宫颈癌是对全球女性健康有重大影响的的恶性肿瘤疾病之一，全球每年的新增宫颈癌病例数量预计为57万例，每年的新增宫颈癌死亡病例数量预计为31万例，因此，对女性子宫颈癌加以干预势在必行，而对适龄女性人群进行大规模筛查和人乳头瘤病毒疫苗的接种是中国乃至世界降低宫颈癌发病率和死亡率的主要手段，故研究疫苗接种对宫颈癌发病率的影响，意在证明和宣传人乳头瘤疫苗的有效性，降低中国女性宫颈癌的发病率。

本研究主要分为两部分，第一部分根据中国宫颈癌预防措施的实际发展情况，构建相应的多状态Markov模型对中国女性的宫颈癌发病率进行长期的预测：2000年至2008年构建宫颈癌自然史模型，针对2009年中国开启妇女两癌筛查项目这一实际情况，构建2009年至2017年的宫颈癌筛查模型，并结合实际发病率进行对比，针对2018年人乳头瘤病毒疫苗在中国审批上市，构建2018至2029年人乳头瘤病毒疫苗接种预测模型，针对预计于2030年上市的男性可接种的人乳头瘤病毒疫苗构建2030年至2065年群体免疫预测模型。第二部分则针对不同频率的宫颈癌筛查方案进行卫生经济学评价，运用第一部分构建的群体免疫模型模拟自2030年开始至2065年的人群分布，结合经过贴现计算的筛查费用，对所提出的四种不同的筛查方案未来三十五年间的中国女性在各状态分布情况情况进行卫生经济学分析，其中包括成本效果分析和成本效用分析。

结果显示自2018年人乳头瘤病毒疫苗在中国上市以来，中国女性宫颈癌的发病率逐年降低，在2033年中国女性宫颈癌发病率会低于10/10万人，于2051年将低于5/10万人，预测数值为4.91/10万人，在2065年宫颈癌发病率为3.34/10万人。而对于卫生经济学评价，筛查频率为三年的筛查干预措施的成本效果比率为9543.20元/LYS，筛查频率为五年的成本效果比率为7139.99元/LYS，筛查频率为十年的成本效果比率为7155.99元/LYS，筛查频率为二十年的成本效果比率为7916.31元/LYS，而这些筛查方案成本效用比率分别为8781.43/QALY、5513.11/QALY、6199.95/QALY、6596.11/QALY。从数据可以看出，在经济允许的情况下，五年一次的筛查频率为最具性价比的筛查方式。文章的结果证明男性接种人乳头瘤病毒疫苗能带来一定的群体免疫，从而在一定程度上降低女性宫颈癌的发病率，有利于人乳头瘤疫苗在中国的推广，也能让适龄女性根据自身的身体健康情况和经济状况来选择自身宫颈癌筛查的频率，以减少中国女性宫颈癌的发病率。

Cervical cancer is one of the malignant tumor diseases that have a significant impact on women's health worldwide. The number of new cases of cervical cancer worldwide every year is estimated to be 570000, and the number of new deaths from cervical cancer is estimated to be 310000. Therefore, it is imperative to intervene in female cervical cancer. Large scale screening and human papillomavirus vaccination for women of appropriate age are the main means to reduce the incidence rate and mortality of cervical cancer in China and the world. Therefore, studying the impact of vaccination on the incidence rate of cervical cancer is intended to prove and promote the effectiveness of human papillomavirus vaccine and reduce the incidence rate of Chinese women.

This study is mainly divided into two parts. In the first part, according to the actual development of China's cervical cancer prevention measures, the corresponding multistate Markov model is constructed to make a long-term prediction of the incidence rate of cervical cancer among Chinese women: the natural history model of cervical cancer is constructed from 2000 to 2008, and the cervical cancer screening model from 2009 to 2017 is constructed based on the actual situation that China started the two cancer screening project for women in 2009, and the actual incidence rate is compared. In view of the approval of human papillomavirus vaccine for listing in China in 2018, the prediction model of human papillomavirus vaccination from 2018 to 2029 is constructed, and the mass immunization from 2030 to 2065 is constructed for male vaccinated human papillomavirus vaccine expected to be listed in 2030 Prediction model. The second part evaluates the health economics of cervical cancer screening programs with different frequencies. The population immunity model constructed in the first part is used to simulate the population distribution from 2030 to 2065, and combined with the discounted screening costs, a health economics analysis is conducted on the distribution of Chinese women in various states for the four different screening programs proposed in the next 35 years, including cost-effectiveness analysis and cost-effectiveness analysis.

