【作者】 李楠；

【导师】 辛桂杰；

【作者基本信息】 吉林大学 ， 临床医学硕士（专业学位）， 2024， 硕士

【摘要】 目的:丙型肝炎病毒（Hepatitis C virus,HCV）的慢性感染是导致原发性肝癌（Primary liver cancer,PLC）的主要原因之一,获得SVR可显著降低PLC的发生率。慢性HCV感染者经直接抗病毒药物（Direct antiviral agents,DAA）治疗后可获得很好的持续病毒学应答（Sustained virological response,SVR）,但临床上观察到获得SVR的部分HCV感染者仍有发展为PLC的风险。本研究回顾性分析DAA治疗获得SVR和未经抗病毒治疗的HCV相关PLC（首次诊断）患者的临床资料和随访资料,为临床丙肝患者随访及治疗提供一定参考。方法:收集2015年1月1日至2022年12月31日于吉林大学第一医院肝胆胰内科住院并经过全院原发性肝癌多学科会诊的首次诊断为HCV相关PLC患者585例,根据纳入排除标准采集患者的临床资料并随访其生存时间（阳性事件为死亡,截止至2023年12月31日）,最终确定338例HCV相关PLC患者为研究对象,分为经DAA治疗获得SVR组（n=68）和未治疗组（n=270）。采用Kaplan-Meier曲线、Log-Rank检验分析比较两组患者的生存期,通过Cox回归分析探索HCV相关PLC死亡的危险因素,并通过倾向性评分匹配（Propensity score matching,PSM）进一步分析DAA治疗获得SVR对HCV相关PLC预后的影响。结果:1.HCV相关PLC患者的人口学特征:纳入研究的338例HCV相关PLC,平均年龄（64.75±8.02）岁,男性200例,女性138例（1.45:1）,肝功能Child-Pugh分级A级占比最多160例（47.3%）;BCLC A期占比最多144例（42.6%）;PLC接受根治性治疗（手术切除、局部消融、肝移植）有135例（39.9%）。2.338例HCV相关PLC患者分为DAA治疗组（n=68）和未治疗组（n=270）,治疗组相比于未治疗组AST、ALT、GGT、ALP、TBil、DBil、TBA、APRI水平较低,Ach E、ALB、Cl^-、Ca²⁺、TC、LDL-C水平较高（P<0.05）。治疗组肝功能Child-Pugh分级A级39例（57.4%）、BCLC分期0期15例（22.1%）、单发肿瘤44例（64.7%）、肿瘤最大直径<5cm 53例（77.9%）、接受根治性治疗40例（58.8%）,构成比均高于未治疗组（P<0.05）。3.在DAA治疗组和未治疗组的生存分析中,治疗组中位生存期65.0个月（95%CI:28.6-101.4）,未治疗组中位生存期26.0个月（95%CI:20.5-31.5）,两组间中位生存期有差异（P<0.05）。多因素Cox回归分析显示肝硬化、Scr水平、AFP≥200ng/ml、BCLC 0/A期、接受根治性治疗、获得SVR是HCV相关PLC患者生存预后的独立影响因素。进一步对性别、年龄、有无肝硬化、肿瘤分期和肿瘤治疗方式进行倾向性评分匹配（治疗组68例、未治疗组68例）,治疗组中位生存期65.0个月（95%CI:28.6-101.4）、未治疗组中位生存期44.0个月（95%CI:29.2-58.8）,两组间中位生存期未发现明显差异（P>0.05）。4.对未治疗组中接受局部消融治疗的患者（HCV RNA均阳性）进行分析,倾向性评分匹配后,分为术后DAA治疗组（n=16）、未治疗组（n=16）,DAA治疗组平均生存期48.8个月（95%CI:43.7-54.0）,未治疗组平均生存期40.1个月（95%CI:29.8-50.3）,两组平均生存期有统计学差异（P<0.05）。结论:1.DAA治疗获得SVR后发生PLC的患者肝功能相对较好、肿瘤BCLC分期相对较早、接受根治性治疗的比例相对较高。2.肝硬化、Scr水平、AFP≥200ng/ml、BCLC 0/A期、接受根治性治疗、获得SVR是HCV相关PLC患者生存预后的独立影响因素。倾向性评分匹配后,DAA治疗获得SVR对PLC患者中位生存期的影响未发现统计学差异。3.对接受局部消融治疗的HCV RNA阳性PLC患者,术后接受DAA治疗对生存预后有益。更多还原

