Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Prevention of HPV-Related Cancers in Norway: Cost-Effectiveness of Expanding the HPV Vaccination Program to Include Pre-Adolescent Boys

  • Emily A. Burger ,

    emily.burger@medisin.uio.no

    Affiliation: University of Oslo, Department of Health Management and Health Economics, Oslo, Norway

  • Stephen Sy,

    Affiliation: Harvard School of Public Health, Department of Health Policy and Management, Center for Health Decision Science Boston, Massachusetts, United States of America

  • Mari Nygård,

    Affiliation: Cancer Registry of Norway Department of Research, Oslo, Norway

  • Ivar S. Kristiansen,

    Affiliation: University of Oslo, Department of Health Management and Health Economics, Oslo, Norway

  • Jane J. Kim

    Affiliation: Harvard School of Public Health, Department of Health Policy and Management, Center for Health Decision Science Boston, Massachusetts, United States of America

Prevention of HPV-Related Cancers in Norway: Cost-Effectiveness of Expanding the HPV Vaccination Program to Include Pre-Adolescent Boys

  • Emily A. Burger, 
  • Stephen Sy, 
  • Mari Nygård, 
  • Ivar S. Kristiansen, 
  • Jane J. Kim
PLOS
x

Abstract

Background

Increasingly, countries have introduced female vaccination against human papillomavirus (HPV), causally linked to several cancers and genital warts, but few have recommended vaccination of boys. Declining vaccine prices and strong evidence of vaccine impact on reducing HPV-related conditions in both women and men prompt countries to reevaluate whether HPV vaccination of boys is warranted.

Methods

A previously-published dynamic model of HPV transmission was empirically calibrated to Norway. Reductions in the incidence of HPV, including both direct and indirect benefits, were applied to a natural history model of cervical cancer, and to incidence-based models for other non-cervical HPV-related diseases. We calculated the health outcomes and costs of the different HPV-related conditions under a gender-neutral vaccination program compared to a female-only program.

Results

Vaccine price had a decisive impact on results. For example, assuming 71% coverage, high vaccine efficacy and a reasonable vaccine tender price of $75 per dose, we found vaccinating both girls and boys fell below a commonly cited cost-effectiveness threshold in Norway ($83,000/quality-adjusted life year (QALY) gained) when including vaccine benefit for all HPV-related diseases. However, at the current market price, including boys would not be considered ‘good value for money.’ For settings with a lower cost-effectiveness threshold ($30,000/QALY), it would not be considered cost-effective to expand the current program to include boys, unless the vaccine price was less than $36/dose. Increasing vaccination coverage to 90% among girls was more effective and less costly than the benefits achieved by vaccinating both genders with 71% coverage.

Conclusions

At the anticipated tender price, expanding the HPV vaccination program to boys may be cost-effective and may warrant a change in the current female-only vaccination policy in Norway. However, increasing coverage in girls is uniformly more effective and cost-effective than expanding vaccination coverage to boys and should be considered a priority.

Introduction

Persistent infection with human papillomavirus (HPV), a known causal agent for cervical cancer, is emerging as an important risk factor for several diseases in both women and men. High-risk, oncogenic HPV infections, most importantly HPV-16 and to a lesser extent HPV-18, are responsible for a proportion of vulva, vaginal, anal, penile and oropharygeal cancers (Figure 1). Infection with low-risk HPV, most notably HPV-6 and -11, are responsible for the majority of genital warts and recurrent respiratory papillomatosis (RRP).

thumbnail
Figure 1. Proportion of human papillomavirus (HPV)-16 and -18 related cancers in Norway, by gender.

For oropharyngeal cancers, we considered three sub-sites: 1) oropharynx, 2) base of tongue and 3) tonsils. For all other cancers, we considered all histologies reported at each sub-site. Percentages have been rounded to the nearest whole number.

http://dx.doi.org/10.1371/journal.pone.0089974.g001

In Norway, a 3-dose schedule of the quadrivalent HPV vaccine, shown to have high efficacy against HPV-16, -18, -6, and -11, has been offered to pre-adolescent girls through school-based delivery in the 7th grade since 2009. The most recent cohort of girls (born in 1999) has achieved 2- and 3-dose coverage rates of 79% and 71%, respectively [1]. Worldwide, a growing number of countries recommend or permit HPV vaccination for males aged 9–26, though few have offered to publicly fund the policy [2]. Given the highly transmissible nature of HPV through sexual activity, high vaccination coverage among pre-adolescent girls may provide a high level of indirect benefit to boys, effectively reducing the burden of HPV-related disease in both sexes [3]. Ecological data from Australia and the U.S. support this finding [4], [5]. Generally, cost-effectiveness analyses evaluating HPV vaccine introduction in several countries have concluded that the incremental benefit of expanding HPV vaccination programs to include pre-adolescent boys may not justify the added cost, particularly if vaccination coverage among girls is high [6][8]. One of the most influential parameters in such analyses is vaccine price. In Norway, the market price is roughly $150 per dose; however, pharmaceutical statistics from Norway in 2011–2012 indicate that the nationally-negotiated tender may be half of the market price (i.e., approximately $75 per dose [9]). It is conceivable that future negotiations may continue to press the vaccine price down.

