suppress to 2000 c/mL Any CD4+countMulticenter Randomized Open-labelScreening*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+EFVLPV/r+2NRTIEFV+2NRTIObserved
10、 VF,n739460Genotype Assays,n567846NRTI Mutations Detected,%11%19%30%NNRTI Mutations Detected,n(%)66%3%44%Major PI Mutations*4%00Mutations in 2 Classes7%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
11、 ImplicationsRiddler 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 failin
12、g EFV+2NRTI regimen also develop resistance to the NRTIs Of the patients failing a LPV/r+2NRTI regimen,none developed major PI mutations治疗失败之后的耐药时间病毒载量阈值Adapted from Gallant,2007M184VCD4病毒学失败免疫学失败临床表现K103NTAM 1TAM 2TAM 3AZT/3TC/EFV二线方案?3TC/LPV/rTAM 4多重耐药患者多重耐药患者LLE抗病毒治疗一览表抗病毒治疗一览表 耐药检测：仅耐药检测：仅TDF敏感、
13、敏感、DRV为低耐，其余均为中、高度耐药99-12DDI+3TC01-8双肽芝+IDV00-3DDI+3TC+IDV03-12D4T+NVP+IDV04-8双肽芝+IDV04-123TC+EFV+IDV05-83TC+NVP+IDV08-33TC+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13.7万二线治疗在中国：我们不知道的？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
14、良反应（TDF的肾毒性）？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Cohort 1Treatment-nave patients（first-line drug）N=500Cohort 3Patients switch to second-line drug due to first-line drug therapeutic failure N=100Drug resistancetest21Hepatic toxicityanaphylactic reactiongastrointest
15、inal complicationsotherCohort 2Patients under long-term HAART(followed up in 10th five-year plan)N=60Clinical efficacyViral loadCD4Adverse eventsEffective concentration monitoringMechanisms and treatment of immune reconstitution failureCardiovascular diseaselipodystrophyInstitutions participated in
16、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 Hospital Yunnan AIDS CenterGuangzhou 8th People Hospital PUMCHBeijing Youan HospitalBei
17、jing Ditan Hospital22Lost 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 res
18、istance 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(I
19、TT)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)Patient genotype resistance analyses at baseline(n=91)Genotype resistanceSubjectsTotal
20、n=913TCHighTDF high01734TDF intermediate9TDF low8IntermediateTDF high15TDF intermediate4TDF low0LowTDF high012TDF intermediate12TDF low03TCHigh2632Intermediate6Low0TDFHigh07Intermediate6Low1LPVrHigh03Intermediate0Low3NNRTIsHigh/intermediate7171/Susceptible77Patient genotype resistance analyses at ba
21、seline(n=91)Patients genotype drug resistance at baseline4W8W12W24W36W48W72W96W原因NO.11SAENO.21SAENO.31DIEDNO.41DIEDNO.51DIEDNO.61UNKNOWNNO.71UNKNOWNNO.81UNKNOWNNO.91UNKNOWNNO.101UNKNOWNNO.111UNKNOWNNO.121UNKNOWN汇总1311203112 12例病人未完成例病人未完成2年研究的原因分析年研究的原因分析Except at 4-week,cd4 t counts at other visit
22、point are significant different from baseline both in ITT(blue)and in PP(red)(p0.05)CD4+T cell countsIncreasing 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 signific
23、ant different from baseline both in ITT(blue)and in PP(red)(p0.05)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0.050.050.05药物不良反应（98例次）Drug-related Adverse EventsTotolGrade IGrade IIGrade IIIGrad
24、e IVHepatotoxicity（%）23（23.5）11（11.2）10（10.2）2（2.1）0Rash（%）14（14.3）8（8.2）4（4.1）2（2.1）0Gastrointestinal disorders(%)27（27.6）17（17.3）10（10.2）00Anemia(%)00000Neutropenia(%)00000lipodystrophy(%)00000muscle weakness2（2.1）02（2.1）00headache1（1.0）01（1.0）00Hearing loss1（1.0）01（1.0）00hyperlipoidemia2（2.1）2（2.
