Human papillomavirus (HPV) can cause cervical cancer, as well as a number of other diseases in both men and women. Both sexes play a role in transmission of the disease, but the cost-effectiveness of HPV vaccination differs between them. It is necessary to determine the best allocation of limited resources between these two populations to produce the most effective strategy for reducing the burden from HPV-related disease. This literature review intends to elucidate the economic and social considerations that will lead to maximum utilization of vaccination programs, which in turn will reduce the burden of HPV-related disease. Current outreach in the United States is based on vaccination against HPV as a means for combating cervical cancer in women. If we are to include males, however, new marketing strategies must focus on educating patients about the full range of the vaccine's benefits. Men who have sex with men (MSM) are also unprotected against HPV in the current system. Social considerations alone may not be enough, however, as economic prediction models suggest that the associated costs outweigh the benefits in most circumstances. Taking this into account, our review also considers alternate methods of maximizing prevention of HPV-associated disease. The most prudent programs will include physician involvement in patient education and the implementation of structured vaccination and screening programs. Unfortunately, many countries do not have the necessary resources to undertake national vaccination programs. HPV testing and cytology screening for women and MSM may be the most financially reasonable option for many countries.

Introduction

H uman papillomavirus (HPV) is the most common sexually transmitted infection (STI) in women, and 80% of women will be infected with the virus at some point in their lifetime (8). Genital HPV infection is the most well-studied and documented, and transmission occurs primarily through sexual intercourse (97). The majority of females are infected within 3 y of their sexual debut, on average 17 y of age (19). There are over 100 types of HPV identified that are implicated in the development of genital warts, as well as cervical and other cancers. About 40 of the 100 different types of the virus, and many of the types associated with a high-risk of causing pre-cancerous lesions, can infect the genitals as well as the mouth and throat (15). Most types are transmitted through vaginal, oral, and anal sexual contact. HPV is described in the literature as a “necessary” cause of cervical cancers, an assertion that is corroborated by the incidence of HPV in 99.7% of cervical cancer cases worldwide (94). Of particular importance are HPV subtypes 16, 18, 6, and 11. Types 16 and 18 cause 70% of cervical cancers worldwide, while HPV types 6 and 11 have been implicated in 90% of cases of genital warts (3). The majority of HPV infections are transient and cleared within 2 y, especially in women under age 25 y. However, a very high percentage (>75% in some estimates) of cervical intraepithelial neoplasias (CIN) are associated with HPV infection (69).

HPV is also estimated to be associated with approximately 40% of cancers of the external genitalia of men and women, 35% of oropharyngeal cancers, 25% of oral cavity cancers, and 90% of anal cancers (65,83,95). HPV types 6, 11, 16, and 18 are the primary types implicated in the etiology of both genital and non-genital cancers. The incidence of anal and oral cancers in HPV-infected individuals is attributed primarily to types 16 and 18 (51,82,85,97). In addition to the significant burden from CIN, there are many non-CIN-related morbidities associated with HPV infection that must be considered when estimating the value of a vaccination program (87).

The HPV vaccine and the purpose of this review

While there are plenty of generalized treatments for the resultant cancers and warts, there is currently no specific treatment for HPV infection. Two prophylactic vaccines, however, have been developed to combat infection by HPV. The first, Gardasil, developed by Merck & Co., is a quadrivalent vaccine targeting HPV types 6, 11, 16, and 18. It was approved by the U.S. Food and Drug Administration (FDA) for use in females aged 9–26 y in 2006, as well as for use in males aged 9–26 in 2009. The second, Cervarix, developed by GlaxoSmithKline, is a bivalent vaccine which targets HPV types 16 and 18, and was approved in 2009 by the FDA for use in females aged 10–25 y. Generally, both vaccines have proven to be extremely effective in preventing infection in naïve patients by the vaccine-type specific HPV types (3,44,57,64).

The HPV vaccine is currently being considered for administration to males in the U.S. in an effort to reduce the incidence of CIN and other HPV-associated morbidities. CIN is a female disease, but males can act as vectors for the transmission of the virus, and are thus considered a factor in the prevalence and incidence of cervical cancer in women. Public information concerning HPV vaccination in the U.S. has thus far been mainly based on the marketing campaigns of pharmaceutical companies and not on information provided by physicians (55). This method of public education has led to several unintended side effects that have complicated the prospect of reducing the incidence of the diseases caused by the protected types of HPV. Specifically, this educational strategy does not encourage males to actively seek vaccination for HPV. Since there is no publicly-funded male vaccination program for schoolchildren in the U.S., as there is in other developed countries like Australia, effective distribution of the vaccine is even more challenging (43,86). As a result of insufficient marketing and distribution strategies, there has been a low utilization of vaccine, and thus an unnecessarily high incidence of HPV infection. Including men in vaccination programs would lead to increased herd immunity to the disease (37).

This potential solution is not without controversy. Extending vaccine coverage to males would decrease overall HPV infection, but economically-speaking, this strategy fails numerous cost-benefit analyses (12,46). The developing body of literature on the topic has demonstrated that the costs of male HPV vaccination may outweigh the benefits. Our review article aims to dissect the public health and economic considerations of the HPV vaccine, and the inclusion of males both domestically and internationally, with a specific focus on the data and methods used to gauge the scope of the problem.

