【作者】 徐静；

【导师】 马立宪；

【作者基本信息】 山东大学 ， 内科学（传染病学）（专业学位）， 2021， 博士

【摘要】 第一部分聚乙二醇干扰素α-2a治疗HBeAg阳性初治慢性乙型肝炎患者的个体化研究目的探讨聚乙二醇干扰素(Peg-IFN)α-2a个体化治疗HBeAg阳性初治慢性乙型肝炎(CHB)患者的临床疗效及相关预测因素。方法对139例HBeAg 阳性初治CHB患者给予Peg-IFNα-2a 180μg每周1次皮下注射48周,随访48周。治疗前留取2ml血标本分离后提取血浆上清液放置-20℃冰箱保存。所有患者均检测乙肝病毒(HBV)基因型,并分别于治疗前、治疗12周、24周、36周、48周、72周检测HBVDNA、ALT、乙肝五项定量、血常规、甲状腺功能、抗核抗体全套等指标,根据治疗24周HBVDNA应答情况后进行个体化治疗并根据患者意愿分为四组。(1)常规治疗组:如果24周HBVDNA下降≥1log copies/ml,继续治疗疗程达48周。(2)延长疗程组:如果24周HBVDNA下降<1log copies/ml,继续治疗至72周。(3)联合治疗组:如果24周HBVDNA下降<1log copies/ml,加用恩替卡韦(ETV)0.5mg,1 次/天,联合 Peg-IFNα-2a 应用至 48 周。(4)序贯治疗组:如果24周HBVDNA下降<1log copies/ml,停用Peg-I FNα-2a序贯ETV0.5mg,1次/天抗病毒治疗达48周以上。观察治疗12周、24周、36周、48周、72周HBVDNA阴转率、ALT的复常率、HBeAg的阴转率及血清转换率、HBsAg定量下降幅度及阴转率、血清转换率。分析HBV基因型与Peg-IFNα-2a治疗疗效的相关性。观察并记录治疗中的不良反应,一旦出现严重不良反应则给予停用Peg-IFNα-2a。根据ALT、HBVDNA、HBeAg应答情况进行疗效判断,分为完全应答(CR)、部分应答(PR)、无应答(NR)三组。(1)CR:ALT 恢复正常,HBVDNA<103 copies/ml,HBeAg 血清学转换。(2)NR:所有指标均未达到上述标准。(3)PR:介于完全应答与无应答之间。应用统计学方法进行分析,P<0.05为差异有统计学意义。结果1基线特征139例患者纳入常规治疗组65例、延长疗程组24例、联合治疗组23例、序贯治疗组27例,各组性别、年龄、基因型、治疗前ALT值、HBVDNA及HBsAg定量相比较无统计学差异(P>0.05),具有可比性。2各组间疗效比较比较常规治疗组与延长治疗组48周时ALT复常率、HBVDNA阴转率、HBeAg阴转率及血清转换率、HBsAg水平平均下降幅度,前者均高于后者(67.7%vs12.5%、66.2%vs16.7%、53.8%vs12.5%、33.8%vs0%、1.62±1.15logIU/ml vs0.39±0.52logIU/ml)(P<0.05);给予延长治疗组 Peg-IFNα-2a 治疗至 72 周时与常规治疗组48周比较,上述各项指标仍低于常规治疗组(P<0.05)。四组间进行比较,结果显示,除HBsAg阴转率无统计学差异(P>0.05),其他指标均有统计学差异(P<0.05)。常规治疗组HBeAg阴转率(53.8%)及血清转换率(33.8%)、HBsAg平均下降幅度(1.62±1.15logIU/ml)均高于联合治疗组(13.04%、0%、0.41±0.16 logIU/ml)及序贯治疗组(0%、0%、0.35±0.141ogIU/ml)(P<0.05),而三组间ALT复查率、HBVDNA阴转率无统计学差异(P>0.05)。延长治疗组、联合治疗组、序贯治疗组三组比较,延长治疗组ALT复常率(29.2%)、HBVDNA 阴转率(16.7%)低于其他两组(69.6%、66.7%;87.0%、85.2%)(P<0.05),HBeAg阴转率(12.5%)及血清转换率(12.5%)高于其他两组(13.04%、0%;0%、0%)(P<0.05)。联合治疗组和序贯治疗组比较除HBeAg阴转有统计学差异,前组高于后组(13.04%vs0%)(P<0.05),其他指标两组均无统计学差异(P>0.05)。3基因型与疗效相关性比较各组中基因B型和C型临床疗效比较无统计学差异(P>0.05)。4 Peg-IFNα-2a治疗影响因素分析以年龄、性别、基线HBVDNA载量、HBV基因型、ALT水平、HBsAg水平共6个因素为自变量(X),以抗病毒治疗24周HBVDNA下降≥1 log copies/ml应答与否(0=无,1=有)为因变量(Y)进行多因素logistic回归分析,结果为性别与治疗前HBsAg的水平与Peg-IFNα-2a治疗24周时HBVDNA应答有相关性,女性和HBsAg水平≤4 log copies/ml治疗24周时HBVDNA应答高(P<0.05)。5不良反应比较比较常规治疗组、延长治疗组、联合治疗组三组Peg-IFNα-2a治疗不良反应,结果显示,发热、流感样症状、白细胞减少、血小板减少、疲劳、ALT升高、脱发等不良反应三组之间无差异(P值>0.05),139例患者并未出现严重不良反应而停药。结论对于HBeAg阳性CHB初治患者,如果为女性且治疗前HBsAg水平≤4 logIU/ml可优先选择Peg-IFNα-2a抗病毒治疗,并根据治疗24周HBVDNA应答情况给予患者个体化治疗:如果24周HBVDNA下降≥1logcopies/ml则给予继续原方案治疗;如果下降<1log copies/ml则建议停用Peg-IFNα-2a改为ETV等核苷(酸)类似物单药抗病毒治疗,本研究中对于HBVDNA24周下降<1log copies/ml患者并未发现Peg-IFNα-2a延长疗程和联合ETV方案临床疗效的优势,故不推荐应用。第二部分联合聚乙二酵干扰素α-2a治疗恩替卡韦经治慢性乙型肝炎患者的疗效分析目的探讨联合Peg-IFNα-2a治疗ETV经治CHB患者的疗效;分析与疗效相关的影响因素。方法选择经ETV抗病毒治疗6月以上病毒学阴转且HBsAg定量<1500IU/L CHB患者95例,根据患者意愿分为两组:(1)联合治疗组:共35例,原有ETV基础上联合Peg-IFNα-2a 180ug皮下注射,1次/周,Peg-IFNα-2a治疗达48周,如果出现不良反应,则给予对症处理,严重者则停用。(2)单药组:共60例,继续应用ETV。联合治疗组患者治疗前均留取2ml血标本分离后提取血浆上清液放置-20℃冰箱保存。所有患者均检测HBV基因型,并于治疗前、治疗12周、24周、36周、48周检测HBVDNA、ALT、乙肝五项定量、血常规、甲状腺功能等指标。