ARV药物血脂异常的诊断和治疗吴昊

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level,2021/3/2,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,ARV,药物血脂异常的诊断和治疗,吴昊教授,首都医科大学附属北京佑安医院,PP-CN-0528,2021/3/2,1,即使是在,HIV,患者中，传统的高危因素仍然是导致冠心病和相关心血管疾病的重要原因,*Metabolic syndrome,共,7,分,HIV,感染,1,分,ART,家族史,腹部肥胖,1,分,高血压,1,分,高血脂,1,分,糖尿病和,胰岛素抵抗,1,分,不健康饮食,不运动,年龄,1,分,性别,吸烟,1,分,橙色为可改变的因素,绿色为不可改变的因素,HAART,SMART,研究坚持治疗非常重要，不能因噎废食！,中断,ART,治疗会进一步提高,CVD,风险,中断,ART,(n = 2,720),坚持,ART,(n = 2,752),HR,P,CVD,(,致死性,/,非致死性,),48,个,CVD,事件,（,1.3,个事件,/100,患者,-,年）,31,个,CVD,事件,（,0.8,个事件,/100,患者,-,年）,1.6 (1.02.5),0.05,SMART Study Group. N Engl J Med. 2006;355:22832296.,在,HIV,感染的情况下心肌梗死,(MI),的风险上升,Triant VA et al. J Clin Endocrinol Metab 2007;92:25062512,*,经年龄、性别、种族、高血压、糖尿病和血脂异常校正。,HIV,阳性队列中患者患有高血压、糖尿病和血脂异常的患者比例显著高于,HIV,阴性队列,RR 1.75p0.0001*,0,2,4,6,8,10,12,HIV,非,-HIV,事件,/1000,人年,n=1,044,589,n=3,851,MI,数,189 26,142,0,20,40,60,80,100,1834,3544,4554,5564,6574,年龄组（岁）,HIV,感染患者患有,MI,的风险至少为非感染者两倍,事件,/1000,人年,2021/3/2,4,Triant J et al. J Clin Endocrinol Metab. 2007;92:2506-2512.,基于卫生保健系统的回顾性、观察性研究,. N = 3,851,例,HIV,阳性者和,1,044,589,例非,HIV,患者,HIV,感染者中的传统危险因素,高血压,糖尿病,血脂异常,诊断（依据,ICD,代码）,HIV,阴性,对于,HIV,阳性者,vs HIV,阴性者的所有比较，,p,.0001,每,100,人中的发生率,HIV,阳性,瑞士,HIV,队列研究参与者在,3,个不同时期以及,2007,年瑞士人群的死因,HIV,阳性患者,vs,瑞士人群的死亡年份,Weber R, et al. HIV Med. 2013;14:195-207.,非,AIDS,事件,瑞士队列,:,改变了死亡原因模式,AIDS,非,AIDS,恶性肿瘤,非,AIDS,感染,肝脏,心脏,CNS,肾脏,肠道,/,胰脏,肺,自杀,物质使用,事故,/,他杀,其他,未知,HIV,是心血管疾病,(CVD),的一个独立危险因素,在,HIV,感染中已观察到持续性炎症,在,SMART,研究中，炎症标志物,IL-6,和,D-,二聚体与全因死亡率强烈相关,在接受,ART,的患者,(VL 350,细胞,/mm,3,的,HIV,阳性患者,HIV,感染者有过度,CVD,风险,脂肪代谢障碍：不同药物引起脂肪异常的假设机制,NRTIs,线粒体,DNA,聚合酶,-,g,抑制和线粒体,RNA,的耗竭,PIs,（,IDV,，,SQV,，,RTV,，,APV,）,胰岛素抵抗,细胞的凋亡,减少脂肪细胞的分化,NNRTIs,依非韦仑可能抑制体外的脂肪细胞的脂肪生成相关途径,Carr A, et al. AIDS. 2000;14:F25-32; McComsey GA, et al. AIDS. 2005;19:1523; Domingo P, et al. AIDS. 1999;13:226167; Mynarcik D, et al. J AIDS. 2005;38:5356; Walker UA, et al. J AIDS. 2002;29:11721; Roche R, et al. AIDS. 2002;16;1320; Vernochet C, et al. AIDS. 2003;17:217780. Domingo P, et al. AIDS. 1999 