Efficacy of the HPV vaccine varieties

A series of large, double-blind, randomized Phase II and III clinical trials have shown that administration of Gardasil to 16- to 26-year-old females is highly efficacious in preventing CIN grades 2 and 3 and adenocarcinoma in situ (AIS) due to HPV types 16 and 18, which comprise the majority of cervical cancers worldwide. Other benefits include prevention of HPV 6-, 11-, 16-, and 18-related anogenital warts, and vulvar or vaginal intraepithelial neoplasia (VIN and VaIN, respectively) grades 1–3 (3,30,62). An extension to one of aforementioned Phase II trials demonstrated that Gardasil induced a consistent immune response and prevented breakthrough cases over 5 y, the longest efficacy study of that vaccine to date (92). A large, double-blind, randomized Phase III clinical trial has shown that Cervarix is also highly efficacious in preventing HPV 16- and 18-related CIN grade 2+ lesions in females aged 15–25 y (64). Another study demonstrated that Cervarix is efficacious and maintains high immunogenicity for 6.4 y (33,81).

Data are limited for efficacy studies of the HPV vaccine in males, and for the incidence of non-cervical HPV-induced cancers. The FDA approved the use of Gardasil in males to prevent genital warts based on a report that the vaccine is highly efficacious in preventing external genital lesions by HPV 6 and 11, and also induces high immunogenicity. Furthermore, it showed some efficacy in the prevention of vaccine-type HPV persistent infections, and penile, perianal, or perineal intraepithelial neoplasia grade 2+ (73). A recent study published in the New England Journal of Medicine examined the efficacy of the quadrivalent vaccine Gardisil against anal cancer, with a particular focus on MSM, and found a significant reduction in anal intraepithelial neoplasia of grades 1–3 (66). No efficacy studies of Cervarix have been conducted in males, although one study has shown that the bivalent vaccine does induce high immunogenicity in males (67). Aside from the report by Garland et al. regarding the efficacy of Gardasil in preventing both low- and high-grade VaIN and VIN in females, there are no studies providing any statistically significant efficacy data for either vaccine in preventing penile, vaginal, vulvar, oropharyngeal, oral, or anal cancers. Of note, neither of these two vaccines has been in use long enough to create significant long-term data for this purpose.

Public perceptions of the HPV vaccine

Before considering the addition of males in vaccination strategies, public perceptions of the vaccine must be discussed. Since the introduction of the HPV vaccine in 2006, private marketing campaigns have ensured its acceptance internationally as an important measure in the prevention of cervical cancer. Still, several public policy decisions can be made to increase the acceptance, use, and impact of the vaccine further. For example, administration of the HPV vaccine to schoolchildren could be mandated or administered as part of a government funded, opt-out program. This is a policy that has driven high vaccination rates, with Australia as a prime example (38,40,89). The U.S. has no such program, and as a result vaccination rates of women are much lower than in countries where a program similar to Australia's is in place (13). As a result, increased physician involvement in patient education about the benefits of the vaccine may be necessary for boosting vaccination rates further in the U.S., as personal physicians can tailor recommendations specifically for the patient, especially since a number of studies have shown a lack of patient understanding when it comes to HPV and its available vaccines (36,50,72). Unfortunately, it is often the case that other players in the marketplace determine the course of patient education about the vaccine. In many developed countries like Denmark, for example, most women did not learn about the vaccine from their personal physicians, but rather from corporate marketing campaigns that focused primarily on the prevention of cervical cancer. These outreach campaigns so far have failed to educate women about other possible benefits from vaccination, including protection from genital warts (55). The effect of overly-specific marketing practices has been especially pronounced in the United States, where vaccination campaigns, largely funded by Merck & Co., have only raised awareness of only the cancer-prevention benefits of the vaccine (75).

The net result of this focus has been a strong reliance on the vaccine for prevention of cervical cancer, leading to a potential decrease in the use of other necessary preventive measures such as screenings with regular Pap smears (36). It has been argued that the increase in cervical cancer risk from less frequent screening would be negligible in a population where over 35% of women are vaccinated (4). Though 37% of adolescents in the U.S. have begun the vaccine series, only 18% have received all three injections necessary to confer maximum immunity, meaning that screening in populations of sexually-active Americans remains a necessary preventive measure to combat HPV effectively (14). Additionally, while the current vaccines can prevent 70% of cervical cancers caused by types 16 and 18, the remaining 30% of cases are caused by types of HPV not covered by the vaccine. As such, the pathologies resulting from the remaining 30% of HPV types can only be prevented through regular screenings for those problems. Until optimal coverage of the vaccine can be achieved, regular check-ups and proper education from personal physicians is needed to continue the fight against HPV effectively (38,40,41,59,75).

