China-CareHPV-CE-Clean-version-Sep-16-2009-3

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1、Cost-effectiveness of primary HPV DNA testing for cervical cancer screening in rural China在中国农村应用HPV基因检测法进行宫颈癌初步筛查的成本效益分析Authors: 作者：Ju-Fang Shi1,2, Karen Canfell2,3*, Jie-Bin Lew2, Fang-Hui Zhao1, Rosa Legood4, Yan Ning5, Leonardo Simonella2,3, Li Ma5, Yoon Jung Kang2,3, Yong-Zhen Zhang6, Megan A.

2、Smith2, Jun-Feng Chen5, Mark Clements7, Xiang-Xian Feng8, Gary Clifford9, Silvia Franceschi9, and You-Lin Qiao1*Affiliations:合作机构1. Department of Cancer Epidemiology, Cancer Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P.R. China中国北京协和医学院中国医学科学院癌症所癌症流行病室2. C

3、ancer Epidemiology Research Unit, Cancer Council NSW, Sydney, Australia澳大利亚悉尼新南威尔士癌症理事会癌症流行病学研究部3. School of Public Health, The University of Sydney, Australia澳大利亚悉尼大学公共卫生学院4. The London School of Hygiene and Tropical Medicine, UK英国伦敦卫生学与热带医学学院5. Dalian Medical University, Dalian, China中国大连医科大学推荐精选6

4、. Shanxi Cancer Institute/Hospital, Taiyuan, China山西省肿瘤医院研究所7. Australian National University, Canberra, Australia澳大利亚国立大学8 Changzhi Medical College, Shanxi, China山西长治医学院9. International Agency for Research on Cancer, Lyon, France法国里昂国际癌症研究署Running title: Cost-effectiveness of screening for HPV in C

5、hina 推荐精选Corresponding authors: 通讯作者Dr Karen Canfell Sydney Rotary Research FellowCancer Epidemiology Research Unit, Cancer Council NSW153 Dowling Street, Woolloomooloo, New South Wales, AustraliaEmail: karencnswcc.org.auTel: + 61 2 93341852; Fax: +61 2 93341778ORProfessor You-Lin QiaoChief of Depar

6、tment of Cancer EpidemiologyCancer Institute/Hospital, Chinese Academy of Medical SciencesPeking Union Medical College17 South Panjiayuan Lane, Chaoyang District, Beijing, 100021, Peoples Republic of ChinaEmail: qiaoyTel: +86 10 8778 8489; Fax: +86 10 6771 3648Key words: Cervical screening; Primary

7、HPV screening; Cost-effectiveness; China关键词：宫颈筛查；HPV初步筛查；成本效益；中国Summary:248 words推荐精选摘要：248字Main article:4, 292 words正文：4292字推荐精选Title page封二Ju-Fang Shi PhDACSBI Research Fellow, Dept. of Cancer Epidemiology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical Col

8、lege, Beijing, P.R. China; and Cancer Epidemiology Research Unit, Cancer Council NSW, Sydney, AustraliaDr Karen Canfell DPhilSydney Rotary Research FellowCancer Epidemiology Research Unit, Cancer Council NSW, Sydney, Australia; andSchool of Public Health, University of SydneyJie-Bin Lew BScSenior Re

9、search ProgrammerCancer Epidemiology Research Unit, Cancer Council NSW, Sydney, AustraliaYan NingLecturer, College of Social Science and Administration, Dalian Medical University, Dalian, China.Dr Rosa Legood DPhilLecturer, Decision Modelling, London School of Hygiene and Tropical Medicine.推荐精选Fang-

10、Hui Zhao MDAssistant Professor, Dept. of Cancer Epidemiology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.Li Ma MDAssociate Professor, Department of Epidemiology, Dalian Medical University, Dalian, China.Leonardo Simonella MPHP

11、hD Student, Cancer Epidemiology Research Unit, Cancer Council NSW, Sydney, Australia; and School of Public Health, University of SydneyYoon Jung Kang MPHPhD Student, Cancer Epidemiology Research Unit, Cancer Council NSW, Sydney, Australia; and School of Public Health, University of SydneyMegan A. Sm

