Objective: To compare the efficacy and safety of different antiviral and antifibrotic regimens in patients with chronic hepatitis B (CHB) and hepatic fibrosis and the incidence of hepatocellular carcinoma (HCC) associated with these therapies.
Methods: A total of 840 patients with CHB and concurrent hepatic fibrosis, who received antiviral therapy in Nanfang Hospital between June, 2010 and June, 2018, were enrolled in this follow-up cohort study. The patients were assigned to 3 cohorts matched for gender, age (difference≤5 years), HBeAg status and liver stiffness measurement (LSM) for treatment with one of the 3 antiviral drugs, namely entecavir, tenofovir dipivoxil and adefovir dipivoxil; each cohort was divided into 2 groups, with one of the groups having a combined treatment with Fufang Biejiaruangan tablet. The cumulative negative conversion rate of HBV DNA, normalization rate of ALT, hepatic fibrosis regression and the incidence of HCC were compared among the 3 cohorts and across the 6 groups at 144 weeks.
Results: A total of 749 patients were available to follow-up at 144 weeks. Compared with the baseline data, the cumulative negative conversion rate of HBV DNA increased gradually and the abnormal rate of ALT decreased significantly over time during the treatment in all the 6 groups (all P < 0.001). Compared with the any of the antiviral drugs used alone, the combined treatments all resulted in significantly better antifibrotic effects (χETV cohort2=11.345, χTDF cohort2=10.160, χADV cohort2=6.358; all P < 0.05). At 144 weeks, the incidence of HCC were 2.2%, 1.7%, 1.7% and 3.3% in enecavir group, enecavir with Biejiaruangan tablet group, adefovir group, and adefovir with Biejiaruangan tablet group, respectively, showing no significant difference between the two cohorts (4 groups; χ2=6.813, P=0.138). None of the patients in the 2 groups with tenofovir treatment had HCC by the end of the observation.
Conclusions: Antiviral therapy combined with antifibrotic therapy can effectively reverse hepatic fibrosis and reduce the incidence of HCC in patients with CHB; among the 3 antiviral drugs, tenofovir dipivoxil can be a better option for reducing the incidence of HCC in these patients.
目的: 比较不同抗病毒和抗肝纤维化联合方案治疗慢性乙型肝炎（CHB）-肝纤维化的疗效、安全性及肝细胞癌（HCC）的发生率。
方法: 2010年6月~2018年6月在南方医科大学南方医院接受抗病毒治疗的CHB肝纤维化患者840例构成随访队列。性别、年龄（相差≤5岁）、HBeAg状态、肝脏硬度值测定（LSM）基本匹配后按1:1分别进入3个队列的单用抗病毒药组（恩替卡韦、替诺福韦酯及阿德福韦酯3个抗病毒药，为对照组）和联合用药组（3个抗病毒药分别与复方鳖甲软肝片组联合，为观察组）。比较3个队列6组患者各随访时间点HBV DNA累积转阴率、丙氨酸转氨酶复常率、肝纤维化逆转程度及HCC的发生率等。
结果: 随访满144周纳入分析的病例共749例。随着治疗时间的延长，与基线时比较，6组患者的HBV DNA累积转阴率均逐渐增加（均P < 0.001）；丙氨酸转氨酶复常率也随着治疗时间的延长而逐渐升高（均P < 0.001）。联合用药组均比单用药组显示出更好的逆转肝纤维化效果（χETV队列2=11.345，χTDF队列2=10.160，χADV队列2=6.358，均P < 0.05）。观察到144周访视点，单用恩替卡韦组、恩替卡韦联合复方鳖甲软肝片组、单用阿德福韦酯组以及阿德福韦酯联合复方鳖甲软肝片组的HCC发生率分别为2.2%、1.7%、1.7%、3.3%，替诺福韦酯队列的2组均无HCC病例发生，各组间的差别无统计学意义（χ2=6.813，P=0.138）；与文献报道的未抗病毒治疗的CHB随访3年7.2%的HCC发生率比较，本研究3年积累HCC发生率（1.3%，P < 0.05）明显较低。
结论: 抗病毒联合抗纤维化治疗能有效逆转CHB-肝纤维化，降低HCC发生率；替诺福韦酯可能在降低HCC发生方面更有优势。
Keywords: anti-fibrosis; anti-viral; chronic; hepatitis B; hepatocellular carcinoma; liver fibrosis.