核苷（酸）类似物治疗慢性乙型肝炎发生病毒学突破的预测因素研究

发布时间：2018-08-11 12:47

【摘要】：目的：核苷（酸）类似物（nucleos(t)ide analogues, NAs）因其强大的抗病毒能力、良好的耐受性、不良反应少、使用方便等优点，在慢性乙型病毒性肝炎（chronic hepatitis B，CHB）抗病毒治疗中被广泛应用。但NAs在CHB抗病毒治疗过程中的原发无应答、病毒学突破、耐药变异等问题，一直是NAs优化治疗的重点所在。本研究旨在通过回顾性调查研究，探讨临床实际NAs治疗CHB获得完全病毒学应答后发生病毒学突破的影响因素，以期为NAs优化治疗，获得维持应答提供依据。方法：研究对象为2003年1月至2010年12月河北医科大学第三医院、石家庄市五院门诊及住院的CHB及肝硬化患者，，共收集病例233例。其中HBeAg阳性者139例，阴性患者94例，每例患者应用NAs抗病毒治疗达3年以上。其中拉米夫定组87人、拉米夫定+阿德福韦酯组40人、阿德福韦酯组41人、替比夫定组17人、恩替卡韦组48人。了解患者年龄、性别、既往是否有NAs治疗史、有无垂直传播等基本情况。并监测基线及抗病毒治疗过程中生化指标、HBV标志物、HBV DNA载量、AFP水平腹部B超或影像学变化。有条件者抗病毒前后行肝组织病理诊断。本研究以发生病毒学突破为随访截点。用SPSS16.0对观察数据进行相关性分析。结果： 1NAs治疗后病毒学应答情况经NAs抗病毒治疗后，共190例患者获得完全病毒学应答，其中第12、24、48、72、96周，完全病毒学应答率分别为42.9%、65.7%、77.7%、81.5%、81.5%。其中有62例（18.5%）发生病毒学突破，第1、2、3、5、8年累计病毒学突破率分别为4.7%,13.7%,22.6%,29.5%和32.6%。拉米夫定组为69.4%，阿德福韦酯组为22.7%，替比夫定组为33.3%，拉米夫定+阿德福韦酯组为5.6%，恩替卡韦组为0%。 2患者依从性纳入患者中有57例（23.1%）依从性差，其中30例接受问卷调查，主要原因为遗忘（62%），经济困难和药物不良反应者分别占19%和10%，因病情缓解认为无需继续治疗及其他原因的占9%。 3NAs治疗病毒学突破的预测因素分析纳入此研究患者接受NAs治疗后，有190例（81.5%）获得完全病毒学应答。将基线特征及早期病毒学应答情况进行赋值，并纳入单因素及多因素Logistic回归（α入=0.05，α出=0.10），对发生完全病毒学应答的190例患者进行分析发现，疗法（OR=0.358，P0.001），基线HBV DNA高载量（107, copies/ml, OR=2.356， P=0.036），无早期病毒学应答（OR=4.173，P=0.001）及依从性差（OR=2.740， P=0.039）是NAs抗病毒治疗发生病毒学突破的影响因素。将41例基线肝组织病理结果纳入单因素及多因素Logistic回归（α入=0.10，α出=0.15），发现疗法（OR=0.220，P=0.008）及无早期病毒学应答（OR=19.162，P=0.009）是病毒学突破的影响因素。将40例基线HBsAg定量结果纳入单因素Logistic回归分析，结果显示基线HBsAg水平与病毒学突破的相关性无统计学意义（P0.05）。将37例12周时HBsAg定量结果纳入单因素和多因素Logistic回归（α入=0.10，α出=0.15），结果显示：疗法（OR=0.108，P=0.045）、无早期病毒学应答（OR=9.312，P=0.062）及12周时血清HBsAg高水平（1500IU/ml, OR=9.990，P=0.045）是病毒学突破的影响因素。 4NAs治疗影响维持应答时间的相关因素分析 190例实现完全病毒学应答的患者中，随访期间62例患者发生了病毒学突破，赋值为1，维持应答时间24-384周。删失病例128例，赋值为0。以血清HBV DNA转阴后的随访为时间轴，以出现病毒学突破为截点，采用log-rank、χ2检验及Cox比例风险模型对190例患者维持应答时间进行单因素筛选及多因素回归分析(α入=0.05，α出=0.06)。结果提示：疗法（HR=0.481，P0.001），无早期病毒学应答（HR=3.624，P0.001），依从性不好（HR=3.626，P0.001）是病毒学突破的危险因素。结论： 1NAs能够快速有效的抑制病毒复制，但随着疗程的延长，病毒学突破率逐渐升高。 2NAs治疗患者发生病毒学突破受疗法、基线HBV DNA载量、早期病毒学应答情况、依从性及12周时血清HBsAg水平的影响。 3NA治疗患者维持病应答时间受疗法、早期病毒学应答情况及依从性的影响。 4依从性差是影响抗病毒疗效的重要且可控因素，提高患者依从性有待医患的共同努力。
[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.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R512.62

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