艾病抗病毒失敗研究進(jìn)展

1、艾滋病抗病毒治療艾滋病抗病毒治療失敗研究進(jìn)展失敗研究進(jìn)展hiv 感染：目前我們所知道的感染：目前我們所知道的haart治療：過去治療：過去15年的最大進(jìn)展年的最大進(jìn)展（ hiv-rna 6大類，大類，25種藥物種藥物 艾滋病的病死率顯著下降艾滋病的病死率顯著下降 藥物的毒副作用，耐藥，費(fèi)用藥物的毒副作用，耐藥，費(fèi)用費(fèi)用費(fèi)用終身用藥終身用藥耐藥耐藥毒副作用毒副作用持續(xù)存在的免疫激活持續(xù)存在的免疫激活組織對藥物的屏障組織對藥物的屏障 inflammation persistante抗病毒治療的局限性抗病毒治療的局限性可持續(xù)性長期抗病毒治療可持續(xù)性長期抗病毒治療:我們需要什么？我們需要什么？the

2、antiretroviral therapy cohort collaboration. cid 2010重要臟器并發(fā)導(dǎo)重要臟器并發(fā)導(dǎo)致的非艾滋死亡致的非艾滋死亡耐藥引起的治療耐藥引起的治療失敗和死亡失敗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療方案毒治療方案可持續(xù)性的適宜可持續(xù)性的適宜治療方案治療方案綜合治療模式綜合治療模式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, #

3、642c d 4 c o u n tviral loadvirologic failureimmunologic failureclinical failuredrug resistance臨床失敗只是冰山的一角 病毒學(xué)失敗病毒學(xué)失敗 導(dǎo)致 免疫學(xué)失敗免疫學(xué)失敗導(dǎo)致 臨床失敗臨床失敗7murri r, et al. jaids. 2006;41:23-30.losina e et al, 15th croi 2008, #823臨床失敗臨床失敗免疫學(xué)失敗免疫學(xué)失敗病毒學(xué)失敗病毒學(xué)失敗treatment treatment durationduration(months)(months)vira

4、l 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 (7.0)29 (7.0)41 (9.9)41 (9.9) 416416 24, n (%)24

5、, 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抗病毒治療后病毒學(xué)失敗與治療時(shí)間的關(guān)系抗病毒治療后病毒學(xué)失敗與治療時(shí)間的關(guān)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 fuji

6、e et al. clin infect dis. 2010病毒學(xué)失敗的原因病毒學(xué)失敗的原因原因例子依從性差忘記服藥，藏匿藥物病毒耐藥之前使用過art，傳播的耐藥性不正確的藥物使用nelfinavir沒有餐中服用藥物儲(chǔ)存不正確ritonavir受熱吸收差gi功能藥物藥物相互作用nvp或pi和利福平, 草藥毒性gi，神經(jīng)系統(tǒng)毒性依從性和hiv病毒抑制之間的關(guān)系*886名未治hiv病人系列;cd4 5000 copies/ml.名hiv病人前瞻性觀察性研究mems, 藥物事件監(jiān)測系統(tǒng)1. low-beer s et al. jaids. 2000;23:360-361. letter. 2. pa

7、terson dl et al. ann intern med. 2000;133:21-30.21120例例nvp耐藥患者血藥濃度監(jiān)測耐藥患者血藥濃度監(jiān)測耐藥患者nvp谷濃度監(jiān)測 024681012followm1m3m6m12nvpctrough g/ml70%曾低于曾低于3.0g /ml，90%曾低于曾低于3.9g /ml。耐藥患者服藥依從性差耐藥患者服藥依從性差是導(dǎo)致血藥濃度低和耐是導(dǎo)致血藥濃度低和耐藥的重要因素藥的重要因素增加 ec50藥物特點(diǎn)和耐藥屏障藥物特點(diǎn)和耐藥屏障ec50低波谷ec50高波谷高波谷drug classgbnnrti/nrti1-2整合酶抑制劑整合酶抑制劑1-2

