【作者】 张华；

【导师】 刘沛；

【作者基本信息】 东南大学 ， 劳动卫生与环境卫生， 2015， 博士

【摘要】 研究背景与目的：乙型病毒性肝炎是全球公认的重大公共卫生问题,不仅严重影响健康给个人、家庭造成沉重的负担,而且给社会发展带来巨大影响。进行乙型病毒性肝炎疾病负担及防治策略评价研究有助于卫生管理和资源分配的政策规划。本研究旨在系统分析江苏省乙型肝炎疾病负担,构建模型对新生儿乙肝疫苗接种策略进行长期效果评估,对成人筛查免疫与抗病毒治疗进行经济学分析,为江苏省乙型肝炎的防治提供科学依据。研究内容与方法：(1)疾病负担研究主要通过发病率、死亡率(流行病学)、直接、间接、无形经济负担(经济学)、伤残调整寿命年(Disality adjusted life year, DALYs)进行描述评价,流行病学分析资料来源于江苏省卫生厅、江苏省疾病预防控制中心传染病报告信息管理系统、江苏省疾病预防控制中心死因登记监测系统。经济负担资料通过现场调查和医院电子病例回顾性调查,获取不同类型乙肝相关疾病患者经济负担情况。运用SPSS19.0进行描述性统计和多元线性回归分析。DALYs计算通过乙肝相关疾病死亡资料得出早逝所致的健康生命年损失(Years of life lost, YLL),利用全球疾病负担(GBD)研究中介绍的间接法估算残疾造成的健康生命年损失(Years lost due to disability, YLD),用Excel 2007完成计算。(2)新生儿免疫策略评价通过构建决策树-马尔科夫(Markov)模型进行长期临床和经济学效果评估。根据江苏省新生儿接种方案及未来势,构建乙肝疫苗免疫策略多级决策树模型,同时构建马尔科夫模型用以模拟感染乙肝病毒(Hepatitis B virus, HBV)后的转归过程。(3)成人筛查免疫治疗策略研究根据《中国成人乙型肝炎免疫预防技术指南》和《慢性乙型肝炎防治指南(2010年版)》,结合江苏实际应用TreeAge软件对成人普遍接种疫苗、筛查表面抗体接种和筛查表面抗原抗体接种进行决策分析,应用WinBUGS软件对慢性乙型肝炎抗病毒治疗进行成本效益分析。研究结果：(1)江苏省1990年-2013年乙肝发病率在14.26/10万～33.10/10万之间。报告发病率在2004年前后有所波动,2005年以后发病率逐年下降,不同于全国其它地区呈总体上升的报告趋势。其中,江苏省男性发病率明显高于女性,男性在19.61/10万-247.31/10万之间；女性在8.60/10万～18.66/10万之间。1990年-2013年乙肝发病病例主要集中在15-45岁人群,占总数的69.36%,15岁及以上人群发病率远高于15岁以下人群。2012年乙肝死亡率1.20/10万,死亡率随着年龄增加而升高,男性的死亡率高于女性(P<0.05)。2002年-2013年肝癌死亡率为30/10万左右,男性死亡率均显著高于女性,随着年龄的增加死亡率逐渐增高,不同年龄段的肝癌死亡率在年度问有下降趋势。(2)医院调查结果显示被调查对象月门诊就诊率8.60%,年因乙肝看门诊人均6.5次,一年内因乙肝住院率26.98%。门诊患者直接医疗费用平均751.24元,药品费占到65.57%。门诊费的主要影响因素是药品费、检查费、是否抗病毒治疗。乙肝相关疾病患者平均住院天数为34天,本次住院费用平均为18312.62元,本次住院费用构成中药品费所占比例最高为63.77%,本次住院费用占家庭年收入的32.55%,本次住院费用超过人均年收入,占人均年收入的比例为118%。次住院经济负担为28971元,直接经济负担达到68.7%。乙肝相关疾病患者住院经济负担影响因素包括住院天数、药占比和年龄。乙肝相关疾病患者年人均医疗费用27575.68元,年人均经济负担40791.95元与家庭年收入相近,不同病型患者经济负担有差异。乙肝相关疾病门诊患者无形负担平均29319.3元,肝癌患者无形负担最重,慢性乙肝患者最低：住院患者无形负担高于门诊患者平均为36363.97元,肝癌、乙肝肝硬化代偿期无形负担较重。(3)采用世界卫生组织推荐的伤残调整寿命年(DALYs)测量江苏省乙型肝炎病毒感染(Hepatitis B virus, HBV)相关疾病健康生命年损失,结果显示乙肝、肝硬化、肝癌的YLLs均男性高于女性,45岁-59岁年龄组YLLs最高,采用间接法估算出2012年江苏省由HBV感染所致的伤残调整寿命年损失约为304510人年,2013年比2012年低约为290072人年。(4)新生儿免疫的临床效果,通过决策树-马尔科夫模型模拟得出,相对于未接种组,2012年出生队列新生儿接种3剂5gg重组乙肝疫苗,可以减少新发感染数17296人,减少慢性肝炎3793例,减少肝癌498例,减少相关死亡214729。接种3剂10μg重组乙肝疫苗,可以减少新发感染数18257人,减少慢性肝炎4003例,减少肝癌526例,减少相关死亡226658,显示新生儿接种3剂10gg重组乙肝疫苗具有更好的临床效果。经济学评价结果表明研究的新生儿不同接种方案的效益成本比(Benefit-cost ratio,BCR)均大于1,目前调整实行的对新生儿直接接种3针10μg乙肝疫苗为较优接种方案。孕妇筛检HBsAg方案为次优方案,提示针对HBsAg阳性孕妇之新生儿,采用3针10μg乙肝疫苗,加注1针100IU乙肝免疫球蛋白(HBIG),可以作为乙肝母婴阻断的备选方案。采用一维灵敏度分析(One-way Sensitivity Analysis)结果表明,在引入模型的众参数中,对方案较为敏感的因素为疫苗保护率、接种率。(5)成人筛查免疫策略研究结果表明,对成人筛检表面抗体后接种3剂20μg为最优方案,直接接种20gg重组乙肝疫苗为次优方案。本次研究的直接接种和筛检表面抗体后接种的方案BCR均大于1。将成人乙肝疫苗筛检后表面抗原阳性者且需要治疗的提供一线核苷类似物治疗分析发现BCR小于1,可能与抗病毒药物成本较高而疗效不显著有关。逐项替代法的敏感度分析结果显示,乙肝疫苗的筛查接种率、贴现率、疫苗保护率、成人表面抗体阳性率对策略的影响较大,而免疫策略对疫苗接种费、筛检费的变化敏感性较小。研究中通过引入定量方法估计模型对参数的敏感程度,结果表明各参数对模型影响的大小与逐项替代法一致。抗病毒治疗研究结果表明恩替卡韦治疗方案的成本效益比为18036低于拉米夫定的25675,更具有成本效益,成本-效益比随着年龄增大而增加,即年龄组越低越具有成本效益。应用贝叶斯统计方法进行成本效益分析发现,使用马尔科夫蒙特卡洛(MCMC)方法,不但能得到成本和效益的平均水平估计值,还可以定量其变异程度大小。研究结论：(1)乙肝病毒感染给患者和社会带来沉重负担,江苏省乙肝防治工作取得一定的成效,考虑到可能引发的未来负担防治工作依然不容轻视；(2)新生儿接种3剂l0μg乙肝疫苗是目前较为有效的免疫策略,免费接种政策需要继续推进；(3)成人筛检表面抗体后接种3剂20μg疫苗为成人免疫的较优方案；恩替卡韦治疗方案较拉米夫定更具成本效益,建议将安全有效的抗病毒治疗药物纳入国家基本药物目录：(4)新生儿免疫的效益成本比远高于成人,实际工作中需要密切关注模型中对策略影响较大的疫苗保护率、接种率等参数。更多还原