In light of declining vaccine prices and the growing evidence of vaccine impact on reducing multiple HPV-related conditions in both women and men [10], countries such as Norway must assess whether including boys in the publicly funded childhood vaccination program is warranted. In addition, alternate dosing schedules (i.e., two versus three doses) may further reduce the cost per vaccinated individual without decreasing efficacy [11]. A comprehensive analysis across a broad range of vaccine prices for developed countries has not been undertaken. In addition, evaluating the value of expanding the Norwegian HPV vaccination program to include boys has not been conducted but is essential for guiding setting-specific health care policy and is required inter alia for priority-setting in Norway [12]. We aim to assess whether HPV vaccination of pre-adolescent boys is a cost-effective use of finite resources by explicitly considering HPV transmission dynamics, including a wide range of HPV-related conditions, and exploring the impact of different vaccine tender prices.

Methods

Decision analytic approach

We adapted a dynamic model of HPV sexual transmission and multiple disease simulation models to reflect the health and economic burden of HPV-related conditions in Norway across multiple birth cohorts of men and women [7], [13]. We compared the current HPV vaccination program that targets only 12-year-old girls to an expanded program that includes 12-year-old boys. The analysis included outcomes related to the HPV types targeted by the quadrivalent vaccine, including carcinogenic types 16 and 18 and non-carcinogenic types 6 and 11. We simulated the female vaccination program starting in 2009, while male vaccination was assumed to be implemented in 2014; to isolate the impact of vaccinating boys, the costs and benefits for the first five years of the female-only program were not counted. Taking into consideration all HPV-related conditions, we projected long term outcomes across the entire lifetime of the first 30 male and female cohorts under a gender-neutral vaccination program compared to a female-only program. Monetary costs were measured in 2010 Norwegian Kroner (NOK) and converted to US dollars using the average annual 2010 exchange rate ($1 = NOK6.05) [14]. We adopted a societal perspective and discounted costs and health benefits by 4% per year over the lifetime of each simulated cohort, consistent with Norwegian guidelines [15]. We assessed cost-effectiveness by calculating the incremental cost-effectiveness ratio (ICER), defined as the additional cost divided by the additional quality-adjusted life year (QALY) gained associated with one strategy compared to the next less costly strategy. We used a commonly cited Norwegian threshold of NOK500,000 per QALY gained (≈$83,000) to represent a “cost-effective” intervention [16], but also considered alternative thresholds ($30,000–$100,000 per QALY) to reflect the lack of consensus for a single threshold value in Norway15 and a range of threshold values cited in other settings.

Models

We refined a previously-developed dynamic model of HPV-16 and -18 transmission [7], [13] to simulate heterosexual behavior between men and women in Norway and an individual-based disease model [17] to simulate HPV-induced cervical cancer in the context of the current Norwegian screening program. For all non-cervical HPV-related conditions, we used an incidence-based modeling approach to capture the health and economic burdens in both genders.

The dynamic model is age-structured in yearly intervals and simulates multiple birth cohorts over their lifetimes. Individuals are designated into one of four sexual activity groups (i.e., none, low, moderate, high), which governs the rate of partner change per year and varies by age and gender, based on data from two Norwegian sexual behavior surveys [18], [19]. HPV transmission occurs as a function of the number of new partners, prevalence of HPV in the opposite gender, and HPV-type and gender-specific probabilities of transmission from an infected partner to an uninfected partner. We assumed that male-to-female transmission was 0.80 times as much as female-to-male transmission estimated from an empirical study [20]. After clearance from an initial HPV infection, partial gender- and type-specific immunity develops, reducing future rates of acquiring the same type of HPV.

The individual-based stochastic model, previously adapted to the Norwegian context [17], mimics the natural history of cervical cancer and allows for complex screening algorithms to be simulated. Individual girls enter the model and face age-specific monthly probabilities of acquiring HPV, categorized as 16, 18, other high-risk or low-risk types. Individuals can develop precancerous lesions, which may regress naturally, or progress to invasive cervical cancer. Survival from cervical cancer was estimated from the Cancer Registry of Norway and varied based on stage of detection [21].

Initial parameters for both models were based on data from epidemiological and demographic studies [7], [13], [22]. We calibrated the models using a likelihood-based method to fit empirical outcomes observed in Norway, such as HPV prevalence and cervical cancer incidence. Additional explanation of the Norwegian-specific calibration process can be found in (File S1). The natural history of HPV-related non-cervical conditions is not well known; therefore, we elected to develop simplified models simulating the disease incidence rates by age and gender [21] and attributable fraction of vaccine-targeted HPV types for each of these conditions [23], [24]. We used the transmission model to project the reductions in vaccine-type HPV incidence attributable to vaccination, including both direct and indirect protection (i.e., herd immunity). These reductions in HPV infections were used as inputs into the disease simulation models to then project the corresponding reductions in related diseases. For all models, individuals faced all-cause mortality at each time step, and when applicable, excess mortality after disease onset.

