【摘要】：目的：核苷（酸）類似物（nucleos(t)ide analogues, NAs）因其強(qiáng)大的抗病毒能力、良好的耐受性、不良反應(yīng)少、使用方便等優(yōu)點(diǎn)，在慢性乙型病毒性肝炎（chronic hepatitis B，CHB）抗病毒治療中被廣泛應(yīng)用。但NAs在CHB抗病毒治療過程中的原發(fā)無應(yīng)答、病毒學(xué)突破、耐藥變異等問題，一直是NAs優(yōu)化治療的重點(diǎn)所在。本研究旨在通過回顧性調(diào)查研究，探討臨床實(shí)際NAs治療CHB獲得完全病毒學(xué)應(yīng)答后發(fā)生病毒學(xué)突破的影響因素，以期為NAs優(yōu)化治療，獲得維持應(yīng)答提供依據(jù)。 方法：研究對(duì)象為2003年1月至2010年12月河北醫(yī)科大學(xué)第三醫(yī)院、石家莊市五院門診及住院的CHB及肝硬化患者，，共收集病例233例。其中HBeAg陽(yáng)性者139例，陰性患者94例，每例患者應(yīng)用NAs抗病毒治療達(dá)3年以上。其中拉米夫定組87人、拉米夫定+阿德福韋酯組40人、阿德福韋酯組41人、替比夫定組17人、恩替卡韋組48人。了解患者年齡、性別、既往是否有NAs治療史、有無垂直傳播等基本情況。并監(jiān)測(cè)基線及抗病毒治療過程中生化指標(biāo)、HBV標(biāo)志物、HBV DNA載量、AFP水平腹部B超或影像學(xué)變化。有條件者抗病毒前后行肝組織病理診斷。本研究以發(fā)生病毒學(xué)突破為隨訪截點(diǎn)。用SPSS16.0對(duì)觀察數(shù)據(jù)進(jìn)行相關(guān)性分析。 結(jié)果： 1NAs治療后病毒學(xué)應(yīng)答情況 經(jīng)NAs抗病毒治療后，共190例患者獲得完全病毒學(xué)應(yīng)答，其中第12、24、48、72、96周，完全病毒學(xué)應(yīng)答率分別為42.9%、65.7%、77.7%、81.5%、81.5%。其中有62例（18.5%）發(fā)生病毒學(xué)突破，第1、2、3、5、8年累計(jì)病毒學(xué)突破率分別為4.7%,13.7%,22.6%,29.5%和32.6%。拉米夫定組為69.4%，阿德福韋酯組為22.7%，替比夫定組為33.3%，拉米夫定+阿德福韋酯組為5.6%，恩替卡韋組為0%。 2患者依從性 納入患者中有57例（23.1%）依從性差，其中30例接受問卷調(diào)查，主要原因?yàn)檫z忘（62%），經(jīng)濟(jì)困難和藥物不良反應(yīng)者分別占19%和10%，因病情緩解認(rèn)為無需繼續(xù)治療及其他原因的占9%。 3NAs治療病毒學(xué)突破的預(yù)測(cè)因素分析 納入此研究患者接受NAs治療后，有190例（81.5%）獲得完全病毒學(xué)應(yīng)答。將基線特征及早期病毒學(xué)應(yīng)答情況進(jìn)行賦值，并納入單因素及多因素Logistic回歸（α入=0.05，α出=0.10），對(duì)發(fā)生完全病毒學(xué)應(yīng)答的190例患者進(jìn)行分析發(fā)現(xiàn)，療法（OR=0.358，P0.001），基線HBV DNA高載量（107, copies/ml, OR=2.356， P=0.036），無早期病毒學(xué)應(yīng)答（OR=4.173，P=0.001）及依從性差（OR=2.740， P=0.039）是NAs抗病毒治療發(fā)生病毒學(xué)突破的影響因素。將41例基線肝組織病理結(jié)果納入單因素及多因素Logistic回歸（α入=0.10，α出=0.15），發(fā)現(xiàn)療法（OR=0.220，P=0.008）及無早期病毒學(xué)應(yīng)答（OR=19.162，P=0.009）是病毒學(xué)突破的影響因素。將40例基線HBsAg定量結(jié)果納入單因素Logistic回歸分析，結(jié)果顯示基線HBsAg水平與病毒學(xué)突破的相關(guān)性無統(tǒng)計(jì)學(xué)意義（P0.05）。將37例12周時(shí)HBsAg定量結(jié)果納入單因素和多因素Logistic回歸（α入=0.10，α出=0.15），結(jié)果顯示：療法（OR=0.108，P=0.045）、無早期病毒學(xué)應(yīng)答（OR=9.312，P=0.062）及12周時(shí)血清HBsAg高水平（1500IU/ml, OR=9.990，P=0.045）是病毒學(xué)突破的影響因素。 4NAs治療影響維持應(yīng)答時(shí)間的相關(guān)因素分析 190例實(shí)現(xiàn)完全病毒學(xué)應(yīng)答的患者中，隨訪期間62例患者發(fā)生了病毒學(xué)突破，賦值為1，維持應(yīng)答時(shí)間24-384周。刪失病例128例，賦值為0。以血清HBV DNA轉(zhuǎn)陰后的隨訪為時(shí)間軸，以出現(xiàn)病毒學(xué)突破為截點(diǎn)，采用log-rank、χ2檢驗(yàn)及Cox比例風(fēng)險(xiǎn)模型對(duì)190例患者維持應(yīng)答時(shí)間進(jìn)行單因素篩選及多因素回歸分析(α入=0.05，α出=0.06)。結(jié)果提示：療法（HR=0.481，P0.001），無早期病毒學(xué)應(yīng)答（HR=3.624，P0.001），依從性不好（HR=3.626，P0.001）是病毒學(xué)突破的危險(xiǎn)因素。 結(jié)論： 1NAs能夠快速有效的抑制病毒復(fù)制，但隨著療程的延長(zhǎng)，病毒學(xué)突破率逐漸升高。 2NAs治療患者發(fā)生病毒學(xué)突破受療法、基線HBV DNA載量、早期病毒學(xué)應(yīng)答情況、依從性及12周時(shí)血清HBsAg水平的影響。 3NA治療患者維持病應(yīng)答時(shí)間受療法、早期病毒學(xué)應(yīng)答情況及依從性的影響。 4依從性差是影響抗病毒療效的重要且可控因素，提高患者依從性有待醫(yī)患的共同努力。
[Abstract]:AIM: Nucleoside (t) ide analogues (NAs) are widely used in antiviral therapy of chronic hepatitis B (CHB) because of their strong antiviral ability, good tolerance, fewer adverse reactions and convenient use. The aim of this study was to explore the influencing factors of virological breakthroughs after complete virological response to NAs treatment of CHB in order to provide the basis for optimal treatment of NAs and sustained response.
Methods: 233 cases of HB and cirrhosis were collected from the Third Hospital of Hebei Medical University from January 2003 to December 2010. Among them, 139 were HBeAg positive and 94 were HBeAg negative. Each patient received NAs antiviral therapy for more than three years. 87 patients in Lamivudine group, lamivudine + amidovir group There were 40 patients in the defovir dipivoxil group, 41 patients in the adefovir dipivoxil group, 17 patients in the tibivudine group and 48 patients in the entecavir group. Pathological diagnosis of liver tissues was performed before and after antiviral therapy in the conditioned patients. The breakthrough of Virology was used as the cut-off point for follow-up. Correlation analysis was performed on the observed data with SPSS 16.0.