Marketing campaigns in the U.S. which are focused on even the most pressing HPV-related health concerns in women have failed to induce compliance with vaccination recommendations. As described above, the net result has been a low rate of vaccination, and potentially decreasing rates of screening for cervical cancer in the U.S. (75). Since vaccinating additional females seems to be increasingly difficult in the U.S. (4), vaccination of males becomes an ever-more viable option for increasing herd immunity to HPV. As we have previously stated, HPV types 16 and 18 are implicated in the development of many head, neck, anal, and penile cancers, in addition to CIN and other cancers of the female reproductive system, and types 6 and 11 are implicated in up to 90% of cases of genital warts. Furthermore, several studies have shown that Gardasil is efficacious in reducing the development of genital warts caused by HPV types 6 and 11, as well as anal intraepithelial neoplasia caused by HPV types 6, 11, 16, and 18 (32). Because of this added protection and the proven high level of immunogenicity of the current vaccines in men, it is definitely beneficial from a social standpoint to increase vaccination of males (67). Private companies and public health agencies might encourage men to seek vaccination, and thus immunity to HPV types 6, 11, 16, and 18. This could be done by adjusting marketing strategies to encompass HPV-related health concerns that specifically affect males, including genital warts, and head, neck, anal, and penile cancers. Increased immunity in the male population would also reduce the male role in transmission of the disease, thereby reducing the average risk of contracting cervical cancer in the population of females who have sex with males. Additionally, including males in the vaccination process will reduce the social burden of cancer prevention on females. Protection from additional HPV-related morbidities, as well as anal intraepithelial neoplasia, provides a possible incentive for males to seek out the vaccine, and marketing strategies must be adjusted accordingly if this means of HPV prevention is to be successful.

The economics of HPV vaccination in males

Because funding for vaccination campaigns is scarce, economic analyses in conjunction with public health and social welfare considerations are necessary for determining the cost-effectiveness of including males in strategies for HPV vaccination programs. While a plethora of studies have proven the HPV vaccine to be effective in producing immunological resistance to the virus in both male and female patients, there is some debate in the literature as to which strategy is the most cost-effective for enhancing population-level immunity (20). Castle and Scarinci (12), in particular, cite a study that determined that the inclusion of boys in vaccination programs in the United States “would ‘exceed conventional thresholds of good value for money’ ” (12,46). Limited impact on cost-effectiveness associated with vaccinating males stems from the role of males in spreading the disease, as well as the different mix of cancers suffered by males infected with HPV. In a direct rebuttal published just 2 months later in the same journal, Hibbitts (37), a proponent of male vaccination, cites the very same study with a very different perspective. She indicates that the inclusion of males in the vaccination strategy was technically shown to be cost-effective for eradicating HPV when lifelong vaccine efficacy of 90% against all HPV-associated diseases and a 75% coverage rate among boys and girls were assumed (37). However, further analysis of the literature should demonstrate that there seems to be disagreement on what is meant by “cost-effective” prevention, as well as which parameters are appropriate to utilize when modeling these real-world phenomena (Table 1). For instance, a study by Garland (28) shows that given a particular set of conditions, vaccinating males could become cost-effective, though she fails to note the particular metrics she used to determine this. A strong point she does make is that the economic burden of HPV infection in males should be taken into account when determining the cost-effectiveness of vaccinating males. When one takes this into account, the value of vaccinating males becomes much more than simply the prevention of cervical cancer (39).

Table 1. Summary of Findings from Current Modeling Studies as They Pertain to the Cost-Effectiveness of Vaccination Strategies Authors Year Type/subjects Model assumptions Cost per QALY/outcomes Institute of Medicine 2000 Markov • Vaccine efficacious in both males and females $4000–$6000 Hughes et al. 2002 Two different models:

- Dynamic

- Markov • Risk of HPV infection depends on age and sexual activity

• Examined only long-term impact of vaccination

• Risk of infection depends on duration of infection, age and sexual activity

• Infection does not regress Epidemiological outcomes only Sanders and Taira 2003 Markov • Vaccine cost $300, booster cost $100

• 10-Year duration of protection with booster shots

• Annual infection incidence at age 15 y (10%), peaks at age 19 y (18%)

• Discounting at 3%

• No utility decrement for undiagnosed infection or lesion, diagnosed lesions measure at 0.97 $22,755 with a range $12,682–$52,398 Kulasingam and Myers 2003 Markov • Vaccine costs $200

• Duration of protection 10 y

• Progression from low- to high-grade cervical lesion not differentially affected by the vaccine

• Future costs and life-years discounted by 3%

• Disutility of precancerous lesions about 1 mo, for cancer for 5 y of follow-up $44,889 with biennial Pap screening at age 24 y to $236,250 with annual Pap screening at 18 y Goldie et al. 2003 Markov • Includes both low- and high-risk HPV infections

• Included cross-protection, reactivation of latent infections



• Semi-annual Markov cycle Epidemiological outcomes only; prompted questions about heterogeneity of vaccine response, effect of type-specific vaccination on other HPV types; and the degree to which efficacy persists Goldie et al. 2004 Markov • Vaccine costs $377

• 6-Month transitions between disease states

• No cross-protection of the vaccine against non-vaccine HPV types

• Future costs and life years discounted at 3%

• Utilities based on previous literature varied “with stage of disease” $20,600 with 100% efficacy and coverage, and $24,300 with 90% efficacy/100% coverage, with a range of $17,200–$3,867,500 Taira et al. 2004 Hybrid • Vaccine cost $300, booster cost $100

• 10-Year duration of protection with booster shots

• Annual infection incidence at age 15 y (10%), peaks at age 19 y (18%)