Costs

Baseline costs associated with HPV vaccination included costs for all three vaccine doses using the estimated tender price of $75 per dose [9], wastage and supplies. We assumed that 10% [1] of those who initiate vaccine do not complete all three doses, thereby incurring some vaccine costs but no vaccine benefit; however, we examined alternative benefit assumptions in sensitivity analysis. Estimation of costs associated with cervical cancer screening, diagnosis, and treatment is documented in a previous cost-effectiveness analysis [17]. Norwegian-specific treatment costs associated with the other non-cervical HPV-related conditions included all direct medical and nonmedical costs associated with diagnosis, treatment and post-treatment surveillance, if applicable (Table 1). Future costs and benefits for juvenile-onset RRP were discounted to the time of vaccination of the mother. See (File S1) for further explanation of costing methods.

Health-related quality of life

Health state utility weights for cervical cancer varied according to stage (Table 1) [25]. For non-cervical cancers, we opted to use a study that elicited utility values for multiple non-cervical cancers simultaneously. Valuations were elicited using standard gamble from the general population in Australia [26]. In Norway, the long-term impact after surviving a gynecological cancer (average of 12 years) on quality of life has been shown not to differ from the general public [27]. Furthermore, a Danish study that followed women with advanced stage cervical cancer found that quality of life among women 18-months post radiation treatment was comparable to the general population [28]. Based on these data, we conservatively assumed that individuals with detected cancer remained in a state of reduced quality of life for five years, after which individuals returned to their gender- and age-specific utility values elicited from the general population in a neighboring Scandinavian country [29]. For HPV-6 and -11 related conditions, we applied disease-specific utility values for the average duration of the disease (i.e., 3-months for genital warts and 4.2 years for RRP) [30], [31].

Other model inputs

We synthesized available data from Norway, or from surrounding countries when Norwegian-specific data were not available, to inform parameter inputs, such as disease incidence, survival and cases attributable to vaccine-targeted HPV types (Table 1). Our base case assumed vaccine efficacy against disease outcomes related to vaccine-targeted HPV types of 100% for females and 90% for males over the lifetime, in line with a recent systematic review [10]. Additional information may be obtained from the authors upon request.

Analysis

We compared a scenario of routine HPV vaccination of 12-year-old girls only at the current Norwegian 3-dose coverage level (71%) to a scenario that assumes similar coverage is achieved by 12-year-old boys. We calculated the health outcomes and costs of the different HPV-related conditions and explored the impact of different vaccine prices ranging from $20–$160 per dose. We evaluated the impact of model assumptions on cost-effectiveness using one- and multi-way sensitivity analysis. For one-way sensitivity analysis, we varied vaccine efficacy, duration, incidence of oropharyngeal cancer and considered an alternate vaccine dose schedule (assuming two doses confer the same vaccine protection as three doses). To provide an approximate estimate of the impact of the men who have sex with men (MSM) population on results, we systematically reduced the herd immunity benefits conferred to the male-population in the female-only vaccination strategy. For the multi-way sensitivity analysis, we simultaneously varied treatment costs and the attributable fraction of HPV-16 and -18 in each HPV-related condition to determine “optimistic” and “pessimistic” results. We also varied analytic assumptions, such as the discount rate (0% and 3%) and consideration of direct costs only, consistent with Norwegian guidelines [15]. Lastly, we considered a third scenario which involved increasing the coverage rate among pre-adolescent girls to 90%, the level currently achieved by the measles, mumps, rubella (MMR) vaccine administered to pre-adolescent Norwegians aged 11–12. Expanding HPV vaccination coverage for girls was directly compared to extending coverage to boys in order to determine which strategy minimizes the burden of HPV-related conditions in Norway at a reasonable cost.

Results

Epidemiological outcomes

Assuming the current 3-dose vaccination coverage rate among pre-adolescent girls remains constant at 71% with 100% lifelong efficacy, the girls-only vaccination program was projected to substantially reduce future cancer incidence (Table 2). The additional reductions in cancer incidence by adding male vaccination (assuming equal coverage) were modest. We project that, for the same future cohort, female genital warts may decrease by 77% and male genital warts may decrease by 62%, under a female-only vaccination program. For a gender-neutral vaccination program, reductions in genital warts may increase to 85% and 84% among females and males, respectively.

Cost-effectiveness

At the assumed tender price of $75 per dose, the cost per QALY gained from routine vaccination of girls only (compared to no vaccination) was $20,600 when including only benefits related to cervical outcomes and $5,000 when including benefits associated with all female and male HPV-related conditions (Table 3). Expanding the vaccination program to include pre-adolescent boys, assuming the same 3-dose coverage rate and 90% lifelong vaccine efficacy in males, the cost per QALY gained was $145,500 accounting for cervical cancer outcomes only, but fell to $60,100 per QALY gained when including all HPV-related outcomes. The incremental cost-effectiveness ratios of vaccinating both genders compared to vaccinating girls only over a wide range of vaccine prices is shown in Figure 2. Accounting for all HPV-related outcomes, expanding HPV vaccination to boys would be considered cost-effective at a vaccine cost per dose of approximately $101, $62 and $36 for willingness-to-pay thresholds of $83,000, $50,000 and $30,000 per QALY gained, respectively. Therefore, at the current market price, expanding the current HPV vaccination program to include boys would not be considered ‘good value for money.’ When restricting vaccine benefit to only cancers (i.e., no genital warts or RRP), the vaccine cost per dose would have to be at least 30% lower for male vaccination to be considered cost-effective, compared to girls-only vaccination.

thumbnail
Figure 2. Incremental cost effectiveness ratios (ICER) of vaccinating pre-adolescent girls and boys compared to vaccinating pre-adolescent girls only.

