To date, a total of three systematic reviews and meta-analyses have been performed to demonstrate the prevalence of HPV infection among MSM, including two studies assessing the prevalence of anal HPV [13, 157] and one study investigating the prevalence of oral HPV [158]. However, there are some differences between our study and the other three studies, which make our study more enriched and credible. In this regard, our study is the first to report the prevalence of penile and urethral HPV infection in the MSM population in the world. Furthermore, since the current study included a larger sample size of MSM than papers published before for assessment of anal and oral HPV infection, it allows for high and reliable precision estimates. For example, in a study performed by King et al., a total of 3632 MSM during a period of 19 years (1997–2015) were included in the meta-analysis for estimation of pooled prevalence of oral HPV infection [158], while in our meta-analysis, it was 9616 MSM in a period of 8 years (2012–2019). Similarly, in the recent systematic review and meta-analysis conducted by Marra et al., 20971 MSM across the world, during a period of 33 years (1986–2018), were included into the meta-analysis to provide an estimate of pooled prevalence of anal HPV infection [13], whereas this was increased to 39426 MSM in a shorter time frame (8 years; 2012–2019) in the present meta-analysis. This indicates that comprehensive literature searches were not undertaken in the previous meta-analysis studies. In addition, pooling data from studies published more than two decades ago is a major drawback in their approach. So that it does not reflect the current status of the prevalence of HPV infection among MSM. Therefore, we decided to include data collected during the last 8 years for the present meta-analysis to achieve more accurate and timely results. Another unique feature of our study is that more than 50 HPV genotypes were investigated among MSM, while the previous studies assessed the prevalence of limited HPV genotypes, mainly the most important high-risk and low-risk genotypes including HPV-16, HPV-18, HPV-6, and HPV-11.
Our findings were consistent with the results of the previous meta-analyses. We found a striking prevalence of anal HPV infection, 86.3% in HIV-positive MSM, and 64.5% in HIV-negative MSM. Similar results were found in a meta-analysis done by Machalek et al., which showed a prevalence of 92.6% and 63.9% for HIIV-positive and HIV-negative MSM, respectively [157], before the year 2011. Also, Marra et al. found a prevalence of 81% and 47% among HIV-positive and HIV-negative MSM, respectively, before the year 2018 [13]. Overall, these results confirm that HIV positivity is associated with a higher prevalence of HPV at the oral cavity, anal, and genital sites. The higher prevalence of HPV among HIV positive subjects may be because of an increased persistence of HPV infection due to the depression of immunity caused by HIV infection, leading to a failure to clear HPV infection. Moreover, the transmission of HIV is facilitated by the lesions caused by HPV infection. Infection with HIV may also elevate the risk of initial HPV infection. Both HIV Tat (transactivator) and gp120 proteins can be found in the tissue microenvironment of patients infected with HIV. It has been documented that epithelial tight junctions are disrupted by these proteins [159], and following that, HPV reaches the basal cell layer where initial HPV infection usually starts.
Our results have also shown that the prevalence of HPV infection is more common in the anus (78.11%) than in the penis (36.26%), oral cavity (17.33%), and urethra (15.4%). Three reasons may explain the high prevalence of anal HPV infection in MSM: i) regarding the sexual behaviors, MSM tend to have more anal intercourse with their partners than men who have sex with women (MSW), leading to the higher possibility of HPV transmission. The finding is consistent with previous researches performed in MSW. For instance, Nyitray et al. conducted a study to assess the prevalence of HPV infection in the anal canal of 902 MSW in Brazil, Mexico, and the United States [160]. They found an overall prevalence of 12% for infection with any HPV genotypes. Similarly, a study conducted in China by Liu et al. indicated that the prevalence of anal HPV infection in HIV-positive and HIV-negative MSM was 74.1% and 29.2%, respectively. In comparison, the values in HIV-positive and HIV-negative heterosexual men were 30.6% and 8.3%, respectively [32]. ii) Infection with HPV is more persistent in the anus than in the other genital organs [161]. iii) Anorectal mucosa is more prone to HPV acquisition. Oral cavity, vaginal cavity, and urethra are lined by multilayered stratified squamous epithelium, which acts as a substantial barrier to viral invasion and withstands mechanical trauma. In contrast, the anus and rectum are lined by a single and thin layer columnar mucosal epithelium, which are likely more susceptible to mechanical injury than the vagina or penis during sexual intercourse, facilitating HPV entry [162].
