Original Article

A Cost-Effectiveness Analysis of Human Papillomavirus Vaccination of Boys for the Prevention of Oropharyngeal Cancer Donna M. Graham, MB, BCh, MRCPUK1; Wanrudee Isaranuwatchai, PhD2; Steven Habbous, MSc1; Claire de Oliveira, PhD3; Geoffrey Liu, MD, FRCPC1; Lillian L. Siu, MD, FRCPC1; and Jeffrey S. Hoch, MA, PhD2

BACKGROUND: Many western countries have established female human papillomavirus (HPV) vaccination programs for the prevention of cervical cancer. The quadrivalent HPV vaccine (HPV4) has proven efficacy against additional HPV-related disease in both sexes, but the cost effectiveness of male HPV vaccination remains controversial. To assess the cost effectiveness of male HPV vaccination in Canada with respect to oropharyngeal cancer (OPC), the authors performed a preliminary cost-effectiveness analysis. METHODS: After an extensive literature review regarding HPV-related OPC in Canadian males, health care costs and clinical effectiveness estimates were obtained. A Markov model was used to compare the potential costs and effectiveness of HPV4 versus no vaccination among boys aged 12 years. A theoretical cohort based on a Canadian population of 192,940 boys aged 12 years in 2012 was assumed to apply the model. A 3-month cycle length was used with a “lifetime” time horizon. The outcome of the analysis was the incremental cost per quality-adjusted life-year (QALY). Sensitivity analyses were conducted on variables, including the vaccine uptake rate and vaccine efficacy. RESULTS: Assuming 99% vaccine efficacy and 70% uptake, HPV4 produced 0.05 more QALYs and saved $145 Canadian dollars (CAD) per individual compared with no vaccine (QALYs and costs were discounted at 5% per year). Assuming 50% vaccine efficacy and 50% uptake, HPV4 produced 0.023 more QALYs and saved $42 CAD. The results indicated that HPV4 in males may potentially save between $8 and $28 million CAD for the theoretical cohort of 192,940 over its lifetime. CONCLUSIONS: On the basis of this model, HPV vaccination for boys aged 12 years may be a cost-effective strategy for the prevention of OPC in C 2015 American Cancer Society. Canada. Cancer 2015;121:1785-92. V KEYWORDS: economic issues and research/treatment, head and neck cancer, statistical methods and models, mathematical methods and models, computer methods and models.

INTRODUCTION The quadrivalent human papillomavirus (HPV) vaccine (HPV4) prevents preinvasive lesions of the cervix, vulva, and vagina and benign HPV-associated lesions in women.1-6 Many countries include female HPV vaccination in their national immunization programs. However, the uptake of such programs varies (Table 1).7-15 Efficacy has been demonstrated for HPV4 in sexually active men with reductions in external genital lesions and anal intraepithelial neoplasia (AIN) by 77.5% to 91.7%.16,17 However, currently, there is no direct evidence of efficacy against other HPV-related malignancies in men. In addition, studies have demonstrated potential benefits to men by optimizing female vaccination because of herd immunity.5,18-20 In western countries, the incidence of HPV-related oropharyngeal carcinoma (HPV-OPC) is increasing more rapidly among men than among women.21-25 It is projected that OPC will become the most common HPV-related cancer in the United States by 2020, surpassing cervical cancer.23 Three published cost-effectiveness analyses that assessed male HPV vaccination and included OPC using differing assumptions about the cost and incidence of HPV-OPC resulted in various assessments of the benefit of HPV vaccination (Supporting Table 1; see online supporting information).26-29 The escalating incidence of HPV-OPC among men has generated discussion about the potential preventative benefit of HPV4 for OPC. In the absence of direct evidence, no consensus has been reached, making HPV-OPC a valid endpoint for the current preliminary analysis. Policy makers in Australia, Canada, and the United States have recommended HPV vaccination for boys.10,30,31 However, male HPV vaccination remains unfunded and is excluded from national immunization programs in many countries worldwide. To assess the potential cost effectiveness of male HPV vaccination in Canada with regard to OPC, we performed a cost-effectiveness analysis using a static model. Corresponding author: Lillian L. Siu, MD, Drug Development Program, Princess Margaret Cancer Center, 610 University Avenue, 5-718, Toronto, Ontario, Canada M5G 2M9; Fax: (011) 416-946-4467; [email protected] 1 Princess Margaret Cancer Center, Toronto, Ontario, Canada; 2Pharmacoeconomics Research Unit, Cancer Care Ontario, Toronto, Ontario, Canada; 3Department of Social and Epidemiological Research, Center for Addiction and Mental Health, Toronto, Ontario, Canada.

