發(fā)布時間：2018-10-10 07:45

【摘要】：背景：乙型肝炎病毒感染呈全球性分布，慢性乙型肝炎是全球十大死亡原因之一。我國是HBV感染的高發(fā)區(qū)。據(jù)統(tǒng)計(jì)，全世界每年死于HBV感染相關(guān)性疾病的大約100萬人。目前，對HBV的感染己經(jīng)采取了較好的預(yù)防措施，但仍存在大量的CHB病人，有效控制HBV感染仍是我們的艱巨任務(wù)。CHB治療最重要的是抗病毒治療：包括干擾素、核苷和核苷酸類似物。因干擾素的應(yīng)用有一定限制[1]，核苷和核苷酸類似物由于安全性較好、適應(yīng)證較廣且服用方便等優(yōu)點(diǎn)，在臨床得以廣泛應(yīng)用。阿德福韋酯由美國Gilead SciencesIn公司研制，于2002年9月被美國FDA批準(zhǔn)上市。替諾福韋酯于2001年10月被美國FDA批準(zhǔn)上市。2008年被批準(zhǔn)用于治療慢性乙型肝炎。目前，替諾福韋酯尚未在我國上市，，處于Ⅲ期臨床試驗(yàn)中。 目的：目前，國內(nèi)關(guān)于阿德福韋酯、替諾福韋酯抗病毒的療效與血藥濃度之間是否有關(guān)的研究較少，本實(shí)驗(yàn)中我們采用LC-MS/MS技術(shù)監(jiān)測患者血漿中阿德福韋、替諾福韋的血藥濃度：谷濃度，利用統(tǒng)計(jì)學(xué)分析方法比較：阿德福韋酯、替諾福韋酯的療效與谷濃度之間是否存在一定關(guān)系；同種藥物之間的谷濃度是否存在個體差異（例如性別、年齡、體重、體表面積、體重指數(shù)等）；臨床觀察到的個別患者出現(xiàn)的耐藥或病毒學(xué)應(yīng)答不佳是否與谷濃度有關(guān)。為臨床治療提供一定參考。 方法：本次研究為雙模擬、雙盲、隨機(jī)、活性藥物對照研究，將入組的24例核苷和核苷酸類似物初治的CHB受試者，按1:1隨機(jī)分入TDF300mg/d組和ADV10mg/d組。入選后受試者將在初期12周治療期間每4周進(jìn)行一次常規(guī)的療效和安全性評估，此后每12周一次，總計(jì)48周。監(jiān)測肝功能、乙肝病毒標(biāo)志物、HBV DNA定量，同時以LC-MS/MS技術(shù)為平臺，監(jiān)測24例患者在六個時間點(diǎn)的谷濃度，經(jīng)軟件分析，比較阿德福韋酯、替諾福韋酯治療CHB藥物的療效與谷濃度之間是否存在相關(guān)性。 結(jié)果： 1.經(jīng)過阿德福韋酯、替諾福韋酯治療截止至36周和48周時，ALT、AST等肝功能指標(biāo)均明顯下降，且已全部降至正常，ALT、AST復(fù)常率均為100%。HBVDNA定量也呈明顯下降趨勢，治療至36周和48周時，HBV DNA水平與基線相比均明顯下降，在36周和48周時兩組藥物之間HBV DNA水平的比較均有統(tǒng)計(jì)學(xué)差異（p=0.04和p=0.02）。治療截止至36周，ADV、TDF治療組分別有3位（25%）、7位（58.33%）患者的HBV DNA水平低于檢測限以下（20IU/mL），兩種藥物之間比較無統(tǒng)計(jì)學(xué)差異（p=0.21）。截止至48周時，ADV、TDF治療組分別有3位（25%）、10位（83.33%）患者的HBV DNA水平低于檢測限以下（20IU/mL），兩種藥物之間比較有統(tǒng)計(jì)學(xué)差異（p=0.01）。 2．阿德福韋酯基線時，HBeAg陽性者有7例，截至48周時，無一例發(fā)生血清學(xué)轉(zhuǎn)換，而替諾福韋酯基線時，HBeAg陽性患者有8例，截止到48周時，有3例轉(zhuǎn)陰(1例是在12周轉(zhuǎn)陰，2例是在24周轉(zhuǎn)陰)，HBeAg血清學(xué)轉(zhuǎn)換率為37.5%，兩組HBeAg血清學(xué)轉(zhuǎn)換率比較無統(tǒng)計(jì)學(xué)差異（p=0.2）。 3．阿德福韋酯、替諾福韋酯谷濃度與年齡無相關(guān)性，與性別有相關(guān)性，女性患者體內(nèi)谷濃度普遍高于男性。阿德福韋酯谷濃度與體重、體重指數(shù)、體表面積無相關(guān)性，替諾福韋酯服用至4周時谷濃度與體重、體重指數(shù)、體表面積呈顯著負(fù)相關(guān)，其余幾個時間點(diǎn)無相關(guān)性。 4.阿德福韋酯、替諾福韋酯各個時間點(diǎn)的ALT、AST復(fù)常與未復(fù)常患者之間的谷濃度比較均無統(tǒng)計(jì)學(xué)差異。 5.阿德福韋酯治療組，HBV DNA＜1000IU/ml和≥1000IU/ml谷濃度各個時間點(diǎn)比較除24周有統(tǒng)計(jì)學(xué)差異（p=0.02）外，其余各時間點(diǎn)比較均無統(tǒng)計(jì)學(xué)差異。HBV DNA＜20IU/ml組和≥20IU/ml組谷濃度在各個時間點(diǎn)比較均無統(tǒng)計(jì)學(xué)差異。替諾福韋酯治療后HBV DNA＜1000IU/ml和≥1000IU/ml谷濃度在各個時間點(diǎn)比較8周具有統(tǒng)計(jì)學(xué)差異（p=0.03），24周、36周差異具有邊緣顯著性（p=0.06，p=0.08），12周無統(tǒng)計(jì)學(xué)差異。但應(yīng)答者谷濃度平均值在各個時間點(diǎn)均高于無應(yīng)答者。HBV DNA＜20IU/ml和≥20IU/ml谷濃度在各個時間點(diǎn)比較均無統(tǒng)計(jì)學(xué)差異。但替諾福韋酯組應(yīng)答者谷濃度平均值在各個時間點(diǎn)均高于無應(yīng)答者。 6.替諾福韋酯治療至48周時，血清學(xué)轉(zhuǎn)換者與未轉(zhuǎn)換者谷濃度比較有統(tǒng)計(jì)學(xué)差異（p=0.01），24周、36周時比較無統(tǒng)計(jì)學(xué)差異。但三個時間點(diǎn)血清學(xué)轉(zhuǎn)換者谷濃度平均值高于未轉(zhuǎn)換者。將TDF組治療截止至48周時，分為血清學(xué)轉(zhuǎn)換者（n=3）與未轉(zhuǎn)換者（n=5）兩組，比較兩組在各個時間點(diǎn)谷濃度差異。血清學(xué)轉(zhuǎn)換者與未轉(zhuǎn)換者谷濃度比較在4周、12周、48周有統(tǒng)計(jì)學(xué)差異，其他各時間點(diǎn)雖無統(tǒng)計(jì)學(xué)差異，但所有時間點(diǎn)好轉(zhuǎn)組谷濃度平均值均高于未好轉(zhuǎn)組。 7.阿德福韋酯治療至48周時組織學(xué)應(yīng)答好轉(zhuǎn)組與未好轉(zhuǎn)組在各個時間點(diǎn)的谷濃度比較無統(tǒng)計(jì)學(xué)差異，但是在各個時間點(diǎn)，好轉(zhuǎn)組的谷濃度平均值除4周外均高于未好轉(zhuǎn)組。替諾福韋酯治療至48周時，組織學(xué)好轉(zhuǎn)組與未好轉(zhuǎn)組在各個時間點(diǎn)谷濃度比較無統(tǒng)計(jì)學(xué)差異。但好轉(zhuǎn)組谷濃度平均值均高于未好轉(zhuǎn)組。 8.阿德福韋酯、替諾福韋酯個別出現(xiàn)病毒學(xué)應(yīng)答不佳或病毒學(xué)反彈的患者，谷濃度較自身其他時間點(diǎn)更低。 結(jié)論： 1．阿德福韋酯、替諾福韋酯在改善肝功能指標(biāo)ALT、AST上均有很好效果。替諾福韋酯相較于阿德福韋酯，病毒學(xué)應(yīng)答效果更好，血清學(xué)轉(zhuǎn)換率更高，治療CHB的療效更加顯著。 2.阿德福韋酯、替諾福韋酯谷濃度與年齡無相關(guān)性，與性別有一定相關(guān)性，女性患者體內(nèi)谷濃度較男性普遍更高，女性患者可能更利于藥物在體內(nèi)的吸收。阿德福韋酯谷濃度與體重、體重指數(shù)、體表面積無相關(guān)性，替諾福韋酯谷濃度可能與體重、體重指數(shù)、體表面積三要素之間存在一定關(guān)系，體重越重、體重指數(shù)越高、體表面積越大的患者體內(nèi)藥物谷濃度相對越低，考慮在藥物劑量許可范圍內(nèi)，對于上述患者可酌情將藥物加量。 3.阿德福韋酯治療CHB的臨床療效中，組織學(xué)應(yīng)答與谷濃度可能有關(guān)，其他與谷濃度高低可能無關(guān)。替諾福韋酯治療CHB的臨床療效與谷濃度有一定相關(guān)性，對于臨床療效不佳的患者可在劑量許可范圍內(nèi)酌情增加藥物劑量。且兩種藥物谷濃度越低，可能越容易導(dǎo)致治療病毒學(xué)應(yīng)答不滿意或出現(xiàn)病毒學(xué)耐藥，可臨床監(jiān)測谷濃度在患者治療過程中的動態(tài)變化，可能對疾病治療提供一定參考。
