Marge Berer, RHM Editor; Lisa Hallgarten, RHM Online Editor

Reproductive Health Matters, member of HPV Action

This paper, sent to the UK Joint Committee on Vaccination and Immunisation (JCVI) is in support of universal vaccination of all boys aged 12-13 against human papillomavirus (HPV) as a cause of genital warts and HPV-linked cancers that affect men regardless of their sexual orientation

Background

The UK has had a universal policy of vaccinating all girls aged 12-13 with a bivalent vaccine since 2008, and with the quadrivalent vaccine Gardasil since 2012 which, in addition to protection against HPV types 16 and 18, offers protection against two strains of HPV that are responsible for 90% of genital warts, types 6 and 11. According to the Royal Society for Public Health’s September 2014 newsletter, Gardasil also protects against most anal cancers, and while there is currently no data on the efficacy of the vaccine to prevent cancers of the penis, most HPV-related cancers of the penis are also caused by the HPV types prevented by Gardasil. [1]

From September 2014 the vaccine schedule was changed from three to two doses for 12-13 year-old girls in the UK.  Costs will fall concomitantly, freeing up resources. Another vaccine, which has just completed clinical trials, has been found to offer even further protection against the four original HPV types in Gardasil (6, 11, 16, 18), plus five additional variants linked to cervical and vaginal cancers. If it is approved, costs will be altered.

Overall uptake by girls for the vaccination programme has been reported as good. [1] Data for 2012-13 suggest that around 86% of girls had received all three doses of the vaccine in England, and 82% in Scotland. Prevalence of HPV types 16 & 18 in girls has significantly fallen since the introduction of the programme. However, some groups have shown disproportionally low uptake. Research suggests that there is lower knowledge of HPV and lower acceptability of the HPV vaccine in non-white ethnic groups, which may also be linked to religion. High levels of deprivation have also been linked to low HPV uptake. Other research suggests that poor school attenders or those not in school at all, for example those from travelling communities, are at risk of missing vaccination, particularly where schools do not have systems in place to stop girls falling through the net. [1]

Another issue with uptake appears to be the setting in which vaccination is offered. School-led vaccination programmes appear to be more successful than those offered through GP surgeries. Health services in Cornwall, where uptake has been particularly poor, are now moving their vaccination programme into the school setting. [1]

All of this information, before even looking at HPV in men, has implications for extending protection to boys and men. First and most immediately, it shows that opting for a more limited policy ‒ i.e. choosing in 2008 the bivalent vaccine over the quadrivalent one, presumably on grounds of cost, in spite of evidence supporting the wider protection offered by the quadrivalent vaccine[*] ‒ can end up causing a long delay in increasing the level of public health protection available. Four years were lost in this instance, and it took action such as an online survey of members of the British Association for Sexual Health and HIV to convince the government to change its policy. That survey collected responses from 407 doctors and 113 nurses and other health staff in January-February 2011 regarding the two types of vaccines. 93% of respondents said they would advise patients to pay privately for the quadrivalent vaccine, rather than accept the government-funded bivalent vaccine. Of those surveyed who had daughters in the school vaccination programme, 61% had actually paid themselves for their daughters to be vaccinated with the quadrivalent vaccine, and some had given their daughters the quadrivalent vaccine after they had had the bivalent one. [2]

Secondly, gender-specific immunisation programmes have been demonstrably less effective historically than gender-neutral immunisation programmes. This was exemplified by 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, who had not been vaccinated. Yet it was only in 1995 that the programme was modified to include boys as well as girls, a delay of 25 years. [3]

The evidence from Denmark (where the national HPV vaccination programme is for girls only) on the impact of HPV vaccination on the incidence of genital warts shows that incidence has fallen in women but not in men. The authors believe this is almost certainly because men are having sex with unvaccinated women from Denmark and/or other countries. [4] Or they may be having sex with other men, or both.

Thirdly, since GP- and other non-school venues for vaccination are leading to lower uptake rates than school-based programmes, and the uptake among some girls is better than among others, policy on vaccinating boys needs to take both these limitations into account. Focusing only on boys over 16 years old means school-based programmes have far less chance of reaching boys from a young age. Secondly, focusing only on men who have sex with men (MSM) aged 16-40 raises issues of how to reach them effectively as a “group” and whether focusing only on MSM who attend a GUM clinic will achieve too little, too late as regards near-universal protection.

Given that there are many communities where coverage rates among girls are much lower, vaccinating boys would help to protect unprotected girls/women. Boys/men would also be protected from acquiring HPV infection from non-vaccinated girls/women both from the UK and from other countries, and as well as from non-vaccinated boys/men.