Shaded area represents the broad range of willingness-to-pay thresholds ($30,000–$100,000 per QALY gained) accepted across developed countries. Dotted line represents a threshold often cited in Norway ($83,000 per QALY gained).16 Cost per dose excludes the administration cost (≈$14 per dose).

http://dx.doi.org/10.1371/journal.pone.0089974.g002

thumbnail
Table 3. Incremental cost-effectiveness ratios of including pre-adolescent boys in the childhood vaccination program compared to vaccination of pre-adolescent girls only.

http://dx.doi.org/10.1371/journal.pone.0089974.t003

Sensitivity analysis

The impact of model assumptions on the incremental cost-effectiveness ratio of a gender-neutral vaccine program compared to a girls-only program (including outcomes related to all HPV-related conditions) for three vaccine prices is shown in Table 4. The incremental cost-effectiveness ratios associated with including boys in the vaccination program (at $75 per dose) begin to exceed a threshold of $83,000 per QALY either when the cost-effectiveness results were expressed in terms of life years (not QALY) gained or when the lower bound of the disease-specific HPV-16 and -18 attributable fractions and lower disease treatment costs (“pessimistic scenario”) were assumed simultaneously. At the market price of the vaccine ($150 per dose), vaccination of both genders was never cost-effective across key parameter variations given a threshold of $83,000 per QALY gained. The incremental cost-effectiveness ratio only fell below $100,000 per QALY gained when we considered the benefit and costs associated with a 2-dose vaccination schedule or lower discount rates. At $50 per dose, the ratios generally remained above $30,000 per QALY gained. For a vaccine price of $75 per dose, we found that the cost per QALY gained fell below $50,000 only when the herd immunity benefits conferred to the male-population in the girls-only vaccination program was reduced by more than 15% (i.e., assuming the female-only HPV vaccination program produced smaller herd immunity benefits due to the MSM population). When we doubled the incidence of oropharyngeal cancer in both genders, we found that the incremental cost-effectiveness ratios of vaccinating boys fell by approximately 15–17%, depending on the cost per dose of the vaccine.

thumbnail
Table 4. Impact of parameter assumptions on the cost-effectiveness of including boys in a vaccination program against human papillomavirus (HPV) (including all HPV-16,-18,-6,-11 related conditions).

http://dx.doi.org/10.1371/journal.pone.0089974.t004

Apart from vaccine price, the discount rate and increasing vaccination coverage in pre-adolescent girls had the most influence on results. For example, increasing vaccination coverage of girls alone to 90% was more effective and less costly, and therefore dominated, a scenario of vaccinating both genders with 71% coverage. We calculated that more than twice the amount per vaccinated girl – or six times the amount, if the funds were targeted specifically to those who did not previously uptake – could be spent before adding boys to the vaccination program would be equally cost-effective as increasing participation among girls only. Although extending HPV vaccination to boys provides benefits to both genders, increasing coverage within a girls-only program prevents more HPV-16,-18 related female cancers than a gender-neutral program that achieves 71% coverage. Through additional herd immunity benefits, increasing female-only vaccine uptake can prevent nearly as many HPV-related cancers among men as by vaccinating boys directly (Figure 3). Even if increasing coverage among girls did not provide any additional herd immunity benefits to the boys, the scenario still provided greater overall reductions in cancer cases than vaccinating both genders (see Table S9 in File S1).

thumbnail
Figure 3. Projected impact of vaccinating both pre-adolescent girls and boys at 71% coverage compared to increasing coverage to 90% for a girls-only program on non-cervical human papillomavirus (HPV)-16, -18 related cancers.

Dotted lines represent the theoretical maximum attributable fraction of HPV-16, -18 for each condition.

http://dx.doi.org/10.1371/journal.pone.0089974.g003

Discussion

Our findings confirm that vaccine price is one of the most influential parameters when determining cost-effectiveness of extending the current female-only HPV vaccination program to include boys. In order to aid policy decisions in settings where stakeholders are privy to the national tenders procured at a lower price per dose than the publicly available price, we express the incremental cost-effectiveness ratios across a range of plausible vaccine prices. Our analysis suggests that there may be some combinations of vaccine price and willingness-to-pay thresholds where adding boys is cost-effective, even when current 3-dose coverage rates are already high (i.e., 70% among girls).