[Abstract]:Background: Hepatitis B virus infection is globally distributed, and chronic hepatitis B is one of the top ten causes of death worldwide. Our country is the high incidence area of HBV infection. According to statistics, the world died every year of about 1 million people infected with HBV infection. At present, the infection of HBV has been taken a good preventive measure, but there still exist a lot of CHB patients, and the effective control of HBV infection is still our arduous task. Treatment of the most important of the treatment of CHB is antiviral therapy: interferon, hepatitis A and the like. Because the application of interferon has certain limitation[1], it is widely used in clinic because of the advantages of better safety, wide adaptability and convenient administration. Adefovir was developed by Gilead Sciences In Inc., which was approved by the U.S. FDA in September 2002. Tinofovir was approved by the U.S. FDA in October 2001. It was approved for treatment of chronic hepatitis B in 2008. Currently, tenofovir esters have not been marketed in our country and are in Phase III clinical trials. Objective: At present, we use LC-MS/ MS technique to monitor the plasma concentration of adefovir diadefovir and tenofovir in patients by using LC-MS/ MS technique. The concentration was compared with the statistical analysis method: whether there was a relationship between the efficacy of adefovir and the concentration of valley, whether there was individual difference between the same drug (e.g. sex, age, body weight, body surface area, body weight index). et al.; no good clinical observations of drug resistance or virologic response in individual patients is not better than the trough concentration It is related to the clinical treatment. Reference. Methods: This study was conducted as a double-analog, double-blind, randomized, active drug control study, which was randomized into the TDF300mg/ d group and the ADV10 at 1: 1 for CHB subjects treated at the early stage of the treatment group. mg/ d group. After inclusion, subjects will undergo a routine efficacy and safety assessment every 4 weeks during the initial 12-week treatment, once every 12 weeks thereafter, A total of 48 weeks was used to monitor liver function, HBV markers, HBV DNA quantification, and LC-MS/ MS technology was used as a platform to monitor the trough concentrations of 24 patients at six time points. Presence of phase Results: 1. The liver function indexes such as ALT, AST, ALT and AST were all decreased and all decreased to normal, ALT and AST were 100%. HBV DNA levels were significantly lower compared to baseline at 36 and 48 weeks, and there was a statistically significant difference in HBV DNA levels between the two groups at 36 and 48 weeks (p = 0. 04 and p = 0. 02). Treatment cutoff to 36 weeks, the ADV, TDF treatment groups had 3 (25%), 7 (58. 33%) patients had HBV DNA levels below the detection limit (20IU/ mL), and there was no statistical comparison between the two drugs There were 3 (25%) and 10 (83. 33%) HBV DNA levels below the detection limit (20IU/ mL) in the ADV and TDF groups, respectively. There were 7 cases in HBeAg-positive patients at baseline of adefovir diadefovir ester. There were 8 cases of HBeAg-positive patients at baseline of 48 weeks, and 8 in HBeAg-positive patients at the end of 48 weeks. In the end of 48 weeks, there were 3 cases of HBeAg (1 case was at 12 The seroconversion rate of HBeAg seroconversion was 37. 5%, HBeAg seroconversion rate was higher than that in two groups. There was no statistically significant difference (p = 0. 2). 3. Adefovir diadefovir was not correlated with age and was related to sex. There was no correlation with body weight, body weight index and body surface area in female patients, and the trough concentration and body weight, body weight index and body surface area were measured at 4 weeks for tenofovir. Significant negative correlation was found, but there was no correlation between the rest of the time points. There was no statistical difference in the trough concentrations between patients without relapse. 