【作者】 张猛；

【导师】 张建营；

【作者基本信息】 郑州大学 ， 流行病与卫生统计学， 2021， 博士

【摘要】 背景我国肝癌新发病例占全球肝癌总发病例数的45.3%,死亡病例占全球的47.1%。我国肝癌疾病负担特别是经济负担依然沉重。肝癌筛查以高危人群为对象,以便进行合理的早期干预,降低肝癌死亡率,改善患者生命质量。我国超过80%的肝癌患者合并感染乙型肝炎病毒(hepatitis B virus,HBV,乙肝),即慢性乙肝(chronic hepatitis B,CHB)相关肝癌,其中CHB相关肝硬化(下文简称为CHB肝硬化)患者的肝癌发病率高达3%-8%,是我国肝癌的首要病因。因此,对CHB肝硬化患者制定有效的筛查策略是减轻我国肝癌疾病负担的关键手段。肝癌筛查措施除了常用的影像学检查,如超声、计算机断层扫描技术(computerized tomography,CT)和磁共振成像技术(magnetic resonance imaging,MRI)以及甲胎蛋白(alpha fetoprotein,AFP)以外,本课题组长期致力于肿瘤相关抗原自身抗体(anti-tumor associated antigen autoantibody,TAAb)用于肝癌筛查和诊断应用价值的研究。对肝癌筛查策略的评价除了筛查措施的准确性、人群接受度筛查成本等关键因素之外,筛查策略的成本效果分析(cost-effectiveness analysis,CEA)结果是至关重要的。肝癌筛查经济学评价的目的在于为有限的医疗资源和财政资源的分配提供科学依据以及对在临床开展CHB肝硬化患者肝癌筛查和管理工作提供依据。评价对CHB肝硬化患者进行肝癌筛查成本效果价值时,不仅需要关注抗病毒治疗作为一种预防癌症的方法带来的益处,也不可忽视抗病毒治疗药物成本对其经济学价值的限制。医疗卫生相关成本效果分析指南推荐的质量调整生命年(Quality Adjusted Life Years,QALYs)为最终的效果评价指标,但现有的CHB相关疾病患者健康效用值数据尚不能满足本研究CEA的需求。因此,本研究在评价各种肝癌筛查策略经济学价值之前,还需要测量CHB相关疾病患者的健康效用值。目的在多个临床中心的CHB相关疾病患者开展问卷调查,基于我国人群偏好的6维健康状况简表(Short Form-Six Dimension,SF-6D)健康效用值积分体系计算健康效用值;构建符合我国国情的CHB肝硬化患者肝癌筛查的马尔科夫模型;从经济学角度探索对CHB肝硬化患者进行肝癌筛查的最优策略,同时评估抗病毒治疗对肝癌筛查策略经济学价值的影响;探讨TAAb用于肝癌筛查的经济学价值。方法1.乙肝相关性疾病患者健康效用值的测量方法采用时间阶段整群抽样法,在北京市、河南省郑州市三个肝病临床中心,采用健康相关生命质量36简表第二版中文版(Short Form 36 Health Survey version 2,SF-36v2)和个人信息问卷,对CHB相关疾病患者(包括CHB无并发症患者、代偿期肝硬化、失代偿期肝硬化、肝癌)进行问卷调查,根据中国常模数据计算各诊断分型患者的生命质量,使用我国人群偏好的SF-6D健康效用值积分体系计算健康效用值,采用非参数检验的Kruskal-Wallis秩和检验比较组间差异。采用多元线性回归分析方法,进行CHB相关疾病患者生命质量的影响因素的多因素分析。2.乙肝相关肝硬化患者肝癌筛查的马尔科夫模型的构建根据马尔科夫链基本原理,充分考虑我国CHB肝硬化患者抗病毒治疗和筛查依从性等肝癌防治实际,依据CHB相关疾病自然转归史和巴塞罗那分期(Barcelona Clinic Liver Cancer,BCLC)系统,构建肝癌筛查的马尔科夫模型。制定模型运转条件并且采用文献分析法、专家咨询法、专项调查法等进行模型参数的收集。采用TreeAge Pro 2020完成模型的构建、运行和验证。3.乙肝相关肝硬化患者肝癌筛查成本效果分析方法及策略优化方法以40岁CHB肝硬化患者为模拟对象,充分考虑进行抗病毒治疗情况,采用Tree Age Pro 2020软件模拟3种CHB肝硬化患者筛查队列,分别为接受抗病毒治疗的CHB肝硬化患者队列(队列A)、不接受抗病毒治疗的CHB肝硬化患者队列(队列B)和80%的CHB肝硬化患者接受抗病毒治疗20%的患者不接受抗病毒治疗(队列C)。同时构建肝癌筛查的决策分析马尔科夫模型,筛查措施分别为超声、超声联合AFP(下文简写为超声+AFP)、CT和MRI,筛查频率为每半年一次或每年一次,共8种筛查策略。以我国2019年3倍人均GDP为支付意愿,确定不同模拟队列肝癌筛查的最优策略。并进行对筛查人群的年龄、筛查措施的灵敏度和特异度、成本、效用值等重要参数进行一维敏感性分析和概率敏感性分析以及绘制成本效果可接受曲线,评价主要参数对模型稳定性的影响。4.肿瘤相关抗原自身抗体用于肝癌筛查的成本效果分析方法以40岁CHB肝硬化患者为模拟对象,构建肝癌早期筛查的决策分析马尔科夫模型。本文以指南推荐的每半年一次肝脏超声联合AFP(超声+AFP)为对照策略,单独TAAb筛查或TAAb与AFP联合(TAAb+AFP)两种筛作为研究策略,设置模型运转10年、运转30年和运转至99.9%的人群死亡三种终止条件。以我国2019年3倍人均GDP和发达国家阈值(5万美元)为支付意愿评价基线分析结果,确定不同模型终止条件下的TAAb用于肝癌筛查的成本效果价值。并进行一维敏感性分析,概率敏感性分析以及绘制成本效果可接受曲线评价主要参数对模型稳定性的影响。结果1.CHB相关疾病患者生命质量和健康效用值测量结果本次最终共收集有效问卷1071份,平均年龄为42.49岁。其中CHB无并发症患者639例、代偿期肝硬化患者125例、失代偿期肝硬化患者85例和肝癌患者患者222例。CHB无并发症,代偿期肝硬化,失代偿期肝硬化和肝癌的健康效用值的(?)(S)分别为0.796(0.132)、0.752(0.189)、0.664(0.203)和0.562(0.258)。BCLC(0/A)、BCLC(B)和BCLC(C/D)各期健康效用值的(?)(S)分别为0.580(0.267)、0.555(0.247)和0.513(0.262)。在CHB无并发症阶段,患者生理相关HRQoL未下降,而心理相关HRQoL明显下降。随着疾病进展,患者的生理总评得分比心理总评得分的下降幅度更大。2.CHB肝硬化患者肝癌筛查的马尔科夫模型构建结果本研究构建的CHB肝硬化患者肝癌筛查的马尔科夫模型有5类,分别为:CHB肝硬化患者疾病自然转归的马尔科夫模型,CHB肝硬化患者不接受抗病毒治疗且不进行肝癌筛查的马尔科夫模型,CHB肝硬化患者不接受抗病毒治疗进行肝癌筛查的马尔科夫模型,CHB肝硬化患者接受抗病毒治疗不进行肝癌筛查的马尔科夫模型和CHB肝硬化患者接受抗病毒治疗且进行肝癌筛查的马尔科夫模型。模型效度检验结果为抗病毒治疗的CHB肝硬化患者中第2-5年的肝癌累积发病率实际值和预测值拟合优度分别为0.994和0.969,提示模型稳定可靠。