12、ith BECervical Modelling Program ManagerCancer Epidemiology Research Unit, Cancer Council NSW, Sydney, AustraliaYong-Zhen Zhang MPHChief and Associate Professor, Shanxi Cancer Institute/Hospital, Taiyuan, China.推荐精选Jun-Feng Chen MBAProfessor and Director, College of Social Science and Administration

13、, Dalian Medical University, Dalian, China.Mark Clements PhDResearch Fellow, The National Centre for Epidemiology and Population Health, The Australian National University, Canberra, Australia.Xiang-Xian FengProfessor and Vice-Director, Changzhi Medical College, Shanxi, ChinaGary Clifford PhDScienti

14、st, Infection and Cancer Epidemiology Group, International Agency for Research on CancerSilvia Franceschi MDHead, Infection and Cancer Epidemiology Group, International Agency for Research on CancerYou-Lin Qiao PhDProfessor and Chief of Dept. of Cancer Epidemiology, Cancer Institute/Hospital, Chines

15、e Academy of Medical Sciences and Peking Union Medical 推荐精选College, Beijing, P.R. China.推荐精选Summary摘要：Background Human papillomavirus (HPV) screening has been shown to reduce cervical cancer mortality in low-resource settings and a new lower cost rapid-throughput test modality, careHPV (Qiagen, Gait

16、hersburg, USA), has been shown to have high sensitivity and specificity. The objective of this study was to assess cost-effectiveness of careHPV screening in rural China, compared to visual inspection using acetic acid, when used alone (VIA) or in combination with Lugols iodine (VIA/VILI).背景：hpv筛查能够

17、降低有限医疗资源配置下宫颈癌死亡率并且一种新的成本更低的快速处理量检测方式careHPV试剂 (Qiagen, Gaithersburg, USA)，已经显示出高度的敏感性与特异性。本项研究旨在通过与醋染或醋碘联合染色的肉眼观察进行对比，评价在中国农村使用careHPV进行筛查的成本效益。Methods Using data on sexual behaviour, test accuracy, diagnostic practices and costs from studies performed in rural China, we estimated the incremental c

18、ost-effectiveness ratio (ICER) and associated long term reduction in cancer incidence and mortality for once or twice-lifetime screening strategies, and for routine screening at 5-yearly, 10-yearly and IARC-recommended intervals, compared to no intervention.方法：通过使用已完成的中国农村性行为习惯、检验准确性、临床诊断以及成本方面的研究数据

19、，我们对一生进行一至两次筛查的策略和在每5年、10年以及国际癌症研究署推荐的周期内进行的日常筛查活动中增加的成本效益比率并且联系长期以来癌症发病率与死亡率的减少进行评估，并于不做任何干预进行比较。推荐精选Findings For all strategies, the relative ordering of test technologies in reducing cervical cancer incidence and mortality was VIAVIA (least effective); VIA/VILI; careHPV1.0pg/mL threshold and care

20、HPV0.5pg/mL (most effective). Assuming a participation rate of 71%, once-lifetime screening at age 35 years would reduce age-standardised cervical cancer mortality in the population by 8-12% over the long term, with an ICER of US$368-601 per life year saved (LYS). Regular screening would reduce cerv

21、ical cancer mortality by 18-52%, with an ICER of US$459-1547 per LYS (compared to a local per capita GDP of US$2,975).发现：对所有策略而言，减少宫颈癌发病率和死亡率的同类检验技术，效果排序为VIAVILI careHPV1.0pg/mL careHPV0.5pg/mL。经过长期观察，假定一个参与率为71%，在35岁时进行的一生仅有的一次筛查将降低8-12%的宫颈癌死亡率，并且每LYS获得368-601美元。规律的筛查将进一步将宫颈癌死亡率降低18-52%，每LYS获得459-1

22、547美元（人均国内生产总值按2975美元计算）。Interpretation Once-lifetime screening strategies would result in cervical cancer mortality reductions of less than 15%. However, if used as part of a program of more regular screening, careHPV would be an effective and cost-effective method of primary screening in rural Chi

