Economic evaluation of HPV DNA test as primary screening method for cervical cancer: A health policy discussion in Greece

Autoři: Anastasios Skroumpelos aff001;  Theodoros Agorastos aff002;  Theodoros Constantinidis aff003;  Kimon Chatzistamatiou aff002;  John Kyriopoulos aff004
Působiště autorů: Roche Pharmaceuticals (Hellas) S.A., Athens, Greece aff001;  Medical School, Aristotle University, Thessaloniki, Greece aff002;  Medical School, Dimocrition University, Komotini, Greece aff003;  Department of Health Economics, National School of Public Health, Athens, Greece aff004
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226335



HPV test appears to be more effective in cervical cancer (CC) screening. However, the decision of its adoption as a primary screening method by substituting the established cytology lies in the evaluation of multiple criteria. Aim of this study is to evaluate the economic and clinical impact of HPV test as primary screening method for CC.


A decision tree and a Markov model were developed to simulate the screening algorithm and the natural history of CC. Fourteen different screening strategies were evaluated, for women 25–65 years old. Clinical inputs were drawn from the HERMES study and cost inputs from the official price lists. In the absence of CC treatment cost data, the respective Spanish costs were used after being converted to 2017 Greek values. One-way and probabilistic sensitivity analyses were conducted.


All screening strategies, that offer as primary screening method triennial HPV genotyping (simultaneous or reflex) alone or as co-testing with cytology appear to be more effective than all other strategies, with regards to both annual CC mortality, due to missed disease (-10.1), and CC incidence(-7.5) versus annual cytology (current practice). Of those, the strategy with HPV test with simultaneous 16/18 genotyping is the strategy that provides savings of 1.050 million euros annually. However, when the above strategy is offered quinquennially despite the fact that outcomes are decreased it remains more effective than current practice (-7.7 deaths and -1.3 incidence) and more savings per death averted (1.323 million) or incidence reduced (7.837 million) are realized.


HPV 16/18 genotyping as a primary screening method for CC appears to be one of the most effective strategies and dominates current practice in respect to both cost and outcomes. Even when compared with all other strategies, the outcomes that it generates justify the cost that it requires, representing a good value for money alternative.

Klíčová slova:

Cancer screening – Cervical cancer – Cytology – Genotyping – Health screening – Human papillomavirus – Human papillomavirus infection – Reflexes


1. International Agency for Research on Cancer. 2018; Available from:

2. Organization for Economic Co-operation and Development. OECD statistics. 2015; Available from:

3. World Health Organization. Global burden of disease. 2016; Available from:

4. Papanicolaou GN. Atlas of Exfoliative Cytology. Boston, Massachusetts: Commonweath Fund University Press; 1954.

5. Gakidou E, Nordhagen S, Obermeyer Z. Coverage of Cervical Cancer Screening in 57 Countries: Low Average Levels and Large Inequalities. PLoS Med.2008; 5(6): e132. doi: 10.1371/journal.pmed.0050132 18563963

6. Agorastos T, Chatzistamatiou K, Zafrakas M, Siamanta V, Katsamagkas T, Constantinidis TC, et al. Epidemiology of HPV infection and current status of cervical cancer prevention in Greece: final results of the LYSISTRATA cross-sectional study. Eur J Cancer Prev. 2014;23:425–31. doi: 10.1097/CEJ.0000000000000060 24977385

7. zur Hausen H. Human papillomaviruses and their possible role in squamous cell carcinomas. Curr Top Microbiol Immunol. 1977;78:1–30. doi: 10.1007/978-3-642-66800-5_1 202434

8. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–9. doi: 10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F 10451482

9. De Vuyst H, Clifford G, Li N, Franceschi S. HPV infection in Europe. Eur J Cancer. 2009;45:2632–9. doi: 10.1016/j.ejca.2009.07.019 19709878

10. Whitlock EP, Vesco K.K., Eder M, JS, Senger CA, Burda BU. Liquid-based cytology and human papillomavirus testing to screen for cervical cancer: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:687–97. doi: 10.7326/0003-4819-155-10-201111150-00376 22006930

11. Cuzick J, Szarewski A, Mesher D, Cadman L, Austin J, Perryman K, et al. Long-term follow-up of cervical abnormalities among women screened by HPV testing and cytology—Results from the Hammersmith study. Int. J. Cancer. 2008;122:2294–300. doi: 10.1002/ijc.23339 18240149