5. There was a statistically significant difference in the concentrations of HBV DNA <1000IU/ ml and Z1000IU/ ml in the treatment group (p There was no statistical difference between the rest of the time points except for 0. 02). The HBV DNA <20IU/ ml group and CD20I There was no statistical difference between the concentrations of the U/ ml groups at various time points. After treatment, the concentrations of HBV DNA <1000IU/ ml and SG1000IU/ ml were statistically different at each time point (p = 0. 03), and the difference between 24 weeks and 36 weeks had marginal significance (p = 0. 06, p = 0. 08), there was no statistical difference between 12 weeks. however, that mean value of the trough concentration of the responder was higher than that of the replicator at all time points. HBV DNA <20IU/ ml and HBV DNA 20 The IU/ ml trough concentrations were not statistically different at each time point, but for tenofovir esters The mean value of trough concentration in group responders was higher than that of responders at all time points. 6. At 48 weeks for tenofovir, there was a statistical difference between serologic and untransformed valley concentrations. Difference (p = 0.01), 24-week, 36-week comparisons showed no statistical difference The mean trough concentrations of the three time points were higher than those of the non-transformed subjects. The TDF group was divided into the serologic converter (n = 3) and none at the end of 48 weeks. The difference of trough concentrations between the two groups at various time points was compared between the two groups (n = 5). There was a statistical difference between the serologic converter and the untransformed valley at 4 weeks, 12 weeks and 48 weeks. The other time points were not statistically significant. There was no statistical difference between the histological response improvement group and the unimproved group at all time points compared with those in the unimproved group at all time points. At each time point, the mean trough concentration of the improvement group was higher than that of the unimproved group except 4 weeks. and the histological improvement group and the unimproved group at each time point There was no statistical difference in the trough concentration. However, the mean value of trough concentration in the improved group was higher than that of the unimproved group. appearance of disease In patients who responded poorly or virologic rebound, the trough concentration was lower than its other time points. Conclusion: 1. adefovir ester and tenofovir ester have good effect on improving ALT and AST of liver function indexes. Compared with adefovir ester, the virologic response effect is better, the seroseroconversion rate is higher, the curative effect of the treatment of CHB is more significant. There is a certain correlation, in female patients, the trough concentration is higher than that in men, and female patients may be more beneficial to the absorption of drugs in the body. The concentration of adefovir ester is not related to body weight, body weight index, body surface area, and tetenofovir ester. The ratio of trough concentration may be related to body weight, body weight index, body surface area, body weight, body weight index and body surface area. The lower the concentration of drug in the patient, the lower the concentration of drug in the patient, considering that in the range of drug dose permits, the amount of drug may be added to the above-mentioned patients. 3 In the clinical efficacy of adefovir in the treatment of CHB, the histological response may be related to the trough concentration, and others may not be related to the trough concentration. Treatment of CHB with tenofovir There is a correlation between clinical efficacy and trough concentration. For patients with poor clinical efficacy, the drug dosage may be increased as appropriate within the scope of the dose. The lower the concentration of the two drug valleys, the more likely it may be to cause unsatisfactory virologic response
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R512.62

