Lorena Mija1, François Lagacé, MD2, Ivan V. Litvinov, MD, PhD, FRCPC2

1Faculté de médecine, Université de Montréal, Montréal, Québec
2Division of Dermatology, McGill University, Montreal, Quebec

Conflicts of Interest: Ivan V. Litvinov received research grant funding from Novartis, Merck, AbbVie and Bristol Myers Squibb and honoraria from Janssen, Bausch Health, Galderma, Novartis, Pfizer, Sun Pharma, Johnson & Johnson and Actelion. Other authors declare no competing financial interests.

Introduction

Human Papillomavirus (HPV) is the most common sexually transmitted disease. Its lifetime
prevalence is >75% and this rate continues to increase.1 This virus infects keratinocytes and is primarily transmitted by skin-to-skin contact.2

Chronic HPV infection, especially from low-risk strains such as 6, 11, 42, 43, and 44, plays an important role in the pathogenesis of cutaneous warts.3 For example, HPV strains 6 and 11 are responsible for 90% of anogenital warts (condyloma acuminate).4 Warts can also be found in the mouth, throat, penis/vagina and elsewhere on the skin.5

While many HPV infections are asymptomatic6, some can result in malignancies. A classic example of this in the skin is represented by carcinoma cuniculatum, a rare form of squamous cell carcinoma (SCC) that often presents on feet in the setting of a longstanding exophytic plantar wart, several decades after the initial infection.7 High-risks strains with the potential to lead to cancer or squamous intraepithelial lesions include 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 and 70.3 The Canadian Cancer Society lists HPV as the fifth most preventable cause of cancer.8 However, this ranking likely underestimates the role of HPV in carcinogenesis since cutaneous SCCs, where HPV is recognized as a co-carcinogen, are not included in cancer statistics. Cutaneous SCCs and Basal Cell Carcinomas (BCCs), together called keratinocyte carcinomas, are the most common cancers with an estimated ~5.4 million new cases diagnosed every year in the United States alone.9

Notably, a high proportion of HPV-associated cancers are diagnosed in males.10 Since males are under-vaccinated and are increasingly disproportionately affected by certain HPV-associated cancers, namely oropharyngeal and penile cancers, current vaccination efforts should be refocused on male patients.6,11-13 Effective vaccination protocols can help promote both physical health as well as mental health since male patients with HPV often encounter numerous psychosocial impacts secondary to their infection, namely depression, reduction in quality of life and sexual dysfunction.6

Male HPV Vaccination Statistics and Guidelines

HPV vaccination programs and guidelines have changed several times in the past decade, causing important gaps in vaccination rates between males vs. females. In 2007, the first Canadian vaccination program for school-aged females was implemented, and by 2010 all Canadian provinces had established vaccination programs for females.6 In Alberta, before the start of the vaccination program for school-aged males, 98.3% of vaccinated individuals were females.14 The first Canadian public vaccination program for males was launched in 2012, while national coverage for the vaccine was only established in 2017.6 In Ontario, even after the sex-neutral school vaccination programs were created, there was still a gap in HPV vaccination rates between males and females.6 Hence, most males remain unvaccinated for HPV, especially the middle age population, which is at risk of developing the aforementioned cancers in the future. One narrative review investigating reasons for suboptimal vaccination in males found that lack of information, the misconception that the virus only affects females, vaccine hesitancy, lack of recommendations from healthcare providers, costs and logistics all acted as barriers to vaccination.15

According to the National Advisory Committee on Immunization (NACI) of Canada, the HPV vaccine was previously only recommended for males ages 9 through 26 years to prevent anogenital warts and other HPV-associated cancers.16 However, now there is no age limit on receiving a quadrivalent or nonavalent HPV vaccine. While the vaccine before was not routinely recommended for males ages 27 to 45 years, the guidelines state that the vaccine may be administered to this age group if there is an ongoing risk of HPV exposure,6 for example, healthcare providers treating warts.17 Recent reports, however, strongly argued that this vaccine should be given to middle aged males.18 On the other hand, there is currently insufficient research to encourage HPV vaccination in males over 45 years of age.

Natural Immunity Post HPV Exposure in Males and Cancer Risks

There are important differences between males and females regarding their immune response to HPV. A study has shown that males are 4 to 10 times less likely to seroconvert after an HPV infection, regardless of the infected anatomic site.19 In fact, within 36 months after HPV DNA was detected as a result of an oral, anal or genital HPV infection (strains 6, 11, 16, 18), only 7.7% of men developed detectable serum HPV antibodies.19 In the same study, the seroconversion rate following a genital HPV 16 infection was only 4.1% in males compared to 60% in females.19 Further, the HPV in Men (HIM) study showed that healthy males do not have a reduced risk of subsequent HPV oral infection from natural HPV L1 antibodies (immunoglobulin G antibodies to the L1 capsid protein in serum) following an HPV infection, as it was previously thought.20 Thus, these antibodies are not protective against future HPV infection and, unlike females, males are at risk of reinfection with the same HPV strain.20 On the other hand, females’ existing antibodies confer partial immunity.19 As such, males acquire HPV infections at a steady rate.21 The prevalence of male genital HPV infections, which do not decrease with age (Figure 1), highlights the suboptimal natural immunity against HPV in males.