8、ccr5 抑制劑抑制劑1-2融合抑制劑融合抑制劑1-增強(qiáng)的蛋白酶抑制劑增強(qiáng)的蛋白酶抑制劑38不同種類藥物的基因屏障數(shù)量不同種類藥物的基因屏障數(shù)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 patients (a5142)primary endp

9、oints*: 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 2000 c/ml any cd4+ countmulticenter randomized open-labelscreening*multiple between-arm comparisons and interim analyses adjusted

10、significance level = 0.016.riddler sa, et al. xvi iac, toronto 2006, #thlb0204.96 weeks lpv/r + efvlpv/r + 2nrtiefv + 2nrtiobserved 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%* defin

11、ed 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 implicationsriddler s, haubrick r, dirienzo g, et al. class-sparing regimens for initial treatment of hiv-1 infection. n engl j med 2008;358:2095-21

12、06. 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

13、治療失敗之后的耐藥時(shí)間病毒載量閾值adapted from gallant, 2007m184vcd4病毒學(xué)失敗免疫學(xué)失敗臨床表現(xiàn)k103ntam 1tam 2tam 3azt/3tc/efv二線方案?3tc/lpv/rtam 4多重耐藥患者多重耐藥患者lle抗病毒治療一覽表抗病毒治療一覽表 耐藥檢測：僅耐藥檢測：僅tdf敏感、敏感、drv為低耐，其余均為中、高度耐藥99-12ddi+3tc01-8雙肽芝+idv00-3ddi+3tc+idv03-12d4t+nvp+idv04-8雙肽芝+idv04-123tc+efv+idv05-83tc+nvp+idv08-33tc+efv+lpv/r擬更

14、換方案為drv+tdf+ral+lpv/r體重增加，體力恢復(fù)低熱，乏力，體重下降體重增加，血小板開始下降，在16萬之間波動(dòng)需要用lpv/r，但購買不到進(jìn)入國家免費(fèi)治療血小板恢復(fù)正常13.7萬二線治療在中國二線治療在中國：我們：我們不不知道的知道的？病毒學(xué)失敗病人的耐藥發(fā)生率？二線治療的效果如何？影響治療效果的因素？二線藥物的不良反應(yīng)（tdf的腎毒性）？課題責(zé)任單位：中國醫(yī)學(xué)科學(xué)院北京協(xié)和醫(yī)院課題負(fù)責(zé)人： 李太生課題編號(hào): 2008zx10001-006課題起止年限：2008年10月2010年12月cohort 1treatment-nave patients（first-line drug）

15、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 loadcd4a

16、dverse eventseffective concentration monitoringmechanisms and treatment of immune reconstitution failurecardiovascular diseaselipodystrophyinstitutions participated in the project of the “11th five-year plan” shanghai public health center fuzhou infectious desease hospital zhengzhou infectious disea

17、se hospital the fourth military medical university, tangdu hospital 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 re

18、ceive 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)

19、 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

20、(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 resistancesubjectstotaln=913tchightdf high01734tdf intermediate9tdf low8intermediatetdf high15tdf intermediate4tdf low0lowtdf hi

21、gh012tdf intermediate12tdf low03tchigh2632intermediate6low0tdfhigh07intermediate6low1lpvrhigh03intermediate0low3nnrtishigh/intermediate7171/susceptible77patient genotype resistance analyses at baseline (n=91)patients genotype drug resistance at baseline4w8w12w24w36w48w72w96w原因no.11saeno.21saeno.31di

22、edno.41diedno.51diedno.61unknownno.71unknownno.81unknownno.91unknownno.101unknownno.111unknownno.121unknown匯總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 point are significant different from baseline both in itt (blue) and in pp(red) (p0.05) cd4+t cell cou

23、ntsincreasing 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 治療2年vl水平（中位數(shù)） vls at each visit point are significant different from baseline both in itt (blue) and in pp(red) (p0.05)治療2年vl下降的水平decreasing vl