23、na.说明：一生进行一次的筛查策略对宫颈癌死亡率的降低少于15%。但是，如果将其作为规律性筛查的一部分，careHPV将是非常有效的。Funding Chinese Ministry of Science and Technologys program “National Key Technology R&D Program in the 11th Five-Year Plan”; Cancer Foundation of China; Cancer Council NSW, Australia; and UICC ACSBI fellowship.资金：推荐精选Introduction前言：

24、Cancer of the uterine cervix is thought to be a major cancer and a significant cause of death amongst women in The Peoples Republic of China. The projected rates of cervical cancer are increasing in younger women, especially in urban populations, and the number of new cases of cervical cancer is als

25、o increasing due to population ageing.1-2 Based on limited data, it has been suggested that certain rural areas of China have amongst the highest rates of cervical cancer incidence and mortality in the world.3宫颈癌是中国妇女所患的主要癌症，也是导致死亡的重要原因。罹患宫颈癌的人群中，年轻女性特别是城市女性的比例在不断加大，并且新增病例也由于人口老龄化而不断增加。有限的数据表明，中国农村地

26、区已经成为世界上宫颈癌发病率与死亡率最高的地区。Various approaches to screening in rural China and other low resource settings have been considered. Given the critical nature of the role of human papillomavirus (HPV) infection in the causation of cervical cancer, a potential screening strategy is to perform primary testing

27、 for cervical infection with high risk types of HPV. However, to date, the high cost of HPV DNA testing has precluded its use as part of large scale screening programs in low resource settings. Recent efforts have been made to develop a lower cost rapid throughput test. CareHPV is a new technology w

28、hich has been developed via a public/private partnership between Qiagen Inc (Gaithersburg, MD) and PATH Technologies (Seattle, WA, USA), and which has recently been shown to have high sensitivity and specificity for screening women in rural China.4推荐精选在中国农村和其他资源配置较低的地区，多种多样的筛查方法都被考虑过。鉴于HPV感染与宫颈癌的高度正

29、相关性，一种有潜力的筛查策略将被用作对宫颈感染高危险型HPV的初步筛查方法。但迄今为止，在低资源配置地区，HPV基因筛查的高昂费用严重阻碍着其被用作为大规模筛查的一部分。近期的研究成果已经被应用于开发一种更低成本的快速处理量检测方法。Qiagen公司与Path科技以半公开的方式合作开发的新型试剂careHPV已经在近期的中国农村妇女筛查中显示出高度的敏感性和特异性。The objective of the current study was to use local data on sexual behaviour, HPV infections, test accuracy and cost

30、s in rural Shanxi province to construct a model of cervical screening in this setting and to assess the cost-effectiveness and the potential impact on cancer incidence and mortality from various screening strategies. We simulated screening with careHPV at 0.5pg/mL and 1.0pg/mL thresholds, and compar

31、ed outcomes with screening with visual inspection using acetic acid, when used alone (VIA) or in combination with Lugols iodine (VIA/VILI). For each screening test, a number of different strategies were considered, including once or twice-lifetime mobile screening among women aged 35 and/or 45 years

32、, 10-yearly or 5-yearly regular program-based screening among women aged 30-59 years, or International Agency for Research on Cancer (IARC)-recommended intervals of every 3-years in women aged 25-49 years and every 5 years in women aged 50-64 years.5 To parameterise the model, we used data from a nu

33、mber of studies of cervical cancer screening in conducted in rural Chinese populations.4,6,7推荐精选当前研究的目的在于，应用山西省农村性行为习惯、HPV感染、检验准确性和成本等局部数据来建立一个宫颈筛查模型并评估其成本效益和其对不同筛查策略对宫颈癌发病率和死亡率的潜在影响。我们假定使用careHPV at 0.5pg/mL and 1.0pg/mL thresholds，并与VIA或VILI肉眼观察法进行比较。对每种筛查试验而言，许多不同的筛查策略都被考虑过，包括对35岁或45岁妇女进行一生一次或两次的