【Abstract】 Background and Objectives:Globally, Hepatitis B is recognized as a major public health problem. It not only influences the health seriously and causes heavy burden to individuals and families, but also has a strong impact on social development. Evaluation study on disease burden and prevention and treatment strategy of Hepatitis B will contribute to the health policy planning on health management and resource allocation. The objectives of the study is to analyze disease burden of hepatitis B in Jiangsu province systematically, construct the model of neonatal hepatitis B vaccination strategy for long-term effects evaluation, carry out the economics analysis on screening immune and treatment for adult, which will provide a scientific basis for the prevention and treatment of hepatitis B in Jiangsu province.Methods:(1) The research on disease burden is to describe mainly through the epidemiology, economics and disability adjusted life years (DALYs). Epidemiological analysis of data comes from the health department of Jiangsu province, infectious diseases report information management system of the center for disease control and prevention in Jiangsu province, the death registration and monitoring system of the center for disease control and prevention in Jiangsu province. Through the sampling investigation, the retrospective investigation of hospital electronic medical records, the data of economic burden in patients with different types of hepatitis B-related diseases is obtained. SPSS 19.0 is used to do descriptive statistics and multivariate linear regression analysis. DALYs is to calculate the year of life lost (YLL) caused by the premature death through the death data of hepatitis B-related disease, use the loss of healthy life years (YLD) caused by the indirect method to estimate disability described in the study of the global burden of disease (GBD) and complete the calculation with Excel2007. (2) Neonatal immunization strategy evaluation is to evaluate the long-term clinical and economic effect by building decision tree-markov model that accords with Jiangsu’s reality. According to the project of neonatal immunization and the future trend in Jiangsu province, the hepatitis B vaccine immunization strategy multistage decision tree model is built, at the same time Markov model is established to simulate the outcome of process after infecting HBV. (3) The research on adult prevention and treatment strategy is to set three strategies-universal vaccination, the screening of the surface antibody vaccination and the screening of the surface antibody antigen vaccination in combination with the practical set of Jiangsu, and carry on the decision analysis through the application of TreeAge, WinBUGS software, according to the guide of Chinese adult hepatitis B immune prevention technology and the chronic hepatitis B prevention guide (2010 edition).Results:(1) The incidence of hepatitis B in Jiangsu province from 1990 to 2013 is between 14.26/100000 and 33.10/100000. The report incidence is fluctuating around 2004, while it was declining year by year after 2005, different from other demostic report-the overall rising trend. Male incidence is higher than female significantly. Male is between 19.61/100000 and 247.31/100000, while female is between 8.60/100000 and 18.66/100000. In 1990-2013 hepatitis B cases mainly concentrated in the 15 to 45 years old, which accounted for 69.36% of the total. The incidence on the people over 15 years old is much higher than the people under