• Discounting at 3%

• No utility decrement for undiagnosed infection or lesion, diagnosed lesions measure at 0.97 $14,583 with 90% efficacy and 70% coverage, $442,039 with 90% efficacy and 70% coverage, with a range of $14,583–$800,000 Barnabas and Garnett 2004 Dynamic • Age structure

• Regression of HPV infection is age-dependent

• Examined short- and long-term impact Epidemiological outcomes only; HPV control should be the goal of vaccination Elbasha and Galvani 2005 Dynamic • Analytical modeling Epidemiological outcomes only; mass vaccination may reduce prevalence of types not targeted by the vaccine Elbasha et al. 2007 Dynamic • Vaccine cost $360

• Costs and QALY discounted at 3%

• Utility for precancerous lesions (0.87–0.91); for cancer (0.48–0.76); for cancer survivors (0.76) $4666 with 90% efficacy and 100% coverage, $45,056 with 90% efficacy and 100% coverage, with a range of $997–$124,063 Elbasha et al. 2010 Dynamic • Direct and indirect protection (men) taken into account

• Threshold $20K cost/QALY, only 23% of simulations show vaccinating men to be cost-effective Mean cost-effectiveness: $25,700 (range: $13,600–$48,800) per QALY gained if vaccination protects against all HPV 6/11/16/18-associated diseases Rogoza et al. 2008 Markov • Vaccine costs $474

• Costs and outcomes discounted 3%

• Utility for precancerous lesions (0.92–0.99); for treated cancer (0.73); and for cancer follow-up (0.62–0.97) $7828 with 95% efficacy for HPV vaccine types and 50–80% efficacy for non-vaccine types and 100% coverage, range $7,828–$79,581 Goldhaber-Fiebert 2008 Markov • Vaccine costs $402

• Costs and outcomes discounted 3% annually

• Utilities decrease with increasing age

• Utilities for cancer (0.48–0.68) $41,000 with 100% efficacy, 100% coverage, and screening every 5 y; with a range of $6000–$12,749,000 Chesson et al. 2008 Dynamic • Vaccine cost $360

• Costs and QALY discounted at 3%

• Age-specific cancer incidence rates from 2003; population-based registries

• Vaccine coverage rates increased linearly for the first 5 y $5336 quadrivalent, U.S. females, 100% efficacy and coverage; $10,318 bivalent, U.S. females, 100% efficacy and coverage; with a range of $0–$122,976 Chesson et al. 2010 Dynamic • Male vaccination program added to a female vaccination program

• More cost-effective if in a situation of low female coverage Vaccination of 12-year-old males might potentially be cost-effective, if female coverage is low and if all health benefits of vaccination are included in the analysis Kim and Goldie 2008 Dynamic • Vaccine cost $360; booster cost $250

• Costs and QALY discounted at 3%

• Utility for cancer (0.48–0.76); warts (0.91)

• 75% of targeted population covered within 5 y

• Quadrivalent vaccine

• 100% efficacy, 75% coverage

• U.S. population of females $43,600 vaccinated at 12 y; $97,300 vaccinated at 18 y; $120,400 vaccinated at 21 y; and $152,700 vaccinated at 26 y; with a range of $34,900–$324,200 Kim and Goldie 2009 Dynamic • Vaccine cost $360

• Costs and QALY discounted at 3%

• Utility for cancer (0.48–0.76); warts (0.91)

• Whole population of U.S., including males and females, vaccinated at age 12 y

• Females: 100% efficacy, 75% coverage

• Males: 85% efficacy, 75% coverage $290,290 with a range of $88,930–$390,440 Kim et al. 2009 Dynamic • Vaccine cost $500

• Costs and QALY discounted at 3%

• Whole U.S. population of females $116,950 with vaccination at age 35 y; $272,350 with vaccination at 45 y; and with a range of $78,751–$448,989

Kim and Goldie's study (46) used sophisticated models to analyze the cost of medical intervention per quality-adjusted life-year (QALY) in assessing the cost-effectiveness (CE) of including pre-adolescent boys in a vaccination program along with pre-adolescent girls. Assuming a commonly-cited reasonable CE ratio threshold of roughly $100,000 for developed countries (24), Kim and Goldie found that the strategy which included vaccinating boys and girls had a CE ratio of $90,870, which is considered cost-effective within the constraints presented in the Eichler study (24). It is worth noting, however, that though vaccine efficacy in females for these types is indicated at nearly 100%, the literature is relatively less abundant supporting such high efficacy in males. Kim and Goldie took this into account by running an additional simulation including male vaccination, holding all other variables constant, but reducing the efficacy to 75%, to yield a ratio of $123,940. So, we might conclude from these results that within a reasonable doubt, the actual CE ratio for the vaccine used in males hovers somewhere near the high-end of Eichler's $100,000 cut-off, if not above it. Preliminary evaluation of this finding suggests that the cost-effectiveness of vaccinating males for HPV is expensive at best. Thus, cost may be a significant inhibiting factor when considering the inclusion of males in any vaccination strategy. This point becomes especially clear when considering the range of CE ratios offered by different strategies. Girls-only vaccination programs consistently show lower CE ratios than programs that include both boys and girls.

