Association of Known and Unknown Oncoviruses with External Genital Lesion (EGL) Manifestations in a Multinational Cohort of Men

Human papillomaviruses (HPV) are double-stranded, DNA, epitheliotropic viruses that infect skin and mucosal membranes. Over 200 types of HPV have been identified and classified into alpha (α), beta (β), gamma (γ), mu (µ), and nu (ν) genera. HPV in the genus α mainly infect mucosal membranes, cause the majority of the ano-genital cancers, and are widely studied. However, epidemiology of HPV in the other genera, which mainly infect skin, is poorly understood. Few studies have reported the seroprevalence of cutaneous HPV among healthy individuals, and to date, no study has prospectively examined the association between cutaneous HPV seropositivity and development of external genital lesions (EGLs) in men. The objectives of this study were to estimate the seroprevalence of cutaneous HPV types and investigate factors associated with the seropositivity, and evaluate the association between seropositivity to cutaneous HPV types and the risk of development of EGLs. Several studies have reported the seroprevalence of mucosal HPV types (6, 11, 16 and 18) in the 4-valent HPV vaccine among men. However, few studies have reported the seroprevalence of the five additional HPV types (31, 33, 45, 52 and 58) in the recently approved 9-valent HPV (9vHPV) vaccine specifically among men across a broad age range. Baseline data on seroprevalence prior to vaccine introduction and dissemination are needed to establish the effectiveness of vaccines over time. Also, this study estimated the seroprevalence of 9vHPV vaccine types and investigated factors associated with the seropositivity among men residing in Brazil, Mexico, and the United States (U.S.). To estimate the seroprevalence of cutaneous HPV types and 9vHPV vaccine types, 600 men were randomly selected from the HPV Infection in Men (HIM) Study. To examine the association between seropositivity to cutaneous HPV types and development of EGLs, a case-control study of 163 incident EGL cases and 352 EGL-free controls nested in the HIM cohort was conducted. Cases were ascertained through visual inspection at each of up to 10 biannual clinical visits, confirmed through biopsy, and categorized into condyloma, suggestive of condyloma, penile intraepithelial neoplasia (PeIN) and other EGLs. Archived serum specimens were tested for antibodies against 14 cutaneous HPV types, β types (5, 8, 12, 14, 17, 22, 23, 24, 38 and 47), α type 27, γ type 4, µ type1 and ν type 41, and 9vHP types (6, 11, 16, 18, 31, 33, 45, 52 and 58) using a glutathione S-transferase (GST) L1-based multiplex serology assay. Socio-demographic and sexual behavior data were collected through a questionnaire. Binomial proportions were used to estimate seroprevalence, and logistic regression was used to examine factors associated with seropositivity. Overall, seroprevalence of ≥1 cutaneous HPV types was 65.4%, 1≥ β-HPV types was 39.0%, α-HPV 27 was 8.9%, γ-HPV 4 was 30.9%, µ-HPV 1 was 28.6%, and ν-HPV 41was 9.4%. Higher educational attainment was significantly associated with seropositivity to ≥1 cutaneous HPV types (adjusted odds ratio [AOR] 1.75 for ≥16 years of education vs. ≤12 years of education, 95% confidence interval [CI] 1.08-2.83), and seropositivity of ≥1 β-HPV types was significantly associated with increasing age (AOR 1.72 for men aged 31-44 years vs. men aged 18-30 years, 95% CI: 1.12–2.63,). Country of residence, circumcision status, and lifetime number of male anal sex partners were other factors significantly associated with various type-specific cutaneous HPV seropositivity. No statistically significant association was observed between grouped or individual cutaneous HPV seropositivity and the risk of development of EGLs across all pathological diagnoses. The seroprevalence of grouped and individual cutaneous HPV types was similar across different EGL categories and controls, with the most frequent types being ɤ-HPV 4, µ-HPV 1, and β-HPV 8. The seroprevalence of ≥1 9vHPV vaccine types was 28.3%, ≥1 high-risk types was 14.0%, five additional high-risk types was 11.2%, and low-risk types (6/11) was 17.4%. Compared to men with no male anal sex partners, men with ≥2 partners were two times more likely to be seropositive for grouped 9vHPV vaccine types, ≥1 high-risk types and ≥1 low-risk types, in addition to individual HPV types 6, 16, 33, and 58, with AORs ranging from 2.19 to 7.36. Older age, current smoking, and being single were other factors significantly positively associated with different grouped and type-specific seropositivity. In conclusion, our data show that exposure to cutaneous HPV was common in men although different risk factors were independently associated with grouped and type-specific cutaneous HPV seropositivity. It appears that exposure to cutaneous HPV is not likely to increase the risk of EGLs among men. Similarly, exposure to 9vHPV vaccine types was also common in men and seropositivity to 9vHPV vaccine types was positively associated with older age and lifetime number male anal sex partners