Jasmine J. Han, MD
John W. Song, MD
Section Editor Steven A. Kaplan, MD
Human papillomavirus (HPV) is estimated to be the most common sexually transmitted infection that is the major cause of anogenital and oropharyngeal cancers in men.1-4 HPV infections can be classified into two categories: low-risk (LR) HPV or high-risk (HR) HPV. LR HPV infection can lead to cutaneous warts, whereas persistent HR HPV infection in a susceptible host can lead to cancer.
To prevent HPV-associated cancers, prophylactic vaccine was first available in 2006 for women only. In 2009, the FDA approved HPV vaccination for men, and the Centers of Disease Control and Prevention’s Advisory Committee on Immunization Practices provided guidance on HPV vaccination for genital warts prevention only. This guidance was further expanded in 2011 similar to women to the age of 26, to decrease HPV transmission and HPV-associated cancers.5 The age cutoff in men mimicked the vaccination program in women, but this was determined without reliable epidemiologic data on the genital HPV infection prevalence among men.
Previously, a quadrivalent HPV (4vHPV) vaccine against types 6, 11, 16, and 18 was available. Subsequently, a 9-valent HPV (9vHPV) vaccine received FDA approval for HPV-related cancers that include additional HR HPV types 31, 33, 45, 52, and 58, which would cover 90% of HPV types responsible for cervical cancer.6 Recent epidemiologic data have led the CDC to issue guidelines that only two doses of HPV vaccine are recommended for young adolescents aged to 14 years, instead of the traditional three-shot series.7
The recent Han et al study from the National Health and Nutrition Examination Survey (NHANES), which represents a national sample of 76.9 million U.S. men aged 18 to 59 years, found that men have a high burden of overall penile HPV infection at 45.2%. The distribution of genital HPV infection in U.S. men appeared to be widespread among all age groups and followed a bimodal pattern, with a peak among men aged 28 to 32 years (50.8%) and a second higher peak among men aged 58 to 59 years (59.6%). The HPV vaccination coverage in men who were eligible for vaccine was only 10.7%.8 Over 25 million eligible U.S. men did not receive HPV vaccination.
According to estimates, approximately 79 million people are infected with some type of HPV, and approximately 50% of new infections occur before the age of 24 years.1 In addition, more than 11,000 cases of HPV-related cancers occur in men annually and are responsible for 63% of penile cancer, 89% of anal cancer, and 72% of oropharyngeal cancer. It is important to emphasize the indirect causal factor for cervical cancer via men serving as reservoirs for HPV transmission.9
LR HPV infection is not without consequence. HPV 6 and HPV 11 are responsible for 90% of genital warts affecting 160,000 men annually.10 HPV may also lead to recurrent respiratory papillomatosis.11
The prevalence of oral HPV is relatively low compared to that of genital infection, occurring in 10.1% of men, but the distribution pattern of oral HR HPV infection associated with oropharyngeal cancer is similar to penile HPV infection with a bimodal pattern. Although the oral HPV prevalence is lower than genital HPV infection, the number of oropharyngeal cancers associated with HPV has increased significantly over time.12 With this continued trend, the annual incidence of HPV-related oropharyngeal cancers surpassed the annual number of cervical cancers in 2015, despite the availability of a highly efficacious prophylactic vaccine against HPV.9
Using NHANES, Han et al also revealed that the genital oncogenic HR HPV infection prevalence for men was 25.1%, which was widespread among all age groups. The HPV prevalence with at least one of the 4vHPV types in adults aged 18 to 59 was 8.5%, representing over 6.5 million U.S. men. The overall prevalence of infection with at least one of the 9vHPV types was 15.1%. Prevalence of 9vHPV types was similarly elevated in the vaccine non-eligible group (14.6%), questioning the rationale behind the current age cutoff of HPV vaccination in men.
Similarly, overall HPV 16 and 18 infection prevalence was 4.3% and 1.7%, respectively, without showing the difference between vaccine-eligible and vaccine non-eligible men. Prevalence of overall HPV infection was lowest in males aged 18 to 22 years at 28.9%, which may reflect the current practice of providing HPV vaccination to the younger age group in men.8
Demographic characteristics associated with genital HPV infection included age, race/ethnicity, marital status, education, and age at first sex. The prevalence of genital HPV was found to be highest among non-Hispanic black men (65.0%) and lowest in non-Hispanic Asian men (24.4%). Men who reported never having been married, living with a partner, or separated from a spouse were twice as likely to have overall genital HPV infections than married men. In the HR HPV group, this prevalence increased to 2.8 times if separated from a spouse. In addition, current tobacco use was not associated with male genital HPV infection, whereas tobacco use is a known risk factor for female genital and oropharyngeal infections.8
The overall genital HPV prevalence in men8 is similar to Denmark data (41.8%), with the same HR HPV type 51 being the most prevalent type.13 In comparison, HR HPV types 16 and 18 are responsible for 79% of all anogenital cancer in men.14 This inconsistency of the most prevalent HR HPV subtype in infection and in cancer may reflect a difference in aggressiveness of HPV subtype. Furthermore, the most prevalent HPV subtype may not reflect putative potency of carcinogenesis. This high burden of genital HPV prevalence in men has been reported in the past. The multinational HPV Infection in Men cohort study previously reported HPV prevalence of 65.2%,15 which is higher than overall HPV prevalence in U.S. men (45.2%).
The difference in prevalence may also be due to the types of test used, the location of the male genital area swabbed, and/or the study population. Nevertheless, other study populations were heavily concentrated in the younger age groups with under-representation of men above age 40.13,15 Perhaps the cumulative high prevalence of chronic, persistent infections would be expected to increase as it was shown in oral HPV infection secondary to decreased immune response to natural infection in aging men.
Clearance of genital HPV infection in men has been reported to be between 6 to 18 months, which is comparable to women.16 However, men have lower circulating HPV antibodies than women despite higher HPV infection prevalence.17 This phenomenon may explain the difference in the HPV immune responses between genders, which may reflect persistent or reactivation of HPV infection in later years of age. In addition, a multinational cohort study reported that the number of partners and new partners in the last 3 months was similar for all age groups. Thus, this behavioral pattern may potentially provide continued HPV exposure throughout life in men.15 Therefore, vaccination programs for older men might be warranted, if men generate a lower and weaker HPV immune response in the setting of remaining at high risk of acquiring new HPV infections throughout their lives.
Any sexually active person is at risk for HPV infection given the high prevalence of this infection. Traditionally, sexually transmitted infections have a disproportionate burden among adolescents and young adults.1 However, HPV is unique in that prevalence in men is high and widespread among all age groups. In addition, most of these HPV infections are silent, asymptomatic, and do not cause disease until later years with persistent infection that presents as cancer.
Higher HPV prevalence among men suggests that there is a greater opportunity for increased vaccine effectiveness as a society, as the vaccine coverage increases with the benefit of herd immunity. HPV vaccination may have a profound impact on the prevention of HPV-attributable cancers in both men and women, as one serves as a silent host for the other in addition to being a direct cause of anogenital and oropharyngeal cancers. Furthermore, widespread HPV infection in all age groups of men questions the rationale regarding the current vaccination age cutoff, which warrants further evaluation. Only by significantly increasing vaccination coverage will progress be made in eradicating most HPV-associated cancers in the United States.
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