34、筛查、对3059岁的妇女进行10年一次或5年一次的例行筛查、或者是IARC所推荐的“2549岁3年一次、5064岁5年一次”的周期。为了将这一模型进行量化，我们使用了大量研究中国农村宫颈癌筛查的数据作为指导。推荐精选Methods方法Structure and parameterisation of the HPV transmission and natural history modelsHPV传播和自然历程模型的结构化和参数化We performed a dynamic simulation of HPV transmission in rural China, which was ba

35、sed on self-reported sexual behavioral data for a population of 662 females aged 15-59 years in Yangcheng County, Shanxi Province from the IARC / Cancer Institute of Chinese Academy of Medical Sciences (CICAMS) survey.6 The structure of the transmission model was based on previously developed models

36、 for Finland and Australia.8-9 No information on male or high risk female behaviour was available. Therefore, we assumed that male behaviour was as reported in the IARC survey for female. However, in a small group of males over 40 years of age, people, we assumed a higher annual number of the partne

37、rships to fit to the observed age-specific cross-sectional HPV prevalence in females in Yangcheng study (Table 1).6我们通过IARC的CICAMS的观测，完成了一项基于山西阳城县622名15至59岁妇女关于性行为自述数据的HPV传播的动态仿真过程。传播模型的结构式基于先前芬兰和澳大利亚的发展模型。没有获得关于男性或高危妇女行为的信息。因此，我们假设男性行为和IARC所报告的对女性的观察是一致的。然而，在一小组超过40岁的男性中，我们假定更高的每年合作次数是与在阳城研究中所观察到的女

38、性HPV流行的年龄分组代表性相一致的。推荐精选We adapted and updated a previously developed Markov model of cervical intraepithelial neoplasia (CIN) and invasive cervical cancer natural history,10 which was informed by recently published data on the probability of CIN 3 progressing to invasive cervical cancer.11 The param

39、eters for CIN progression and regression were based on a review of the literature10 and were then fit to data from a well characterised screened population (Australia) after accounting for screening compliance.12 For rural China the model incorporated stage-specific invasive cancer survival data com

40、piled from low resource settings by FIGO.13 In order to calculate age-standardized cancer incidence and mortality rates, we applied the WHO world standard population14 and to estimate total predicted crude cancer incidence rates, we applied the population structure of Yangcheng County.15我们改编和更新了先前开发

41、的关于CIN和侵入性宫颈癌自然进程的Markov模型，这一模型是根据最近发表的关于侵入性宫颈癌CIN 3个阶段可能性的数据来完成的。CIN发展和转归的参数是基于以往文献的综述的，而且它与特征化的澳大利亚筛查人口接受筛查的依从性计数是相符的。对中国农村来说，这个模型还掺杂着由FIGO编译的在低资源配置下时期专一的侵入性癌症的存活数据。为了计算年龄标准化后的癌症发病率和死亡率，我们应用了WHO得世界标准人口概念，并且对总的癌症自然发病率进行预估。我们还应用了阳城县的人口结构数据。Comprehensive data from Yangcheng County on local cancer inc

42、idence and mortality data were not available. Therefore, we assessed the predicted age-specific cancer incidence in relation to the average value for 24 less developed counties using data from IARCs Cancer Incidence in Five Continents.16 推荐精选我们没有获得阳城县当地的癌症发病与死亡率的综合数据。因此，我们使用了IARC在五大洲的癌症发病率数据，对与24 个欠

43、发达县平均值有关的年龄分组癌症发病率进行了预估。Structure and parameterisation of the screening, diagnosis and treatment model筛查、诊断与治疗模型的结构与参数化Shanxi province is divided into 119 counties incorporating over 1000 townships or communities, and villages are the lowest administrative units under townships. Villages usually hav

44、e a small clinic whereas the county-level cities generally have a larger hospital. The screening and management pathways considered included mobile screening conducted by screening teams travelling to village communities, visiting each village on average either once or twice in the lifetime of the t