13(16):2261-7.,8,ART,和血脂异常,TDF,D4T,AZT,ABC,RAL,DTG,ATV/RTV or,LPV/r,ATV/COBI,DRV/RTV or DRV/COBI,EVG/COBI,EFV,RPV,ETV,9,总结：抗病毒药物与血脂,分类,ARV,血脂异常,NRTIs,d4TZDVABC,LDL,和,TG,上升,NNRTIs,EFV,TG, LDL, HDL,上升,PIs,All bPIs,LDL, TG, HDL,上升,提高,TG: LPV/r=FPV,和,LPV/rDRV/r,和,ATV/r,1,、,DAmico R, et al. 14,th,ADR, Washington 2012, #P027,2,、,10,First-line study: ART可在48周内使脂质代谢改变: NNRTI 对照研究,This slide is an illustration only and not meant to be a cross-study comparison.,1. Lennox J, et al. Lancet. 2009;374:796-806. 2.,Daar E, et al.,Ann Intern Med. 2011;154:445-456.,.,EFV + TDF/FTC,ATV/RTV + TDF/FTC,P, .001,ACTG 5202,2,TC,LDL,HDL,TG,Median Change (mg/dL),0,10,20,30,40,50,60,70,22,10,40,15,12,21,13,24,10,8,2,5,14,8,13,29,EFV + ABC/3TC,ATV/RTV + ABC/3TC,P, .001,P, .001,P, .001,P, .001,P,= .002,21,70,34,13,22,9,-14,184,P, .0001,STARTMRK,1,TC,LDL,HDL,TG,Mean Change (mg/dL),0,10,20,30,40,50,60,70,RAL + TDF/FTC,EFV + TDF/FTC,P, .0001,P,1,年的患者（,n=80),血脂变化但仍在正常范围内,P0.001,P=0.494,SPSS13.0,配对,t,检验,注：,TG,正常值,1.7mmol/L,，,TC,正常值,5.2mmol/L,，,HDL,正常值，,LDL,正常值,克力芝与依非韦伦初治,1,年患者血脂情况比较,血脂升高患者比例（,%,）,TG,TC,HDL,LDL,LPV/r,组（,n=80,）,22.4,15.1,4.6,10.1,EFV,组（,n=120,）,22.3,11.7,1.7,21.7,P,值,0.001,0.385,0.200,0.017,SPSS13.0,卡方检验,注：,TG,正常值,1.7mmol/L,，,TC,正常值,2,年患者血脂变化（,207,人）,P=0.015,注：,TG,正常值,1.7mmol/L,，,TC,正常值,190 mg/dL,糖尿病,年龄,40-75,岁,伴,LDL-C 70-189 mg/dL,10,年,ASCVD,风险,7.5%,他汀类治疗应该基于,ASCVD,风险大小和他汀类强度,不推荐或反对,LDL-C,目标,2021/3/2,18,胆固醇高,就是坏事，胆固醇越低越好。,答：错误，胆固醇主要分为低密度脂蛋白胆固醇（以下简称,LDL),，和,高密度脂蛋白,胆固醇（以下简称,HDL,），,LDL,高于正常是坏事，但,HDL,高于,3.0,是大大的好事，它是,脂质,的清道夫。,高密度脂蛋白,HDL,可将血液中的多余的胆固醇转运到肝脏，处理分解成,胆酸,盐，通过胆道排泄出去，从而形成一条血脂代谢的专门途径，也称“逆转运途径”。,2021/3/2,19,LPV/r =,洛匹那韦,/,利托那韦,ATV/r =,阿扎那韦,/,利托那韦,HIV,感染者和血脂异常,2,种策略,处理血脂异常,转换策略,LPV/r, ATV/r,加用策略,LPV/r +,降脂药物,2021/3/2,20,不良事件,转换前,转换后,血脂异常,高甘油三酯血症,(,伴或不伴高水平的低密度脂蛋白水平,),RTV,或,cobi,增强的方案或,EFV,RAL, DTG, RPV, NVP,或未增强的,ATV*,DHHS.,Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. April 2015.,*,相比于其他,RTV,增强的,PIs,，,LPV/r,和,FPV/r,方案更常发生,TG,和,LDL,水平升高。将,LPV/r,转换 为,RTV,增强和未增强的,ATV,后，观察到,TG,和,LDL,水平降低。