本文選題：乙型肝炎 + 慢性��； 參考：《重慶醫(yī)科大學(xué)》2013年碩士論文

【摘要】：背景與目的：慢性乙型肝炎(Chronic hepatitis B，CHB)抗病毒治療的基本目標(biāo)是HBeAg血清學(xué)轉(zhuǎn)化、HBV-DNA轉(zhuǎn)陰。醫(yī)生和患者期望的理想目標(biāo)為停藥后的持久應(yīng)答、血清HBsAg清除甚至抗-HBs轉(zhuǎn)化。目前大多數(shù)研究通過延長核苷（酸）類似物的治療時(shí)間、停藥后使用免疫調(diào)節(jié)劑等方法，，實(shí)現(xiàn)停藥后的持久應(yīng)答。是否有其他方法，既可以縮短核苷（酸）類似物的療程，又能實(shí)現(xiàn)停藥后的持久應(yīng)答？本研究以期實(shí)現(xiàn)替比夫定的有限療程和停藥后的持久應(yīng)答。觀察接受替比夫定治療的HBeAg陽性的慢性乙肝患者獲完全應(yīng)答后，替比夫定鞏固治療6個(gè)月后，根據(jù)患者意愿分別選擇不同的停藥方式：序貫IFN鞏固治療或單一LDT鞏固治療。觀察停藥后療效的持久性，并利用治療期間留置血清檢測HBsAg的定量水平，探索其對停藥后療效持久性的預(yù)測價(jià)值。 方法：選擇2007年4月-2008年12月于重慶醫(yī)科大學(xué)附屬第二醫(yī)院感染科門診接受替比夫定治療的20例HBeAg陽性的CHB患者，獲完全應(yīng)答的時(shí)間≤52W，獲完全應(yīng)答后予以替比夫定鞏固治療6個(gè)月，再根據(jù)患者意愿，10例選擇單一LDT鞏固治療6個(gè)月，另外10例選擇序貫IFN鞏固治療6個(gè)月(即給予普通干擾素α-1b500萬iu，肌肉或皮下注射，隔天1次)。分別于停藥后1、2、3、6、12、18、24、30、36個(gè)月對肝生化、HBV-DNA定量、乙肝病毒標(biāo)志物進(jìn)行檢測，在序貫IFN鞏固治療組需監(jiān)測甲功、血圖分析等，分析停藥后的持久應(yīng)答時(shí)間。替比夫定停藥標(biāo)準(zhǔn)為：血清HBV-DNA轉(zhuǎn)陰、HBeAg血清學(xué)轉(zhuǎn)化、肝生化指標(biāo)正常分別達(dá)12個(gè)月以上，總療程≤100W。復(fù)發(fā)標(biāo)準(zhǔn)為：HBV-DNA≥104copies／ml或ALT≥2×ULN。未復(fù)發(fā)組停藥隨訪期間研究時(shí)間均≥12個(gè)月。 HBV-DNA定量檢測采用Roche實(shí)時(shí)熒光定量PCR儀，HBV-DNA檢測下限為1×103copies/ml。HBV血清標(biāo)志物(HBsAg、抗一HBs、HBeAg、抗一HBe、抗一HBc)檢測采用Roche Cobas E601電化學(xué)發(fā)光分析法。HBsAg定量采用MOUDULAR E170系統(tǒng)電化學(xué)發(fā)光法檢測，試劑由上海羅氏(Roche)制藥有限公司提供，HBsAg檢測值0.5IU/ml為陰性。 應(yīng)用SPSS17.0軟件進(jìn)行統(tǒng)計(jì)分析，累計(jì)復(fù)發(fā)率的計(jì)算采用乘積限法(Kaplan-Meier法)。將血清HBsAg定量數(shù)據(jù)經(jīng)對數(shù)轉(zhuǎn)換后進(jìn)行分析，兩組間比較采用t檢驗(yàn)。血清HBsAg水平對停藥后復(fù)發(fā)的預(yù)測價(jià)值運(yùn)用受試者工作特征曲線（receiver operating characteristic curve，ROC曲線）面積分析。兩樣本頻率的比較采用Fisher精確概率法。以P0．05為差異具有統(tǒng)計(jì)學(xué)意義。 結(jié)果：（1）在停藥后3年的隨訪期間共有13例持續(xù)應(yīng)答，總的持久應(yīng)答率為65%，持續(xù)有效維持最長的時(shí)間為40個(gè)月。其中有7例復(fù)發(fā)，在停藥后3、6、12個(gè)月的復(fù)發(fā)累計(jì)病例分別占復(fù)發(fā)病例的14.3％(1例)、42.9％(3例)、85、7％(6例)，復(fù)發(fā)最長的l例為34個(gè)月。隨訪到目前為止序貫IFN鞏固治療組總的復(fù)發(fā)率低于單一LDT鞏固治療組(30%vs40%,P0．05)，差異無統(tǒng)計(jì)學(xué)意義。序貫IFN鞏固治療組和單一LDT鞏固治療組的累積復(fù)發(fā)率分別為30%和65%（χ2=0.141，ν=1，Р=0.70），兩組之間的累積復(fù)發(fā)率無統(tǒng)計(jì)學(xué)意義。（2）替比夫定治療前后血清HBsAg水平分別為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，差異有統(tǒng)計(jì)學(xué)意義。（3）未復(fù)發(fā)組在替比夫定治療12周、24周、48周時(shí)，血清HBsAg水平較基線逐步下降，復(fù)發(fā)組血清HBsAg水平下降不明顯。（4）較基線時(shí)的血清HBsAg水平，分別在治療12周、24周、48周時(shí)的下降幅度對停藥后復(fù)發(fā)有一定的預(yù)測價(jià)值，但差異無統(tǒng)計(jì)學(xué)意義（P0．05)。在治療24周時(shí)的ROC曲線面積0.689，大于治療12周時(shí)的0.652、48周時(shí)的0.545，因此24周時(shí)血清HBsAg水平下降幅度對預(yù)測停藥后復(fù)發(fā)的價(jià)值更大。（5）治療24周時(shí)血清HBsAg水平下降幅度≥1000IU/ml的患者其持久應(yīng)答率較下降幅度＜1000IU/ml的患者高[91.0%(10/11) vs33.3%(3/9), P＜0.05],差異有統(tǒng)計(jì)學(xué)意義。（6）治療結(jié)束時(shí)的血清HBsAg水平＜200IU/ml的患者其復(fù)發(fā)率低于≥200IU/ml的患者[0vs46.7%, P＜0.05],差異有統(tǒng)計(jì)學(xué)意義。（7）治療期間有3例患者出現(xiàn)HBsAg血清學(xué)轉(zhuǎn)化，達(dá)到臨床治愈。 結(jié)論：（1）HBeAg陽性的CHB患者接受LDT達(dá)停藥標(biāo)準(zhǔn)后（總療程≤1年），可獲得較長時(shí)間的持續(xù)應(yīng)答。（2）序貫普通干擾素α-1b鞏固治療，并不能降低停藥后復(fù)發(fā)率。（3）LDT治療24周時(shí)血清HBsAg水平下降幅度≥1000IU/ml的患者其持久應(yīng)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).

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R512.62

【共引文獻(xiàn)】

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5 楊s

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