Human papillomavirus vaccination in the United Kingdom: what about boys?

Abstract

In September 2008 the UK Department of Health initiated a human papillomavirus (HPV) immunisation programme for girls aged 12–13 for prevention of cervical cancer, which is most often caused by two HPV types. An important question, yet to be addressed, is whether boys should also be vaccinated. Men also get HPV and transmit it sexually, not just women. Certain HPV types are associated with genital warts, which have significant morbidity, and with difficult to treat non-cervical malignancies, including vulval, penile, anal and oro-pharyngeal cancer, which are best prevented through vaccination. Moreover, increased persistence of HPV infection is associated with HIV infection. A review of the literature and evidence from modelling suggest that vaccinating boys would increase vaccination impact and may be necessary to achieve herd immunity targets. Excluding boys sends the wrong message that girls and women alone are responsible for sexual health. Although protective efficacy of the vaccine in men has not yet been fully established, the rationale for vaccinating boys as well as girls at an early age is strong, assuming efficacy is established. Meanwhile, provision of the quadrivalent vaccine should become UK policy, in order to include protection against genital warts, the argument for which is strengthened if boys are also vaccinated.

Résumé

En septembre 2008, le Département britannique de la santé a lancé un programme de vaccination contre le papillomavirus humain (PVH) pour les filles âgées de 12–13 ans afin de prévenir le cancer du col de l’utérus, qui est le plus souvent causé par deux types de PVH. Une question importante, encore en suspens, est de savoir s’il convient de vacciner également les garçons. Les hommes contractent aussi le PVH et le transmettent sexuellement. Certains types de PVH sont associés aux verrues génitales, qui ont assez répandues, et à des formes malignes difficiles à traiter de cancer de la vulve, du pénis, de l’anus et du pharynx, pour lesquelles la vaccination est la meilleure prévention. De plus, l’accroissement des infections à PVH est associé à l’infection à VIH. Une analyse des publications et des données des modélisations suggère que vacciner les garçons augmenterait l’impact de la vaccination et pourrait être nécessaire pour parvenir aux objectifs de l’immunité de groupe. Exclure les garçons donne à penser à tort que seules les femmes sont responsables de la santé sexuelle. Bien que l’effet protecteur du vaccin n’ait pas été encore totalement établi chez l’homme, les arguments en faveur de la vaccination précoce des garçons sont convaincants, pour autant que son efficacité soit établie. En attendant, le Royaume-Uni devrait décider d’administrer le vaccin quadrivalent afin de protéger contre les verrues génitales, un argument qui a plus de poids si les garçons sont aussi vaccinés.

Resumen

En septiembre de 2008, el Departamento de Salud del Reino Unido inició un programa de inmunización contra el virus del papiloma humano (VPH) para niñas de 12 – 13 años de edad, para la prevención del cáncer cervical, que es causado con mayor frecuencia por dos tipos de VPH. Una interrogante importante, que aún no se ha contestado, es si también se debe vacunar a los niños. No sólo las mujeres adquieren y transmiten el VPH sexualmente, sino también los hombres. Algunos tipos de VPH están asociados con verrugas genitales, que presentan considerable morbilidad, y con malignidades no cervicales difíciles de tratar, como el cáncer vulvar, peneal, anal y orofaríngeo, que se evitan con mayor eficacia mediante vacunas. Más aún, la creciente persistencia de la infección por VPH está asociada con la infección por VIH. Un estudio del material publicado al respecto y la evidencia de los modelos indican que vacunar a los niños aumentaría el impacto de la vacunación y podría ser necesario para lograr los objetivos de inmunidad colectiva. Excluir a los niños transmite un mensaje erróneo de que las mujeres son las únicas responsables de la salud sexual. Aunque aún no se ha establecido completamente la eficacia protectora de la vacuna en los hombres, suponiendo que se establezca su eficacia, se justifica vacunar tanto a los niños como a las niñas a temprana edad. Mientras tanto, el suministro de la vacuna cuadrivalente debería ser política del Reino Unido, a fin de incluir la protección contra las verrugas genitales; el argumento a favor se fortalece al vacunar a los niños también.