25、1）000ITT分析PP分析分析ITT分析PP分析分析ITT分析PP分析分析肾脏功能分析（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=66aValues are expres
26、sed 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)Resistance and LPV concentration in Viral failure patients during 3TC/DF/LPVr treatment(n=17)病毒学失败与
27、Lopinavir血药浓度总结3TC/TDF/LPVr(even only remaining 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
28、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抗病毒治疗的局限性骨密度降低骨密度降低Prvalence accrue dostoporose ou dostopnie au niveau vertbral,des hanches ou des bras:63%des patients肾脏问题肾脏问题30%des patients VIH ont des anomalies de la fonction rnale心血管病心血管病变变中枢神中枢神经经Chez plus de la moiti des patients恶恶性性肿肿瘤瘤Risque accr de cancers non
29、 SIDA:anus,vagin,foie,poumons,colon,rein.Augmentation de 75%du risque dinfarctus aigu疲疲劳综劳综合征合征Risque accr par 3-14 fois chez VIH;corrl au taux de CD4治疗治疗10年以上年以上治疗治疗10-15年以上年以上治疗治疗10年以上年以上治疗治疗15年以上年以上Distribution of Causes of Death Among HOPS Patients,USuMortality in the highly active antiretrovira
30、l therapy era:changing causes of death and disease in the HIV outpatient study,J AIDS,2006;43:2734.-Primary or secondary causeDistribution of Causes of Death Among Mortalite 2000 and 2005 surveys,France-Primary or secondary causeuChanges in Causes of Death Among Adults Infected by HIV Between 2000 a
31、nd 2005:The Mortalite 2000 and 2005 Surveys(ANRS EN19 and Mortavic),J AIDS,2008;48:590598.20002005-Deaths with non-AIDS defining illnessesDistribution of Causes of Death Among Mortalite 2000 and 2005 surveys,FranceuChanges in Causes of Death Among Adults Infected by HIV Between 2000 and 2005:The Mor
32、talite 2000 and 2005 Surveys(ANRS EN19 and Mortavic),J AIDS,2008;48:590598.可持续性长期抗病毒治疗可持续性长期抗病毒治疗:我们需要什么？我们需要什么？The Antiretroviral Therapy Cohort Collaboration.CID 2010重要脏器并发导重要脏器并发导致的非艾滋死亡致的非艾滋死亡耐药引起的治疗耐药引起的治疗失败和死亡失败和死亡艾滋病引起的死艾滋病引起的死亡亡安全有效的抗病安全有效的抗病毒治疗方案毒治疗方案可持续性的适宜可持续性的适宜治疗方案治疗方案综合治疗模式综合治疗模式CD4+T细
33、胞计数细胞计数CD4+T细胞计数细胞计数血浆病毒载量血浆病毒载量血浆病毒载量血浆病毒载量050100150200250300350400036912151821242730012345050100150200250300350400036912151821242730012345抗病毒治疗时间抗病毒治疗时间(月月)CD4+T 细胞计数细胞计数(/mm3)病毒载量病毒载量 log10 拷贝拷贝/ml免疫重建49同时选取年龄、性别相匹配的健康对照组患者17人50Flow Chart of MethodSince 2003,55 pts under regular follow up in PUMC
34、H,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 HAARTRecord clinical manifestation,test serum viral load,analysis the fresh subset of T lymphocyte,freeze PBMC for later use.After effective HAART,patients wh
35、o 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
36、 level or CD4+T cell count200/ulYes:immune non-responder(INR)n=17No:Immune responder(IR)pick 13Thaw 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.Memo
37、ry CD4+T lymphocyte percentage Early(CD27+CCR7+),middle(CD27+CCR7-)and late(CD27-CCR7-)Taisheng LI,et al.CID,2011免疫重建障碍的纯真/记忆亚群的动力学变化510408012016006121824303604080120160061218243036免疫重建障碍免疫重建障碍免疫重建免疫重建免疫重建障碍免疫重建障碍免疫重建免疫重建抗病毒治疗时间（月）抗病毒治疗时间（月）抗病毒治疗时间（月）抗病毒治疗时间（月）CD4+T 细胞计数增加量细胞计数增加量(/mm3)CD4+T 细胞计数增加量
38、细胞计数增加量(/mm3)CD4增加与胸腺新生亚群(CD31%)显著正相关52Taisheng Li,et al.Clinical Infectious Diseases.2011.N(t)N(t)：某一时刻：某一时刻CD4+TCD4+T细胞计数细胞计数B B：CD4+TCD4+T细胞增加的理论最大值（常数）细胞增加的理论最大值（常数）e e：自然底数：自然底数 ：重建指数：重建指数数学模型：数学模型：免疫学无应答组患者免疫学无应答组患者CD4+T淋巴细胞无显著增淋巴细胞无显著增长的主要原因在于胸腺功能的衰竭长的主要原因在于胸腺功能的衰竭艾滋病期艾滋病期免疫学无应答免疫学无应答免疫学应答免疫学
39、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免疫学无应答组患者CD4+T淋巴细胞无显著增淋巴细胞无显著增长的主要原因在于胸腺功能的衰竭长的主要原因在于胸腺功能的衰竭艾滋病期艾滋病期免疫学无应答免疫学无应答免疫学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免疫重建障碍的治疗策略应当是促进胸腺功能恢复是促进胸腺功能恢复rhGH(基因重组人生长因子基因重组人生长因子)IL-7IL-255病毒储存库在哪里病毒储存库在哪里?HIV储存库和储存库和Sanctuair
40、es CNS,EyesLungRES/Vascular poolsGenital tractProductive InfectionChronic Infection Latent infection GALTBone MarrowThymusOther sitesCSFPeripheral BloodLymph nodesFDC艾滋患者泪液研究入选艾滋患者泪液研究入选20112011年度国内年度国内十大医学新闻十大医学新闻58Shacker T.Nature Med 2010;16:373-4强化的抗病毒治疗强化的抗病毒治疗Published by AAAS D.D.Richman et al.,Science 323,1304-1307(2009)唤醒病毒储存库唤醒病毒储存库促进细胞增殖促进细胞增殖Thank you
