【作者】 王佳；

【导师】 李太生； 叶敏；

【作者基本信息】 北京协和医学院 ， 临床医学， 2009， 博士

【摘要】 研究背景高效抗逆转录病毒疗法(Highly Active Antiretroviral Therapy,HAART)被认为是现今治疗HIV/AIDS行之有效的办法。包括个体间药代动力学差异在内的诸多因素影响药物在体内发挥作用。为了提高药物的治疗效果,使得药物在有效浓度水平发挥效能,并且减小毒性,国外已经开展了治疗药物监测(therapeutic drugmonitoring,TDM)以帮助个体化用药剂量。针对国内一线的抗逆转录病毒药物,目前尚无大样本量的以中国人为研究对象的有效血药浓度数据。研究目的探讨奈韦拉平(NVP)、齐多夫定(AZT)和司他夫定(d4T)血药浓度与疗效、耐药和不良反应的相关性。对象与方法随机选取HIV/AIDS门诊规律随诊,服用固定HARRT方案,自愿签署知情同意书的患者共计244人(男123人,女121人),在服药前或服药后2-4小时抽取EDTA抗凝静脉血2ml,用高效液相色谱法方法检测药物血浆浓度。详细记录患者治疗前及每次随诊的一般情况及实验室检查结果。结果1.血浆NVP谷浓度在病毒学失败组(3.81μg/ml)显著低于病毒抑制组(5.40μg/ml,P=0.018),在对NVP耐药组(3.23μg/ml)显著低于未发生耐药组(5.92μg/ml,P=0.004)。2.与国外通用的3μg/ml相比,3μg/ml是更适合中国人群的治疗浓度下限。NVP血浆谷浓度低于3.9时,发生病毒学失败和耐药的几率是NVP血浆谷浓度高于3.9μg/ml时的5.4倍和6.3倍。3.男性人群中,发生严重肝损的患者的NVP血浆谷浓度中位值(8.20μg/ml)显著高于未发生严重肝损的患者(5.48μg/ml, P=0.015)。NVP血浆谷浓度超过8μg/ml时,发生严重肝损的几率是NVP血浆谷浓度低于8μg/ml时的2.4倍。4.皮疹的发生与NVP血浆峰谷浓度均无显著相关性。5.服用AZT后出现骨髓抑制的患者其AZT血浆峰浓度中位值(0.68)显著高于未发生骨髓抑制的患者(0.25μg/ml, P=0.001)。6.d4T血药浓度与血脂异常、周围神经病、脂肪异常分布无显著相关性。结论1.NVP早期病毒学应答和病毒耐药的发生与奈韦拉平血浆谷浓度有显著的相关性。NVP血浆谷浓度低于治疗浓度下限将增加病毒学失败和耐药的风险。2.NVP血浆谷浓度高于治疗浓度上限将增加严重肝毒性的发生。3.适合中国人的NVP谷浓度的治疗浓度范围是3.9-8.0μg/ml。4.AZT血浆峰浓度与骨髓抑制有显著相关性。5.d4T血浆峰浓度与其常见不良反应的发生无显著相关性。更多还原

【Abstract】 BackgroundHighly active antiretroviral therapy is considered to be the only effective therapy of HIV/AIDS. Pharmocokinetics is different from person to person. In order to improve outcomes, reduce toxicity, and increase efficacy, therapeutic drug monitoring is used to adjust the individual dose. However, we don’t have the data of effective drug plasma concentration in Chinese population.ObjectiveTo evaluate the relationship between NVP/AZT/d4T concentrations and viralogical response, drug resistance and adiverse events in Chinese population.Materials and Methods244outpatients (male123, femal121) of HIV/AIDS clinic were enrolled randomly, all of whom were treated with HAART (NVP/AZT/d4T) and follow-up regularly. Blood samples were taken before administration, or2to4hours thereafter. Drug concentreation were detected by HPLC. Clinical informations and lab data were collected at the same time. The relationships between the concentration and clinic outcomes were analyzed.Results1. NVP-Ctrough (Trough concentration of NVP) in viralogical failure group (3.81μg/ml) or resistant group (3.23μg/ml) was lower than viralogical response group (5.40μg/ml, P=0.018).2.3.9μg/ml was a better low limit of NVP-Ctrough in Chinese population. The risk of viralogical failure and NVP resistance increased5.4times and6.3times when NVP-Ctrough was below3.9μg/ml.3. NVP-Ctrough in the severe hepatotoxicity group (8.20μg/ml) was higher than control group and mild hepatotoxicity group (5.48μg/ml, P=0.015) in male. The risk of severe hepatotoxicity increased2.4times when NVP-Ctrough is above8μg/ml. 4. NVP-Ctrough and Cpeak showed no correlation with rash.5. Peak concentration of AZT (AZT-Cpeak) in the hematotoxicity group (0.68μg/ml) was higher than the control group (0.25μg/ml, P=0.001).6. d4T Cpeak showed no correlation with hyperlipidemia, peripheral neuropathy or lipodystrophy.Conclusions1. NVP Ctrough showed significant correlation with viralogical response and resistant. Reduction of NVP Ctrough showed significant correlation with efficacy and resistant mutation.2. Elevation of NVP Ctrough showed significant correlation with severe hepatotoxicity, especially in male.3.3.9-8.0μg/ml were an appropriate effective drug plasma concentration in Chinese population.4. AZT Cpeak showed significant correlation with hematotoxicity.5. d4T Cpeak showed no correlation with hyperlipidemia, peripheral neuropathy or lipodystrophy.更多还原