Despite a well-organised screening programme in the UK, and a marked decrease in cervical cancer incidence since 1988, there were 3,181 new cervical cancer cases and 1,529 deaths reported in 2002. In 2003, the National Health Service Cervical Screening Programme modified its recommendations by increasing the age to begin screening from 20 years to 25 years combined with a more frequent screening interval (every 3 years in women aged 25 to 49 years and 5 years for women between 50 and 64).

Invasive carcinoma of the cervix is preceded by premalignant lesions. These precancerous lesions are defined as cervical intraepithelial neoplasia (CIN), and classified as low grade (CIN 1) or high grade (CIN 2 or CIN 3) according to severity. Prevention of cervical cancer has been based on early detection of these precancerous lesions using conventional Pap smear tests or, more recently, liquid-based cytology (LBC) tests. However, with the knowledge that infection with oncogenic human papillomavirus (HPV) is necessary for the development of cervical cancer 1, alternative methods, beside the Pap smear are being researched to improve cervical cancer prevention. In 2006, the first prophylactic quadrivalent HPV recombinant vaccine (HPV types 6,11,16,18) (Gardasil^®, Merck, Sharpe and Dohme (MSD), Whitehouse Station, New Jersey, USA) has been granted a marketing authorisation in the European Union 2. This vaccine is indicated for the prevention of high grade cervical dysplasia (CIN 2/3), cervical carcinoma, high grade vulvar dysplastic lesions (VIN 2/3) and external genital warts causally related to HPV types 6, 11, 16 and 18. More recently, the European Commission has granted a marketing authorisation for a second cervical cancer vaccine (Cervarix, GlaxoSmithKline Biologicals s.a., Rixensart, Belgium) that is indicated for the prevention of precancerous cervical lesions (high-grade cervical intraepithelial neoplasia [CIN] grades 2 and 3) and cervical cancer causally related to human papillomavirus (HPV) types 16 and 18 3. Although the UK Health Minister has recommended the use of the HPV vaccine for girls aged 12–13 and catch-up for girls aged up to 19 years, a decision has not yet been made regarding which vaccine to use in the National Immunization program 4.

The quadrivalent vaccine showed >90% efficacy in preventing pre-cancerous high grade lesions due to these two HPV types 56. This vaccine presents an opportunity to further reduce cancer incidence and mortality.

Genital warts are the most common sexually transmitted infection in the UK. In 2004, 79,678 first attack cases of genital warts were reported in Genitourinary Medicine (GUM) clinics 7. Of these, 47% were diagnosed in women and 53% in men. Current methods for treating warts include therapies such as cryotherapy, electrocautery, podophyllotoxin and imiquimod. However, up to 40% of patients experience a recurrence of genital warts post-treatment 8. The psychological impact of warts can be high; both men and women report feelings of embarrassment and depression 9. Over 90% of genital warts are attributable to infection with HPV types 6 and 11 10. Results from a Phase III trial of a quadrivalent vaccine that includes HPV types 6 and 11, in addition to the oncogenic HPV types 16 and 18, showed that vaccination prevented >90% of warts 11.

We examined the potential effectiveness and cost-effectiveness of a quadrivalent vaccine targeted at HPV types 6, 11, 16 and 18, administered to a cohort of girls aged 12 through a school-based vaccination programme in conjunction with the current screening programme in the UK over a lifetime period.

We adapted a previously published and validated state-transition Markov model of HPV infection and cervical cancer 1213 to estimate total lifetime costs, life expectancy and incremental cost-effectiveness ratios (ICERs) associated with different screening strategies either alone or in combination with vaccination to prevent HPV types 6, 11, 16 and 18 in the UK. Estimates and ranges used in the model for the natural history are presented in Table 1. Briefly, the model simulates a cohort of women at age 12 and follows them until age 85 years. Movement through the health states of the model (i.e. HPV infection, CIN 1, CIN 2, CIN 3, Cancer [Stages I–IV]) over time is based on yearly transition probabilities derived from the literature. Women who are infected with HPV can have their infection clear, progress, or persist. For those women whose infections persist, the majority is assumed to develop CIN 1 but a minority is assumed to develop CIN 2 directly; these rates are age-dependant. Women who develop CIN 1, CIN 2, or CIN 3 can have their disease progress, regress, or persist. Women with cancer (stages I, II, III, IV) can have their cancer detected during screening or if they present to a health care provider based on symptoms. Women who do not have their disease detected can progress to the next stage, remain in the same stage, or die of cervical cancer. Each year, women also face an age-specific risk of dying from other causes.

These results suggest that adding vaccination to the current screening programme in the UK, to prevent infection with HPV types 6, 11, 16 and 18 is potentially cost-effective. The key parameters that affect this conclusion are the duration of vaccine efficacy and whether a booster is needed to achieve a duration that is sufficiently long to provide protection during the years of peak HPV incidence (modelled as a lifetime duration for this analysis). Our findings are consistent with previous analyses performed in the US that show that duration affects the cost-effectiveness of screening and vaccination compared to screening only 2430. However, in contrast to these analyses, our results suggest that a vaccination programme added to screening in the UK would be cost-effective without the need to change screening interval and/or the age of first screen. In the UK, screening is started at a later age, and a less frequent screening interval is used, compared to the US. The current UK strategy thus avoids the increased costs associated with detecting HPV-related changes, especially in younger women, that are more likely to regress.

