The epidemiological and economic impact of a quadrivalent human papillomavirus vaccine (6/11/16/18) in the UK

Transcription

1 DOI: /j x Epidemiology The epidemiological and economic impact of a quadrivalent human papillomavirus vaccine (6/11/16/18) in the UK EJ Dasbach, RP Insinga, EH Elbasha Health Economic Statistics, Biostatistics and Research Decision Sciences, Merck Research Laboratories, UG1C-60, North Wales, PA, USA Correspondence: Dr EJ Dasbach, Health Economic Statistics, Merck Research Laboratories, UG1C-60, PO Box 1000, North Wales, PA , USA. erik_dasbach@merck.com Accepted 10 March Published OnlineEarly 23 May Objective To assess the potential epidemiological and economic impact of a prophylactic quadrivalent human papillomavirus (HPV) (6/11/16/18) vaccine for preventing cervical cancer, cervical intraepithelial neoplasia grades 2 and 3 (CIN2/3), CIN1 and genital warts. Design Cost-utility analysis. Setting UK. Population Female and male UK population 12 years or older. Methods We adapted a previously developed multi-hpv type dynamic transmission to compare four female vaccination strategies, routine vaccination at age 12 years, and routine vaccination at age 12 years combined with temporary catch-up vaccination at ages 12 14, and years. Main outcomes measures Costs, cases avoided, incremental cost per quality-adjusted life year (QALY). Results The model projected that at year 100, each vaccination strategy could reduce the number of HPV 6/11/16/18-related cervical cancer, CIN2/3, CIN1 and genital wart cases among women by 86, 85, 79 and 89% respectively. Over 25 years, routine vaccination at age 12 years combined with a 12- to 24-year-old catch-up programme was the most effective strategy, reducing the cumulative number of cases of cervical cancer, CIN2/3, CIN1 and genital warts by 5800, , , and 1.1 million respectively. Over 100 years, the incremental cost-effectiveness ratios across all strategies ranged from 5882 to 11,412 per QALY gained. Conclusion In the UK, a quadrivalent HPV vaccination programme that includes a catch-up strategy can reduce the incidence of cervical cancer, CIN and genital warts at a cost per QALY ratio within the range typically regarded as cost-effective. Keywords Cervical intraepithelial neoplasia, cost-effectiveness analysis, economics, epidemiology, human papillomavirus, uterine cervical neoplasms, vaccines. Please cite this paper as: Dasbach E, Insinga R, Elbasha E. The epidemiological and economic impact of a quadrivalent human papillomavirus vaccine (6/11/16/18) in the UK. BJOG 2008;115: Introduction The prophylactic quadrivalent vaccine, Gardasil Ò (Merck & Co. Inc., Whitehouse Station, NJ, USA) has been approved for use in the European Union for the prevention of highgrade cervical dysplasia (cervical intraepithelial neoplasia grades 2 and 3 [CIN2/3]), cervical carcinoma, high-grade vulval dysplastic lesions (vulval intraepithelial neoplasm grades 2 and 3) and external genital warts (condyloma acuminata) causally related to human papillomavirus (HPV) types 6, 11, 16 and 18. 1,2 To formulate HPV vaccination guidelines and to support reimbursement decisions, policy makers will seek information on the epidemiological and economic consequences of immunisation programmes using this quadrivalent HPV vaccine. 3 One source for such information will be projections from mathematical models. 4 For instance, in a previous analysis based on a mathematical model, we projected the epidemiological and economic consequences of a vaccination programme using a quadrivalent HPV vaccine in the USA and found that the programme can be costeffective. 5 In 2007, in the UK, the Department of Health recommended HPV vaccination for the NHS immunisation programme. 6 This HPV immunisation schedule recommends targeting girls aged years of age for routine vaccination ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 947

2 Dasbach et al. and girls up to 18 years of age for a catch-up programme that would last for 2 years. The purpose of this article was to review the results from a model developed to project and examine the epidemiological and economic consequences of a quadrivalent HPV vaccine in the UK. Specifically, this study answers the following questions: What is the potential impact of a prophylactic quadrivalent HPV vaccination on CIN, cervical cancer, cervical cancer mortality and genital warts in the population in the UK? What is the cost-effectiveness of a quadrivalent HPV vaccine immunisation programme when added to the current standard of care (i.e. cervical cancer screening and clinical management of CIN, cervical cancer and genital warts) from the perspective of the healthcare system in the UK? Materials and methods We adapted a previously developed mathematical model for evaluating the public health impact of immunisation programmes using a quadrivalent HPV vaccine in the USA for application in the UK. 5 Details on the model structure and equations have been previously published. 