艾滋病抗病毒失敗研究進展課件

1、艾滋病抗病毒失敗研究進展,艾滋病抗病毒治療失敗研究進展,HIV 感染：目前我們所知道的,HAART治療：過去15年的最大進展 （ HIV-RNA50cp的HIV感染者，預(yù)期壽命超過30-40年甚至更長! ) 只要藥物有效、病人依從性好、未出現(xiàn)耐藥，HAART存在長期效力 可應(yīng)用的藥物種類增加: 6大藥物種類：超過20種化合物,艾滋病抗病毒失敗研究進展,抗病毒治療的成功和限制性,6大類，25種藥物 艾滋病的病死率顯著下降 藥物的毒副作用，耐藥，費用,艾滋病抗病毒失敗研究進展,費用 終身用藥 耐藥 毒副作用 持續(xù)存在的免疫激活 組織對藥物的屏障,Inflammation persistante,抗

2、病毒治療的局限性,艾滋病抗病毒失敗研究進展,可持續(xù)性長期抗病毒治療:我們需要什么,The Antiretroviral Therapy Cohort Collaboration. CID 2010,重要臟器并發(fā)導(dǎo)致的非艾滋死亡,耐藥引起的治療失敗和死亡,艾滋病引起的死亡,安全有效的抗病毒治療方案,可持續(xù)性的適宜治療方案,綜合治療模式,艾滋病抗病毒失敗研究進展,病毒學(xué)失敗所導(dǎo)致的嚴(yán)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,

3、Los Angeles 2007, #642,CD4 COUNT,VIRAL LOAD,VIROLOGIC FAILURE,IMMUNOLOGIC FAILURE,CLINICAL FAILURE,DRUG RESISTANCE,艾滋病抗病毒失敗研究進展,臨床失敗只是冰山的一角,病毒學(xué)失敗 導(dǎo)致 免疫學(xué)失敗 導(dǎo)致 臨床失敗,7,Murri R, et al. JAIDS. 2006;41:23-30. Losina E et al, 15th CROI 2008, #823,艾滋病抗病毒失敗研究進展,抗病毒治療后病毒學(xué)失敗與治療時間的關(guān)系,Treatment failure defined a

4、s 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,艾滋病抗病毒失敗研究進展,病毒學(xué)失敗的原因,艾滋病抗病毒失敗研究進展,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.

5、 JAIDS. 2000;23:360-361. Letter. 2. Paterson DL et al. Ann Intern Med. 2000;133:21-30,2,艾滋病抗病毒失敗研究進展,11,20例NVP耐藥患者血藥濃度監(jiān)測,耐藥患者NVP谷濃度監(jiān)測,70%曾低于3.0g /ml，90%曾低于3.9g /ml,耐藥患者服藥依從性差是導(dǎo)致血藥濃度低和耐藥的重要因素,增加 EC50,藥物特點和耐藥屏障,突變增加,EC50,低波谷,EC50,高波谷,高波谷,NRTI 每個突變改變少 但是 藥物濃度低,非核苷類 藥物濃度高 但是 每個突變改變大,增強PI 每個突變改變小 而且 藥物水平

6、高,艾滋病抗病毒失敗研究進展,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 Endpoints*: To compare, pairwise between ar

7、ms: Time to virologic failure (VF) Early VF: Lack of suppression by 1_log10 or rebound before week 32 Late VF: Failure to suppress to 200 copies/mL or rebound after week 32 Time to regimen completion VF OR treatment-limiting toxicity or intolerance, as assessed by the site investigator, to any regim

8、en component,ARV-nave HIV RNA 2000 c/mL Any 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 2006, #THLB0204,96 Weeks,Defined as 30N, 32I, 33F, 46I, 47A/V, 48V, 50L/V,

9、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 2008;358:2095-2106,Almost half failing EFV + 2NRTI regimen d

10、evelop 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,艾滋病抗病毒失敗研究進展,治療失敗之后的耐藥,時間,病毒載量,閾值,Adapted fr

11、om Gallant, 2007,M184V,CD4,病毒學(xué)失敗,免疫學(xué)失敗,臨床表現(xiàn),K103N,TAM 1,TAM 2,TAM 3,AZT/3TC/EFV,二線方案? 3TC/LPV/r,TAM 4,多重耐藥患者LLE抗病毒治療一覽表 耐藥檢測：僅TDF敏感、DRV為低耐，其余均為中、高度耐藥,99-12 DDI+3TC,01-8 雙肽芝+IDV,00-3 DDI+3TC+IDV,03-12 D4T+NVP+IDV,04-8 雙肽芝+IDV,04-12 3TC+EFV+IDV,05-8 3TC+NVP+IDV,08-3 3TC+EFV+LPV/r,擬更換方案為 DRV+TDF+RAL+LP

12、V/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,需要用LPV/r，但購買不到,進入國家免費治療,血小板恢復(fù)正常13.7萬,艾滋病抗病毒失敗研究進展,d4T, 3TC, Nevirapine,NRTIs: ABC, AZT, ddI, d4T,TDF ABC, AZT, ddI, d4T,TDF NNRTIs: 無 無 PIs: 所有 所有,NRTIs: 無 AZT NNRTIs: 無 無 PIs: 所有 所有,臨床失敗 (晚期病毒失敗,早期病毒失敗,可選的治療選擇,治療失敗的策略,TDF, 3TC, Nevirapine,二線治療在中國：我們不知