45、arget population; versus programs for repeated recall for screening at centralised county hospitals, which would potentially occur at 10-yearly, 5-yearly and IARC-recommended intervals. Screening participation assumptions were informed by prior experience in a study in Yangcheng County6 and by unpub

46、lished data from a government-sponsored VIA/VILI screening demonstration project in 3492 women aged 30-59 years who were screened using VIA/VILI in Xiangyuan, Shanxi Province in 2006 (Personal Communication, Professor You-Lin Qiao). Based on these data, we assumed an overall participation rate of 71

47、% for one screening round implemented by a mobile service. For regular program-based screening conducted at county hospitals we assumed an overall age-standardised participation rate of 62% (Table1). 推荐精选山西省划分为199个县，共有超过1000个乡镇和社区。村是最小的行政区划单位。村里通常有小诊所，而县城一般都有大一点的医院。筛查与管理的途径包括：一、移动筛查，即筛查工作组走村串户对目标人群进

48、行仅有的一次或两次走访；二、按照程序在县级医院进行集中筛查，有可能10年一次、5年一次，或者按照IARC推荐的周期进行。筛查的参与率是根据在阳城县先前的研究经验以及一个由政府资助的VIA/VILI筛检试点项目的未公开数据得出的，该项目于2006年在山西襄垣进行，对3492名3059岁妇女应用了VIA/VILI筛检。基于这些数据，我们认为使用一轮移动服务进行一次筛查的总参与率是71%。对在县级医院进行的有规律计划基础的筛查，我们认为标化年龄总参与率为62%。（见表一）Figure 1 depicts the structure of the screening, diagnosis and tr

49、eatment pathways used for each of the test modalities; and the model parameters for screening and diagnosis are given in Table 1 and Appendix Table 1. For VIA screening, test positives were assumed to have immediate colposcopy and therefore no women were lost to diagnostic follow-up. For combined VI

50、A/VILI strategies, VIA positives had immediate colposcopy whereas VIA negatives underwent VILI testing. However, VILI-positive women could not have immediate colposcopy since the use of Lugols iodine precludes full colposcopic examination with acetic acid. In this case, Colposcopy after positive VIL

51、I was assumed to be performed on the next day with some women (10%) lost to follow-up. An age-specific probability of having unsatisfactory visual screening results (in which the original squamocolumnar junction was not fully visible) was incorporated using data from a previous study (Table 1).6 A p

52、roportion (10%) of women with unsatisfactory and negative 推荐精选VIA or VILI test results were assumed to undergo endocervical curettage (ECC) on the same day. We also incorporated an age-specific unsatisfactory rate for colposcopy.6,17图1描述了为每种检验模式的所使用的筛查、诊断与治疗途径的结构。筛查和诊断的模型参数由表1和附录的表1给出。对VIA筛查呈阳性的病例我们

53、直接使用阴道镜检，因此没人会在诊断性随访中被漏掉。对于VIA/VILI复合策略，VIA阳性直接使用阴道镜检，VIA阴性则进一步进行VILI检测。然而，自使用复方碘溶液防碍了利用乙酸进行完整阴道镜检查以来，VILI阳性的妇女便不能直接使用阴道镜检。在这种情况下，因VILI筛查中呈阳性而进行阴道镜检的妇女中，有10%的人在次日完成阴道镜检后在随访中被漏掉了。肉眼检测无法获得满意结果（由于原始鳞柱状上皮交界处无法完全看清）的年龄分组几率联合使用了之前的研究数据（表1）。10%的妇女在无法获得满意结果或VIA/VILI阴性后还要忍受在同一天进行颈内刮除术的痛苦。我们也一并使用了年龄分组化的阴道镜检查不

54、满意率的数据。For careHPV strategies, alternative sampling methods and different thresholds for test positivity were considered. In mobile screening strategies it was assumed that women perform self-sampling using a vaginal brush. Self-sampling and later specimen analyses would occur in a community or vill

55、age clinic. For regular screening strategies where women attend the county hospital for screening, cervical samples were assumed to be taken by a health care provider. In both cases it was assumed that samples were processed on the same day, with HPV-positive women receiving immediate colposcopy and

