慢性乙型肝炎核苷(酸)类似物经治患者序贯联合干扰素治疗达临床治愈的早期预测因素分析

Early predictors for clinical cure by sequential combined interferon therapy in nucleos(t)ide analogues experienced patients with chronic hepatitis B

目的探索慢性乙型肝炎(chronic hepatitis B,CHB)核苷(酸)类似物[nucleos(t)ide analogues,NAs]经治患者序贯联合干扰素治疗达临床治愈的早期预测因素。方法纳入2016年6月至2019年9月中山大学附属第三医院收治的NAs经治1年及以上、乙型肝炎表面抗原(hepatitis B surface antigen,HBsAg)≤1500 IU/mL、乙型肝炎e抗原阴性、乙型肝炎病毒(hepatitis B virus,HBV)DNA<100 IU/mL的CHB患者。根据治疗方案分为干扰素单用治疗48周组(A组);干扰素联合NAs治疗12周后停用干扰素,继续NAs治疗至48周组(B组);干扰素联合NAs治疗48周组(C组)。收集患者年龄、性别等基本资料,分析48周临床治愈率,监测治疗4、8、12、24、36、48周时HBsAg、乙型肝炎表面抗体(hepatitis B surface antibody,抗-HBs)、丙氨酸转氨酶(alanine aminotransferase,ALT)的变化及HBsAg较基线的下降幅度。统计学分析采用独立样本t检验、χ^(2)检验和秩和检验。采用logistic回归分析48周达临床治愈的早期预测指标。结果规律随访至少5次的CHB患者共1020例,A、B、C组48周临床治愈率分别为34.6%(157/454)、32.7%(69/211)和33.5%(119/355),差异无统计学意义(χ^(2)=0.25,P=0.883)。根据48周临床治愈情况将患者分为治愈组345例和未治愈组675例,治愈组患者的年龄[(38±13)岁比(43±12)岁]、基线HBsAg[131.00(359.80)IU/mL比437.60(531.50)IU/mL]、男性患者比例[81.7%(282/345)比89.5%(604/675)]均低于未治愈组,差异均有统计学意义(t=6.32,Z=12.67,χ^(2)=11.99;均P<0.050)。212例(61.45%)治愈组患者在治疗24周内达临床治愈。治疗4周时HBsAg较基线下降者的48周临床治愈率高于较基线上升组[41.6%(149/358)比28.2%(108/383)],差异有统计学意义(χ^(2)=14.13,P<0.001)。治疗12周时HBsAg下降幅度≤基线的34.03%的患者的48周临床治愈率仅为6.9%(13/188)。多因素logistic回归分析发现,年龄[比值比(odds ratio,OR)=0.962,95%可信区间(confidence interval,CI)0.936~0.989,P=0.006]、治疗24周HBsAg水平(OR=0.950,95%CI 0.934~0.966,P<0.001)、治疗24周抗-HBs水平(OR=1.012,95%CI 1.005~1.019,P=0.001)是NAs经治CHB患者治疗48周达临床治愈的早期预测因素。结论NAs经治CHB患者序贯联合干扰素治疗达临床治愈多发生在治疗早期(治疗24周内),其中年龄、治疗24周HBsAg水平、治疗24周抗-HBs水平可成为治疗48周达临床治愈的早期预测指标。

Objective To explore the early predictors for clinical cure by sequential combined interferon therapy in nucleos(t)ide analogues(NAs)experienced patients with chronic hepatitis B(CHB).Methods CHB patients received NAs treatment≥one year with hepatitis B surface antigen(HBsAg)≤1500 IU/mL,hepatitis B e antigen(HBeAg)negative and hepatitis B virus(HBV)DNA<100 IU/mL in the Third Affiliated Hospital of Sun Yat-sen University from June 2016 to September 2019 were included.According to the different treatment regimens,the patients were divided into interferon alone for 48 weeks group(group A),interferon combined with NAs for 12 weeks and continued NAs treatment for 48 weeks group(group B),interferon combined with NAs for 48 weeks group(group C).Basic data such as age and gender of patients were collected.HBsAg,hepatitis B surface antibody(anti-HBs)and alanine aminotransferase(ALT)were monitored at week 4,8,12,24,36 and 48.The decline of HBsAg from baseline,and the rates of clinical cure at 48 weeks were analyzed.The independent sample t test,chi-square test and rank sum test were used for statistical analysis.Logistic regression analysis was used to achieve the early prediction index of clinical cure at week 48.Results A total of 1020 CHB patients were followed up regularly for at least five time points.The rates of clinical cure at week 48 in group A,B and C were 34.6%(157/454),32.7%(69/211)and 33.5%(119/355),respectively,with no statistical significance(χ^(2)=0.25,P=0.883).Patients were divided into the cured group(345 cases)and the uncured group(675 cases)according to the clinical outcomes at week 48.The age((38±13)years old vs(43±12)years old),baseline HBsAg(131.00(359.80)IU/mL vs 437.60(531.50)IU/mL)and the proportion of male patients(81.7%(282/345)vs 89.5%(604/675))of patients in the cured group were all lower than those of patients in the uncured group.The differences were all statistically significant(t=6.32,Z=12.67,χ^(2)=11.99,respectively,all P<0.050).There were 212 patients in the cured group who achieved clinical cure within 24 weeks of treatment.The rate of clinical cure at 48 weeks in patients whose HBsAg at week 4 decreased from baseline was higher than that in patients with increased HBsAg(41.6%(149/358)vs 28.2%(108/383)).The difference was statistically significant(χ^(2)=14.13,P<0.001).The rate of clinical cure at week 48 in patients with HBsAg at week 12 decreased≤34.03% of baseline was only 6.9%(13/188).Multivariate logistic regression analysis showed that age(odds ratio(OR)=0.962,95%confidence interval(CI)0.936 to 0.989,P=0.006),HBsAg level at week 24(OR=0.950,95%CI 0.934 to 0.966,P<0.001)and anti-HBs level at week 24(OR=1.012,95%CI 1.005 to 1.019,P=0.001)were early predictors for clinical cure at week 48 of treatment in NAs experienced CHB patients.Conclusions Clinical cure of NAs experienced CHB patients received sequential combined interferon therapy mostly occurs in the early stage(within 24 weeks).Age,HBsAg level at week 24,and anti-HBs level at week 24 are early predictors for clinical cure of 48-week sequential combined interferon treatment.