Our study found that the most common HPV genotype in the anorectal region of MSM was HPV-16, followed by HPV-51 and HPV-18. In this context, a recent meta-analysis performed by Lin et al. showed that the predominant genotype associated with anal cancer is HPV-16 [5]. These data show that MSM are at extreme risk of acquiring anal malignancies. Our study also indicated that the most frequent HPV genotypes detected in the penis were HPV-16 and HPV-18. In this regard, the results of two recent meta-analysis studies suggested that the main oncogenic HPV genotypes in penile cancer were HPV-16 and HPV-18 [8, 163]. Overall, these findings support the belief that MSM are also at elevated risk of developing penile cancer. HPV-16, as one of the most carcinogenic HPV genotypes, was also prevalent in the oral cavity of MSM in our study.
MSM constitute approximately 2% of the US population [164, 165]. According to the US Census Bureau's population clock, the estimated 2020 United States population (March 2020) is 329.35 million [166]. Based on these statistics, the number of MSM living in the US is nearly 6.587.000. On the other hand, our findings showed that the prevalence of anal HPV infection among US MSM is 81.61%. This means that around 5.375.000 MSM in the US are infected with any type of HPV in the anus, and a large portion of them are associated with HPV-16 and other high-risk genotypes. Therefore, we expect that the incidence of anal cancer among US MSM will increase dramatically over the next several years. Such a trend is also expected in many other countries such as Germany, France, Hungary, Austria, and India.
Vaccination against HPV is one of the most effective ways to reduce the incidence of HPV-associated diseases and cancers in sexually active subjects. Currently, there are three safe and effective FDA-approved prophylactic HPV vaccines: Cervarix®, a bivalent vaccine (targeting HPV-16 and HPV-18); Gardasil®, a quadrivalent vaccine (targeting HPV-6, HPV-11, HPV-16, and HPV-18); and Gardasil®9, a nonavalent vaccine (targeting HPV-6, HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52, and HPV-58) [167]. According to the results of the present meta-analysis, HPV-51 is amongst the most prevalent high-risk genotype in anal and penile HPV infection, which can be included in future generations of HPV vaccines. By March 2017, 71 countries in the world had introduced an HPV vaccination in their national immunization programs for adolescent girls. However, only 11 countries had organized HPV vaccination programs for adolescent boys [168].
It has been revealed that circumcision is associated with remarkably reduced odds of penile HPV infection among MSM. Male circumcision leads to a decreasing number of host cells for HPV to infect, removing microenvironments that support the replication and survival of HPV, and decreasing the risk of microabrasions during sexual intercourse that facilitates the entry of HPV into the body [169]. The estimated prevalence rate of male circumcision is approximately 38.7% across the world [170], and it is a routine practice for Muslims and Jews [171].
Another explanation for the increased prevalence of anal HPV infection among MSM can be attributed to the reduced use of condoms during anal sex. This is consistent with reports of increases in condomless sex among MSM in the US [172, 173]. The majority of MSM use condoms infrequently and inconsistently, elevating their risk for acquiring sexual transmitted diseases such as HPV infection. Condoms can significantly reduce the risk of HPV infection. Therefore, condom use during both anal and oral sex as a major preventive strategy should be promoted within the MSM community.
This study has limitations that should be considered; 1) Homosexuality is illegal in many countries, mostly in the Middle East, Africa, and Asia, and therefore, there are no published studies showing the prevalence of HPV in these regions to include in our meta-analysis. However, it is believed that MSM constitute a hidden population in these areas, and maybe experiencing high levels of HPV infection and HPV-associated malignancies. 2) The age of sexual debut is a risk factor for HPV infection. The majority of studies included in the current meta-analysis did not categorize HPV-infected and -uninfected MSM based on the age of sexual debut, and subsequently, we were not able to perform a subgroup analysis in this regard.