5 Components of the model that were modified for the UK included the demographic characteristics (e.g. mortality), screening, 7 treatment and vaccination strategies as well as clinical, behavioural (i.e. sexual mixing), 8 and economic input parameters. The following describes the screening and vaccination strategies evaluated, model parameters, model output, validation analyses and sensitivity analyses. Screening and vaccination strategies We assumed that all evaluated quadrivalent HPV vaccination strategies would be combined with current cervical cancer screening and HPV disease treatment practices in the UK. We defined the reference vaccination strategy for this analysis to be routine HPV vaccination of girls at age 12 years. We also examined the following HPV vaccination strategies in combination with screening: (1) routine female vaccination at age 12 years and catch-up female vaccination for ages years, (2) routine female vaccination at age 12 years and catch-up female vaccination for ages years and (3) routine female vaccination at age 12 years and catch-up female vaccination for ages years. The catch-up programmes were assumed to be temporary, lasting only for a period of 2 years. Routine vaccination of 12-year-old girls was assumed to be permanent. Model parameters The model requires input values for demographic, behavioural, epidemiological, screening, treatment, vaccine and economic parameters. A comprehensive search of the literature was conducted to obtain values for these parameters. The baseline values and sources for key model parameters for the UK are summarised in Tables 1 and 2 and Tables S1 and S2. Screening and vaccination programme strategy parameters We used data from the Cervical Cancer Screening Programme in England to estimate compliance rates for cytology screening. 7 The prophylactic efficacy of the vaccine against incident HPV 6, 11, 16 and 18 infections was assumed to be 90%. 14 We assumed the prophylactic efficacy of the vaccine against HPV 6-, 11-, 16- and 18-related CIN and genital warts to be 95.2 and 98.9% respectively. 1 Vaccination was assumed not to have an effect on the natural course of HPV infection or disease prevalent at the time of vaccination or occurring after vaccination. We assumed the duration of protection of HPV vaccination to be lifelong for the base case consistent with previous models. 4 The percentage of girls in the population at age 12 years receiving the three-dose vaccine (i.e. coverage) was assumed to be 80%. 15 Vaccine coverage for the catch-up programme was assumed to vary by the age of the target group. In particular, we assumed that the coverage for 12 14, and years of age would be 40, 30 and 25%, respectively, in the first year of the catch-up programme. In the second year, the coverage rates were assumed to be double those of the first year. Economic parameters All costs are reported in 2006 pounds sterling ( ) (Table 1). Total costs of each strategy included the cost of cytology screening; cost of vaccination; total cost of diagnosing and treating detected invasive cervical cancer, CIN or genital wart cases; and the cost of following false-positive results of the Pap screening test. Although the NHS price of the HPV vaccine is 80.50, a volume-based discount is usual for vaccines procured centrally in bulk, as is the case in the UK. For the Table 1. Costs of diagnosing and treating HPV disease ( ) in the UK Parameter Estimate Source Genital wart treatment 133 Langley et al. 9 Liquid-based cytology 29 Karnon et al. 10 screening examination Colposcopy 86 Sherlaw-Johnson et al. 11 Biopsy 72 CIN1 3 treatment* 497 Wolstenholme et al. 39 Localised cervical cancer treatment Regional cervical cancer treatment Distant cervical cancer treatment *CIN1 cases treated (versus passively managed) 5 50% (estimate). 948 ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

3 Impact of quadrivalent HPV vaccine in the UK Table 2. Health utility values 12,13 Condition Estimate Genital wart 0.91 CIN CIN CIN Localised cervical cancer treatment 0.76 Regional cervical cancer treatment 0.67 Distant cervical cancer treatment 0.48 Cervical cancer survivor 0.76 purposes of this analysis, we assumed a cost per dose for the vaccine of 75. A vaccination programme is likely to be predominantly school based and the cost for administration was assumed to be 3.40 per dose for the base case. 16 Hence, the total cost of the HPV vaccine for three doses and administration was assumed to be 236. We did not include productivity costs (i.e. indirect costs) in the analyses. The planning horizon used in the analysis was 100 years. We assumed the size of the population of over 12-year olds at any given point in time over the 100-year horizon to be , with a female male sex ratio of 1. Finally, all costs and effects were discounted to present value at an annual rate of 3.5%. 17 Health utility parameters We measured the impact of screening and vaccination on quality of life and survival using quality-adjusted life years (QALYs). Table 2 shows the health utility estimates used to construct the QALYs. In the absence of UK-specific population data, health utility data collected in the USA were used. 12,13 Behavioural parameters The model simulates the rate at which susceptible individuals acquire HPV infection by accounting for the age-specific frequency and assortativeness of sexual partnerships in the population, the fraction of infected partners and the likelihood of transmission of infection per partnership. We used population data from the 2nd National Survey of Sexual Attitudes and Lifestyles in the UK to model the frequency of sexual partnerships by age and within sexual activity groups. 