In this study of anal HPV duration and clearance among healthy adult women, we found that anal HPV infections were moderately common [16
], and had relatively short duration. Most anal HPV infections in our study were transient, with 87% of cleared infections clearing within 1 year. The median duration of anal HR-HPV infections was 5 months, shorter than the median duration of 8 months for cervical HR-HPV in the same group of women [19
]. The latter figure is in agreement with the 8–20 month median duration of cervical HR-HPV reported by most other studies [30
]. It is unclear whether the much lower incidence of anal cancer compared to cervical cancer is due to faster clearance of anal HPV or to different biology. Faster clearance of anal HR-HPV, as compared to cervical HR-HPV, may result from a number of factors. A higher concentration of keratinized cells in the epithelial tissues of the anus may hinder HPV persistence and facilitate more rapid clearance. Whether non-specific immunity of the gastrointestinal tract could contribute to reduced duration of anal HR-HPV is unclear and warrants further investigation. Association between cervical and anal HPV in our cohort will be the subject of a separate report.
The effect of multiple genotypes on clearance of anal HPV is largely unexplored. Hernandez et al. [17
] speculated that women with multiple-type anal HPV infections are more susceptible to such infections due to impaired immune function or other factors. In the present study, clearance of both HR-and LR-HPV anal infections was enhanced in the presence of one or more other HPV genotypes. This could possibly be explained by competition among the established HPV infections, generally not found in the cervix [31
]. An effect of multiple infections has also been found in our cohort for anal HPV acquisition. Goodman et al. [16
] reported that the risk of acquisition of a new anal HPV infection was increased in the presence of another HPV genotype, and that certain genotypes, such as HPV-16, had greater effect on the acquisition of new HPV infections.
Overall, anal infections with LR-HPV types took longer to resolve in our cohort than did HR-HPV types. This is in contrast to findings from most cervical HPV natural history studies in which LR-HPV types generally clear faster than HR-HPV types [30
]. HPV-16, the most common oncogenic genotype found in association with cervical malignancy, tends to persist longer in cervical tissue than other types [34
]. In contrast, anal HPV-16 infections generally cleared within ~4 months in our study, much faster than many other genotypes. The ability to rapidly clear HPV-16 may protect anal cells from clonal progression of the persistently infected epithelium to anal pre-cancer and invasion. Our observation supports the hypothesis that certain HPV types have different tropism to the anus than to the cervix [17
]. Frisch et al. [6
] found LR-HPV DNA in only 4% of anal cancers; therefore, longer persistence of LR-HPV types is unlikely to influence their oncogenic potential. Nonetheless, the presence of LR-HPV genotypes may delay clearance of concurrent HR-HPV infections or, through weakening the host’s immune system, increase susceptibility to subsequent acquisition of high-risk anal HPV.
Non-viral factors that delayed clearance of anal HPV in our study included long-term tobacco smoking. Tobacco smoking has been established as a risk factor for anal cancer [4
], but it is not associated with increased risk of anal HPV acquisition in our cohort [16
] and other studies [10
]. The results of the present analysis suggest that the effect of smoking in the etiology of anal cancer is in part due to a longer clearance time, but not higher acquisition rate of anal HPV. Behavioral factors, such as current practice of anal sex, also reduced the risk of anal HPV clearance in our cohort. One possible explanation is that increased exposure through anal intercourse contributes to continued reinfection. Since we are unable to distinguish HPV infections that were resolved and reacquired between clinic visits from those that persisted from one visit to the next, this reinfection with the same HPV genotype may help explain the slower clearance we have found in this study. An association of douching with reduced clearance time may also be a result of inadvertent reinfection of the anus with HPV.
If anal cancer rates continue increasing in the U.S., more consideration should be given to the implementation of anal cancer screening programs. However, it is unclear whether anal HPV testing would be an effective cancer screening technique. The potential benefits of cervical HR-HPV testing as a cancer screening tool have recently been addressed in the literature. In a study of 10,154 women, Mayrand et al. [36
] reported sensitivity of HPV testing for cervical intraepithelial neoplasia to be 94.6%, as compared to 55.4% sensitivity for the Pap smear. Given the highly transient nature of anal HPV infections and a relatively low incidence of anal cancer, a test for anal HPV is more likely to pick up short-term infections that resolve spontaneously, rather than persistent infections with the potential to progress to precancerous lesions. Therefore, as a cancer screening tool, anal HPV testing would likely have lower sensitivity and positive predictive value than cervical HPV testing and thus may not be as cost-effective.
Further, because we do not completely understand how specific HPV types affect anal cancer development, it is unclear which HPV genotypes should be targeted in a population-wide anal HPV testing program. Further research is necessary to address these issues. The risk factors identified in this report that hinder clearance of anal HPV may be helpful in designing a screening program based on risk stratification, whereby individuals with higher perceived risk for anal cancer would be given priority screening [37
The advantages of this study include a long mean follow-up period of ~16 months and a relatively short interval between visits. The unique ethnic composition of Hawaii population enabled us to compare anal HPV clearance rates in women from various racial and ethnic groups. Limitations of this study included its recruitment scheme. Study subjects were recruited among college students and patients of health maintenance organizations, so our results may not be generalizable to the entire population. In addition, collection of anal specimens was optional; women who chose to provide them comprised 66% of cervical study participants and differed from those who did not with respect to age and ethnicity [17
]. Another limitation of this and other longitudinal studies of HPV infection is the assumption that the same genotype detected at consecutive visits represents the same persistent infection, rather than reinfection after clearance. We defined clearance as a single negative visit after a positive, whereas some investigators have argued in favor of a two-negative-visit definition. In our study, the same genotype reappeared after a negative in 39 subjects, indicating that these genotypes could have been missed during PCR hybridization-based genotyping.
In summary, the differences in duration between anal and cervical HPV infections found in this cohort suggest a different disease natural history at these two sites. Shorter overall duration of anal HPV infection could reduce sensitivity of anal HPV testing, rendering it less cost-effective than cervical HPV testing as a cancer screening tool. The potential of anal HPV testing for anal cancer prevention should be re-evaluated when more affordable, cost-effective HPV testing is developed and when the longer-term effects of HPV vaccination on the prevalence of HPV-16 are better understood.