阿德福韦酯、替诺福韦酯治疗CHB疗效与血药浓度（谷浓度）关系的研究

发布时间：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。我国是HBV感染的高发区。据统计，全世界每年死于HBV感染相关性疾病的大约100万人。目前，对HBV的感染己经采取了较好的预防措施，但仍存在大量的CHB病人，有效控制HBV感染仍是我们的艰巨任务。CHB治疗最重要的是抗病毒治疗：包括干扰素、核苷和核苷酸类似物。因干扰素的应用有一定限制[1]，核苷和核苷酸类似物由于安全性较好、适应证较广且服用方便等优点，在临床得以广泛应用。阿德福韦酯由美国Gilead SciencesIn公司研制，于2002年9月被美国FDA批准上市。替诺福韦酯于2001年10月被美国FDA批准上市。2008年被批准用于治疗慢性乙型肝炎。目前，替诺福韦酯尚未在我国上市，，处于Ⅲ期临床试验中。目的：目前，国内关于阿德福韦酯、替诺福韦酯抗病毒的疗效与血药浓度之间是否有关的研究较少，本实验中我们采用LC-MS/MS技术监测患者血浆中阿德福韦、替诺福韦的血药浓度：谷浓度，利用统计学分析方法比较：阿德福韦酯、替诺福韦酯的疗效与谷浓度之间是否存在一定关系；同种药物之间的谷浓度是否存在个体差异（例如性别、年龄、体重、体表面积、体重指数等）；临床观察到的个别患者出现的耐药或病毒学应答不佳是否与谷浓度有关。为临床治疗提供一定参考。方法：本次研究为双模拟、双盲、随机、活性药物对照研究，将入组的24例核苷和核苷酸类似物初治的CHB受试者，按1:1随机分入TDF300mg/d组和ADV10mg/d组。入选后受试者将在初期12周治疗期间每4周进行一次常规的疗效和安全性评估，此后每12周一次，总计48周。监测肝功能、乙肝病毒标志物、HBV DNA定量，同时以LC-MS/MS技术为平台，监测24例患者在六个时间点的谷浓度，经软件分析，比较阿德福韦酯、替诺福韦酯治疗CHB药物的疗效与谷浓度之间是否存在相关性。结果： 1.经过阿德福韦酯、替诺福韦酯治疗截止至36周和48周时，ALT、AST等肝功能指标均明显下降，且已全部降至正常，ALT、AST复常率均为100%。HBVDNA定量也呈明显下降趋势，治疗至36周和48周时，HBV DNA水平与基线相比均明显下降，在36周和48周时两组药物之间HBV DNA水平的比较均有统计学差异（p=0.04和p=0.02）。治疗截止至36周，ADV、TDF治疗组分别有3位（25%）、7位（58.33%）患者的HBV DNA水平低于检测限以下（20IU/mL），两种药物之间比较无统计学差异（p=0.21）。截止至48周时，ADV、TDF治疗组分别有3位（25%）、10位（83.33%）患者的HBV DNA水平低于检测限以下（20IU/mL），两种药物之间比较有统计学差异（p=0.01）。 2．阿德福韦酯基线时，HBeAg阳性者有7例，截至48周时，无一例发生血清学转换，而替诺福韦酯基线时，HBeAg阳性患者有8例，截止到48周时，有3例转阴(1例是在12周转阴，2例是在24周转阴)，HBeAg血清学转换率为37.5%，两组HBeAg血清学转换率比较无统计学差异（p=0.2）。 3．阿德福韦酯、替诺福韦酯谷浓度与年龄无相关性，与性别有相关性，女性患者体内谷浓度普遍高于男性。阿德福韦酯谷浓度与体重、体重指数、体表面积无相关性，替诺福韦酯服用至4周时谷浓度与体重、体重指数、体表面积呈显著负相关，其余几个时间点无相关性。 4.阿德福韦酯、替诺福韦酯各个时间点的ALT、AST复常与未复常患者之间的谷浓度比较均无统计学差异。 5.阿德福韦酯治疗组，HBV DNA＜1000IU/ml和≥1000IU/ml谷浓度各个时间点比较除24周有统计学差异（p=0.02）外，其余各时间点比较均无统计学差异。HBV DNA＜20IU/ml组和≥20IU/ml组谷浓度在各个时间点比较均无统计学差异。替诺福韦酯治疗后HBV DNA＜1000IU/ml和≥1000IU/ml谷浓度在各个时间点比较8周具有统计学差异（p=0.03），24周、36周差异具有边缘显著性（p=0.06，p=0.08），12周无统计学差异。但应答者谷浓度平均值在各个时间点均高于无应答者。HBV DNA＜20IU/ml和≥20IU/ml谷浓度在各个时间点比较均无统计学差异。但替诺福韦酯组应答者谷浓度平均值在各个时间点均高于无应答者。 6.替诺福韦酯治疗至48周时，血清学转换者与未转换者谷浓度比较有统计学差异（p=0.01），24周、36周时比较无统计学差异。但三个时间点血清学转换者谷浓度平均值高于未转换者。将TDF组治疗截止至48周时，分为血清学转换者（n=3）与未转换者（n=5）两组，比较两组在各个时间点谷浓度差异。血清学转换者与未转换者谷浓度比较在4周、12周、48周有统计学差异，其他各时间点虽无统计学差异，但所有时间点好转组谷浓度平均值均高于未好转组。 7.阿德福韦酯治疗至48周时组织学应答好转组与未好转组在各个时间点的谷浓度比较无统计学差异，但是在各个时间点，好转组的谷浓度平均值除4周外均高于未好转组。替诺福韦酯治疗至48周时，组织学好转组与未好转组在各个时间点谷浓度比较无统计学差异。但好转组谷浓度平均值均高于未好转组。 8.阿德福韦酯、替诺福韦酯个别出现病毒学应答不佳或病毒学反弹的患者，谷浓度较自身其他时间点更低。结论： 1．阿德福韦酯、替诺福韦酯在改善肝功能指标ALT、AST上均有很好效果。替诺福韦酯相较于阿德福韦酯，病毒学应答效果更好，血清学转换率更高，治疗CHB的疗效更加显著。 2.阿德福韦酯、替诺福韦酯谷浓度与年龄无相关性，与性别有一定相关性，女性患者体内谷浓度较男性普遍更高，女性患者可能更利于药物在体内的吸收。阿德福韦酯谷浓度与体重、体重指数、体表面积无相关性，替诺福韦酯谷浓度可能与体重、体重指数、体表面积三要素之间存在一定关系，体重越重、体重指数越高、体表面积越大的患者体内药物谷浓度相对越低，考虑在药物剂量许可范围内，对于上述患者可酌情将药物加量。 3.阿德福韦酯治疗CHB的临床疗效中，组织学应答与谷浓度可能有关，其他与谷浓度高低可能无关。替诺福韦酯治疗CHB的临床疗效与谷浓度有一定相关性，对于临床疗效不佳的患者可在剂量许可范围内酌情增加药物剂量。且两种药物谷浓度越低，可能越容易导致治疗病毒学应答不满意或出现病毒学耐药，可临床监测谷浓度在患者治疗过程中的动态变化，可能对疾病治疗提供一定参考。
[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
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R512.62

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