8 Model output We used a number of measures to assess the epidemiological impact and cost-effectiveness of each vaccination strategy. Epidemiological output included CIN2/3, CIN1, invasive cervical cancer, genital wart cases and cervical cancer-related deaths. The economic output of interest from the model included total costs, quality-adjusted survival and incremental cost per QALY. We measured quality-adjusted survival time by weighting survival time by the quality-of-life adjustment weights associated with each health state (i.e. the health utility values) and integrating the sum of all these weights over the planning horizon. We measured the cost per QALY ratio as the incremental cost difference between two strategies divided by the incremental QALY difference between the two strategies. Simulation method We programmed all model equations and inputs in Mathematica Ò (Wolfram Research, Champaign, IL, USA). We used the NDSolve subroutine in Mathematica version 5.2 to generate numerical solutions for the differential equations making up the model. The following strategy for simulations was followed: First, the baseline parameter estimates were used to solve the model for the prevaccination steady-state values of the variables. Second, we used the prevaccination data as initial values for the vaccination model. Next, we solved for the entire time path of the variables until the system approached a steady state (approximately 100 years). Finally, we used this solution to generate the previously described output for each of the screening and vaccination strategies. Validation analyses Validation and calibration of the natural history component of the model has been described in detail previously. 5 For the UK adaptation, we assessed the predictive validity of the model by comparing model predictions to observed epidemiological data from the literature on the incidence of cervical cancer and genital wart cases in the UK. Sensitivity analyses Extensive sensitivity analyses with previous models 5,18 have identified those parameters that most influenced the results. Hence, we used these prior analyses, as well as those parameters with the largest uncertainty, to guide our sensitivity analyses. These parameters included duration and degree of vaccine protection, vaccine coverage rates, quality-of-life weights, vaccine series cost and the discount rate. In addition, we conducted a pessimistic scenario sensitivity analysis. For this analysis, we assumed that the costs and quality-of-life decrements for HPV diseases and duration of vaccine protection would be less than the values used for the reference case analysis. Finally, given the interest from policy makers on the additional value of protecting against infection with type HPV 6 and 11, we conducted a sensitivity analysis on the effect of protecting against infection with HPV 6 and Results Model validation The model predicted with current screening, in the absence of vaccination, an annual incidence of HPV 16/18-related ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 949

4 Dasbach et al. cervical cancer of 7.0 per among girls and women aged 12 years. The overall incidence of cervical cancer observed in the UK among girls and women aged 12 years is estimated to be 10.2 per , 20 of which approximately 70% is estimated to be attributable to HPV 16/ In addition, the model predicted an incidence of HPV 6/11-related female genital warts of 127 per among girls and women aged 12 years in the absence of vaccination. The overall incidence of genital warts in women observed in the UK is estimated to be 159 per , 22,23 of which approximately 90% are attributable to HPV 6/ (A) Incidence per (B) Incidence per (C) Incidence per (D) 140 Incidence per No vaccination 12-year-old women 12-year-old women+12-to-14 year-old female catch up 12-year-old women+12-to-17 year-old female catch up 12-year-old women+12-to-24 year-old female catch up Time since start of vaccine programme No vaccination 12-year-old women 12-year-old women+12-to-14 year-old female catch up 12-year-old women+12-to-17 year-old female catch up 12-year-old women+12-to-24 year-old female catch up Time since start of vaccine programme No vaccination 12-year-old women 12-year-old women+12-to-14 year-old female catch up 12-year-old women+12-to-17 year-old female catch up 12-year-old women+12-to-24 year-old female catch up Time since start of vaccine programme No vaccination 12-year-old women 12-year-old women+12-to-14 year-old female catch up 12-year-old women+12-to-17 year-old female catch up 12-year-old women+12-to-24 year-old female catch up Time since start of vaccine programme Figure 1. Impact of vaccination strategies on HPV-related disease in girls and women age 12+ years. (A) HPV 16/18-related cervical cancer incidence, (B) HPV 6/11/16/18-related CIN2/3 incidence, (C) HPV 6/11/16/ 18-related CIN1 incidence, (D) HPV 6/11-related genital warts incidence. Epidemiological impact of the HPV vaccination strategies (reference case) Figure 1A shows the incidence of HPV 16/18-related cervical cancer cases over time by vaccination strategy. Across all strategies, the effect of vaccination was to steadily reduce the incidence of cervical cancer cases and deaths until the system approached a steady state, about 100 years after vaccination is initiated in the population. Compared with no vaccination, all vaccination