【Abstract】 Objective:Chronic infection of hepatitis C virus（HCV）is one of the main causes of primary liver cancer（PLC）,obtaining SVR can significantly reduce the incidence of PLC.Chronic HCV-infected people can get a good sustained virological response（SVR）after direct antiviral drugs（DAA）treatment,but it is observed that some HCV-infected people who get SVR are still at risk of developing into PLC.In this study,the clinical data and follow-up data of HCV-related PLC（first diagnosis）patients who were treated with DAA and untreated were analyzed retrospectively,so as to provide some reference for clinical follow-up and treatment of hepatitis C patients.Methods:From January 1,2015 to December 31,2022,585 patients who were hospitalized in the Department of Hepatobiliary and Pancreatic Medicine of the First Hospital of Jilin University and were diagnosed as HCV-related PLC for the first time after multidisciplinary consultation of primary liver cancer in the whole hospital were collected.According to the inclusion and exclusion criteria,the clinical data of patients were collected and their survival time was followed up（the positive event was death until December 31,2023）.Finally,338 HCV-related PLC patients were selected as the research objects,which were divided into SVR group with DAA treatment（n=68）and group without DAA treatment（n=270）.Kaplan-Meier curve and Log-Rank test were used to analyze and compare the survival time of the two groups.Exploring the risk factors of HCV-related PLC death by Cox regression analysis.The influence of SVR obtained by DAA treatment on the prognosis of HCV-related PLC was further analyzed by propensity score matching（PSM）.Results:1.Demographic characteristics of HCV-related PLC patients:338 cases of HCV-related PLC included in the study,the average age was（64.75±8.02）years old,including 200 males and 138 females（1.45:1）,with 160 cases（47.3%）of A grade according to Child-Pugh classification of liver function.BCLC A accounted for 144 cases（42.6%）.135 cases（39.9%）received radical treatment（surgical resection,local ablation and liver transplantation）with PLC.2.338 HCV-related PLC patients were divided into DAA treatment group（n=68）and untreated group（n=270）.Compared with the untreated group,the levels of AST,ALT,GGT,ALP,TBil,DBil,TBA and APRI in the treatment group were lower,while the levels of Ach E,ALB,Cl^-,Ca²⁺,TC and LDL-C were higher,with statistical significance（P<0.05）.In the treatment group,there were 39 cases（57.4%）with Child-Pugh grade A,15（22.1%）with BCLC stage 0,44（64.7%）with single tumor,53（77.9%）with the largest diameter of tumor<5 cm,and 40（58.8%）with radical treatment,all of which were higher than those in the untreated group（P<0.05）.3.In the survival analysis of DAA treatment group and untreated group,the median survival time was 65.0 months（95%CI:28.6-101.4）in the treatment group and 26.0 months（95%CI:20.5-31.5）in the untreated group,and there was a difference between the two groups（P<0.05）.Multivariate Cox regression analysis showed that liver cirrhosis,Scr level,AFP≥200ng/ml,BCLC 0/A stage,receiving radical treatment and obtaining SVR were independent influencing factors for the survival and prognosis of HCV-related PLC patients.Further,the gender,age,liver cirrhosis,tumor stage and tumor treatment mode were matched by propensity score（68 cases in the treatment group and 68 cases in the untreated group）.The median survival time of the treatment group was 65.0 months（95%CI:28.6-101.4）,and that of the untreated group was 44.0months（95%CI:29.2-58.8）.There was no significant difference between the two groups（P>0.05）.4.The patients who received local ablation therapy（HCV RNA positive）in the untreated group were analyzed.After propensity score matching,they were divided into DAA treatment group（n=16）and untreated group（n=16）.The average survival time of DAA treatment group was 48.8 months（95%CI:43.7-54.0）,while that of untreated group was 40.1months（95%CI:29.8-50.3）.There was a statistical difference between the two groups（P<0.05）.Conclusions:1.Patients with PLC after SVR after DAA treatment have relatively good liver function,relatively early BCLC stage of tumor,and relatively high proportion of patients receiving radical treatment.2.Liver cirrhosis,Scr level,AFP≥200ng/ml,BCLC 0/A stage,receiving radical treatment and obtaining SVR are independent factors affecting the survival and prognosis of HCV-related PLC patients.After propensity score matching,there was no statistical difference in the effect of SVR obtained by DAA treatment on the median survival time of PLC patients.3.For HCV RNA positive PLC patients receiving local ablation,DAA treatment after operation is beneficial to survival and prognosis.更多还原