【作者】 陈琦；

【导师】 陆红；

【作者基本信息】 上海交通大学 ， 内科学（消化系病）， 2017， 博士

【摘要】 目的:幽门螺杆菌（Helicobacter pylori,H.pylori）感染与多种上消化道疾病有关,根除H.pylori可以终生受益。但目前我国H.pylori根除失败的问题比较突出,临床上亟需安全有效的补救方案,因此本研究第一部分将评估大剂量阿莫西林替代四环素的改良铋剂四联补救治疗方案的疗效和安全性。此外,是否在我国无症状人群中实施H.pylori筛查-根除策略尚未达成共识,因此,本研究第二部分将利用Markov模型分析对H.pylori筛查-根除策略用于预防H.pylori相关疾病进行卫生经济学评价。方法:第一部分的临床研究中,共招募312例H.pylori根除失败至少两次（用过阿莫西林、克拉霉素、甲硝唑、左氧氟沙星）的患者,随机分为两组:分别给予14天疗程的兰索拉唑30mg bid、枸橼酸铋钾600mg bid、甲硝唑400mg qid、阿莫西林1000mg tid（阿莫西林组）或四环素500mg qid（四环素组）;胃镜下采集胃黏膜组织分离培养H.pylori进行琼脂稀释法药敏试验;治疗结束后至少6周行¹³C-尿素呼气试验以评估根除疗效。第二部分的卫生经济学研究中,根据H.pylori感染到H.pylori相关疾病（消化不良、消化性溃疡、胃癌）的自然病程来建立Markov模型;通过文献检索和专家咨询确定Markov模型运算所需要的参数;比较我国20～29岁无症状人群中实施H.pylori筛查-根除策略和无干预策略的远期成本和效果,首先应用成本-效果分析评估我国无症状人群中实施H.pylori筛查-根除策略是不是优于无干预策略,然后应用单因素敏感性分析和概率敏感性分析评估Markov模型的稳健性和参数的不确定性。结果:第一部分研究中,阿莫西林组和四环素组的H.pylori根除率按意向性治疗分析分别为88.5%（138/156）、87.2%（136/156）,按方案分析分别为93.7%（133/142）、95.3%（122/128）,按改良ITT分析分别为92.6%（138/149）、90.7%（136/150）。两组之间根除率没有差异（p>0.05）,并且阿莫西林组的根除率不劣于四环素组。H.pylori对阿莫西林、四环素、甲硝唑的耐药率分别为8.3%、1.0%和87.8%。甲硝唑耐药对阿莫西林组和四环素组的根除率均无影响（p>0.05）。与四环素组相比,阿莫西林组的依从性更高,不良反应率更低。第二部分研究中,基线分析显示,与无干预策略相比,H.pylori筛查-根除策略在消化不良、消化性溃疡、胃癌、综合Markov模型中的增量成本-效果比分别为146590元/质量调整生命年（QALY）、173343元/QALY、21219.3元/QALY、18116.0元/QALY。敏感性分析示,消化不良、消化性溃疡、胃癌3个Markov模型对部分参数的敏感性较高,而H.pylori相关疾病综合Markov模型的稳健性好,对所有参数均不敏感。结论:含大剂量阿莫西林的改良铋剂四联方案依从性高、不良反应率低,并且根除率不劣于含四环素的经典四联方案,因此改良铋剂四联方案可替代经典四联方案用于H.pylori感染补救治疗。与无干预策略相比,H.pylori筛查-根除策略在中国20～29岁无症状人群中用于综合预防3种H.pylori相关疾病（胃癌、消化性溃疡、消化不良）具有更高的性价比。更多还原

【Abstract】 Aims:Helicobacter pylori（H.pylori）infection is associated with a variety of upper gastrointestinal diseases.Successful eradication of H.pylori can benefit for life.However,the problem of H.pylori eradication failure in China is more prominent.It is urgent to have a safe and effective H.pylori rescue therapy.Therefore,the first part of this study will evaluate the efficacy and safety of high-dose amoxicillin-containing modified bismuth quadruple regimen.In addition,there is no consensus on the implementation of H.pylori screen-and-treat strategy in Chinese asymptomatic populations.Therefore,the second part of this study will use the Markov model to present a health economic evaluation of H.pylori screen-and-treat strategies for the prevention of H.pylori-related diseases.Methods:In the first part,312 patients who failed of H.pylori eradication at least twice were assigned.They were randomly divided into two groups:lansoprazole 30mg bid,bismuth potassium citrate 600mg bid,metronidazole 400mg qid,amoxicillin1000mg tid（in amoxicillin group）or tetracycline 500mg qid（in tetracycline group）for14 days.Antibiotic susceptibility was determined by the agar-dilution method.H.pylori eradication was assessed by ¹³C-urea breath test at least 6 weeks after treatment.In the second part,the Markov model was established based on the natural course of H.pylori infection to H.pylori-related diseases（dyspepsia,peptic ulcer,gastric cancer）.Markov model inputs were derived from literature searching and expert consultation.The long-term cost and effect of H.pylori screen-and-treat strategy and non-intervention strategy in Chinese asymptomatic population from 20 to 29 years old were compared.First,cost-effectiveness analysis were used to evaluate whether H.pylori screen-and-treat strategy is superior to non-intervention strategy,and then one-way sensitivity analysis and probabilistic sensitivity analysis were used to evaluate the robustness of Markov model and the uncertainty of parameters.Results:In the first part of the study,the H.pylori eradication rates in amoxicillin group and tetracycline group were 88.5%（138/156）and 87.2%（136/156）in intention-to-treat analysis,93.7%（133/142）and 95.3%（122/128）in per-protocol analysis,92.6%（138/149）and 90.7%（136/150）in modified intention-to-treat analysis,respectively.There was no significant difference in the eradication rate between the two groups（p>0.05）,and the eradication rate of the amoxicillin group was not inferior to that of the tetracycline group.The resistance rates of H.pylori to amoxicillin,tetracycline and metronidazole were 8.3%,1.0%and 87.8%,respectively.Metronidazole resistance did not affect the eradication rate of either amoxicillin or tetracycline group（p>0.05）.Compared with the tetracycline group,the amoxicillin group had higher compliance and less adverse events.In the second part of the study,baseline analysis showed that the incremental cost-effectiveness ratio of H.pylori screen-and-treat strategy in dyspepsia,peptic ulcer,gastric cancer and integrated Markov model was￥146,590/Quality adjustment life year（QALY）,￥173,343/QALY,￥21,219.3/QALY,and￥18,116.0/QALY.Sensitivity analysis showed that three Markov models of dyspepsia,peptic ulcer,and gastric cancer were sensitive to some parameters,and H.pylori-related disease integrated Markov model was very robust and was not sensitive to all parameters.Conclusions:The modified bismuth-containing quadruple therapy with metronidazole and amoxicillin is an alternative to classical bismuth quadruple therapy for H.pylori rescue therapy as it provides similar eradication rate with superior safety and compliance.Compared with the non-intervention strategy,H.pylori screen-and-treat strategy in 20 to 29-year-old Chinese asymptomatic population for the comprehensive prevention of three H.pylori-related diseases（gastric cancer,peptic ulcer,dyspepsia）is more cost-effective.更多还原