Higher Incidence of HPV-Driven Cancers in Males Calls for an Update to Current HPV Vaccination Guidelines and Implementation - image
Figure 1: Comparison of the prevalence of genital HPV infection with high-risk strains and with all strains among males 14-59 years of age in the United States between 2013 and 2014. The rate of infection of genital HPV in men does not decrease with age.21

Importantly, in recent years the number of oropharyngeal SCC cancers has surpassed the number of cervical cancers caused by HPV. In fact, most of the oropharyngeal SCC cancer patients are males (Figure 2).22 Cervical cancer rates are declining, whereas oropharyngeal cancer rates in Canadian males are on the rise (Figure 3).12 Anal cancer rates are also on the rise, while the incidence rates of penile and oral cancers, unfortunately, remain unchanged (Figure 3).11-13

Figure 2: The estimated annual number of warts and HPV-related cancers by sex in Canada (based on the data from the 2016 Canadian Cancer Statistics). The rate of HPV-associated oropharyngeal cancer, which is mainly affecting men, has surpassed the rate of HPV-associated cervical cancer.
Figure 3: The incidence of HPV-driven cancers from 1992 to 2012. While the rate of cervical cancer is decreasing, the rate of oropharyngeal cancer in males is increasing. Penile and female oropharyngeal cancer rates remain stable.

Some males are at a particularly higher risk for HPV-associated cancers. Males who have sex with males (MSM), especially MSM who have Human immunodeficiency virus (HIV), have higher rates of anal carcinoma.23 Males who are solid organ transplant recipients also have higher rates of penile and anal cancer.23 Additionally, there is currently no approved HPV DNA test for males in Canada.24 In contrast, females who get a Pap test can be co-tested for HPV using a sample of cervical cells taken at the same visit.25

Recommendations for Vaccinations Should Focus on Males and Health Care Professionals at Risk of HPV Exposure

Side Effects of Spironolactone

Taking into consideration the above important points, we recommend that all males at risk of exposure to HPV between the ages of 9 and 45 receive the vaccine. Sufficient data exists to update the current guidelines, which only recommend vaccination for males between the ages of 9 and 27.6 The recommended vaccine is HPV9 (GARDASIL®9) a nonavalent vaccine that prevents HPV infections caused by strains 6, 11, 16, 18, 31, 33, 45, 52 and 5826 and received in 2022 Health Canada approval for the prevention of oropharyngeal cancer and other head & neck cancers (along with the prevention of cervical, vulvar, vaginal and anal intraepithelial neoplasia) caused by HPV.27 The nonavalent vaccine is preferred to the quadrivalent vaccine since it protects against a wider range of high-risk strains.28

The effectiveness of the vaccine in males aged 27 to 45 is inferred from the efficiency data in females of the same age and by the immunogenicity data from the Mid-Adult-Aged Men (MAM) Trial.29 The MAM Trial evaluating response to the quadrivalent vaccine showed a 100% seroconversion rate 6 months after vaccination in 150 males between the ages of 27 and 45.28 Another study reported 95% seroconversion rate 28 weeks following the quadrivalent vaccine administered in males with HIV between the ages of 22 and 61.30

The vaccine is also proven to be safe. In fact, a study demonstrating the safety profile of the quadrivalent HPV vaccine in adult men 27 to 45 years of age with HIV-1 found no grade 4 (life-threatening) or 5 (death) adverse events.29 Most adverse events were of either mild or moderate intensity.29 Given these promising results, the vaccine should be strongly recommended to unvaccinated males aged 27 to 45.

HPV Vaccination for Healthcare Professionals

HPV vaccination is also recommended to all physicians, nurses and residents in obstetrics and gynecology, oncology, dermatology and any staff that treat patients with warts.31 HPV DNA was found in the vapour of 62% and 57% of plantar warts treated with ablative laser and electrocautery, respectively.32 Normal non-lesioned skin was shown to contain in >60% of cases pathogenic HPV strains.33 Hence, use of cautery on normal skin can too produce plume with HPV particles. This poses an occupational risk for dermatologists and other health care providers,17 which is why the vaccine is highly recommended in this group. In addition, reports indicate that (1) using local exhaust ventilation, (2) general room ventilation and (3) full personal protective equipment including a fit tested particulate respirator of at least N95 grade can decrease operator from HPV inhalation exposure.34 Another study mentions that even though protective equipment, mainly gloves, can get contaminated with HPV, transmissions to medical professional is less likely to occur if the equipment is disposed of properly.35

Conclusion

While the incidence of cervical cancer is decreasing in females, the incidence of oropharyngeal and other HPV-driven cancers is increasing at an alarming rate, especially in males. As such, vaccination efforts should be aimed at addressing this important public health concern. Males are significantly under-vaccinated compared to females and acquire HPV infections at a steady rate, with a very low rate of seroconversion following infection. Therefore, we advocate to provide routine vaccination against HPV in all males between the ages of 27 and 45, and continue to actively vaccinate males ages 9 to 26. Vaccines are effective, as shown by the high rate of post-vaccination seroconversion, which is an important factor in preventing oropharyngeal SCCs and other HPV-related cancers. Finally, it is crucial to routinely promote the HPV vaccination for all patients and healthcare professionals at risk of exposure to HPV, the same way we promote sun safety for all.

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