The PREHDICT Project: health-economic modelling of PREvention strategies for Hpv-related Diseases in European CounTries.

Cervical Cancer in Europe

Cervical cancer remains an important health problem in the European Union (EU) where standardized incidence rates vary from 4.7 to 22.3/100,000 women-years and mortality rates vary from 1.1 to 13.7 (Arbyn et al. 2007). Cervical cancer screening programmes have been implemented in many European countries where the incidence of cervical cancer has been substantially reduced. Nevertheless, cervical cancer remains a common disease across the EU countries and prevention needs to be improved.

HPV and vaccination

Cervical cancer is caused by a persistent infection of the human papillomavirus (HPV). There are at least fourteen HPV types that have oncogenic potential and are termed high-risk types (Munoz et al. 2003). They are not only responsible for virtually all cervical cancer cases, but are also linked to penile cancer in men, vaginal and vulvar cancer in women, and to oropharyngeal, laryngeal, and anal cancer in both men and women (Parkin and Bray, 2006). Among the oncogenic types, HPV16 and HPV18 stand out as the most important ones and are found in about 75% of cervical cancer cases (Clifford, et al. 2003). The “low-risk” HPV types are rarely found in cervical cancer but cause other diseases. In particular, HPV6/11 infections are the main cause of genital warts.

Currently, two prophylactic HPV vaccines have been registered by the European Medicines Agency: Gardasil (Merck) that targets HPV types 6, 11, 16, and 18 and Cervarix (GlaxoSmithKline) that targets HPV types 16 and 18. These vaccines have been shown to provide nearly 100% protection against cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3) caused by HPV16 and/or HPV18 in women who had not been exposed to these types before vaccination (Ault, 2007; Paavonen et al. 2007). However, the vaccines offered no protection in women who were infected with either of these HPV types at the time of vaccination and vaccination is therefore expected to be most effective when given to girls before sexual debut and HPV infection is uncommon. Several European countries including the UK, Sweden and the Netherlands, have decided to offer vaccination to girls aged 12 years.

HPV and screening

Cervical screening based on the Pap test has reduced the incidence of cervical cancer but its performance is suboptimal with clinical sensitivity for detecting CIN2/3 of only 50-75% and performance varies across populations. Because HPV causes cervical cancer, testing for HPV DNA is being investigated as an alternative to the Pap test. HPV DNA testing is more sensitive than cytology (sensitivity 90-95%) and shows less variability across populations (Arbyn et al. 2006; Cuzick et al. 2006; Dillner et al, 2008). However, HPV DNA testing is less specific than cytology so it may increase the number of women referred for gynaecological examination. Therefore, the use of HPV DNA testing for screening programme requires careful consideration of the expected costs and benefits. Currently, large clinical trials are ongoing in Sweden (Naucler et al., 2007), the UK (Kitchener et al. 2006), the Netherlands (Bulkmans et al. 2007), and Italy (Ronco et al. 2008) to evaluate the effectiveness of HPV DNA testing for screening.

One of the most important problems with screening is getting women to attend. Some women are not reached by screening and the cervical cancer rates in women that have never had a Pap test is substantial. Attitude studies have shown that non-attenders have a negative view of screening so attendance may improve if these women are offered self-sampling, as found in a Dutch trial where 3,500 non-attending women were invited to be screened by self-sampling (Bais et al. 2007).

Finally, HPV vaccination is expected to decrease the incidence of cervical cancer substantially but not eliminate it because there are at least fourteen different HPV types with oncogenic potential. Therefore, screening will remain necessary after implementation of vaccination but the reductions in CIN and cervical cancer will alter the balance between the costs and benefits. Therefore, new strategies that optimally exploit both vaccination and screening need to be developed.