12. Agorastos T, Chatzistamatiou K, Katsamagkas T, Koliopoulos G, Daponte A, Constantinidis T et al. Primary screening for cervical cancer based on High-Risk Human Papillomavirus (HPV) detection and HPV16 and HPV18 genotyping, in comparison to cytology. PLoS One. 2015; 20;10(3):e0119755. doi: 10.1371/journal.pone.0119755 25793281

13. Wright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136:189–97. doi: 10.1016/j.ygyno.2014.11.076 25579108

14. Gage JC, Katki HA, Schiffman M, Fetterman B, Poitras NE, Lorey T, et al. Age-stratified 5-year risks of cervical precancer among women with enrollment and newly detected HPV infection. Int J Cancer. 2015;136:1665–71. doi: 10.1002/ijc.29143 25136967

15. Ronco G, Dillner J, Elfström KM, Tunesi S, Snijders PJ, Arbyn M, et al. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet. 2014; 383:524–32. doi: 10.1016/S0140-6736(13)62218-7 24192252

16. Elfström KM, Smelov V, Johansson AL, Eklund C, Nauclér P, Arnheim-Dahlström L, et al. Long term duration of protective effect for HPV negative women: follow-up of primary HPV screening randomised controlled trial. BMJ. 2014;348: doi: 10.1136/bmj.g130 24435414

17. Cochrane AL, Holland WW. Validation of screening procedures. British Medical Bulletin. 1971;27:3–8. doi: 10.1093/oxfordjournals.bmb.a070810 5100948

18. Holland WW, Stewart S, Masseria C. Policy brief: screening in Europe. Copenhagen: European Observatory on Health Systems and Policies; 2006.

19. Hellenic Statistical Authority. 2016; Available from

20. Kulasingam SL, Havrilesky LJ, Ghebre R, Myers ER. Screening for cervical cancer: a modeling study for the US Preventive Services Task Force. J Low Genit Tract Dis. 2013;17:193–202. doi: 10.1097/LGT.0b013e3182616241 23519288

21. Kjær SK, Frederiksen K, Munk C, Iftner T. Long-term absolute risk of cervical intraepithelial neoplasia grade 3 or worse following human papillomavirus infection: role of persistence. J Natl Cancer Inst. 2010;102:1478–88. doi: 10.1093/jnci/djq356 20841605

22. Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072–9. doi: 10.1093/jnci/dji187 16030305

23. Insinga RP, Dasbach EJ, Elbasha EH, Liaw KL, Barr E. Progression and regression of incident cervical HPV 6, 11, 16 and 18 infections in young women. Infect Agent Cancer. 2007; doi: 10.1186/1750-9378-2-15 17626624

24. Insinga RP, Perez G, Wheeler CM, Koutsky LA, Garland SM, Leodolter S, et al. Investigators. Incident cervical HPV infections in young women: transition probabilities for CIN and infection clearance. Cancer Epidemiol Biomarkers Prev. 2011;20:287–96. doi: 10.1158/1055-9965.EPI-10-0791 21300618

25. Kataja V, Syrjänen K, Mäntyjärvi R, Väyrynen M, Syrjänen S, Saarikoski S et al. Prospective follow-up of cervical HPV infections: life table analysis of histopathological, cytological and colposcopic data. Eur J Epidemiol. 1989;51:1–7.

26. Holowaty P, Miller AB, Rohan T, To T. Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst. 1999;91:252–58. doi: 10.1093/jnci/91.3.252 10037103

27. Matsumoto K, Yasugi T, Oki A, Fujii T, Nagata C, Sekiya S et al. IgG antibodies to HPV16, 52, 58 and 6 L1-capsids and spontaneous regression of cervical intraepithelial neoplasia. Cancer Lett. 2006;231:309–13 doi: 10.1016/j.canlet.2005.02.023 16399232

28. Guedes AC, Zeferino LC, Syrjänen KJ, Brenna SM. Short-term outcome of cervical intraepithelial neoplasia grade 2: considerations for management strategies and reproducibility of diagnosis. Anticancer Res. 2010;306:2319–23.