The results show that since the human papillomavirus vaccine was launched in China in 2018, the incidence rate of cervical cancer among Chinese women has been decreasing year by year. In 2033, the incidence rate of cervical cancer among Chinese women will be lower than 10/100000 people, and in 2051, it will be lower than 5/100000 people. The predicted value is 4.91/100000 people, and in 2065, the incidence rate of cervical cancer will be 3.34/100000 people. For the evaluation of health economics, the cost-effectiveness ratio of screening interventions with a screening frequency of three years is 9543.20 yuan/LYS, the cost-effectiveness ratio of screening interventions with a screening frequency of five years is 7139.99 yuan/LYS, the cost-effectiveness ratio of screening interventions with a screening frequency of ten years is 7155.99 yuan/LYS, and the cost-effectiveness ratio of screening interventions with a screening frequency of twenty years is 7916.31 yuan/LYS. The cost-effectiveness ratios of these screening programs are 8781.43/QALY, 5513.11/QALY, 6199.95/QALY, and 6596.11/QALY, respectively. From the data, it can be seen that, under economic conditions, the five-year screening frequency is the most cost-effective screening method. The results of this article prove that male vaccination of human papillomavirus vaccine can bring about a certain group immunity, thus reducing the incidence rate of cervical cancer in women to a certain extent, which is conducive to the promotion of human papillomavirus vaccine in China, and also allows women of appropriate age to choose their own frequency of cervical cancer screening according to their own health and economic conditions, so as to reduce the incidence rate of cervical cancer in women in China.

[1] World Health Organization. Global strategy to accelerate the elimination of cervical cancer as a public health problem [EB/OL]. World Health Organization, 2020-11-22.

[2] World Health Organization. Cervical cancer incidence and mortality in low-and middle-income countries: A systematic analysis [J]. The Lancet, 2018, 392(10156):1343-1355.

[3] ICO/IARC HPV Information Centre. Human Papillomavirus and Related Diseases Report. China [EB/OL]. ICO/IARC HPV Information Centre, 2023-03-10.

[4] Li Xueting, Zheng Rongshou, Li Xuemei, et al. Trends of incidence rate and age at diagnosis for cervical cancer in China, from 2000 to 2014 [J]. Chinese Journal of Cancer Research, 2017, 29 (6): 477-486.

[5] World Health Organization. Comprehensive cervical cancer control: basic principles and guidelines (2nd edition) [EB/OL]. World Health Organization, 2014-12-03.

[6] World Health Organization. Global strategy to accelerate the elimination of cervical cancer as a public health problem [EB/OL]. World Health Organization, 2022-11-22.

[7] 关于印发加速消除宫颈癌行动计划（2023-2030年）的通知 [J]. 中华人民共和国国家卫生健康委员会公报, 2023, 1(1): 1-3.

[8] Patti Olusola, Hirendra Nath Banerjee, et al. Human papilloma virus-associated cervical cancer and health disparities [J]. Cells, 2019, 8(6):622.

[9] Jiayao Lei, Alexander Ploner, et al. HPV vaccination and the risk of invasive cervical cancer [J]. Obstetrical&Gynecological Survey, 2020, 383(14):1340-1348.

[10]Palmer TJ, Kavanagh K, Cuschieri K, et al. Invasive cervical cancer incidence following bivalent human papillomavirus vaccination: a population-based observational study of age at immunization, dose, and deprivation [J], Journal of the National Cancer Institut, 2024, 22:63.

[11]Milena Falcaro, Alejandra Castañon, Busani Ndlela, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study [J].The Lancet, 2021, 398(10316):2084-2092.

[12]Basu P, Malvi SG, Joshi S, et al. Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study [J]. The Lancet Oncology, 2021, 22(11):1518-1529.

[13]Mélanie Drolet, Élodie Bénard, et al. Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis [J].The Lancet, 2018, 394(10197):497-509.

[14]Yoon D, Lee J-H, et al. Association between human papillomavirus vaccination and serious adverse events in South Korean adolescent girls: nationwide cohort study [J]. The Journal of the American Medical Association, 2022, 25(12):199.

[15]Bruni L, Albero G, Rowley J, et al.. Global and regional estimates of genital human papillomavirus prevalence among men: a systematic review and meta-analysis [J]. Lancet Global Health, 2023, 11(9):1345-1362.

[16]Goldstone SE, Giuliano AR, Palefsky JM, et al. Efficacy, immunogenicity, and safety of a quadrivalent HPV vaccine in men: results of an open-label, long-term extension of a randomised, placebo-controlled, phase 3 trial [J].The Lancet Infectious Diseases, 2022, 22(3):413-425.