In our base case scenario, which considers a realistic Norwegian vaccine tender price of $75 per dose, we found that adding 12-year-old boys to the current HPV vaccination program may be considered ‘good value for money’ at a willingness-to-pay threshold of $83,000 per QALY gained. However, the most recent Norwegian guidelines for economic evaluation emphasize that consensus surrounding a single Norwegian threshold value has not been established [15]. In addition, there is support for a change in screening guidelines for unvaccinated women to a 6-year interval with primary HPV testing (for women aged 34 years or older) [38], a strategy estimated at approximately $30,000 for each additional year of life saved [17]. At this lower willingness-to-pay threshold, it would not be considered cost-effective to expand the current program, unless the vaccine price was less than $36 per dose (Figure 2). At a price of $120 to $150 per dose, expanding the HPV vaccination program to include boys is unlikely to be cost-effective even when considering the higher threshold value ($83,000 per QALY gained), a finding that is generally consistent with other studies [6][8]. Of note, the Norwegian Ministry of Health has approved cancer medications for reimbursement at threshold values beyond $83,000 per QALY gained; however, the total budget impact of these pharmaceuticals is often small as the targeted health conditions are relatively uncommon [39]. The same cannot be said for expanding a childhood vaccination policy to include all boys, which would essentially double the current HPV vaccination budget.

To our knowledge, there are only three other studies that have assessed the potential value of adding boys to the pre-adolescent HPV vaccination program that simultaneously account for HPV transmission dynamics, consider all HPV-related outcomes, and report results in terms of cost-effectiveness [6], [7], [40]. Other studies, however, have addressed epidemiological endpoints and the incremental benefit of adding boys to the vaccination program using static or dynamic models considering one or more HPV-related outcomes [3], [8], [29], [41][47]. The importance of certain assumptions for model structure (particularly for transmission dynamics and non-cervical HPV-related conditions), natural immunity, coverage and costs have been discussed previously [48]. A recent U.S.-based study concluded that for lower coverage rates (20–30%) among girls, adding vaccination of boys becomes an attractive policy, but if baseline coverage is 75% among girls, the incremental cost-effectiveness ratio exceeds $100,000 per QALY gained [6]. This study, however, did not consider the impact of vaccine price per dose of less than $120. Male HPV vaccination in Norway may be more attractive than those found in other settings due to several reason that include (but are not limited to) the comparatively higher prevalence of HPV-16 and -18 infections reported in Norway, higher attributable fraction of HPV-16 and -18 in oropharyngeal cancers [24], the higher baseline burden of disease (pre-vaccination), and higher Norwegian labor costs that may contribute to higher direct medical and non-medical treatment costs. In addition, we used health-related quality of life estimates reported by Conway and colleagues [26] and with the exception of penile cancer, these estimates are consistently lower than those reported and used in other studies.

For a specified vaccine price, our findings were generally stable to variations in critical parameters, with the notable exception of considering a scenario in which we compared expanding vaccination to boys versus increasing the coverage rate among girls, consistent with another study [6]. If feasible, higher uptake in girls may lead to further reduction in the total burden of HPV-related diseases, even considering an extreme scenario where increasing girls' coverage did not yield any further herd immunity benefits in males. Another modeling study showed that the most effective strategy to reduce population prevalence is by optimizing coverage in a single-sex vaccination program [47]. In addition, the feasibility of achieving 71% coverage among males, in whom the disease burden is considerably less than in females (Figure 1), also requires consideration. On the other hand, overall vaccine acceptability with a gender-neutral policy may increase without additional investments, resulting in higher coverage among girls. When we considered an alternative dosing schedule (using optimistic assumptions surrounding vaccine duration and efficacy), we found that a 2-dose regimen resulted in one of the most appealing strategies for vaccinating boys; however, there is substantial uncertainty with respect to the duration of protection from two doses [11]. As expected for programs with large upfront costs, the discount rate for vaccination programs that avert future disease was particularly impactful and should be taken into consideration when interpreting the results of a long-term cost-effectiveness analysis of preventative programs.

Finally, as both genders are responsible for HPV transmission, one may argue on equity grounds that both genders should get vaccinated to share the burden in reducing the risk of HPV-related disease, as well as have equal access to direct vaccine benefits. Equity versus efficiency arguments should be considered along-side the decision-making process and are particularly relevant in Norway where guidelines explicitly emphasize this trade-off [15].

Limitations

Limitations of our modeling approach have been previously discussed [7], [13], but some deserve particular consideration. Simplifying assumptions were inherently necessary due to data limitations or modeling constraints. For example, we assumed that the burden of HPV-related diseases remain constant over time while evidence suggests the incidence of oropharyngeal cancer related to HPV may be increasing [49]. When we considered this possibility, we found vaccinating boys to be more attractive, but the overall conclusions of the analysis were stable. Alternatively, we also did not account for the better prognosis among HPV-positive cancers compared to their HPV-negative counterparts, potentially overestimating vaccine benefit. We modeled heterosexual behavior while transmission among MSM was not explicitly considered. Although the burden of disease estimates did reflect cases among all individuals (including MSM), this omission likely overestimated the level of herd immunity conferred to males in a female-only vaccination program. Even so, we found that the herd immunity benefits in the female-only HPV vaccination program would have to be overestimated by more than 15% in order for the cost per QALY gained to fall below $50,000. Norwegian sexual behavior data suggest that the proportion of MSM is between 0.6% and 2.8% (depending on age) whereby more individuals identify with bisexual behavior compared to exclusively being homosexual, particularly prior to age 30, when the majority of HPV transmission takes place (see File S1). While a small proportion of herd immunity may be overestimated in our model, bisexual behavior may continue to propagate herd immunity benefits and the expected herd immunity reduction with at-most a 3% exclusively-male MSM population would be less than the threshold of 15%.

