失代偿期乙型肝炎肝硬化抗病毒治疗耐药增加肝细胞癌风险研究

Increased incidence of hepatocellular carcinoma due to antiviral drug resistance in patients with hepatitis B-related decompensated cirrhosis

目的分析失代偿期乙型肝炎肝硬化患者队列肝细胞癌(hepatocellular carcinoma,HCC)发生的危险因素及抗病毒方案的优化。方法选择2008年1月—2011年10月随访2年的193例乙型肝炎肝硬化患者队列,包括拉米夫定(LAM)组29例、阿德福韦(ADV)组57例、替比夫定(LDT)组30例、恩替卡韦(ETV)组38例及对照组39例。按HCC发生前是否耐药将接受抗病毒治疗患者分为耐药组(31例)和无耐药组(123例),分析各组Child-Pugh评分、病毒学指标、耐药率、HCC发生率、患者生存率及安全性。结果各抗病毒治疗组在随访2年时Child-Pugh评分较基线均显著下降(P均<0.05);血清HBVDNA水平明显低于基线值,各组HBeAg血清学转换率和HBeAg阴转率差异无统计学意义;ETV组累计2年耐药率低于LAM组、ADV组和LDT组(P均<0.05);抗病毒治疗各组及对照组间累计2年HCC发生率、患者生存率差异无统计学意义,但耐药组HCC发生率明显高于无耐药组和对照组(P均<0.05);在2年随访中各组均未出现严重肌病等不良反应。结论 ETV治疗失代偿期乙型肝炎肝硬化疗效优于其他单药治疗,抗病毒治疗耐药可增加HCC发生风险。

Objective To investigate the risk factors for hepatocellular carcinoma （HCC） in patients with hepatitis B-related decompensated cirrhosis and the optimization of antiviral therapy. Methods Totally 193 patients with hepatitis B-related decompensated cirrhosis treated in our hospital from Jan. 2008 to Oct. 2011, who were followed up for two years, were included in the study, including 29 receiving LAM therapy （LAM group）, 57 receiving ADV therapy （ADV group）, 30 receiving LDT therapy （LDT group）, 38 receiving ETV therapy （ETV group） and 39 not receiving any antiviral therapy （control group）. According to whether drug resistance occurred before being diagnosed with HCC, the patients receiving antiviral therapy were divided into drug-resistant group （n=31） and non-drug-resistant group （n=123）. Child-Pugh scores, virological markers, the incidence of HCC, survival rate and safety were analyzed. Results Child-Pugh scores in each antiviral therapy group significantly decreased at 2-year follow-up, compared with those at baseline （P〈0.05）. HBV DNA level of each antiviral group during 2-year follow-up was significantly lower than that at baseline, and the differences in the rates of HBV DNA undetectable in each group weren＇t significant. HBeAg seroconversion rate and negative conversion rate of each antiviral group during 2-year follow-up were not significandy different. Cumulative drug-resistant rate at 2-year follow-up in ETV group was lower than those in LAM, ADV and LDT groups （P〈0.05）. Cumulative incidence of HCC and survival rates were not significantly different between each antiviral therapy group and the control group. However, the incidence of HCC of drug-resistant group was significantly higher than that of non-drug-resistant group and the control group （P〈0.05）. No adverse reactions such as severe cardiomyopathy were found in each antiviral therapy group during 2-year follow-up. Conclusions The efficacy of ETV therapy is superior to that of LAM, ADV and LDT therapy in patients with hepatitis B-related decompensated cirrhosis, and antiviral drug resistance may increase the incidence of HCC.