Key Words:

• human papillomavirus
• cervical cancer prevention
• genital warts
• health policy and programmes
• United Kingdom

In September 2008, the UK Department of Health initiated a human papillomavirus (HPV) immunisation programme. The vaccine has been billed as the “cervical cancer vaccine”, which is accurate in that the link between certain high risk HPV sub-types and cervical cancer has been conclusively shown.¹² However, the new HPV vaccines prevent more than just cervical cancer. The same HPV types 16 and 18 that cause most cervical cancer also cause other genital cancers in both women and men, and HPV subtypes 6 and 11 are responsible for approximately 90% of all genital warts, which also affect both sexes.^2–7 The fact that both women and men are affected by HPV-related disease calls for a discussion to take place about who should be vaccinated and with which of the two currently existing vaccines.

In the UK, HPV vaccination is initially being introduced for girls aged 12–13.³ Vaccination has already commenced in Scotland. A catch-up programme will begin in September 2009 in England, Wales and Northern Ireland.⁸ The Department of Health had the choice of a quadrivalent vaccine, which protects against HPV subtypes 6, 11, 16 and 18 (Gardasil™) or a bivalent vaccine against HPV subtypes 16 and 18 (Cervarix™).¹ They opted for the bivalent vaccine, presumably because it is less expensive. As the quadivalent vaccine offers additional protection against HPV subtypes 6 and 11, to be cost-effective the bivalent vaccine must be less expensive.⁹ A recent study estimated the bivalent vaccine to be £13–21 less expensive per dose than the quadrivalent vaccine.¹⁰ However, worldwide the quadrivalent vaccine is considered the vaccine of choice. It has been selected by health authorities in the United States, Australia, New Zealand, Canada, Switzerland, Italy, Spain and Sweden for regional and national immunisation programmes.⁵ Sexual health organisations in the UK have questioned the decision to use the bivalent vaccine, terming it a “missed opportunity”, as it does not offer protection against genital warts.⁴⁵ Additionally a recent editorial criticised the Department of Health for allowing foregone health benefits and long-term cost savings to replace averting cases of genital warts, for the sake of the reduced short-term financial outlay.⁹

It is estimated that most men and women are infected with at least one HPV subtype during their sexual lifetime though in most people it does not persist nor progress to cancer.^1,11 However, HPV infection rates as high as 70% have been reported in male sexual partners of women with cervical intraepithelial neoplasia (CIN) in the Netherlands.¹²¹³ HPV infection rates in women in the UK vary from 7.1% in those with normal cervical cytology (sample size 13,890) to 91.5% in those with high-grade cervical lesions and cervical cancer (sample size 597).¹⁴ Furthermore, a study in England, which tested serum specimens from 1483 females aged 10–29, obtained from the Health Protection Agency Sero-Epidemiology Unit, found the age-standardised seroprevalence was 10.7% for HPV 6, 2.7% for HPV 11, 11.9% for HPV 16, 4.7% for HPV 18, and 20.7% for any of the four types.¹⁵

An important question, yet to be fully addressed, is whether boys should be included in any HPV immunisation programme as well as girls. The quadrivalent vaccine is already licensed in the UK for use in boys aged 9–15,¹⁶ although phase III clinical trials concerning the immunogenicity and efficacy of HPV vaccines in men are still ongoing.^2,17 Their publication may trigger a greater consideration of the issue of HPV vaccination of boys. Yet, one published multi-centre study of a quadrivalent vaccine similar to Gardasil (supplied by Merck Research Laboratories), administered to 10–15 year olds (506 girls and 510 boys) showed high levels of immunogenicity (>99%) to all four HPV types (6,11,16,18) in both boys and girls.¹⁸

Krafty, an MC, with his girlfriend in Poplar, East London, 2005

This paper reviews the literature on the question of whether to include boys in HPV immunisation programmes, assuming the vaccines are effective in them, and argues that excluding boys misses a number of targets, undermines the objective of reducing cervical cancer, excludes men at risk of HPV-related viral infections and cancers from any benefit and sends the wrong health promotion message – that girls and women alone should shoulder societal responsibility for sexual health.

Literature review

A literature review was carried out by searching Medline and Embase. The search terms used were: “HPV”, “human papillomavirus”, “vaccine”, “men”, “boys” and “male”. Articles from 1 January 1990 through 31 May 2008 were included. Only English language papers were reviewed. References from relevant articles were also included. The literature review sought to identify published work which addressed issues related to vaccination coverage and herd immunity; HPV and genital warts; the association of HPV with non-cervical malignancies and with HIV, as well as the social implications of a gender-specific immunisation programme.