13、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）,艾滋病抗病毒失敗研究進展,艾滋病和病毒性肝炎等重大傳染病防治項目,成人艾滋病患者抗病毒 治療和免疫重建 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 課題負責(zé)人： 李太生 課題編號: 2008ZX10001-006 課題起止年限：2008年10月2010年12月,艾滋病和病毒性肝炎等重大傳染病防治項目,艾滋病抗病毒失敗研究進展,研究設(shè)計,Cohort 1 Treatment-nave patients （first-line drug） N=500,Cohort 3 Patient

14、s switch to second-line drug due to first-line drug therapeutic failure N=100,Drug resistance test,21,艾滋病抗病毒失敗研究進展,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 Mi

15、litary Medical University, Tangdu Hospital,Shenzhen Donghu Hospital,Yunnan AIDS Center,Guangzhou 8th People Hospital,PUMCH Beijing Youan Hospital Beijing Ditan Hospital,22,艾滋病抗病毒失敗研究進展,艾滋病抗病毒失敗研究進展,Lost follow-up at 96 weeks (n=12) Death (n=3) SAE withdrawal (n=2) Unknown missing (n=7,Enrolled subje

16、cts 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 successfully performed (N=91,Nested RT-PCR failure (n=3,No genotypic mutation found in pol g

17、ene (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,Patients taking 3TCTDFLPVr for 2

18、 year (N=82,Total 17 virological failure patients including 8 VL non-respondent and 9 VL rebound at endpoint (ITT,艾滋病抗病毒失敗研究進展,Patient genotype resistance analyses at baseline (n=91,艾滋病抗病毒失敗研究進展,Patient genotype resistance analyses at baseline (n=91,Patients genotype drug resistance at baseline,艾滋病抗

19、病毒失敗研究進展,12例病人未完成2年研究的原因分析,艾滋病抗病毒失敗研究進展,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 counts,艾滋病抗病毒失敗研究進展,Increasing cd4 t counts at other visit point are significant different from 4-week-point both in

20、 ITT (blue) and in PP(red) (p0.05,Increasing CD4T counts,艾滋病抗病毒失敗研究進展,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,艾滋病抗病毒失敗研究進展,治療2年VL下降的水平,Decreasing VLs at other visit point are significant different from at 4-week-point both

21、 in ITT (blue) and in PP(red) (p0.05,艾滋病抗病毒失敗研究進展,治療2年病毒抑制率分析,按照VL40和400cps/ml進行分組分析 藍色為ITT分析，紅色為PP分析,艾滋病抗病毒失敗研究進展,The virological response according baseline drug resistance,艾滋病抗病毒失敗研究進展,藥物不良反應(yīng)（98例次,艾滋病抗病毒失敗研究進展,ITT分析,PP分析,艾滋病抗病毒失敗研究進展,ITT分析,PP分析,艾滋病抗病毒失敗研究進展,ITT分析,PP分析,艾滋病抗病毒失敗研究進展,腎臟功能分析（ITT,aVal

22、ues 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,艾滋病抗病毒失敗研究進展,腎臟功能分析（PP）N=66,aValues are expressed as median (interquartile

23、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,艾滋病抗病毒失敗研究進展,Resistance and LPV concentration in Viral failure patients during 3TC/DF/LPVr treatment (n=17,艾滋病抗病毒失敗研究進

24、展,病毒學(xué)失敗與Lopinavir血藥濃度,艾滋病抗病毒失敗研究進展,總結(jié),3TC/TDF/LPVr (even only remaining LPVr monotherapy) 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,艾滋病抗病毒失敗研究進展,艾滋病治療研究的熱點,長期成功抗病毒治

25、療后艾滋病死亡原因和機制(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）的機制和治療 根治艾滋病的策略（清除病毒儲存庫,艾滋病抗病毒失敗研究進展,抗病毒治療的局限性,艾滋病抗病毒失敗研究進展,Distribution 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;43:2

26、734,Primary or secondary cause,艾滋病抗病毒失敗研究進展,Distribution of Causes of Death Among Mortalite 2000 and 2005 surveys, France,Primary 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, 20

27、08;48:590598,艾滋病抗病毒失敗研究進展,2000,2005,Deaths with non-AIDS defining illnesses,Distribution of Causes of Death Among Mortalite 2000 and 2005 surveys, 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 AID

28、S, 2008;48:590598,艾滋病抗病毒失敗研究進展,可持續(xù)性長期抗病毒治療:我們需要什么,The Antiretroviral Therapy Cohort Collaboration. CID 2010,重要臟器并發(fā)導(dǎo)致的非艾滋死亡,耐藥引起的治療失敗和死亡,艾滋病引起的死亡,安全有效的抗病毒治療方案,可持續(xù)性的適宜治療方案,綜合治療模式,艾滋病抗病毒失敗研究進展,49,CD4+T細胞計數(shù),CD4+T細胞計數(shù),血漿病毒載量,血漿病毒載量,免疫重建,長期治療后免疫功能重建障礙,免疫重建障礙（約20,同時選取年齡、性別相匹配的健康對照組患者17人,50,Flow Chart of Me

29、thod,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, 18, 24, 30, 36 months after HAART,Record clinical manifestation, test serum viral load, analysis the fresh subset of T ly

30、mphocyte, 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/ul,Yes: immune non-responder(INR) n=17,No: Immune responder (IR) pick 13,Thaw PBMC and test: 1.Nave CD4+ T lymphocyte percentage (CD4+CD45RA+CD31+/CD4+) 2.Apoptosis