Result:
Virological response after 1NAs treatment
A total of 190 patients received complete virological response after NAs antiviral therapy, including 42.9%, 65.7%, 77.7%, 81.5% and 81.5% at 12, 24, 48, 72, 96 weeks. Among them, 62 (18.5%) had virological breakthroughs, with cumulative virological breakthroughs of 4.7%, 13.7%, 22.6%, 29.5% and 32.6% at 1, 2, 3, 5 and 8 years, respectively. 9.4%, adefovir dipivoxil group 22.7%, telbivudine group 33.3%, lamivudine + adefovir dipivoxil group 5.6%, entecavir group 0%.
2 patient compliance
Fifty-seven patients (23.1%) had poor compliance. Among them, 30 received questionnaires. The main causes were amnesia (62%), 19% had financial difficulties and 10% had adverse drug reactions, and 9% had no need for further treatment because of remission.
Predictors of virological breakthrough in 3NAs treatment
One hundred and ninety patients (81.5%) received complete virologic responses after NAs treatment. Baseline characteristics and early virologic responses were assigned, and logistic regression (alpha-in = 0.05, alpha-out = 0.10) was used to analyze 190 patients with complete virologic responses. Therapy (OR = 0.358, P 0.001) High baseline HBV DNA loading (107, copies / ml, OR = 2.356, P = 0.036), no early virological response (OR = 4.173, P = 0.001) and poor compliance (OR = 2.740, P = 0.039) were the influencing factors for virological breakthroughs in NAs antiviral therapy. Treatment (OR = 0.220, P = 0.008) and no early virological response (OR = 19.162, P = 0.009) were the influencing factors of virological breakthroughs. Quantitative results of 40 baseline HBsAg cases were included in the single factor Logistic regression analysis. The results showed that there was no significant correlation between baseline HBsAg levels and virological breakthroughs (P 0.05). Factor and multivariate logistic regression (alpha in = 0.10, alpha out = 0.15) showed that treatment (OR = 0.108, P = 0.045), no early virological response (OR = 9.312, P = 0.062) and high serum HBsAg levels at 12 weeks (1500IU/ml, OR = 9.990, P = 0.045) were the influencing factors for virological breakthroughs.
Analysis of factors related to maintenance response time by 4NAs treatment
Among 190 patients who achieved complete virological response, 62 had virological breakthroughs during the follow-up period, assigning a value of 1 and maintaining a response time of 24-384 weeks. The results showed that the treatment (HR = 0.481, P 0.001), no early virological response (HR = 3.624, P 0.001), poor compliance (HR = 3.626, P 0.001) were risk factors for virological breakthrough.
Conclusion:
1NAs can inhibit virus replication rapidly and effectively, but with the extension of treatment, the virological breakthrough rate gradually increased.
Virological breakthroughs in patients treated with 2NAs are influenced by treatment, baseline HBV DNA load, early virological response, compliance, and serum HBsAg levels at 12 weeks.
Maintenance response time of patients treated with 3NA is influenced by treatment, early virological response and compliance.
4. Poor compliance is an important and controllable factor affecting the efficacy of antiviral therapy.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R512.62

