核苷(酸)类似物对ALT正常或轻度升高的HBeAg阴性慢性乙型肝炎患者的疗效分析

Therapeutic effect of nucleoside/nucleotide analogues on HBeAg-negative chronic hepatitis B patients with normal or slightly elevated alanine aminotransferase

目的分析核苷/核苷酸类似物(NAs)对丙氨酸氨基转移酶(ALT)正常或轻度升高的HBeAg阴性慢性乙型肝炎(CHB)患者的疗效。方法纳入2018年6月-2021年7月期间淮安市第四人民医院肝病科收治的HBeAg阴性CHB患者102例,其中男性68例,女性34例,年龄(41.7±9.2)岁。根据血清ALT基线水平将纳入病例分为ALT正常组(n=59)和ALT轻度升高组(n=43)[ALT低于2倍正常值上限(ULN)]。比较NAs治疗后两组病毒应答(VR)率、HBV DNA、ALT以及肝脏硬度值(LSM)变化。结果ALT正常组男性比例、ALT、AST及HBV DNA为34例(57.6%)、(25.4±8.0)U/L、(24.2±8.3)U/L及(4.4±1.0)log_(10) IU/mL,分别显著低于ALT轻度升高组[34例(79.1%)、(70.3±17.5)U/L、(52.3±16.2)U/L及(5.2±1.3)log_(10) IU/mL,P<0.05]。正常ALT组VR率在第12、24、36、48、72和96周分别为49.2%(29/59)、66.1%(39/59)、81.4%(48/59)、84.7%(50/59)、93.2%(55/59)及93.2%(55/59),对应的ALT轻度升高组VR率分别为41.9%(18/43)、58.1%(25/43)、69.8%(30/43)、76.7%(33/43)、86.0%(37/43)及95.3%(41/43)。对数秩检验得出两组VR率差异无统计学意义(P>0.05)。NAs抗病毒治疗期间,HBV DNA载量显著降低。ALT正常组在治疗48周和96周后HBV DNA水平分别下降(2.8±1.2)log_(10) IU/mL、(3.7±1.1)log_(10) IU/mL;对应的ALT轻度升高组HBV DNA水平分别下降(3.6±1.5)log_(10) IU/mL、(4.3±1.5)log_(10) IU/mL。两组患者HBV DNA平均下降程度比较差异无统计学意义(P>0.05)。正常ALT组在第12、24、36、48、72和96周时ALT复常率分别为71.2%(42/59)、86.4%(51/59)、91.5%(54/59)、94.9%(56/59)、96.6%(57/59)及96.6%(57/59),对应的ALT轻度升高组ALT复常率分别为53.5%(23/43)、76.7%(33/43)、83.7%(36/43)、88.4%(38/43)、95.3%(41/43)及100%(43/43)。两组ALT复常率比较差异无统计学意义(P>0.05)。有37例ALT正常、轻度升高HBeAg阴性CHB患者在NAs治疗48周时接受FibroScan检查,发现LSM值显著改善[(7.9±3.2)kPa比(6.6±2.9)kPa,P<0.05];NAs治疗96周后对25例患者进行FibroScan检查,结果显示治疗后LSM值显著改善[(8.1±3.3)kPa比(6.2±2.7)kPa,P<0.05]。结论NAs有效抑制了ALT正常或轻度升高的HBeAg阴性CHB患者HBV DNA水平,并改善了肝脏组织学表现。因此,即便是ALT正常的HBeAg阴性CHB也建议行抗病毒治疗。此外ALT正常或轻度升高的HBeAg阴性CHB患者中显著肝纤维化病例并不少见,应该对他们常规进行肝纤维化评估。

Objective To investigate the therapeutic effect of nucleoside/nucleotide analogues(NAs)on hepatitis B e antigen(HBeAg)-negative chronic hepatitis B(CHB)patients with normal or mildly elevated alanine aminotransferase(ALT).Methods A total of 102 HBeAg-negative CHB patients from June 2018 to July 2021 in our hospital were included,including 68 males and 34 females,with an average of(41.7±9.2)years.According to the baseline level of serum ALT,the cases were divided into normal ALT group(n=59)and slightly elevated ALT group(n=43)[ALT lower than 2 times the upper limit of normal value(ULN)].The changes of viral response(VR)rate,hepatitis B virus(HBV)DNA,ALT and liver hardness(LSM)were compared between the 2 groups after NAs treatment.Results The male ratio,ALT,aspartate aminotransferase(AST)and HBV DNA in normal group were 57.6%,(25.4±8.0)U/L,(24.2±8.3)U/L and(4.4±1.0)log_(10) IU/mL,which were significantly lower than those in mildly elevated ALT group[79.1%,(70.3±17.5)U/L,(52.3±16.2)U/L and(5.2±1.3)log_(10) IU/mL,P<0.05].The VR rates of normal ALT group were 49.2%(29/59),66.1%(39/59),81.4%(48/59),84.7%(50/59)and 93.2%(55/59)at the 12th,24th,36th,48th,72nd and 96th week respectively.The corresponding VR rates in the group with mild elevation of ALT were 41.9%(18/43),58.1%(25/43),69.8%(30/43),76.7%(33/43),86.0%(37/43)and 95.3%(41/43).Logarithmic rank test showed that there was no significant difference in VR rate between the 2 groups(P>0.05).HBV DNA load decreased significantly during NAs antiviral treatment.In the normal group,after 48 weeks and 96 weeks of treatment,the average level of HBV DNA decreased by(2.8±1.2)log_(10) IU/mL and(3.7±1.1)log_(10) IU/mL.The level of HBV DNA in the group with slight elevation of ALT decreased(3.6±1.5)log_(10) IU/mL and(4.3±1.5)log_(10) IU/mL on average.There was no significant difference in the average decline of HBV DNA between the 2 groups(P>0.05).At the 12th,24th,36th,48th,72nd and 96th week,the normal group's ALT normalization rates were 71.2%(42/59),86.4%(51/59),91.5%(54/59),94.9%(56/59)and 96.6%(57/59),respectively.The ALT normalization rates of the corresponding mildly elevated ALT group were 53.5%(23/43),76.7%(33/43),83.7%(36/43),88.4%(38/43),95.3%(41/43)and 100%(43/43).There was no significant difference in the normalization rate of ALT between the 2 groups(P>0.05).Thirty-seven HBeAg-negative CHB patients with normal ALT and slightly elevated ALT were examined by FibroScan at 48 weeks after NAs treatment,and LSM was significantly improved[(7.9±3.2)kPa compared with(6.6±2.9)kPa,P<0.05];FibroScan examination was performed in 25 patients after 96 weeks of NAs treatment,which showed that LSM value was significantly improved after treatment[(8.1±3.3)kPa vs(6.2±2.7)kPa,P<0.05].Conclusion NAs effectively inhibited the HBV DNA level of HBeAg-negative CHB patients with normal or slightly elevated ALT,and improved the liver histology.Therefore,even HBeAg-negative CHB cases with normal ALT are recommended for antiviral treatment.In addition,significant liver fibrosis is not uncommon in HBeAg-negative CHB patients with normal or mildly elevated ALT,and they should be routinely evaluated for liver fibrosis such as FibroScan.