观察治疗12周、24周、36周、48周HBsAg定量值及阴转率、血清转换率;分析Peg-IFNα-2a联合治疗疗效的相关因素;观察记录治疗中的不良反应。应用统计学方法进行分析,P<0.05为差异有统计学意义。结果1两组基线特征两组间性别、年龄、ALT水平、HBeAg阳性比例、HBsAg定量水平、基因型比例均无统计学差异(P>0.05),具有可比性。2比较两组HBsAg的定量变化、48周HBsAg阴转率及HBsAg血清转换率治疗36周、48周联合治疗组较单药组HBsAg定量水平下降明显(P<0.05);48周联合治疗组有7例(20%)出现HBsAg血清学阴转,3例(8.57%)出现HBsAg血清转换,单药组无一例HBsAg血清阴转及血清转换,两组间比较有显著性差异(P<0.05)。3 HBsAg下降百分数对Peg-IFNα-2a联合治疗应答的疗效预测建立ROC曲线分析35例联合治疗的患者12周、24周、36周的HBsAg水平下降百分数对48周疗效的预测价值,结果显示24周HBsAg下降百分数曲线下面积0.824(95%CI=0.669～0.999),最佳Cut-off值为51.52%,此时的敏感性为0.714,特异性为0.893(P<0.05);36周HBsAg下降百分数曲线下面积为0.878(95%CI=00.699～1),最佳Cut-off值为90.22%,此时的敏感性为0.857,特异性为0.929(P<0.05),表明第24周、36周的HBsAg水平下降与48周时HBsAg应答有显著的相关性。4不良反应比较联合治疗组28例(80%)早期出现发热,25例(71.4%)患者出现白细胞、中性粒细胞、血小板计数下降;单药组无一例患者出现不良反应。两组均未因严重不良反应而停药。结论对于通过恩替卡韦实现病毒学抑制且HBsAg定量水平<1500IU/ml的患者,联合有限疗程的Peg-IFNα-2a可以显着提高HBsAg清除率和血清转化率;治疗后24周和36周HBsAg的显著降低可以提示HBsAg清除的可能性,并确定获得最大成功机会的患者。第三部分CYP27B1-1260基因多态性与聚乙二醇干扰素α-2a治疗慢性乙型肝炎疗效相关性研究目的探讨CYP27B1-1260基因多态性与Peg-IFNα-2a单药治疗HBeAg阳性CHB患者疗效相关性;探讨CYP27B1-1260基因多态性与Peg-IFNα-2a联合治疗ETV经治的CHB患者疗效相关性。方法对第一部分及第二部分进行Peg-IFNα-2a治疗患者共174例留取的血标本,采用聚合酶链反应-限制性片段长度多态性分析(PCR-RFLP)方法检测Cyp27B1-1260A/C多态性位点。将第一部分研究人群Peg-IFNα-2a单药治疗的疗效判断分为CR、PR、NR三组(同第一部分);将第二部分研究人群联合治疗患者疗效判断分为两组:(1)HBsAg 阴性组:HBsAg 转阴,肝功能正常、HB VDNA<103copies/ml。(2)HBsAg阳性组:HBsAg未转阴,肝功能正常、HBVDNA<103copies/ml。上述指标进行统计学方法分析,P<0.05为差异有统计学意义。结果1第一部分研究人群结果139 例患者 CYP27B1-1260 多态性 AA49 例(35.3%)、CC46 例(33.1%)、AC44 例(31.7%)。1.1 CYP27B1-1260多态性和Peg-IFNα-2a治疗24周HBVDNA应答的相关性根据Peg-IFNα-2a应用24周HBVDNA应答情况不同,将研究对象分为两组:HBVDN下降≥1logcopies/ml为下降明显组,HBVDNA<1logcopies/ml为下降不明显组,判断CYP27B1-1260多态性与HBVDNA24周应答有无相关性。结果显示,CYP27B1-1260基因CC型在两组间有统计学差异,24周HBVDNA下降不明显组基因CC型发生频率(33.8%)高于24周下降明显组(32.3%)(P<0.05)。1.2 CYP27B1-1260多态性和Peg-IFNα-2a治疗48周疗效相关性分析分析常规治疗组65例患者(其他组因病例数过少不做分析),结果显示,CC型在Peg-IFNα-2a治疗无应答组(55.0%)比例中明显高于AA型(20.0%)及 AC 型(25.0%)(P<0.05)。2第二部分研究人群结果选择第二部分研究人群中联合治疗组共35例CHB患者,CYP27B1-1260多态性结果为 AA11 例(31.4%)、AC14 例(40.0%)、CC10 例(28.6%)。2.1 CYP27B1-1260多态性与联合治疗疗效的关系经统计学分析,CYP27B1-1260多态性与联合治疗疗效无相关性(P>0.05)2.2 联合治疗影响因素分析以年龄、性别、CYP27B1-1260基因多态、HBV基因型共4个因素为自变量(X),以抗病毒治疗48周HBsAg阴转(0=无,1=有)为因变量(Y)进行多因素logistic回归分析,结果为上述各指标与联合治疗48周HBsAg阴转均无相关性(P>0.05)。结论CYP27B1-1260基因多态性可能与Peg-IFNα-2a治疗应答有关,其CC型可能是Peg-IFNα-2a治疗HBeAg阳性初治慢性乙型肝炎应答不佳的影响因素。更多还原

【Abstract】 Part Ⅰ Individualized study of pegylated interferon alfa-2a in the initial treatment of HBeAg-positive chronic hepatitis B patientsObjectivesTo investigate the clinical efficacy and related predictors of pegylated interferon(Peg-IFN)α-2a individualized treatment in the treatment-naive HBeAg-positive CHB patients.Methods139 HBeAg-positive patients with chronic hepatitis B were treated with Peg-IFNα-2a 180 μg subcutaneously once a week for 48 weeks and followed up for 48 weeks.Two milliliters of blood samples were obtained and separated before treatment,and the