As mentioned above, Hibbitts (37) interpreted the results of the Kim and Goldie (46) article as an indication that the vaccination strategy that included both boys and girls was barely within the CE bounds defined by Eichler et al. (24) and Castle and Scarinci (12). However, Hibbits (37) pre-empted this position by indicating that Kim and Goldie were only able to produce a CE ratio within the cut-off defined by Eichler's group by introducing the “most favorable” conditions possible to the model. While the variables chosen by Kim and Goldie to simulate the male response to vaccine did indeed assume favorable performance of the vaccine in preventing infection with the virus, some of their assumptions may be reasonable. The conditions to which Castle and Scarinci (12) refer—the aforementioned assumed values of lifelong efficacy of 90% against all HPV-associated diseases, and a coverage rate of 75% for both sexes in a developed nation—remain unproven in peer-reviewed literature. Since the vaccines have only been available for few years, we do not yet have a full understanding of the longevity and efficacy of the vaccine in males (33). However, vaccination programs in Australia have shown that a high coverage rate in females is possible (86). Castle and Scarinci (12) also make the observation that a $100,000 CE ratio is quite a generous threshold, suggesting that $50,000 may be “perhaps a more fiscally-responsible threshold,” given the need to reduce health care spending in the United States, a threshold consistently met by girls-only vaccination programs (46). As far as we are aware, these thresholds have been chosen by a developing consensus and not necessarily by economic analysis. It may also be worth noting that these recommendations, and the studies supporting them, are generally tailored to the United States, which is one of the wealthiest nations in the world. The development of inexpensive HPV vaccination strategies will be important for the future of HPV care in the United States, as well as other less privileged nations around the world, as implied by Hibbitts (37).

While definitive literature on the economics of vaccinating men still seems to be forthcoming, it is clear that HPV vaccination in boys is highly expensive compared to girls-only programs. As Hibbitts (37) has indicated, HPV vaccination in boys may meet the threshold established by Eichler et al. (24), but only just barely, and despite favorable assumptions. It is also unclear that lifelong efficacy of any fixed amount is possible for the HPV vaccine. These results place HPV vaccination for males at the very high end of a cost-effectiveness range that is generous by most standards in the U.S. as well as abroad. For the sake of fair argument, it is necessary to note that these studies were conducted within the vacuum of comparing the CE ratios of two primary options for vaccination programs with seemingly predetermined budget constraints. Inherent in the studies cited above is the assumption that ratios in excess of $100,000 or even $50,000, are “too much” for a well-developed nation—and by implication, for a developing nation—to pay for this sort of medical intervention.

In order to truly engage with this question, case-by-case analyses are necessary to gauge just what kind of investment a national health care system can make in HPV vaccination, including evaluation of any additional funding sources to optimize the reduction of the burden from HPV-related disease. Drawing from the studies cited above, however, we can say that girls-only vaccination programs, without a doubt, represent a more economically efficient option than extending the same preventive measures to boys. As such, if scarcity of resources requires a choice to be made, we can ensure greater health return for our investment by vaccinating girls. From an economic perspective, we should consider vaccination of boys only if the availability of additional resources permits (Table 2).

Table 2. Cost-Effectiveness of Including Boys in a Vaccination Program Against Human Papillomavirus (HPV) Types 16 and 18 in the Context of Current Screening for Cervical Cancera Cancers in women only Cancers in both sexes Strategyb Cervicalc Including other HPV 16 and HPV 18 cancers (50% efficacy)d Including other HPV 16 and HPV 18 cancers (100% efficacy)e Including other HPV 16 and HPV 18 cancers (50% efficacy)d Including other HPV 16 and HPV 18 cancers (100% efficacy) Current screening using cytology with HPV DNA testing for triage No vaccination or screening Vaccination of girls >12 y old and screening $40,310 $31,530 $25,680 $272,370 $20,990 Vaccination of girls and boys >12 y old and screening $290,290 $242,520 $283,110 $164,580 $114,510 Current screening using cytology with HPV DNA testing for triage until age 30, then combined cytology and HPV DNA testing after age 30 No vaccination or screening Current screening using cytology with HPV DNA testing for triage $42,450 $30,370 $23,310 $25,270 $18,130 Vaccination of girls >12 y old and screening $350,040 $281,170 $234,760 $179,510 $120,300

Several recent studies are part of a growing body of evidence that shows the value of taking into account non-cervical cancers in the CE modeling for HPV vaccination. Included are oropharyngeal and anal cancers (16,42). The inclusion of non-cervical cancers in CE modeling is especially important considering the population of men who have sex with men. Research has shown that not only is anal HPV infection in MSM linked with an increased risk for anal cancer (11,45), but there is also increased human immunodeficiency virus (HIV) seropositivity. If these data prove to be true, then HPV vaccination in MSM could possibly help prevent the spread of HIV (27). Kim (45) constructed decision-analytic models of vaccination for several possible scenarios of MSM. She found that, compared to no vaccination, vaccinating MSM at age 12 carried a cost of $15,290 CE. This is well below the $50,000 CE limit which we have previously referred to as “fiscally-responsible.” Age 12 was chosen because it has been found that most MSM do not begin sexual activity until after this age (35). The problem with attempting to vaccinate only MSM is that sexual preferences and behavior are not easily qualifiable in patients as young as 12 y of age, making determining the need to vaccinate more difficult. The many psychosocial pressures placed on MSM in the U.S. will unfortunately hinder early vaccination programs aimed at protecting MSM specifically (17). Fortunately, Kim (45) also found that even if MSM were vaccinated against HPV as late as age 26 (long after first MSM contact in most individuals), the program still carried a CE of $37,830. This number even assumes a 50% chance of previous exposure to HPV. These CE ratios also fall when considering the QALYs from genital warts. The conclusion is that if one considers $50,000 a “fiscally-responsible” CE limit, then MSM should definitely be vaccinated for HPV. A composite study must be done to combine the CE ratios of all men, those having sex with men, and those having sex with women. Without this dataset it will be difficult to decide whether vaccinating all boys will fall under our $50,000 limit of fiscal responsibility.