Perhaps most importantly from the point of view of sexual health information, particularly addressed to children under 16 and young men and women in school, excluding boys sends absolutely the wrong message ‒ that girls and women alone are responsible for sexually transmitted infections and sexual health.

What is known about the effects of HPV and the HPV vaccine in boys and men

HPV is the cause of nearly all cervical cancer cases and also causes cancer of the vagina, vulva, anus, penis and the head and neck. It is estimated to be the causal agent in 5% of all human cancers and is heavily implicated in the recent rapid rise in anal and head and neck cancers. HPV is also the cause of genital warts, the commonest sexually transmitted viral disease. [5] These diseases affect males as well as females; indeed, it has been estimated that in the UK more than 2,000 cases of cancer in men are caused each year by HPV as are some 48,000 cases of genital warts. [6]

The risk of acquiring HPV infection is linked primarily to sexual behaviour, including having more than one lifetime sexual partner. No one would ever 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. The National Survey of Sexual Attitudes and Lifestyles 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. 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. [7]

HIV infection is strongly associated with increased persistence of HPV infection and the re-activation of latent HPV infection. While much of the research on the increased risk of anal and other HPV-related cancers in men has been in MSM, due to the increased risk of HIV in that population, 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. Number of partners is the issue here, not sexual orientation.

A study recruited 1,159 men aged 18–70 years residing in Brazil, Mexico and the USA who were HIV negative and reported no history of cancer; they were recruited from the general population, universities and health care facilities. The incidence of a new genital HPV infection among them was 38.4 per 1,000 person-months. Oncogenic HPV infection was significantly associated with having a high number of lifetime female sexual partners, and a high number of male anal sexual partners. [8] Thus, the problem of HPV, including oncogenic HPV, is an issue for men who have sex with women too. The data seem to suggest that there are high infection rates and low disease rates in men, while in women there are low infection and high disease rates. [9]

The rapid increase in the incidence of HPV-related head and neck cancers over the past 20 years is also an issue for all men. [10]

A large, national cohort study of Danish men and women examined national patient register data for long-term health outcomes, and specifically the risk of cancer in people with genital warts. The study was among 16,155 men and 32,933 women who had been diagnosed with genital warts from 1978 to 2008. These findings were compared to the general population cancer registry for the relative risk of specific cancers/cancer sites. The total number of cancers observed in the study population was 2,362, compared to an estimated 1,807 cancers in the general population. Overall, patients with genital warts were 30% more likely to develop a cancer compared to those without genital warts. A diagnosis of genital warts was strongly related to anal, vulvar, vaginal, cervical, penile, and head and neck cancer, including sub-sites of head and neck cancer with confirmed HPV association. The risks remained elevated for more than ten years following a genital warts diagnosis. In addition, there were moderately increased relative risk estimates for non-melanoma skin cancer, smoking-related cancers, and Hodgkin’s and non-Hodgkin’s lymphoma. Many of these cancers were also associated with high-risk strains of HPV. [11]

Thus, the risks from HPV for men as well as women are incontestable.

Data on age at vaccination

A systematic review of data in 64 studies, which reported age-specific HPV prevalence, among more than 14,800 men in 23 countries, generally limited to men >18 years old, found that HPV prevalence was high among the sexually active men in all regions but with considerable variation, depending on age, country and region, ranging from 1% to 84% among low-risk men and from 2% to 93% among high-risk men. Peak HPV prevalence spanned a wide range of ages and, compared with that in women, seemed to peak at slightly older ages and remained constant or slightly decreased with increasing age, suggesting longer-term persistence of high-risk HPV infection in men or a higher rate of re-infection. [12]

In every year that passes, over 400,000 boys miss out on the opportunity to be protected against a virus that causes 5% of all cancers.

Immunity against HPV is greater if the vaccine is administered before age 16. The US Centers for Disease Control and Prevention say:

“Data on immunogenicity in males are available from the phase III trial conducted among males aged 16 through 26 years and from bridging immunogenicity studies conducted among males aged 9 through 15 years. Seroconversion was high for all four HPV vaccine types and post-vaccination antibody titers were significantly higher in males aged 9 through 15 years compared with males aged 16 through 26 years.” [13]

MSM are at risk of HPV infection immediately after sexual debut. A study of young MSM in Australia found that early and high per partner transmission of HPV occurred between men soon after their first sexual experiences. It therefore recommended that HPV vaccination should commence early for maximal prevention of HPV among MSM. [14] [15]

Why vaccinating only MSM is not good enough

The reason the term “men who have sex with men” was coined was because many MSM may not identify as “homosexual” or “bisexual” and because they may have sex with girls/women and boys/men over the years. We repeat ‒ because it is the sexual activity that puts them at risk, services need to focus on attracting the people whose sexual activities put them at risk. Moreover, expecting boys and young men (who may not be sexually active yet or sure of their sexual identity) to have to identify whether they have had or will have sex with other boys/men presents both practical and ethical difficulties.