strategies reduced the incidence of cervical cancer cases and deaths by 86% at year 100. A similar dynamic can be seen for the reductions in CIN2/3, CIN1 and genital wart cases as displayed in Figure 1B D. These curves share similar qualitative features with those of cervical cancer. However, because CIN2/3, CIN1 and genital warts occur sooner following HPV infection, the curves are shifted to the left compared with the cervical cancer curves. In the long run, the model predicted that all vaccination strategies would reduce the incidence of CIN2/3, CIN1 and genital warts by 85, 79 and 89% respectively. The primary reason the long-run impact did not differ among the vaccination strategies was because the catch-up vaccination programmes were temporary. Although the long-run reductions in HPV-related disease do not differ significantly among the vaccination strategies, the catch-up vaccination strategies realised both earlier and greater reductions in HPV-related diseases than the routine vaccination strategy that targets girls at the age of 12 years. Moreover, broadening the age range of the catch-up vaccination strategies resulted in greater and earlier reductions in disease. This is evidenced by the area between the curves in Figure 1 and is summarised quantitatively in Table 3. In particular, Table 3 shows the cumulative cases of HPV 6/11/16/18 disease events prevented overall and by HPV type with the most effective vaccination strategy (i.e. routine vaccination at age 12 years combined with a 12- to 24-year-old catch-up programme) relative to no vaccination 25 years after the introduction of the vaccine into the population. For example, under the overall heading in row 3, the model projected that women of CIN2/3 could be prevented over 25 years in the UK by vaccinating girls and women aged years compared with no vaccination. Table 3 also highlights that the benefits of vaccination could be realised early with a large portion of the HPV disease events avoided attributable to preventing infection of HPV types 6 and 11. For example, 97% of the HPV disease events prevented in the first 5 years were attributable to preventing infection of HPV types 6 and ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

5 Impact of quadrivalent HPV vaccine in the UK Table 3. Cumulative HPV 6/11/16/18 disease events prevented over time with routine female vaccination at age 12 years combined with a 12- to 24-year-old female catch-up programme relative to no vaccination in the UK HPV disease event Years since start of vaccination programme HPV types 6/11 related Genital warts (women) Genital warts (men) CIN CIN Total HPV types 16/18 related CIN CIN2/ Cervical cancer Cervical cancer deaths Total Overall Genital warts CIN CIN2/ Cervical cancer Cervical cancer deaths Total Finally, one visual difference among the curves for the different HPV diseases can be seen in Figure 1D. In particular, the incidence of genital warts increases slightly after year 19, decreases again after year 29 and reaches equilibrium after year 70. The reason for this increase in genital wart cases is because the reduction in the pool of susceptible individuals in the population is not great enough to eradicate infection and disease in the population. As a result, the pool of individuals susceptible to infection slowly accrues. This pool of susceptible individuals eventually reaches a critical threshold size by year 19, which results in a slight, temporary increase in cases before decreasing again at year 29. This phenomenon of low disease levels followed by an increase in disease is a recognised dynamic that occurs in vaccinated populations, with coverage levels that are close to the critical coverage level necessary for eradication. 25,26 Economic impact of HPV vaccination strategies (reference case) For each vaccination strategy, we also measured the costs from the HPV diseases avoided relative to no vaccination. Figure 2 summarises the annual, discounted, HPV disease treatment costs prevented in the population in the UK by the most effective vaccination strategy (i.e. the 12- to 24-year-old female vaccination programme) relative to the screening programme without vaccination, stratified by HPV disease. For the first 20 years, the majority of costs avoided are attributable to the prevention of genital wart cases. This is consistent with the notion that genital wart cases occur sooner following HPV infection than cervical cancer and CIN. 27 However, after year 20, the majority of costs avoided through vaccination are attributable to the prevention of cervical cancer. In addition to examining HPV disease costs avoided, we examined total costs incurred and the cost-effectiveness of each strategy in preventing disease. To assess the cost-effectiveness of the vaccination strategies in preventing disease with respect to costs, we began by estimating the total discounted costs and effects (i.e. QALYs) accrued over a 100-year period for Discounted costs avoided 7,000,000 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000,000 0 Genital warts CIN Cervical cancer Years since vaccination Figure 2. Discounted annual HPV disease treatment costs avoided in the population in the UK by a 12- to 24-year-old female routine and catch-up vaccination programme relative to no vaccination programme, stratified by HPV disease. ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 951