【參考文獻(xiàn)】

相關(guān)期刊論文 前8條

1 李韋杰;李伯安;趙景民;韓佳琪;劉妍;江玲;毛遠(yuǎn)麗;魯鳳民;徐東平;;54例慢性乙型肝炎患者肝組織乙型肝炎病毒共價(jià)閉合環(huán)狀DNA與血清HBsAg定量檢測(cè)結(jié)果分析[J];中華肝臟病雜志;2011年11期

2 梁盼盼;郭進(jìn)軍;李青嶺;羅強(qiáng);石小楓;黃愛龍;;慢性乙型肝炎患者抗病毒治療中的病毒準(zhǔn)種演變[J];中華肝臟病雜志;2011年07期

3 王錚;;血清乙型肝炎病毒DNA水平的生物學(xué)梯度與肝細(xì)胞肝癌的風(fēng)險(xiǎn)性相關(guān)[J];世界核心醫(yī)學(xué)期刊文摘(胃腸病學(xué)分冊(cè));2006年Z1期

4 ;慢性乙型肝炎防治指南[J];中華傳染病雜志;2005年06期

5 馮輝;何國(guó)平;;慢性乙型病毒性肝炎患者治療依從性及其影響因素分析[J];中華護(hù)理雜志;2005年12期

6 肖揚(yáng),周岳進(jìn),王開鑒,張文靜,胡操寒,謝慶榮,朱冰星,鄭金莉,胡俠;乙型肝炎病毒前核心區(qū)及基本啟動(dòng)子變異對(duì)干擾素抗病毒治療應(yīng)答的影響[J];肝臟;2005年01期

7 姚光弼,崔振宇,姚集魯,張定鳳,籍納新,黃瑛;國(guó)產(chǎn)拉米夫定治療2 200例慢性乙型肝炎的Ⅳ期臨床試驗(yàn)[J];中華肝臟病雜志;2003年02期

8 中華醫(yī)學(xué)會(huì)傳染病與,寄生蟲病學(xué)分會(huì),肝病學(xué)分會(huì);病毒性肝炎防治方案[J];中華肝臟病雜志;2000年06期

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