3.CHB肝硬化患者肝癌筛查成本效果分析及策略优化结果对我国进行抗病毒治疗的40岁CHB肝硬化患者队列,每半年超声+AFP策略具成本效果价值,其成本效果比33683元/QALY;不进行抗病毒治疗的CHB肝硬化患者队列进行肝癌筛查时,每半年CT筛查策略的成本效果比为25524元/QALY,最具有成本效果价值;对于80%患者进行抗病毒治疗队列,每半年超声+AFP筛查策略为最优策略,成本效果比为32339元/QALY。敏感性分析结果表明,经济学评价结果可靠,当支付意愿为3倍人均GDP时,上述三种优势策略具有成本效果价值的概率分别为96.6%、69.9%和89.1%。4.肿瘤相关抗原自身抗体用于肝癌筛查的成本效果分析结果对我国40岁CHB肝硬化患者进行肝癌筛查时,与超声+AFP相比,采用TAAb+AFP策略不同模型运转终止条件(运转10年、运转30年、运转至99.9%的人群死亡)下的增量成本效果比(incremental cost-effectiveness ratio,ICER)分别为1356548元/QALYs、203207元/QALYs、144548元/QALYs,具有成本效果价值;而单独TAAb策略不具成本效果价值。敏感性分析结果表明,TAAb筛查成本参数最为敏感,TAAb+AFP策略的经济学评价结果稳定可靠。当支付意愿阈值为3倍的人均GDP时,该策略在不同终止条件下具有成本效果的概率分别为47.5%、72.7%和78.5%。结论1.本研究健康效用值的结果不仅为本研究提供重要参数,还可以为CHB相关疾病或肝癌相关的成本效果分析提供重要的数据支持。减缓慢性乙肝相关疾病的进展,同时在CHB相关疾病早期阶段提供心理支持可以帮助患者保持更好的生命质量。2.本研究构建的CHB肝硬化患者肝癌筛查的马尔科夫模型模拟结果可信,可以满足我国CHB肝硬化患者肝癌筛查策略经济学评价的需要。3.对于40岁以上不进行抗病毒治疗的CHB肝硬化患者人群,每半年CT筛查策略为最优策略;CHB肝硬化患者人群抗病毒治疗依从性越高,每半年超声联合AFP筛查策略的成本效果越好。抗病毒治疗作为预防肝癌的手段之一,对肝癌筛查策略的成本效果价值的影响不可忽视。4.TAAb联合AFP策略作为我国40岁CHB肝硬化患者肝癌早期筛查方法,具有成本效果价值,该策略与我国现阶段经济社会发展水平相适应,可进行临床推广。更多还原

【Abstract】 New cases of liver cancer accounted for 45.3% and deaths accounted for 47.1%of the total global cases of liver cancer in China.The burden of liver cancer in China,especially the economic burden,is still heavy.Liver cancer screening targets high-risk population carry out reasonable early intervention,reduce liver cancer mortality and improve the quality of life of patients.More than 80% of liver cancer are co-infected with hepatitis B virus(HBV)in China,that is,chronic hepatitits B(CHB)related liver cancer,of which liver cirrhosis when they are diagnosed with liver cirrhosis.The incidence of hepatocellular carcinoma(HCC)in liver cirrhosis patients is as high as 3%-8%,which is the leading cause of HCC in China.Therefore,formulating effective screening strategies for liver cirrhosis patients is a key means to reduce the burden of liver cancer in China.In addition to the commonly used imaging tests for HCC screening,such as ultrasound,computerized tomography(CT),magnetic resonance imaging(MRI),and alpha fetoprotein(AFP),our research group has been evaluating the application value of anti-tumor associated antigen autoantibody(TAAb)for HCC screening and diagnosis for a long time.For evaluation of HCC screening strategies,in addition to the accuracy of screening measures,population acceptance,costs and other key factors,the cost-effectiveness analysis(CEA)of screening strategies is also crucial.The purpose of economic evaluation of HCC screening is to provide a scientific basis for the allocation of limited medical resources and financial resources,as well as to provide a basis for clinical screening for HCC in liver cirrhosis patients.When evaluating the cost-effectiveness value of liver cancer screening for liver cirrhosis,not only the benefits of antiviral therapy as a method to prevent cancer should be paid attention to,but also the economic value of antiviral therapy can not be ignored.The medical and health-related cost-effectiveness analysis guidelines recommend that the quality adjusted life years(QALYs)should be the final effect evaluation indicators,while the existing health