Article Text

HPV vaccination to prevent anal cancer in men who have sex with men
1. Mark D Lawton1,
2. Mayura Nathan2,
3. David Asboe3
1. 1Liverpool Centre for Sexual Health, Royal Liverpool University Hospital, Liverpool, UK
2. 2Department of Sexual Health, Homerton University Hospital, London, UK
3. 3Kobler Clinic, Chelsea and Westminster Hospital, London, UK
1. Correspondence to Dr Mark D Lawton, Liverpool Centre for Sexual Health, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, UK

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Prevention of cancer remains a challenge in many areas of medicine. The discovery of the association of human papillomavirus (HPV) to anogenital cancers has led to the successful development of preventative vaccines.

Men who have sex with men (MSM) are disproportionately affected by HPV-related cancer, particularly anal cancer, where rates are over 15 times higher than in heterosexual men (OR 17.3; 95% CI 8.2 to 36.1).1 This is driven by disease in HIV-positive MSM in whom the very high rates of anal cancer are increasing despite highly active antiretroviral treatment (HAART). The incidence of anal cancer during the HAART period (post-1996) was estimated to be 131 cases per 100 000 person years (py), corresponding to a demographically adjusted rate ratio of 80.3.2 This compares with cervical cancer rates of 15.0 and 9.8 per 100 000 py before and after the introduction of the cervical screening programme.3 There are only a few studies of anal cancer in HIV-negative MSM, but rates also appear to be increased. In the Multicenter AIDS cohort study (MACS) the incidence of confirmed anal squamous cell carcinomas was 5 (95% CI 1 to 18) per 100 000 py.4 Oncogenic HPV types are estimated to cause 80% or more of anal cancers.5

The UK has vaccinated girls for HPV through school programmes since 2008. Initially using the bivalent vaccine Cervarix, it moved to the quadrivalent HPV (qHPV) vaccine Gardasil in September 2012. Like many other countries, the UK decided to vaccinate girls only, on the basis of the likely herd immunity benefit that will accrue to boys. Data from Australia support this hypothesis. A dramatic decline in anogenital warts was seen just 1 year after the introduction of qHPV, not only in the vaccinated women but also heterosexual men of corresponding age. However, there was no change seen in the incidence of warts in MSM, suggesting they are not benefitting from this approach.6 From February 2013, Australia has extended the national school-based HPV vaccination programme to include males 12–13 years old, with a catch-up programme of 14–15-year-olds.

Recent studies establish the efficacy of HPV vaccination in men including MSM. qHPV vaccine in HIV-negative men with a reported 1–5 sexual partners was highly immunogenic and effective in preventing infection, reducing HPV persistence and preventing development of external genital lesions. Additionally, vaccination reduced rates of anal intraepithelial neoplasia (AIN).7 ,8 For MSM without serological or PCR evidence of infection with relevant HPV types, seroconversion to HPV-6, 11, 16 and 18 was seen in 96.5% (95% CI 91.3 to 99.0), 97.4% (95% CI 92.5 to 99.5), 94.1% (95% CI 88.7 to 97.4) and 89.7% (95% CI 83.2 to 94.0) of participants. The efficacy of the vaccine to prevent persistent HPV-16 or 18 was 95.8% (95% CI 74.1 to 99.9) and 57.5% (95% CI 33.2 to 73.6) in the per-protocol (PP) versus intention-to-treat (ITT) populations. The data were similar for efficacy against HPV-16 or 18 related AIN 78.6% (95% CI −0.4 to 97.7) PP and 55.2% (95% CI 8.5 to 79.3) ITT. While this supports the notion that the vaccine is of greater benefit to those with no prior exposure to HPV-16 and 18, vaccination did still demonstrate substantial efficacy in the ITT group which included those with serological or DNA evidence of HPV-16 or 18 infection.8 ,9

qHPV vaccine is also immunogenic in HIV-positive MSM.10 In men without evidence of both HPV-16 and 18, PP seroconversion was at least 98% for each of the four vaccine types. CD4 count, nadir and age were not associated with antibody concentrations. Efficacy by clinical outcomes has not been confirmed by clinical studies in this population.