plasma supernatant was extracted and stored in the freezer at-20℃.Hepatitis B virus genotypes were measured in all patients,and HBV DNA,ALT,five hepatitis B quantitative,blood routine,thyroid function,antinuclear antibody panel and other in-dicators were measured before treatment and at 12 weeks,24 weeks,36 weeks,48 weeks and 72 weeks of treatment.All patients were divided into four groups and giv-en individualized treatment according to the HBVDNA response at 24 weeks.(1)Conventional treatment group:If HBVDNA decreased≥ 1 logcopies/ml at 24 weeks,the course of treatment was continued to 48 weeks.(2)Prolonged treatment group:If HBV DNA decreased<1 logcopies/ml at 24 weeks,treatment was continued until 72 weeks.(3)Combination therapy group:If HBV DNA decreased<1 logcopies/ml at 24 weeks,Entecavir(ETV)0.5 mg once a day combined with Peg-IFN a-2a was applied until 48 weeks.(4)Sequential treatment group:If HBVDNA decreased l<1 logcopies/ml at 24 weeks,Peg-IFNα-2a was discontinued and sequential ETV 0.5mg was given once a day for 48 weeks or more.The HBVDNA negative conversion rate,ALT recovery rate,HBeAg negative conversion rate and seroconversion rate,HBsAg quantitative decrease range,negative conversion rate and seroconversion rate were observed at 12 weeks,24 weeks,36 weeks 48 weeks and 72 weeks of treatment.The correlation between HBV genotypes and the therapeutic efficacy of Peg-IFN a-2a was analyzed.Adverse reactions during treatment were observed and recorded,and Peg-IFN a-2a was discontinued once serious adverse reactions occurred.According to the response of ALT,HBV DNA and HBeAg,the patients were di-vided into three groups:complete response(CR),partial response(PR)and nonre-sponse(NR).(1)CR:ALT returned to normal,HBVDNA<103 copies/ml,HBeAg serocon-version.(2)NR:None of the indicators meet the above criteria.(3)PR:between CR and NR.Statistical methods were applied for analysis,and P<0.05 was considered statiscally significant.Results1.Baseline characteristicsAmong the 139 patients,65 were included in the conventional treatment group,24 in the extended treatment group,23 in the combined treatment group,and 27 in the sequential treatment group.There were no statistical differences in gender,age,geno-type,and the ALT,HBVDNA and HBsAg quantitative before treatment among all groups(P>0.05),which showed a comparability.2.Comparison of curative effect between the groupsThe recovery rate of ALT,HBV DNA negative conversion rate,HBeAg negative conversion rate,seroconversion rate and average decrease of HBsAg level in the con-ventional treatment group were higher than those in the extended course group(67.7%vs 12.5%,66.2%vs 16.7%,53.8%vs 12.5%,33.8%vs 0%,1.62 ± 1.15 logIU/ml vs 0.39 ± 0.52 logIU/ml)(P<0.05);After 72weeks of Peg-IFNα-2a treatment,the above indicators were