We did not account for any level of vaccine cross-protection related to non-vaccine types observed in clinical trials [50]. The duration of cross-protection is uncertain, and the majority of male HPV-related diseases are attributed to HPV-16 and -18, so the inclusion of cross-protection is likely to be nominal in reducing the burden of disease among males. Inclusion of cross-protection may reinforce the argument for increasing female coverage rate, however.

The quality and completeness of the Norwegian Cancer Registry have been documented [51], but little research has been done on the burden of HPV infection in Norway, particularly in men, or more recent sexual mixing patterns by age and by sexual activity. We used empirical data from one large city in Norway to inform our bounds for HPV prevalence in Norway (Mari Nygård, personal communication), but there may be considerable geographic variation with respect to sexual behavior and HPV prevalence. In order to fit the observed data, our calibrated transmission probabilities may have been higher in order to fit a high observed prevalence. Conversely, we did not allow for the potential of cross-border behavior, which may overestimate herd immunity, given vaccination rates among girls may not be as high in other countries. Lastly, our understanding of the natural history and HPV type attribution of non-cervical HPV-related diseases is limited but growing; analyses can be revisited as new detection methods and systematic reviews continue to define the natural history and attributable fraction of HPV on associated cancers.

Conclusions

At Norway's assumed HPV vaccine tender price, vaccinating boys seems attractive and may warrant a change in the current female-only vaccination policy. However, increasing coverage in girls is uniformly more effective and cost-effective than expanding vaccination coverage to boys and should be considered a priority.

Supporting Information

File S1.

Supplementary appendix providing additional information on model inputs, the Norwegian-specific calibration process, and additional results.

doi:10.1371/journal.pone.0089974.s001

(DOCX)

Acknowledgments

Transparency declaration

EAB affirms that the manuscript is an honest, accurate, and transparent account of the study being reported.

Previous presentations

A preliminary version of this analysis was orally presented at the 2013 Annual Meeting for Medical Decision Making, Baltimore, Maryland.

Author Contributions

Conceived and designed the experiments: EAB MN ISK JJK. Performed the experiments: EAB SS. Analyzed the data: EAB SS JJK ISK. Wrote the paper: EAB SS MN ISK JJK.