56、 directed biopsy (as required).对careHPV策略来说，二选其一的抽样方法和各不相同的检测积极性都被考虑到了。在移动筛查策略中，妇女使用阴道刷自己进行采样。而在规律筛查中，妇女们参加的是在县级医院进行的推荐精选采样，采样是由医护人员完成的。在两种策略下，采样都是在当天进行处理的，HPV阳性的需要立即接受阴道镜检和直接的活组织检查。For all strategies, we assumed diagnostic confirmation of the screening results would occur prior to any treatment, be

57、cause in this setting see-and-treat procedures would not currently be clinically acceptable. The diagnostic process involved colposcopy, directed biopsy, and ECC for unsatisfactory colposcopy (Figure 1). The majority of women with a histologically-confirmed CIN2-3 were assumed to be treated with loo

58、p electrocautery excision procedure (LEEP). For once or twice lifetime screening strategies, we assumed that all detected CIN1 were treated by LEEP. 对所有的策略而言，筛查结果的诊断性特征将先于任何形式的治疗之前，因为在这种设置下，发现一例治疗一例的程序在当前临床上是无法被接受的。诊断过程与阴道镜检、活检以及EEC（对不满意阴道镜检者使用）有关（见图1）。多数妇女在CIN23阶段进行LEEP治疗。在一生进行一至两次的筛检策略中，所有被检测到的CIN

59、1期全部使用LEEP进行治疗。For each screening test, we characterised the probability of a positive test result given a satisfactory test and given the underlying health states in the natural history model, which included normal, PCR-HPV positive and CIN1, CIN2 and CIN3+ states. In order to characterise the accu

60、racy of careHPV testing, we used the findings of a study in rural Shanxi (N=2388).4 对每一种筛检试验来说，我们对来自满意度检验和自然进程模型中潜在的健康状态的阳性结果之几率进行特征化。潜在的健康状况包括正常、PCR-HPV阳性以及CIN1、2、3状态。为了特征化careHPV检测的准确度，我们使用了山西农村的研究结果（N=2388）。推荐精选In the study careHPV testing from cervical samples taken by health providers was found

61、 to have a sensitivity for (CIN2+) of 90% and 84% at cut-off thresholds of 0.5pg/mL and 1.0 pg/mL, respectively, with corresponding test specificities of 84% and 88%. The study also found that the sensitivity of careHPV testing for CIN2+ when women provided self-sampled vaginal specimens was compara

62、ble but slightly lower than that of cervical specimens (Table 2). 在对医务工作者所采宫颈样本进行careHPV检测的研究中，我们发现0.5pg/mL和1.0 pg/mL浓度的试剂，对CIN2状态的灵敏度分别是90%和84%，特异性分别为84%和88%。研究还发现，当妇女自己采样是，使用careHPV对CIN2状态进行检测，阴道样本的灵敏度要比宫颈样本灵敏度略低（表2）。Two studies conducted in Shanxi Province have examined the accuracy of VIA screen

63、ing compared to a gold standard of 4-quadrant biopsy; and both found that in this setting the sensitivity of VIA testing was low at 46-48%, but with a corresponding high specificity of 94-96%,4,18 and we used these data to inform the model (Table 2). 在山西省进行的两个研究充分验证了VIA筛查的准确性堪比四分仪活检的“黄金标准”，并且都发现，在这种

64、设置下，VIA筛查的灵敏度低达46-48%，但其对应的特异性却高达94-96%，这些数据都被应用于模型中。To characterise VILI accuracy after negative VIA, we reanalysed and adjusted the sensitivity of VILI testing a Yangcheng County study downwards to account for a potential inflation of up to 20 percentage points in sensitivity in studies of visual

65、inspection which use colposcopic-directed biopsy as the gold standard.18 For the colposcopy performance, we used data from a study which assessed colposcopic accuracy against 4-quadrant biopsy, and found that colposcopy had an推荐精选 81% sensitivity for CIN2+.7 The assumed test characteristics are summarised in Table 2.为