Additional Supporting Information may be found in the online version of this article. DOI: 10.1002/cncr.29111, Received: June 23, 2014; Revised: August 18, 2014; Accepted: September 5, 2014, Published online April 13, 2015 in Wiley Online Library (wileyonlinelibrary.com)

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Original Article TABLE 1. Western Countries With Female Human Papillomavirus Vaccination Programs With Year Introduced, Target Age, and Coverage Country

Year Vaccine Introduced

Target Age for Female Population, y

Estimated 3-Dose Coverage, %

Canada US Australia Denmark Norway Sweden UK

2007-2009 2006 2007 2009 2009 2006 2008

9-13: Varies by province 11-12 12-13 12 11-12 13-17 12-13

50-85: Varies by province 33.4 71.2 79 63 24.7 82.8-92

Reference Shearer 20117 CDC 2013,8 Jemal 20139 Immunise Australia Program 201310 Dorleans 201011 Sander 201212 Leval 201213 UK Department of Health 201314 Information Services Division Scotland 2013,15

Abbreviations: CDC, Centers for Disease Control and Prevention.

horizon was lifetime (ie, participants could move between health states every 3 months, and they were followed until death). The outcome of the analysis was the incremental cost per quality-adjusted life-year (QALY). The analysis was conducted from the perspective of the Canadian Ministry of Health and Long-Term Care. In accordance with Canadian economic evaluation guidelines, a 5% discount rate was used to adjust costs and outcomes to current values.32 Data Source

Figure 1. The health states used in the Markov model on human papillomavirus (HPV) vaccination are illustrated among boys aged 12 years. The model begins with a cohort of healthy boys aged 12 years. After each cycle, they may be in 1 of 5 mutually exclusive health states. OPC indicates oropharyngeal cancer.

MATERIALS AND METHODS Patient Population

The population for our study cohort was Canadian boys aged 12 years (the average age of eighth-grade students when female HPV vaccination is provided) (Table 1). Model Structure

We developed a Markov state-transition model using Microsoft Excel (2010; Microsoft Corporation, Redmond, Wash) to compare the costs and effectiveness of HPV4 against the current standard of care (no vaccine) among boys aged 12 years. The model included 5 health states, as outlined in Figure 1, with a 3-month cycle length. This duration was chosen to allow for the completion of single-modality or multimodality treatment with curative intent for OPC within a single cycle. The time 1786

To accurately reflect local practice and costs, we populated the model with data collected from patients with HPVOPC who received treatment at our institution over a 10year period from 2000 to 2010.33,34 Because the data were from the largest provincial treatment center for this disease, they were deemed to be representative of the regional experience. We also used cost data for direct medical costs of patients who received diagnoses of OPC in Ontario from 1997 to 2007 (Supporting Table 2; see online supporting information).35,36 Secondary data from the literature were used to estimate values and ranges for each of the variables within the model, including vaccine efficacy, the oral HPV-infection development rate, the rate of developing HPV-OPC, disease-specific survival from HPV-OPC, and all-cause mortality. The exact numbers and sources of these data are reported in Table 2.16,21,29,33,34,45 The movement of patients between health states was determined by transition probabilities obtained from these data sources. The model began with a cohort of healthy boys aged 12 years in the “well” state. After each cycle, participants could acquire oral HPV infection and enter the “HPV infection” health state. It is known that the majority of HPV infections clear naturally and that disease risk is highly associated with the persistence of infection (ie, longer time infected is associated with higher risk) in a Cancer

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Male HPV Vaccination for OPC Prevention/Graham et al