Findings and discussion

Vaccination coverage and herd immunity

Under optimal circumstances, with high vaccination uptake and coverage, a vaccine will not only directly protect individuals, but will also indirectly protect the population as a whole, through what is called herd immunity,¹⁹ because the risk of coming into contact with an infected individual falls as more people are vaccinated. This is how the vaccination of only one sex can theoretically protect the other. However, vaccination coverage needs to be above a threshold of around 75%; if it falls below this, then vaccinating both sexes is essential to increase effectiveness.²⁰²¹ Evidence from epidemiological modelling suggests that vaccination coverage and herd immunity would benefit from a gender-neutral immunisation programme.¹⁹ Studies have shown that a female-specific vaccination approach would be only 60–75% as efficient at reducing HPV prevalence in women as a gender-neutral vaccination strategy.²¹²²

Historically, gender-specific immunisation programmes have been demonstrably less effective than gender-neutral immunisation programmes. This was exemplified, for example, with the UK’s rubella immunisation programme, which began in 1970. An initial decline in the incidence of rubella was followed by a resurgence of the disease in young men and pregnant women. This was due to low herd immunity, partly as a result of the gender-specific approach. In 1995 the programme was modified to include boys as well as girls.^22–24 With HPV vaccination, in order to get it right from the start, surely boys should be vaccinated too.

The risk of HPV infection and sexual behaviour

The risk of acquiring HPV infection is linked primarily to sexual behaviour, including having more than one lifetime sexual partner.^1,25,26 We would never consider treating only women for sexually transmitted infections (STIs) when they are also transmitted by and to men. Surely the same holds true with vaccination against HPV, which is primarily sexually transmitted. The National Survey of Sexual Attitudes and Lifestyles (NATSAL) 2000 found that 34.6% of men in Britain aged 16–44 had had ten or more lifetime sexual partners compared with 19.4% of women.²⁷ British men are therefore at even greater risk of being exposed to, contracting and transmitting HPV infection than women. Each man who is vaccinated would therefore reduce the infection risk for more than one woman.

HPV association with genital warts

Genital warts are associated with HPV 6 and HPV 11. These two HPV subtypes are responsible for approximately 90% of all genital warts, and 70–100% of exophytic genital wart tissue contains one of these types.¹² Genital warts are the most commonly diagnosed viral STI in genitourinary medicine clinics in the UK. In 2006, 83,745 new diagnoses of genital warts were made in the UK, comprising 22% of all new STIs diagnosed. Among men, the highest rates of new cases were found in 20–24 year olds (793/100,000) and among women in 16–19 year olds (767/100,000), reflecting the fact that women tend to have sexual relationships with men somewhat older than themselves.²⁷²⁸

A study to determine the prevalence of HPV infection among 463 men aged 18–40 in the USA, who had had sexual intercourse with a woman in the past year and with no history of genital warts, found that 51.2% of them were positive for at least one oncogenic or non-oncogenic HPV type.^6,29 Evidence also indicates that there is a high rate of transmission of HPV from men with pre-existing penile warts to their female partners.³⁰

Although not malignant, genital warts are associated with significant physical and psychological morbidity as well as placing a substantial treatment burden on health care systems.^2,31 Typically, genital warts require multiple physician visits for diagnosis and treatment, with the cost to the National Health Service in the UK estimated at £120 million annually.^7,31,32 The quadrivalent vaccine targets both oncogenic HPV types and those responsible for genital warts, and offers direct benefits to men as well as women, leading to public health and health economics benefits. Both the extensive morbidity and costs associated with genital warts could be reduced if young boys and girls were included in the national HPV immunisation programme, not just girls, and the quadrivalent vaccine used.

