In young heterosexual men with genital α9 HPV infection, rates of seroconversion were low at 24 months, ranging from 4% for HPV-52 to 36% for HPV-31. Generally, type-specific HPV seroconversion was higher, and time to seroconversion was shorter, after prevalent infection than after incident infection. Among men with incident genital HPV infection, report of ever smoking and genital site(s) infected were statistically significantly associated with seroconversion.
This is the first longitudinal study of HPV seroconversion in HPV infected men, and the low rates of seroconversion are consistent with the HPV-16 seroprevalence literature. In a study population representative of the general US population (2003-4 National Health and Nutrition Examination Survey (NHANES)), HPV-16 seroprevalence was 0.3% in males 20–24 years of age [8
]. In sexually transmitted disease (STD) clinic populations, male HPV-16 seroprevalence tends to be higher [9
]. Among men recruited by multiple methods in 2 US cities (Tucson, Arizona, and Tampa, Florida), HPV-16 seroprevalence was approximately 5% in 18- to 24-year-olds [23
]. The seroprevalence observed in this study cannot be directly compared with most seroprevalence studies, because it is only among men with an observed genital α9 HPV infection. In 1 cross-sectional study of STD clinic patients in Demark and Greenland, HPV-16 seropositivity was observed among 20% of Danish men and 0% of Greenlandic men with prevalent genital HPV-16 infection [11
There have been few investigations of type-specific HPV seroprevalence for types other than HPV-16, perhaps partially because of the assays used. Unlike the enzyme-linked immunoassay (ELISA) used in most seroprevalence studies thus far, LBMA is a multiplex assay that allows testing of multiple types. The level of concordance between the ELISA and LBMA assay is high [19
]. Using the LBMA assay on specimens from the general German population, seroprevalences for HPV-16, -33, -52, and -58 in males aged 15–24 years were all between 1% and 4%. HPV-31 and -67 were not included, and these estimates were not stratified by HPV infection status.
The gender difference observed in HPV-16 seroprevalence [7
] appears to extend to seroconversion among HPV-16 infected individuals. In this study of young men, HPV-16 seroconversion estimates 24 months after prevalent or incident genital HPV-16 infection (20% and 7%, respectively) were much lower than the published estimates of a female cohort of University of Washington students (94% and 67%, respectively) [14
]. It is possible that some of the difference between these studies is because of different serology assays (LBMA for males and ELISA for females). Using the LBMA assay in a more recent cohort of female university students (described in Winer et al [25
]), cumulative HPV-16 seroconversion at 24 months among women with incident HPV-16 infections was 58% (authors’ unpublished data). It is not known why females might be more likely to seroconvert than males. Possible contributors to a lower seroconversion rate in men include a higher ratio of infections in more-keratinized (eg, penile shaft) versus less well-keratinized epithelium (eg, glans) [1
], lower HPV viral load [28
], or lower likelihood of persistent infection [29
]. It is also possible that because we are comparing across studies, the apparent difference between young males and females in seroconversion could be, in part, due to differences in seroconversion risk factors. However, regarding the nonanatomical factor associated with seroconversion in this study, females in the recent cohort of university students were only slightly more likely to be current smokers [33
It should be noted that the consequences of seroconversion are not clear. Whereas the high levels of anti-HPV antibodies achieved following HPV vaccination prevent infection in both males and females [34
], the considerably lower anti-HPV titers achieved after natural infection appear to protect only partially against reinfection or redetection of the same HPV type [36
]. In this study, it is unknown whether the HPV infections detected after seroconversion were new infections of the same HPV type, reactivations, or prevalent infections that were missed at earlier visits.
A lower likelihood of seropersistence has been observed in males than in females [13
], and in our study population, only 62% of seroconversions were followed by another seropositive visit. Lower seropersistence may make protection against subsequent type-specific infection less likely in men than in women. Interestingly, the median time to seroconversion following incident infection was shorter than that which has been observed in women [37
]. It is unlikely that this result is related to visit schedule (every 4 months vs every 6 months) because 1 of the studies of women [38
] also used a 4-month visit schedule. Because of the small number of seroconversions observed in men, chance must be considered a possible explanation.
The association between ever cigarette smoking and seroconversion among men with incident HPV infection was strong and statistically significant when adjusted for genital site(s) of infection. An association between HPV seroprevalence in males and cigarette smoking has been found in some previous studies [23
], but not others [7
]. The relationship between seroconversion and cigarette smoking seems inconsistent with the prevailing theory that cigarette smoking weakens the local immune system, which may leave a person more vulnerable to persistent HPV infection and, thus, HPV-related cancer [31
]. Conversely, it is likely that persistent infection, at least initially, results in more virus production [41
], thus more L1 antigen to induce an antibody response.
Seroprevalence studies among males have shown associations with sexual-history characteristics, though which characteristic(s) varies by study. For example, lifetime number of partners was associated with seroprevalence in some studies [7
] and not others [10
], and the same is true of recent number of partners [13
]. Although these characteristics and other sexual history characteristics showed some evidence of an association with seroconversion after incident genital HPV infection in this study, they did not approach statistical significance. A sexual history characteristic that is consistently associated with seroprevalence in males is sex with males [7
]. We were not able to examine this characteristic in our heterosexual population.
In this study, we were able to examine infection characteristics in males, which have not been assessed in seroprevalence investigations. Seroconversion after incident genital infection with an α9 HPV type was associated with the genital site(s) where HPV was incidentally detected. A reason cited for lower seropositivity in males compared with that in females is the difference in the infected tissue type, with males less likely than females to be infected in minimally keratinized genital sites. However, in this study, none of the men who seroconverted were infected only in the less well-keratinized genital sites of the glans or urethral meatus. Men who were infected in the glans or urethral meatus as well as the more highly keratinized epithelium of the shaft or scrotum were most likely to seroconvert. This suggests that a higher viral load or infection of a larger surface area may be important predictors of seroconversion in men. Our study did not find a relationship between type-specific seroconversion and repeated detection of the same type of HPV DNA at 2 or more visits. In females, there is some evidence of an association between repeated detection of HPV DNA and seroconversion [38
], though not when examined as a time-varying covariate [37
This is the first longitudinal study of seroconversion following α9 HPV infection in young men, but it was not without limitations. It was a relatively small study and, thus, larger studies are needed to verify our results. Also, given that male genital HPV infections tend to have low viral loads, it is possible that infections could have been missed, even though our DNA assay was sensitive and our specimen collection method was thorough. This could also lead to misclassification of HPV DNA detection as incident, as well as a bias toward a study population with higher viral loads. Additionally, this study did not measure HPV infection at nongenital sites, which, if present, could have resulted in seropositivity (eg, the oropharynx [10
]). Although the LBMA assay has been used successfully in other investigations, standards for HPV types other than HPV-16 are not currently available. Lastly, the results of this study may not be generalizable to older men, men who have sex with men (MSM), or high-risk populations.
In summary, this study showed that detectable type-specific HPV seroconversion within 2 years of a genital type-specific α9 HPV infection was very low in young men. This suggests that seropositivity is an even less sensitive marker of prior HPV infection in men than it is in women. Among men with incident genital HPV infections, seroconversion was associated with cigarette smoking and genital site(s) infected. Further investigation into why α9 HPV infections appear to be poorly immunogenic in men is warranted.