TABLE 2. Summary of Key Model Parameters Variable

Value (Range)

Vaccine uptake rate, % Vaccine efficacy, % Rate of developing persistent HPV infection, % Rate of developing HPV-positive OPC, % 10-Year DSS from OPC, % All-cause mortality by age and sex: Life tables Cost, $CAD Total costs associated with having OPC: “Cancer” state Total costs associated with living with OPC: “Survival” state Total costs associated with the last year of life with OPC Vaccine Utility Utility score for having OPC: “Cancer” state

Utility score for living with OPC: “Survival” state

50 (30-70) 83.8 (50-99.7) 0.5 (0.25-1)

0.4 (0.2-0.8) 57

12,343 (11,760-12,989

the treatment was effective, or 3) they died from cancer and moved to the “death” state. Among those in the “survival” state, participants could relapse into the “cancer” state at the end of each cycle. While in any of these health states, participants may die from either OPC or another cause.39 HPV vaccination was not associated with any change in health states, because side effects from vaccination, although reported, are rare and transient.8

Reference/ Source See Table 1 Giuliano 2011,16 Chesson 2011 29 Gillison 2012,37 Liberato 201238 Johnson-Obaseki 2012 21 Habbous 201334 Statistics Canada, 2011 39 de Oliveira 2013

Clinical Inputs Transition probabilities

35

496 (421-570

de Oliveira 201335,36

13,671 (12,866-14,507

de Oliveira 201336

400 0.597

0.769

City of Toronto 2012

40

Habbous 2013,33 Habbous 2014,34 Yong 2012,41 Ackerstaff 2009,42 Borggreven 2007,43 Hannouf 2012,44 Kreimer 2013 45 Habbous 2013,33 Habbous 2014,34 Yong 2012,41 Ackerstaff 2009,42 Borggreven 2007,43 Hannouf 2012,44 Kreimer 201345

Abbreviations: $CAD, Canadian dollars; DSS, disease-specific survival; HPV, human papillomavirus; OPC, oropharyngeal cancer

minority of patients.46 Therefore, we focused only on persistent HPV infection, meaning that, once participants had an HPV infection, they could remain in this state until death. The rarity of premalignant oral lesions identified in HPV-OPC47 and the findings of oral HPV infection in asymptomatic individuals48 allowed us to assume a lack of additional health care costs compared with individuals who did not have HPV infection. The utility associated with this state was also similar to the utility associated with the “well” state. Subsequently, from the “HPV infection” health state, participants could develop HPV-OPC (ie, they could move to the “cancer” state). They would stay in the “cancer” state until they met 1 of the following 3 criteria: 1) they remained in this “cancer” state if the first-line anticancer treatment was not effective, 2) they completed treatment and moved to the “survival” state (remission) if Cancer

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We derived transition probabilities from the published literature and institutional data,21,33,34,37-39 and the estimates we used in the model are listed in Table 2. The values obtained using institutional data correlated with those obtained using published data and were deemed representative for the region. Because no current data were available for rates of oral HPV infection progressing to OPC, the estimates were based on incidence and population data. On the basis of the incidence of OPC in males21 expressed as a proportion of the total population of males aged >12 years,49 we obtained an overall OPC incidence of 0.004% in Canadian males aged >12 years. HPV-OPC represents 60% to 75% of all cases of OPC.33,34,50-52 Therefore, we estimated that the proportion of the Canadian male population aged >12 years with HPV-OPC was between 0.002% and 0.003%. In our model, we assumed that, of those 0.5% with oral HPV16/HPV18 infection, 0.4% would develop HPV-OPC (0.002% overall), supporting the more conservative estimate. Effects

The main effect variable was the QALY, a preferencebased utility measure of health-related quality of life. QALYs incorporate both length and quality of life into a single measure.53 From previously published literature and observational studies in patients with head and neck squamous cell cancer (HNSCC),33,34,42-45 we assigned a utility of 0.597 to patients in the “cancer” stage and a utility of 0.769 to patients living in the “survival” stage (Table 2). The utility was weighted based on the probability of receiving different types of treatment (namely, radiotherapy, chemoradiotherapy, chemotherapy, and surgery) in our institution at diagnosis and at disease progression and the utility values used for each of these treatment modalities in HNSCC. The utility associated with the”well” state was 1.0. Cost Inputs

