中国接受HAART的艾滋病患者依非韦伦血药浓度分析

发布时间：2018-06-24 01:01

本文选题：依非韦伦 + 抗逆转录病毒治疗　；参考：《北京协和医学院》2016年博士论文

【摘要】：研究背景艾滋病 (acquired immunodeficiency syndrome, AIDS)是人类免疫缺陷病毒(human immunodeficiency virus, HIV)感染导致的一种危害极大的传染病。然而,随着抗逆转录病毒治疗(Antiretroviral Therapy, ART)的不断发展完善,ART已经可以实现病毒抑制、免疫重建,从而延长HIV/AIDS患者生存期,提高生存质量。依非韦伦(Efavirenz, EFV)是一种在国际上广泛应用的非核苷类逆转录酶抑制剂,而且是中国抗逆转录病毒治疗的一线药物。但EFV的不良反应一直是其临床应用中非常重要的一个问题。而血药浓度则是和EFV不良反应显著相关的。所以EFV的血浆药物浓度分析有着极大的价值。研究目的检测中国HIV患者的EFV血浆药物浓度,探讨其与其它临床指标之间的关系,并讨论EFV药物减量的可行性。研究对象与方法本研究是一项前瞻性多中心研究,选取了来自中国大陆9个研究中心共428名接受EFV治疗的HIV/AIDS患者,用药方案为TDF 300mg qd + 3TC 300mg qd + EFV 600mg qn。入组患者在治疗开始后4周、24周、48周的血浆标本会被用于EFV血药浓度统一检测,检测采用高效液相色谱-紫外检测法(HPLC-UV).血常规、肝肾功能、HIV病毒载量、淋巴细胞亚群等临床指标也会在每次随访时进行检测记录。采用Spearman秩和检验、相关样本T检验、相关样本wilcoxon秩和检验、单因素MannWhitney U检验以及多因素Logistic回归来分析这些临床指标与血浆EFV浓度的关系。研究结果本研究中随访患者4W、24W、48W血浆EFV浓度的中位数分别为3.059μg/mL(IQR 2.313-4.215)、3.454μg/mL(IQR 2.698-4.684)、3.781μg/mL(IQR3.019-4.928),随着治疗时间的推移,EFV血药浓度显著升高,48周血药浓度24周血药浓度4周血药浓度(P=0.000).在Spearman秩和检验中,血药浓度与体重有着最显著的相关性, 基线体重与4周血药浓度的Spearman相关系数为-0.221(p=0.000)。在包含体重、性别、年龄的多因素logistic分析中,仅体重与EFV血药浓度显著相关(P=0.000)。在体重小于60kg的亚组分析中,有50.6%的患者EFV血药浓度4mg/l,显著高于其他海外研究团队的结果。还有许多其他的因素与4周,24周或48周的血药浓度相关,比如基线、4W/24W/48W较高的CD4计数与4W低血药浓度相关；高ALT、AST及TBIL与低血药浓度相关；高血药浓度的患者也倾向于有更高的TC及HDL,但这些因素与血药浓度的相关性并不能在每个随访点观察到,而且这些相关性在Spearman秩和检验和logistic回归中并不完全一致。有43名患者在24周或48周出现了病毒学失败,其中27人在随后实现了病毒学抑制。在病毒学失败的患者中仅3人被发现存在依从性不佳。共有9名患者在.10个随访点上出现了血药浓度1mg/l,其中2名患者在3个随访点上出现了病毒学失败。结论本研究的人群依从性较好,仅在9名患者的10个随访点观察到血浆依非韦伦浓度低于1mg/l。中国艾滋病患者的依非韦伦血药浓度偏高,有更高的比例超出依非韦伦的治疗窗口；且依非韦伦血药浓度与病毒载量无显著相关性。血浆依非韦伦浓度与体重呈显著的负相关,低体重患者有更高的血药浓度。血浆依非韦伦浓度与患者TC,HDL显著正相关,该结果与既往研究相符,但临床意义尚不明确。治疗失败的患者中,仅有3人存在明确的依从性不佳,可能耐药的发生是导致治疗失败更主要的原因。有必要进行进一步的研究,探讨EFV在中国人群中用药剂量下调的可能性,并可针对患者的体重、基因型、血药浓度来调整EFV用药剂量,实现用药方案的个体化。
[Abstract]:Background acquired immunodeficiency syndrome (AIDS) is a very harmful infection caused by the human immunodeficiency virus (HIV) infection. However, with the continuous development of the antiretroviral therapy (Antiretroviral Therapy, ART), the ART has been able to suppress the virus. The reconstruction of the pestilence to prolong the life of HIV/AIDS patients and improve the quality of life. Efavirenz (EFV) is an internationally widely used non nucleoside reverse transcriptase inhibitor, and is the first line of antiretroviral therapy in China. But the adverse reaction of EFV is a very important problem in its clinical application. Blood concentration is significantly associated with EFV's adverse effects. So the plasma concentration analysis of EFV is of great value. The purpose of this study is to detect the plasma concentration of EFV in Chinese HIV patients and to explore the relationship between the plasma drug concentration and other clinical indicators, and to discuss the feasibility of the EFV drug reduction. The research object and methodology are a prospective study. The multicenter study selected a total of 428 patients receiving EFV treatment from 9 research centers in mainland China. The medication scheme was TDF 300mg QD + 3TC 300mg QD + EFV 600mg qn. group. The plasma specimens of 4 weeks, 24 weeks and 48 weeks after the treatment would be used for uniform detection of the concentration of EFV blood drugs, and high performance liquid chromatography UV was used. Detection methods (HPLC-UV). Clinical indicators such as blood routine, liver and kidney function, HIV viral load and lymphocyte subgroup were also recorded at each