肝硬化患者HBV rtA181T突变与肝癌发生相关分析

Analysis on rt A181T mutant in HBV related and hepatocellular carcinoma in patients with liver cirrhosis

目的研究HBV相关肝硬化患者核苷(酸)类似物(NUCs)治疗过程中,HCC发生与HBV P区耐药突变模式及患者治疗方案的关系,为评估HCC发生风险,指导HBV相关肝硬化抗病毒治疗提供帮助。方法回顾性分析2012年5月至2014年5月青岛市传染病医院收治的79例基线(治疗前)为HBV相关肝硬化患者,既往服用NUCs出现疗效不佳或病毒学突破,此次住院采用焦磷酸测序检测到HBV P区耐药突变患者的临床资料,根据有无进展为HCC将病例分为肝癌组和对照组,比较两组间在基线肝硬化水平(代偿期/失代偿期)、基线HBV DNA、基线ALT、基线AST、性别、年龄、HBs Ag、HBe Ag、AFP及耐药突变模式等方面的差异。根据既往初始用药,分析初始服用阿德福韦酯(ADV)患者与初始服用拉米夫定(LAM)患者在HCC发生和病毒突变模式上的差异。结果 79例患者中,有10例进展为HCC。肝癌组患者平均年龄[(58.30±6.40)岁]大于对照组[(51.64±7.69)岁](t=2.609,P=0.011);肝癌组患者平均AFP水平[(566.24±563.79)ng/ml]大于对照组[(17.32±77.04)ng/ml](t=-7.879,P=0.000);肝癌组出现rt A181T突变的比例(70.0%)、年龄>50岁患者的比例(100.0%)均显著高于对照组(分别为24.6%、52.2%)(χ2=6.488,P=0.011;χ2=6.365,P=0.012)。初始服用ADV出现疗效不佳或病毒学突破患者HCC发生率(23.7%)显著大于初始服用LAM出现疗效不佳或病毒学突破患者(2.8%)(χ2=5.240,P=0.022)。结论 HBV相关肝硬化患者NUCs治疗过程中,HBV rt A181T突变可能与HCC的发生有关;年龄>50岁的HBV相关肝硬化患者,服用ADV出现疗效不佳或病毒学突破,需进行HBV P区耐药突变检测,并密切监测HCC发生;肝硬化患者初始服用ADV发生耐药突变较初始服用LAM发生耐药突变可能更容易进展为HCC。

Objective During hepatitis B virus-related cirrhosis patients with nucleos（t） ide analogues（NUCs） treatment, to investigate the relationship between hepatocellular carcinoma（HCC） with hepatitis B virus（HBV） mutations and patient initial taking NUCs. Methods The clinical data of 79 patients with baseline for HBV related liver cirrhosis, who experienced poor efficacy or virological breakthrough during NUCs treatment and genotyped by pyroscquencing for 9 mutation sites in the HBV P gene that have been previously correlated to NUC efficacy, were analyzed, retrospectively. Analysis of patients with previous drug use, drug-resistant mutation patterns. According to HCC occurred, we divided 79 patients into two groups to compare the differences in cirrhosis at baseline levels（compensated/decompensated）, baseline HBV DNA, baseline alanine aminotransferase（ALT）, baseline aspartate aminotransferase（AST）, sex, age, HBs Ag, HBe Ag and resistance mutation patterns and other aspects of comparison, respectively. According to previous initial application LAM or ADV, patients were divided into two groups to compare the differences in HCC patients and virus mutation patterns, respectively. Results HCC patients were found in 12.66%（10/79） of the 79 patients. The average age of HCC group was older than that of liver cirrhosis（LC） group [（58.30 ± 6.40） years old vs.（51.64 ± 7.69） years old; t = 2.609, P = 0.011]. The serum AFP level at HCC group was higher than that at LC group [（566.24 ± 563.79） ng/ml vs.（17.32 ± 77.04） ng/ml; t =-7.879, P = 0.000]. The presence of rt A181 T mutation and age 50 years occurred more frequently in HCC group（70.0%, 100.0%） than those in LC group（24.6%, 52.2%）（χ2 = 6.488, P = 0.011; χ2 = 6.365, P = 0.012）, respectively. The initial taking ADV or LAM patients were found in 48.10%（38/79） or 45.57%（36/79） of the 79 patients, respectively. HCC occurred more frequently in the initial taking ADV group（23.7%） than that in the initial taking LAM group（2.8%）（χ2 = 5.240, P = 0.022）. Conclusions During HBV-related cirrhosis patients with NUCs treatment, emergence of the rt A181 T mutant might be associated with occurrence of HCC. HBVrelated cirrhosis patients who are older than 50 years old and initial taking ADV poor efficacy or virologic breakthrough occurs, needed to detect HBV P gene mutation and close follow-up of HCC development in the subsequent courses of antiviral therapy. An initial dose of ADV-resistant mutation in patients with cirrhosis compared with an initial dose of LAM-resistant mutation may be more likely to progress to HCC.