Unraveling the Epidemiology of Oral Human Papillomavirus Infection

The burden of oral cancer in the United States has been evolving for at least 2 decades. Gains in head and neck cancer control afforded by a period effect of reduced tobacco exposure have been displaced by competing cohort effects of increasing sexual exposure to human papillomavirus (HPV) infection and subsequent increases in HPV-associated head and neck cancer, particularly oropharyngeal cancer (1). The male predominance of oropharyngeal cancer in the United States is paralleled by a much higher prevalence of oral HPV infection and a stronger relationship between number of sexual partners and oral HPV prevalence in men than women (2). The reason the risk for oral HPV infection differs between men and women remains unclear, particularly because the prevalence of genital HPV infection is similar in both sexes. As reported in their current Annals article, Sonawane and colleagues (3) used a publicly available national data resourceNHANES (National Health and Nutrition Examination Survey), 2011 to 2014to analyze the differences between men and women in oral HPV prevalence and the concordance of oral and genital HPV infection. Their results confirm previous findings of a higher prevalence of oral HPV infection in both men (4) and women (5) with concurrent genital HPV infections. In an extension of previous analyses, the authors report that the association between oral HPV prevalence and demographic and behavioral risk factors, such as age, race, and lifetime number of sex partners, is similar in the presence or absence of concurrent genital HPV infection. A notable exception was found in the trend for increasing HPV infections with increasing age, which seems to be reversed in women without concurrent genital HPV infections. To better understand the relevance of these results, it is important to note that in this article, oralgenital concordance refers to detection of 1 or more of 37 HPV genotypes in both oral and genital sites and high-risk concordance refers to detection of 1 or more of 18 high-risk HPV genotypes in both regions. However, if the clinical and epidemiologic interest resides in factors associated with dual infection due to co-transmission, persistence, or autoinoculation, type-specific concordance is more meaningful. Previous reports showed that a minority of men (32.6%) defined as having concordant oralgenital HPV infection in the NHANES data set from 2013 to 2014 had concordance for at least 1 of the same HPV genotypes (4). Similar results were shown for concordance between oral and genital HPV infection in women in the NHANES data from 2009 to 2010 (5). The policy implications of the predominately nontype-specific concordance reported here for oral HPV infection and associated cancer control are unclear. Despite the in-depth analysis presented by Sonawane and colleagues (3), these data do not lend much clarity to why oral HPV infection risk increases with age or why men have a greater prevalence of oral HPV infection and incidence of oropharyngeal cancer. This uncertainty is largely the result of the inherent difficulty in teasing out independent effects of age and current and lifetime sexual behaviors from cross-sectional surveillance statistics. For example, the final multivariate models reported by Sonawane and colleagues (3) suggest that oral HPV prevalence and oralgenital HPV concordance are associated with lifetime number of oral but not vaginal sexual partners. The validity of this conclusion is questionable, given the high correlation between oral and vaginal sexual behaviors and the associated effect of collinearity between these variables when examined in the same multivariate model. In addition, cohort effects of the sexual revolution in both U.S. men and women obscure the ability to interpret cross-sectional HPV prevalence estimates by age (6). In other words, differences in HPV prevalence by age may represent an effect of aging (in the absence of cohort effects), inherent differences in HPV risk across birth cohorts, or a net effect of both. In the United States, older men and women had substantially fewer vaginal sex partners than more recent birth cohorts (7). Although this cohort effect might explain the decline in HPV seroprevalence and HPV DNA prevalence in the genital tract of older women, it does not seem to fit the opposite age-specific pattern of increasing oral HPV infection with age. The reason for this paradox is unclear. The authors correctly conclude that more research is needed to identify targeted strategies for primary and secondary prevention of oral HPV infection and associated types of oral cancer. Arguments can be made that standard epidemiologic analyses will continue to be fraught with inferential limitations (8) and that advancement will require a systems approach using dynamic, agent-based, and mechanistic mathematical models to fully capture the complexity of the natural history of HPV infection. Such models must avoid oversimplifying estimates of HPV incidence and clearance as fully representative of HPV acquisition and eradication probabilities. Data are now quite clear that both genital and oral HPV DNA testing from a single cross-sectional sample underestimates true infection prevalence because of the significant interindividual variability in type-specific detection (9, 10). Therefore, future observational studies should be designed explicitly to estimate the transitional probabilities not only for acquisition of oral HPV infection from a recent sexual partner, but also autoinoculation from other anogenital sites and recurrent detection of an immunologically controlled (that is, latent) infection. Prospective natural history studies of sexually active and inactive adults may prove to be particularly illuminating. Such data will be critical for estimating the potential effect of policy proposals for disease prevention, such as HPV vaccination of middle-aged men, as suggested by Sonawane and colleagues (3). Although the data in their article demonstrate substantially reduced vaccine-type HPV prevalence when vaccine is administered to currently eligible men and women aged 18 to 33 years, the effectiveness of vaccinating older persons with a higher accumulation of infection is uncertain. Effectiveness will depend on both the population-attributable fraction of prevalent oral HPV at older ages due to recent acquisition and the ability of vaccination to limit or prevent autoinoculation or reactivation. Estimation of these variables is critical for responsible, evidence-based policy development and will be best derived from study designs anchored on a conceptual model of the inter- and intraindividual dynamics of HPV infection over the lifespan.