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不同策略治疗rtN236T位点变异的HBeAg阳性慢性乙型肝炎的疗效观察

Clinical efficacy of various antiviral-based strategies to treat chronic hepatitis patients with positivity for hepatitis B e antigen and rtN236T mutation

摘要:

目的 观察rtN236T位点变异的阿德福韦酯(ADV)耐药HBeAg阳性的慢性乙型肝炎(CHB)患者,ADV分别联合聚乙二醇干扰素(Peg-IFN) α-2a及拉米夫定(LAM)进行治疗的疗效及安全性,并分析影响疗效的因素.方法 收集rtN236T位点变异的ADV耐药HBeAg阳性CHB患者65例,随机分为A组(33例)和B组(32例),A组ADV联合Peg-IFN α-2a治疗,连续48周后停用.B组ADV联合LAM治疗,连续48周后,继续使用24周.在治疗前、治疗后24、48周及随访24周,比较两组HBV DNA载量下降≥2log10拷贝/ml和HBV DNA≤500拷贝/ml患者数及HBeAg阴转率、HBeAg血清学转换率、ALT复常率.比较两组行肝穿刺活组织检查患者治疗前后的肝脏炎症分级、纤维化分期及肝组织学活动指数(HAI)评分.根据数据类型用t检验或x2检验进行统计分析.结果 治疗后24、48周及随访24周时,HBV DNA载量下降≥2log10拷贝/ml的患者,A组分别为81.8%、90.9%、75.8%,B组分别为53.1%、56.2%、59.4%;HBV DNA≤500拷贝/ml的患者,A组分别为48.5%、60.6%、42.4%,B组分别为31.3%、34.4%、31.3%;HBeAg阴转率,A组分别为39.4%、60.6%、54.5%,B组分别为12.5%、37.5%、37.5%;HBeAg血清学转换率,A组分别为27.3%、54.5%、48.5%,B组分别为6.3%、15.6%、18.8%;ALT复常率,A组分别为72.7%、84.8%、78.8%,B组分别为46.9%、56.3%、46.9%;A组均明显高于B组,差异有统计学意义(P值均<0.05).治疗48周后,A组的肝组织HAI积分、炎症分级及纤维化分期改善情况均明显优于B组(P值均< 0.05).除肌酐升高发生率差异无统计学意义外,A组的不良反应发生率均高于B组(P值均< 0.05),但未发生终止治疗或危及患者安全的不良反应.A组停药随访24周,5例患者HBVDNA升高≥2log10拷贝/ml,其中4例治疗期间HBV DNA≤500拷贝/ml,此4例患者均发生ALT升高,且均未发生HBeAg血清学转换.结论 rtN236T位点变异的ADV耐药HBeAg阳性CHB患者,ADV联合Peg-IFN α-2a的疗效优于联合LAM,但不良反应发生率更高;未发生HBeAg血清学转换的患者,停药后易出现病毒反跳及ALT升高.

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abstracts:

Objective To compare the efficacy and safety of the common antivirals,including adefovir dipivoxil (ADV),pegylated-interferon a-2a (peg-IFN) and lamivudine (LAM),used as combination therapies to treat chronic hepatitis B (CHB) patients with positivity for the hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) harboring the ADV-resistanee mutation,rtN236T,and to explore the factors associated with curative outcome.Methods Sixty-five adult CHB patients (age range:20-60 years) who were unresponsive to ADV therapy (HBeAg-positive;HBV DNA ≥ 10s copies/ml),LAM-naive,and tested positive for the rtN236T HBV mutation were enrolled in the study and randomly divided into two treatment groups:Group A (n =33),who were administered ADV (10 mg/day,orally) plus peg-IFN (180 μg/week,subcutaneous injection) for 48 weeks;and Group B (n =32 patients),who received the ADV plus LAM (100 mg/day,orally) for 48 weeks followed by continued LAM treatment for an additional 24 weeks.Pre-(baseline),during and post-treatment measurements of HBV viral loads and hepatitis B markers were made by quantitative PCR and electrochemiluminescence assays,respectively.All patients underwent liver biopsies to determine the histological activity index (HAI) and treatment response regarding inflammation and fibrosis stage.The rates of virological response (VR),HBeAg-negativity,HBeAg seroconversion,and alanine aminotransferase (ALT) normalization were calculated,and the significance of differences between groups were assessed by Student's t-test and x2 test.Results There were no significant differences between the two groups in regards to sex,age,or baseline levels of HBV DNA,ALT,and total bilirubin (P > 0.05).At weeks 24 and 48 of treatment and 24 after treatment end,group A showed significantly higher (vs.group B,P < 0.05) rates of reduced HBV DNA viral loads (81.8%,90.9%,and 75.8% vs.53.1%,56.2%,and 59.4%),VR (48.5%,60.6%,and 42.4% vs.31.3%,34.4%,and 31.3%),HBeAg-negativity (39.4%,60.6%,and 54.5% vs.12.5%,37.5%,and 37.5%),HBeAg seroconversion (27.3%,54.5%,and 48.5% vs.6.3%,15.6%,and 18.8%),and ALT normalization (72.7%,84.8%,and 78.8% vs.46.9%,56.3%,and 46.9%).After 48 weeks oftreatment,group A showed significantly improved HAI (vs.group B,P < 0.05).With the exception of treatment-related increased creatinine (P < 0.05),group A showed significantly higher rates of adverse reactions;although,none was serious enough to threaten patient safety or necessitate early termination of the treatment regimen.Twenty-four weeks after treatment completion,five patients had HBV viral loads of ≥ 2log10 copies/ml and four had ≤ 500 copies/ml,and ALT was normalized in 28 patients.The four patients in group A with HBV DNA ≤ 500 copies/ml and elevated ALT during treatment did not show HBeAg seroconversion.Conclusion Peg-IFN plus ADV combination therapy produced better outcomes than the ADV plus LAM combination therapy in regards to HBV viral loads,VR rate,HBeAg-negative rate,HBeAg seroconversion rate,ALT normalization rate,and HAI,but was associated with a higher rate of adverse reactions (none of which were severe).Lack of HBeAg seroconversion was associated with higher virus load and ALT levels.

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