29. Omori M, Hashi A, Nakazawa K, Yuminamochi T, Yamane T, Hirata S et al. Estimation of prognoses for cervical intraepithelial neoplasia 2 by p16INK4a immunoexpression and high-risk HPV in situ hybridization signal types. Am J Clin Pathol. 2007;128:208–17. doi: 10.1309/0UP5PJK9RYF7BPHM 17638654

30. McCredie MR, Sharples KJ, Paul C, Baranyai J, Medley G, Jones RW et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9:425–34. doi: 10.1016/S1470-2045(08)70103-7 18407790

31. Sasieni P, Castanon A, Parkin DM. How many cervical cancers are prevented by treatment of screen-detected disease in young women? Int J Cancer. 2009;124:461–4. doi: 10.1002/ijc.23922 18844220

32. Goldie SJ, Kim JJ, Wright TC. Cost-effectiveness of human papillomavirus DNA testing for cervical cancer screening in women aged 30 years or more. Obstet Gynecol. 2004;103:619–31. doi: 10.1097/01.AOG.0000120143.50098.c7 15051550

33. Mandelblatt JS, Lawrence WF, Womack SM, Jacobson D, Yi B, Hwang YT et al. Benefits and costs of using HPV testing to screen for cervical cancer. JAMA. 2002;287:2372–81. doi: 10.1001/jama.287.18.2372 11988058

34. Insinga RP, Dasbach EJ, Elbasha EH. Epidemiologic natural history and clinical management of Human Papillomavirus (HPV) Disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model. BMC Infect Dis. 2009; doi: 10.1186/1471-2334-9-119 19640281

35. National Cancer Institute. 2016;

36. Bulkmans NW, Berkhof J, Bulk S, Bleeker MC, van Kemenade FJ, Rozendaal L et al. High-risk HPV type-specific clearance rates in cervical screening. Brit J Cancer. 2007;96:1419–24. doi: 10.1038/sj.bjc.6603653 17342094

37. Meyskens FL Jr, Surwit E, Moon TE, Childers JM, Davis JR, Dorr RT et al. Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. J Natl Cancer Inst. 1994;86(7):539–43. doi: 10.1093/jnci/86.7.539 8133537

38. Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol. 2009;113:18–25. doi: 10.1097/AOG.0b013e31818f5008 19104355

39. National Organization for the Provision of Health Services (EOPYY). 2016;

40. Diaz M, de Sanjose S, Ortendahl J, O’Shea M, Goldie SJ, Bosch FX, et al. Cost-effectiveness of human papillomavirus vaccination and screening in Spain Eur J Cancer. 2010;46:2973–85. doi: 10.1016/j.ejca.2010.06.016 20638840

41. Organization for Economic Co-operation and Development (OECD). OECD Statistics. 2017;

42. Kim JJ, Burger EA, Regan C, Sy S. Screening for Cervical Cancer in Primary Care. A Decision Analysis for the US Preventive Services Task Force. JAMA. 2018; 320:706–714. doi: 10.1001/jama.2017.19872 30140882

43. Lew JB, Simms KT, Smith MA, Hall M, Kang YJ, Xu XM et al. Primary HPV testing versus cytology-based cervical screening in women in Australia vaccinated for HPV and unvaccinated: eff ectiveness and economic assessment for the National Cervical Screening Program. Lancet Public Health 2017; 2: e96–107. doi: 10.1016/S2468-2667(17)30007-5 29253402

44. Holmes J, Hemmett L, Garfield S. The cost-effectiveness of human papillomavirus screening for cervical cancer. A review of recent modelling studies. Eur J Health Econ. 2005;6:30–7. doi: 10.1007/s10198-004-0254-1 15682286

45. Huh WK, Williams E, Huang J, Bramley T, Poulios N. Cost effectiveness of human papillomavirus-16/18 genotyping in cervical cancer screening. Appl Health Econ Health Policy. 2015;13:95–107. doi: 10.1007/s40258-014-0135-4 25385310

46. Kim JJ, Wright T, Goldie SJ. Cost-effectiveness of Human Papillomavirus DNA testing in the United Kingdom, the Netherlands, France and Italy. J Natl Cancer Inst. 2005;97:888–95. doi: 10.1093/jnci/dji162 15956650

47. Sroczynskia G, Schnell-Indersta P, Mühlbergera N, Langb K, Aidelsburgerb P, Wasemc J, et al. Cost-effectiveness of primary HPV screening for cervical cancer in Germany–a decision analysis. Eur J Cancer. 2011;47:1633–46. doi: 10.1016/j.ejca.2011.03.006 21482103

48. van Rosmalen J, de Kok IMCM, van Ballegooijen M. Cost-effectiveness of cervical cancer screening: cytology versus human papillomavirus DNA testing. BJOG. 2012;119:699–709. doi: 10.1111/j.1471-0528.2011.03228.x 22251259