6 Dasbach et al. each strategy. These total costs and QALYs are shown in columns 2 and 3, respectively, in Table 4. The strategies in the table are ordered from least effective at the top to most effective at the bottom as measured in QALY units. Next, we calculated the incremental cost incurred to achieve an incremental gain in benefit of each successive strategy. These incremental costs and effects are shown in columns 4 and 5. The final column shows the ratio of the incremental costs to incremental QALYs gained (i.e. the incremental cost-effectiveness ratio). Note that the most effective strategy in the bottom row (i.e. vaccinating girls and women years of age) has the highest cost-effectiveness ratio, 11,412 per QALY gained relative to vaccinating girls and women years of age. In addition, the least effective vaccination strategy (i.e. routine vaccination of girls by the age of 12 years) has a slightly higher cost-effectiveness ratio (i.e per QALY gained) than the cost-effectiveness ratio for the 12- to 14-year-old female vaccination strategy. Hence, routine female 12-year-old vaccination combined with a 12- to 14-year-old female catch-up vaccination strategy would be considered the preferred strategy relative to routine vaccination of girls by the age of 12 years because it is both more effective and more efficient. Thus, we note in Table 4 that routine vaccination of girls at age 12 years combined with catch-up vaccination of 12- to 14- year-old girls and women weakly dominates the routine female 12-year-old vaccination strategy. We conducted a variety of sensitivity analyses on the incremental cost-effectiveness ratios. Table 5 summarises these results. The two most influential parameters on the results were the health utility values and the duration of vaccine protection. Assuming a shorter duration of vaccine protection or smaller quality-of-life benefits decreased the efficiency and the cost-effectiveness of all the vaccination strategies. In fact, when examined collectively with the pessimistic scenario, the cost-effectiveness ratio for the 12- to 24-year-old vaccination strategy increased threefold compared with the reference case cost-effectiveness ratio for this strategy using a scenario in which duration of efficacy was limited, quality-of-life benefits were less and HPV disease costs were lower. Discussion The results from this model can be useful for deciding which age groups are appropriate to target for introducing a quadrivalent HPV (types 6/11/16/18) vaccination programme in the UK. The model showed that during the long run, all vaccination strategies reduced the incidence of HPV-related disease similarly compared with screening without vaccination. However, one of the key findings from this analysis was that introducing a temporary, catch-up vaccination programme may reduce the incidence of HPV-related diseases earlier, more efficiently, and more effectively than a vaccination strategy that does not have a catch-up programme and only targeted girls at the age of 12 years. Moreover, we found that increasing the age band targeted by the catch-up programme resulted in greater reductions in HPV-related disease. Hence, the 12- to 24-year-old vaccination programme had the greatest impact on reducing HPV-related disease among the vaccination strategies evaluated. Targeting broader age groups for vaccination, however, will also result in greater costs. To address this issue, we assessed the cost-effectiveness of each of the vaccination strategies. Based on this assessment, we found that the cost-effectiveness ratios for all of the vaccination strategies fell within the range of what would be considered cost-effective. 28,29 In particular, the cost-effectiveness ratios of the four vaccination strategies were 5890, 5882, 5971 and 11,412 per QALY gained for the routine vaccination strategy at the age of 12 years and the routine plus catch-up vaccination strategies at the ages of 12 14, and years, respectively. Thus, although the current NHS HPV immunisation programme recommendation targets girls up to 18 years of age for catch-up vaccination, broadening the recommendation to target girls and women up to the age of 24 can reduce HPV-related disease Table 4. Cost-effectiveness analysis of alternative vaccination strategies* Strategy Costs ( ) QALYS Incremental costs ( ) Incremental QALYS /QALY** Screening only 9,045, Routine 12-year olds 11,826, ,780, Weakly dominated 112- to 14-year-old catch-up 11,976, ,930, to 17-year-old catch-up 12,129, , to 24-year-old catch-up 12,504, , ,412 *Assumes cost of vaccination series is 236 and duration of protection is lifelong. All costs are measured in 2006 pounds sterling ( ), and costs and QALY are discounted at 3.5%. Time horizon is 100 years. **Compared with the preceding nondominated strategy. Strategy A is weakly dominated if there is another strategy; B, that is both more effective and more efficient than strategy A. 952 ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