HPV modelling

Mathematical modelling is required to predict the impact of screening and vaccination on cancer incidence and life-years gained, as well as the medical and non-medical costs. To assess the cost-effectiveness of HPV vaccination, it is important to accurately model the natural process of acquiring and clearing HPV infections. By modelling HPV transmission, the effects of low/moderate vaccination coverage, waning immunity, partial cross-protection against HPV types not included in the vaccines, type-replacement, and adding male vaccination can be assessed. The cost-effectiveness of vaccination and screening can be assessed by means of an individual-based Markov simulation model. In this model, health patterns of individual women are described by switches between health states occurring at discrete time points. By collecting individual health trajectories, longitudinal dependencies can be included which enable modelling of for example, various screening non-attendance patterns, association between vaccination non-attendance and screening non-attendance, and event-related disease development. The dynamic transmission model and the individual-based Markov simulation model can be integrated via the force of infection function (Kim et al., 2008) which describes the instantaneous rate of HPV transmission. In a non-vaccinated population, this rate can be estimated from the data and is substituted into a simulation-based screening model. In a (partially) vaccinated population, the force of infection will be lower both for vaccinated and non-vaccinated individuals (due to herd immunity), and needs to be redetermined by means of the dynamic transmission model. The integrated modelling approach enables us to assess both the effect of vaccination and the impact on screening programmes for the European setting.

Reference List

Arbyn M, Raifu AO, Autier P, Ferlay J (2007) Burden of cervical cancer in Europe: estimates for 2004. Ann Oncol 18: 1708-1715

Arbyn M, Kyrgiou M, Simoens C, Raifu AO, Koliopoulos G, Martin-Hirsch P, Prendiville W, Paraskevaidis E (2008) Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ 337:a1284.

Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J (2006) Chapter 9: Clinical applications of HPV testing: A summary of meta-analyses. Vaccine 24, Suppl 3: S78-S89

Ault KA (2007) Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 369: 1861-1868

Bais AG, van Kemenade FJ, Berkhof J, Verheijen RH, Snijders PJ, Voorhorst F, Babovic M, van BM, Helmerhorst TJ, Meijer CJ (2007) Human papillomavirus testing on self-sampled cervicovaginal brushes: an effective alternative to protect nonresponders in cervical screening programs. Int J Cancer 120: 1505-1510

Barnabas RV, Laukkanen P, Koskela P, Kontula O, Lehtinen M, Garnett GP (2006) Epidemiology of HPV 16 and cervical cancer in Finland and the potential impact of vaccination: mathematical modelling analyses. PLoS Med 3: e138.

Berkhof J, de Bruijne MC, Zielinski GD, Bulkmans NW, Rozendaal L, Snijders PJ, Verheijen RH, Meijer CJ (2006) Evaluation of cervical screening strategies with adjunct high-risk human papillomavirus testing for women with borderline or mild dyskaryosis. Int J Cancer 118: 1759-1768

Bistoletti P, Sennfalt K, Dillner J (2008) Cost-effectiveness of primary cytology and HPV DNA cervical screening. Int J Cancer 122: 372-376

Bulkmans NW, Berkhof J, Rozendaal L, van Kemenade FJ, Boeke AJ, Bulk S, Voorhorst FJ, Verheijen RH, van Groningen K, Boon ME, Ruitinga W, van Ballegooijen M, Snijders PJ, Meijer CJ (2007) Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial. Lancet 370: 1764-1772

Clifford GM, Smith JS, Aguado T, Franceschi S (2003) Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: a meta-analysis. Br J Cancer 89: 101-5

Coupe VM, Berkhof J, Bulkmans NW, Snijders PJ, Meijer CJ (2008) Age-dependent prevalence of 14 high-risk HPV types in the Netherlands: implications for prophylactic vaccination and screening. Br J Cancer 98: 646-651

Coupe, V. M., van Ginkel, J., de Melker, H. E., Snijders, P. J., Meijer, C. J., and Berkhof, J. HPV 16/18 vaccination in the Netherlands: model-based cost-effectiveness. Int J Cancer: 2009;124(4):970-8..

Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, Szarewski A, Birembaut P, Kulasingam S, Sasieni P, Iftner T (2006) Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 119:1095-101.

Dillner J, Rebolj M, Birembaut P, Petry KU, Szarewski A, Munk C, de SS, Naucler P, Lloveras B, Kjaer S, Cuzick J, van BM, Clavel C, Iftner T (2008) Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ 337:a1754

French KM, Barnabas RV, Lehtinen M, Kontula O, Pukkala E, Dillner J, Garnett GP (2007) Strategies for the introduction of human papillomavirus vaccination: modelling the optimum age- and sex-specific pattern of vaccination in Finland. Br J Cancer 96: 514-518

Garland SM, Hernandez-Avila M, Wheeler CM, Perez G, Harper DM, Leodolter S, Tang GW, Ferris DG, Steben M, Bryan J, Taddeo FJ, Railkar R, Esser MT, Sings HL, Nelson M, Boslego J, Sattler C, Barr E, Koutsky LA (2007) Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 356: 1928-1943

Garnett GP (2005). Role of herd immunity in determining the effect of vaccines against sexually transmitted disease. J Infect Dis 191:S97-102.

