Our results demonstrate that uncircumcised men have poorer ability to resolve HPV infections of the penis glans/coronal sulcus. The reduced viral clearance among uncircumcised men was observed for both oncogenic and non-oncogenic HPV types. We previously observed a higher prevalence of any HPV and oncogenic HPV infection in the glans/coronal sulcus of uncircumcised men [6
]. The present analysis suggests that the higher prevalence of HPV may be attributed to longer duration of infection in the glans/coronal sulcus of uncircumcised men rather than to a greater rate of acquisition of infection.
Our results are consistent with two other longitudinal investigations of HPV in men which have demonstrated that reduced persistence and greater clearance of genital HPV among circumcised men [11
]. Lu et al similarly observed greater clearance of oncogenic HPV as well as any HPV [12
]. In this study, however, site-specific estimations were not included as individual genital specimens (glans/coronal sulcus, shaft, and scrotum) were combined for testing.
A major limitation of our study as well as other longitudinal investigations of HPV is the inability to distinguish clearance of infection from failure to detect an infection. Lack of viral detection may be due to fluctuations in viral levels, sampling variability, as well as limitations in assay sensitivity.
It is not likely that the greater specimen sufficiency in the glans/corona of uncircumcised compared to circumcised men explains the observed differences in viral clearance. Measurement of HPV acquisition and clearance was limited to specimens that were positive for beta-globin. Moreover, a lower percentage of sufficient glans/corona samples among circumcised men would make it less likely to detect a clearance event, and therefore may lead to a longer estimated duration of HPV infection among circumcised men. However, the opposite was observed in our data, that is, circumcised men had a shorter duration of infection of the glans/corona.
A major strength of this investigation is the short interval between visits (2 months), which enhanced our ability to examine the acquisition of new infections and the duration of these incident infections. Estimates of viral duration and clearance events were made more robust by limiting these observations to incident infections and excluding prevalent HPV infections detected at baseline. We were able to account for sexual history, including condom use and number of sexual partners, and for other potential confounders related to either circumcision status or HPV infection. Site-specific sampling and testing allowed us to separately evaluate genital subsites.
Our study demonstrates that the apparent protective influence of circumcision against genital HPV infection may not involve a reduction in new infections but rather the enhanced ability to resolve existing HPV infections. Similar to what has been observed in females, HPV infections are generally transient infections in men [11
]. It is not understood how circumcision facilitates greater clearance of HPV. It is possible that HPV persists more efficiently within the mucosal surface to the inner foreskin of uncircumcised men compared to the keratinized penile surface of circumcised men. Thorough washing of the genitals may be more difficult for uncircumcised men as this requires retraction of the foreskin to expose the inner surface [13
]. To what extent genital washing influences HPV clearance is not known. Nonetheless, we did not observe a longer duration of HPV infection in the foreskin compared to the glans/corona of uncircumcised men indicating that the infections did not persist longer in the mucosal surface.
Our observation of reduced clearance time of oncogenic HPV infection specifically in the glans/corona of uncircumcised men has clinical significance. Uncircumcised men have an increased risk of penile cancer [1
] and the glans penis is the primary subsite of penile cancers [14
]. Partners of uncircumcised men have an increased risk of cervical cancer [3
], underscoring the possibility that transmission of HPV to sexual partners is more efficient among uncircumcised men due to greater duration of their infection.
Strategies to minimize the persistence of HPV infection combined with those to prevent acquisition of infection may be the most effective means of controlling HPV-associated disease. Whether circumcision is an effective means to facilitate HPV clearance has yet to be demonstrated.