Our study found that MC was not associated with overall prevalence of genital HPV for any HPV, oncogenic HPV infections, or unclassified HPV infections. However, MC was negatively associated with non-oncogenic HPV infections. After adjustment for potential confounders and stratification by lifetime number of female sexual partners, the protective association between MC and non-oncogenic HPV detection was particularly evident in men reporting 1 to 4 lifetime female sexual partners. The lack of an effect of MC among men with a greater number of lifetime sexual partners might be explained by immunity to HPV acquired over time by men who were repeatedly exposed to HPV infections
. Other studies have observed a plateau in risk for HPV detection despite increasing number of lifetime sexual partners
[3, 6]. However, in another analysis of the HIM Study, anti-HPV 16 serum antibody status at enrollment was not associated with the risk of a subsequent genital HPV 16 infection
A preliminary analysis of the HIM study that included the first 1158 men who completed both the pre-enrollment and the enrollment visits, showed that MC was negatively associated with the detection of both non-oncogenic and oncogenic HPV types
. However, after increasing the sample size to 3969 men in this analysis, the association was only found for non-oncogenic HPV types after adjusting for potential confounders. Three other studies have reported statistically significant associations between MC and detection of non-oncogenic HPV types
[5, 14, 32]. One MC RCT conducted in South Africa observed significantly lower prevalence of both oncogenic and non-oncogenic HPV types in urethral swab samples among circumcised men than uncircumcised men
[13, 32]. In another clinical trial in Uganda, the prevalence of both oncogenic and non-oncogenic HPV types using samples of the coronal sulcus/glans penis was lower among circumcised men than uncircumcised men
. Further, a study conducted among men attending a public STI clinic, found that MC was associated with reduced risk for both oncogenic and non-oncogenic HPV types using samples of the coronal sulcus/glans penis
. However, results from three other studies did not support a protective role of MC on genital non-oncogenic HPV infection
[3, 19, 20].
The study of the effects of MC on genital HPV infections poses inherent complexities. Inconsistency of results across studies may be due to the genital site selected for HPV sampling or by the procedure used to collect exfoliated cells. Most studies sampled only a single anatomical site or a pooled combination of a few sites for the detection of HPV. It has been suggested that sampling of the penile shaft, the coronal sulcus/glans penis, and the scrotum is necessary for optimal overall genital HPV detection
. In a US study, an inverse association was found between MC and HPV detection in samples from the urethra, coronal sulcus/glans penis, and penile shaft, but not in samples from the scrotum, semen, anal canal, and perianal area
. In another US study, the inverse association between MC and HPV detection was restricted to the coronal sulcus/glans penis
. A recently published longitudinal study conducted in the US among 477 male university students, uncircumcised men were also more likely to have HPV-positive glans and urine specimens than circumcised men, whereas circumcised men were more likely to be positive in the shaft/scrotum
Taken together, results from these studies consistently show that the protective effect of MC may be restricted to infections occurring at the distal part of the penis, including the urethra, the coronal sulcus, and the glans. Since MC is limited to the removal of the foreskin, it seems unlikely that MC has any effect on infections occurring in the rest of the penis or the scrotum. Indeed the use in our study of an aggregate outcome that combined infections in more than one anatomical site greatly limited our ability to identify a true protective effect in specific anatomical subsites, possibly resulting in an overall underestimation of a MC protective effect.
It is interesting to note that this anatomical site-specific pattern of HPV infections is also observed for genital warts in at least two clinical studies
[35, 36]. One study of men attending an STD clinic in England found that circumcised men presented genital warts more often on the shaft of the penis and less often on the glans penis than uncircumcised men
. Similarly, in a study of heterosexual men attending an STD clinic in Washington, circumcised men presented genital warts more often on the penile shaft whereas uncircumcised men presented genital warts more often on the glans, corona, frenulum or meatus
. It is clear from these clinical studies that MC differentially reduces the risk of genital warts in the glans as compared to the rest of the genital area. As approximately 90% of genital warts are related to HPV 6/11 infections
, these data are consistent with our finding that MC is associated with a significantly reduced prevalence of HPV 11.
It is unclear why MC would be associated with a reduced detection of non-oncogenic HPV types but not of oncogenic HPV types. One possible explanation is that MC infers a weak protective effect capable of preventing only less virulent HPV infections such as those caused by non-oncogenic types. Indeed, some studies provide evidence that non-oncogenic HPV types have a shorter persistence than oncogenic HPV types
[7, 38, 39]. However, our own previous data from the HIM Study showed that the median time to clearance was not substantially different between non-oncogenic and oncogenic HPV types
In this study, the distribution of the most common HPV types was not different by MC status. However, for less common types, such as HPV types 11, 40, 61, 71 and 81, we did find a lower prevalence in circumcised men than in uncircumcised men. Four studies have reported on the type-specific HPV distribution by MC status
[20, 32, 34, 41]. In a clinical trial of MC among young men in South Africa, HPV types 40, 42, 53, 70, 84, and CP6108 were found in the intention-to-treat analysis to be less frequently detected in circumcised men as compared to uncircumcised men when using urethral samples
. In another study of university males in Hawaii, the distribution of non-oncogenic HPV types in the coronal sulcus/glans penis did not vary by circumcision status, HPV 84 being the most common non-oncogenic type in both circumcised and uncircumcised men. However, the distribution of oncogenic HPV types did vary by MC status. Thus, while the most common oncogenic HPV types among circumcised men were types 16 and 39, those among uncircumcised men were types 66, 52, 53, and 73
. Consistent with these two studies on type-specific prevalence, an RCT in Uganda found that type-specific incidence rates of HPV types 18 and 33 were lower in circumcised men than in uncircumcised men. Similarly, type-specific clearance rates for HPV types 39, 51, and 58 over a 24-month period were increased in circumcised men as compared to uncircumcised men when using samples from the coronal sulcus/glans penis
. Finally, in a longitudinal study of university males in Washington using samples from the penile shaft/scrotum, corona sulcus/glans, and urine, the incidence of the most common HPV types did not vary by circumcision status. The most common oncogenic HPV types at the 36-month cumulative incidence were 16, 18, and 51, and the most common non-oncogenic HPV types were 6, 53, and 66 in both circumcised and uncircumcised men
The mechanism by which circumcision might protect against HPV infection remains unclear. Removal of the foreskin could minimize the chance of acquisition of new infections or could result in an increased clearance of preexisting infections
[4, 42]. Additional data on HPV acquisition and clearance according to MC status and anatomical site are necessary to better assess the role of MC in the natural history of HPV infections in men.