49. Vijayaraghavan A, Efrusy M, Lindeque G, Dreyer G, Santas C. Cost effectiveness of high-risk HPV DNA testing for cervical cancer screening in South Africa. Gynecol Oncol. 2008;112:377–83. doi: 10.1016/j.ygyno.2008.08.030 19081611

50. Vijayaraghavan A, Efrusy MB, Mayrand MH, Santas CC, Goggin P. Cost-effectiveness of High-risk Human Papillomavirus Testing for Cervical Cancer Screening in Québec. Can J Public Health. 2010;101:220–5. 20737813

51. Wright T, Huang J, Baker E, Garfield S, Hertz D, Cox JT. The Budget Impact of Cervical Cancer Screening Using HPV Primary Screening. Am J Manag Care. 2016;22:95–105.

52. Stoler MH, Schiffman M. Interobserver reproducibility of cervical cytologic and histologic interpretations: realistic estimates from the ASCUS-LSIL Triage Study. JAMA. 2001;21;285:1500–5.

53. Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008;

54. Wright TC, Stoler MH, Behrens CM, Sharma A, Sharma K, Apple R. Interlaboratory variation in the performance of liquid-based cytology: insights from the ATHENA trial. Int J Cancer, 2014; 134(8): 1835–43. doi: 10.1002/ijc.28514 24122508

55. Starfield B. Primary care: balancing health needs, services, and technology. New York: Oxford University Press; 1998.

56. World Health Organization. The Financial Crisis and Global Health. WHO. 2009; doi: 10.1186/1744-8603-5-17

57. World Health Organization. Health in times of global economic crisis: Implications for the WHO European Region. 2009;

58. Sheikh S, Biundo E, Courcier S, Damm O, Launay O, Maes E. A report on the status of vaccination in Europe. Vaccine.2018; 36:4979–4992. doi: 10.1016/j.vaccine.2018.06.044 30037416

59. Goldhaber-Feibert JD, Stout NK, Salomon JA, Kuntz KM, Goldie SJ. Cost-effectiveness of cervical cancer screening with human papillomavirus DNA testing and HPV-16, 18 vaccination. J Natl Cancer Inst. 2008;100:308–20. doi: 10.1093/jnci/djn019 18314477

60. Newhouse JP. Free for all? Lessons from the RAND Health Insurance Experiment. Cambridge, MA: Harvard University Press, 1993.

61. Kue J, Zukoski A, Keon KL, Thorburn S. Breast and cervical cancer screening: exploring perceptions and barriers with Hmong women and men in Oregon. Journal Ethnicity & Health. 2014;19: 311–327.

62. Trivedi AN, Rakowski W, Ayanian JZ. Effect of Cost Sharing on Screening Mammography in Medicare Health Plans. N Engl J Med 2008; 358:375–383. doi: 10.1056/NEJMsa070929 18216358

63. Huh WK, Ault KA, Chelmow D, Davey DD, Goulart RA, Garcia FAR. Use of primary high-risk human papillomavirus testing for cervical cancer screening: Interim clinical guidance. Gynecologic Oncology. 2015;136:178–182. doi: 10.1016/j.ygyno.2014.12.022 25579107

64. World Health Organization. WHO guidelines for screening and treatment of precancerous lesions for cervical cancer prevention. Geneva: WHO press; 2013.

65. US Preventive Services Task Force. Cervical Cancer: Screening. 2016;.

66. Food and Drug Administration. 2016;

67. UK National Screening Committee. 2016;

68. von Karsa L., et al (2015). European guidelines for quality assurance in cervical cancer screening. Summary of the supplements on HPV screening and vaccination. Papillomavirus Research, 1: 22–31.

69. National Institute for Public Health and the Environment. Cervical cancer screening in the Netherlands. 2016;

70. Department of Health, National cervical screening program. 2016;

71. National Screening Unit. 2016;

72. Gültekin M, Akgül B. HPV screening in Islamic countries. The Lancet. 2017;17:368.

73. Rodriguez RC. Cervical Cancer Control in Latin America and the Caribbean: Roundtable Policy Brief. 2016;

74. Ronco G, Giorgi Rossi P, Giubilato P, Del Mistro A, Zappa M, Carozzi F, et al. A first survey of HPV-based screening in routine cervical cancer screening in Italy. Epidemiol Prev. 2015;39:77–83.

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