7 Impact of quadrivalent HPV vaccine in the UK Table 5. Summary of incremental cost-effectiveness ratios for sensitivity analyses Input variable Routine to 14-year-old strategy ( ) Routine to 17-year-old strategy ( ) Routine to 24-year-old strategy ( ) Reference case ,412 No effect on types 6 and 11 Weakly dominated* 10,147 16,989 Duration of protection 5 10 years Weakly dominated Weakly dominated 16,091 Degree of protection 5 75% Weakly dominated ,627 Greater coverage 5 90% routine, 80% catch-up ,107 Lower coverage 5 50% routine, 25% catch-up Weakly dominated ,015 Utility estimate for HPV-related diseases Weakly dominated 11,835 22,105 No quality-of-life benefits Weakly dominated 15,071 25,815 No discounting Weakly dominated Cost of vaccination series increases 25% Weakly dominated ,828 Pessimistic scenario** Weakly dominated Weakly dominated 32,586 *Compared with the preceding nondominated strategy. Strategy A is weakly dominated if there is another strategy, B, that is both more effective and more efficient than strategy A. **HPV disease costs decreased by 25%, health utility for any HPV-related diseases equals 0.97, and duration of protection equals 10 years. further at a cost-effectiveness ratio that falls within the range of what has typically been considered cost-effective. 30 One factor that contributed to this favourable costeffectiveness ratio was the economic and quality-of-life benefits conferred by preventing genital warts. Figure 2 shows that preventing genital warts had the greatest impact on reducing costs during the first 20 years following introduction of vaccination in the population. This is further illustrated in a sensitivity analysis that excluded the benefits of preventing genital warts (i.e. eliminated protection against HPV 6/11). Specifically, we found that the cost-effectiveness ratio for the 12- to 24-year-old strategy when compared with vaccinating girls and women aged years increased nearly 50% to 16,989 per QALY gained. Another influential parameter in the model included the duration of vaccine protection. High sustained efficacy of the quadrivalent HPV vaccine has been demonstrated through 5 years of follow up to date. 31 Decreasing the duration of vaccine protection to 10 years increased the cost-effectiveness ratios for the 12- to 24-year-old vaccination strategy. An interesting finding from this sensitivity analysis is that all the less-effective vaccination strategies were dominated, and hence were less efficient from a cost-effectiveness standpoint than the most effective vaccination strategy. The reason for this is that when the duration of protection is not lifelong, a more sustained impact on reducing infection and disease in the population can be achieved by targeting a broader age group for vaccination. Finally, we would like to note that the vaccination strategy that did not include a catch-up programme was always dominated by a more effective vaccination strategy that included a catch-up programme in all analyses. Unless coverage is more than 95% for routine vaccination of girls before the age of 12 years, catch-up vaccination programmes appear to be a more effective and efficient vaccination strategy. We believe the dynamic modelling approach used in this evaluation has a number of strengths. First, modelling transmission dynamics can account for both the direct and indirect benefits of vaccination. 25,32 For example Kohli et al. 33 noted that the indirect, secondary benefits of herd immunity were not accounted for in their cohort modelling approach used to evaluate routine, prophylactic bivalent HPV vaccination strategies in the UK. Second, given that the output from this dynamic model is population based, the comparison with population statistics is better aligned than comparison of cohort model output with national registry data. Finally, a dynamic modelling approach is better suited for evaluating vaccination programmes that target heterogeneous populations (e.g. routine vaccination of 12-year olds combined with a 12- to 24-year-old catch-up population) than cohort models that tend to focus on specific age cohorts (e.g. routine vaccination of 12-year olds). However, as with any model, there are limitations. First, we limited the vaccination strategies evaluated to those within the approved age range for vaccination. 1 If the indication for vaccination expands to other age groups, we can expand the model to evaluate these strategies. Second, we did not model any potential interactions between demand for vaccination and demand for cervical cancer screening. In particular, we assumed that the sexually active population had equal access to health care, be it vaccination, screening or treatment. Moreover, if coverage rates for screening decrease with time, then the cost-effectiveness of vaccination will improve. ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 953