HPV association with non-cervical malignancies

HPV subtypes 16 and 18 are also associated with non-cervical malignancies, including vulval, penile, anal and oro-pharyngeal cancers, as well as precursor lesions such as anal intraepithelial neoplasia.^2,7,8 Worldwide, over 28,000 male cancers annually are attributable to HPV subtypes 16 and 18.³³ For example, in Denmark and Sweden 90% of anal carcinomas among women and 100% of anal carcinomas among homosexual men were positive for high-risk HPV DNA.^2,34 In fact, anal carcinoma has been found to be more commonly associated with HPV 16 than cervical cancer.³⁵

D’Souza and colleagues have found a significant association between head and neck squamous cell carcinoma and HPV 16 as well.³⁶ Some studies have found that HPV 16 accounts for 87–95% of HPV-positive oro-pharyngeal cancers.³⁷ Mork and colleagues found a 14-fold increase in the risk of oro-pharyngeal cancer among patients seropositive for HPV 16, and it has been suggested that exposure to HPV can precede the appearance of oro-pharyngeal cancer by ten or more years.³⁸ Oral cancers account for over 1,700 deaths in the UK annually, and this figure has been increasing in recent years.³⁹ It has been found that over one-third of patients with oro-pharyngeal cancer in the UK are seropositive for HPV, with HPV 16 being the most common HPV subtype detected.⁴⁰

Although less common, these difficult-to-treat cancers in men and women would be best prevented through vaccination. The strong association of HPV 16 with anal and oro-pharyngeal cancer provides an additional rationale for exploring HPV vaccination in men in tandem with the goal of reducing the risk of cervical cancer by reducing transmission of HPV 16 and 18 to women.^2,33,37,38

HPV association with HIV

HIV infection is strongly associated with increased persistence of HPV infection and the re-activation of latent HPV infection.⁸ One study, which compared data from over a million men, using population-based cancer and AIDS registries in the USA and Puerto Rico, found that the incidence of anal cancer in HIV-positive homosexual men was twice that of HIV-negative men.⁴¹

A study of 608 men who have sex with men in San Francisco found the prevalence of anal HPV infection to be 61% among those who were HIV-negative and 93% among those who were HIV-positive. 73% of the HIV-positive men were infected with more than one HPV type.⁴² Detection of multiple HPV types is associated with both anal intraepithelial neoplasia and progression to higher grade lesions over time.² In addition, an American study of 257,605 men who were HIV-positive found that the relative risk for developing anal cancer among them was 37-fold higher than in the general population. Furthermore, HIV-positive men who had sex with men were at 60-fold higher risk of developing anal cancer compared to the general population.⁴³⁴⁴ The incidence of anal carcinomas and anal intraepithelial neoplasia is currently rising in the UK and the USA among both homosexual men, and heterosexual men and women.^2,45 This may, in part, be related to HIV infection.²

Furthermore, it has been reported that homosexual men in the UK, seeking to protect themselves against genital warts, anal and penile cancers and to prevent transmission of HPV to their partners, are now attending private clinics in order to obtain HPV vaccination “off licence”.⁴⁶

Sexual health burden falling to women

The gender-specific HPV immunisation programme has been regarded by some as another example that women and not men are singled out as the sole target for sexual health interventions, giving the impression that sexual health is a woman’s problem.⁴⁷ Women should not feel that the physical and psychological burden falls disproportionally upon them. Furthermore, sex educators have argued that the message given to young people, with the gender-specific HPV immunisation programme, is that women are still responsible for managing sex and therefore boys are permitted to take less responsibility.⁴⁸ Family Health International have stated that a gap remains between the rhetoric of promoting male involvement and the realities of female-oriented sexual and reproductive health care. Providing HPV vaccination to girls only contributes to this imbalance.⁴⁹

Conclusions and recommendations

One of the principles of epidemiology is to identify the source of an infection and the at-risk populations in order to implement control and prevention strategies. HPV infections can cause pre-cancerous and cancerous genital and oro-pharyngeal lesions in addition to genital warts, in both men and women. Men can contract HPV infection as well as transfer it to their partners. Excluding men may lower herd immunity, which may render the HPV immunisation programme less successful. Consideration should be given to the cost-effectiveness of including both boys and girls in national HPV immunisation programmes.

Although protective efficacy has not yet been fully established in men, the quadrivalent vaccine is licensed in the UK for use in boys aged 9–15, though the bivalent vaccine is not. Studies are ongoing in men internationally. The rationale for vaccinating boys as well as girls at an early age is strong, assuming efficacy is established. Meanwhile, provision of the quadrivalent vaccine should become UK policy, in order to include protection against genital warts, the argument for which is strengthened even more if boys are also vaccinated.