24、s at other visit point are significant different from at 4-week-point both in itt (blue) and in pp(red) (p0.05)治療2年病毒抑制率分析按照vl40和0.050.050.05藥物不良反應(yīng)（98例次）drug-related adverse eventstotolgrade igrade iigrade iiigrade 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）0g

25、astrointestinal 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）000itt分析pp分析分析itt分析pp分析分析itt分析pp分析分析腎臟功能分析（itt）avalues are expressed as median (inter

26、quartile 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)腎臟功能分析（pp）n=66avalues are expressed as median (interquartile range) or number (percentage). begfr = 175 (serum

27、 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) 病毒學(xué)失敗與lopinavir血藥濃度總結(jié) 3tc/tdf/lpvr (even only remaining lpvr monotherapy)

28、 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艾滋病治療研究的熱點(diǎn) 長期成功抗病毒治療后艾滋病死亡原因和機(jī)制(非艾滋病直接死亡和異常免疫激活） 免疫重建障礙（重建不全）的機(jī)制和治療 根治艾滋病的策略（清除病毒儲(chǔ)存庫）抗病毒治療的局限性抗病毒治療的局限性骨密度降低骨密度降低prvalence

29、 accrue dostoporose ou dostopnie au niveau vertbral, des hanches ou des bras: 63% des patients腎臟問題腎臟問題30% des patients vih ont des anomalies de la fonction rnale心血管病心血管病變變中樞神中樞神經(jīng)經(jīng)chez plus de la moiti des patients惡惡性性腫腫瘤瘤risque accr de cancers non sida:anus, vagin, foie, poumons, colon, rein. augmen

30、tation de 75% du risque dinfarctus aigu疲疲勞綜勞綜合征合征risque accr par 3-14 fois chez vih; corrl au taux de cd4治療治療10年以上年以上治療治療10-15年以上年以上治療治療10年以上年以上治療治療15年以上年以上distribution of causes of death among hops patients, usumortality in the highly active antiretroviral therapy era: changing causes of death and

31、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 and 2005: the mortalite 2000 and 2005 sur

32、veys (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 mortalite 2000 and 2005 surveys (anrs

33、 en19 and mortavic), j aids, 2008;48:590598.可持續(xù)性長期抗病毒治療可持續(xù)性長期抗病毒治療:我們需要什么？我們需要什么？the antiretroviral therapy cohort collaboration. cid 2010重要臟器并發(fā)導(dǎo)重要臟器并發(fā)導(dǎo)致的非艾滋死亡致的非艾滋死亡耐藥引起的治療耐藥引起的治療失敗和死亡失敗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療方案毒治療方案可持續(xù)性的適宜可持續(xù)性的適宜治療方案治療方案綜合治療模式綜合治療模式cd4+t細(xì)胞計(jì)數(shù)細(xì)胞計(jì)數(shù)cd4+t細(xì)胞計(jì)數(shù)細(xì)胞計(jì)數(shù)血漿病毒載量血漿病毒

34、載量血漿病毒載量血漿病毒載量050100150200250300350400036912151821242730012345050100150200250300350400036912151821242730012345抗病毒治療時(shí)間抗病毒治療時(shí)間(月月) cd4+t 細(xì)胞計(jì)數(shù)細(xì)胞計(jì)數(shù) (/mm3)病毒載量病毒載量 log10 拷貝拷貝/ml免疫重建49長期治療后免疫功能重建障礙長期治療后免疫功能重建障礙免疫重建障礙（約免疫重建障礙（約20%20%）同時(shí)選取年齡、性別相匹配的健康對照組患者17人50flow chart of methodsince 2003, 55 pts under reg

35、ular 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 haartrecord clinical manifestation, test serum viral load, analysis the fresh subset of t lymphocyte, freeze pbmc for later us

36、e. 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 lym

37、phocytes was less than 20% of their basic 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.memory cd4+ t lymphocyte percentage early (cd27+ccr7+), middle (cd27+ccr7-) and late (cd27-ccr7-) t