utility value data for patients with CHB-related diseases cannot meet the needs of CEA in this study.Therefore,it is also necessary to measure the health utility value of patients with CHB-related diseases before evaluating the economic value of HCC screening strategies.ObjectivesThe purpose of this study was to conduct a questionnaire survey of CHB-related diseases patients in multiple clinical centers,and to calculate the health utility value based on the Short Form-Six Dimension(SF-6D)health utiliy value points system preferred by the Chineses population.Another purpose was constructed Markov model for HCC screening in patients with liver cirrhosis that meets our national conditions and to explore the optimal strategy for CHB liver cancer screening from an economic perspective,The third aim of this study was to evaluate the impact of antiviral therapy on the economic value of liver cancer screening strategies and to explore the economic value of TAAb for HCC screening in China.Methods1.The method of measuring the health utility value of CHB-related disease patients.We conducted a questionnaire survey on the patients with CHB-related diseases(including CHB,compensated cirrhosis,decompensated cirrhosis,HCC)by using time-phase cluster sampling and the Chinese version of SF-36v2 and the personal information questionnaire in quality of life in three liver disease clinical centers in Beijing and Zhengzhou,Henan Province.We calculated the quality of life of patients with each diagnostic classification based on Chinese norm data,to convert life quality into health utility value via SF-6D and used non-parametric test Kruskal-Wallis rank sum test for comparison of differences between groups.Multivariate linear regression analysis was used to conduct a multivariate analysis of factors affecting the quality of life of patients with CHB-related diseases.2.Construction of Markov model for CHB-related HCC screeningThe Markov model for HCC screening was constructed according to the basic principles of the Markov chain,the natural outcome history of CHB-related diseases and the Barcelona Staging(Barcelona Clinic Liver Cancer,BCLC)system.The model parameters were collected through the formulation of operating conditions of the model in combination with the literature analysis method,expert consultation method,special survey method and so on.Some of the regression rate parameters were converted by the life decline index approximation method.3.Cost-effectiveness analysis methods and strategy optimization methods for liver cancer screeningTaking 40-year-old patients with liver cirrhosis as the simulation object,three screening cohorts of patients with liver cirrhosis were constructed according to the different antiviral treatments of patients in the simulation cohort,and a Markov model was construct by Tree Age Pro 2020 software for decision analysis of HCC screening.Screeing methods were ultrasound,ultrasound combined with AFP,CT,and MRI.Screening frequency were once every six months or once a year.Totally,there