Some recent studies take into account the net health benefits sustained by males and females by including a male vaccination program in addition to already-operating female vaccination programs. A recent article by Chesson et al. shows that vaccinating males at age 12 could be considered cost-effective when taking into account the net health benefits for both sexes (18). Another paper that takes this into account is a recent publication by Elbasha and Dasbach, which shows a median CE of $25,700, assuming that the vaccine protects against all four types of HPV as advertised (25).

The future of HPV prevention

Discrepancies between predictive models and reality have led to considerable discussion in the literature as to how resources should be used in the future to reduce the burden of HPV-related disease. In essence, the question becomes one of resolving the tension between ethics and economics: Should national health care strategies strive to reach the 75% threshold of female coverage that is assumed in some of the models considered above, or should public health professionals consider a group of target populations that may be easier to reach (5,46)? Including males in the vaccination strategy may increase overall vaccine coverage and represent a viable solution for populations for which additional female patients are difficult to reach. This approach may also reduce the burden placed on females for the prevention of HPV transmission (12). At the same time, the cost per QALY gained by vaccinating males may not be economically feasible when only considering the reduction of disease burden from cervical cancer. Cost-effectiveness modeling becomes much more feasible when one takes into account the many other HPV-related morbidities that result from infection. The complexity of this debate is compounded by the fact that not all communities, even in the U.S., have access to the resources needed to combat HPV optimally, and thus future strategies must be crafted on a case-specific basis to utilize the methods that are locally available. Considerations should include the economic, social, and health status of each community when determining the true impact of the HPV vaccine.

Lessons from HPV prevention in developing countries

Though it has been shown that the CE of the HPV vaccine is appropriate in the developing world when considering only women and the burden of disease from CIN (34), the cost per QALY of HPV vaccines is extremely high. Since implementing a male HPV vaccination model is far from becoming a reality in developing countries (29,61), we must consider the alternatives to further our goal of reduction of the burden from HPV-related disease in the most efficacious and financially feasible way. Screenings are relatively less expensive than vaccination, thus Pap smears may represent a more cost-effective form of detecting, mitigating, and preventing cervical cancer for women in developing countries (6,23,49,54,63). However, many recently published papers indicate that the use of Pap smears is not the most judicious screening method, especially in low-resource areas. This is partly due to low utilization rates, and thus there is a place for other strategies that do not require yearly medical care, as is the case with current Pap cytology recommendations (10,26,44,48,58,74,76,77). However, it is economic considerations that are often the prohibitive factors when attempting to institute a cervical cancer prevention program in low-income areas (84). Sankaranarayanan et al. (77) compared three screening methods: visual inspection with acetic acid (VIA), cytologic testing (Pap smears), and HPV testing using the Hybrid Capture II® (HCII) Test (formerly Digene, now QIAGEN, Valencia, CA), and concluded that the HCII-tested group saw a considerable decline in the rate of advanced cervical cancer and associated death within 8 y compared to cytologic and VIA testing. Qiao et al. (68) used a similar product in their study in rural China. That group screened 2530 women aged 30–54 and found that careHPV (QIAGEN) yielded comparable sensitivities and specificities to HCII tests, but required far less time, cost, and lab space.

The importance of these findings cannot be overstated. Economically-disadvantaged areas desperately need a cheap but accurate testing procedure that requires little infrastructure (78,80). Emerging HPV testing data also point to higher effectiveness with fewer screenings starting at a later age, two factors that will certainly reduce cost and improve patient compliance in developing countries. Schiffman and Castle (80) argue that testing performed 15–20 y after first intercourse will detect many treatable conditions while avoiding overtreatment. Sankaranarayanan et al. (77) agree, stating that most infections in women under 30 resolve themselves, and that HPV testing used as a primary screening method before then would lead to overtreatment.

While HPV testing provides a promising means to lower the prevalence of HPV and its related conditions in the developing world, an effective screening program still requires steady financing to develop marketing campaigns, implement guidelines, and train personnel to carry out the screenings in an efficient manner. Othman and Rebloj also illustrated the importance of developing a screening program acceptable to cultural and economic norms in the target country (63). A broader study conducted by Tsu discussed the necessary cultural considerations in a range of developing countries, including Vietnam, Uganda, and India. She asserts that a prevailing concern among females in those countries is that governments must actively facilitate the improvement of HPV prevention to make it effective. She also refers to differences in sexual stigmas, religion, and social status, to name a few, that can affect a country's perception of HPV preventive measures (90).