How would policymakers propose to find boys who say they are, or might in the future be MSM, in order to single them out from other boys in order to vaccinate them? What if boys do not identify themselves as MSM publicly, or even in their own minds, given the stigma that still exists? Would a leaflet be enough to bring them in to be immunised in herd-protective numbers? Would talking to their parents, to whom they may have said nothing about their sexuality?

UK data suggest that GUM clinics will not see young MSM before they become infected with HPV. [16] The median age of MSM at first attendance at a Southampton GUM clinic was 32; thus, most MSM would have had multiple sexual partners with high risk of HPV acquisition before they had attended any clinic. Also, many gay and bisexual men do not use GUM clinics. The 2011 Stonewall Gay and Bisexual Men’s Health Survey, with 6,861 respondents, found that one in four had never been tested for any sexually transmitted infection and 44% had never discussed STIs with a health care professional. One in ten had had sex with women as well as with men in the previous five years. [17]

Given the data summarised above, GUM clinics would therefore not be an effective place to vaccinate sufficient numbers of still uninfected MSM. In fact, the evidence suggests that vaccinating MSM aged 16-25 and those who attend GUM clinics is not the best way to protect even the MSM population as a whole, let alone their sexual partners.

The issue of discrimination under the Equality Act 2010

Lastly, there is the question of discrimination under the Equality Act 2010, which lists the following as some of the relevant characteristics protected in law against discrimination: age, sex, and sexual orientation. [18] Given the substantial evidence of the protective effect of HPV vaccination for all boys and men as well as all girls and women, the failure to ensure that HPV vaccination policy is aimed at universal protection could be construed as discriminatory under the Equality Act 2010, and a case could be taken against the government for withholding the vaccine from boys who identify as MSM aged 12-15 and all boys and men who identify as heterosexual.

We believe the JCVI recommendation is discriminatory under the Equality Act 2010. We also think it is not the best policy from a public health perspective either. We question why further information is required before making a recommendation for a universal vaccination programme.

Growing support for vaccination of all boys against HPV

The US Advisory Committee on Immunization Practices of the US Centers for Disease Control & Prevention has recommended that adolescent boys and young men aged 11–21 should be vaccinated against HPV, and that all gay and bisexual men and HIV-positive men aged 26 and under should be vaccinated. [19]

A number of countries, including Australia, Austria and some parts of Canada, have already extended the vaccine to boys as well.

An editorial introducing a group of articles about HPV in the Journal of Adolescent Health in 2010 argued that the most acceptable way to achieve high uptake of HPV vaccine was to offer voluntary school-based vaccination, supported by effective consent processes, training, and best practice guidelines for those providing the vaccination, and education for parents, adolescents, and teachers. School delivery programmes, it argued, were also the most feasible for vaccinating both boys and girls, with new data suggesting that older adolescent boys’ health care practices were exceptionally low. [20]

Conclusions and recommendation

In conclusion, we believe the case for universal vaccination of all adolescents aged 12-13 is strong. In September 2014, in a letter to the BMJ, the All-Party Parliamentary Group on Cancer called for vaccination of all boys in the UK. [21] This approach is supported by the 35 organisations that make up HPV Action, of which we are one. Cancer Research UK also believes that “vaccinating boys would be beneficial for public health”.

HPV Action estimates that the additional cost of extending the HPV vaccination programme to boys in the UK would be in the region of £20–22 million a year. This relatively small cost has to be set against the economic impact of HPV-related disease. The cost of treating genital warts in England alone is estimated to be over £52 million a year.

Gardasil, the quadrivalent vaccine, is already licensed in the UK for use in boys aged 9–15.

We therefore call on the JCVI to adopt and put forward to the UK government the following recommendation: that the most effective way to eliminate HPV and HPV-related diseases is through a gender-neutral, universal vaccination programme for all children aged 12‒13.

Anything else is discriminatory, inequitable, less effective, and difficult to explain or justify.