The total costs for each stage of OPC were derived from studies in which the cost variable included costs associated 1787

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1 (Base) 2 3 4 5 6 7 8 9 10 11 12 13

Abbreviations: $CAD, Canadian dollars; DSS, disease-specific survival; QALY, quality-adjusted life year. a These values represent the potential costs saved to the health care system. The model assumes that the population of males aged 12 years in Canada in 2012 was 192,940. In the calculations, decimal places were rounded to the nearest integer.

18,230,901 8,491,289 27,970,512 15,645,505 20,829,802 8,082,257 18,165,301 18,340,876 18,230,901 18,165,301 18,340,876 18,230,901 18,230,901 0.0385 0.0231 0.0539 0.0385 0.0385 0.0225 0.0401 0.0373 0.0611 0.0401 0.0373 0.0611 0.0159 294.49 244.01 2144.97 281.09 2107.96 241.89 294.15 295.06 294.49 294.15 295.06 294.49 294.49 13,671 13,671 13,671 12,866 14,507 13,671 13,671 13,671 13,671 13,671 13,671 13,671 13,671 496 496 496 421 570 496 496 496 496 496 496 496 496 57 57 57 57 57 57 57 57 57 41 73 57 57 83.80 83.80 83.80 83.80 83.80 50 99.70 83.80 83.80 83.80 83.80 83.80 83.80

Scenario

0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.2 1.0 0.5 0.5 0.5 0.5

50 30 70 50 50 50 50 50 50 50 50 50 50

0.40 0.40 0.40 0.40 0.40 0.40 0.40 0.80 0.20 0.40 0.40 0.40 0.40

0.597 0.597 0.597 0.597 0.597 0.597 0.597 0.597 0.597 0.597 0.597 0.478 0.716

0.769 0.769 0.769 0.769 0.769 0.769 0.769 0.769 0.769 0.769 0.769 0.615 0.923

12,343 12,343 12,343 11,760 12,989 12,343 12,343 12,343 12,343 12,343 12,343 12,343 12,343

Terminal State Survival State Cancer State In Survival State In Cancer State 10-Year DSS Estimate, % Rate of Developing Cancer, % Uptake Rate, % Rate of Infection, % Vaccine Efficacy, %

TABLE 3. Base Case and Sensitivity Analysis Results

Health Utility

Cost, $CAD

Incremental Cost, $CAD

Incremental Effect (QALY)

Potential Cost Saved, $CADa

Original Article

with either the “cancer” stage or the “survival” stage (Table 2).16,21,33-45 Direct medical costs were estimated for patients aged 19 years from the Ontario Cancer Registry who were diagnosed with OPC in Ontario from 1997 to 2007.36 Data were accessed through the Institute for Clinical Evaluative Sciences or Cancer Care Ontario from the databases outlined in the supporting tables (see online supporting information).35,36 Our estimates included all costs incurred with physician services and those associated with diagnosis, treatment, and subsequent management, including home care and long-term care (see online supporting information). Costs either were calculated using the resource intensity weight method (if data were obtained from the Discharge Abstract Database and/or the National Ambulatory Care Supporting System), or they already were available in the data set, or they were obtained from other sources.35,36 The 1-time cost of HPV4 was $400 CAD.40 All costs were reported in 2009 CAD. Sensitivity Analyses