While vaccination before sexual activity commences is the optimal strategy, there are data supporting the alternative approach of vaccinating young MSM after sexual debut. The key question is: What is the proportion of young, identifying MSM, accessing health services who are unexposed to HPV-16 and or 18, and who will therefore benefit maximally from vaccination? Published evidence consistently demonstrates only a minority of young MSM have prevalent high-risk HPV infection (HPV DNA detection) or, more importantly, evidence of a past history of high-risk HPV infection (type-specific antibodies). In a recently published meta-analysis, the prevalence of anal canal HPV-16 and 18 DNA in HIV-negative MSM was 12.5% (95% CI 9.8% to 15.4%) and 4.9% (2.7% to 7.1%).11 In a seroprevalence study, only 19% of MSM younger than 35 years were HPV-16 seropositive at baseline.12 Seroincidence remained above 3% per year until age 45 years, illustrating the value of HPV vaccination.

Additionally, there are now data reporting the prevalence of high-risk HPV in MSM attendees at sexually transmitted infection (STI) clinics. This is important as it might be expected that STI clinics are where many young MSM will first disclose their sexual orientation to healthcare providers. The UK Health Protection Agency's anonymous prevalence study, testing residual urine samples from STI clinic attendees, demonstrated any high-risk HPV type in fewer than 5% of MSM younger than 25 years, and fewer than 10% in 25–44-year-olds.13 The prevalence of HPV-16 or 18 was fewer than 5% across all age strata. While urine testing has been shown to underestimate the prevalence of anal HPV infection, it gives some support to the hypothesis that a majority of young MSM will be unexposed to HPV-16 or 18.14

Prior exposure to HPV has an impact on cost effectiveness. Despite this, targeted HPV vaccination of MSM is still considered to be cost-effective.15 In a US study, estimates of vaccination costs vary from US$15 290 per quality-adjusted life-year (QALY) gained for vaccination at age 12 years in MSM without previous exposure to HPV to US$37 830 per QALY for vaccination of MSM at 26 years when previous exposure to all vaccine-targeted HPV types was assumed to be 50%. The Centers for Disease Control and Prevention in the USA recommends universal vaccination of boys aged 11 and 12 years, but additionally the vaccination of MSM up to age 26 years.

AIN screening, particularly of HIV-positive MSM, has been proposed to reduce the incidence of anal cancer. However, unanswered questions remain about the effectiveness of this approach. While the relationship between cervical intraepithelial neoplasia and cervical cancer is well understood, data linking AIN and anal cancer are largely indirect. Furthermore, there are barriers to effective intervention. Dysplasia often involves large areas of the anal squamo-columnar junction, and ablative methods are more problematic in this setting. Only small AIN treatment studies, with short follow-up periods, have been published.16 ,17 There are no data at present that any intervention to AIN disease actually prevents anal cancer, and AIN screening is not currently recommended by any national guidelines.

STI clinics are ideally placed to provide HPV vaccination alongside primary care. In 2010, 17 000 MSM aged 16–26 years attended a sexual health clinic within England. An HPV vaccination programme would build on a long-standing programme of vaccination of MSM for Hepatitis B which has an uptake of 85%. Also, the offer of HPV vaccination would give focus to initiatives to improve access for young gay men who remain at the greatest risk of acquiring HIV, and may increase willingness to attend an STI service, and to disclose sexual orientation.

There are now ample data testifying the increased burden of HPV-related conditions and cancer in MSM. The introduction of national cervical cancer screening programmes have contributed to significant falls in cervical cancer rates and associated mortality. Such a programme for MSM is unlikely in the absence of a reliable screening method or accepted treatment for AIN. While the biggest challenge will be to identify and vaccinate before HPV acquisition, recent data illustrates HPV vaccination of sexually active MSM is effective, and modelling using conservative analyses suggests vaccination is cost-effective. In the light of this evidence, and in the absence of universal vaccination of boys, the argument for introducing targeted HPV vaccination for MSM up to age 26 years is strong.

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## Footnotes

• Contributors All authors contributed to the content and writing of the editorial.

• Competing interests David Asboe has received lecture fees from Sanofi–Pasteur.

• Provenance and peer review Commissioned; externally peer reviewed.

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