肝组织病理学在恩替卡韦治疗慢性乙型肝炎中的预测价值

Predictive value of liver pathologic changes in determining the effectiveness of entecavir treatment for chronic hepatitis B-An analysis of 1 366 cases

目的分析基线肝脏病理改变与恩替卡韦（ETV）疗效之间的关系，探讨基线肝脏病理对抗病毒疗效的预测价值，为慢性乙型肝炎（CHB）个体化精准医疗提供可靠依据。方法回顾性收集1366例自2006年1月至2016年6月在解放军第八十八医院行肝穿刺活检术并应用ETV（口服0．5mg／d）治疗96周以上CHB患者的临床资料，分析基线肝脏病理与治疗48、96周不同应答状态之间的相关性。结果CHB患者行肝组织病理检查，确定其炎症活动度（G）及纤维化程度（S），按不同炎症活动度分级和纤维化分期，各分为4组（G1、G2、G3、C4和S1、S2、S3、S4）。ETV治疗48周时，HBeAg阳性患者G1、G2、G3、G4组的完全应答率分别为26．3％（10／38）、30．9％（121／391）、35．3％（101／286）、44．4％（52／117），差异有统计学意义（X^2=8．510，P〈0．05）；HBeAg阴性患者G1、G2、G3、G4组的完全应答率分别为61．5％（24／39）、80．4％（148／184）、82．4％（201／244）、88．1％（59／67），差异有统计学意义（X^2=12．054，P〈0．05）。延长至96周，各组间差异仍有统计学意义（P〈0．05）。ETV治疗48周时，HBeAg阳性患者S1、S2、S3、S4组的完全应答率分别为39．0％（41／105）、37．8％（127／336）、30．9％（97／314）、24．7％（19／77），呈下降趋势，但差异无统计学意义（X^2=7．765，P〉0．05）；HBeAg阴性患者S1、S2、S3、S4组的完全应答率分别为85．7％（30／35）、84．4％（92／109）、83．9％（162／193）、75．1％（148／197），呈下降趋势，但差异无统计学意义（X^2=6．729，P〉0．05）。但进一步细化分组，当肝脏炎症活动度相同时，随着纤维化程度的加重，无论HBeAg阳性还是阴性，除G1组外，G2、G3、G4组治疗48周完全应答率逐渐下降，差异均有统计学意义（均P〈0．05）；延长至96周，各组间差异仍有统计学意义（均P〈0．05）。结论基线肝脏病理学与ETV抗病毒疗效关系密切，炎症活动度高、纤维化程度低者CHB更易获得应答。基线肝脏炎症活动度和纤维化程度可作为ETV治疗CHB的早期疗效预测指标。

Objective To analyze the relationship between baseline liver pathologic changes and the effectiveness of entecavir（ETV） and investigate the predictive value of baseline liver pathologic changes in determining the effectiveness of ETV, to provide reliable basis for precision medicine in patients with chronic hepatitis B（CHB）. Methods A total of 1 366 cases with CHB were retrospectively recruited who underwent liver biopsy between January 2006 to June 2016 and were treated with ETV over 96 weeks. The relationship between baseline fiver pathologic changes and the antiviral responses to ETV at 48, 96 weeks were compared. Results Liver pathology was employed to make the definite inflammation grade and the fibrosis stage. According to the liver inflammation and fibrosis, patients were divided into 4 groups （ G1, G2, G3, G4 and S1 ,S2,S3, S4 respectively）. The complete response rate of G1 , G2, G3 and G4 after 48 weeks ETV treatment was 26. 3% （ 10/38 ）, 30. 9% （ 121/391 ）, 35.3% （ 101/286 ）, 44. 4% （ 52/117 ） respectively in HBeAg positive patients and was 61.5% （24/39） ,80.4% （148/184） ,82.4% （201/244） ,88. 1% （59/67） respectively in HBeAg negative patients. There was statistical difference in the complete response rates amongliver inflammation grades both in HBeAg positive patients （ X^2 = 8. 510, P 〈 0. 05 ） and in HBeAg negative patients（ X^2 = 12. 054 ,P 〈 0.05 ）respectively. The differences were still statistical significant after 96 weeks ETV treatment （ P 〈 0. 05 ）. The complete response rates of S1, S2, S3 and S4 after 48 weeks ETV treatment were 39. 0% （41/105） ,37.8% （127/336） ,30. 9% （97/314） ,24. 7% （ 19/77）, respectively in HBeAg positive patients and was 85.7% （ 30/35 ）, 84. 4% （ 92/109 ）, 83. 9% （ 162/193 ）, 75. 1% （ 148/197 ） respectively in HBeAg negative patients. Whether HBeAg was positive or not, the rates were in decline but there was no statistical difference in the complete response rates among liver fibrosis stages（ X^2 = 7. 765 ,P 〉 0.05 ;X^2 = 6. 729, P 〉 0.05 ） . The differences were still not statistical significant after 96 weeks ETV treatment （P 〉 0. 05 ）. But after further grouping, whether HBeAg was positive or not, as the degree of fibrosis stage was aggravating, the complete response rate of G2, G3 and G4 after 48 weeks ETV treatment decreased at the same degree of inflammation grade and the differences were statistically significant （P 〈 0.05）. The differences were still statistical significant after 96 weeks ETV treatment （P 〈0. 05）. Conclusions The responses to ETV treatment are closely related with baseline liver pathology. The CHB patients with higher score of inflammation and lower score of fibrosis will have a good response to ETV treatment. The degree of inflammation grades and fibrosis stages can be used as early predictors of ETV treatment for CHB.