follow-up. Spearman rank sum test, related sample T test, related sample Wilcoxon rank test, single factor MannWhitney U test, and multiple factor Logistic return analysis were used to analyze these clinical indexes. The relationship between the concentration of plasma EFV and plasma concentration of 4W, 24W, and 48W in this study was 3.059 mu g/mL (IQR 2.313-4.215), 3.454 micron (IQR 2.698-4.684), 3.781 micron g/mL. With the time of treatment, the concentration of blood drugs increased significantly, and the concentration of blood drugs at 48 weeks was 24 weeks, and the concentration of blood drug concentration was 24 weeks in 4 weeks. Degree (P=0.000). In the Spearman rank sum test, the blood concentration and weight have the most significant correlation, the Spearman correlation coefficient of the baseline weight and the 4 week blood concentration is -0.221 (p=0.000). In the multifactor logistic analysis containing body weight, sex and age, only weight is significantly associated with the concentration of EFV blood (P=0.000). In a subgroup of less than 60kg In the analysis, 50.6% of the patients with EFV blood concentration 4mg/l were significantly higher than the results of other overseas research teams. There were many other factors associated with the concentration of blood drugs at 4 weeks, 24 or 48 weeks, such as baseline, higher CD4 counts of 4W/24W/48W and 4W low blood concentration; high ALT, AST and TBIL associated with low blood concentration; high blood concentration They also tended to have higher TC and HDL, but the correlation between these factors and blood concentration was not observed at every point of follow-up, and these correlations were not exactly the same in the Spearman rank test and the logistic regression. 43 patients had virological failure at 24 or 48 weeks, and 27 of them subsequently realized virological inhibition. Only 3 of the patients who failed in virology were found to have poor compliance. A total of 9 patients had a blood concentration of 1mg/l at.10 follow-up points, and 2 of them had a virological failure at 3 follow up points. Conclusion the population compliance of this study was better and the plasma einween concentration was observed at only 10 follow-up points in 9 patients. The blood concentration of the non weenten blood was higher than that of the 1mg/l. Chinese AIDS patients. There was a higher proportion beyond the treatment window of the non weentlen; and there was no significant correlation between the concentration of non weenten blood and the viral load. The plasma concentration was negatively correlated with the body weight, and the low weight patients had higher plasma concentration. The results were positively correlated with the patient's TC and HDL. The results were consistent with previous studies, but the clinical significance was not clear. Only 3 of the patients who had failed in the treatment had a definite compliance, and the possible occurrence of resistance was the main cause of the failure of the treatment. Further studies were necessary to explore the dosage of EFV in Chinese people. The possibility of adjustment can be adjusted, and the dosage of EFV can be adjusted according to the patient's weight, genotype and blood concentration, so as to realize the individualization of the medication plan.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R512.91

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