were 8screening strategies.The optimal strategy for liver cancer screening was determined.Taking 3 times of China per capita GDP in 2019 as the baseline analysis result of willingness to pay.And one-way sensitivity analysis,probability sensitivity analysis,and plotting of payable curve were performed to evaluate the influence of main parameters on the stability of the model.4.Cost-effectiveness analysis method of TAAb for HCC screeningA Markov model of decision analysis for early screening of HCC was constructed taking 40-year-old patients with liver cirrhosis as a simulation object.This study used liver ultrasound combined with AFP.recommended by the guidelines as the control strategy,TAAb screening alone or TAAb combined with AFP two screenings were used as the research strategy.Three termination conditions were set up for the model to run for 10 years,30 years and run to death of 99.9% of the population deaths.,the cost-effective value of TAAb for HCC screening under different model termination conditions was determined by taking 3 times per capita GDP of China in 2019 and the commonly used threshold in developed countries($50,000)as willingness to pay to evaluate the results of the baseline analysis One-way sensitivity analysis,probability sensitivity analysis were also performed to evaluate the influence of main parameters on the stability of the model.Results1.Results of the health related quality of life(HRQoL)and health utility value of CHB-related diseases patients.A total of 1071 valid questionnaires were collected included 639 CHB patients,125 CC patients,85 DC patients and 222 HCC patients with an average age of patients at 42.49.The health utility values of chronic hepatitis B,compensated cirrhosis,decompensated cirrhosis and HCC were 0.796(0.132),0.752(0.189),0.664(0.203)and 0.562(0.258),respectively.The health utility values of BCLC(0/A),BCLC(B)and BCLC(C/D)were 0.580(0.267),0.555(0.247)and 0.513(0.262),respectively.In the CHB stage,the patients’ physiologically related HRQoL did not decrease,while the psychologically related HRQoL decreased significantly.As the disease progresses,the overall physiological score of patients has a greater decline than the psychological related HRQoL.2.Results of Markov model construction of HCC screening.There were 4 Markov models constructed in this study for HCC screening in patients with liver cirrhosis,namely: Markov model for liver cirrhosis patients not receiving either antiviral therapy or liver cancer screening,Markov model for liver cirrhosis patients not receiving antiviral therapy but undergoing cancer screening,Markov model for liver cirrhosis patients receiving antiviral therapy without liver cancer screening,and Markov model for liver cirrhosis patients with both antiviral therapy and liver cancer screening.The goodness of fit between the actual and predicted values of the cumulative incidence of liver cancer in patients with liver cirrhosis treated with antiviral therapy were 0.994 and 0.969,respectively.3.Cost-effectiveness analysis