To explore uncertainty, the following key parameters in the model were subjected to 1-way sensitivity analyses: vaccine efficacy, HPV infection rate, vaccine uptake rate, the rate of developing cancer from infection, and the cost of having OPC. In the baseline model, we used a vaccine efficacy of 83.8% (95% confidence interval [CI], 61.2%94.4%). This was the per-protocol, observed efficacy against anogenital lesions in the largest published study to date of male vaccination.16 The rate of oncogenic HPV infection was set at 0.5%37,45 with a vaccine uptake rate of 50%, and the rate of developing cancer after infection was 0.4%. Ranges of variables for sensitivity analyses were based on published data whenever available, with a wider range for vaccine efficacy (range, 50%-99.7%). RESULTS In our model, compared with no vaccination for the prevention of HPV-OPC, male HPV vaccination could result in QALYs gained and cost savings favoring the use of HPV4. Because the estimated incremental costeffectiveness ratios were negative, details on differences in costs and effects between the study groups were reported to clarify the meaning of these results. The incremental costs, incremental effects, and potential cost savings for the cohort for each scenario are provided in Table 3. In the base case, when we assumed that vaccine efficacy was 83.8% and that the uptake rate was 50%, the use of HPV4 produced 0.0385 more QALYs and saved $94.49 CAD per individual compared with no vaccine. Cancer

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When the vaccine uptake rate was increased to 70%, the use of HPV4 produced 0.0539 more QALYs and saved $144.97 CAD per individual than no vaccine. When our assumptions were modified to reflect 50% vaccine efficacy and 50% uptake, the use of HPV4 produced 0.0225 more QALYs and saved $41.89 CAD per individual compared with no vaccine. On the basis of a population of 192,940 Canadian boys aged 12 years in 2012, the model indicated that male HPV vaccination potentially could save from $8 to $28 million CAD for this cohort over its lifetime (Table 3). In 1-way sensitivity analyses, cost savings increased when: the vaccine uptake rate increased, cancer treatment costs increased, vaccine efficacy increased, the infection rate increased, and the survival probability increased. Conversely, according to our model, male HPV vaccination may become more costly and less effective than no vaccination in the following scenarios: 1) the vaccine uptake rate is 12% (base case 5 50%); 2) the rate of developing persistent oral HPV infection is 0.11% (base case 5 0.5%); 3) after persistent oral HPV infection, the rate of developing HPV-OPC is 0.09% (base case5 0.4%); and 4) the efficacy rate of HPV4 for preventing OPC is 21% (base case 5 83.8%). DISCUSSION To our knowledge, this is the first study of its kind to use a simplified model that includes assumptions about the pathogenesis and treatment course of HPV-OPC. Prior dynamic cost-effectiveness analyses of male HPV vaccination incorporated OPC but estimated cost data for OPC and underestimated the incidence of HPV-OPC, resulting in differing outcomes (Supporting Table 1; see online supporting information).26-29 Because of the increasing risks of HPV-OPC in men as causes of mortality and morbidity, and because OPC constitutes 78.2% of HPVassociated cancers in men,9 we focused on HPV-OPC to estimate the potential benefit from vaccination. In addition, because the pathway to developing HPV-OPC from infection remains poorly understood, we performed a review of the literature to generate appropriate assumptions regarding the behavior of this disease. The published literature and population-based data were used to approximate the rate of persistent oral HPV infection and subsequent development of HPV-OPC. In addition, given the paucity of data regarding vaccine efficacy against OPC, efficacy estimates were based on results in sexually active men for the prevention of other precancerous lesions, resulting in a lower estimate of vaccine efficacy for boys than for girls. However, higher immune Cancer