still lower than those in the conventional treatment group by 48 weeks(P<0.05).Comparison among the four groups showed that except for HBsAg negative conversion rate,which had no statistically difference(P>0.05),other indicators were statistically different(P<0.05).The HBeAg negative conversion rate(53.8%),seroconversion rate(33.8%)and mean decrease in HBsAg(1.62±1.15 logIU/ml)in the conventional treatment group were higher than those in the combined treatment group(13.04%,0%,0.41 ± 0.16 lo-gIU/ml)and the sequential treatment group(0%,0%,0.35±0.14 logIU/ml)(P<0.05),while there was no significant statistically difference in the ALT renormalizing rate and HBVDNA negative conversion rate among the three groups(P>0.05).The ALT normalization rate(29.2%)and HBVDNA negative conversion rate(16.7%)in the prolongation treatment group were lower than those in the other two groups(69.6%,66.7%;87.0%,85.2%)(P<0.05),the negative conversion rate of HBeAg(12.5%)and serum conversion rate(12.5%)were higher than those of the other two groups(13.04%,0%;0%,0%)(P<0.05).3.Comparison of the correlation between genotype and efficacy:There was no significant statistically difference in the clinical efficacy of geno-types B and C in each group(P>0.05).4.Analysis of influencing factors of Peg-IFNα-2a treatmentMultivariate logistic regression analysis was performed with age,gender,base-line HBVDNA load,HBV genotype,ALT level and HBsAg level as independent var-iables(X),and whether the response or not(HBVDNA decreased≥1 logcopies/ml by antiviral therapy after 24 weeks)(0=no,1=yes)as dependent variable(Y).The re-sults showed that gender and the HBsAg level before treatment was correlated with the HBV response at 24 weeks of Peg-IFNα-2a treatment,and female gender and HBsAg level≤4 logcopies/ml had higher HBVDNA response(P<0.05).5.Comparison of adverse reactionsThe adverse reactions of Peg-IFNα-2a treatment were compared among the three groups:conventional treatment group,prolonged treatment group and combined treatment group.The results showed that there was no difference in fever,influen-za-like symptoms,leukopenia,thrombocytopenia,fatigue,elevated ALT,alopecia and other adverse reactions among the three groups(P>0.05).139 patients did not have serious adverse reactions leading to discontinue the therapy.ConclusionsFor treatment-naive HBeAg-positive CHB patients,if they are female and the HBsAg level is less than or equal to 4 logIU/ml before treatment,Peg-IFNα-2a anti-viral therapy can be preferred,and individualized treatment can be given according to the HBVDNA response at 24 weeks;if the HBVDNA decline at 24 weeks is more than 1logcopies/ml,the patients can continue the original treatment;If the decrease was less than llogcopies/ml,it was recommended to discontinue Peg-IFNα-2a and replace it with