[17]Chow Eric P F, Tabrizi Sepehr N, Fairley Christopher K, et al. Prevalence of human papillomavirus in young men who have sex with men after the implementation of gender-neutral HPV vaccination: a repeated cross-sectional study [J]. The Lancet Infectious Diseases, 2021, 21(10):1448-1457.

[18]BrissonM, KimJJ, CanfellK, et al. Impact of HPV vaccination and cervical screening on cervical cancer elimination: acomparative modelling analysis in 78low-income and lower-middle-income countries [J]. Lancet, 2020, 395(10224):575-590.

[19] Castanon A, Landy R, et al. Prediction of cervical cancer incidence in England, UK, up to 2040, under four scenarios: a modelling study [J]. Lancet Public Health, 2018, 3(1): 34-43.

[20]Alkhamis Fatimah H, Alabbas Zainab Alabbas S, et al. Prevalence and Predictive Factors of Cervical Cancer Screening in Saudi Arabia: A Nationwide Study [J]. Cureus, 2023, 15 (11):49331-49331.

[21] Rosa S, Damien G, M G C, et al. Predicting cohort-specific cervical cancer incidence from population-based HPV prevalence surveys: a worldwide study [J]. American Journal of Epidemiology, 2021, 191 (3):402-412.

[22]Feng-Cai Zhu, et al. Head-to-head immunogenicity comparison of an Escherichia coli-produced 9-valent human papillomavirus vaccine and Gardasil 9 in women aged 18–26 years in China: a randomised blinded clinical trial [J]. The Lancet Infectious Diseases, 2023, 23(11):1313-1322.

[23] He WenQiang, Li Chenxi. Recent global burden of cervical cancer incidence and mortality, predictors, and temporal trends [J]. Gynecologic Oncology, 2021, 163(3):583-592.

[24]Shuang L, Min H, Yan Z, et al. Temporal trends in incidence and mortality of cervical cancer in China from 1990 to 2019 and predictions for 2034 [J]. European Journal of Cancer Prevention, 2023, 33(3):252-261.

[25] Lin Shujuan, Gao Kai, et al. Worldwide trends in cervical cancer incidence and mortality, with predictions for the next 15 years [J]. The Journal of Nutrition, 2021, 127(21):4030-4039.

[26]李娟,胡杨,杨雷等. 基于Markov模型不同人乳头瘤病毒疫苗免疫策略下北京市宫颈癌发病的远期预测 [J]. 中国疫苗和免疫, 2019, 25(06): 622-629.

[27]张仲华,刘晨瑛,任会叶等. 2003―2018年间中国女性宫颈癌发病与死亡趋势研究 [J]. 中华疾病控制杂志，2022, 26(01):14-20.

[28]赵敏.云南省宫颈癌发病危险因素和局部晚期宫颈癌治疗效果及卫生经济学评价研究[D].昆明:昆明医科大学, 2023.

[29]Fei Z, Ying W, Yang L, et al. Epidemiologic and Health Economic Evaluation of Cervical Cancer Screening in Rural China [J]. Asian Pacific Journal of Cancer Prevention, 2020, 21(5):1317-1325.

[30]郭建铭,郑斌,李娜,等.人乳头瘤病毒疫苗预防中国女性宫颈癌药物经济学研究的系统评价[J].中国现代应用药学, 2021, 38(04):445-452.

[31]罗燕.人乳头瘤病毒疫苗免疫策略的卫生经济学评价[D].厦门:厦门大学, 2020.

[32]荆丽.马尔科夫决策模型下宫颈癌筛查与疫苗接种的经济学评价及策略优化[D].武汉：华中科技大学, 2021.

[33]Foziya Ahmed Mohammed, Kula Kekeba Tune, et al. Cervical cancer stages, human papillomavirus integration, and malignant genetic mutations: integrative analysis of datasets from four different cohorts [J]. Cancers, 2023, 15 (23).

[34]郎景和. 中华妇产科杂志临床指南荟萃 [Ｍ]．北京：人民卫生出版社，2015.

[35]曹泽毅. 中华妇产科学 [Ｍ]．北京：人民卫生出版社，2014.

[36] Wang Tiannan, Zhang Huina, et al. Updates in cervical cancer screening guidelines, the Bethesda system for reporting cervical cytology, and clinical management Recommendations [J]. Journal of Clinical and Translational Pathology, 2023, 3(2):75-83.

[37]沈铿，崔恒. 常见妇科恶性肿瘤诊治指南（第4版）[Ｍ].北京:人民卫生出版社，2014.

[38]Choi S C. Truncated sequential designs for clinical trials based on Markov chains [J]. Biometrics, 1968, 24(1):159-168.