References

  1. 1. Norwegian Institute of Public Health (2012) [Annual Report for HPV-vaccine in the childhood vaccination program 2012]. Available: http://www.fhi.no/dokumenter/7ff40bd3b6.pdf. Accessed 2013 Aug 6.
  2. 2. David B (2013) Australia launches national scheme to vaccinate boys against HPV. BMJ 346: f924. doi: 10.1136/bmj.f924
  3. 3. Brisson M, van de Velde N, Franco EL, Drolet M, Boily MC (2011) Incremental Impact of Adding Boys to Current Human Papillomavirus Vaccination Programs: Role of Herd Immunity. Journal of Infectious Diseases 204: 372–376. doi: 10.1093/infdis/jir285
  4. 4. Ali H, Donovan B, Wand H, Read TRH, Regan DG, et al. (2013) Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. BMJ 346: f2032. doi: 10.1136/bmj.f2032
  5. 5. Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, et al. (2013) Reduction in Human Papillomavirus (HPV) Prevalence Among Young Women Following HPV Vaccine Introduction in the United States, National Health and Nutrition Examination Surveys, 2003–2010. Journal of Infectious Diseases 208: 385–393. doi: 10.1093/infdis/jit192
  6. 6. Chesson HW, Ekwueme DU, Saraiya M, Dunne EF, Markowitz LE (2011) The cost-effectiveness of male HPV vaccination in the United States. Vaccine 29: 8443–8450. doi: 10.1016/j.vaccine.2011.07.096
  7. 7. Kim JJ, Goldie SJ (2009) Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ 339: b3884. doi: 10.1136/bmj.b3884
  8. 8. Mark J, Yoon HC, Edmunds WJ (2008) Economic evaluation of human papillomavirus vaccination in the United Kingdom. BMJ 337: a769. doi: 10.1136/bmj.a769
  9. 9. Farmastat AS website. Available: http://www.farmastat.no. Accessed 2013 May 3
  10. 10. Schiller JT, Castellsague X, Garland SM (2012) A Review of Clinical Trials of Human Papillomavirus Prophylactic Vaccines. Vaccine 30: F123–F138. doi: 10.1016/j.vaccine.2012.04.108
  11. 11. Dobson SRM, McNeil S, Dionne M, Dawar M, Ogilvie G, et al. (2013) Immunogenicity of 2 Doses of HPV Vaccine in Younger Adolescents vs 3 Doses in Young Women A Randomized Clinical Trial. Jama-Journal of the American Medical Association 309: 1793–1802. doi: 10.1001/jama.2013.1625
  12. 12. Norwegian Ministry of Health [Prioritising for new: Revision of guidelines for priority-setting within Norwegian Health]. Available: http://www.regjeringen.no/Rpub/NOU/19971997/018/PDFA/NOU199719970018000DDDPDFA.pdf. Accessed 2013 June 30.
  13. 13. Kim JJ, Goldie SJ (2008) Health and economic implications of HPV vaccination in the United States. New England Journal of Medicine 359: 821–832. doi: 10.1056/nejmsa0707052
  14. 14. Federal Reserve. Historical Rates for the Norwegian Krone. Available: http://www.federalreserve.gov/RELEASES/H10/Hist/dat00_no.htm. Accessed 2011 Jun 13.
  15. 15. Norwegian Directorate of Health (2012) [Economic Evaluation of Healthcare - A Guide] Available: http://helsedirektoratet.no/publikasjoner/okonomisk-evaluering-av-helsetiltak-en-veileder/Publikasjoner/IS-1985.pdf. Accessed 2013 Jan 15
  16. 16. Norwegian Directorate of Health [Health Effects of Socio-Economic Analyses] (2007) Available: http://www.helsedirektoratet.no/publikasjoner/helseeffekter-i-samfunnsokonomiske-analyser/Publikasjoner/helseeffekter-i-samfunnsokonomiske-analyser.pdf.Accessed 2011 Jan 6.
  17. 17. Burger EA, Ortendahl JD, Sy S, Kristiansen IS, Kim JJ (2012) Cost-effectiveness of cervical cancer screening with primary human papillomavirus testing in Norway. Br J Cancer 106: 1571–1578.
  18. 18. Pedersen W, Samuelsen SW (2003) [New patterns of sexual behavior among adolescents]. Journal of the Norwegian Medical Society (Tidsskrift for Den norske legeforening) 21: 3006–3009.
  19. 19. Træen B, Stigum H, Magnus P (2003) [Report from the sexual behavior survey in 1987, 1992, 1997, 2002]. Norwegian Institute for Public Health, Division of Epidemiology
  20. 20. Hernandez BY, Wilkens LR, Zhu X, Thompson P, McDuffie K, et al. (2008) Transmission of human papillomavirus in heterosexual couples. Emerging Infectious Diseases 14: 888–894. doi: 10.3201/eid1406.070616
  21. 21. Cancer Registry of Norway: Institute of population-based cancer research. http://www.kreftregisteret.no.
  22. 22. Kim JJ, Kuntz KM, Stout NK, Mahmud S, Villa LL, et al. (2007) Multiparameter calibration of a natural history model of cervical cancer. American Journal of Epidemiology 166: 137–150. doi: 10.1093/aje/kwm086
  23. 23. World Health Organization. ICO (Institut Català d'Oncologia). Information Centre on Human Papilloma Virus (HPV) and Cervical Cancer: Data Query System. Available: http://www.who.int/hpvcentre/en/. Accessed 2012 Nov 15.
  24. 24. Mork J (2012) Prevalence of HPV in oropharyngeal carcinomas in patients diagnosed at Oslo University Hospital 2010–1011 [conference proceeding]. MD Anderson GAP Conference 2012. Available: http://webtv.medinfo.no/Mediasite/Play/99a9cb5b7412477c8a92e0413db5321b1d?catalog=54190625-deb6-433e-869c-b4fbf3b58b6c. Accessed 2013 Feb 2.
  25. 25. Myers E, Green S, Lipkus I (2004) Patient preferences for health states related to HPV infection: visual analygue scales versus time trade-off eliciation [abstract]. Proceeding of the 21st International Papillomavirus Conference. Mexico City, Mexico.
  26. 26. Conway EL, Farmer KC, Lynch WJ, Rees GL, Wain G, et al. (2012) Quality of life valuations of HPV-associated cancer health states by the general population. Sexually Transmitted Infections 88: 517–521. doi: 10.1136/sextrans-2011-050161
  27. 27. Rannestad T, Skjeldestad FE (2008) Long-term survivors of gynaecological cancer are like other women in terms of pain and quality of life (QoL). Psychology & Health 23: 219.