,DHHS,指南,: ARV,转换,2021/3/2,21,将洛匹那韦,/r,转换为阿扎那韦,/r VS,加用阿托伐他汀组,Data on file: Wangpatharawanit P, et al. presented at IAS 2015. Abstract WEPEB349.,24,周时的血脂平均改变幅度,*,p,= 0.004,*,p, 0.001,*,*,2021/3/2,22,他汀类降脂药物与,EFV,和,LPV/R,之间的相互影响,EFV,使阿托伐他汀的,AUC,下降,32%,到,43%,，使普伐他汀的血药浓度下降,44%,，也肯能会使辛伐他汀的血药浓度下降，所以和这些药物合用时，需要根据临床血脂控制情况调整他汀类药物的用量，但不要超过最大推荐用量。,LPV/r,可能会增加他汀类药物的血药浓度，比如或增加阿托伐他汀的,AUC488%,，因此阿托伐他汀应当从最小剂量谨慎使用。,辛伐他汀则禁止与,LPV/r,同用,。普伐他汀不需要调整剂量。,他汀类降脂药不能与烟酸类、贝特类降脂药联合使用。,EACS Guidelines. Version 7.02. June 2014,2021/3/2,23,药物间相互作用（,EACS,指南）,EACS Guidelines. Version 7.02. June 2014.,阿托伐他汀,氟伐他汀,普伐他汀,瑞舒伐他汀,辛伐他汀,阿托伐他汀,氟伐他汀,普伐他汀,瑞舒伐他汀,辛伐他汀,阿托伐他汀,氟伐他汀,普伐他汀,瑞舒伐他汀,辛伐他汀,HIV/AIDS,的降脂药物剂量推荐（,EACS,指南）,EACS Guidelines. Version 7.02. June 2014.,他汀类,药物种类,药物种类,他汀类,胆固醇摄取下降,胆固醇摄取下降,药物,药物,剂量,副作用,胃肠道症状、头痛、失眠、横纹肌溶解,(,罕见,),和中毒性肝炎,胃肠道症状,阿托伐他汀,氟伐他汀,普伐他汀,瑞舒伐他汀,辛伐他汀,依折麦布,依折麦布,辛伐他汀,瑞舒伐他汀,普伐他汀,氟伐他汀,阿托伐他汀,关于他汀类与,ART,同时使用的建议,和,PI/r,同时使用,和,NNRTI,同时使用,以低剂量开始,(,最大剂量：,40mg),考虑较高剂量,考虑较高剂量,考虑较高剂量,考虑较高剂量,考虑较高剂量,考虑较高剂量,以低剂量开始,以低剂量开始,(,最大剂量：,20mg),禁用,与,ART,无已知的药物相互作用,佑安医院临床案例举例,患者男，,50,岁，,MSM,，无高血压、高血糖、吸烟酗酒等高危因素。,2012,年,11,月开始,ART,治疗，基线,CD4,细胞,328,个,/ul,，治疗方案,TDF+3TC+LPV/r,非诺贝特,200mg/d,病例,1,：部分血脂异常患者降脂治疗效果分析,患者男，,50,岁，,MSM,，无高血压、高血糖、吸烟酗酒等高危因素。,2012,年,11,月开始,ART,治疗，基线,CD4,细胞,328,个,/ul,，治疗方案,TDF+3TC+LPV/r,非诺贝特,200mg/d,P8753,患者男，,50,岁，,MSM,，无高血压、高血糖、吸烟酗酒等高危因素。,2012,年,11,月开始,ART,治疗，基线,CD4,细胞,328,个,/ul,，治疗方案,TDF+3TC+EFV,，治疗一年后因头晕不适更换治疗方案为,TDF+3TC+LPV/r,更换,EFV,为,LPV/r,病例,2,：部分血脂异常患者降脂治疗效果分析,非诺贝特,200mg/d+,普伐他丁,10mg/d,患者男，,41,岁，,MSM,，无高血压、高血糖、吸烟酗酒等高危因素。,2012,年,7,月开始,ART,治疗，基线,CD4,细胞,6,个,/ul,，治疗方案,TDF+3TC+EFV,，治疗,3,年后因肾损伤更换治疗方案为,EFV+LPV/r,（,AZT,贫血），,10,个月后因血脂升高更换治疗方案为,LPV/r+3TC,目前病毒载量阴性，,CD4128,个,/ul,更换治疗方案为,EFV+LPV/r,非诺贝特,200mg,普伐他丁,30mg,更换治疗方案为,3TC+LPV/r,病例,3,：部分血脂异常患者降脂治疗效果分析,血脂异常的原因,原因,LDL-C,升高,甘油三酯升高,饮食,药物,疾病,代谢障碍和代谢状态改变,饱和或反式脂肪、体重增加、神经性厌食症,体重增加、极低脂肪饮食、过高摄入精制碳水化合物、过度饮酒,利尿剂、环孢素、糖皮质激素、胺碘酮,口服雌激素、糖皮质激素、胆酸螯合剂、蛋白酶抑制剂、维甲酸、合成类固醇、西罗莫司、雷洛昔芬、他莫昔芬、,受体阻滞剂,(,非卡维地洛,),、噻嗪类,胆道梗阻、肾病综合征,肾病综合征、慢性肾衰竭、脂肪代谢障碍,甲状腺功能减退症、肥胖、妊娠,糖尿病,(,控制较差,),、甲状腺功能减退症、肥胖、妊娠,2021/3/2,31,致 谢,孙丽君、代丽丽主任 佑安医院门诊,2021/3/2,32,