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responses have been noted in boys after vaccination with HPV4 compared with girls of a similar age.54 We performed sensitivity analyses on these variables to account for the assumptions made. At the time of OPC diagnosis, treatment strategies for each patient differ, with surgery, radiation, and chemotherapy playing a role either alone or in combination. At the time of disease recurrence, similar complexities exist, and treatment is individualized for each patient. In view of this, we used institutional data to clarify the proportion of patients receiving each treatment modality and to estimate their actual, direct medical costs of care.33-36,42-44 By using these proportions, we calculated weighted health utilities for patients during and after cancer treatment. We acknowledge that practice differs between institutions, depending on local expertise; therefore, costs also may differ by institution. Direct medical costs in the survival stage included home care and outpatient costs; thus, we also incorporated some costs relating to treatmentassociated toxicities. The use of detailed cost data for OPC strengthens this analysis. Indirect costs were not captured for this analysis because there was a lack of comprehensive data. The addition of these costs could have enhanced the study further by demonstrating the effect of disease-related and treatment-related toxicity on work productivity. This is an important consideration, because HNSCC may be associated with a greater impact on quality of life55 and loss of productivity than other cancers.31,56 Indirect costs associated with OPC were assessed in a US study using short-term disability costs for 1 year after diagnosis. For patients with OPC, these costs were $17,876 US dollars (USD) compared with $6916 USD per individual for a matched comparison group.57 Ignoring potential productivity costs generates more conservative results. Although there are distinct similarities between patterns of disease and treatment strategies for HPV-OPC in Canada and the United States, the cost of treatment for HNSCC may differ between the 2 countries. The mean cost of health care for US patients with OPC or oral cancer for 1 year after diagnosis was $79,151 USD for patients with commercial insurance, $59,404 USD for those with Medicaid, and $48,410 USD for those with Medicare.57 This compares with a cost of $25,697 CAD for Canadian males with OPC for the equivalent time period, highlighting the potential magnitude of cost savings in the United States from male HPV vaccination.35 The cost of vaccination was fixed at $400 CAD in the current analysis. Cost has been a major barrier to HPV vaccination in developing-world countries. This should be improved by the recent price reduction for 1789

Original Article

HPV4 in these regions, resulting in a cost of administration for the full vaccine schedule of $13.50 USD.58 Although the magnitude of cost reduction recently applied to HPV4 in developing-world countries is unlikely to be replicated in the developed world, a reduction in vaccine cost would improve cost effectiveness. To our knowledge, only 1 study has provided insight into the efficacy of HPV vaccination against oral infection. In a population of Costa Rican girls who had received the bivalent HPV vaccine, oral HPV infection (HPV16 and HPV18) from oral rinse samples was reduced by 93.3% at 4 years (95% CI, 62.5%-99.7%).59 Unlike other HPV-related cancers, OPC is not associated with precursor lesions. Oral HPV infection may be the only surrogate endpoint available to obtain data on vaccine effectiveness. Therefore, information about the true impact of HPV vaccination on incidence rates of OPC may not be available for decades. Several confounding factors have been implicated in the risk of developing HPV-OPC. These include smoking status and lifetime number of sexual partners and oral sex partners.60 Smoking has an additive effect on the development of oral HPV infection, HPV persistence, and OPC34,60 and adversely affects the prognosis of patients with OPC.34 In our simplified model, we did not account for these variables. Given the existence of established vaccination programs for girls in Canada and the western world, the issue of herd immunity undoubtedly will have an impact on the rate of HPV infection in boys. Studies have highlighted reductions in HPV-related diseases in men since commencing HPV vaccination programs for girls. Australian data have indicated that 28% fewer heterosexual men were diagnosed with genital warts since the introduction of HPV4 in 2007 with estimated vaccine uptake rates for girls of 65%.5 In addition, a 2.7-fold protective effect against penile and scrotal HPV infection among male partners of vaccinated women was reported (odds ratio, 0.37; 95% CI, 0.083-1.6).20 Other models that incorporated OPC for assessing the cost effectiveness of male HPV vaccination (Supporting Table 1; see online supporting information) assumed that the rates of infection transmission, clearance, and progression to malignancy were similar to the rates observed for anogenital cancers. The current simplified, static model does not address herd immunity, because the need for more accurate parameters required to develop a dynamic transition model cannot be fulfilled with the current knowledge about HPV-OPC. We acknowledge that this is a limitation of our study. Although dynamic modeling is preferable to address a 1790

