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The incidence of cancer related to human papillomavirus (HPV) cancer in men is on the rise, along with the incidence of certain HPV-related cancers, including anal and oropharyngeal cancers.

Currently, few countries have available data on male HPV infection and seroprevalence, and prevention of HPV-related cancers in men lags behind measures in women that include HPV vaccination and screening of pre-cancerous lesions.

An analysis of a global HPV vaccine trial, which evaluated baseline data from 1,399 HIV-negative heterosexual men (HM) and men who have sex with men (MSM), increases understanding about HPV infection in men across a broader geographic area, and in relation to multiple HPV types, according to Joel M. Palefsky, MD, of the University of California San Francisco (UCSF), and colleagues.

Among men with baseline HPV infection, MSM had higher seroprevalence for concordant HPV types than HM (39.5% vs 10.8%), they reported in .

The investigators also found that seropositivity was three times higher among MSM compared with HM. The risk factors for seropositivity, which included sexual initiation at a younger age, a greater number of receptive anal sex partners, and less frequent condom use, were not associated with seropositivity in HM.

"The current study extends from our group focusing on 4vHPV [4-valent HPV] vaccine types and provides new insight on seropositivity as a function of anatomic site, risk factors for seropositivity, antibody titer levels among seropositive men, and how these factors differ according to sexual orientation," they stated.

In the following interview, Palefsky, who is a professor of medicine and infectious disease at UCSF, discussed the findings in greater detail. He also is the founder and chair of the HPV Working Group of the NCI AIDS Malignancy Consortium and the head of the AMC HPV Virology Core Lab, as well as founder and director of the Anal Neoplasia Clinic, Research and Education Center.

Were you surprised by your group's results?

Palefsky: I would say that the results were more alarming than surprising, insofar as they show how quickly young men, both HM and MSM, acquire anogenital HPV infection after initiation of sexual activity. This is particularly true for young MSM, in whom HPV infection was more common, and more likely to be anal or peri-anal.

What do your data add to current understanding about HPV infection in men?

Palefsky: This was one of the largest studies ever done in terms of participant numbers and countries looking at HPV DNA positivity at multiple anatomic sites and correlating it with seropositivity, among both HM and MSM.

The combination of seropositivity and DNA positivity gives a more complete picture of HPV exposure, and our analysis of the correlation between seropositivity and DNA positivity for a concordant HPV type gave us some information about the implications of detection of HPV at these different sites. For example, among MSM who were HPV DNA-positive, the highest proportion who had concordant seropositivity were those with anal HPV DNA. This implies a difference in the biology of HPV infection in the anus versus infection at the more keratinized external genital sites such as the penis.

Any thoughts on what this relative lack of seropositivity among men with external genital infection could mean?

Palefsky: It suggests that the humoral immune response to HPV infection at this site is less robust than that of a mucosal site, such as the anus. It could also mean that a higher proportion of external genital site infections may not have represented true infection, but rather, represented a carrier status that did not elicit a systemic humoral immune response.

To what do you attribute the overall higher seroprevalence seen among MSM versus HM?

Palefsky: Although this is likely attributable to the higher number of MSM with anal canal HPV infection, it is also noteworthy that a higher proportion of MSM with penile infection were seropositive than HM with penile infection. This could mean that MSM have a more robust natural immune immune response to external genital infection than HM, or that the detection of HPV infection in MSM is more likely to represent a 'true' HPV infection than in HM.

It is also possible that the HPV infections may have been present longer in MSM than in HM, since seroconversion may take several months after natural infection. Baseline antibody titers in response to natural HPV infection among seropositive MSM were generally higher than those of seropositive HM, but were not substantially different.

What is the take-home message from this study?

Palefsky: One of the main messages for physicians is to vaccinate boys and young men as early as possible. Maximal protection occurs when the HPV vaccine is given prior to initiation of sexual activity, and routine HPV vaccination is recommended for boys as early as 9 years of age, but with a target age of 11-12 years. In those who are unvaccinated, 'catch-up' vaccination is also recommended as early as possible, through age 26.

The HPV vaccine currently available in the U.S. protects against nine different HPV types that commonly infect the anogenital region. It should be noted, however, that although the vaccine is protective against initial infection with a given type, it is not protective against that type if infection with that type has already occurred prior to vaccination.

How would you characterize the story told by your data?

Palefsky: It's a good news/bad news story. The bad news is that unvaccinated young men -- both HM and MSM, but especially MSM -- acquire anogenital HPV infection quickly after initiation of sexual activity. Among MSM, anal HPV exposure is particularly common.

The good news is that even though some men have acquired HPV infection soon after initiating sexual activity, a high proportion showed no signs of exposure to most of the HPV types in the 9-valent vaccine. This is where catch-up vaccination comes in.

What barriers remain to routine HPV vaccination in young, sexually active men, and to early detection of HPV-related cancers in men overall?

Palefsky: Some of the most common barriers include parental hesitancy, hesitancy among some providers to give a confident recommendation to vaccinate, vaccine misinformation, and missed opportunities to vaccinate. There is also a common misconception that HPV only poses risks to women, and the COVID pandemic has certainly disrupted HPV vaccination programs.

The main cancers associated with HPV in men are oropharyngeal cancer and anal cancer. Here, the barriers to early detection are different. While there are still no proven tests for early detection of either of these cancers, the [Palefsky is the protocol chair] provides evidence that the detection and treatment of anal cancer precursor lesions can reduce the progression to anal cancer.

What's the next step for research in this area?

Palefsky: Much remains to be done in the field of HPV vaccination in general, including vaccination of boys and men. Recent data show persistence of vaccine immunogenicity and efficacy for as long as vaccinated boys and men have been followed -- about 10 years. Further studies are needed to determine how long that efficacy persists, and to define the minimum number of vaccine doses needed to ensure long-term efficacy.

Also, there is substantial evidence for an impact of the HPV vaccine on the incidence of anogenital condyloma in boys and men in the general population, but studies are needed to document the impact of HPV vaccination on the incidence of HPV-related cancers in men.

And finally, vaccination to prevent HPV would be considered primary cancer prevention, and we now know that secondary prevention of anal cancer is possible through detection and treatment of anal cancer precursor lesions. However, we still need to determine how these programs can be effectively implemented in high-risk populations.

You can ready the study abstract here.