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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-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,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 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
2、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, #823 Pillay D, et al. 14th CROI, Los Angeles 2007, #642,CD4 COUNT,VIRAL LOAD,VIROLOGIC FAILURE,IMMUNOLOGIC FAILURE,CLINICAL 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. J
3、AIDS. 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, Zhang 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
4、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
5、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 Strategies in ARV-Nave Patien
6、ts (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 32 Late VF: Failure to suppress to 2000 c/mL Any CD4+ count,Multicenter Randomized Open-label,Screening,* Multiple between-arm comparisons
7、and interim analyses Adjusted significance level = 0.016.,Riddler SA, et al. XVI IAC, Toronto 2006, #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,Riddle
8、r 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 + 2NR
9、TI 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, 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
10、，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,d4T, 3TC, Nevirapine,NRTIs: ABC, AZT, ddI, d4T,TDFABC
11、, 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,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）？,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
12、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 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,Institutions participated in the project of the “11th five-year plan”,Shanghai
13、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 8th People Hospital,PUMCH Beijing Youan Hospital Beijing Ditan Hospital,22,Lost follow-up at 96
14、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 success
15、fully 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),
