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

摘要/Abstract

摘要： 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)log₁₀ 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)log₁₀ 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)log₁₀ IU/mL、(3.7±1.1)log₁₀ IU/mL;对应的ALT轻度升高组HBV DNA水平分别下降(3.6±1.5)log₁₀ IU/mL、(4.3±1.5)log₁₀ 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。

关键词: 慢性乙型肝炎, 乙型肝炎e抗原, 核苷/核苷酸类似物, 丙氨酸氨基转移酶, 肝脏硬度值

Abstract: 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) log₁₀ 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) log₁₀ 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) log₁₀ IU/mL and (3.7±1.1) log₁₀ IU/mL. The level of HBV DNA in the group with slight elevation of ALT decreased (3.6±1.5) log₁₀IU/mL and (4.3±1.5) log₁₀IU/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.

Key words: Chronic hepatitis B, Hepatits B e antigen, Nucleoside/nucleotide analogues, Alanine aminotransferase, Liver stiffness measurement

曹晶晶, 李荣, 李晶, 潘峰. 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[J]. 肝脏, 2023, 28(4): 432-435.

CAO Jing-jing, LI Rong, LI Jing, PAN Feng. Therapeutic effect of nucleoside/nucleotide analogues on HBeAg-negative chronic hepatitis B patients with normal or slightly elevated alanine aminotransferase[J]. Chinese Hepatolgy, 2023, 28(4): 432-435.

参考文献

[1] European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol, 2017, 67(2):370-398.
[2] Yuan J, Zhou B, Tanaka Y, et al. Hepatitis B virus (HBV) genotypes/subgenotypes in China: mutations in core promoter and precore/core and their clinical implications. J Clin Virol, 2007, 39(2):87-93.
[3] Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology, 2018, 67(4):1560-1599.
[4] Sarin SK, Kumar M, Lau GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int, 2016, 10(1):1-98.
[5] Liao B, Wang Z, Lin S, et al. Significant fibrosis is not rare in Chinese chronic hepatitis B patients with persistent normal ALT. PLoS One, 2013, 8(10):e78672.
[6] Zhao Q, Liu K, Zhu X, et al. Anti-viral effect in chronic hepatitis B patients with normal or mildly elevated alanine aminotransferase. Antiviral Res, 2020, 184:104953.
[7] Su SY. The impact of national viral hepatitis therapy program and hepatitis B vaccination program on mortality from acute and chronic viral hepatitis in Taiwan. Hepatol Int, 2019, 13(2):157-164.
[8] Liu Y, Liu H, Hu Z, et al. Hepatitis B virus virions produced under nucleos(t)ide analogue treatment are mainly not infectious because of irreversible DNA chain termination. Hepatology, 2020, 71(2):463-476.
[9] Sun Y, Wu X, Zhou J, et al. Persistent low level of hepatitis B virus promotes fibrosis progression during therapy. Clin Gastroenterol Hepatol, 2020, 18(11):2582-2591.e6.
[10] Liu C, Wang L, Xie H, et al. The relationship between serum hepatitis B virus DNA level and liver histology in patients with chronic HBV infection. PLoS One, 2018, 13(11):e0206060.
[11] Li Q, Chen L, Zhou Y. Diagnostic accuracy of liver stiffness measurement in chronic hepatitis B patients with normal or mildly elevated alanine transaminase levels. Sci Rep, 2018, 8(1):5224.
[12] Goyal R, Mallick SR, Mahanta M, et al. Fibroscan can avoid liver biopsy in Indian patients with chronic hepatitis B. J Gastroenterol Hepatol, 2013, 28(11):1738-1745.
[13] Fung J, Lai CL, Fong DY, et al. Correlation of liver biochemistry with liver stiffness in chronic hepatitis B and development of a predictive model for liver fibrosis. Liver Int, 2008, 28(10):1408-1416.
[14] Du X, Wang J, Shao L, et al. Histological improvement of long-term antiviral therapy in chronic hepatitis B patients with persistently normal alanine aminotransferase levels. J Viral Hepat, 2013, 20(5):328-335.
[15] Yan JY, Li ZQ, Yu ZJ, et al. Management of individuals with chronic hepatitis B virus infection and persistent normal or mildly elevated aminotransferase levels. J Cell Biochem, 2019, 120(4):6632-6641.