age 15. Hepatitis B mortality is 1.20/100000 in 2012. The death rate is increasing with the increase of age, and the male mortality is higher than female mortality. Liver cancer mortality rate is 30/100000 from 2002 to 2013, in which the male is significantly higher than female. With the increase of age the mortality is increasing gradually, liver cancer mortality has declining trend between different age groups among years. (2) Hospital survey results show that the outpatient rate is 8.60% monthly. The times of outpatient service is 6.5 per capita every year due to liver disease, and the hospitalization rate is 26.98% because of hepatitis B within a year. The direct medical costs of outpatient are 751.24 yuan, in which the medical expense accounted for 65.57%. The main influence factors of outpatient expense are medical expense, examination expense and antiviral treatment. The average hospitalization days for patients with hepatitis B-related diseases is 34 days, meanwhile the average hospitalization cost is 18312.62 yuan. In the hospitalization fee structure, the proportion of medical expense is the highest-63.77%. The hospitalization expenses account for 32.55% of household income, and account for 118% of the annual per capita income. The economic burden of inpatients is 28971 yuan, and direct economic burden is up to 68.7%. So the hospital stays, medicine proportion and age have regression relationship with the economic burden of hepatitis B-related patients in hospital. The annual medical costs per capita in patients with hepatitis B-related disease is 27575.68 yuan, and the annual economic burden per capita is 40791.95 yuan, in addition, there are differences in economic burden of patients with different disease. The intangible burden of the outpatient with Hepatitis B-related disease is 29319.3 yuan on average, and intangible burden of the liver cancer patients is the highest, while the one of chronic hepatitis B is the lowest. The intangible burden of in-patients is higher than that of outpatients by 36363.97 yuan on average, besides the intangible burden is heavier with hepatocellular carcinoma and hepatitis B cirrhosis compensatory period. (3) Through measuring hepatitis B virus (HBV) infection related disease healthy life years loss in Jiangsu province, it shows that male YLLs is higher than female in the hepatitis B, liver cirrhosis and liver cancer according to the disability adjusted life year (DALY) recommended by the world health organization, and the YLLs in the group aged 45 to 59 years old is the highest. The disability adjusted life years loss caused by HBV infection in Jiangsu province is 304510 in 2012 and 290072 in 2013, which is estimated by indirect method. (4) Through the simulation from decision tree-markov model, relative to the unvaccinated group, the clinical effect of neonatal immune shows that the vaccination in newborns of 2012 Birth cohort with 3 doses of 5μg recombinant hepatitis B vaccine can reduce the number of new infections by 17296, reduce one of chronic hepatitis by 3793 cases, reduce one of the liver cancer by 498 cases and reduce one of related death by 214729. While the vaccination with 3 doses of 10μg recombinant hepatitis B vaccine can reduce the number of new infections by 18257, reduce that of