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Department of Epidemiology, University of Washington, Seattle
In this issue of the Journal of Infectious Diseases, 2 articles and a brief report on large, population-based studies highlight age-related trends in human papillomavirus (HPV) infection, with a particular emphasis on infections detected early and late in life. Most of the worldwide burden of cervical cancer is attributable to HPV infections acquired during the reproductive years. In the era of prophylactic HPV vaccines, however, an understanding of the risk and natural history of HPV infection across the entire span of life will be important for the development of appropriate and effective cervical cancer prevention strategies.
In related studies, Castle et al. [1] and Herrero et al. [2] explore age-related variations in HPV DNA prevalence in a previously unscreened population of women in Guanacaste, Costa Rica, who were participating in the Proyecto Epidemiológico Guanacaste. In cross-sectional analyses, U-shaped age-specific prevalence curves were observed both at baseline and after 57 years of follow-up, a pattern that has been observed in several [38], but not all [5, 911], studies in various countries. Although the first peak in prevalence, in women <25 years old, reflects the rapid acquisition [12] and subsequent resolution [13] of most new infections, the observed increase in the number of detectable infections in the oldest age group, women 65 years old, is more difficult to interpret. The aim of the longitudinal analysis by Castle et al. was to examine this second peak in older women, with a focus on patterns of acquisition and persistence of both oncogenic and nononcogenic HPV types. Their data support the notion that viral persistence, rather than acquisition of new infections, accounts for the majority of HPV infections detected in older women. The likelihood of persistence (defined as detection of the same type at enrollment and after 57 years of follow-up) increased steadily with age, and the likelihood of testing positive for new types at follow-up decreased with age.
Although persistence seems to be the predominant source of detectable HPV infections in older women, the Costa Rica data suggest that new acquisition clearly does occur. Without long-term follow-up from the time of sexual debut, it is impossible to discern whether a newly detected infection represents new acquisition or reactivation of a latent infection. Alternatively, Castle et al. allude to the possibility that changes in the cervicovaginal epithelium may enhance HPV detection in older women. That recent and lifetime numbers of sex partners were risk factors for HPV detection in all age groups in Castle et al.'s study, however, suggests that at least some newly detected infections in older women are the result of new acquisition. The likelihood that such newly acquired infections will persist should be addressed in studies that include repeated follow-up.
Furthermore, it will be worthwhile to identify any population-specific cohort effects that influence age-related patterns of HPV detection. This was not likely an important factor in the Costa Rica data, because Castle et al. report that only weak evidence could be found to indicate that the U-shaped age-specific prevalence curves were shifted from baseline to follow-up (although they plan to explore this possibility further during additional follow-up). However, Castle et al. suggest that, in the United States, cohorts of women who were born after the sexual revolution and the accompanying widespread acceptance of oral contraceptives should be differentiated from cohorts of older women. As women born after the sexual revolution age, it will be important to determine whether sexual history, in addition to the biological characteristics of age, alters the risk of acquiring a new, persistent HPV infection. Data from a study in Danish prostitutes showed that, despite continual exposure to new sex partners, HPV DNA prevalence decreased significantly with age [14]. Because the timing of new exposures may also be relevant, it would be interesting to explore whether a change in sex partners later in life (e.g., by divorcing and remarrying) alters the risk of new infection.
Age-related differences between infections with nononcogenic and oncogenic HPV types were also explored in the Costa Rica data. Castle et al. propose that potential differences between the epidemiological profiles of nononcogenic and oncogenic types may partially explain why the second peak in prevalence was stronger for nononcogenic types. It will be interesting to see whether the authors, on further investigation, do indeed find evidence that some nononcogenic types survive preferentially in vaginal squamous epithelium, as is suggested by their previous findings that some types are preferentially detected in vaginal samples from women who have undergone a hysterectomy, compared with detection in cervical samples from women who have not [15]. Although, in the Costa Rica data, the trend toward increased HPV prevalence in women 65 years old was more pronounced for nononcogenic types than for oncogenic types, the relationship between older age and increased persistence held true for both categories. Thus, the potential censoring effect discussed by Herrero et al. should not be overlooked as a possible explanation for the difference; even in an unscreened population, one would expect some older women persistently infected with oncogenic types to be selectively removed from the population because of death and hysterectomies performed as a result of cervical cancer.
That rates of persistence were comparable for oncogenic and nononcogenic types emphasizes that persistence per se is not the only important determinant of progression to cervical cancer. In future studies, it will be worthwhile to explore how other viral characteristics (such as viral load) vary by age. As more data are collected, different patterns may emerge with respect to individual HPV types. In the Costa Rica data, for example, HPV-16 was distinguished from other oncogenic types in that acquisition was as likely as clearance, a characteristic that was consistent until age 65.
At the other end of the age spectrum, Dunne et al. [16] report on HPV-16 seroprevalence in children 611 years of age in the United States. Consistent with the results of studies conducted in other countries (see table 2 in Dunne et al.), seroprevalence was low (2.4% overall), and the authors conclude that exposure to HPV-16 is rare in preadolescent children. Although reports of HPV DNA detection in sexually abused preadolescent girls [17] and of juvenile-onset recurrent respiratory papillomatosis (a documented rare outcome of infection with HPV-6 or -11) in infants [18] show that infection with genital HPV types does occur before adolescence, it is reassuring that the preadolescent population as a whole appears to be largely unexposed.
Consideration of age-related HPV trends will be instrumental in the development of cervical cancer prevention strategies that are appropriate for younger and older women. Although the available data suggest that widespread vaccination of adolescents before the onset of sexual debut should be an effective strategy for younger women, more data are needed to develop optimal strategies for older women. Additional longitudinal studies with longer and more-frequent follow-up will be necessary to determine how age affects the proportion of detectable infections that result from new acquisition and from reactivation or persistence of previously acquired infections. These relationships must be clarified before decisions are made on how to manage perimenopausal and postmenopausal women, including whether to target certain at-risk women for continued screening or vaccination. The described future directions of the Proyecto Epidemiológico Guanacaste, including further follow-up to examine immune correlates of HPV infection and type-specific patterns of both persistence and progression to cervical intraepithelial neoplasia grade 3 and cancer, should offer important insights. Furthermore, variant analysis will be needed to determine whether repeated detection of type-specific HPV DNA truly represents the same infection [19, 20]. It would also be worthwhile to explore age-related behavioral risk factors in depth and to test older women's male partners for HPV infection.
References
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