and strategy optimization results of HCC screening.For the 40-year-old antiviral treatment cohort in China,the ultrasound with AFP screening strategy every half yeaf was the most cost-effective,and its cost-effectiveness ratio was 33683 yuan/QALY.When the cohort of patients with liver cirrhosis not receiving antiviral treatment was screened for HCC,the cost-effectiveness ratio of the half-year CT screening strategy was 25524 yuan/QALY,which has the most cost-effective value.For a cohort in which 80% of the patients receive the antiviral treatment,the ultrasound with AFP screening strategy every six months was the optimal strategy,and the cost-effectiveness ratio was 32339 yuan/QALY.The sensitivity analysis results show that the economic evaluation results were reliable.When the willingness to pay was 3 times per capita GDP,the probability that the above three optimal strategies have cost-effective value is 96.6%,69.9% and 89.1%,respectively.4.Results of cost-effectiveness analysis of TAAb for HCC screening.For HCC screening in 40-year-old patients with liver cirrhosis in China,if the model runed for 10 years,compared with ultrasound with AFP strategy,ICER adopting TAAb with AFP strategy was 13568548 yuan/QALY,which has no cost-effective value.If the model runed for 30 years or when 99.9% of the population die,ICER was 203207 yuan/QALY and 144548 yuan/QALY,which has cost-effective value.Sensitivity analysis results showed that the economic evaluation results of TAAb+AFP strategy were reliable.When the willingness to pay threshold is 3 times the per capita GDP,the probability of this strategy being cost-effective is47.5%,72.7% and 78.5%.Conclusion1.The results of the health utility value not only provide parameters for this study,but also provide important data support for the cost-effectiveness analysis of CHB-related diseases or liver cancer.CHB-related patients maintain a better quality of life by slowing down the progression of chronic hepatitis B-related diseases and providing psychological support for patients in the early stages of the disease.2.The Markov models constructed in this study for HCC screening in liver cirrhosis patients are credible and can meet the needs of economic evaluation of HCC screening strategies for patients with liver cirrhosis in China.3.For cirrhosis patients over 40 years old who do not receive antiviral therapy,the CT screening every six months strategy is the optimal strategy.Improving the adherence of antiviral therapy in patients with liver cirrhosis will increase the costeffectiveness value of ultrasound combined with AFP screening strategy.Antiviral therapy is one of the means to prevent HCC,and its impact on the cost-effectiveness value of HCC screening strategies cannot be ignored.4.The TAAb with AFP strategy as an early screening method for HCC in40-year-old patients with liver cirrhosis in China has cost-effective value.This strategy is compatible with the current level of economic and social development in our country and can be clinically promoted.更多还原