It is unclear how many HPV-infected women who become HPV DNA negative actually have complete viral clearance and how many continue to harbor the viral genome in the basal cells of the squamous epithelium, but at such a low copy number that they cannot be detected using standard molecular tests. Such undetectable, low-level infections are usually referred to as “latent infections” and are similar to the latent infections that are seen with herpes simplex virus and varicella zoster. The finding that almost all HIV-infected individuals become HPV DNA positive as they become more profoundly immunosuppressed suggests that HPV viral latency clearly occurs.12
Reactivation of a latent infection secondary to senescence of HPV-directed cellular immunity could easily explain many of the HPV infections that are detected in older women with a previously normal screening history and no new sexual partners.8 Currently, it is impossible to distinguish between reactivation of a latent HPV infection and a newly acquired infection. It should also be noted that the risk for subsequently developing either cervical intraepithelial neoplasia (CIN) 2,3 or cervical cancer after reactivation of a latent infection appears to be relatively low in women who have a history of 3 or more normal cervical cytology results.13 This conclusion is based on the fact that although 4% to 5% of women 45 years and older are at high risk for becoming HPV DNA positive at any single point in time, the risk that these women will have CIN 2,3 or cervical cancer detected during routine screening is minimal (≤0.05%).13
FIGURE 1
Clearance of HPV infections
HPV, human papillomavirus.
Kaplan-Meier estimates of clearance time of high-risk (HR) and low risk (LR) HPV infection. The median clearance time for high-risk HPV was 226 days.
Reprinted with permission from Brown DR, et al. J Infect Dis. 2005:191:182-192. Copyright 2004 by the Infectious Diseases Society of America, University of Chicago Press. All rights reserved.
Persistent HPV infections and the development of CIN 2,3
Only about 10% of HPV infections persist for more than 3 years. The longer a specific HPV infection persists, the lower the probability that the lesion will clear spontaneously and the higher the probability that a CIN 2,3 lesion or cervical cancer will develop.8 Prevalent HPV infections detected at the time of cervical cancer screening tend to persist longer in older women compared to younger women. This may be due to the fact that the infections identified in older women are more likely to represent infections that have already been persistent for several years, whereas infections in younger women are more likely to represent recently acquired infections. There is no established definition of what constitutes clinically important persistence, but most management recommendations consider persistence for 12 months to be clinically significant and therefore warrant colposcopy.
Since high-risk HPV DNA is detected in almost all CIN 2,3 lesions and invasive cervical cancers, it is clear that persistence of infection with a high-risk HPV is a requirement for the development of these lesions. New data demonstrate that the time required for an initial HPV infection to progress to a CIN 2,3 lesion can be quite short. In college-aged women, incident infection associated with any HPV type results in an 11% cumulative incidence of biopsy-confirmed CIN 2,3 by 36 months.14 For incident HPV 16 or HPV 18 infections, the cumulative incidence of CIN 2,3 at 36 months is 27% (FIGURE 2). Similarly, Mao et al followed young women in the placebo arm of an HPV 16 vaccine trial and found that all but one case of CIN 2,3 occurring after an incident HPV 16 infection developed within 12 months (FIGURE 2).15 It should be emphasized, however, that it takes almost a decade for a CIN 2,3 lesion to progress to invasive cervical cancer; therefore, it is safe to extend the screening interval to 3 years or more in women who are found to be both high-risk HPV DNA and cytology negative during routine screening.
We also have a much better understanding of the risk of being diagnosed with CIN 2,3 or cervical cancer in older, high-risk HPV DNA-positive women. In a records linkage study of Danish women who were initially cytologically negative after 3 years, CIN 2,3 or cervical cancer had been diagnosed in 6.3% of high-risk HPV-positive women.16 The cumulative detection of CIN 2,3 was 11.3% and 22.9% after 5 and 10 years of follow-up, respectively. In comparison, CIN 2,3 was diagnosed after 10 years of follow-up in only 1.9% of the HPV-negative women. A Swedish study that included all women, irrespective of cytology results, detected CIN 2,3 in 37% of women who were HPV 16 positive and 26% of those who were HPV 18 positive after 4 years of follow-up ( TABLE ).17 Importantly, in this Swedish study, CIN 2,3 lesions were detected in a substantial number of women infected with other high-risk types of HPV, including HPV 31, 33, 52, and 58. This finding contrasts with the results from a study by the National Cancer Institutes (NCI), at Kaiser, Portland, Oregon.18 In a Kaiser follow-up study of 20,810 women, the cumulative detection of CIN 3 after 10 years of follow-up was 20.7% in HPV 16-positive women >30 years of age with negative cytology; 17.7% for those with HPV 18; 1.5% for those with other high-risk types of HPV; and 0.5% for HPV DNA-negative women.