Gregson S, Nyamukapa CA, Garnett GP, et al (2002). Sexual mixing patterns and sex-differentials in teenage exposure to HIV infection in rural Zimbabwe. Lancet 359:1896-1903.

Hughes JP, Garnett GP, Koutsky L (2002). The theoretical population-level impact of a prophylactic human papilloma virus vaccine. Epidemiology 13:631-639.

Jit M, Choi YH, Edmunds WJ (2008) Economic evaluation of human papillomavirus vaccination in the United Kingdom. BMJ 337:a769

Kim JJ, Brisson M, Edmunds WJ, Goldie SJ (2008) Modeling cervical cancer prevention in developed countries. Vaccine 26 Suppl 10:K76-K86

Kim JJ, Kuntz KM, Stout NK, Mahmud S, Villa LL, Franco EL, Goldie SJ (2007) Multiparameter calibration of a natural history model of cervical cancer. Am J Epidemiol 166: 137-150

Kitchener HC, Almonte M, Wheeler P, Desai M, Gilham C, Bailey A, Sargent A, Peto J (2006) HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Br J Cancer 95: 56-61

Legood R, Gray A, Wolstenholme J, Moss S (2006) Lifetime effects, costs, and cost effectiveness of testing for human papillomavirus to manage low grade cytological abnormalities: results of the NHS pilot studies. BMJ 332: 79-85

Lehtinen M, Herrero R, Mayaud P, et al (2006).Chapter 28: Studies to assess the long-term efficacy and effectiveness of HPV vaccination in developed and developing countries.Vaccine 24S:233-241, 2006

Lehtinen M, French K, Dillner J, et al. Future Med (Therapy) 5:289-294, 2008

Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ (2003) Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348: 518-27

Myers ER, McCrory DC, Nanda K, Bastian L, Matchar DB (2000) Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis. Am J Epidemiol 151: 1158-71

Naucler P, Ryd W, Tornberg S, Strand A, Wadell G, Elfgren K, Radberg T, Strander B, Johansson B, Forslund O, Hansson BG, Rylander E, Dillner J (2007) Human papillomavirus and Papanicolaou tests to screen for cervical cancer. N Engl J Med 357: 1589-1597

Paavonen J, Jenkins D, Bosch FX, Naud P, Salmeron J, Wheeler CM, Chow SN, Apter DL, Kitchener HC, Castellsague X, De Carvalho NS, Skinner SR, Harper DM, Hedrick JA, Jaisamrarn U, Limson GA, Dionne M, Quint W, Spiessens B, Peeters P, Struyf F, Wieting SL, Lehtinen MO, Dubin G (2007) Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 369: 2161-2170

Parkin DM, Bray F (2006) Chapter 2: The burden of HPV-related cancers. Vaccine 24 Suppl 3:S3/11-25.: S3-11-S3/25

Rogoza RM, Ferko N, Bentley J, Meijer CJ, Berkhof J, Wang KL, Downs L, Smith JS, Franco EL (2008) Optimization of primary and secondary cervical cancer prevention strategies in an era of cervical cancer vaccination: a multi-regional health economic analysis. Vaccine 26 Suppl 5:F46-F58.

Ronco G, Giorgi-Rossi P, Carozzi F, Confortini M, Dalla PP, Del MA, Gillio-Tos A, Minucci D, Naldoni C, Rizzolo R, Schincaglia P, Volante R, Zappa M, Zorzi M, Cuzick J, Segnan N (2008) Results at recruitment from a randomized controlled trial comparing human papillomavirus testing alone with conventional cytology as the primary cervical cancer screening test. J Natl Cancer Inst 100: 492-501

Schafer JL, Schenker N. Inference with imputed conditional means. J Am Stat Assoc 95:144-154.

Smith MA, Canfell K, Britherton JML, et al. The predicted impact of vaccination on human papillomavirus infections in Australia. Int J Cancer 123:1854-1863, 2008