We found no differences by circumcision status in overall HPV acquisition or in number of HPV types acquired. Findings held for all clinically-relevant HPV types, as well as for the subgroups of high-risk types, high-risk alpha-9 types, and HPV-16. This observation is consistent with findings from other longitudinal studies.15, 22
It does, however, differ from recently reported RCTs of circumcision for prevention of HIV infection in Africa where residual specimens collected from the glans were tested for HPV DNA.12–14
In the Ugandan trial, a decrease in oncogenic HPV detection was observed among HIV-positive and HIV-negative men in the circumcision treatment group relative to the control group (adjusted RR=0.67,95%CI:0.51–0.89). When single versus multiple-type oncogenic HPV infections were evaluated as separate outcomes, however, the protective associations were restricted to multiple-type infections.12–14
Several factors may contribute to differences in observed effects between RCTs and longitudinal studies. In our cohort, all but one circumcised man underwent the procedure shortly after birth. The circumcision intervention in the RCTs was performed on adult subjects. This intervention may have altered exposure for a period of time after the procedure was performed. Additionally, the RCTs collected data on HPV infection for only one genital site (glans). Due to higher numbers of shaft infections detected in circumcised men relative to glans infections, basing estimates on glans infections alone would inflate the estimate of risk reduction afforded by circumcision. Work by Weaver et al7
suggests that sampling the glans only (and not the shaft) will underestimate HPV prevalence in circumcised men (whereas the overall HPV prevalence was similar for circumcised and uncircumcised men in that study, sampling the glans only would have underestimated HPV prevalence by 51% in circumcised men, versus only 11% in uncircumcised men). It is likely that differences in site sampling contribute to the different results observed in previous RCTs and cohort studies.
We observed site-specific differences in HPV acquisition by circumcision status. While incident infection at all 3 genital sites was uncommon, simultaneous detection in all 3 genital sites (versus one site only) was 10-fold more common in uncircumcised versus circumcised men. Uncircumcised men were also more likely to have HPV-positive glans and urine specimens than circumcised men while circumcised men were more likely to be positive in the shaft/scrotum. The observed difference in number of sites infected between circumcised and uncircumcised men was driven by these site-specific differences. Other studies have shown a similar difference in infection of the glans/corona based on circumcision status,11, 16, 17
but not in urine specimens.11, 16
Methodological differences in urine collection methods could account for inter-study variations in results. In our study, we collected first-void urine; we did not collect data about retraction of the foreskin prior to urine collection by uncircumcised subjects. If the foreskin was not retracted prior to urine void, it could have led to contamination of the urine with any HPV present in the interior foreskin, which would bias the results toward a higher incidence of HPV detection in the urine of uncircumcised subjects.
It is possible that lack of circumcision could prolong contact between the virus and the epithelial cells of the glans and inner foreskin, increasing the risk of HPV acquisition in the glans/corona in uncircumcised men. Alternative mechanistic hypotheses from the field of HIV research may be relevant for HPV transmission. The keratin layer of the interior foreskin in uncircumcised men was shown by some studies to be thinner than that of the outer foreskin or glans, suggesting an increased susceptibility to viral infection.23, 24
Other studies, however, have found either no difference or a thicker keratin layer in the inner foreskin;25, 26
the issue remains controversial.27
The observed difference in number and anatomic location of infected sites by circumcision status might have potential implications for increased transmissibility to sex partners. This study, however, was not designed to evaluate male to female HPV transmission. The role of male circumcision on female acquisition of HPV has not been consistent in previous studies. Recent work in Uganda showed a reduction of HPV infection in female partners of HIV-negative men receiving the circumcision intervention in a RCT of male circumcision and HPV.28
A longitudinal study of HPV acquisition in female university students found no association between circumcision status of the male partner and risk of HPV acquisition by the female subject.29
Studies of male circumcision’s effect on cervical cancer risk have likewise yielded conflicting results.30
A multi-center case-control study found an association between circumcision and reduced cervical cancer risk, but only among women with male partners who exhibited high-risk sexual behavior (e.g. multiple lifetime partners and/or history of sex with prostitutes).31
The study had a methodological limitation in that it focused on the current male partner of women with cervical cancer, while transmission of the oncogenic HPV may have occurred with an earlier partner.30
Moreover, the glans was the only site tested for HPV in that study.
Differences in viral load at various male genital sites might also affect the relationship between circumcision and HPV transmission. Evidence suggests a higher viral load in the penile shaft than the glans/corona;32
a higher viral load implies a higher risk of transmission to a sex partner. While incident HPV infection was detected more frequently in shaft/scrotum specimens than in glans or urine specimens of both circumcised and uncircumcised men in our study, the incidence of shaft/scrotum infections was higher in circumcised relative to uncircumcised men. Finally, the risk of transmission is also related to infection duration.33
While this manuscript focuses solely on HPV acquisition, in the same cohort, we found that circumcision status had no effect on the likelihood of detecting a persistent versus transient HPV infection over an 8-month time period (Laura Koutsky, personal communication).
Limitations of our study include the potential for misclassification of prevalent infection as incident, which would inflate our estimates of cumulative incidence. Based on findings in a similar cohort study of young female university students (where similar rates of HPV acquisition were observed for those who did and did not report sexual activity prior to enrolment), this potential misclassification is likely to be minimal.29
Also our results may not be generalizable to other populations of men; we studied a cohort of heterosexual university students with a narrow age range, and their HPV histories may not be similar to that of older populations or to men who have sex with men. Finally, there may have been some unmeasured confounding due to religious or cultural practices related to circumcision that we were not able to assess.
Further research is needed to determine how circumcision impacts HPV transmission and whether the number of genital sites infected in the male affects female risk of HPV acquisition. While circumcision does not appear to affect male acquisition of HPV overall, it is important to fully investigate the potential public health implications of the site-specific differences in acquisition attributable to circumcision status, in order to help reduce the burden of HPV-related cancers and genital warts.