chronic hepatitis by 4003 cases, reduce that of the liver cancer by 526 cases and reduce one of related death by 226658. It can be seen that the clinical effect of vaccination in newborns with 3 doses of 10μg recombinant hepatitis B vaccine is better. It shows from economics evaluation results that the BCR of different neonatal immunization scheme is more than 1; therefore the neonatal direct vaccination with 3 doses of 10μg hepatitis B vaccine is the optimal strategy, which was adjusted in the last two years. The strategy of screening HBsAg for pregnant women is suboptimum. For newborns of HBsAg positive pregnant women, using 3 doses of 10μg hepatitis B vaccine, filling 1 dose of 100IU HBIG can be used as the alternatives of hepatitis B maternal and child block. Using one dimensional sensitivity analysis, the result shows that the more sensitive factors include protection rate of vaccine and vaccination rate among the parameters of the model. (5) According to the research on adult control strategy, it shows that the inoculation with 3 doses of 20μg for adults after screening surface antibody is the optimal strategy, and direct inoculation with 20μg recombinant hepatitis B vaccine is suboptimal solution. BCR is greater than 1 for direct inoculation and inoculation after screening surface antibody. We provide a line of nucleoside analogues treatment analysis on adult of surface antigen positive after screening on hepatitis B vaccine and needing treatment, from which we can draw a conclusion that BCR is less than 1, or the benefit is less than the cost. Probably because of antiviral drugs cost is higher and the curative effect is not significant. By item by item alternative method of sensitivity analysis, it has greater influence on the strategy-screening coverage rate for hepatitis B vaccine, the discount rate, vaccine protection rate, the rate of surface antibody positive. However the strategy has less sensitivity on the change of vaccination fee and screening fee. In our study, we also try to introduce quantitative method to estimate the sensitivity of model to the parameters; the result is that the impact of various parameters on model is in accordance with the one by item by item alternative method. Cost effectiveness ratio for entecavir is 18,036 which is lower than lamivudine 25675, cost-effectiveness ratio increases with age. Applying Bayesian methods to cost-effectiveness analysis, especially when using Markov Monte Carlo (MCMC), we get not only the average estimate of costs and benefits, but also the variation of the quantitative.Conclusions:(1) Hepatitis B virus infection brings heavy burden to patients and society, and it has achieved certain effect on hepatitis B prevention and control in Jiangsu province. (2) It is the more effective immune strategy to inoculate 3 doses of 10μg hepatitis B vaccine to newborns, which was adjusted currently. (3) It is the optimal strategy to inoculate 3 doses of 20μg to adult after screening surface antibody. Entecavir is a cost-effective strategy compared with lamivudine for CHB patients. (4) The benefit cost ratio of newborns immunity is far higher than that of adult. In practical work, close attention should be paid to the parameters that have greater influence on the strategy in the model.更多还原