References

1. Royal Society for Public Health. September 2014 newsletter.
2. Doctors bypass NHS for their daughters’ HPV vaccination. British Association for Sexual Health and HIV (BASHH) press release, 15 February 2011. http://www.thefreelibrary.com/British+doctors+recommend+bypassing+free+National+Health+Service…-a0259077137
3. Kubba T. Human papillomavirus vaccination in the United Kingdom: what about boys? Reproductive Health Matters 2008;16(32):97–103. http://www.rhm-elsevier.com/article/S0968-8080(08)32413-6/fulltext
4. Baandrup L, Blomberg M, Dehlendorff C, et al. Significant decrease in the incidence of genital warts in young Danish women after implementation of a national human papillomavirus vaccination program. Sexually Transmitted Diseases2013 40(2):130-5. http://www.ncbi.nlm.nih.gov/pubmed/23324976
5. http://www.cancerresearchuk.org/cancer-info/cancerstats/types/anal-cancer/Incidence/anal-incidence
6. Baker P. Going gender-neutral with the HPV vaccine. British Journal of Nursing 2014;23(11):550. http://www.theswallows.org.uk/wp-content/uploads/BJ-Nursing-HPV-june-2014.pdf

7. Johnson AM, Mercer CH, Erens, B et al. Sexual behaviour in Britain: partnerships, practices and HIV risk behaviours.Lancet2001;358:1835–42. http://www.sciencedirect.com/science/article/pii/S0140673601068830# Cited in Kubba [3].
8. Giuliano AR, Lee J-H, Fulp W, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study. Lancet 2011;377:932–40. http://www.sciencedirect.com/science/article/pii/S0140673613608090
9. Monsonego J. Genital infection with HPV in men: research into practice. Lancet 2011;377:881–83. http://www.sciencedirect.com/science/article/pii/S0140673611602778
10. Potentially HPV-related head and neck cancers. National Cancer Intelligence Network (NCIN) http://www.ncin.org.uk/publications/data_briefings/potentially_hpv_related_head_and_neck_cancers 
11. Blomberg M, Friis S, Munk C, et al. Genital warts and risk of cancer – a Danish study of nearly 50,000 patients with genital warts. Journal of Infectious Diseases 2012;205(10):1544‒53. http://www.ncbi.nlm.nih.gov/pubmed/22427679
12. 12.Smith JS, Gilbert PA, Melendy A, et al. Age-specific prevalence of human papillomavirus infection in males: a global review. Journal of Adolescent Health 2011;48(6):540–52. http://www.ncbi.nlm.nih.gov/pubmed/21575812
13. Recommendations on the Use of Quadrivalent Human Papillomavirus Vaccine in Males — Advisory Committee on Immunization Practices (ACIP)Centers for Disease Control and Prevention 2011; 60(50);1705-1708  http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6050a3.htm.
14. Zou H, Tabrizi SN, Grulich AE, et al. Early acquisition of anogenital human papillomavirus among teenage men who have sex with men. Journal of Infectious Diseases 2014;209(5):642‒51. http://www.ncbi.nlm.nih.gov/pubmed/24265440
15. Zou H, Tabrizi SN, Grulich AE, et al. Site-specific human papillomavirus infection in adolescent men who have sex with men (HYPER): an observational cohort study. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099%2814%2970994-6/fulltext
16. Clarke E, Board C, Patel N. Why are anogenital warts diagnoses decreasing in the UK: bivalent human papillomavirus (HPV) vaccine cross-protection or failure to examine? Sexually Transmitted Infections 2014;90(8):587. http://www.ncbi.nlm.nih.gov/pubmed/25398729
17. Stonewall Gay and Bisexual Men’s Health Survey. http://www.stonewall.org.uk/documents/stonewall_gay_mens_health_final.pdf.
18. Equality Act 2010. http://www.equalityhumanrights.com/legal-and-policy/legislation/equality-act-2010
19. Advisory Committee on Immunization Practices. Recommended Adult Immunization Schedule: United States, 2012. Annals of Internal Medicine 2012;156(3):211–17. http://www.ncbi.nlm.nih.gov/pubmed/22298576
20. Skinner SR, Cooper Robbins SC. Voluntary school-based human papillomavirus vaccination: an efficient and acceptable model for achieving high vaccine coverage in adolescents. Journal of Adolescent Health 2010;47(3):215–18. Doi: http://www.sciencedirect.com/science/article/pii/S1054139X10003186
21. John Baron MP and chair, All Party Parliamentary Group on Cancer, et al. Time to vaccinate boys against HPV infection and cancer, say parliamentarians with special interest in public health [letter]. BMJ 2014;349:g5789. Doi: 10.1136/bmj.g5789. http://www.bmj.com/content/349/bmj.g5789

[*] By 2008, worldwide the quadrivalent vaccine was already considered the vaccine of choice and had been selected by health authorities in the United States, Australia, New Zealand, Canada, Switzerland, Italy, Spain and Sweden for regional and national immunisation programmes.