[39]Furukawa T, Inada H, Kajiya F, et al. Statistical estimation of the prognosis of chronic renal failure: application of the Markov chain [J]. Saishinigaku, 1970, 5(2):346.

[40]Leviton A, Schulman J, Kammerman L, et al. A probability model of headache recurrence [J]. Journal of Chronic Diseases, 1980, 33(7):407-412.

[41]Hillis A, Maguire M, Hawkins B S, et al. The Markov process as a general method for nonparametric analysis of right-censored medical data [J]. Journal of Chronic Diseases, 1986, 39(8):595-604.

[42]Silverstein M D, Albert D A, Hadler N M, et al.Prognosis in SLE: comparison of Markov model to life table analysis [J]. Journal of Clinical Epidemiology, 1988, 41(7): 623-633.

[43]Longini I M, Clark W S, Byers R H, et al. Statistical analysis of the stages of HIV infection using a Markov model [J]. Statistics in Medicine, 1989, 8(7):831-843.

[44]唐晓，乔友林，李国荣等.Markov模型在DALY计算中的应用[J].中国卫生统计, 2012, 29(2):296-298.

[45]林曦敏,丁玎.干扰素治疗慢性乙型肝炎患者的成本效果分析[J].中华肝脏病杂志,1999,7(2):84-87.

[46]刘秋萍,高培,唐迅,等.马尔可夫模型在流行病学筛查成本效果分析中的应用[J].中华流行病学杂志,2021,42(4):728-734.

[47] Oeding F J, Marigi M E, Sotelo S J, et al. Anatomic total shoulder arthroplasty is cost-effective in patients over 67 years of age with glenohumeral osteoarthritis and an intact rotator cuff: a decision-analytic Markov model-based cost-utility analysis [J]. Seminars in Arthroplasty, 2024, 34(1):146-155.

[48]Song D, Wang L. Cost-utility analysis of treating mild stage normal tension glaucoma by surgery in China: a decision-analytic Markov model [J]. Cost Effectiveness and Resource Allocation .2024, 22(1):13-13.

[49]杨馥宁,贺小宁,吴晶. 基于Markov模型对新型抗病毒药物治疗基因1b型慢性丙型肝炎的药物经济学评价 [J]. 中国药学杂志, 2019, 54 (15):1276-1284.

[50] Stevenson Maximillian H, Protus Bridget McCrate, et al. A Pharmacoeconomic Study of Respiratory Medications for Hospice Patients with End-Stage Respiratory Disease [J]. Journal of Palliative Medicine, 2022, 25(12):227-227.

[51]周挺,马爱霞. 生存分析在药物经济学评价Markov模型转移概率计算中的应用[J].中国循证医学杂志, 2018, 18 (10):1129-1134.

[52]Eastin Matthew D, Delmelle Eric, et al. Intra- and interseasonal autoregressive prediction of dengue outbreaks using local weather and regional climate for a tropical environment in Colombia [J]. The American Journal of Tropical Medicine and Hygiene, 2014, 91(3):598-610.

[53] Alrawi Sarmed Saadi Salih, Al-Najjar Eman Younis Mahmoud, et al. Predicting the Food Gap of White Sugar in Iraq using (Autoregressive Integrated Moving Average) (ARIMA) Models [J]. IOP Conference Series: Earth and Environmental Science, 2023, 1262(10).

[54] Matsena Zingoni Zvifadzo, Chirwa Tobias F, et al. HIV Disease Progression Among Antiretroviral Therapy Patients in Zimbabwe: A Multistate Markov Model [J]. Frontiers in Public Health, 2019, 7:326.

[55]Farid Z, Anita M, Ali S, et al. Evaluation of the Trends of Stomach Cancer Incidence in Districts of Iran from 2000-2010: Application of a Random Effects Markov Model [J]. Asian Pacific Journal of Cancer Prevention, 2016, 17(2):661-5.

[56] Matthew R Palmer, Eiko Saito, et al. The impact of alternate HPV vaccination and cervical screening strategies in Japan: a cost-effectiveness analysis [J]. The Lancet Regional Health - Western Pacific, 2024, (44) 101018-101022.

[57]Oaknin Ana, Gladieff Laurence, et al. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial [J]. The Lancet, 2023, 403(10421):31-43.

[58]DeMartel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancerattributable to infections in 2018: a worldwide incidence analysis [J]. Lancet Global Health, 2020, 8(2):180–190.

