慢性乙型肝炎接受替比夫定达完全应答后序贯普通干扰素巩固治疗疗效的临床观察

发布时间：2018-05-03 00:47

本文选题：乙型肝炎 + 慢性　；参考：《重庆医科大学》2013年硕士论文

【摘要】：背景与目的：慢性乙型肝炎(Chronic hepatitis B，CHB)抗病毒治疗的基本目标是HBeAg血清学转化、HBV-DNA转阴。医生和患者期望的理想目标为停药后的持久应答、血清HBsAg清除甚至抗-HBs转化。目前大多数研究通过延长核苷（酸）类似物的治疗时间、停药后使用免疫调节剂等方法，，实现停药后的持久应答。是否有其他方法，既可以缩短核苷（酸）类似物的疗程，又能实现停药后的持久应答？本研究以期实现替比夫定的有限疗程和停药后的持久应答。观察接受替比夫定治疗的HBeAg阳性的慢性乙肝患者获完全应答后，替比夫定巩固治疗6个月后，根据患者意愿分别选择不同的停药方式：序贯IFN巩固治疗或单一LDT巩固治疗。观察停药后疗效的持久性，并利用治疗期间留置血清检测HBsAg的定量水平，探索其对停药后疗效持久性的预测价值。方法：选择2007年4月-2008年12月于重庆医科大学附属第二医院感染科门诊接受替比夫定治疗的20例HBeAg阳性的CHB患者，获完全应答的时间≤52W，获完全应答后予以替比夫定巩固治疗6个月，再根据患者意愿，10例选择单一LDT巩固治疗6个月，另外10例选择序贯IFN巩固治疗6个月(即给予普通干扰素α-1b500万iu，肌肉或皮下注射，隔天1次)。分别于停药后1、2、3、6、12、18、24、30、36个月对肝生化、HBV-DNA定量、乙肝病毒标志物进行检测，在序贯IFN巩固治疗组需监测甲功、血图分析等，分析停药后的持久应答时间。替比夫定停药标准为：血清HBV-DNA转阴、HBeAg血清学转化、肝生化指标正常分别达12个月以上，总疗程≤100W。复发标准为：HBV-DNA≥104copies／ml或ALT≥2×ULN。未复发组停药随访期间研究时间均≥12个月。 HBV-DNA定量检测采用Roche实时荧光定量PCR仪，HBV-DNA检测下限为1×103copies/ml。HBV血清标志物(HBsAg、抗一HBs、HBeAg、抗一HBe、抗一HBc)检测采用Roche Cobas E601电化学发光分析法。HBsAg定量采用MOUDULAR E170系统电化学发光法检测，试剂由上海罗氏(Roche)制药有限公司提供，HBsAg检测值0.5IU/ml为阴性。应用SPSS17.0软件进行统计分析，累计复发率的计算采用乘积限法(Kaplan-Meier法)。将血清HBsAg定量数据经对数转换后进行分析，两组间比较采用t检验。血清HBsAg水平对停药后复发的预测价值运用受试者工作特征曲线（receiver operating characteristic curve，ROC曲线）面积分析。两样本频率的比较采用Fisher精确概率法。以P0．05为差异具有统计学意义。结果：（1）在停药后3年的随访期间共有13例持续应答，总的持久应答率为65%，持续有效维持最长的时间为40个月。其中有7例复发，在停药后3、6、12个月的复发累计病例分别占复发病例的14.3％(1例)、42.9％(3例)、85、7％(6例)，复发最长的l例为34个月。随访到目前为止序贯IFN巩固治疗组总的复发率低于单一LDT巩固治疗组(30%vs40%,P0．05)，差异无统计学意义。序贯IFN巩固治疗组和单一LDT巩固治疗组的累积复发率分别为30%和65%（χ2=0.141，ν=1，Р=0.70），两组之间的累积复发率无统计学意义。（2）替比夫定治疗前后血清HBsAg水平分别为3.413±0.725log10IU／ml和2.957±0.688log10IU／ml（t=2.566，P0.05），替比夫定可降低血清HBsAg水平，差异有统计学意义。（3）未复发组在替比夫定治疗12周、24周、48周时，血清HBsAg水平较基线逐步下降，复发组血清HBsAg水平下降不明显。（4）较基线时的血清HBsAg水平，分别在治疗12周、24周、48周时的下降幅度对停药后复发有一定的预测价值，但差异无统计学意义（P0．05)。在治疗24周时的ROC曲线面积0.689，大于治疗12周时的0.652、48周时的0.545，因此24周时血清HBsAg水平下降幅度对预测停药后复发的价值更大。（5）治疗24周时血清HBsAg水平下降幅度≥1000IU/ml的患者其持久应答率较下降幅度＜1000IU/ml的患者高[91.0%(10/11) vs33.3%(3/9), P＜0.05],差异有统计学意义。（6）治疗结束时的血清HBsAg水平＜200IU/ml的患者其复发率低于≥200IU/ml的患者[0vs46.7%, P＜0.05],差异有统计学意义。（7）治疗期间有3例患者出现HBsAg血清学转化，达到临床治愈。结论：（1）HBeAg阳性的CHB患者接受LDT达停药标准后（总疗程≤1年），可获得较长时间的持续应答。（2）序贯普通干扰素α-1b巩固治疗，并不能降低停药后复发率。（3）LDT治疗24周时血清HBsAg水平下降幅度≥1000IU/ml的患者其持久应答率高于下降幅度＜1000IU/ml的患者（P0.05）。
[Abstract]:Background and purpose: the basic target of antiviral therapy for Chronic hepatitis B (CHB) is HBeAg serological transformation and HBV-DNA conversion. The ideal target for doctors and patients is the persistent response after drug withdrawal, serum HBsAg clearance and even anti -HBs conversion. Most studies have been done by prolonging the treatment time of nucleoside (acid) analogues, If there are other methods that can shorten the course of the nucleoside (acid) analogues and achieve a persistent response after stopping drugs, this study aims to achieve a limited course of telbivudine and a long response after withdrawal. Observe the HBeAg positive in the treatment of telbivudine. After 6 months of complete response to chronic hepatitis B patients, 6 months after the treatment of telbivudine consolidation treatment, the patients were chosen according to their wishes: sequential IFN consolidation therapy or single LDT consolidation therapy. The persistence of the curative effect after the withdrawal was observed and the quantitative level of HBsAg was detected by the retention sera during the treatment. The predictive value of sex.
Methods: 20 patients with HBeAg positive CHB who received telbivudine in the outpatient department of Second Hospital Affiliated to Chongqing Medical University, April 2007 -2008, were treated with HBeAg positive. The time of complete response was less than 52W. After the complete response, telbivudine consolidation therapy was given for 6 months, and then 10 cases of single LDT consolidation therapy were selected for 6 months according to the patient's wishes. The other 10 cases were treated with sequential IFN consolidation therapy for 6 months (i. e. ordinary interferon alpha -1b500 000 IU, muscle or subcutaneous injection, 1 times a day). The liver biochemistry, HBV-DNA quantitative, and hepatitis B virus markers were detected in 1,2,3,6,12,18,24,30,36 months after stopping the drug, and after the sequential IFN Gong fixation group, it was required to monitor the work of the nail and the analysis of blood map and so on. The standard of telbivudine withdrawal was: the standard of withdrawal of telbivudine was: serum HBV-DNA turned negative, HBeAg serological transformation, liver biochemical indexes were normal for more than 12 months, and the total treatment course was less than 100W. recurrence standard: HBV-DNA > 104copies / ml or ALT > 2 x ULN. without relapse, the time of study was more than 12 months.