8 Dasbach et al. Third, we limited the scope of the model to cervical diseases and genital warts. The quadrivalent HPV vaccine has also demonstrated the ability to reduce precancerous vulval and vaginal lesions. 34 In addition, the quadrivalent vaccine has demonstrated evidence of cross protection (i.e. protecting against HPV diseases associated with infection from other HPV types not included in the vaccine). 35 Incorporating these other benefits into the model will most likely improve the cost-effectiveness ratios further. Fourth, we based vaccine degree of protection on what had been published in the label for Gardasil at the time of the analyses. 2 More recent data have been presented showing that vaccine degree of protection is slightly higher than what was assumed in our analyses. 36 Hence, incorporating the latest efficacy data would slightly improve the cost-effectiveness ratios for vaccination. Fifth, we based administration costs of the vaccine on a study that had estimated what the cost of administration of a vaccine would be for a school-based vaccination programme. Not all individuals targeted for vaccination, however, will be school based. Hence, we conducted a sensitivity analysis on the cost of the vaccine series. We found that even with a 25% increase in the cost of the vaccine series, the costeffectiveness ratios for all the strategies would still fall within a range that would be considered cost-effective. Sixth, we did not account for any potential adverse effects associated with vaccination or screening. Quadrivalent HPV vaccination has been found to be generally well-tolerated. 37 However, HPV vaccination has been associated with a higher incidence of injection site adverse events as well as selfreported fever. 37 Given the nature of these adverse events were brief and not serious, we did not account for these effects in the model. We would expect had we accounted for the adverse effects associated with vaccination as well as screening in the model the impact on the cost-effectiveness ratios would have been minor. Other areas of future development for the model include accounting for mortality and productivity costs (i.e. indirect costs), as has been performed in other vaccine cost-effectiveness analyses. 38 Including these costs would further reduce the cost-effectiveness ratios. Including other diseases associated with HPV infection in the model would also reduce the cost-effectiveness ratios for vaccination. For instance, HPV infection has also been associated with cancers of the anus, penis, vagina, vulva and head and neck as well as recurrent respiratory papillomatosis. As evidence becomes available to support modelling the potential effects of vaccination against these other HPV conditions, the scope of the model will be broadened to incorporate them. Finally, we did not account for homosexual transmission of HPV in the model. Future refinements of the model will also explore this. In summary, the results from this model suggest that in a setting of organised cervical cancer screening in the UK, a prophylactic quadrivalent HPV (6/11/16/18) vaccine programme that includes a catch-up strategy can (1) substantially reduce cervical cancer, CIN and genital warts, (2) improve quality of life and survival and (3) be cost-effective when implemented as a vaccination strategy that targets girls and women years of age. Conflict of interest Gardasil was developed and is marketed by Merck & Co. Inc. E.J.D., E.H.E. and R.P.I. are all employees of Merck & Co. Inc. Contribution to authorship The authors contributed to development of the model, analyses and writing of the manuscript. Funding Development of the model and analyses were funded by Merck & Co. Inc. Acknowledgements The authors wish to thank Nathalie Largeron for her support and Karen R. Collins of JK Associates, Inc., for editorial assistance with this manuscript. Supplementary material The following supplementary materials are available for this article: Table S1. Epidemiological natural history model parameters for the UK. Table S2. Clinical and economic parameters for the UK. Reference List. These materials are available as part of the online article from: j x. (This link will take you to the article abstract) Please note: Blackwell Publishing is not responsible for the content or functionality of any supplementary materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article. j References 1 European Agency for the Evaluation of Medicinal Products (EMEA). European Public Assessment Report (EPAR). London, UK: EMEA [ Accessed 30 November Sanofi Pasteur MSD. Gardasil: the vaccine that can prevent cervical cancer approved for use in the European Union. Lyon, France: Sanofi 954 ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology

9 Impact of quadrivalent HPV vaccine in the UK Pasteur MSD [ 20english%20press%20release%20accord%20dif-% pdf]. Accessed 30 November Markowitz L, Dunne E, Gilsdorf J. Development of Recommendations for HPV Vaccine Use in the United States. Papillomavirus 22nd International Conference and Clinical Workshop, Vancouver, Canada, April 30 May 6, Dasbach EJ, Elbasha EH, Insinga RP. Mathematical models for predicting the epidemiologic and economic impact of vaccination against human papillomavirus infection and disease. Epidemiol Rev 2006;28: Elbasha EH, Dasbach EJ, Insinga RP. Model for assessing human papillomavirus vaccination strategies. Emerg Infect Dis 2007;13: Department of Health (National). HPV Vaccine Recommended for NHS Immunisation Programme. Government News Network, 2007 [www. gnn.gov.uk/environment/fulldetail.asp?releaseid=325799&news AreaID=2]. 