[59]Stephen E Goldstone, Anna R Giuliano, Joel M Palefsky, et al. Efficacy, immunogenicity, and safety of a quadrivalent HPV vaccine in men: results of an open-label, long-term extensionof a randomised, placebo-controlled, phase 3 trial [J]. The Lancet Infectious Diseases, 2021, 22(3).

[60]Zhao FangHui, Wu Ting, et al. Efficacy, safety, and immunogenicity of an Escherichia coli-produced Human Papillomavirus (16 and 18) L1 virus-like-particle vaccine: end-of-study analysis of a phase 3, double-blind, randomised, controlled trial [J]. The Lancet Infectious Diseases, 2022, 22(12):1756-1768.

[61]HPV Information Centre. Human papillomavirus and related diseases report China [EB/OL]. HPV Information Centre, 2018-11-30.

[62]Eugenio Suárez, Jennifer Smith, et al. Cost-effectiveness of vaccination against cervical cancer: a multi-regional analysis assessing the impact of vaccine characteristics and alternative vaccination scenarios [J]. Vaccine, 2008, 26(5):29-45.

[63] N Demarteau, CH Tang, et al. Cost-effectiveness analysis of the bivalent compared with the quadrivalent human papillomavirus vaccines in Taiwan [J].Value in Health, 2012, 15(5):622-631.

[64]Insinga Ralph, Dasbach Erik, et al. Progression and regression of incident cervical HPV 6, 11, 16 and 18 infections in young women [J]. Infectious Agents and Cancer, 2007, 2(1):15-24.

[65]Garland Suzanne M, Kjaer Susanne K, et al. Impact and effectiveness of the quadrivalent human papillomavirus vaccine: a systematic review of 10 years of real-world experience [J]. Clinical Infectious Diseases, 2016, 63(4):519-527.

[66]Andrés-Gamboa Oscar, Chicaíza Liliana, et al. Cost-effectiveness of conventional cytology and HPV DNA testing for cervical cancer screening in Colombia [J]. Salud pública De Mexico, 2008, 50(4):276-285.

[67]Gillian D Sanders, Al V Taira. Cost effevtiveness of a potential vaccine for human papillomavirus [J]. Emerging Infectious Diseases, 2003, 9(1):37-48.

[68]Myers E R, McCrory D C, et al. Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis [J]. American Journal of Epidemiology, 2018, 151(12):1158-1171.

[69]毕惠，赵更力.子宫颈癌综合防控技术培训教程 [M].北京:人民卫生出版社, 2015: 27-68.

[70]MOSCICKI AB. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females [J]. Journal of The American Medical Association, 2001, 285(23):2995-3002.

[71]中华预防医学会妇女保健分会.子宫颈癌综合防控指南[M].北京:人民卫生出版社 , 2017: 8-15.

[72]莫秀婷.我国宫颈癌预防策略的经济学评价[D].济南:山东大学, 2015.

[73]石菊芳.我国农村地区子宫颈癌筛查方案的卫生经济学评价研究[D].北京:中国协和医科大学, 2009.

[74]Muñoz Nubia, Méndez Fabián, et al. Incidence, duration, and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytology results [J]. The Journal of Infectious Diseases, 2004, 190(12):2077-2087.

[75]Molano Monica, Van den Brule Adriaan, et al. Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study [J]. American Journal of Epidemiology, 2003, 158(5):486-494.

[76]Anna-Barbara Moscicki, Mark Schiffman, et al. Updating the natural history of human papillomavirus and anogenital cancers [J]. Vaccine, 2012, 30(5):24-33.

[77]Muñoz Nubia, Bosch F Xavier, et al. Epidemiologic classification of human papillomavirus types associared with cervical cancer [J]. The New England Journal of Medicine, 2003, 348(6):518-527.

[78]李娟.探讨HPV、TCT、FRD在宫颈病变筛查中的价值[D].长春:长春中医药大学, 2021.

[79]吴俐俐,杨文丰.妇科门诊宫颈癌高危人群采取阴道镜检查后配合宫颈细胞学检查对宫颈癌筛查临床价值[J].广州医药, 2017, 48 (05): 78-80.

[80]中华人民共和国国家统计局.中国统计年鉴·2001[M]. 北京:中国统计出版社2001.1.

[81]中华人民共和国国家统计局.中国统计年鉴2010[M].北京:中国统计出版社2010.9.

[82]中华人民共和国国家统计局.中国统计年鉴2019[M].北京:中国统计出版社2019.9.

[83]麻雪松.基于Leslie模型和影响因素筛选的中国人口预测研究[D].北京:北京交通大学, 2022.

[84]中华人民共和国国家统计局.中国统计年鉴2023[M].北京:中国统计出版社2023.10.