阿德福韦酯联合恩替卡韦对拉米夫定耐药失代偿期乙型肝炎肝硬化患者肝功能及细胞免疫功能的影响分析

The effect of the combination of Adefovir dipivoxil and Entecavir on the liver function and cellular immune function of Lamivudine-resistant hepatitis B patients with decompensated cirrhosis

目的分析阿德福韦酯联合恩替卡韦治疗拉米夫定耐药的失代偿期乙型肝炎肝硬化的疗效,并观察其对患者肝功能及细胞免疫功能的影响。方法选取2014年7月至2016年7月本院收治的76例对拉米夫定耐药的失代偿期乙型肝炎肝硬化患者为研究对象,将患者依就诊顺序按随机数表法分为试验组和对照组,每组各38例。试验组患者采用阿德福韦酯联合恩替卡韦治疗,对照组患者采用阿德福韦酯单药治疗。分别于治疗前及治疗3、6、12个月后检测患者谷丙转氨酶(alanine aminotransferase,ALT)、谷草转氨酶(aspartate transaminase,AST)、总胆红素(total bilirubin,TBIL)、血尿素氮(blood urea nitrogen,BUN)及血肌酐水平;采用荧光定量聚合酶链反应检测血清HBV-DNA水平;采用酶联免疫吸附测定检测血清乙型肝炎E抗原(hepatitis Be antigen,HBe Ag)、抗HBe、白介素(interleukin,IL)-10及IL-17水平;采用流式细胞术检测外周血CD4^+、CD8^+T淋巴细胞水平及CD4^+/CD8^+比值。结果治疗后两组患者血清ALT、AST、TBIL水平及肝功能Child-Pugh评分均显著低于治疗前(P<0.05);治疗3、6及12个月后,试验组患者血清ALT、AST、TBIL水平均显著低于对照组(P<0.05);治疗3个月和6个月后,试验组患者肝功能Child-Pugh评分均显著低于对照组(P<0.05)。两组患者治疗后血肌酐和BUN水平均显著高于治疗前,但差异无显著性(P>0.05)。治疗后观察组患者血清HBV-DNA转阴率和HBe Ag转阴率均显著高于对照组(P<0.05),两组患者HBe Ag/抗HBe转换率比较无显著差异(P>0.05)。治疗12个月后两组患者血清CD4^+T细胞水平和CD4^+/CD8^+比值均显著高于治疗前(P<0.05),CD8^+T细胞水平显著低于治疗前(P<0.05)。治疗12个月后,试验组患者血清CD4^+T细胞水平和CD4^+/CD8^+比值均显著高于对照组(P<0.05),CD8^+T细胞水平显著低于对照组(P<0.05)。与治疗前相比,治疗后两组患者血清IL-10和IL-17水平均逐渐降低;治疗3个月后开始,IL-10水平与治疗前比较有显著差异(P<0.05);治疗6个月后开始,IL-17水平与治疗前比较有显著差异(P<0.05)。治疗6个月和12个月后,试验组患者血清IL-10水平低于对照组(P<0.05);治疗3个月和6个月后,试验组患者血清IL-17水平低于对照组,但无显著差异(P>0.05);直至治疗12个月后,IL-17水平显著低于对照组(P<0.05)。结论与单用恩替卡韦相比,阿德福韦酯联合恩替卡韦能够更好地改善拉米夫定耐药的失代偿期乙型肝炎肝硬化患者的肝功能,调节外周血T淋巴细胞亚群平衡,减轻肝脏炎性反应和纤维化反应。

ObjectiveTo explore the therapeutic effect of the combination of Adefovir dipivoxil and Entecavir in the treatment of Lamivudine-resistant hepatitis B decompensated cirrhosis, and observe the in？uence on the liver function and cellular immune function. Method76 patients with Lamivudine-resistant hepatitis B decompensated cirrhosis from July 2014 to July 2016 in our hospital were enrolled in the study. According to the order of treatment, the patients were randomly divided into experimental group and control group, 38 cases in each group. Experiment group patients were treated with Adefovir dipivoxil combined with Entecavir, and control group patients were treated with Adefovir dipivoxil alone. The serum level of alanine aminotransferase （ALT）, aspartate transaminase （AST）, total bilirubin （TBIL）, blood urea nitrogen （BUN） and serum creatinine （Scr） were tested before treatment and 3, 6 and 12 months after treatment; HBV-DNA was quantified by PCR; the HBe, anti-HBe, interleukin （IL）-10 and IL-17 levels were assessed by ELISA; the peripheral CD4＋ and CD8＋T lymphocyte and CD4＋/CD8＋ ratio were tested by flow cytometry assay. ResultAfter treatment, two groups of patients with serum ALT, AST, TBIL levels and Child-Pugh score of liver function were signi？cantly lower than those before treatment （P 〈 0.05）; 3, 6 and 12 months after treatment, serum ALT, AST and TBIL levels of experimental group were signi？cantly lower than control group （P 〈 0.05）; 3 months and 6 months after treatment, Child-Pugh scores of liver function in experimental group were signi？cantly lower than control group （P〈 0.05）. The levels of BUN and Scr in the two groups was significantly higher than that before treatment, but the differences were not significant （P 〉 0.05）. After treatment, the serum HBV-DNA negative rate and HBeAg negative rate of experimental group were signi？cantly higher than control group （P〈0.05）. There was no signi？cant di？erence in the HBeAg/anti-HBe conversion rate between the two groups （P〉0.05）. 12 months after treatment, the serum CD4＋T cell level and CD4＋/CD8＋ ratio in the two groups were signi？cantly higher than those before treatment （P〈0.05）, and the level of CD8＋T cells was signi？cantly lower than that before treatment （P〈0.05）. 12 months after treatment,the serum CD4 T cell level and CD4 /CD8 ratio in experimental group were signi？cantly higher than control group （P 〈 0.05）, and the level of CD8＋T cells was signi？cantly lower than control group （P 〈 0.05）. The serum IL-10 and IL-17 levels in both groups were gradually decreased compared with those before treatment. 3 months after treatment, the level of IL-10 was signi？cantly di？erent from before treatment （P 〈 0.05）. 6 months after treatment, the level of IL-17 was signi？cantly di？erent from before treatment （P 〈 0.05）. 6 months and 12 months after treatment, serum IL-10 level in experimental group was lower than control group （P 〈 0.05）. 3 months and 6 months after treatment, serum IL-17 level in experimental group was lower than control group, but no signi？cant di？erence （P 〉0.05）. 12 months after treatment, the level of IL-17 in experimental group was significantly lower than control group （P 〈 0.05）. ConclusionCompared with Adefovir dipivoxil alone, Adefovir dipivoxil combined with Entecavir can better improve the liver function of patients with Lamivudine-resistant hepatitis B decompensated cirrhosis, regulate the balance of peripheral blood T lymphocyte subsets and the inflammatory reaction and ？brosis reaction of liver.