NAs monotherapy for antiviral therapy such as ETV.In this study,no advantage of prolonging the course of Peg-IFNα-2a treatment nor combining NAs regimen was found for patients with HBVDNA decreased by<1 logcopies/ml at 24 weeks,so it was not recommended.Part Ⅱ Efficacy analysis of combined pegylated interferon alfa-2a in the treatment of entecavir-treated patients with chronic hepatitis BObjectivesTo investigate the efficacy of pegylated interferon alfa-2a in the treatment of pa-tients with chronic hepatitis B treated with entecavir;to analyze the influencing fac-tors related to the efficacy.MethodsNinety-five patients with chronic hepatitis B who were virologically negative and HBsAg quantification was<1500 IU/L for more than 6 months of antiviral thera-py with ETV were selected and divided into two groups according to the patient’s wishes:(1)Combination therapy group:a total of 35 patients,combined with Peg-IFNα-2a 180 ug subcutaneous injection once a week on the basis of the origin-al ETV treatment,the treatment lasted for 48 weeks.Symptomatic treatment w as given in case of adverse reactions,or the treatment was discontinued in sev-ere cases.(2)Monotherapy group:60 patients continue to use ETV.In the combination therapy group,two milliliters of blood samples were obtained and separated before treatment,and the plasma supernatant was extracted and stored in the freezer at-20℃.HBV genotypes were measured in all patients,and HBVDNA,ALT,five quantitative items of hepatitis B,blood routine,and thyroid function were measured before treatment and at 12,24,36 and 48 weeks of treatment.The HBsAg quantitative value,negative conversion rate and seroconversion rate were observed at 12 weeks,24 weeks,36 weeks and 48 weeks of treatment;the relat-ed factors of the efficacy of Peg-IFNα-2a combination therapy were analyzed;the ad-verse reactions during treatment were observed and recorded.Statistical methods were used for analysis,and P<0.05 was considered statisti-cally significant.Results1.Baseline characteristics of the two groupsThere were no statistically significant differences in gender,age,ALT level,HBeAg positive proportion,HBsAg quantitative level,and genotype proportion be-tween the two groups(P>0.05),which showed a comparability.2.Comparation of the HBsAg quantitative,HBsAg negative conversion rate at 48 weeks and HBsAg seroconversion rate between the two groups.The quantitative level of HBsAg in the combined treatment group was signifi-cantly lower than that in the single-agent group at 36 weeks and 48 weeks(P<0.05)At 48 weeks,7 patients(20%)had HBsAg seroconversion and 3 patients(8.57%)had HBsAg seroconversion in combination therapy group and there was no HBsAg seroconversion and seroconversion in the monotherapy group.There was a significant difference between the