As the sorts of challenges encountered by Othman and Rebloj (63) and Tsu (90) might be found in any cultural context, it should be clear that such a pressing public health need as the reduction of the burden from HPV-related disease would require the adaptation of any strategy to the native culture to ensure compliance with the prevention program and control HPV transmission. With this information in mind, we can recommend that in the United States, the primary cervical cancer prevention method in low-resource areas should continue to be Pap cytology screenings. This is due to the relatively high cost that HPV testing currently incurs, and the relatively low cost and wide availability Pap cytology testing has in the United States, even in economically-disadvantaged areas. It has also been shown that Pap cytology could be performed every other year without significant losses in preventive value; however, this may not be advisable due to the risk of lowering utilization by the elimination of a yearly schedule (77,88). Due to low utilization of preventive medicine visits in low-income areas, if HPV testing becomes possible economically, it would improve coverage for the prevention of cervical cancer due to the need to test for HPV only every 3 y, as opposed to yearly cytology screenings. In areas where resources permit, testing for the presence of HPV in women over age 30 should be sufficient to prevent cervical cancer cases in most women until a national vaccination program becomes economically feasible. After more studies have been done, there is also the possibility that HPV testing in women aged 25–29 y could be prudent (77,88).

Lessons from HPV prevention in developed countries

As most have the necessary resources, many developed countries are able to implement a HPV vaccination program (7). The full beneficial effects of a vaccinated population are not visible for 10–20 y (56), but developed countries are better able to absorb the initial investment costs, and thus have already incorporated immunization programs (96). Before a country can think about vaccinating men, there must be a strong vaccination program of women and girls in place, especially considering the large body of data supporting the use of HPV vaccination for cervical cancer prevention. If most girls are vaccinated by the age of 12, for example, the incidence of HPV is predicted to decline at a low additional cost of $20,990 per QALY (46). Since the vaccine is relatively new, we have not yet seen the long-term results of vaccination programs (56). However, recent data from Australia show that programs like these can be successful (9,22,70). As such, reduction of the burden from HPV-related disease will be achieved most quickly as a larger percentage of the population receives the vaccine.

Cultural issues can also be of importance in developed nations, especially in countries that are in the infancy of implementing vaccination programs. China is a great example (21), where a recent study showed that the sexual-related concerns accompanying HPV infection caused more psychosocial burden in Chinese women than the threat of cervical cancer. This burden was especially pronounced in urban populations (94). On a more promising note, a study of adolescent girls in metropolitan Hong Kong showed that knowledge and acceptance of HPV vaccination is growing quickly among the urban population (53). The growing national and international awareness of the comorbidities associated with HPV infection will give future vaccination programs a better chance to succeed. Though awareness and acceptance are increasing, potential vaccination programs must always consider potential cultural issues specific to their population (90,94).

Several countries are subscribing to the idea of including males in the vaccination process to help eradicate HPV more effectively. Countries such as Canada, Mexico, and Australia have already licensed the use of HPV vaccines in males (1,31), and the FDA recently approved the use of Gardasil in males to prevent genital warts in the United States (73).

Vaccination of males could one day be the ideal solution to diminish the prevalence of HPV. However, the mathematical models used by Kim and Goldie show that even with the most favorable considerations in place, the cost per QALY is nearly $100,000 (46), an amount above the acceptable threshold for cost per treatment. As a comparison, Armstrong's review of 11 U.S.-based mathematical models stated that under ideal conditions, the cost per QALY for female-only vaccination can be as low as $4666, and the highest estimate calculated was $43,600 (2). Though an ideal condition such as widespread coverage currently seems like an unrealistic goal, there are data to support the contrary. A CE analysis of HPV vaccination of men that takes into account the possible reduction in morbidity from all HPV-related disease in both men and women could provide definitive evidence supporting a stronger pursuit of male vaccination. However, until this type of study is completed, it is only possible to state that calculating the true effectiveness of HPV vaccination in men is a complicated algorithm, and today we can only say that there are certain circumstances in which vaccination is a cost-effective venture.

The success of the government-funded, school-based opt-out HPV vaccination program in Australia has proven that an 80% female coverage rate is possible given these policy decisions (86). While not operating under the same school-driven program, similar publicly-funded vaccination programs in the United States have also shown promising signs, yielding a statistically significant 11% increase in vaccine coverage in lower-income populations (14). National health care governing bodies in developed countries should focus on maximizing female coverage by funding active vaccination programs that increase female coverage, and school-mandated vaccinations could represent one effective means for ensuring compliance. In order to cover the diseases downstream of HPV types not currently included in available vaccines, regular Pap smears are recommended. As in developing countries, the overall focus should be to dramatically reduce the rate of HPV infection in females first. This is because of the plethora of strong data supporting the cost-effectiveness of HPV vaccination as a preventive measure against cervical cancer, as well as the established social constructs that will allow for easier widespread coverage of females when compared to males. At a later date, once sufficient coverage of females has been achieved, it might become cost-effective to consider immunization of males.