  28. 28. Klee M, Thranov I, Machin D (2000) The patients' perspective on physical symptoms after radiotherapy for cervical cancer. Gynecologic Oncology 76: 14–23. doi: 10.1006/gyno.1999.5642
  29. 29. Olsen J, Jepsen MR (2010) Human papillomavirus transmission and cost-effectiveness of introducing quadrivalent HPV vaccination in Denmark. International Journal of Technology Assessment in Health Care 26: 183–191. doi: 10.1017/s0266462310000085
  30. 30. Bishai D, Kashima H, Shah K (2000) The cost of juvenile-onset recurrent respiratory papillomatosis. Archives of Otolaryngology-Head & Neck Surgery 126: 935–939. doi: 10.1001/archotol.126.8.935
  31. 31. Woodhall SC, Jit M, Soldan K, Kinghorn G, Gilson R, et al. (2011) The impact of genital warts: loss of quality of life and cost of treatment in eight sexual health clinics in the UK. Sexually Transmitted Infections 87: 458–463. doi: 10.1136/sextrans-2011-050073
  32. 32. Tjalma WA, Fiander A, Reich O, Powell N, Nowakowski AM, et al. (2013) Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe. International Journal of Cancer 132: 854–867. doi: 10.1002/ijc.27713
  33. 33. Leval A, Herweijer E, Ploner A, Eloranta S, Fridman Simard J, et al. (2013) Quadrivalent Human Papillomavirus Vaccine Effectiveness: A Swedish National Cohort Study. Jnci-Journal of the National Cancer Institute 105: 469–474. doi: 10.1093/jnci/djt032
  34. 34. Health Protection Agency. Number & rates of anogenital warts diagnosed in England, 2002–2011.Available: http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1296688631209. Accessed 2013 Jan 11.
  35. 35. Lacey CJN, Lowndes CM, Shah KV (2006) Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 24: 35–41. doi: 10.1016/j.vaccine.2006.06.015
  36. 36. Brown DR, Schroeder JM, Bryan JT, Stoler MH, Fife KH (1999) Detection of multiple human papillomavirus types in condylomata acuminata lesions from otherwise healthy and immunosuppressed patients. Journal of Clinical Microbiology 37: 3316–3322.
  37. 37. Omland T, Akre H, Vardal M, Brondbo K (2012) Epidemiological aspects of recurrent respiratory papillomatosis: A population-based study. Laryngoscope 122: 1595–1599. doi: 10.1002/lary.23327
  38. 38. Cancer Registry of Norway (2009) Cancer in Norway 2009. Special Issue: Cancer screening in Norway. Available: http://www.kreftregisteret.no/Global/Publikasjoner%20og%20ra-pporter/Special%20Issue/Special_Issue_Cancer_in_Norway_2009.pdf. Accessed 2011 Jan 6.
  39. 39. Norwegian Medicines Agency (2010) [Pharmaceutical assessment: Ipilimumab (Yervoy) for treatment of advanced malignant melanoma in adults with previous treatment]. Available: http://www.legemiddelverket.no/English/Sider/default.aspx. Accessed 2013 Jun 16.
  40. 40. Elbasha EH, Dasbach EJ (2010) Impact of vaccinating boys and men against HPV in the United States. Vaccine 28: 6858–6867. doi: 10.1016/j.vaccine.2010.08.030
  41. 41. Taira AV, Neukermans CP, Sanders GD (2004) Evaluating human papillomavirus vaccination programs. Emerging Infectious Diseases 10: 1915–1923. doi: 10.3201/eid1011.040222
  42. 42. Insinga RP, Dasbach EJ, Elbasha EH, Puig A, Reynales-Shigematsu LM (2007) Cost-effectiveness of quadrivalent human papillomavirus (HPV) vaccination in Mexico: A transmission dynamic model-based evaluation. Vaccine 26: 128–139. doi: 10.1016/j.vaccine.2007.10.056
  43. 43. Kulasingam S, Connelly L, Conway E, Hocking JS, Myers E, et al. (2007) A cost-effectiveness analysis of adding a human papillomavirus vaccine to the Australian National Cervical Cancer Screening Program. Sexual Health 4: 165–175. doi: 10.1071/sh07043
  44. 44. Zechmeister I, de Blasio BF, Garnett G, Neilson AR, Siebert U (2009) Cost-effectiveness analysis of human papillomavirus-vaccination programs to prevent cervical cancer in Austria. Vaccine 27: 5133–5141. doi: 10.1016/j.vaccine.2009.06.039
  45. 45. French KM, Barnabas RV, Lehtinen M, Kontula O, Pukkala E, et al. (2007) Strategies for the introduction of human papillomavirus vaccination: modelling the optimum age- and sex-specific pattern of vaccination in Finland. British Journal of Cancer 96: 514–518.
  46. 46. Choi YH, Jit M, Gay N, Cox A, Garnett GP, Edmunds WJ (2010) Transmission dynamic modelling of the impact of human papillomavirus vaccination in the United Kingdom. Vaccine 28: 4091–4102. doi: 10.1016/j.vaccine.2009.09.125
  47. 47. Bogaards JA, Kretzschmar M, Xiridou M, Meijer CJLM, Berkhof J, et al. (2001) Sex-Specific Immunization for Sexually Transmitted Infections Such as Human Papillomavirus: Insights from Mathematical Models. Plos Medicine 8. doi: 10.1371/journal.pmed.1001147
  48. 48. Seto K, Marra F, Raymakers A, Marra CA (2012) The Cost Effectiveness of Human Papillomavirus Vaccines A Systematic Review. Drugs 72: 715–743. doi: 10.2165/11599470-000000000-00000
  49. 49. Mork J, Møller Br, Dahl T, Bray F (2010) Time trends in pharyngeal cancer incidence in Norway 1981–2005: a subsite analysis based on a reabstraction and recoding of registered cases. Cancer Causes and Control 21: 1397–1405. doi: 10.1007/s10552-010-9567-9
  50. 50. Malagón T, Drolet M, Boily M, Franco EL, Jit M, et al. (2012) Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. The Lancet Infectious Diseases 12: 781–789. doi: 10.1016/s1473-3099(12)70187-1
  51. 51. Larsen TK, Småstuen M, Parkin DM, Bray F (2007) Data Quality at the Cancer Registry of Norway. In: Cancer in Norway 2006-Cancer incidence, mortality, survival and prevalence in Norway. Available: http://www.kreftregisteret.no/Global/Publikasjoner%20og%20rapporter/CiN2006_special_issue.pdf. Accessed 2013 Jul 7.