7 National Health Service (NHS) Cervical Screening Programme Statistics. Cervical Cancer Screening Program [2005/2006]. Leeds, UK: The Information Centre, 2006 [ Accessed 30 November Erens B, McManus S, Prescott P, Field J, Johnson A, Wellings K, et al. National Survey of Sexual Attitudes and Lifestyles II: Reference Tables and Summary Report, Table National Centre for Social Research, 2002 [ 9 Langley PC, White DJ, Drake SM. The costs of treating external genital warts in England and Wales: a treatment pattern analysis. Int J STD AIDS 2004;15: Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N. Liquidbased cytology in cervical screening: an updated rapid and systematic review and economic analysis. Health Technol Assess 2004; 8:iii, 1 iii, Sherlaw-Johnson C, Philips Z. An evaluation of liquid-based cytology and human papillomavirus testing within the UK cervical cancer screening programme. Br J Cancer 2004;91: Insinga RP, Glass AG, Myers ER, Rush BB. Abnormal outcomes following cervical cancer screening: event duration and health utility loss. Med Decis Making 2007;27: Myers ER, Green S, Lipkus I. Patient Preferences for Health States Related to HPV Infection: Visual Analogue Scales vs Time Trade-Off Elicitation. Proceedings of the 21st International Papillomavirus Conference, 390; Mexico City, Mexico Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Giuliano AR, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol 2005;6: Bramley JC, Wallace LA, Ahmed S, Duff R, Carman WF, Cameron SO, et al. Universal hepatitis B vaccination of UK adolescents: a feasibility and acceptability study. Commun Dis Public Health 2002;5: Trotter CL, Edmunds WJ, Ramsay ME, Miller E. Modeling future changes to the meningococcal serogroup C conjugate (MCC) vaccine program in England and Wales. Hum Vaccin 2006;2:68 73 [ org.uk/page.aspx?o=201973]. 17 National Institute for Clinical Excellence (NICE). Guide to the Methods of Technology Appraisal, May London, UK: National Institute for Clinical Excellence [ Accessed 30 November Elbasha EH, Galvani AP. Vaccination against multiple HPV types. Math Biosci 2005;197: Chesson H. The Potential Cost-Effectiveness of HPV Vaccination in the United States: a review of published and ongoing studies. Advisory Committee on Immunization Practices June 29, Altlanta GA, USA: Centers for Disease Control and Prevention, [ recs/acip/downloads/min-jun06.pdf]. Accessed 30 November Office of National Statistics (ONS). Office for National Statistics. Cancer Statistics Registrations: Registrations of Cancer Diagnosed in 2004, England. Series MB1 no. 34. London, UK: Cancer Research UK [ Accessed 30 November Munoz N, Bosch FX, Castellsague X, Diaz M, de Sanjose S, Hammouda D, et al. Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 2004;111: Health Protection Agency (HPA). Diagnoses and Rates of Selected STIs Seen at GUM Clinics, United Kingdom: National, Regional and Strategic Health Authority Summary Tables. London, UK: HPA [ datatables2004.htm]. Accessed 30 November Hillman RJ, Ryait BK, Botcherby M, Taylor-Robinson D. Changes in HPV infection in patients with anogenital warts and their partners. Genitourin Med 1993;69: Wiley D, Masongsong E. Human papillomavirus: the burden of infection. Obstet Gynecol Surv 2006;61(6 Suppl 1):S Brisson M, Edmunds WJ. Economic evaluation of vaccination programs: the impact of herd-immunity. Med Decis Making 2003;23: Scherer A, McLean A. Mathematical models of vaccination. Br Med Bull 2002;62: Winer RL, Kiviat NB, Hughes JP, Adam DE, Lee SK, Kuypers JM, et al. Development and duration of human papillomavirus lesions, after initial infection. J Infect Dis 2005;191: Center on the Evaluation of Value and Risk in Health. The Cost-Effectiveness Analysis Registry. Boston, MA, USA: Tufts-New England Medical Center, ICRHPS, Geneva, Switzerland: WHO [ org/cearegistry/data/docs/phaseiiiacompleteleaguetable.pdf]. Accessed 30 November World Health Organization (WHO). Tables of costs and prices used in WHO-CHOICE analysis [ en/index.html]. Accessed 30 November Devlin N, Parkin D. Does NICE have a cost-effectiveness threshold and what other factors influence its decisions? A binary choice analysis. Health Econ 2004;13: Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer 2006;95: Edmunds WJ, Medley GF, Nokes DJ. Evaluating the cost-effectiveness of vaccination programmes: a dynamic perspective. Stat Med 1999;18: Kohli M, Ferko N, Martin A, Franco EL, Jenkins D, Gallivan S, et al Estimating the long-term impact of a prophylactic human papillomavirus 16/18 vaccine on the burden of cervical cancer in the UK. Br J Cancer 2007;96: Joura EA, Leodolter S, Hernandez-Avila M, Wheeler CM, Perez G, Koutsky LA, et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet 2007;369: Merck & Co. Merck Submits New Cross-Protection Data for Gardasil Ò to the FDA and Seeks New Indications for Vaginal and Vulvar Cancers. Whitehouse Station, NJ, USA: Merck & Co [ newsroom/press_releases/product/2007_0417.html]. Accessed 30 November Haupt RM. GARDASIL Update: End of Study (16 26 Year Olds) Adult Women (24 45 Year Olds). Atlanta, GA, USA: Centers for Disease ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology 955

10 Dasbach et al. Control and Prevention Centers for Disease Control and Prevention/Advisory Committee on Immunization Practices. [ gov/vaccines/recs/acip/meetings.htm#min]. Accessed 5 March Barr E, Tamms G. Quadrivalent human papillomavirus vaccine. Clin Infect Dis 2007;45: Lieu TA, Ray GT, Black SB, Butler JC, Klein JO, Breiman RF, et al. Projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children. JAMA 2000;283: Wolstenholme JL, Whynes DK. Stage-specific treatment costs for cervical cancer in the United Kingdom. Eur J Cancer 1998;34: ª 2008 Merck & Co., Inc. Journal compilation ª RCOG 2008 BJOG An International Journal of Obstetrics and Gynaecology