HBV-DNA quantitative detection using Roche real-time quantitative PCR instrument, HBV-DNA detection limit of 1 x 103copies/ml.HBV serum markers (HBsAg, HBs, HBeAg, anti HBe, anti HBc) detection by Roche Cobas electrochemical electrochemiluminescence detection, the reagent by the Shanghai Roche system The HBsAg test value 0.5IU/ml is negative.
SPSS17.0 software was used to carry out statistical analysis. The cumulative recurrence rate was calculated by the product limit method (Kaplan-Meier method). The quantitative data of serum HBsAg was analyzed after logarithmic conversion, and t test was used in the two groups. The predictive value of serum HBsAg level on the recurrence of the relapse after withdrawal (receiver operating characteris) was used. Tic curve, ROC curve) area analysis. Two sample frequency comparison using Fisher exact probability method. P0.05 as the difference was statistically significant.
Results: (1) there were 13 persistent responses during the 3 year follow-up after the drug withdrawal, the total lasting response rate was 65%, and the longest lasting time was 40 months. 7 recurred, 14.3% (1), 42.9% (3), 85,7% (6), and 13 recurrent l cases with the longest recurrence of L. The total recurrence rate of the sequential IFN consolidation therapy group was lower than that of the single LDT consolidation therapy group (30%vs40%, P0.05). The cumulative recurrence rates of the sequential IFN consolidation therapy group and the single LDT consolidation group were 30% and 65% respectively (x 2=0.141, V =1, and =0.70), and the cumulative recurrence rate between the two groups was not statistically significant. (2) the serum HBsAg levels were 3.413 + 0.725log10IU / ml and 2.957 + 0.688log10IU / ml (t=2.566, P0.05) before and after treatment with telbivudine. Telbivudine could reduce the level of serum HBsAg. (3) the level of serum HBsAg decreased gradually at the 12 week, 24 weeks and 48 weeks in the non relapse group, and the serum HBsA in the recurrent group was in the serum HBsA. The decrease of G level was not obvious. (4) the level of serum HBsAg at the baseline, at 12 weeks, 24 weeks and 48 weeks, had a certain predictive value for the recurrence of the relapse, but the difference was not statistically significant (P0.05). The area of the ROC curve at 24 weeks was 0.689, greater than that of 12 weeks at 12 weeks at 12 weeks, and therefore the serum HBs at 24 weeks. The value of Ag level decline was more valuable for predicting recurrence after drug withdrawal. (5) the persistent response rate of patients with the decrease of serum HBsAg level more than 1000IU/ml at the 24 week of treatment was higher [91.0% (10/11) vs33.3% (3/9), P < 0.05], and the difference was statistically significant. (6) the serum HBsAg level at the end of the treatment was < 200IU/ml. The recurrence rate of the patients was lower than that of [0vs46.7%, P < 0.05], and P < 0.05]. The difference was statistically significant. (7) during the treatment, there were HBsAg serological transformation in the patients, and the clinical cure was achieved.
Conclusion: (1) HBeAg positive CHB patients receive a long time of sustained response after the standard of LDT (total course of treatment is less than 1 years). (2) sequential common interferon alpha -1b consolidation therapy can not reduce the recurrence rate after withdrawal. (3) the lasting response rate of the patients with HBsAg at the serum level of more than 1000IU/ml at the level of serum LDT at 24 weeks is higher than that of the lower decline. Patients with a degree of 1000IU/ml (P0.05).

【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R512.62

【共引文献】