One possibility for the future of cervical cancer prevention in developed countries could be the implementation of an HPV DNA testing procedure for women over the age of 25. Sroczynski et al. noted that HPV screening could replace Pap cytology in the German health care system in a cost-effective manner. They also showed that women of average risk for HPV infection could begin screening using Pap cytology between ages 25 and 29, followed by HPV testing after age 30, without significant decreases in the effectiveness of cervical cancer prevention. In addition, the screening need only take place every other year, further increasing cost-effectiveness (88).

Directions for future research

In future research, the models may need to be adjusted to consider populations outside of heterosexual males and females. Men who have sex with men, for example, ought to be included in future analyses, especially since the prevalence of anal cancer is higher in this population due to the increased practice of anal sex (45,71). Concurrently, as the incidence of HPV transmission declines in the non-MSM population due to the focus on vaccination of females, the MSM population may represent an increasingly influential factor in the rate of transmission of HPV. It has already been shown that HPV-associated disease in MSM who are HIV-positive comprise a significant source of morbidity and mortality (52,60,65). Furthermore, because exclusively vaccinating females will provide no protection to MSM, it may become necessary to explore methods to include this significant minority in prevention policies of the future, before considering the general vaccination of all males. The study by Giuliano's group (32), which includes a large sample of MSM as well as heterosexual men, convincingly shows that Gardasil reduces the incidence of anal cancer, but an economic study comprised of men having sex with men, men having sex with women, and all males, must be done to determine the cost-effectiveness of vaccinating all men, taking into account the increased risk of anal cancer and low CE in MSM.

Second, the conclusions reached in this review may continue to evolve as future research increases the longevity and coverage of high-risk types beyond types 16 and 18 in the vaccines. Extending coverage to other types may continue to reduce the transmission rate of HPV across types, as well as the incidence of genital warts and HPV-associated cancers. These developments may represent an increase in the potency of the vaccine. The models constructed by Kim and Goldie (46,47)—and the policy recommendations provided in this review—will need to be re-evaluated as these advances are made, as they may dramatically affect the role of vaccinating males in HPV prevention.

Third, a program utilizing both Pap cytology before the age of 30 and HPV screening after the age of 30 could be the future of cervical cancer prevention in the United States (78). Schiffman et al. (79) also warn that with increased vaccination rates, Pap cytology testing will begin to lose its predictive value. This is because as more people are vaccinated against HPV types 16 and 18, the percentage of active HPV infections that are predictive of future cervical cancer risk will decrease due to a lower incidence of those types. An interesting avenue of study would be to follow an American population in a bi- or tri-yearly HPV screening program in lieu of annual Pap cytology screening to test for adherence. There is a possibility that if yearly visits are no longer required, adherence to a screening schedule will decrease, thus decreasing the effectiveness of the screening regimen (77). Sroczynski et al. (88) suggest that if adherence to a bi-yearly screening program decreases, then the program should require annual screenings using the HPV screening.

Conclusion

The two current vaccines on the market, Gardasil and Cervarix, have been proven to be highly effective against HPV types 16 and 18, which account for 70% of cervical cancer cases. The current marketing of the vaccine is directed towards prevention of cervical cancer specifically. In order to encourage male participation in HPV vaccination in the United States, a new marketing campaign would have to be developed that outlines the other risks of HPV infection, while describing the potential role of the vaccine in mitigating those undesirable outcomes. In conjunction with this marketing push, vaccination for HPV could be added to the normal vaccination schedules for adolescent males and females. This initiative should be supported by public funding to facilitate its administration, mirroring the highly-effective programs used abroad. Potential positive effects of this strategy include the reduction of the burden of HPV prevention on the shoulders of females, and an increase in herd immunity to HPV, as well as a decline in the prevalence of HPV-related morbidities, especially in MSM.

If we are to view the employment of public resources in light of the tenets of Welfare Economics as discussed by Jacob Viner (93), we are duty-bound to simultaneously “measure subjective quantities, whether they be desires, satisfactions, pleasures or pains…through their manifestations in price offers or other types of behavior.” Whether or not we can produce models that precisely reflect real-world phenomena, it is clear from the developing literature on this topic that we have converged on a number of key findings. Though research has proven the efficacy of the vaccine in females with budding support for use in males, socioeconomic factors challenge its future use in males. The economically rational consensus seems to converge on the finding that the benefits of vaccinating males often do not warrant its high cost when considering prevention of cervical cancer as the only end-point for vaccination. When the most advantageous parameters are used, models currently show that vaccination strategies with high female coverage enjoy roughly the same benefits with greater savings than strategies that include males. We suspect that once adequate CE modeling of HPV-related morbidities in males is completed, the data will support vaccination in men at that time. All things considered, we recommend that resources be committed today towards HPV vaccination in females and MSM. In areas where vaccination is too costly, screenings must be implemented and expanded to prevent the downstream effects of HPV in as many women as possible, and HPV testing is the most promising method to maximize outreach while minimizing cost and infrastructure requirements in places where the infrastructure for regular Pap cytology screenings does not exist. In areas that have the resources to vaccinate women, funding should be directed towards improving vaccine coverage. The MSM population, in addition to being vaccinated, should also be checked regularly, either for anal HPV infection or for abnormal anal cytology.

Author Disclosure Statement

No competing financial interests exist.