【參考文獻(xiàn)】

相關(guān)期刊論文 前4條

1 龔堅(jiān);宋偉明;;奧氮平治療精神分裂癥血藥濃度、劑量與臨床療效、不良反應(yīng)的相關(guān)性分析[J];海峽藥學(xué);2010年01期

2 鐘大放;以加權(quán)最小二乘法建立生物分析標(biāo)準(zhǔn)曲線的若干問題[J];藥物分析雜志;1996年05期

3 曾民德;茅益民;姚光弼;周霞秋;王豪;徐道振;姚集魯;侯金林;王宇明;任紅;陳亞崗;�？∑�;王耀宗;;阿德福韋酯治療HBeAg陽性的中國慢性乙型病毒性肝炎患者52周的多中心臨床研究[J];中華傳染病雜志;2005年06期

4 劉慧;李小青;戰(zhàn)寒秋;;治療慢性乙型肝炎新藥替諾福韋酯研究進(jìn)展[J];中國藥學(xué)雜志;2012年18期

相關(guān)碩士學(xué)位論文 前2條

1 孫德清;健康志愿者口服阿德福韋酯片的耐受性試驗(yàn)及藥代動力學(xué)研究[D];山東大學(xué);2005年

2 張思敏;恩替卡韋分散片與博路定治療慢性乙型肝炎療效觀察及血藥濃度檢測[D];第二軍醫(yī)大學(xué);2012年

本文編號：2261211