低水平乙型肝炎病毒表面抗原核苷类似物经治患者序贯α干扰素治疗的初步研究

Preliminary study on the efficacy of sequential therapy with nucleotide analogues followed by interferon alpha in chronic hepatitis B patients with low HBsAg level

目的观察经核苷(酸)类似物(NA)治疗获得病毒学应答,且HBsAg低水平的HBeAg阴性慢性乙型肝炎(CHB)患者序贯α干扰素(IFNα)治疗的疗效,并探讨HBsAg消失的相关因素。方法长期接受NA治疗并获得病毒学应答(HBV-DNA<1000拷贝/mL,持续时间>12个月),且HBsAg低水平(HBsAg≤2 000 U/mL)的HBeAg阴性CHB患者,转为IFNα治疗48周。检测患者治疗前和治疗12、24、48周时血清HBV-DNA定量,HBV血清学标志物,肝功能和血常规,停药后随访24周。以HBsAg消失或血清学转换、HBsAg<10 U/mL为疗效评价指标。Logistic回归用于分析相关因素,受试者工作特征曲线(ROC曲线)用于确定HBeAg阴转史及HBsAg变化情况对治疗后HBsAg消失的预测价值。结果 83例患者被纳入研究。停药24周时,15例(18.1%)获得HBsAg消失,5例(6.0%)获得HBsAg血清学转换,9例(10.8%)达到HBsAg<10 U/mL。HBsAg消失组中HBeAg自发阴转的患者比例高于HBsAg未消失组,差异有统计学意义(χ~2=9.527,P=0.002)。治疗12周时HBsAg水平较基线下降≥0.5 log U/mL者治疗后更易实现HBsAg消失(χ~2=16.576,P<0.001),其预测HBsAg消失的曲线下面积(AUC)为0.810(95%CI:0.686~0.935,P<0.001)。结论经NA治疗获得病毒学应答,且HBsAg低水平的HBeAg阴性CHB患者,序贯IFNα治疗可获得较高HBsAg消失率;HBeAg阴转史及治疗早期HBsAg变化情况可用于预测及指导治疗。

Objective To investigate the efficacy of interferon alpha （IFNα） followed by nucleotide analogues （NAs） treatment in patients with negative hepatitis B e antigen （HBeAg）, undetectable serum HBV-DNA and low hepatitis B surface antigen （HBsAg） levels. Methods The enrolled HBeAg-negative chronic hepatitis B patients had undetectable HBV-DNA level （HBV-DNA〈 1 000 copies/mL for at least 12 months） and low HBsAg level （HBsAg≤2 000 U/mL） with long-term NAs treatment. These patients switched their therapy sequentially from NAs regimens to IFNu for 48 weeks. The treatment response was evaluated in terms of serum HBV DNA load, serological HBV markers, liver fimction tests and routine blood test before treatment and 12, 24 and 48 weeks of treatment. The patients were followed up for 24 weeks after treatment. The primary endpoint was HBsAg loss or seroconversion and HBsAg〈 10 U/mL. Logistic regression analysis was conducted to examine relevant predictive factors. Receiver operating characteristic curve was used to evaluate the value of prior HBeAg seroconversion and on-treatment HBsAg dynamics in predicting HBsAg loss. Results A total of 83 patients were included in the study. At 24 weeks after the end of treatment, HBsAg loss was found in 15 （18.1%） patients, HBsAg seroconversion in 5 （6.0 %） patients, and HBsAg〈 10 U/mL in 9 （10.8 %） patients. More patients in HBsAg loss group showed spontaneous HBeAg seroconversion than in HBsAg persistence group （X^2=9.527, P=0.002）. HBsAg loss was more likely in the patients who had HBsAg decline at least 0.5 log U/mL from baseline at week 12 of treatment （X^2=16.576, P〈0.001）. The area under the ROC curve for prediction of HBsAg loss was 0.810 （95% CI, 0.686 to 0.935, P〈0.001）. Conclusions The HBeAg-negative chronic hepatitis B patients with positive virological response and low HBsAg level after NAs treatment are more likely to achieve HBsAg clearance when switched to 1FNet treatment. Prior HBeAg seroconversion and on-treatment HBsAg dynamics are useful in predicting and guiding IFNct sequential therapy.