To date, all cost-effectiveness analyses of HPV vaccination show that duration of efficacy will be a key to determining how cost-effective the vaccine will be. The need for a long duration of vaccine efficacy is consistent with our understanding of the natural history of HPV infection: progression to cervical cancer can take more than 10 years 41. Currently, there is approximately 5 years of data of vaccine duration 42. Long term monitoring of women currently participating in the vaccine trial will be needed to determine if and when a booster should be given. If a booster is needed our analyses show that the coverage achieved with a booster will affect the overall cost-effectiveness of vaccination and screening compared to screening only. One possible solution for increasing booster coverage beyond the 50% we modelled is if vaccination could be administered during the cervical cancer screening visit.

We did not use a quadrivalent type-specific model for this analysis. There is a need for population-based data that accounts for the distribution of these specific types within CIN from the UK. In addition, data on the impact of the vaccine on the overall reduction in CIN (as opposed to the type-specific reduction in CIN reported to date) due to these specific types, in previously unexposed girls, is also needed, to confirm the pooled estimates reported in the literature. Work is currently underway to refine existing models, including the one used here, to more accurately reflect the expected type-specific reduction in CIN and cancer when girls are vaccinated using data from the UK (Dr R. Barnabas, personal communication, 2007).

The use of QALYs is important since it allows us to incorporate, among other things, feelings of anxiety and embarrassment due to abnormal Pap test results as well as genital warts. However, the utilities used were derived from a study conducted among college-aged students in the US 39. Although utilities derived from a UK population as well as a study of time spent in a given health state would more accurately reflect the morbidity associated with cancer, CIN and warts, this information has yet to be published. Results from the sensitivity analysis show that duration of symptoms has only a modest influence on the results.

Our model is conservative in that it does not take into account the impact of the vaccine on herd immunity. Prior analyses in the US with transmission models that accounted for herd immunity effects 4344 suggest that the ICER for vaccination and screening compared to screening only would be much more attractive, even if the vaccine was only given to girls. In future analyses, we will also need to determine whether vaccinating boys in addition to girls will be cost-effective, taking into account the potential benefit of the HPV 6 and 11 component of the vaccine in preventing genital warts in men.

Although the vaccine has recently been approved for use in the UK, its use is not mandatory 4. In addition, there has been no decision made on the choice of vaccine (Cervarix or Gardasil). As such, patients and payers will have to decide whether the cost of the vaccine represents value for money. To the extent that one vaccine has a higher cost than the other, and is not covered by a national program, vaccine coverage will differ from what we have modeled. Our analyses suggest that although there has not been a move to change screening to offset the costs of adding a vaccination program, one potential benefit of the vaccine that may make it more attractive for both patients and payers, is if eventually, a successful vaccination program allows women to be screened less frequently. As shown, depending on the characteristics of the vaccine, the age and/or frequency of screening may be delayed and still be cost-effective.

Other limitations include lack of a probabilistic sensitivity analysis and the fact that the model provides a conservative estimate of the true value of a quadrivalent HPV vaccine targeted at HPV types 6, 11, 16 and 18, in terms of health benefits as it does not take into consideration the potential reduction of adenocarcinoma, vulvar and vaginal intraepithelial neoplasia, vulval and vaginal cancers, as well as laryngeal papillomatosis associated with the vaccine HPV types 45. In terms of the latter, the benefits of a quadrivalent vaccine are to some extent underestimated in this analysis. In terms of the former, although one study to date has conducted a probabilistic sensitivity analysis to determine credible intervals for the natural history component of the model 46, there is a lack of information to determine the appropriate distributions for use in models this complex. As such, this analysis used triangular distributions, although these have well known limitations. This highlights the need for epidemiologic studies to include information on the distributions as well as point estimates and confidence intervals.

In conclusion, our results suggest that adding a quadrivalent vaccine to the current screening programme in the UK is potentially cost-effective. In order to more accurately quantify the effect that the vaccine will have, future models will need to account for the actual reduction in CIN and cancer based on data from the vaccine trials conducted in the UK, as well as to incorporate herd immunity effects.

For this project, Dr. Kulasingam and Dr Myers have been supported by a grant from SP-MSD. Dr. Kulasingam and Dr Myers have been supported by grants from Merck and CSL-Australia. Dr. Kulasingam has been a consultant for SP-MSD and CSL-New Zealand. Nathalie Largeron is an employee of SP-MSD. Steve Bernard is a former employee of SP-MSD. Dr. Ruanne Barnabas has been a consultant for SP-MSD.

SLK was responsible for the adaptation of a previously developed model used for this analysis, the analysis of the data, interpretation of results and drafting of the manuscript. SB was responsible for providing data and reviewing the manuscript. RVB was responsible for providing data and reviewing the manuscript. NL was responsible for providing data, reviewing the manuscript and providing independent confirmation of the cost-effectiveness results. EM was responsible for developing the original model used for this analysis, providing supervision for the conduct of the study and reviewing the manuscript. All authors have read and approved the final manuscript.