艾滋病抗病毒失败研究进展

1、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，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6murri r, et al. jaids. 2006;41:23-30.losin

2、a e et al, 15th croi 2008, #823pillay d, et al. 14th croi, los angeles 2007, #642cd4 countviral 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临床失败免疫学失败病毒学失败treatment

3、treatment durationduration(months)(months)viral load (copies/ml)viral load (copies/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) 21821812-23, n (%)12-23, n (%)303 (72.8)303 (72.8)23 (5.5)23 (5.5)20 (4.8)20 (4.8)29 (7

4、.0)29 (7.0)41 (9.9)41 (9.9) 416416 24, 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 (12.0)63 (12.0) 527527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%, r

5、espectivelyma y, zhang fujie et al. clin infect dis. 2010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*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. paterso

6、n dl et al. ann intern med. 2000;133:21-30.211耐药患者nvp谷浓度监测 024681012followm1m3m6m12nvpctrough g/ml70%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 ec50ec50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lpv/r sgc 533/133 mg bi

7、d + 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)primary endpoints*: to compare, pairwise between arms:time to virologic failure (vf)learly vf: lack of suppression by 1_log10 or rebound before week 32llate vf: failure

8、 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 vf, n739460genotype as

9、says, 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.riddler s, haubrick r, di

10、rienzo 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 dev

11、elop resistance to the nrtis of the patients failing a lpv/r + 2nrti regimen, none developed major pi mutations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 499-12ddi+3tc01-8双肽芝+idv00-3ddi+3tc+idv03-12d4t+nvp+idv04-8双肽芝+idv04-123tc+efv+idv05

12、-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l病毒学失败病人的耐药发生率？l二线治疗的效果如何？l影响治疗效果的因素？l二线药物的不良反应（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

13、 drug） n=500cohort 3patients switch to second-line drug due to first-line drug therapeutic failure n=100drug resistancetest21hepatic toxicityanaphylactic reactiongastrointestinal complicationsothercohort 2patients under long-term haart (followed up in 10th five-year plan)n=60clinical efficacyviral l

14、oadcd4adverse eventseffective concentration monitoringmechanisms and treatment of immune reconstitution failurecardiovascular diseaselipodystrophyshanghai public health center fuzhou infectious desease hospital zhengzhou infectious disease hospital the fourth military medical university, tangdu hosp

15、ital shenzhen donghu hospital yunnan aids centerguangzhou 8th people hospital pumchbeijing youan hospitalbeijing 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 stud

16、y 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 n

17、nrtis (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-

18、respondent and 9 vl rebound at endpoint (itt)genotype resistancesubjectstotaln=913tchightdf high01734tdf intermediate9tdf low8intermediatetdf high15tdf intermediate4tdf low0lowtdf high012tdf intermediate12tdf low03tchigh2632intermediate6low0tdfhigh07intermediate6low1lpvrhigh03intermediate0low3nnrtis

19、high/intermediate7171/susceptible77lpatients 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2年研究的原因分析lexcept at 4-week, cd4 t counts at

20、other visit point are significant different from baseline both in itt (blue) and in pp(red) (p0.05) cd4+t cell countslincreasing cd4 t counts at other visit point are significant different from 4-week-point both in itt (blue) and in pp(red) (p0.05)lvls at each visit point are significant different f

21、rom baseline both in itt (blue) and in pp(red) (p0.05)ldecreasing vls at other visit point are significant different from at 4-week-point both in itt (blue) and in pp(red) (p0.05)l按照vl40和0.050.050.05drug-related adverse eventstotolgrade igrade iigrade iiigrade ivhepatotoxicity（%）23（23.5） 11（11.2） 10

22、（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（2.1）000pp分析pp分析pp分析lavalues are express

23、ed as median (interquartile range) or number (percentage). lbegfr = 175 (serum creatinine (mg/dl)-1.234 (age (years)-0.179 (0.79 if female).lccrcl（ml/min）=(140-age(years)weight(kg)(0.85 if female)/(72scr (mg/dl)lavalues are expressed as median (interquartile range) or number (percentage). lbegfr = 1

24、75 (serum creatinine (mg/dl)-1.234 (age (years)-0.179 (0.79 if female).lccrcl（ml/min）=(140-age(years)weight(kg)(0.85 if female)/(72scr (mg/dl)l3tc/tdf/lpvr (even only remaining lpvr monotherapy) was efficace for 1st line treated faileure patientslscond line arv was good tolerenceladherence is key fa

25、ctor for hiv treatment , and tdm might be useful for improving adherencel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）l免疫重建障碍（重建不全）的机制和治疗l根治艾滋病的策略（清除病毒储存库）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30% des patients vih ont des anomalies de

26、 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 dinfarctus 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umortality in the highly

27、active antiretroviral therapy era: changing causes of death and disease in the hiv outpatient study, j aids, 2006;43:2734.-primary or secondary cause-primary or secondary causeuchanges in causes of death among adults infected by hiv between 2000 and 2005: the mortalite 2000 and 2005 surveys (anrs en

28、19 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 mortalite 2000 and 2005 surveys (anrs en19 and mor

29、tavic), j aids, 2008;48:590598.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cd4+t细胞计数cd4+t细胞计数血浆病毒载量血浆病毒载量050100150200250300350400036912151821242730012345050100150200250300350400036912151821242730012345抗病毒治疗时间(月) cd4+t 细胞计数 (

30、/mm3)病毒载量 log10 拷贝/ml49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50flow chart of methodsince 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

31、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/ulyes: immune non-responder(inr) n=17no: immune responder (ir) pick 13th