two groups(P<0.05).3.Prediction of curative effect of HBsAg reduction percentage on response to Peg-IFNα-2a combination therapyThe ROC curve was established to analyze the predictive value of the percentage decrease of HBsAg level at 12 weeks,24 weeks and 36 weeks for the efficacy at 48 weeks in 35 patients treated with combination therapy.The results showed that the area under the curve of the decrease percentage of HBsAg at 24 weeks was 0.824(95%CI=0.669～0.999),the optimal Cut-off was 51.52%,the sensitivity was 0.714,and the specificity was 0.893(P<0.05);the area under the curve of the decrease per-centage of HBsAg at 36 weeks was 0.878(95%CI=00.699～1),the optimal Cut-off was 90.22%,the sensitivity was 0.857,and the specificity was 0.929(P<0.05),indi-cating that the decrease of HBsAg level at 24 weeks and 36 weeks was significantly correlated with the HBsAg response at 48 weeks.4 Comparison of adverse reactionsIn the combined treatment group,28 patients(80%)developed fever at an early stage and 25 patients(71.4%)showed decreased counts of white blood cells,neutro-phils and platelets.No adverse reactions occurred in the monotherapy group.There were no discontinuations due to serious adverse effects in either group.ConclusionsFor patients who achieve virological suppression by entecavir and whose HBsAg quantitative level is less than 1500IU/ml,combined with a limited cour-se of Peg-IFNα-2a can significantly improve the HBsAg clearance and serocon version rate;the significant reduction of HBsAg at 24 and 36 weeks post-treat ment could indicate the possibility of HBsAg clearance and identify patients w ho had the greatest chance of success.Part Ⅲ Study on the correlation between CYP27B1-1260 gene polymorphism and the efficacy of pegylated interferon alfa-2a in the treatment of chronic hepatitis BObjectivesTo investigate the correlation between CYP27B1-1260 gene polymorphism and Peg-IFNα-2a monotherapy in the treatment of HBeAg-positive chronic hepatitis B;To investigate the correlation between CYP27B1-1260 gene polymorphism and Peg-IFNα-2a combined treatment of entecavir-treated chronic hepatitis B.MethodsA total of 174 blood samples obtained from patients treated with Peg-IFNα-2a in the first and second parts were used to detect the Cyp27B1-1260A/C polymorphism by polymerase chain reaction-restriction fragment length polymorphism analysis(PCR-RFLP).The efficacy judgment of interferon therapy in the first part of the study popula-tion was divided into three groups:CR,PR,and NR(the same as the first part);the efficacy judgment of patients treated with combination therapy in the second part of the study population was divided into two groups:(1)HBsAg negative group:HBsAg negative,normal liver function,and HBVDNA<103 copies/ml.