range of questions, a static model may be useful to provide initial estimates of impact when herd immunity is unlikely to produce negative effects.61 Having both dynamic and static models on the same topic would allow us to assess the extent of herd immunity effect in this specific context in the future. The first modeling studies of HPV vaccination programs for the prevention of cervical cancer were based on static models and provided timely and useful information on the cost effectiveness of vaccinating young girls.61 Vaccination uptake rates for girls in the United States and parts of Canada remain low, with variable rates of 32% in the United States and 53% in Ontario (Table 1). Dynamic modeling investigating the effect of vaccination on HPV infection has suggested that female vaccine uptake rates may need to be >80% to limit the need for male vaccination.18,19,29 Men who have sex with men (MSM) do not benefit from herd immunity after female vaccination and would be an ideal target for vaccination programs. In addition, there are higher rates of HPV seropositivity in this group.62 However, reduced efficacy of the vaccine in an older, already sexually active MSM population17 and the complexities around identifying MSM at a young age make selective vaccination for this cohort an infeasible strategy. Lack of inclusion of herd immunity may mean our results overestimate the true potential benefit of male vaccination. Although it was 1 of the key factors prompting the current analysis, the increasing incidence of HPV-OPC is not accounted for in our simplified model. The variables and ranges used in this model are based on currently available data, and, when possible, a more moderate estimate was used. The escalating incidence of OPC in males is documented in North America21,23 but is also pronounced in Japan, England, and Scandinavia.22,24,25 Future research may involve contextualizing the findings of this study using data from other jurisdictions. We have not conducted a probabilistic sensitivity analysis63 given the lack of existing data. Future research should consider presenting uncertainty using probabilistic sensitivity analysis based on empirical data. Additional research may also focus on acquiring further data to support a more complex model to explore HPV vaccination in males, taking into account the issues associated with herd immunity, productivity loss, and confounding factors for the development of HPV-OPC. Performing a direct randomized study is not feasible because of the practical limitations outlined above. Female vaccination has already been proven as a cost-effective strategy for the prevention of benign and premalignant HPV-related conditions in men and Cancer

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women. According to the findings of this preliminary analysis, HPV vaccination for boys aged 12 years may be a cost-effective strategy in relation to the prevention of OPC alone, strengthening the cost effectiveness of a male vaccination program. The argument for funding male HPV vaccination in North America is becoming more compelling given the additional benefits of reductions in genital warts and anal cancer and the potential benefits for the female population because of increased herd immunity. Prospective data collection for male HPV vaccination and OPC may validate these findings in the future. FUNDING SUPPORT No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES Dr. Liu serves on the advisory boards of Pfizer and Novartis.

REFERENCES 1. FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:1915-1927. 2. Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res. 2009;2:868-878. 3. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med. 2007;356:1928-1943. 4. Fairley CK, Hocking JS, Gurrin LC, et al. Rapid decline in presentations of genital warts after the implementation of a national quadrivalent human papillomavirus vaccination programme for young women. Sex Transm Infect. 2009;85:499-502. 5. Donovan B, Franklin N, Guy R, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis. 2011;11:3944. 6. Brotherton J, Gertig D, Chappell G, et al. Catching up with the catch-up: HPV vaccination coverage data for Australian women aged 18-26 years from the National HPV Vaccination Program Register. Commun Dis Intell Q Rep. 2011;35:197-201. 7. Shearer BD. HPV vaccination: understanding the impact on HPV disease. National Collaborating Center for Infectious Diseases Purple Paper, Issue 34. Winnipeg, Manitoba, Canada: National Collaborating Center for Infectious Diseases; 2011:1-18. 8. Centers for Disease Control and Prevention (CDC). Human papillomavirus vaccination coverage among adolescent girls, 2007-2012, and postlicensure vaccine safety monitoring, 2006-2013—United States. MMWR Morb Mortal Wkly Rep. 2013;62:591-595. 9. Jemal A, Simard EP, Dorell C, et al. Annual Report to the Nation on the Status of Cancer, 1975-2009, featuring the burden and trends in human papillomavirus (HPV)-associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013;105:175-201. 10. Immunise Australia Program. Human Papillomavirus (HPV): Information about the National Human Papillomavirus (HPV) Vaccination Program funded under the Immunise Australia Program. Available at: http://health.gov.au/internet/immunise/publishing.nsf/ Content/immunise-hpv. Accessed July 25, 2013. 11. Dorleans F, Giambi C, Dematte L, et al. The current state of introduction of human papillomavirus vaccination into national immunisation schedules in Europe: first results of the VENICE2 2010 survey [serial online]. Euro Surveill. 2010;15:19730.

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