(2)HBsAg positive group:HBsAg did not turn negative,normal liver function,HBVDNA<103 cop-ies/ml.The above indicators were analyzed by statistical methods,and P<0.05 was considered statistically significant.Results1 Results of study population in part 1Among the CYP27B1-1260 polymorphisms in 139 patients,49 cases(35.3%)were AAs,46 cases(33,1%)were CCs,and 44 cases(31.7%)were ACs.1.1 Association of CYP27B1-1260 polymorphism and HBVDNA response at 24 weeks of Peg-IFN-α-2a treatmentAccording to the different HBV DNA responses at 24 weeks of Peg-IFNα-2a treatment,the study subjects were divided into two groups:the group with significant decrease with the HBVDNA decrease≥1 logcopies/ml and the group with insignifi-cant decrease with the HBVDNA decrease<1 logcopies/ml to determine whether there was a correlation between CYP27B1-1260 polymorphism and HBV DNA re-sponse at 24 weeks.The results showed that the CC type of CYP27B1-1260 gene was statistically different between the two groups,and the frequency of CC type of gene was higher in the group with insignificant HBV DNA decrease at 24 weeks(33.8%)than in the group with significant decrease at 24 weeks(32.3%)(P<0.05).1.2 Analysis of the correlation between CYP27B1-1260 polymorphism and efficacy at 48 weeks of Peg-IFNα-2a treatmentSixty-five patients in the conventional treatment group were analyzed(the other groups were not analyzed due to the small number of cases),and the results showed that the CC type was significantly higher in the proportion of non-responders to Peg-IFN-α-2a treatment(55.0%)than the AA type(20.0%)and AC type(25.0%)(P<0.05).2 Results of study population in part 2Thirty-five CHB patients were selected from the combination therapy group in the second part of the study population,and the CYP27B1-1260 polymorphism results were 11 patients of AA type(31.4%),14 patients of AC type(40.0%),and 10 patients of CC type(28.6%).2.1 Relationship between CYP27B1-1260 Polymorphism and Efficacy of Combina-tion TherapyAccording to statistical analysis,CYP27B1-1260 polymorphism has no correla-tion with the efficacy of combination therapy(P>0.05).2.2 Analysis of influencing factors in combination therapyMultivariate logistic regression analysis was performed with four factors includ-ing age,gender,CYP27B1-1260 gene polymorphism,and HBV genotype as inde-pendent variables(X)and HBsAg negative conversion at 48 weeks of antiviral thera-py(0=none,1=yes)as dependent variables(Y),and the results showed that there were no correlations between the above indicators and HBsAg negative conversion at 48 weeks in combination therapy(P>0.05).ConclusionsCYP27B1-1260 gene polymorphism may be associated with Peg-IFNα-2a treat-ment response,and its CC type may be an influencing factor for poor response to Peg-IFNα-2a treatment in treatment-naive HBeAg-positive chronic hepatitis B.更多还原